Enantioselective Synthesis of 5,7-Bicyclic Ring Systems from Axially Chiral Allenes Using a Rh(I)-Catalyzed Cyclocarbonylation Reaction

Abstract

A transfer of chirality in an intramolecular Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) to access tetrahydroazulenones, tetrahydrocyclopenta[c]azepinones and dihydrocyclopenta[c]oxepinones enantioselectively (22 – 99% ee) is described. The substitution pattern of the allene affected the transfer of chiral information. Complete transfer of chirality was obtained for all trisubstituted allenes, but loss of chiral information was observed for disubstituted allenes. This work constitutes the first demonstration of a transfer of chiral information from an allene to the 5-position of a cyclopentenone using a cyclocarbonylation reaction. The absolute configuration of the corresponding cyclocarbonylation product was also established, something that is rarely done.

Introduction

Cyclopentanes serve as valuable building blocks in organic synthesis and are present in many naturally occurring compounds. Among the various polycyclic skeletons possessing five-membered carbocycles, the fused 5,5-, 5,6- and 5,7-bicyclic ring systems are common structural features found in many biologically relevant compounds.¹ For many natural products, the five-membered rings are characterized by a relatively high oxidation state (Figure 1). Swartzianin D (1) is an excellent example of this, where every carbon of the five-membered ring is occupied with a double bond, a carbonyl or a hydroxyl group.² There are a number of synthetic methods available to prepare these highly oxidized rings, but the options narrow rapidly when constructing five-membered carbocycles with stereogenic centers enantioselectively.³

Figure 1.

Bioactive and Natural Compounds Containing Cyclopentanes with Stereogenic Centers

There is a diverse array of methods to create stereogenic centers of cyclopentanes in a stereoselective manner. A common synthetic strategy is to take advantage of the chiral pool as a source of enantiopure materials. One example is the asymmetric synthesis of (+)-chinensiolide B (2), where the cyclopentane moiety of this compound is generated via a Favorskii rearrangement of (R)-carvone.⁴ Moreover, the cyclopentane ring of tecomanine (3), possessing a tetrahydrocyclopentapyridinone ring system, was also prepared from (−)-carvone.⁵ Other approaches to install stereogenic centers utilize existing stereocenters on rings adjacent to the five-membered carbocycle. For instance, the methyl group located at the C4 position of grosshemin (4) was installed by classic alkylation of an enol acetate of a 5,7-bicyclic ring system to yield a single product diastereoselectively.⁶ However, this diastereoselective approach is not always reliable for cyclopentenone-containing 5,7-ring systems. For example, in the synthesis of (+)-achalensolide (5), reduction of the C1-C11 double bond of a dienone group via a hydrogenation reaction afforded a 1:1 mixture of diastereomers.⁷ In some cases, asymmetric reactions are used to introduce stereogenic atoms but in less direct ways. For example, the five-membered carbocycle of arglabin (6) was obtained via an enantioselective cyclopropanation of a furan followed by a rearrangement to produce a protected hydroxy-2-cyclopentenone.⁸ The key stereodetermining step for C4 and C5 stereocenters of connatusin B (7) were established using a Diels-Alder reaction starting with cyclopentenone and enantiomerically pure cis-1,2-dihydrocatechol.⁹

Other synthetic methods implemented for the preparation of chiral non-racemic 2-cyclopentenones are the Nazarov cyclization and the Pauson-Khand reaction (PKR). The asymmetric Nazarov cyclization has been made possible by the use of chiral auxiliaries, chiral Lewis acids and transfer of axial to tetrahedral chirality when using allenes.¹⁰ However, the electrocyclization process requires an enantioselective formation of the stereogenic carbon beta to the carbonyl controlled by torquoselectivity, followed by a diastereoselective addition of an electrophile to the intermediate enol to form a second stereogenic center adjacent to the newly formed carbonyl.¹¹ The asymmetric PKR has been performed using chiral metal complexes of rhodium,¹² titanium,¹³ iridium¹⁴ and cobalt¹⁵ to provide cyclopentenone-containing bicyclic ring systems in good enantioselectivities. Nevertheless, like the Nazarov cyclization, all reactions establish a stereogenic carbon beta to the carbonyl. There are exceptions for both intra- and intermolecular PKRs where a stereocenter adjacent to the carbonyl is set. These reactions typically involve functionalization of the alkene component with a chiral auxiliary and for nearly all cases this chiral auxiliary is removed and the stereogenic center is lost.¹⁶ While there are methods to synthesize 2-cyclopentenones possessing a stereogenic center at the C5 position stereoselectively, the scope of these protocols is limited.¹⁷

Previously, we demonstrated that a complete transfer of chirality is obtained for chiral, non-racemic allenes 10 in the molybdenum- or zirconium-mediated PKR to afford 2-cyclopentenones 11 enantioselectively (Scheme 1).¹⁸ For both of these transformations, the reaction occurs with the proximal double bond of the allene to provide E-α-alkylidene or E-α-silylidene 2-cyclopentenones with the stereogenic center beta to the carbonyl group.¹⁹ Since a general protocol for the asymmetric synthesis of C5-substituted bicyclic cyclopentenones is valuable, we considered employing chiral allenes in a PKR to gain access to this motif. Based on these prior results, we envisioned that transfer of chiral information from allene 10 to a stereogenic center adjacent to the carbonyl group of 2-cyclopentenone 12 should also be possible for the Rh(I)-catalyzed cyclocarbonylation reaction, a transformation performed by the selective reaction with the distal π-bond of allene 10 (Scheme 1). Herein are reported studies directed toward a Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) to afford 5,7-bicyclic ring systems enantioselectively.

Scheme 1.

APKR: Transfer of Axial Chirality

Results and Discussion

Investigations into the scope and limitations of the transfer of allene axial chirality in the Rh(I)-catalyzed cyclocarbonylation reaction began with the synthesis of a series of enantiomerically enriched allene-ynes. The substitution pattern of the allene was varied to include trisubstituted allenylsilane 13, trisubstituted non-silylated allenes 14 – 16 and disubstituted allenes 17 – 19 (Figure 2). The terminus of the alkyne was substituted with either hydrogen, alkyl, aryl, heterocyclic or silyl groups (R³ = H, Me, cyclopropyl, Ph, 2- and 3-thiophene and TMS) and three different tethers were prepared, two heteroatom-containing (X = NTs, O) and one all carbon-containing (X = C(CO₂Et)₂).

Figure 2.

Allene-yne Precursors

Synthesis of enantiomerically enriched allenes

Synthesis of trisubstituted chiral allenyl alcohol (R_a)-22 was performed in four steps starting from commercially available (±)-3-butyn-2-ol (20) in a manner analogous to that reported by Brawn and Panek (Scheme 2, eq 1).²⁰ Addition of n-butyllithium to alkyne 20 in the presence of lithium chloride followed by addition of phenyldimethylchlorosilane afforded silylated alkyne 21 in 90% yield. Kinetic resolution of racemic propargyl alcohol 21 using lipase AK “Amano” provided enantioenriched propargyl alcohol (S)-21 (47% yield, >98% ee) and the corresponding propargyl acetate (43% yield, >99% ee, not shown). Enantioenriched propargyl alcohol (S)-21 was reacted with trimethylorthoacetate and propionic acid to produce the corresponding allenyl ester via a Johnson-Claisen rearrangement. The methyl ester was reduced with lithium borohydride to afford enantioenriched allenylsilane (R_a)-22 in >93% ee. The enantiomeric excess was determined by chiral HPLC analysis. Synthesis of racemic allenyl alcohol 25 involved silylation of hept-2-yn-1-ol (23) followed by a retro-Brook rearrangement to afford propargyl alcohol 24 in 55% yield for the two steps (Scheme 2, eq 2). A Johnson-Claisen rearrangement performed on alcohol 24 followed by reduction of the methyl ester with lithium aluminum hydride provided allene 25. Disubstituted allene (R_a)-26 was prepared by a Johnson-Claisen rearrangement of commercially available (R)-3-butyn-2-ol (20) followed by lithium aluminum hydride reduction of the corresponding methyl ester (Scheme 2, eq 3). The enantiomeric excess of (R_a)-26 was based upon chiral HPLC analysis of p-nitrobenzoyl ester 27, for which a >99% ee was obtained. Allenyl alcohol (R_a)-29 was prepared from 1-hexyne by a palladium-catalyzed carbonylation reaction followed by reduction of the corresponding ynone carbonyl with (R)-alpine borane (Scheme 2, eq 4).²¹ The resulting propargyl alcohol (R)-28 was converted into a propargyl vinyl ether with ethyl vinyl ether and mercury acetate. A gold(I)-catalyzed [3,3]-sigmatropic rearrangement of the vinyl ether followed by in situ reduction of the intermediate aldehyde afforded allenyl alcohol (R_a)-29 in >79% ee.²² The enantiomeric excess was determined by chiral HPLC analysis.

Scheme 2.

Synthesis of Racemic and Nonracemic Allenes

Preparation of the Allenic Pauson-Khand Precursors

Allene-ynes 13a – 13e, 13g, 14c – 14e, 14g, 17c, 17d and 17f were all prepared using a Mitsunobu reaction of the corresponding allenols and the appropriately substituted propargyl tosylamides 30a – 30g (Scheme 3). Reacting (R_a)-22 with 3- and 2-thiophene-substituted propargyl tosylamides 30a and 30b gave allene-ynes 13a and 13b in 90% and 70% yield, respectively. Similarly, high yields were obtained for the Mitsunobu reaction between (R_a)-22 and 30c, 30d, 30e and 30g giving 13c, 13d, 13e and 13g in 92%, 92%, 90% and 73% yield, respectively. Allene-ynes 14c, 14d, 14e and 14g were obtained in a similar manner in high yields (77% – 93%) from the reaction of trisubstituted allene (R_a)-29 and propargyl tosylamides 30c, 30d, 30e and 30g, respectively. Reacting (R_a)-26 with propargyl tosylamides 30c, 30d and 30e afforded 17c, 17d and 17e in 74%, 85% and 84% yield, respectively. The trimethylsilyl-substituted alkynes 13f, 14f and 17f were prepared by deprotonation of allene-ynes 13e, 14e and 17e with lithium hexamethyldisilylazide followed by addition of trimethylsilyl chloride to provide the corresponding silylated alkynes in 87%, 80% and 84% yield, respectively.

Scheme 3.

Synthesis of Allene-ynes 13, 14 and 17 Containing a Tosylamide Tether

Allene-ynes 15c, 15d, 15f and 18c, 18d, 18f containing an oxygen atom in the tether were synthesized by a Williamson etherification reaction (Scheme 4). Reacting (R_a)-26 with propargyl bromides 31c, 31d and 31e afforded allene-ynes 18c, 18d and 18e in 83%, 63% and 41% yield, respectively. Reacting (R_a)-29 with propargyl bromides 31c, 31d and 31e produced ethers 15c, 15d and 15e in 27%, 35% and 20% yield, respectively. Low yields for this series of compounds were attributed to the sterically congested environment at the proximal double bond of the allene. This hypothesis is supported by the complete recovery of starting material for the reaction of trisubstituted allenyl alcohol (R_a)-22 with 31d. The trimethylsilyl-substituted alkynes 15f and 18f were prepared by deprotonation of allene-ynes 15e and 18e using the same conditions as for allene-ynes 13f, 14f and 17f to provide the corresponding silylated alkynes in 65% and 69% yield, respectively.

Scheme 4.

Synthesis of Allene-ynes 15 and 18 Containing an Oxygen Tether

Preparation of allene-ynes 16c – 16e was accomplished by reaction of alcohol (R_a)-26 with methanesulfonyl chloride to produce mesylate 32. Addition of the mesylate to the sodium salt of malonates 34c – 34e provided the desired allene-ynes in 42 – 75% yields (Scheme 5). Allene-ynes 19c – 19e were obtained in an analogous manner from alcohol (R_a)-29 with yields ranging from 57% to 63%. Reaction of 16e and 19e with lithium hexamethyldisilylazide and trimethylsilylchloride afforded allene-ynes 16f and 19f in 84% and 80% yield, respectively. Attempts to convert alcohol (R_a)-22 to the corresponding allene-ynes using these conditions resulted in an inseparable mixture of silylated and desilylated products. For this reason, the silylated allene series of compounds bearing the oxygen tether was not further pursued.

Scheme 5.

Synthesis of Allene-ynes 16 and 19 Containing a Malonate Tether

Optimization of the Cyclocarbonylation Reaction

A brief examination of the cyclocarbonylation reaction conditions was performed using 13c and it was shown that the standard conditions developed in our group for the Rh(I)-catalyzed APKR provided compound 35 in 95% yield (Scheme 6 and Table 1, entry 1). Attempts to lower the catalyst loading to 5 mol % decreased the yield of the cyclocarbonylation product 35 to 75% and resulted in a 9% yield of cross-conjugated triene 36 (Scheme 6 and Table 1, entry 2). Cross-conjugated triene 36 results from a competing β-hydride elimination of rhodium metallocycle 37 to produce the alkene of intermediate 39. The rhodium hydride of 39 then undergoes a reductive elimination to generate the exocyclic alkene of 36 as a single diastereomer. This side product has previously been observed for the formation of seven-membered rings from allenes bearing a phenylsulfonyl group.²³ Increasing the reaction temperature to 120 °C afforded dienone 35 in 61% yield and triene 36 in 35% yield (Table 1, entry 3). Decreasing the catalyst loading and increasing the reaction temperature afforded dienone 35 and triene 36 in a 1:1 ratio (Table 1, entries 4 and 5). Interestingly, the addition of silver tetrafluoroborate and triphenylphosphine afforded cyclocarbonylation product 35 in only 72% yield based upon recovered starting material. While the generality of this reaction could benefit from the lower reaction temperatures possible for the cationic Rh(I), our inability to take this reaction to completion is deemed problematic.

Scheme 6.

Cyclocarbonylation Reaction and Triene Formation

Table 1.

Optimization of the Cyclocarbonylation Reaction Conditions

Entry	[Rh(CO)2CI]2 (mol %)	Time (h)	T(°C)	Product and yield (%)	Solvent
1	10	3	90	35c (95); 36c (0)	PhMe
2	5	9	90	35c (75); 36c (9)	PhMe
3	10	7	120	35c (61); 36c (35)	PhMe
4	5	7	120	35c (42); 36c (48)	PhMe
5	1	24	120	35c (29); 36c (26)	PhMe
6a	10	24	40	35cb (72); 36c (0)	DCE

^aPPh₃ (30 mol %), AgBF₄ (22 mol %);

^bYield based on recovered starting material (conversion : 54%)

Transfer of Chirality in the Rh(I)-catalyzed APKR

Each of the silyl-substituted allene-ynes 13a – 13g was subjected to the optimized cyclocarbonylation reaction conditions. High yields of the cyclocarbonylation products were obtained for the allene-ynes bearing an internal alkyne (Table 2, entries 1 – 4, 6 and 7). The presence of heterocyclic-containing systems on the alkyne did not affect the reaction (Table 2, entries 1 and 2). Terminal alkyne 13e was converted to cyclocarbonylation product 35e in 66% yield, along with a 13% yield of triene 36 (Table 2, entry 5). The enantiomeric purity of each of the allene-ynes 13a – 13g was based upon the enantiomeric excess obtained for allenylsilane (R_a)-22, which was determined to be greater than 93%. Each of the cycloadducts 35a – 35g was examined for their enantiomeric purity by HPLC analysis using a ChiralCel OD column. For each of these compounds, the enantiomeric excesses were found to be greater than 96%, constituting a complete transfer of chirality from the allene-ynes to the cyclocarbonylation products. While the transfer of chiral information may not be surprising, the high configurational stability of the dienone to the Rh(I) conditions was not anticipated.

Table 2.

Transfer of Chirality using Trisubstituted Silylated Allene-ynes

Entry	Allene-yne	R	Time (h)	Product, % yield	% eea
1	13a		2.5	35a, 72	>96
2	13b		2.5	35b, 85	>96
3	13c	Me	3	35c, 95	>96
4	13d	Ph	3	35d, 92	>96
5	13e	H	2.5	35e, 66b	>96
6	13f	TMS	3	35f, 89	>99
7	13g		2.3	35g, 83	>99

^aEnantiomeric ratios were determined by HPLC analysis using a ChiralCel OD column;

^bCross-conjugated triene was obtained in 13% yield.

Performing the APKR on trisubstituted allene 40 resulted in the formation the desilylated cyclocarbonylation product 41 in quantitative yield (Scheme 7).²⁴ Desilylation of α-silyl ketones have been reported to occur upon purification by silica gel chromatography.²⁵ However, it appears that desilylation of the resulting cyclocarbonylation product took place during the reaction as evidenced by crude ¹H NMR spectroscopy. Thus, the loss of the stereogenic center precluded further examination of this series of compounds.

Scheme 7.

Desilylation During the Cyclocarbonylation Reaction

A series a trisubstituted allenes 14, 15 and 16 were examined in the cyclocarbonylation reaction, each possessing a phenyl group on the terminus of the allene but differing in their tether (X = NTs, O, C(CO₂Et)₂) and the substitution on the terminus of the alkyne (R = Me, Ph, TMS, cyclopropyl). The enantiomeric purity of each allene-yne was based upon the enantiomeric excess of the starting homoallenyl alcohol (R_a)-29, which was determined to be greater than 79%. For all cases examined, a complete transfer of chirality was obtained (Table 3, entries 1 – 10). For allene-ynes 14c, 14d, 14f and 14g possessing a tosylamide tether the reactions were complete in 30 minutes affording dienones 42c, 42d, 42f and 42g in 75 – 88% yield (Table 3, entries 1 – 4). The highest yielding substrate was found to be allene-yne 14g possessing a cyclopropyl group on the terminus of the alkyne and the lowest yield was obtained with aryl-substituted substrate 14d. For the oxygen containing tethers, the yields varied considerably (Table 3, entries 5 – 7). Methyl-substituted alkyne 15c produced 43c in 46% yield, phenyl-substituted alkyne 15d afforded 43d in 69% yield and trimethylsilyl-substituted alkyne 15f provided 43f in 91% yield. Furthermore, all the reactions in the oxygen-containing series were complete in less than 45 minutes. Finally, for the malonate-containing series, the yields were high for all allene-ynes and ranged from 88% to 92%. For this series (allene-ynes 16c, 16d and 16f) the reactions required 120 – 150 minutes for completion, but the longer reaction time did not affect the enantioselectivity of the products. Thus, for each of the cases examined, the enantioselectivity of the products was not dependent upon the nature of the tether, the substituent on the alkyne terminus, or the reaction time.

Table 3.

Transfer of chirality of Trisubstituted Allene-ynes

Entry	Allene-ynea	X	R	Time (min)	Product, % yield	% eeb
1	14c	NTs	Me	30	42c, 80	74
2	14d	NTs	Ph	30	42d, 75	79
3	14f	NTs	TMS	30	42f, 78	79
4	14g	NTs		30	42g, 88	79
5	15c	O	Me	45	43c, 46	78
6	15d	O	Ph	30	43d, 69	77
7	15f	O	TMS	45	43f, 91	77
8	16c	C(CO2Et)2	Me	150	44c, 88	80
9	16d	C(CO2Et)2	Ph	120	44d, 92	76
10	16f	C(CO2Et)2	TMS	120	44f, 90	76

^aEnantiomeric excess of the disubstituted allenic alcohol >79% ee;

^bDetermined by HPLC analysis using a ChiralCel OD column.

A series of allene-ynes containing disubstituted allenes were also examined for transfer of chiral information in the cyclocarbonylation reaction. The reaction was performed using three different tethers (X = NTs, O, C(CO₂Et)₂) and varying the substitution on the terminus of the alkyne (R = Me, Ph, H, TMS). For each of the allene-ynes reported in Table 4 the enantiomeric purity was based upon the enantiomeric excess obtained for allenyl ester (R_a)-27, which was determined to be greater than 99%. Contrary to the trisubstituted allenes, the degree of chiral information transferred from the disubstituted allenes to the cyclopentenones was dependent upon the tether and alkyne substitution. For example, allene-ynes 17 – 19d containing a phenyl group on the alkyne afforded the corresponding cyclocarbonylation products 45 – 47d in 88% ee for the tosylamide tether (Table 4, entry 2); 52% ee for the oxygen tether (Table 4, entry 5); and 72% ee for the malonate tether (Table 4, entry 9). Furthermore, the decrease in enantiomeric excess was also dependent on the substituent on the alkyne. This was especially prevalent in the ether series of allene-ynes where the enantiomeric excesses of the cycloadducts ranged from 22 – 52% for trimethylsilyl, hydrogen, methyl or phenyl substituents (Table 4, entries 4 – 7). Determination of the enantiomeric excesses of the cyclocarbonylation products 45 – 47 proved to be more difficult than in the trisubstituted series, in that a different chiral column was needed for nearly every product.

Table 4.

Transfer of chirality using Disubstituted Allene-ynes

Entry	Allene-ynea	X	R	Time (h)	Product, % yield	% ee
1	17c	NTs	Me	4.6	45c, 73	81b
2	17d	NTs	Ph	3	45d, 84	88c
3	17f	NTs	TMS	3	45f, 83	84d
4	18c	O	Me	6.5	46c, 40	45c
5	18d	O	Ph	0.5	46d, 90	52c
6	18e	O	H	1.5	46e, 24	30e
7	18f	O	TMS	7	46f, 76	22d
8	19c	C(CO2Et)2	Me	22	47c, 71	58f
9	19d	C(CO2Et)2	Ph	1.5	47d, 96	72c
10	19f	C(CO2Et)2	TMS	10	47f, 94	50d

^aThe enantiomeric excess of the disubstituted allenic alcohol was >99% ee;

^bDetermined using HPLC analysis (ChiralPak IA-3);

^cDetermined using HPLC analysis (ChiralCel OD);

^dDetermined using SFC analysis (ChiralPak IC);

^eDetermined using SFC analysis (ChiralPak IA);

^fDetermined using HPLC analysis (Whelk O-1).

Insight regarding the partial racemization in the disubstituted series was obtained by reacting allene-yne 18c to the standard conditions and allowing it to reach 60% conversion. The enantiomeric excess of the cyclocarbonylation product 46c was measured to be 43% after purification by silica gel chromatography. The enantiomeric excess of 46c was 45% when the reaction was allowed to go to completion, indicating that racemization of the product was not occurring after the product is formed (Table 4, entry 4). Next, the enantiomeric excess of allene-ynes 17d and 18d were measured during the reaction. Stopping the cyclocarbonylation reaction of 18d at 50% conversion afforded the unreacted allene-yne in 11% ee. Similarly, stopping the reaction of allene-yne 17c at 29% conversion afforded the allene in 15% ee. The enantiomeric excesses (ee) of the allenes were determined by HPLC analysis (ChiralPak AS-H). These three experiments provide strong evidence to support the hypothesis that loss of enantiomeric excess is occurring prior to product formation and at the allene-yne stage of the reaction.

A mechanism is proposed to account for the erosion of enantiomeric excesses of the disubstituted allenes. Inspired by the work of Backvall, addition of an internal nucleophile to a rhodium-allene complex is postulated (Scheme 8).²⁶ For the disubstituted allene A, coordination of the rhodium catalyst to the proximal double bond of the allene affords the rhodium complex B. Nucleophilic attack of the tethered heteroatom (oxygen in the example depicted) to the central carbon initially affords the corresponding η¹-rhodium species that isomerizes to the η³ complex C that in turn isomerizes to the η¹-rhodium species D. Free rotation around the designated carbon-carbon bond of D leads to the η³ rhodium-complex E. Reductive elimination from intermediate E leads to the formation allene-yne F, the enantiomer of allene-yne A. Erosion in the enantiomeric excesses correlates well with the relative nucleophilicities of the heteroatoms in the tether. For example, the highest enantiomeric excesses were obtained for the cyclocarbonylation products with a tosylamide tether whereas the lowest enantiomeric excesses were obtained for the oxygen tether. In the case of the malonate tether, formation of an intermediate seven-membered ring would explain the racemization process.

Scheme 8.

Postulated Mechanism for the Erosion of Enantiomeric Excesses of Disubsubstituted Allenes in the Cyclocarbonylation Reaction

For the trisubstituted allene series, the absence of racemization is explained by selective complexation of the rhodium catalyst with the less substituted distal double bond of the allene and complexation from the face opposite of the DPS group (intermediate G, Scheme 8). Moreover, the rhodium metallocycle of intermediate G is not set up for an internal nucleophilic addition but instead is well positioned to undergo complexation with alkyne, ultimately affording the desired cyclocarbonylation product with no loss in enantiomeric excesses.

Determination of the Absolute Configuration of the Cyclocarbonylation Product

The fortuitous crystallization of 35c at −20 °C allowed for the determination of the absolute configuration by X-ray diffraction using the anomalous scattering effect of the silicon and is in agreement with the absolute configuration of that established for allenyl alcohol (R_a)-22 (Scheme 9).²⁷

Scheme 9.

Absolute Configuration of Cyclocarbonylation Product 35c

Furthermore, during attempts to establish the absolute configuration of cyclocarbonylation product 35e by derivatization with (S)-(−)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP), compound 48 was isolated instead of the expected hydrazone (Scheme 10). Structurally similar compounds are usually synthesized by performing the APKR on allenamides.²⁸ This type of isomerization has previously been observed during an APKR.²⁸ The silicon group is shown to have no effect on this unusual isomerization since compound 48 was also obtained when the reaction was performed on the dienone lacking the silicon group.

Scheme 10.

Synthesis of Compound 48

Conclusion

In summary, we have successfully performed a transfer of chirality from a chiral non-racemic allene to a 4-alkylidene cyclopentenone in a Rh(I)-catalyzed APKR. Complete transfer of chirality was obtained for every trisubstituted allene. Investigations regarding the loss of enantiomeric excess observed when the APKR was performed with disubstituted allene-ynes demonstrated that partial racemization of the allenes was occurring during the reaction. Moreover, the mildness of the reaction conditions are highlighted by the absence of epimerization of the stereogenic center during the reaction. The absolute configuration of cyclocarbonylation product 35c was unambiguously established by X-ray crystallographic analysis. The absolute configuration of this dienone corresponds to the predicted assignment, based upon the absolute configuration of the propargylic alcohol precursor. Finally, an unusual isomerization of the dienone was observed during attempts to functionalize the carbonyl group, affording a presumably more stable vinylogous amide.

Experimental Section

Unless otherwise noted, all reactions were performed under N₂ in flame-dried glassware using standard syringe, cannula, and septum techniques. All commercially available compounds were used as received unless otherwise noted. The reaction solvents tetrahydrofuran (THF) and dichloromethane (CH₂Cl₂) were obtained by passing commercially available predried, oxygen-free formulations through activated alumina columns. Toluene, acetonitrile, 2,6-lutidine and triethylamine (Et₃N) were freshly distilled from CaH₂ prior to use. N,N-dimethylacetamide was dried over 4 Å molecular sieves for 12 h prior to use. Flash chromatography was carried out on silica. Thin layer chromatography (TLC) analysis was performed on precoated silica gel F₂₅₄ aluminium plates. ¹H NMR and ¹³C NMR spectra were recorded in deuterated solvents and referenced to residual chloroform (7.26 ppm, ¹H, 77.0 ppm, ¹³C). Chemical shifts are reported in ppm, multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). Coupling constants, J, are reported in hertz. All NMR spectra were obtained at rt. Infrared spectra were recorded neat and are reported in cm⁻¹. HRMS data were collected using a TOF mass spectrometer.

General Procedure for Preparation of Allene-yne via Mitsunobu Reaction

To a solution of the alcohol in THF cooled to 0 °C (ice bath) was added triphenylphosphine (1.2 equiv), the tosylamide (1.2 equiv) and diisopropylazodicarboxylate (1.2 equiv). The reaction mixture was stirred until completion as judged by TLC analysis. Concentration of the reaction mixture under reduced pressure afforded the crude residue. The crude material was purified by flash chromatography.

General Procedure for Preparation of Allene-yne via Williamson Etherification

A solution of the alcohol in THF was cooled to 0 °C (ice bath) and sodium hydride (2 equiv, 60% dispersion in mineral oil) was added portionwise. The mixture was stirred for 30 min at rt. The propargyl bromide (1.5 equiv) was added and the reaction was stirred at rt until completion as judged by TLC analysis. The reaction was quenched by careful dropwise addition of water over 5 min. The two layers were separated and the aqueous layer was extracted with Et₂O. The organic layers were combined, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography.

General Procedure for Preparation of Allene-yne via Alkylation of the Malonate Moiety

The diethyl malonate²³ (2 equiv) was added dropwise to a stirred suspension of sodium hydride (2 equiv, 60% dispersion in mineral oil) in a DMF/THF (1:1) mixture cooled to 0 °C (ice bath). After 1 h at 0 °C, hydrogen evolution had ceased and the mesylate (1 equiv) in THF was added, followed by potassium iodide (1.5 equiv). The reaction mixture was stirred at 70 °C for 12 h. The solution was cooled to rt, diluted with Et₂O and quenched by careful dropwise addition of a saturated solution of NH₄Cl. The layers were separated and the aqueous layer was extracted with Et₂O. The combined organic phases were washed with brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography.

General Procedure for Preparation of Allene-yne via Silylation of the Terminal Alkyne

To a solution of the allene-yne (1 equiv) in THF cooled to −78 °C was added lithium hexamethyldisilylamide (1 M in THF, 1.3 equiv) and the resulting mixture was stirred at −78 °C for 1 h. Trimethylsilyl chloride (2 equiv) was then added and the reaction was stirred for 1 h at −78 °C. The mixture was quenched with a saturated solution of NH₄Cl and diluted with Et₂O. The layers were separated and the aqueous layer was extracted with Et₂O. The combined organic phases were washed with brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography.

General Procedure for the [Rh(CO)₂Cl]₂-Catalyzed Cyclocarbonylation Reaction

A flame dried vial (15 × 45 mm) equipped with a Teflon-coated stir-bar and a septa cap was charged with allene-yne and toluene (0.1 M). The tube was evacuated for 3–5 sec. and refilled with CO (g) (3 ×) using a balloon. To the allene-yne solution was added [Rh(CO)₂Cl]₂ (0.1 equiv) in one portion, and the vial was evacuated and refilled with CO (g) (3 ×). The vial was placed in a preheated 90 °C oil bath and stirred under CO (g). After the reaction was complete as judged by TLC analysis, the mixture was cooled to rt, passed through a short plug of Celite using Et₂O, and concentrated under reduced pressure. The crude material was purified by flash chromatography.

(R_a)-Hexa-3,4-dien-1-yl 4-nitrobenzoate (27)

(R_a)-hexa-3,4-dien-1-ol³²26 (48 mg, 0.49 mmol) was dissolved in N,N-dimethylacetamide (0.9 mL) and 2,6-lutidine (150 μL, 1.32 mmol). This solution was added dropwise to a solution of p-nitrobenzoyl chloride (118 mg, 0.64 mmol), 4-N,N-dimethylaminopyridine (12 mg, 0.098 mmol) in acetonitrile (0.7 mL) at 0 °C (ice bath). After completion of the addition, the reaction mixture was stirred for 1 h at 0 °C. After quenching with a saturated solution of sodium bicarbonate (3 mL), the mixture was extracted with Et₂O (20 mL), washed with water (5 mL), brine (5 mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, gradient of 1–10% Et₂O/hexanes) afforded compound 27 (73.4 mg, 61%) as a colorless oil. ¹H NMR (700 MHz, CDCl₃) δ 8.29 (d, J = 8.7 Hz, 2H), 8.22 (d, J = 8.7 Hz, 2H), 5.12 – 5.10 (m, 2H), 4.45 – 4.43 (m, 2H), 2.48 – 2.43 (m, 2H), 1.62 – 1.61 (m, 3H) ; ¹³C NMR (175 MHz, CDCl₃) δ 205.5, 164.6, 150.5, 135.7, 130.6 (2C), 123.5 (2C), 86.6, 85.8, 64.9, 28.2, 14.3 ; IR (thin film) 3113, 2954, 2901, 2852, 1965, 1720, 1532, 1352, 1274, 1103, 1111, 1013, 874; HRMS (ES+) C₂H₁₃NO₄ [M⁺] Calculated: 247.0845; Found: 247.0867; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-43.6°$ (c 0.55, CH₂Cl₂).

(R_a)-N-(hexa-3,4-dien-1-yl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzene sulfonamide (17d)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, (R_a)-hexa-3,4-dien-1-ol 26 (26.4 mg, 0.27 mmol) in THF (1.9 mL) was reacted with triphenylphosphine (85 mg, 0.32 mmol), 4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide³² (92.1 mg, 0.32 mmol) and diisopropylazodicarboxylate (64 μL, 0.32 mmol) for 12 h. Purification of the crude residue using a Biotage normal phase automated purification system (25 g SNAP column, gradient of 0 – 20% Et₂O/hexanes) afforded compound 17d (83.9 mg, 85%) as a colorless oil.¹H NMR (600 MHz, CDCl₃) δ 7.77 (d, J = 8.0 Hz, 2H), 7.28 – 7.22 (m, 5H), 7.08 (d, J = 7.3 Hz, 2H), 5.11 – 5.08 (m, 1H), 5.08 – 5.03 (m, 1H), 4.36 (s, 2H), 3.33 (t, J = 7.3 Hz, 2H), 2.34 (s, 3H), 2.32 – 2.31 (m, 2H), 1.66 – 1.64 (m, 3H) ; ¹³C NMR (150 MHz, CDCl₃) δ 205.4, 143.3, 136.0, 131.5 (2C), 129.5 (2C), 128.4, 128.1 (2C), 127.7 (2C), 122.2, 86.6, 86.4, 85.6, 81.9, 46.1, 37.3, 27.6, 21.4, 14.4 ; IR (thin film) 3060, 3031, 2987, 2921, 2856, 2235, 1973, 1597, 1487, 1438, 1344, 1168, 1095, 1025, 907; HRMS (ES+) C₂₂H₂₃NO₂NaS [M+Na] Calculated: 388.1347; Found: 388.1364; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-25.5°$ (c 1.45, CH₂Cl₂).

(S)-6-methyl-8-phenyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (45d)

Following the general procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 17d (40.4 mg, 0.11 mmol) and [Rh(CO)₂Cl]₂ (4.3 mg, 0.011 mmol) were reacted in toluene (3.4 mL) for 180 min. Purification of the crude residue using a Biotage normal phase automated purification system (10 g SNAP column, 70% Et₂O/hexanes) afforded compound 45d (36.5 mg, 84%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.54 – 7.53 (m, 2H), 7.46 – 7.45 (m, 2H), 7.41 – 7.39 (m, 1H), 7.29 (d, J = 6.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 5.79 – 5.77 (m, 1H), 4.60 – 4.53 (m, 2H), 3.67 – 3.63 (m, 1H), 3.63 – 3.61 (m, 1H), 2.78 – 2.77 (m, 1H), 2.70 – 2.68 (m, 2H), 2.40 (s, 3H), 1.17 (d, J = 7.5 Hz, 3H) ; ¹³C NMR (150 MHz, CDCl₃) δ 205.3, 160.2, 143.5, 141.2, 140.7, 136.5, 130.4, 129.6 (2C), 129.3 (2C), 128.7, 128.5 (2C), 127.0 (2C), 125.5, 49.1, 49.0, 45.2, 30.8, 21.5, 15.0 ; IR (thin film) 3060, 2974, 2925, 2876, 1699, 1601, 1499, 1450, 1336, 1160, 1095, 952; HRMS (ES+) C₂₃H₂₄NO₃S [M+H⁺] Calculated: 394.1477; Found: 394.1473; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+1.64°$ (c 1.4, CH₂Cl₂).

(R_a)-N-(hexa-3,4-dien-1-yl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (17e)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, (R_a)-hexa-3,4-dien-1-ol 26 (42.1 mg, 0.43 mmol) in THF (3 mL) was reacted with triphenylphosphine (135 mg, 0.51 mmol), 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide³² (108 mg, 0.51 mmol) and diisopropylazodicarboxylate (101 μL, 0.51 mmol) for 6 h. Purification of the crude residue using a Biotage normal phase automated purification system (12 g SNAP column, gradient of 5 – 10% Et₂O/hexanes) afforded compound 17e (105 mg, 84%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 5.10 – 5.07 (m, 1H), 5.02 – 4.99 (m, 1H), 4.14 (d, J = 2.5 Hz, 2H), 3.26 (t, J = 7.4 Hz, 2H), 2.42 (s, 3H), 2.26 (m, 2H), 2.03 (t, J = 2.5 Hz, 1H), 1.65 – 1.63 (m, 3H) ; ¹³C NMR (175 MHz, CD₂Cl₂) δ 205.2, 143.7, 136.0, 129.5 (2C), 127.6 (2C), 86.5, 86.3, 76.7, 73.4, 46.1, 36.4, 27.5, 21.3, 14.2 ; IR (thin film) 3289, 2974, 2925, 2856, 1960, 1593, 1454, 1344, 1160, 1102; HRMS (ES+) C₁₆H₂₀NO₂S [M+H⁺] Calculated: 290.1215; Found: 290.1237; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-37.6°$ (c 1.25, CH₂Cl₂).

(R_a)-N-(hexa-3,4-dien-1-yl)-4-methyl-N-(3-(trimethylsilyl)prop-2-yn-1-yl)benzene sulfonamide (17f)

Following the general procedure for preparation of allene-yne via silylation of the terminal alkyne, allene-yne 17e (70 mg, 0.24 mmol) in THF (1.8 mL) was reacted with lithium hexamethyldisilylamide (314 μL, 1M in THF, 0.31 mmol) and trimethylsilylchloride (61 μL, 0.48 mmol). Purification of the crude residue using a Biotage normal phase automated purification system (10 g SNAP column, gradient of 2 – 7% Et₂O/hexanes) afforded compound 17f (73.2 mg, 84%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.72 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 5.09 – 5.02 (m, 2H), 4.15 (s, 2H), 3.25 (t, J = 7.4 Hz, 2H), 2.42 (s, 3H), 2.28 – 2.25 (m, 2H), 1.66 – 1.63 (m, 3H), −0.01 (s, 9H) ; ¹³C NMR (150 MHz, CDCl₃) δ 205.3, 143.2, 135.9, 129.4 (2C), 127.7 (2C), 97.9, 90.8, 86.5, 86.3, 45.8, 37.3, 27.4, 21.5, 14.4, −0.5 (3C) ; IR (thin film) 2965, 2916, 2857, 2178, 1594, 1455, 1249, 1346, 115536, 1095; HRMS (ES+) C₁₉H₂₈NO₂SSi [M+H⁺] Calculated: 362.1610; Found: 362.1628; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-27.6°$ (c 1.05, CH₂Cl₂).

(S)-6-methyl-2-tosyl-8-(trimethylsilyl)-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (45f)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 17f (42 mg, 0.12 mmol) and [Rh(CO)₂Cl]₂ (4.5 mg, 0.012 mmol) were reacted in toluene (3.6 mL) for 180 min. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, 65% Et₂O/hexanes) afforded compound 45f (37.5 mg, 83%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.64 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 5.70 – 5.67 (m, 1H), 4.53 (s, 2H), 3.56 – 3.52 (m, 2H), 2.64 – 2.59 (m, 3H), 2.41 (s, 3H), 1.07 (d, J = 7.5 Hz, 3H), 0.30 (s, 9H) ; ¹³C NMR (150 MHz, CDCl₃) δ 211.3, 172.6, 143.6, 143.5, 141.9, 136.2, 129.7 (2C), 127.1 (2C), 124.8, 50.6, 48.8, 46.1, 31.0, 21.5, 14.9, −0.5 (3C) ; IR (thin film) 2958, 2921, 2864, 1691, 1536, 1340, 1164, 1091; HRMS (ES+) C₂₀H₂₈NO₃SSi [M+H⁺] Calculated: 390.1559; Found: 390.1549; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+8.3°$ (c 0.8, CH₂Cl₂).

(R_a)-N-(but-2-yn-1-yl)-N-(hexa-3,4-dien-1-yl)-4-methylbenzenesulfonamide (17c)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, (R_a)-hexa-3,4-dien-1-ol 26 (25 mg, 0.26 mmol) in THF (1.8 mL) was reacted with triphenylphosphine (80.2 mg, 0.31 mmol), N-(but-2-yn-1-yl)-4-methylbenzenesulfonamide³² (68.3 mg, 0.31 mmol) and diisopropylazodicarboxylate (61 μL, 0.31 mmol) for 12 h. Purification of the crude residue using a Biotage normal phase automated purification system (10 g SNAP column, gradient of 10% Et₂O/hexanes) afforded compound 17c (57 mg, 74%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.08 – 5.04 (m, 1H), 5.04 – 4.99 (m, 1H), 4.07 – 4.06 (m, 2H), 3.26 – 3.21 (t, J = 7.3 Hz, 2H), 2.42 (s, 3H), 2.26 – 2.23 (m, 2H), 1.66 – 1.63 (m, 3H), 1.57 – 1.55 (t, J = 2.4 Hz, 3H) ; ¹³C NMR (150 MHz, CDCl₃) δ 205.3, 143.1, 136.1, 129.2 (2C), 127.8 (2C), 86.6, 86.3, 81.4, 71.8, 45.9, 36.9, 27.6, 21.5, 14.4, 3.2 ; IR (thin film) 2925, 2852, 1961, 1597, 1442, 1348, 1160, 1099; HRMS (ES+) C₁₇H₂₂NO₂S [M+H⁺] Calculated: 304.1371; Found: 304.1363; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-17.7°$ (c 2.6, CH₂Cl₂).

(S)-6,8-Dimethyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (45c)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 17c (16.9 mg, 0.056 mmol) and [Rh(CO)₂Cl]₂ (2.2 mg, 0.0056 mmol) were reacted in toluene (1.7 mL) for 280 min. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, 70% Et₂O/hexanes) afforded compound 45c (13.5 mg, 73%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J = 8.3 Hz, 2H), 7.29 – 7.26 (d, J = 8.3 Hz, 2H), 5.63 (t, J = 5.0 Hz, 1H), 4.43 – 4.41 (m, 2H), 3.55 – 3.51 (m, 2H), 2.70 – 2.59 (m, 3H), 2.42 (s, 3H), 1.81 (s, 3H), 1.10 (d, J = 7.4 Hz, 3H) ; ¹³C NMR (175 MHz, CDCl₃) 207.0, 159.8, 143.6, 140.8, 138.0, 136.2, 129.7 (2C), 127.0 (2C), 123.7, 49.0, 48.9, 44.6, 31.3, 21.5, 14.9, 8.4 ; IR (thin film) 2062, 2921, 2856, 2002, 1691, 1597, 1446, 1340, 1164, 1095; HRMS (ES+) C₁₈H₂₂NO₃S [M+H⁺] Calculated: 332.1320; Found: 332.1347; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+2.4°$ (c 0.85, CH₂Cl₂).

(R_a)-Hexa-3,4-dien-1-yl methanesulfonate (32)

To a stirred solution of (R_a)-hexa-3,4-dien-1-ol 26 (60.8 mg, 0.62 mmol) in THF (8.7 mL), cooled to 0 °C (ice bath), was added triethylamine (95 μL, 0.68 mmol) followed by methanesulfonyl chloride (53 μL, 0.681 mmol). The resulting solution was stirred at rt for 12 h. The mixture was diluted with Et₂O (60 mL), washed with water (2 × 10 mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification of the crude residue using a Biotage normal phase automated purification system (12 g SNAP column, 35% Et₂O/hexanes) afforded compound 32 (84.1 mg, 77%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.22 – 5.12 (m, 1H), 5.05 – 5.03 (m, 1H), 4.25 (t, J = 6.8 Hz, 2H), 3.00 (s, 3H), 2.44 – 2.39 (m, 2H), 1.65 (dd, J = 7.0, 3.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 205.4, 86.9, 84.8, 69.0, 37.2, 28.5, 14.1; IR (thin film) 3032, 2987, 2942, 1965, 1462, 1344, 1172, 964, 911; HRMS (ES+) C₇H₁₃O₃S [M+H⁺] Calculated: 177.0585; Found: 177.0588; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-32.4°$ (c 1.45, CH₂Cl₂).

(R_a)-Diethyl 2-(hexa-3,4-dien-1-yl)-2-(3-phenylprop-2-yn-1-yl)malonate (19d)

Following the General Procedure for Preparation of Allene-yne via alkylation of the malonate moiety, diethyl malonate 34d (79.3 mg, 0.29 mmol) was reacted with sodium hydride (8.7 mg, 60 wt% in oil, 0.22 mmol), mesylate 32 (25.5 mg, 0.15 mmol) and potassium iodide (36 mg, 0.22 mmol) in DMF-THF (1 : 1, 4 mL). Purification of the crude residue using a Biotage normal phase automated purification system (25 g SNAP column, gradient of 3 – 7% Et₂O/hexanes) afforded compound 19d (35.4 mg, 69%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.38 – 7.35 (m, 2H), 7.29 – 7.27 (m, 3H), 5.09 – 5.05 (m, 2H), 4.22 (q, J = 7.2 Hz, 4H), 3.05 (s, 2H), 2.25 – 2.20 (m, 2H), 1.98 – 1.95 (m, 2H), 1.65 – 1.62 (m, 3H), 1.26 (t, J = 7.1 Hz, 6H) ; ¹³C NMR (175 MHz, CDCl₃) δ 204.6, 170.3 (2C), 131.6 (2C), 128.1 (2C), 127.9, 123.3, 89.4, 86.4, 84.4, 83.4, 61.5 (2C), 56.9, 31.6, 23.8, 23.7, 14.4, 14.1 (2C) ; IR (thin film) 3465, 2987, 2921, 2856, 1965, 1732, 1597, 1487, 1446, 1368, 1270, 1197, 1091, 1030; HRMS (ES+) C₂₂H₂₇O₄ [M+H⁺] Calculated: 355.1909; Found: 355.1885; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-19.6°$ (c 2.5, CH₂Cl₂).

(S)-Diethyl 1-methyl-2-oxo-3-phenyl-1,2,6,7-tetrahydroazulene-5,5(4H)-dicarboxylate (47d)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 19d (22.6 mg, 0.064 mmol) and [Rh(CO)₂Cl]₂ (2.5 mg, 0.0064 mmol) were reacted in toluene (2 mL) for 100 min. Purification of the residue by flash chromatography (45% Et₂O/hexanes) afforded the title compound 47d (23.3 mg, 96%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.44 – 7.26 (m, 5H), 6.04 – 5.92 (m, 1H), 4.15 – 4.02 (m, 4H), 3.39 (s, 2H), 2.94 – 2.87 (q, J = 7.4 Hz, 1H), 2.56 – 2.52 (m, 2H), 2.45 – 2.41 (m, 2H), 1.27 (d, J = 7.5 Hz, 3H), 1.13 (q, J = 7.1 Hz, 6H) ; ¹³C NMR (175 MHz, CDCl₃) δ 206.0, 171.1, 170.9, 161.3, 143.2, 141.9, 131.3, 129.4 (2C), 128.3 (2C), 128.2, 127.9, 61.7, 61.6, 56.3, 44.9, 34.5, 33.8, 25.1, 15.3, 13.9, 13.8 ; IR (thin film) 2966, 2929, 2852, 2365, 1732, 1699, 1450, 1364, 1242, 1176, 1078; HRMS (ES+) C₂₃H₂₇O₅ [M+H⁺] Calculated: 383.1858; Found: 383.1860; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-12.6°$ (c 0.95, CH₂Cl₂).

(R_a)-Diethyl 2-(but-2-yn-1-yl)-2-(hexa-3,4-dien-1-yl)malonate (19c)

Following the General Procedure for Preparation of Allene-yne via alkylation of the malonate moiety, diethyl malonate 34c (94.4 mg, 0.45 mmol) was reacted with sodium hydride (15.3 mg, 60 wt% in oil, 0.38 mmol), mesylate 32 (56 mg, 0.32 mmol) and potassium iodide (79.1 mg, 0.48 mmol) in DMF-THF (1 : 1, 6 mL). Purification of the crude residue using a Biotage normal phase automated purification system (25 g SNAP column, gradient of 4 – 6% Et₂O/hexanes) afforded compound 19c (59.6 mg, 63%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.07 – 5.02 (m, 2H), 4.18 (q, J = 7.1 Hz, 4H), 2.75 (s, 2H), 2.12 – 2.10 (m, 2H), 1.90 – 1.88 (m, 2H), 1.73 (s, 3H), 1.64 – 1.62 (m, 3H), 1.23 (t, J = 7.2 Hz, 6H) ; ¹³C NMR (175 MHz, CDCl₃) δ 204.6, 170.4 (2C), 89.4, 86.3, 78.5, 73.4, 61.3 (2C), 56.8, 31.4, 23.7, 23.1, 14.4, 14.0 (2C), 3.4 ; IR (thin film) 2983, 2934, 2859, 1736, 1438, 1360, 1275, 1225, 1193; HRMS (ES+) C₁₇H₂₅O₄ [M+H⁺] Calculated: 293.1753; Found:293.1778; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-32.9°$ (c 0.85, CH₂Cl₂).

(S)-diethyl 1,3-dimethyl-2-oxo-1,2,6,7-tetrahydroazulene-5,5(4H)-dicarboxylate (47c)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 19c (33.8 mg, 0.11 mmol) and [Rh(CO)₂Cl]₂ (4.4 mg, 0.011 mmol) were reacted in toluene (3.6 mL) for 22 h. Purification of the residue by flash chromatography (40% Et₂O/hexanes) afforded compound 47c (25.7 mg, 71%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 5.81 – 5.79 (m, 1H), 4.23 – 4.15 (m, 4H), 3.21 (s, 2H), 2.76 – 2.68 (m, 1H), 2.51 – 2.47 (m, 2H), 2.39 – 2.33 (m, 2H), 1.84 (s, 3H), 1.27 – 1.22 (m, 6H), 1.16 (d, J = 7.5 Hz, 3H) ; ¹³C NMR (150 MHz, CDCl₃) δ 208.1, 171.3, 171.2, 161.0, 143.6, 139.2, 125.9, 61.7 (2C), 56.2, 44.2, 33.9 (2C), 25.0, 15.0, 14.0 (2C), 8.3 ; IR (thin film) 2978, 2921, 1732, 1703, 1446, 1364, 1287, 1234, 1062, 1095; HRMS (ES+) C₁₈H₂₅O₅ [M+H⁺] Calculated: 321.1702; Found: 321.1723; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-12°$ (c 0.5, CH₂Cl₂).

(R_a)-Diethyl 2-(hexa-3,4-dien-1-yl)-2-(prop-2-yn-1-yl)malonate (19e)

Following the General Procedure for Preparation of Allene-yne via alkylation of the malonate moiety, diethyl malonate 34e (189 mg, 0.95 mmol) was reacted with sodium hydride (28.6 mg, 60 wt% in oil, 0.71 mmol), mesylate 32 (84 mg, 0.48 mmol) and potassium iodide (119 mg, 0.72 mmol) in DMF-THF (1 : 1, 13 mL). Purification of the crude residue using a Biotage normal phase automated purification system (50 g SNAP column, gradient of 2 – 7% Et₂O/hexanes) afforded compound 19e (75.5 mg, 57%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 5.09 – 5.03 (m, 2H), 4.24 – 4.17 (m, 4H), 2.83 (s, 2H), 2.20 – 2.14 (m, 2H), 2.00 (t, J = 2.7 Hz, 1H), 1.96 – 1.87 (m, 2H), 1.66 – 1.63 (m, 3H), 1.25 (t, J = 7.1 Hz, 6H); ¹³C NMR (100 MHz, CD₂Cl₂) δ 204.5, 170.0 (2C), 89.3, 86.3, 78.9, 71.0, 61.6 (2C), 56.4, 31.3, 23.7, 22.7, 14.2, 13.8 (2C) ; IR (thin film) 3293, 2892, 2938, 1736, 1454, 1270, 1193, 1095, 1030. HRMS (ES+) C₁₆H₂₃O₄ [M+H⁺] Calculated: 279.1596; Found: 279.1623; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-40°$ (c 2.2, CH₂Cl₂).

(R_a)-Diethyl 2-(hexa-3,4-dien-1-yl)-2-(3-(trimethylsilyl)prop-2-yn-1-yl)malonate (19f)

Following the general procedure for preparation of allene-yne via silylation of the terminal alkyne, allene-yne 19e (67.6 mg, 0.24 mmol) in THF (1.8 mL) was reacted with lithium hexamethyldisilylamide (365 μL, 1M in THF, 0.36 mmol) and trimethylsilylchloride (62 μL, 0.49 mmol). Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, 5% Et₂O/hexanes) afforded compound 19f (74.4 mg, 88%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.08 – 5.03 (m, 2H), 4.20 – 4.17 (m, 4H), 2.84 (s, 2H), 2.14 – 2.12 (m, 2H), 1.93 – 1.90 (m, 2H), 1.65 – 1.62 (m, 3H), 1.24 (t, J = 7.1 Hz, 6H), 0.12 (s, 9H) ; ¹³C NMR (175 MHz, CDCl₃) δ 204.6, 170.1 (2C), 101.4, 89.4, 88.0, 86.3, 61.5 (2C), 56.7, 31.4, 24.2, 23.7, 14.4, 14.0 (2C), −0.1 (3C) ; IR (thin film) 2958, 2925, 2860, 2186, 1740, 1471, 1442, 1254, 1197, 1103, 1034, 854; HRMS (ES+) C₁₉H₃₁O₄Si [M+H⁺] Calculated: 351.1992; Found: 351.1990; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-30.3°$ (c 1.85, CH₂Cl₂).

(S)-Diethyl 1-methyl-2-oxo-3-(trimethylsilyl)-1,2,6,7-tetrahydroazulene-5,5(4H)-dicarboxylate (47f)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 19f (33.9 mg, 0.097 mmol) and [Rh(CO)₂Cl]₂ (2.5 mg, 0.0097 mmol) were reacted in toluene (3.2 mL) for 10 h. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, 25% Et₂O/hexanes) afforded compound 47f (34.5 mg, 94%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 5.88 – 5.83 (m, 1H), 4.23 – 4.16 (m, 4H), 3.37 – 3.36 (m, 2H), 2.75 – 2.68 (m, 1H), 2.50 – 2.46 (m, 2H), 2.40 – 2.34 (m, 2H), 1.24 (td, J = 7.1, 0.9 Hz, 6H), 1.14 (t, J = 7.4 Hz, 3H), 0.27 (s, 9H) ; ¹³C NMR (100 MHz, CDCl₃) δ 212.3, 173.4, 171.1, 171.0, 145.6, 142.8, 127.3, 61.7, 61.6, 56.3, 46.1, 36.5, 33.7, 25.2, 15.0, 14.0 (2C), −0.3 (3C) ; IR (Thin film) 2970, 2929, 2905, 1736, 1691, 1540, 1446, 1368, 1291, 1230, 1078, 1037, 841; HRMS (ES+) C₂₀H₃₁O₅Si [M+H⁺] Calculated: 379.1941; Found: 379.1967; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-5.5°$ (c 2.2, CH₂Cl₂).

(R_a)-6-(But-2-yn-1-yloxy)hexa-2,3-diene (18c)

Following the general procedure for preparation of allene-yne via Williamson etherification, (R_a)-hexa-3,4-dien-1-ol 26 (32.3 mg, 0.33 mmol) in THF (0.8 mL) was reacted with sodium hydride (26.5 mg, 60% dispersion in mineral oil 0.66 mmol) and 1-bromobut-2-yne (61.3 mg, 0.46 mmol) for 12 h. Purification of the crude residue using a Biotage normal phase automated purification system (12 g SNAP column, gradient of 0 – 3% Et₂O/hexanes) afforded compound 18c (37.4 mg, 83%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 5.09 – 5.04 (m, 2H), 4.10 – 4.08 (m, 2H), 3.56 – 3.51 (m, 2H), 2.29 – 2.25 (m, 2H), 1.86 – 1.84 (m, 3H), 1.66 – 1.62 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 205.2, 86.6, 85.8, 82.1, 75.2, 69.3, 58.5, 29.1, 14.3, 3.5 ; IR (thin film) 2925, 2860, 1446, 1356, 1140, 1095; HRMS (ES+) C₁₀H₁₅O [M+H⁺] Calculated: 151.1123; Found: 151.1150; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-20.5°$ (c 1.85, CH₂Cl₂).

(S)-6,8-Dimethyl-3,4-dihydro-1H-cyclopenta[c]oxepin-7(6H)-one (46c)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 18c (27.1 mg, 0.20 mmol) and [Rh(CO)₂Cl]₂ (7.6 mg, 0.020 mmol) were reacted in toluene (6.4 mL) for 390 min. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, 60% Et₂O/hexanes) afforded compound 46c (14.1 mg, 40%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 5.79 – 5.76 (m, 1H), 4.74 (s, 2H), 3.94 (t, J = 5.3 Hz, 2H), 2.87 – 2.74 (m, 1H), 2.63 – 2.58 (m, 2H), 1.74 (s, 3H), 1.23 (d, J = 7.5 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 207.2, 164.0, 140.6, 136.2, 124.6, 71.6, 71.0, 44.6, 33.8, 15.2, 8.1; IR (thin film) 2966, 2925, 2872, 1695, 1597, 1458, 1372, 1328, 1225, 1205, 1140; HRMS (ES+) C₁₁H₁₅O₂ [M+H⁺] Calculated: 179.1072; Found: 179.1051; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+2.9°$ (c 1.05, CH₂Cl₂).

(R_a)-6-(Prop-2-yn-1-yloxy)hexa-2,3-diene (18e)

Following the general procedure for preparation of allene-yne via Williamson etherification (R_a)-hexa-3,4-dien-1-ol 26 (70.7 mg, 0.72 mmol) in THF (1.7 mL) was reacted with sodium hydride (58 mg, 60% dispersion in mineral oil 1.44 mmol) and propargyl bromide (161 mg, 80 wt% in toluene, 1.08 mmol) for 11 h. Purification of the crude residue using a Biotage normal phase automated purification system (12 g SNAP column, gradient of 0 – 2% Et₂O/hexanes) afforded compound 18e (43.4 mg, 44%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 5.09 – 5.06 (m, 2H), 4.16 (d, J = 2.4 Hz, 2H), 3.58 (t, J = 6.8 Hz, 2H), 2.42 (t, J = 2.4 Hz, 1H), 2.30 – 2.26 (m, 2H), 1.66 – 1.64 (m, 3H) ; ¹³C NMR (150 MHz, CD₂Cl₂) δ 205.1, 86.6, 85.8, 80.0, 73.8, 69.4, 57.9, 29.2, 14.2 ; IR (thin film) 2933, 2852, 1454, 1356, 1099; HRMS (ES+) C₉H₁₁O [M−H⁺] Calculated: 135.0810; Found: 135.0835; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-41.5°$ (c 1.35, CH₂Cl₂).

(S)-6-Methyl-3,4-dihydro-1H-cyclopenta[c]oxepin-7(6H)-one (46e)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 18e (45.5 mg, 0.33 mmol) and [Rh(CO)₂Cl]₂ (13 mg, 0.033 mmol) were reacted in toluene (10.9 mL) for 105 min. Purification of the crude residue using a Biotage normal phase automated purification system (10 g SNAP column, 20 – 65% Et₂O/hexanes) afforded compound 46e (13.3 mg, 24%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 6.00 (s, 1H), 5.91 – 5.89 (m, 2H), 4.78 – 4.77 (m, 2H), 3.96 – 3.92 (m, 2H), 2.88 – 2.84 (m, 1H), 2.63 – 2.61 (m, 1H), 1.25 (d, J = 7.6 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 207.6, 171.4, 141.6, 127.9, 127.6, 71.9, 71.8, 45.8, 33.8, 15.0; IR (thin film) 2925, 2864, 1699, 1565, 1458, 1368, 1201, 1120, 1070; HRMS (ES+) C₁₀H₁₃O₂ [M+H⁺] Calculated: 165.0916; Found: 165.0897; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+14.1°$ (c 0.85, CH₂Cl₂).

(R_a)-(3-(Hexa-3,4-dien-1-yloxy)prop-1-yn-1-yl)trimethylsilane (18f)

Following the general procedure for preparation of allene-yne via silylation of the terminal alkyne, allene-yne 18e (72.4 mg, 0.53 mmol) in THF (4.2 mL) was reacted with lithium hexamethyldisilylamide (798 μL, 1M in THF, 0.80 mmol) and trimethylsilyl chloride (135 μL, 1.06 mmol). Purification of the crude residue using a Biotage normal phase automated purification system (10 g SNAP column, gradient of 0 – 1% Et₂O/hexanes) afforded compound 18f (76 mg, 69%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 5.10 – 5.05 (m, 2H), 4.15 (s, 2H), 3.56 (t, J = 6.8 Hz, 2H), 2.30 – 2.26 (m, 2H), 1.64 – 1.63 (m, 3H), 0.18 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 205.3, 101.7, 91.1, 86.7, 85.9, 69.5, 58.8, 29.1, 14.4, −0.2 (3C); IR (thin film) 2954, 2897, 2178, 1258, 1107, 919, 850; HRMS (ES+) C₁₂H₂₀OSi [M−H]⁺ Calculated: 207.1205; Found: 207.1189; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-33.3°$ (C 1.35, CH₂Cl₂).

(S)-6-Methyl-8-(trimethylsilyl)-3,4-dihydro-1H-cyclopenta[c]oxepin-7(6H)-one (46f)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed cyclocarbonylation Reaction, allene-yne 18f (29.8 mg, 0.14 mmol) and [Rh(CO)₂Cl]₂ (5.6 mg, 0.014 mmol) were reacted in toluene (4.7 mL) for 7 h. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, 40% Et₂O/hexanes) afforded compound 46f (25.6 mg, 76%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 5.85 – 5.84 (m, 1H), 4.84 (s, 2H), 3.94 (t, J = 5.4 Hz, 2H), 2.80 – 2.78 (m, 1H), 2.63 – 2.60 (m, 2H), 1.21 (d, J = 7.5 Hz, 3H), 0.23 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 211.5, 177.1, 142.9, 139.8, 126.1, 73.0, 71.5, 46.2, 33.8, 15.3, −0.4 (3C); IR (thin film) 2958, 2925, 2869, 1687, 1528, 1250, 1193, 1136; HRMS (ES+) C₁₃H₂₁O₂Si [M+H⁺] Calculated: 237.1311; Found: 237.1283; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-1.6°$ (c 1.6, CH₂Cl₂).

(R_a)-(3-(hexa-3,4-dien-1-yloxy)prop-1-yn-1-yl)benzene (18d)

Following the general procedure for preparation of allene-yne via Williamson etherification, (R_a)-hexa-3,4-dien-1-ol 26 (62.8 mg, 0.64 mmol) in THF (1.5 mL) was reacted with sodium hydride (51.2 mg, 60% dispersion in mineral oil, 1.27 mmol) and (3-bromoprop-1-yn-1-yl)benzene (187.2 mg, 0.96 mmol) for 3 h. Purification of the crude residue using a Biotage normal phase automated purification system (10 g SNAP column, gradient of 0 – 3% Et₂O/hexanes) afforded compound 18d (85.2 mg, 63%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.46 – 7.45 (m, 2H), 7.32 – 7.30 (m, 3H), 5.12 – 5.08 (m, 2H), 4.38 (s, 2H), 3.65 (t, J = 6.8 Hz, 2H), 2.34 – 2.31 (m, 2H), 1.67 – 1.64 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 205.3, 131.7 (2C), 128.3, 128.2 (2C), 122.7, 86.7, 86.0, 85.9, 85.3, 69.5, 58.8, 29.2, 14.4; IR (thin film) 3060, 2917, 2845, 1969, 1491, 1442, 1360, 1099; HRMS (ES+) C₁₅H₁₇O [M+H⁺] Calculated: 213.1279; Found: 213.1280; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-41.5°$ (c 0.65, CH₂Cl₂).

(S)-6-Methyl-8-phenyl-3,4-dihydro-1H-cyclopenta[c]oxepin-7(6H)-one (46d)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 18d (29.6 mg, 0.14 mmol) and [Rh(CO)₂Cl]₂ (5.4 mg, 0.014 mmol) were reacted in toluene (4.4 mL) for 30 min. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, 45% Et₂O/hexanes) afforded compound 46d (30 mg, 90%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.41 – 7.34 (m, 3H), 7.25 – 7.24 (m, 2H), 5.96 – 5.94 (m, 1H), 4.85 (s, 2H), 4.03 – 3.98 (m, 2H), 3.01 – 2.98 (m, 1H), 2.69 – 2.67 (m, 2H), 1.34 (d, J = 7.5 Hz, 3H); ¹³C NMR (175 MHz, CDCl₃) δ 205.6, 164.4, 140.7, 139.1, 130.9, 129.3 (2C), 128.4, 128.3 (2C), 126.8, 71.9, 71.5, 45.3, 33.6, 15.5; IR (thin film) 2962, 2925, 2868, 1669, 1446, 1131; HRMS (ES+) C₁₆H₁₇O₂ [M+H⁺] Calculated: 241.1229; Found: 241.1204; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-24°$ (c 0.25, CH₂Cl₂).

(R_a)-N-(But-2-yn-1-yl)-N-(3-(dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-methyl benzenesulfonamide (13c)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-22 (157 mg, 0.675 mmol) in THF (4.4 mL) was reacted with triphenylphosphine (213 mg, 0.81 mmol), N-(but-2-yn-1-yl)-4-methylbenzenesulfonamide³²30c (181 mg, 0.81 mmol) and diisopropylazodicarboxylate (160 μL, 0.81 mmol) for 3 h. Purification of the crude residue using a Biotage normal phase automated purification system (25 g SNAP column, gradient of 0 – 30% Et₂O/hexanes) afforded compound 13c (272 mg, 92%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.65 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.38 – 7.32 (m, 3H), 7.24 (d, J = 7.8 Hz, 2H), 4.92 – 4.80 (m, 1H), 3.96 (d, J = 2.5 Hz, 2H), 3.22 – 3.10 (m, 2H), 2.41 (s, 3H), 2.16 (m, 2H), 1.63 (d, J = 6.9 Hz, 3H), 1.52 (t, J = 2.5 Hz, 3H), 0.36 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 2078.0, 142.9, 137.9, 136.2, 133.7 (2C), 129.1 (2C), 129.0, 127.7 (2C), 127.7 (2C), 91.2, 81.2, 81.2, 72.0, 46.4, 37.1, 27.9, 21.4, 13.7, 3.2, −3.1, −3.2; IR (thin film) 3064, 2962, 2921, 2855, 2300, 2218, 1936, 1593, 1491; HRMS (ES+) C₂₅H₃₂NO₂SSi [M+H⁺] Calculated: 438.1923; Found: 438.1926; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+3.8°$ (c 1.7, CH₂Cl₂).

(S)-5-(Dimethyl(phenyl)silyl)-6,8-dimethyl-2-tosyl-1,2,3,4-tetrahydrocyclo penta [c]azepin-7(6H)-one (35c)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 13c (22.5 mg, 0.051 mmol) and [Rh(CO)₂Cl]₂ (2 mg, 0.005 mmol) were reacted in toluene (1.6 mL) for 3 h. Purification of the crude residue by flash chromatography (55% Et₂O/hexanes) afforded the title compound 35c (22.8 mg, 95%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.55 (d, J = 8.1 Hz, 2H), 7.40 – 7.34 (m, 5H), 7.22 (d, J = 8.1 Hz, 2H), 4.60 (d, J = 17.0 Hz, 1H), 4.46 (d, J = 17.0 Hz, 1H), 3.45 (t, J = 6.1 Hz, 2H), 2.56 – 2.51 (m, 3H), 2.40 (s, 3H), 1.89 (s, 3H), 0.91 (d, J = 7.4 Hz, 3H), 0.38 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 208.4, 160.9, 153.9, 143.5, 138.3, 137.1, 136.4, 133.8 (2C), 133.3, 129.5, 129.4 (2C), 128.0 (2C), 127.1 (2C), 48.0, 43.8, 43.0, 29.7, 21.4, 18.4, 8.2, −1.3, −1.6; IR (thin film) 2978, 2925, 2872, 1703, 1605, 1466, 1344, 1258, 1160, 1102; HRMS (ES+) C₂₆H₃₁NO₃SSiNa [M+Na⁺] Calculated: 488.1692; Found: 488.1708; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+157°$ (c 1.0, CH₂Cl₂).

(Z)-5-(dimethyl(phenyl)silyl)-3-ethylidene-1-tosyl-4-vinyl-2,3,6,7-tetrahydro-1H-azepine (36)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 13c (32.5 mg, 0.074 mmol) and [Rh(CO)₂Cl]₂ (1.4 mg, 0.004 mmol) were reacted in toluene (2.3 mL) for 7 h. Purification of the crude residue by flash chromatography (55% Et₂O/hexanes) afforded the cyclocarbonylation product 35 (14.4 mg, 42%) and triene 36 (15.6 mg, 48%) as yellow oils. ¹H NMR (300 MHz, CDCl₃) δ 7.63 (d, J = 8.3 Hz, 2H), 7.47 – 7.44 (m, 2H), 7.34 – 7.32 (m, 4H), 7.29 (s, 1H), 6.55 (dd, J = 16.9, 10.5 Hz, 1H), 5.52 – 5.45 (m, 1H), 5.15 (dd, J = 16.9, 1.9 Hz, 1H), 5.00 (dd, J = 10.5, 1.9 Hz, 1H), 3.82 (s, 2H), 3.07 – 3.03 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H), 2.34 (t, J = 5.9 Hz, 2H), 1.78 (d, J = 7.0 Hz, 3H), 0.39 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 153.7, 143.0, 138.9, 137.6, 135.7, 134.9, 133.9 (2C), 133.8, 129.6 (2C), 128.9, 127.9 (2C), 127.4 (2C), 127.3, 117.1, 46.6, 46.0, 31.7, 21.5, 13.3, −0.6 (2C); IR (thin film) 2966, 2921, 2847, 2010, 1515, 1462, 1429, 1336, 1254, 1160, 1103; HRMS (ES+) C₂₅H₃₂NO₂SSi [M+H⁺] Calculated: 438.1923; Found: 438.1917.

(R_a)-N-(3-(Dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-methyl-N-(prop-2-yn-1-yl)benzene sulfonamide (13e)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-22 (309 mg, 1.32 mmol) in THF (8.2 mL) was reacted with triphenylphosphine (415.4 mg, 1.58 mmol), 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide³²30e (331 mg, 1.58 mmol) and diisopropylazodicarboxylate (274 μL, 1.58 mmol) for 2 h. Purification of the crude residue using a Biotage normal phase automated purification system (25 g SNAP column, gradient of 0 – 30% Et₂O/hexanes) afforded compound 13e (500 mg, 90%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.65 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.0 Hz, 3H), 7.25 – 7.24 (m, 2H), 4.92 – 4.82 (m, 1H), 4.03 (d, J = 2.6 Hz, 2H), 3.22 – 3.18 (m, 2H), 2.42 (s, 3H), 2.18 – 2.15 (m, 2H), 1.96 (t, J = 2.5 Hz, 1H), 1.63 (d, J = 7.0 Hz, 3H), 0.36 (s, 6H); ¹³C NMR (175 MHz, CD₂Cl₂) 208.0, 143.6, 138.0, 136.1, 133.8 (2C), 129.4 (2C), 129.1, 127.8 (2C), 127.5 (2C), 91.2, 81.4, 76.9, 73.3, 46.5, 36.6, 27.9, 21.3, 13.5, −3.3, −3.4; IR (thin film) 3289, 2962, 2917, 2860, 1936, 1597, 1495, 1450, 1348; HRMS (ES+) C₂₄H₃₀NO₂SSi [M+H⁺] Calculated: 424.1767; Found: 424.1797; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+3.8°$ (c 1.65, CH₂Cl₂).

(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta[c] azepin-7(6H)-one (35e)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 13e (41 mg, 0.097 mmol) and [Rh(CO)₂Cl]₂ (4.2 mg, 0.009 mmol) were reacted in toluene (3 mL) for 2.5 h. Purification of the crude residue by flash chromatography (65% Et₂O/hexanes) afforded the cyclocarbonylation product 35e (28.9 mg, 66%) and triene 49 (6.1 mg, 13%) as yellow oils. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.3 Hz, 2H), 7.39 – 7.35 (m, 5H), 7.34 – 7.24 (m, 2H), 6.04 (s, 1H), 4.54 (q, J = 16.9 Hz, 2H), 3.43 – 3.41 (m, 2H), 2.59 – 2.54 (m, 3H), 2.40 (s, 3H), 0.93 (d, J = 7.5 Hz, 3H), 0.39 (s, 6H); ¹³C NMR (175 MHz, CDCl₃) 208.3, 167.4, 154.1, 143.6, 137.6, 136.7, 136.1, 133.8 (2C), 130.6, 129.7, 129.5 (2C), 128.1 (2C), 127.3 (2C), 47.8, 45.3, 45.3, 29.8, 21.5, 18.4, −1.5, −1.8; IR (thin film) 3056, 2974, 2925, 2868, 2014, 1699, 1573, 1462, 1340, 1164; HRMS (ES+) C₂₅H₃₀NO₃SSi [M+H⁺] Calculated: 452.1716; Found: 452.1693; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+100.4°$ (c 2.5, CH₂Cl₂).

5-(Dimethyl(phenyl)silyl)-3-methylene-1-tosyl-4-vinyl-2,3,6,7-tetrahydro-1H-azepine (49)

¹H NMR (300 MHz, CDCl₃) δ 7.63 (d, J = 8.2 Hz, 2H), 7.50 – 7.44 (m, 2H), 7.35 – 7.33 (m, 3H), 7.29 – 7.26 (m, 2H), 6.55 (dd, J = 16.9, 10.5 Hz, 1H), 5.37 (d, J = 1.5 Hz, 1H), 5.26 – 5.16 (m, 1H), 5.03 (dd, J = 10.5, 1.7 Hz, 1H), 4.99 (s, 1H), 3.88 (s, 2H), 3.13 (t, J = 6.1 Hz, 2H), 2.41– 2.36 (m, 5H), 0.40 (s, 6H); ¹³C NMR (175 MHz, CDCl₃) δ 151.9, 143.4, 143.0, 138.6, 136.9, 136.0, 135.3, 133.8 (2C), 129.5 (2C), 129.0, 127.9 (2C), 127.3 (2C), 117.1, 117.1, 51.1, 45.2, 31.8, 21.4, −0.7 (2C); IR (thin film) 3060, 2962, 2921, 2847, 1343, 1164, 1106; HRMS (ES+) C₂₄H₃₀NO₂SSi [M+H⁺] Calculated: 424.1767; Found: 424.1787;

(R_a)-N-(3-(Dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-methyl-N-(3-(trimethylsilyl) prop-2-yn-1-yl)benzenesulfonamide (13f)

Following the general procedure for preparation of allene-yne via silylation of the terminal alkyne, allene-yne 13e (92 mg, 0.22 mmol) in THF (2 mL) was reacted with lithium hexamethyldisilylamide (0.28 mL, 1 M in THF, 0.28 mmol) and trimethylsilyl chloride (55 μL, 0.434 mmol). Purification of the crude residue by silica gel chromatography using 10% Et₂O/hexanes to afford compound 13f (93.3 mg, 87%) as a clear yellow oil. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (d, J = 8.3 Hz, 2H), 7.52 (dd, J = 7.4, 2.0 Hz, 2H), 7.38 – 7.35 (m, 3H), 7.25 – 7.23 (d, J = 8.3 Hz, 2H), 4.87 (m, 1H), 4.05 (s, 2H), 3.22 – 3.18 (m, 2H), 2.40 (s, 3H), 2.19 – 2.16 (m, 2H), 1.63 (d, J = 7.0 Hz, 3H), 0.36 (d, J = 1.3 Hz, 6H), −0.02 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 208.0, 143.1, 137.9, 136.1, 133.8 (2C), 129.4 (2C), 129.1, 127.8 (2C), 127.6 (2C), 98.2, 91.2, 90.6, 81.3, 46.3, 37.4, 27.8, 21.45, 13.7, −0.5 (3C), −3.0, −3.1; IR (thin film) 3064, 2958, 2913, 2173, 1940, 1601, 1348; HRMS (ES+) C₂₇H₃₈NO₂SSi₂ [M+H⁺] Calculated: 496.2162; Found: 496.2152; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+1.2°$ (c 1.65, CH₂Cl₂).

(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-2-tosyl-8-(trimethylsilyl)-1,2,3,4-tetrahydro cyclopenta[c]azepin-7(6H)-one (35f)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 13f (25 mg, 0.050 mmol) and [Rh(CO)₂Cl]₂ (2 mg, 0.005 mmol) were reacted in toluene (1.6 mL) for 3 h. Purification of the crude residue by flash chromatography (55% Et₂O/hexanes) afforded the title compound 35f (23.4 mg, 89%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.58 (d, J = 8.1 Hz, 2H), 7.39 – 7.33 (m, 6H), 7.23 (s, 1H), 4.65 (d, J = 17.2 Hz, 1H), 4.56 (d, J = 17.2 Hz, 1H), 3.48 – 3.31 (m, 2H), 2.61 – 2.48 (m, 3H), 2.40 (s, 3H), 0.89 (d, J = 7.4 Hz, 3H), 0.36 (d, J = 9.0 Hz, 15H); ¹³C NMR (175 MHz, CDCl₃) δ 212.5, 174.1, 156.1, 143.4, 142.1, 137.1, 136.5, 134.3, 133.9 (2C), 129.5 (3C), 128.0 (2C), 127.2 (2C), 47.3, 45.5, 45.1, 29.7, 21.5, 18.8, −0.5 (3C), −1.23, −1.6; IR (thin film) 3060, 2962, 2921, 2855, 2247, 1932, 1691, 1601, 1544, 1462, 1352, 1254, 1164; HRMS (ES+) C₂₈H₃₈NO₂SSi [M+H⁺] Calculated: 524.2111; Found: 524.2101; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+70.4°$ (c 0.75, CH₂Cl₂).

(R_a)-N-(3-(dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-methyl-N-(3-phenylprop-2-yn-1-yl) benzenesulfonamide (13d)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-22 (93.6 mg, 0.402 mmol) in THF (2.8 mL) was reacted with triphenylphosphine (127 mg, 0.48 mmol), 4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide³²30d (134 mg, 0.48 mmol) and diisopropylazodicarboxylate (95 μL, 0.48 mmol) for 3 h. Purification of the crude residue using a Biotage normal phase automated purification system (25 g SNAP column, gradient of 0 – 30% Et₂O/hexanes) afforded compound 13d (185 mg, 92%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.67 (d, J = 8.4 Hz, 2H), 7.52 – 7.49 (m, 2H), 7.35 – 7.32 (m, 4H), 7.23 – 7.19 (m, 3H), 7.04 (dd, J = 8.0, 1.7 Hz, 2H), 4.90 – 4.86 (m, 1H), 4.24 (s, 2H), 3.29 – 3.23 (m, 2H), 2.33 (s, 3H), 2.23 (td, J = 8.1, 2.7 Hz, 2H), 1.63 (d, J = 7.0 Hz, 3H), 0.36 (d, J = 0.8 Hz, 6H); ¹³C NMR (175 MHz, CDCl₃) δ 208.0, 143.2, 137.9, 136.0, 133.7 (2C), 131.4 (2C), 129.4 (2C), 129.1, 128.3, 128.0 (2C), 127.8 (2C), 127.6 (2C), 122.2, 91.2, 85.4, 82.0, 81.3, 46.5, 37.4, 27.9, 21.4, 13.7, −3.1, −3.1; IR (thin film) 3068, 2953, 2921, 2855, 2238, 1940, 1589, 1486; HRMS (ES+) C₃₀H₃₄NO₂SSi [M+H⁺] Calculated: 500.2080; Found: 500.2086; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+8.7°$ (c 1.15, CH₂Cl₂).

(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-8-phenyl-2-tosyl-1,2,3,4-tetrahydrocyclo penta[c]azepin-7(6H)-one (35d)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 13d (41.5 mg, 0.083 mmol) and [Rh(CO)₂Cl]₂ (3.2 mg, 0.003 mmol) were reacted in toluene (2.5 mL) for 3 h. Purification of the crude residue by flash chromatography (55% Et₂O/hexanes) afforded the title compound 35d (40.1 mg, 92%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.49 – 7.32 (m, 12H), 7.21 (d, J = 8.0 Hz, 2H), 4.63 (s, 2H), 3.51 (t, J = 6.1 Hz, 2H), 2.71 (q, J = 7.3 Hz, 1H), 2.65 – 2.58 (t, J = 5.4 Hz, 2H), 2.40 (s, 3H), 0.97 (t, J = 8.4 Hz, 3H), 0.45 (s, 6H); ¹³C NMR (175 MHz, CDCl₃) δ 206.4, 161.4, 153.7, 143.4, 140.7, 137.0, 136.6, 135.7, 133.9 (2C), 129.9, 129.6 (3C), 129.4 (2C), 128.9, 128.6 (2C), 128.1 (2C), 127.1 (2C), 48.2, 44.6, 43.7, 29.8, 21.5, 18.7, −1.2, −1.5; IR (thin film) 2970, 2917, 2859, 2018, 1736, 1707, 1454, 1340, 1164; HRMS (ES+) C₃₁H₃₄NO₃SSi [M+H⁺] Calculated: 528.2029; Found: 528.2034; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+192°$ (c 0.75, CH₂Cl₂).

4-Methyl-N-(3-(thiophen-3-yl)prop-2-yn-1-yl)benzenesulfonamide (30a)

A mixture of propargyltosylamide (444 mg, 1.97 mmol), 3-bromothiophene (963 mg, 5.91 mmol), palladium dichloride bistriphenylphosphine (27.7 mg, 0.039 mmol), copper iodide (15 mg, 0.079 mmol) in piperidine (3.9 mL) were heated at 80 °C for 17 h. The solution was concentrated under reduced pressure. Purification of the crude residue using a Biotage normal phase automated purification system (25 g SNAP column, gradient of 5 – 25% EtOAc/hexanes) afforded compound 30a (155.6 mg, 27%) as a white foam. ¹H NMR (600 MHz, CDCl₃) δ 7.81 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.24 – 7.15 (m, 2H), 6.84 (d, J = 4.4 Hz, 1H), 4.69 – 4.65 (m, 1H), 4.05 (d, J = 6.1 Hz, 2H), 2.38 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 143.7, 136.8, 129.6 (2C), 129.5, 129.1, 127.5 (2C), 125.2, 121.1, 82.8, 79.9, 33.8, 21.5; IR (thin film) 3265, 1593, 1430, 1324, 1156, 1091, 1042, 813, 788; HRMS (ES+) C₁₄H₁₂NO₂S₂ [M+H⁺] Calculated: 290.0276; Found: 290.0299.

(R_a)-N-(3-(Dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-methyl-N-(3-(thiophen-3-yl)prop-2-yn-1-yl)benzenesulfonamide (13a)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-22 (39.8 mg, 0.171 mmol) in THF (1.2 mL) was reacted with triphenylphosphine (54 mg, 0.21 mmol), 4-methyl-N-(3-(thiophen-3-yl)prop-2-yn-1-yl)benzenesulfonamide 30a (60 mg, 0.21 mmol) and diisopropylazodicarboxylate (41 μL, 0.21 mmol) for 10 h. Purification of the crude residue using a Biotage normal phase automated purification system (10 g SNAP column, gradient of 2 – 4% EtOAc/hexanes) afforded compound 13a (77.6 mg, 90%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.67 (d, J = 8.3 Hz, 2H), 7.51 (dd, J = 7.8, 1.7 Hz, 2H), 7.37 – 7.34 (m, 3H), 7.22 – 7.19 (m, 3H), 7.09 (dd, J = 3.0, 1.1 Hz, 1H), 6.76 (dd, J = 5.0, 1.2 Hz, 1H), 4.90 – 4.86 (m, 1H), 4.22 (d, J = 1.6 Hz, 2H), 3.24 (dd, J = 8.9, 6.9 Hz, 2H), 2.35 (s, 3H), 2.23 – 2.20 (m, 2H), 1.63 (d, J = 7.0 Hz, 3H), 0.36 (d, J = 2.0 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 208.0, 143.2, 137.9, 136.1, 133.8 (2C), 129.6, 129.4 (2C), 129.1, 128.7, 127.8 (2C), 127.7 (2C), 125.1, 121.3, 91.2, 81.7, 81.4, 80.5, 46.6, 37.4, 28.0, 21.5, 13.7, −3.0 (2C); IR (thin film) 3109, 2958, 2921, 2864, 1936, 1732, 1593, 1458, 1434, 1352, 1164, 1111; HRMS (ES+) C₂₈H₃₁NO₂NaS₂Si [M+Na⁺] Calculated: 528.1463 ; Found: 528.1414; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+4°$ (c 1.75, CH₂Cl₂).

(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-8-(thiophen-3-yl)-2-tosyl-1,2,3,4-tetrahydro cyclopenta[c]azepin-7(6H)-one (35a)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 13a (17.8 mg, 0.036 mmol) and [Rh(CO)₂Cl]₂ (1.4 mg, 0.003 mmol) were reacted in toluene (1.2 mL) for 2.5 h. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, gradient of 5 – 25% EtOAc/hexanes) afforded compound 35a (13.5 mg, 72%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.68 – 7.66 (m, 1H), 7.47 – 7.42 (m, 5H), 7.39 – 7.33 (m, 4H), 7.22 (d, J = 8.0 Hz, 2H), 4.73 (s, 2H), 3.52 (t, J = 6.1 Hz, 2H), 2.68 – 2.58 (m, 3H), 2.40 (s, 3H), 0.98 (d, J = 7.4 Hz, 3H), 0.43 (d, J = 1.3 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 206.4, 159.9, 153.8, 143.5, 137.1, 136.5, 135.6, 135.5, 133.9 (2C), 130.4, 129.6, 129.4 (2C), 128.1 (2C), 127.9, 127.1 (2C), 126.8, 125.9, 48.3, 44.5, 43.8, 29.9, 21.5, 18.8, −1.2, −1.5; IR (thin film) 2958, 2925, 1695, 1605, 1467, 1430, 1344, 1246, 1160, 1107, 964; HRMS (ES+) C₂₉H₃₁NO₃NaS₂Si [M+Na⁺] Calculated: 556.1412; Found: 556.1465; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+174°$ (c 1.15, CH₂Cl₂).

4-Methyl-N-(3-(thiophen-2-yl)prop-2-yn-1-yl)benzenesulfonamide (30b)

A mixture of propargyltosylamide (415.9 mg, 1.84 mmol), 2-iodothiophene (215 μL, 2.03 mmol), palladium dichloride bistriphenylphosphine (25.9 mg, 0.037 mmol), copper iodide (14.1 mg, 0.074 mmol) and triethylamine (1.29 mL, 0.092 mmol) in acetonitrile (3 mL) was stirred at rt for 19 h. The residue obtained after removal of acetonitrile was taken up in CH₂Cl₂ (30 mL) and washed with water (10 mL). The organic phase was separated, dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification of the crude residue by silica gel column chromatography (Hex/Et₂O 50%), afforded compound 30b (316 mg, 59%) as a white foam. ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.21 (dd, J = 5.1, 1.2 Hz, 1H), 6.97 (d, J = 3.6 Hz, 1H), 6.92 – 6.89 (m, 1H), 4.63 – 4.62 (m, 1H), 4.09 (d, J = 6.2 Hz, 2H), 2.38 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 143.9, 136.6, 132.4, 129.7 (2C), 127.4 (2C), 126.8, 121.9, 87.1, 78.1, 33.9, 21.6; IR (thin film) 3265, 2361, 1589, 1491, 1422, 1344, 1315, 1160, 1091, 1038, 845; HRMS (ES+) C₁₄H₁₂NO₂S₂ [M−H⁺] Calculated: 290.0309; Found: 290.0316.

(R_a)-N-(3-(dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-methyl-N-(3-(thiophen-2-yl) prop-2-yn-1-yl)benzenesulfonamide (13b)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-22 (35.2 mg, 0.151 mmol) in THF (1.0 mL) was reacted with triphenylphosphine (48 mg, 0.18 mmol), 4-methyl-N-(3-(thiophen-2-yl)prop-2-yn-1-yl)benzenesulfonamide 30b (53 mg, 0.18 mmol) and diisopropylazodicarboxylate (36 μL, 0.18 mmol) for 11 h. Purification of the crude residue using a Biotage normal phase automated purification system (10 g SNAP column, gradient of 2 – 4% EtOAc/hexanes) afforded compound 13b (69.3 mg, 90%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.67 (d, J = 8.0 Hz, 2H), 7.52 – 7.50 (m, 2H), 7.36 – 7.33 (m, 3H), 7.24 – 7.20 (m, 3H), 6.90 (d, J = 3.3 Hz, 2H), 4.90 – 4.86 (m, 1H), 4.25 (s, 2H), 3.25 – 3.20 (m, 2H), 2.36 (s, 3H), 2.24 – 2.18 (m, 2H), 1.63 (d, J = 7.0 Hz, 3H), 0.36 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 208.0, 143.3, 137.9, 135.8, 133.8 (2C), 132.1, 129.5 (2C), 129.1, 127.8 (2C), 127.6 (2C), 127.2, 126.7, 122.2, 91.2, 86.1, 81.4, 78.6, 46.5, 37.5, 27.9, 21.5, 13.7, −3.1 (2C); IR (thin film) 2954, 2925, 2852, 2353, 2329, 1936, 1593, 1430, 1352, 1250, 1185, 1168, 1107; HRMS (ES+) C₂₈H₃₁NO₂NaS₂Si [M+H⁺] Calculated: 528.1463; Found: 528.1494; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+2°$ (c 1.8, CH₂Cl₂).

(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-8-(thiophen-2-yl)-2-tosyl-1,2,3,4-tetrahydro cyclopenta[c]azepin-7(6H)-one (35b)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 13b (28.3 mg, 0.056 mmol) and [Rh(CO)₂Cl]₂ (2.2 mg, 0.006 mmol) were reacted in toluene (1.8 mL) for 3 h. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, gradient of 5 – 25% EtOAc/hexanes) afforded compound 35b (24.9 mg, 84%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.56 (d, J = 5.2 Hz, 2H), 7.45 – 7.35 (m, 8H), 7.21 – 7.19 (m, 3H), 4.89 – 4.82 (m, 2H), 3.55 – 3.53 (m, 2H), 2.63 – 2.60 (m, 2H), 2.39 (s, 3H), 0.95 (d, J = 7.4 Hz, 3H), 0.43 (d, J = 5.6 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 205.3, 158.9, 153.5, 143.5, 136.9, 136.5, 135.8, 133.9 (2C), 133.7, 130.9, 129.6, 129.4 (2C), 129.2, 129.0, 128.1 (2C), 127.4, 127.0 (2C), 48.6, 44.3, 43.9, 30.0, 21.5, 18.8, −1.2, −1.5; IR (thin film) 3060, 2954, 2929, 2872, 1704, 1589, 1434, 1344, 1246, 1152, 1103, 1017; HRMS (ES+) C₂₉H₃₀NO₃S₂Si [M−H⁺] Calculated: 532.1436; Found: 532.1453; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+188°$ (c 1.80, CH₂Cl₂).

tert-Butyl (3-cyclopropylprop-2-yn-1-yl)(tosyl)carbamate (50)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, 3-cyclopropylprop-2-yn-1-ol (283 mg, 2.94 mmol) in THF (21 mL) was reacted with triphenylphosphine (927 mg, 3.53 mmol), tert-butyl tosylcarbamate (959 mg, 3.53 mmol) and diisopropylazodicarboxylate (0.7 mL, 3.53 mmol) for 11 h. Purification of the crude residue by silica gel chromatography using 20% Et₂O/hexanes afforded compound 50 (535 mg, 52%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ¹H NMR 7.93 (d, J = 8.3 Hz, 2H), 7.35 – 7.28 (m, 2H), 4.57 (d, J = 2.0 Hz, 2H), 2.45 (s, 3H), 1.34 (s, 9H), 1.27 – 1.23 (m, 1H), 0.78 – 0.74 (m, 2H), 0.67 – 0.64 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 150.3, 144.2, 136.9, 129.0 (2C), 128.2 (2C), 87.5, 84.5, 70.5, 36.4, 27.8 (3C), 21.6, 7.9 (2C), −0.6; IR (thin film) 2974, 2925, 2251, 2235, 1724, 1597, 1356, 1311, 1279, 1091, 1070; HRMS (ES+) C₁₄H₁₆NO₄S [M-C₅H₁₀O₂+H ] Calculated: 294.0800; Found: 294.0810.

N-(3-Cyclopropylprop-2-yn-1-yl)-4-methylbenzenesulfonamide (30g)

To a solution of tert-butyl (3-cyclopropylprop-2-yn-1-yl)(tosyl)carbamate 50 (102.7 mg, 0.293 mmol) in methanol (1.7 mL) and THF (0.7 mL) was added lithium hydroxide (88 mg, 1.17 mmol). After stirring for 12 h at rt, the mixture was diluted with CH₂Cl₂ (40 mL) and HCl 1 M (10 mL). The organic layer was separated, washed with brine (10 mL) and dried (Na₂SO₄). The solvent was removed under reduced pressure. Purification of the crude residue by silica gel chromatography using 40% Et₂O/hexanes afforded compound 30g (52.3 mg, 71%) as a white foam. ¹H NMR (300 MHz, CDCl₃) δ 7.76 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.55 (br. s, 1H), 3.76 – 3.76 (m, 2H), 2.43 (s, 3H), 1.03 (m, 1H), 0.65 – 0.62 (m, 2H), 0.42 – 0.40 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 143.5, 136.8, 129.5 (2C), 127.4 (2C), 88.4, 69.3, 33.4, 21.5, 7.8 (2C), −0.9; IR (thin film) 3265, 1438, 1315, 1160, 1095, 1058, 1030; HRMS (ES+) C₁₃H₁₆NO₂S [M+H⁺] Calculated: 250.0902; Found: 250.0888.

(R_a)-N-(3-Cyclopropylprop-2-yn-1-yl)-N-(3-(dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-methylbenzenesulfonamide (13g)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-22 (45 mg, 0.19 mmol) in THF (1.4 mL) was reacted with triphenylphosphine (61.1 mg, 0.23 mmol), N-(3-cyclopropylprop-2-yn-1-yl)-4-methylbenzenesulfonamide 30g (58.3 mg, 0.23 mmol) and diisopropylazodicarboxylate (46 μL, 0.23 mmol) for 11 h. Purification of the crude residue using a Biotage normal phase automated purification system (12 g SNAP column, gradient of 1 – 7% EtOAc/hexanes) afforded compound 13g (63.7 mg, 73%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J = 8.3 Hz, 2H), 7.56 – 7.54 (m, 2H), 7.40 – 7.38 (m, 3H), 7.29 – 7.27 (dd, J = 8.8, 1.2 Hz, 2H), 4.92 – 4.89 (m, 1H), 4.00 (d, J = 2.0 Hz, 2H), 3.22 – 3.18 (m, 2H), 2.45 (s, 3H), 2.21 – 2.16 (m, 2H), 1.67 (d, J = 7.0 Hz, 3H), 1.00 – 0.96 (m, 1H), 0.65 – 0.61 (m, 2H), 0.40 (d, J = 1.0 Hz, 6H), 0.33 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 208.0, 142.9, 137.9, 136.3, 133.8 (2C), 129.2 (2C), 129.1, 127.8 (2C), 127.6 (2C), 91.3, 88.9, 81.2, 67.9, 46.3, 37.0, 27.9, 21.5, 13.7, 7.8 (2C), −0.9, −3.0, −3.1; IR (thin film) 2954, 2921, 2251, 1932, 1601, 1454, 1430, 1348, 1254, 1164, 1107, 1030; HRMS (ES+) C₂₇H₃₄NO₂SSi [M+H⁺] Calculated: 464.2080; Found: 464.2053; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+5.7°$ (c 0.70, CH₂Cl₂).

(S)-8-Cyclopropyl-5-(dimethyl(phenyl)silyl)-6-methyl-2-tosyl-1,2,3,4-tetrahydro cyclopenta[c]azepin-7(6H)-one (35g)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 13g (24.5 mg, 0.053 mmol) and [Rh(CO)₂Cl]₂ (2.1 mg, 0.0053 mmol) were reacted in toluene (1.8 mL) for 135 min. Purification of the crude residue by silica gel chromatography using 40% Et₂O/hexanes afforded compound 35g (22.1 mg, 83%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J = 8.0 Hz, 2H), 7.36 – 7.32 (m, 5H), 7.25 – 7.21 (m, 2H), 4.65 – 4.64 (m, 2H), 3.43 – 3.43 (m, 2H), 2.55 – 2.51 (m, J = 4.8 Hz, 2H), 2.41 – 2.38 (m, 4H), 1.62 – 1.57 (m, 1H), 1.30 – 1.25 (m, 2H), 0.93 – 0.90 (m, 2H), 0.81 (d, J = 7.4 Hz, 3H), 0.36 – 0.35 (t, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 207.5, 160.6, 153.2, 143.4, 141.4, 137.2, 136.3, 133.8 (2C), 132.2, 129.5, 129.3 (2C), 127.9 (2C), 127.3 (2C), 48.1, 44.3, 42.5, 29.5, 21.5, 18.4, 8.1, 6.1, 6.0, −1.2, −1.5; IR (thin film) 2962, 2925, 2868, 2018, 1695, 1589, 1467, 1348, 1250, 1160, 1103; HRMS (ES+) C₂₈H₃₄NO₃SSi [M+H⁺] Calculated: 492.2029; Found: 492.2042; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+113.8°$ (c 1.45, CH₂Cl₂).

(R_a)-N-(Hexa-3,4-dien-1-yl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzene sulfonamide (14d)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-29 (45 mg, 0.21 mmol) in THF (1.5 mL) was reacted with triphenylphosphine (65.5 mg, 0.25 mmol), 4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide³⁰30d (71.2 mg, 0.25 mmol) and diisopropylazodicarboxylate (49 μL, 0.25 mmol) for 11 h. Purification of the crude residue by silica gel chromatography using 1% Et₂O/hexanes afforded compound 14d (80.2 mg, 92%) as a colorless oil. ¹H NMR (700 MHz, CDCl₃) δ 7.70 (d, J = 8.3 Hz, 2H), 7.27 – 7.25 (m, 5H), 7.20 – 7.16 (m, 5H), 7.00 (d, J = 7.0 Hz, 2H), 6.15 – 6.13 (m, 1H), 4.34 (d, J = 18.5 Hz, 2H), 4.27 (d, J = 18.5 Hz, 2H), 3.47 – 3.43 (m, 1H), 3.34 – 3.30 (m, 1H), 2.44 – 2.41 (m, 2H), 2.29 (s, 3H), 2.15 – 2.09 (m, 2H), 1.45 – 1.44 (m, 1H), 1.35 – 1.32 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H); ¹³C NMR (175 MHz, CDCl₃) δ 202.3, 143.4, 135.6, 135.4, 131.4 (2C), 129.4 (2C), 128.6 (2C), 128.3, 128.1 (2C), 127.7 (2C), 126.6, 126.5 (2C), 122.1, 105.4, 96.0, 85.7, 81.6, 44.8, 37.31, 32.1, 31.2, 29.7, 22.4, 21.4, 13.9; IR (thin film) 2958, 2925, 2855, 1597, 1495, 1458, 1352, 1160, 1095, 918; HRMS (ES+) C₃₁H₃₄NO₂S [M+H⁺] Calculated: 484.2310; Found: 484.2283; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-54.3°$ (c 1.15, CH₂Cl₂).

(S)-6-Methyl-8-phenyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (42d)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 14d (22.7 mg, 0.054 mmol) and [Rh(CO)₂Cl]₂ (2.1 mg, 0.0054 mmol) were reacted in toluene (1.7 mL) for 30 min. Purification of the crude residue by silica gel chromatography using 60% Et₂O/hexanes afforded compound 42d (21.6 mg, 76%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.50 – 7.32 (m, 7H), 7.24 – 7.20 (m, 5H), 6.96 – 6.93 (m, 2H), 4.83 (d, J = 16.9 Hz, 1H), 4.61 (d, J = 16.8 Hz, 1H), 3.91 (s, 1H), 3.72 – 3.65 (m, 2H), 2.76 – 2.71 (m, 1H), 2.59 – 2.50 (m, 1H), 2.41 (s, 3H), 1.93 – 1.87 (m, 2H), 1.02 – 0.98 (m, 2H), 0.88 – 0.86 (m, 2H), 0.69 (t, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 201.8, 162.8, 143.5, 141.4, 139.4, 137.8, 136.8, 136.0, 130.3, 129.6 (2C), 129.5 (2C), 128.7 (2C), 128.6, 128.5 (2C), 127.6 (2C), 127.2 (2C), 126.9, 55.4, 47.9, 44.3, 37.1, 31.1, 29.2, 22.7, 21.6, 13.7; IR (thin film) 2954, 2929, 2864, 1699, 1499, 1339, 1164, 1095; HRMS (ES+) C₃₂H₃₄NO₃S [M+H⁺] Calculated: 512.2259; Found: 512.2232; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+61.1°$ (c 0.90, CH₂Cl₂).

(R_a)-N-(Hexa-3,4-dien-1-yl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzene sulfonamide (14c)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-29 (50.7 mg, 0.23 mmol) in THF (1.7 mL) was reacted with triphenylphosphine (74 mg, 0.28 mmol), N-(but-2-yn-1-yl)-4-methylbenzenesulfonamide³⁰ (63 mg, 0.28 mmol) and diisopropylazodicarboxylate (56 μL, 0.28 mmol) for 12 h. Purification of the crude residue by silica gel chromatography using 10% Et₂O/hexanes afforded compound 14c (91.9 mg, 93%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.69 – 7.68 (d, J = 8.3 Hz, 2H), 7.30 – 7.26 (m, 4H), 7.23 – 7.22 (m, 3H), 6.14 (t, J = 2.9 Hz, 1H), 4.08 – 3.99 (m, 2H), 3.36 – 3.32 (m, 1H), 3.28 – 3.23 (m, 1H), 2.39 (s, 3H), 2.37 – 2.36 (m, 2H), 2.13 – 2.07 (m, 2H), 1.51 (t, J = 2.4 Hz, 3H), 1.46 – 1.43 (m, 2H), 1.37 – 1.33 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 202.2, 143.1, 135.9, 135.5, 129.2 (2C), 128.5 (2C), 127.7 (2C), 126.6, 126.5 (2C), 105.4, 95.9, 81.5, 71.7, 44.7, 37.0, 32.1, 31.2, 29.7, 22.4, 21.5, 13.9, 3.2; IR (thin film) 2954, 2925, 2864, 1593, 1499, 1458, 1344, 1164, 1091, 915; HRMS (ES+) C₂₆H₃₂NO₂S [M+H⁺] Calculated: 422.2154; Found: 422.2120; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-43.5°$ (c 1.15, CH₂Cl₂).

(S)-5-Butyl-8-methyl-6-phenyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (42c)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 14c (33.5 mg, 0.079 mmol) and [Rh(CO)₂Cl]₂ (3.1 mg, 0.0079 mmol) were reacted in toluene (2.5 mL) for 90 min. Purification of the crude residue using a Biotage normal phase automated purification system (12 g SNAP column, gradient of 5 – 30% EtOAc/hexanes) afforded compound 42c (29.1 mg, 82%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.68 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.19 – 7.18 (m, 3H), 6.89 – 6.88 (m, 2H), 4.67 (d, J = 16.9 Hz, 1H), 4.50 (d, J = 16.9 Hz, 1H), 3.77 (s, 1H), 3.61 – 3.60 (m, 2H), 2.61 – 2.53 (m, 2H), 2.42 (s, 3H), 1.86 (s, 3H), 1.83 – 1.78 (m, 2H), 1.12 – 1.10 (m, 1H), 1.02 – 0.95 (m, 2H), 0.84 – 0.83 (m, 1H), 0.67 (t, J = 7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 203.6, 162.3, 143.7, 139.2, 137.9, 136.4, 136.3, 135.9, 129.7 (2C), 128.6 (2C), 127.5 (2C), 127.1 (2C), 126.8, 54.9, 47.8, 44.6, 36.9, 31.8, 29.3, 22.6, 21.6, 13.7, 8.6; IR (thin film) 2954, 2925, 2860, 2361, 2333, 1699, 1597, 1487, 1454, 1344, 1266, 1152, 1095; HRMS (ES+) C₂₇H₃₂NO₃S [M+H⁺] Calculated: 450.2103; Found: 450.2058; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+112.2°$ (c 0.90, CH₂Cl₂).

(R_a)-4-Methyl-N-(3-(2-phenylvinylidene)heptyl)-N-(prop-2-yn-1-yl)benzene sulfonamide (14e)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-29 (114.4 mg, 0.53 mmol) in THF (3.8 mL) was reacted with triphenylphosphine (166 mg, 0.63 mmol), 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide³⁰30e (133 mg, 0.63 mmol) and diisopropylazodicarboxylate (125 μL, 0.63 mmol) for 12 h. Purification of the crude residue using a Biotage normal phase automated purification system (25 g SNAP column, gradient of 0 – 7% EtOAc/hexanes) afforded compound 14e (182.1 mg, 85%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J = 8.1 Hz, 2H), 7.29 – 7.24 (m, 4H), 7.22 – 7.19 (m, 3H), 6.13 – 6.11 (m, 1H), 4.10 – 4.07 (m, 2H), 3.37 – 3.26 (m, 2H), 2.42 – 2.33 (m, 5H), 2.09 – 2.07 (m, 2H), 1.98 (t, J = 2.5 Hz, 1H), 1.43 – 1.31 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CD₂Cl₂) δ 202.2, 143.7, 135.8, 135.5, 129.5 (2C), 128.5 (2C), 127.6 (2C), 126.7, 126.5 (2C), 105.4, 95.9, 76.7, 73.6, 44.8, 36.6, 32.1, 31.1, 29.7, 22.5, 21.3, 13.7; IR (thin film) 3289, 2958, 2929, 2872, 1949, 1712, 1593, 1491, 1462, 1352, 1160, 1091 1001; HRMS (ES+) C₂₅H₂₉NO₂S [M⁺] Calculated: 407.1919; Found: 407.1888; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-63.8°$ (c 0.80, CH₂Cl₂).

(R_a)-4-methyl-N-(3-(2-phenylvinylidene)heptyl)-N-(3-(trimethylsilyl)prop-2-yn-1-yl) benzenesulfonamide (14f)

Following the general procedure for preparation of allene-yne via silylation of the terminal alkyne, allene-yne 14e (81.7 mg, 0.20 mmol) in THF (1.6 mL) was reacted with lithium hexamethyldisilylamide (301 μL, 1M in THF, 0.30 mmol) and trimethylsilylchloride (51 μL, 0.40 mmol). Purification of the crude product using a Biotage normal phase automated purification system (12 g SNAP column, gradient of 0 – 8% EtOAc/hexanes) afforded compound 14f (76.8 mg, 80%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.70 (d, J = 8.1 Hz, 2H), 7.33 – 7.26 (m, 4H), 7.23 – 7.21 (m, 3H), 6.17 (t, J = 3.0 Hz, 1H), 4.22 – 4.06 (m, 2H), 3.44 – 3.37 (m, 1H), 3.33 – 3.26 (m, 1H), 2.44 – 2.39 (m, 5H), 2.16 – 2.14 (m, 2H), 1.51 – 1.37 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H), −0.02 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 202.2, 143.2, 135.7, 135.4, 129.4 (2C), 128.5 (2C), 127.7 (2C), 126.6, 126.5 (2C), 105.3, 97.8, 95.9, 90.9, 44.6, 37.4, 32.1, 31.1, 29.7, 22.4, 21.5, 13.9, −0.5 (3C); IR (thin film) 3031, 2958, 2929, 2868, 2118, 1953, 1598, 1503, 1458, 1356, 1246, 1164, 1103, 1021, 919; HRMS (ES+) C₂₈H₃₇NO₂SSi [M⁺] Calculated: 479.2314; Found: 479.2278; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-58.8°$ (c 1.70, CH₂Cl₂).

(S)-5-Butyl-6-phenyl-2-tosyl-8-(trimethylsilyl)-1,2,3,4-tetrahydrocyclopenta [c]azepin-7(6H)-one (42f)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 14f (32.8 mg, 0.068 mmol) and [Rh(CO)₂Cl]₂ (2.7 mg, 0.068 mmol) were reacted in toluene (2.2 mL) for 30 min. Purification of the crude product using a Biotage normal phase automated purification system (4 g SNAP column, gradient of 5 – 25% EtOAc/hexanes) afforded compound 42f (26.9 mg, 78%) as a white foam. ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.20 – 7.18 (m, 3H), 6.92 – 6.89 (m, 2H), 4.80 (d, J = 16.9 Hz, 1H), 4.53 (d, J = 16.9 Hz, 1H), 3.76 (s, 1H), 3.59 – 3.57 (m, 2H), 2.59 – 2.50 (m, 2H), 2.43 (s, 3H), 1.84 – 1.80 (m, 2H), 1.02 – 0.90 (m, 4H), 0.66 (t, J = 7.1 Hz, 3H), 0.31 (s, 9H); ¹³C NMR (175 MHz, CDCl₃) δ 207.8, 175.4, 143.5, 140.5 (2C), 139.4, 138.3, 136.0, 129.7 (2C), 128.7 (2C), 127.4 (2C), 127.2 (2C), 126.6, 56.6, 47.3, 46.1, 37.4, 31.5, 29.2, 22.6, 21.6, 13.7, −0.4 (3C); IR (thin film) 3024, 2954, 2921, 2864, 1683, 1593, 1540, 1491, 1454, 1348, 1242, 1164, 1099; HRMS (ES+) C₂₉H₃₇NO₃SSi [M⁺] Calculated: 507.2263; Found: 507.2297; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+105°$ (c 1.15, CH₂Cl₂).

(R_a)-3-(2-Phenylvinylidene)heptyl methanesulfonate (33)

To a stirred solution of alcohol (R_a)-29 (197.2 mg, 0.911 mmol) in THF (19 mL), cooled to 0 °C (ice bath), was added triethylamine (152 μL, 1.09 mmol) followed by methanesulfonyl chloride (85 μL, 1.09 mmol). The resulting solution was stirred at rt for 18 h. The mixture was diluted with Et₂O (60 mL) and washed with water (2 × 10 mL). The organic phase was dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification of the crude residue by silica gel chromatography using 40% Et₂O/hexanes afforded compound 33 (247 mg, 92%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.37 – 7.32 (m, 4H), 7.26 – 7.25 (m, 1H), 6.29 – 6.28 (m, 1H), 4.43 – 4.36 (m, 2H), 2.90 (s, 3H), 2.61 – 2.59 (m, 2H), 2.19 – 2.18 (m, 2H), 1.55 – 1.53 (m, 2H), 1.45 – 1.41 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 201.7, 134.7, 128.4 (2C), 126.6, 126.3 (2C), 103.9, 96.6, 67.6, 36.7, 32.3, 31.8, 29.3, 22.1, 13.6; IR (thin film) 3027, 2958, 2925, 2864, 1953, 1597, 1495, 1462, 1364, 1181, 960, 899; HRMS (ES+) C₁₆H₂₂O₃S [M⁺] Calculated: 294.1290; Found: 294.1284; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-16.3°$ (c 0.95, CH₂Cl₂).

(R_a)-Diethyl 2-(3-phenylprop-2-yn-1-yl)-2-(3-(2-phenylvinylidene)heptyl) malonate (16d)

Following the General Procedure for Preparation of Allene-yne via alkylation of the malonate moiety, diethyl malonate 34d (87.2 mg, 0.32 mmol) was reacted with sodium hydride (10.6 mg, 60 wt% in oil, 0.26 mmol), mesylate 33 (62.5 mg, 0.18 mmol) and potassium iodide (44 mg, 0.27 mmol) in DMF-THF (1 : 1, 3.6 mL). Purification of the crude residue by silica gel chromatography using 5% Et₂O/hexanes afforded compound 16d (58.7 mg, 70%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.31 – 7.27 (m, 5H), 7.25 – 7.14 (m, 5H), 6.17 (t, J = 2.9 Hz, 1H), 4.23 (q, J = 7.2 Hz, 4H), 3.08 (s, 2H), 2.37 – 2.31 (m, 2H), 2.16 – 2.06 (m, 4H), 1.50 – 1.38 (m, 2H), 1.36 – 1.31 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H), 0.87 (t, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 202.0, 170.2 (2C), 135.8, 131.6 (2C), 128.4 (2C), 128.1 (2C), 127.8, 126.4 (2C), 126.3, 123.2, 107.8, 96.0, 84.2, 83.5, 61.6 (2C), 56.9, 32.4, 30.5, 29.8, 27.5, 23.9, 22.5, 14.1 (2C), 13.9; IR (thin film) 2966, 2925, 2864, 1736, 1499, 1462, 1438, 1266, 1189, 1099, 1074, 1025; HRMS (ES+) C₃₁H₃₁O₄ [M+H⁺] Calculated: 473.2692; Found: 473.2734; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-35.7°$ (c 1.85, CH₂Cl₂).

(S)-Diethyl 8-butyl-2-oxo-1,3-diphenyl-1,2,6,7-tetrahydroazulene-5,5(4H)-dicarboxylate (44d)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 16d (36.8 mg, 0.078 mmol) and [Rh(CO)₂Cl]₂ (3 mg, 0.0078 mmol) were reacted in toluene (2.6 mL) for 2 h. Purification of the crude residue by flash chromatography (40% Et₂O/hexanes) afforded the title compound 44d (35.6 mg, 92%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.37 – 7.34 (m, 2H), 7.30 – 7.28 (m, 3H), 7.21 – 7.19 (m, 5H), 4.15 – 4.10 (m, 2H), 4.09 (s, 1H), 4.02 – 3.99 (m, 1H), 3.96 – 3.93 (m, 1H), 3.59 (d, J = 14.9 Hz, 1H), 3.50 (d, J = 14.9 Hz, 1H), 2.58 – 2.42 (m, 4H), 1.97 – 1.93 (m, 2H), 1.28 – 1.25 (m, 2H), 1.10 – 1.08 (td, J = 7.1, 2.1 Hz, 6H), 1.01 – 0.96 (m, 2H), 0.71 (t, J = 7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 202.2, 171.3, 171.2, 164.4, 146.3, 140.9, 138.3, 137.1, 131.4, 129.4 (2C), 128.7 (2C), 128.1 (2C), 127.8, 127.6 (2C), 126.8, 61.8, 61.7, 56.1, 55.7, 37.5, 33.5, 32.7, 29.1, 28.6, 22.7, 13.8 (3C); IR (thin film) 2962, 2925, 2856, 1728, 1699, 1605, 1577, 1503, 1454, 1373, 1274, 1234, 1181; HRMS (ES+) C₃₂H₃₇O₅ [M+H⁺] Calculated: 501.2641; Found: 501.2623; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+105°$ (c 1.60, CH₂Cl₂).

(R_a)-Diethyl 2-(3-(2-phenylvinylidene)heptyl)-2-(prop-2-yn-1-yl)malonate (16e)

Following the General Procedure for Preparation of Allene-yne via alkylation of the malonate moiety, diethyl malonate 34e (98 mg, 0.49 mmol) was reacted with sodium hydride (16.5 mg, 60 wt% in oil, 0.41 mmol), mesylate 33 (97 mg, 0.27 mmol) and potassium iodide (68.3 mg, 0.41 mmol) in DMF-THF (1 : 1, 5.6 mL). Purification of the crude residue using a Biotage normal phase automated purification system (25 g SNAP column, gradient of 0 – 5% EtOAc/hexanes) afforded compound 16e (45.5 mg, 42%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.28 – 7.26 (m, 4H), 7.17 – 7.15 (m, 1H), 6.15 (t, J = 3.0 Hz, 1H), 4.21 – 4.18 (q, J = 7.1 Hz, 4H), 2.84 (d, J = 2.7 Hz, 2H), 2.27 – 2.24 (m, 2H), 2.10 – 2.08 (m, 2H), 2.04 – 1.99 (m, 1H), 1.97 (t, J = 2.7 Hz, 1H), 1.45 – 1.42 (m, 2H), 1.36 – 1.32 (m, 2H), 1.23 (td, J = 7.1, 2.8 Hz, 6H), 0.87 (t, J = 7.3 Hz, 3H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 201.9, 169.9 (2C), 135.8, 128.4 (2C), 126.5 (2C), 126.4, 107.9, 95.9, 78.8, 71.1, 61.6 (2C), 56.4, 32.4, 30.2, 29.8, 27.2, 22.7, 22.5, 13.8 (2C), 13.7; IR (thin film) 3297, 2962, 2925, 2868, 1740, 1467, 1438, 1270, 1193, 1099, 1070; HRMS (ES+) C₂₅H₃₂O₄ [M+H⁺] Calculated: 397.2379; Found: 397.2376; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-52.7°$ (c 1.5, CH₂Cl₂).

(R_a)-diethyl 2-(3-(2-phenylvinylidene)heptyl)-2-(3-(trimethylsilyl)prop-2-yn-1-yl)malonate (16f)

Following the general procedure for preparation of allene-yne via silylation of the terminal alkyne, allene-yne 16e (44.1 mg, 0.11 mmol) in THF (1 mL) was reacted with lithium hexamethyldisilylamide (200 μL, 1M in THF, 0.20 mmol) and trimethylsilylchloride (35 μL, 0.28 mmol). Purification of the crude product using a Biotage normal phase automated purification system (4 g SNAP column, gradient of 1 – 3% EtOAc/hexanes) to afford compound 16f (43 mg, 84%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.28 – 7.26 (m, 4H), 7.18 – 7.14 (m, 1H), 6.16 – 6.14 (m, 1H), 4.22 – 4.15 (m, 4H), 2.85 (s, 2H), 2.27 – 2.21 (m, 2H), 2.12 – 1.99 (m, 4H), 1.46 – 1.33 (m, 4H), 1.23 (td, J = 7.1, 1.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H), 0.08 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 202.1, 170.1 (2C), 135.8, 128.5 (2C), 126.5 (2C), 126.4, 107.8, 101.2, 95.9, 88.1, 61.5 (2C), 56.8, 32.3, 30.4, 29.8, 27.5, 24.2, 22.5, 14.0 (2C), 13.9, −0.1 (3C); IR (thin film) 2950, 2921, 2856, 2178, 1941, 1728, 1458, 1437, 1266, 1193, 1030; HRMS (ES+) C₂₈H₄₁O₄Si [M+H⁺] Calculated: 469.2774; Found: 469.2762; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-34.7°$ (c 2.65, CH₂Cl₂).

(S)-Diethyl 8-butyl-2-oxo-1-phenyl-3-(trimethylsilyl)-1,2,6,7-tetrahydroazulene-5,5(4H)-dicarboxylate (44f)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 16f (26.1 mg, 0.056 mmol) and [Rh(CO)₂Cl]₂ (2.2 mg, 0.0056 mmol) were reacted in toluene (1.9 mL) for 2 h. Purification of the crude residue by flash chromatography (15% Et₂O/hexanes) afforded compound 44f (24.8 mg, 90%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.29 – 7.21 (m, 2H), 7.20 – 7.18 (m, 1H), 7.12 – 7.10 (m, 2H), 4.31 – 4.18 (m, 4H), 3.93 (s, 1H), 3.56 (d, J = 14.8 Hz, 1H), 3.46 (d, J = 14.8 Hz, 1H), 2.56 – 2.54 (m, 1H), 2.50 – 2.46 (m, 1H), 2.42 – 2.39 (m, 2H), 1.94 – 1.87 (m, 2H), 1.29 (td, J = 7.1, 2.4 Hz, 6H), 1.26 – 1.22 (m, 1H), 1.11 – 0.94 (m, 3H), 0.71 (t, J = 7.3 Hz, 3H), 0.25 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 208.5, 176.3, 171.4, 171.3, 145.6, 141.4, 139.9, 138.9, 128.6 (2C), 127.5 (2C), 126.5, 61.8, 61.7, 57.1, 56.3, 37.8, 34.7, 33.6, 29.1, 28.9, 22.7, 14.0, 14.0, 13.8, −0.3 (3C); IR (thin film) 2954, 2921, 2856, 1732, 1683, 1540, 1454, 1266, 1242, 1185, 1050; HRMS (ES+) C₂₉H₄₁O₅Si [M+H⁺] Calculated: 497.2723; Found: 497.2733; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+55.6°$ (c 2.1, CH₂Cl₂).

(R_a)-Diethyl 2-(but-2-yn-1-yl)-2-(3-(2-phenylvinylidene)heptyl)malonate (16c)

Following the General Procedure for Preparation of Allene-yne via alkylation of the malonate moiety, diethyl malonate 34c (96 mg, 0.35 mmol) was reacted with sodium hydride (11.7 mg, 60 wt% in oil, 0.29 mmol), mesylate 33 (68.7 mg, 0.19 mmol) and potassium iodide (48.3 mg, 0.29 mmol) in DMF-THF (1 : 1, 4 mL). Purification of the crude residue by flash chromatography (5% Et₂O/hexanes) afforded compound 16c (60.1 mg, 75%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.26 – 7.24 (m, 4H), 7.16 – 7.13 (m, 1H), 6.14 (t, J = 2.8 Hz, 1H), 4.17 (q, J = 7.1 Hz, 4H), 2.76 – 2.75 (m, 2H), 2.24 – 2.19 (m, 2H), 2.10 – 2.07 (m, 2H), 2.06 – 1.97 (m, 2H), 1.66 (t, J = 2.6 Hz, 3H), 1.44 – 1.42 (m, 2H), 1.36 – 1.32 (m, 2H), 1.21 (td, J = 7.1, 1.0 Hz, 6H), 0.86 (t, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 202.1, 170.5 (2C), 135.9, 128.4 (2C), 126.5 (2C), 126.4, 107.9, 95.9, 78.8, 73.2, 61.4 (2C), 56.8, 32.4, 30.2, 29.8, 27.3, 23.1, 22.5, 14.0 (2C), 13.9, 3.4; IR (thin film) 2958, 2933, 2860, 1728, 1462, 1446, 1266, 1193, 1103, 1066; HRMS (ES+) C₂₆H₃₅O₄ [M+H⁺] Calculated: 411.2535; Found: 411.2528; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-53°$ (c 1.35, CH₂Cl₂).

(S)-Diethyl 8-butyl-3-methyl-2-oxo-1-phenyl-1,2,6,7-tetrahydroazulene-5,5(4H)-dicarboxylate (44c)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 16c (33.2 mg, 0.081 mmol) and [Rh(CO)₂Cl]₂ (3.2 mg, 0.0081 mmol) were reacted in toluene (2.7 mL) for 2.5 h. Purification of the crude residue by flash chromatography (30% Et₂O/hexanes) afforded compound 44c (31.2 mg, 88%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.29 – 7.27 (m, 3H), 7.22 – 7.19 (m, 1H), 7.13 – 7.12 (m, 2H), 4.26 – 4.23 (m, 4H), 3.95 (s, 1H), 3.39 (m, 2H), 2.50 – 2.47 (m, 3H), 2.39 – 2.36 (m, 1H), 1.90 – 1.89 (m, 2H), 1.85 (s, 3H), 1.30 (td, J = 7.1, 2.5 Hz, 6H), 1.26 – 1.22 (m, 2H), 1.10 – 0.87 (m, 2H), 0.72 (t, J = 7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 204.3, 171.5, 171.4, 164.1, 143.4, 138.5, 137.7, 137.3, 128.6 (2C), 127.5 (2C), 126.6, 61.8 (2C), 55.9, 55.1, 37.1, 33.8, 32.6, 29.1, 28.6, 22.6, 14.0 (2C), 13.8, 8.5; IR (thin film) 2950, 2921, 2856, 1732, 1691, 1597, 1450, 1381, 1361, 1270, 1230, 1185; HRMS (ES+) C₂₇H₃₅O₅ [M+H⁺] Calculated: 439.2484; Found: 439.2467; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+128°$ (c 2.0, CH₂Cl₂).

(R_a)-(3-(2-((3-Phenylprop-2-yn-1-yl)oxy)ethyl)hepta-1,2-dien-1-yl)benzene (15d)

Following the general procedure for preparation of allene-yne via Williamson etherification, alcohol (R_a)-29 (95.8 mg, 0.44 mmol) in THF (1 mL) was reacted with sodium hydride (35.4 mg, 60% dispersion in mineral oil, 0.89 mmol) and (3-bromoprop-1-yn-1-yl)benzene (130 mg, 0.66 mmol) for 11 h. Purification of the crude residue by flash chromatography (1% Et₂O/hexanes) afforded compound 15d (51.3 mg, 35%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.39 – 7.38 (m, 2H), 7.29 – 7.26 (m, 7H), 7.17 – 7.15 (m, 1H), 6.17 – 6.16 (m, 1H), 4.35 – 4.29 (m, 2H), 3.76 – 3.70 (m, 2H), 2.44 – 2.42 (m, 2H), 2.13 – 2.12 (m, 2H), 1.50 – 1.44 (m, 2H), 1.39 – 1.34 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 202.3, 135.8, 131.7 (2C), 128.5 (2C), 128.3, 128.2 (2C), 126.5 (2C), 126.4, 122.7, 105.5, 95.9, 86.1, 85.2, 68.3, 58.8, 32.8, 32.7, 29.8, 22.5, 13.9; IR (thin film) 3060, 3019, 2962, 2929, 2864, 1949, 1675, 1605, 1495, 1462, 1442, 1352, 1099, 1030; HRMS (ES+) C₂₄H₂₇O₁ [M+H⁺] Calculated: 331.2062; Found: 331.2025; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-12.4°$ (c 1.05, CH₂Cl₂).

(S)-5-Butyl-6,8-diphenyl-3,4-dihydro-1H-cyclopenta[c]oxepin-7(6H)-one (43d)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 15d (41 mg, 0.124 mmol) and [Rh(CO)₂Cl]₂ (4.8 mg, 0.0124 mmol) were reacted in toluene (4.1 mL) for 30 min. Purification of the crude residue by flash chromatography (30% Et₂O/hexanes) afforded compound 43d (30.6 mg, 69%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.38 – 7.28 (m, 7H), 7.25 – 7.22 (m, 3H), 4.88 (s, 2H), 4.20 (s, 1H), 4.08 – 4.04 (m, 2H), 2.84 – 2.75 (m, 1H), 2.63 – 2.56 (m, 1H), 2.06 – 1.99 (m, 2H), 1.30 – 1.26 (m, 2H), 1.13 – 1.06 (m, 3H), 0.73 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 201.8, 167.6, 141.8, 138.3, 138.2, 136.1, 130.9, 129.4 (2C), 128.7 (2C), 128.2 (2C), 128.1, 127.6 (2C), 126.9, 70.0, 67.3, 56.2, 36.9, 35.1, 29.7, 22.7, 13.8; IR (thin film) 3064, 3031, 2958, 2925, 2860, 2030, 1695, 1605, 1499, 1458, 1373, 1275, 1140; HRMS (ES+) C₂₅H₂₇O₂ [M+H⁺] Calculated: 359.2011; Found: 359.1980; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=124.2°$ (c 1.2, CH₂Cl₂).

(R_a)-(3-(2-(But-2-yn-1-yloxy)ethyl)hepta-1,2-dien-1-yl)benzene (15c)

Following the general procedure for preparation of allene-yne via Williamson etherification, alcohol (R_a)-29 (105 mg, 0.442 mmol) in THF (1.1 mL) was reacted with sodium hydride (38.8 mg, 60% dispersion in mineral oil, 0.97 mmol) and 1-bromobut-2-yne (97 mg, 0.73 mmol) for 11 h. Purification of the crude residue by flash chromatography (1% Et₂O/hexanes) afforded compound 15c (33 mg, 27%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.29 – 7.27 (m, 4H), 7.19 – 7.14 (m, 1H), 6.16 – 6.12 (m, 1H), 4.04 – 4.03 (m, 2H), 3.65 – 3.58 (m, 2H), 2.40 – 2.35 (m, 2H), 2.10 – 2.07 (m, 2H), 1.80 (t, J = 2.3 Hz, 3H), 1.46 – 1.32 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); ¹³C NMR (175 MHz, CDCl₃) δ 202.2, 135.8, 128.5 (2C), 126.6 (2C), 126.5, 105.5, 95.8, 82.3, 75.2, 68.2, 58.7, 32.8, 32.6, 29.7, 22.5, 13.9, 3.6; IR (thin film) 2954, 2929, 2852, 1495, 1462, 1356, 1140, 1095; HRMS (ES+) C₁₉H₂₅O [M+H⁺] Calculated: 269.1905; Found: 269.1889; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-16.1°$ (c 2.3, CH₂Cl₂).

(S)-5-butyl-8-methyl-6-phenyl-3,4-dihydro-1H-cyclopenta[c]oxepin-7(6H)-one (43c)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 15c (19 mg, 0.0719 mmol) and [Rh(CO)₂Cl]₂ (2.8 mg, 0.00719 mmol) were reacted in toluene (2.5 mL) for 45 min. Purification of the crude residue by flash chromatography (20% Et₂O/hexanes) afforded compound 43c (10 mg, 46%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.44 – 7.27 (m, 2H), 7.27 – 7.15 (m, 3H), 4.82 – 4.80 (m, 2H), 4.03 – 3.94 (m, 3H), 2.59 (t, J = 5.5 Hz, 2H), 1.98 – 1.89 (m, 2H), 1.74 (s, 3H), 1.18 – 0.97 (m, 4H), 0.70 (t, J = 7.1 Hz, 3H); ¹³C NMR (175 MHz, CDCl₃) δ 203.3, 166.8, 140.4, 138.5, 134.9, 134.8, 128.7 (2C), 127.5 (2C), 126.8, 70.4, 69.6, 55.7, 37.1, 36.8, 29.9, 22.7, 13.8, 8.3; IR (thin film) 2950, 2921, 2852, 1691, 1458, 1270, 1152; HRMS (ES+) C₂₀H₂₅O₂ [M+H⁺] Calculated: 297.1855; Found: 297.1834; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+191°$ (c 1.0, CH₂Cl₂).

(R_a)-(3-(2-(Prop-2-yn-1-yloxy)ethyl)hepta-1,2-dien-1-yl)benzene (15e)

Following the general procedure for preparation of allene-yne via Williamson etherification, alcohol (R_a)-29 (221.6 mg, 2.05 mmol) in THF (2.4 mL) was reacted with sodium hydride (82 mg, 60% dispersion in mineral oil, 0.97 mmol) and propargyl bromide (229 mg, 1.54 mmol) for 11 h. Purification of the crude residue by flash chromatography (0.7% Et₂O/hexanes) afforded compound 15e (51.9 mg, 20%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.26 – 7.22 (m, 4H), 7.16 – 7.11 (m, 1H), 6.11 (m, 1H), 4.05 (t, J = 2.0 Hz, 2H), 3.66 – 3.58 (m, 2H), 2.38 – 2.33 (m, 3H), 2.10 – 2.04 (m, 2H), 1.43 – 1.30 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H); ¹³C NMR (175 MHz, CD₂Cl₂) δ 202.2, 135.8, 128.4 (2C), 126.5 (2C), 126.4, 105.5, 95.5, 79.9, 73.8, 68.2, 57.9, 32.6, 32.6, 29.7, 22.5, 13.7; IR (thin film) 3309, 2954, 2921, 2856, 1728, 1663, 1593, 1467, 1360, 1254, 1160, 1103; HRMS (ES+) C₁₈H₂₃O [M+H⁺] Calculated: 255.1749; Found: 255.1756; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-14.0°$ (c 1.0, CH₂Cl₂).

(R_a)-Trimethyl(3-((3-(2-phenylvinylidene)heptyl)oxy)prop-1-yn-1-yl)silane (15f)

Following the general procedure for preparation of allene-yne via silylation of the terminal alkyne, allene-yne 15e (48 mg, 0.19 mmol) in THF (1.7 mL) was reacted with lithium hexamethyldisilylamide (340 μL, 1M in THF, 0.34 mmol) and trimethylsilylchloride (60 μL, 0.47 mmol). Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, gradient of 0 – 2% EtOAc/hexanes) to afford compound 15f (39.9 mg, 65%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.30 – 7.28 (m, 4H), 7.20 – 7.18 (m, 1H), 6.17 – 6.16 (m, 1H), 4.12 – 4.11 (m, 2H), 3.70 – 3.62 (m, 2H), 2.43 – 2.40 (m, 2H), 2.14 – 2.12 (m, 2H), 1.50 – 1.46 (m, 2H), 1.40 – 1.34 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H), 0.17 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 202.2, 135.7, 128.5 (2C), 126.5 (2C), 126.4, 105.4, 101.6, 95.7, 91.2, 68.2, 58.9, 32.7, 32.6, 29.7, 22.5, 13.9, −0.2 (3C); IR (thin film) 2954, 2925, 2856, 2169, 1949, 1716, 1597, 1491, 1458, 1356, 1250, 1099; HRMS (ES+) C₂₁H₃₁OSi [M+H⁺] Calculated: 327.2144; Found: 327.2128; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-18.8°$ (c 0.85, CH₂Cl₂).

(S)-5-butyl-6-phenyl-8-(trimethylsilyl)-3,4-dihydro-1H-cyclopenta[c]oxepin-7(6H)-one (43f)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 15f (25.1 mg, 0.077 mmol) and [Rh(CO)₂Cl]₂ (3 mg, 0.0077 mmol) were reacted in toluene (2.5 mL) for 45 min. Purification of the crude residue by flash chromatography (15% Et₂O/hexanes) afforded compound 43f (24.9 mg, 91%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.29 – 7.25 (m, 2H), 7.21 – 7.14 (m, 3H), 4.94 – 4.82 (m, 2H), 4.02 – 3.97 (m, 3H), 2.72 – 2.65 (m, 1H), 2.60 – 2.52 (m, 1H), 2.00 – 1.91 (m, 2H), 1.27 – 1.26 (m, 1H), 1.08 – 1.03 (m, 3H), 0.71 (t, J = 7.1 Hz, 3H), 0.21 (s, 9H); ¹³C NMR (175 MHz, CDCl₃) δ 207.5, 180.1, 141.8, 138.8, 138.4, 138.2, 128.7 (2C), 127.4 (2C), 126.6, 69.8, 69.7, 57.4, 37.3, 36.0, 29.7, 22.7, 13.8, −0.3 (3C); IR (thin film) 2954, 2925, 2964, 1695, 1544, 1446, 1250, 1152, 841; HRMS (ES+) C₂₂H₃₁O₂Si [M+H⁺] Calculated: 355.2093; Found: 355.2114; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+191.0°$ (c 2.3, CH₂Cl₂).

(R_a)-N-(3-Cyclopropylprop-2-yn-1-yl)-4-methyl-N-(3-(2-phenylvinylidene) heptyl) benzenesulfonamide (14g)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol (R_a)-29 (37.8 mg, 0.18 mmol) in THF (1.3 mL) was reacted with triphenylphosphine (55 mg, 0.21 mmol), N-(3-cyclopropylprop-2-yn-1-yl)-4-methylbenzenesulfonamide 30g (52.3 mg, 0.21 mmol) and diisopropylazodicarboxylate (42 μL, 0.21 mmol) for 11 h. Purification of the crude residue using a Biotage normal phase automated purification system (12 g SNAP column, gradient of 0 – 6% EtOAc/hexanes) afforded compound 14g (78.2 mg, 78%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 7.9 Hz, 6H), 7.29 – 7.24 (m, 4H), 7.21 – 7.16 (m, 3H), 6.12 (s, 1H), 4.07 – 3.96 (m, 2H), 3.36 – 3.29 (m, 1H), 3.25 – 3.18 (m, 1H), 2.37 (s, 3H), 2.36 – 2.34 (m, 2H), 2.15 – 2.06 (m, 2H), 1.45 – 1.41 (m, 2H), 1.36 – 1.30 (m, 2H), 0.91 – 0.90 (m, 1H), 0.86 (t, J = 7.2 Hz, 3H), 0.56 – 0.53 (m, 2H), 0.26 – 0.24 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 202.3, 143.1, 135.9, 135.5, 129.3 (2C), 128.5 (2C), 127.7 (2C), 126.6, 126.5 (2C), 105.4, 95.9, 89.3, 67.7, 44.6, 37.0, 32.1, 31.2, 29.7, 22.5, 21.5, 13.9, 7.8 (2C), −0.9; IR (thin film) 3027, 2962, 2940, 2860, 2251, 1945, 1593, 1491, 1458, 1348, 1164, 1099; HRMS (ES+) C₂₈H₃₄NO₂S [M+H⁺] Calculated: 448.2310; Found: 448.2329; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=-83.6°$ (c 0.55, CH₂Cl₂).

(S)-5-butyl-8-cyclopropyl-6-phenyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta[c]azepin -7(6H)-one (42g)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 14g (31 mg, 0.069 mmol) and [Rh(CO)₂Cl]₂ (2.7 mg, 0.0069 mmol) were reacted in toluene (2.2 mL) for 35 min. Purification of the crude residue by silica gel chromatography using 40% Et₂O/hexanes afforded compound 42g (29.1 mg, 88%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.75 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.15 (m, 3H), 6.75 – 6.73 (m, 2H), 4.88 (d, J = 16.9 Hz, 1H), 4.61 (d, J = 16.9 Hz, 1H), 3.67 – 3.65 (m, 1H), 3.64 (s, 1H), 3.57 – 3.53 (m, 1H), 2.68 – 2.63 (m, 1H), 2.53 – 2.48 (m, 1H), 2.41 (s, 3H), 1.78 – 1.72 (m, 2H), 1.62 – 1.59 (m, 1H), 1.30 – 1.27 (m, 1H), 1.21 – 1.18 (m, 1H), 1.08 – 1.06 (m, 1H), 1.01 – 0.96 (m, 1H), 0.94 – 0.90 (m, 1H), 0.87 – 0.85 (m, 2H), 0.80 – 0.77 (m, 1H), 0.66 (t, J = 7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 202.7, 162.1, 143.6, 139.4, 138.4, 137.9, 136.0, 135.7, 129.6 (2C), 128.6 (2C), 127.4 (2C), 127.3 (2C), 126.7, 55.3, 47.9, 43.8, 36.9, 31.2, 29.2, 22.6, 21.6, 13.7, 8.3, 5.9, 5.7; IR (thin film) 2962, 2917, 2860, 1695, 1454, 1344, 1172, 1087, 1021; HRMS (ES+) C₂₉H₃₄NO₃S [M+H⁺] Calculated: 476.2259; Found: 476.2271; ${\left[\alpha \right]}_{\mathrm{D}}^{20}=+72°$ (c 0.75, CH₂Cl₂).

1-(Dimethyl(phenyl)silyl)hept-2-yn-1-ol (24)

To a solution of hept-2-yn-1-ol 23 (5.48 g, 48.9 mmol) in THF (74 mL) cooled to −78 °C was added n-BuLi (33.6 mL, 1.0 M in hexanes, 53.7 mmol) and chlorodimethylphenylsilane (9.17 g, 53.7 mmol). After the addition was complete, the bath was removed and the reaction mixture was stirred at rt for 20 h. The solution was cooled to −78 °C and tert-butyllithium (34.5 mL, 1.7 M in hexanes, 58.6 mmol) was added dropwise. The mixture was then stirred at −45 °C for 2 h. The solution was cooled to −78 °C and quenched slowly with a 10% solution of acetic acid in THF (20 mL). The mixture was diluted with NaHCO₃ (100 mL) and extracted with Et₂O (400 mL). The organic phase was separated and extracted with NaHCO₃ (4 × 150 mL). The organic phase was washed with brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification of the crude residue using a Biotage normal phase automated purification system (120 g SNAP column, gradient of 1 – 25% EtOAc/hexanes) afforded compound 24 (6.65 g, 55%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.63 – 7.62 (m, 2H), 7.40 – 7.37 (m, 3H), 4.25 (t, J = 2.4 Hz, 1H), 2.25 – 2.23 (m, 2H), 1.49 – 1.45 (m, 2H), 1.40 – 1.37 (m, 2H), 0.94 – 0.93 (m, 1H), 0.90 (t, J = 7.3 Hz, 3H), 0.43 (d, J = 7.0 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 135.5, 134.3 (2C), 129.6, 127.8 (2C), 89.0, 79.9, 56.2, 30.9, 21.9, 18.7, 13.6, −5.5, −5.9; IR (thin film) 3440, 2954, 2929, 2860, 1248, 1120, 968; HRMS (ES+) C₁₅H₂₃OSi [M+H⁺] Calculated: 247.1518; Found: 247.1496.

Methyl 3-(2-(dimethyl(phenyl)silyl)vinylidene)heptanoate (51)

A 25 mL round bottom flask was charged with propargyl alcohol 24 (1.01 g, 4.1 mmol), trimethylorthoacetate (3.13 mL, 24.5 mmol) and propionic acid (52 μL, 0.69 mmol). The resulting solution was stirred at 160 °C for 12 h using a Dean-Stark apparatus. After cooling to rt, the mixture was concentrated under a 10 mmHg vacuum for 2 h. Purification of the crude residue by silica gel chromatography using 2% Et₂O/hexanes afforded compound 51 (940 mg, 76%) as a colorless oil. ¹H NMR (700 MHz, CDCl₃) δ 7.55 – 7.54 (m, 2H), 7.36 – 7.35 (m, 3H), 5.15 (t, J = 3.4 Hz, 1H), 3.66 (s, 3H), 2.96 (qd, J = 15.1, 3.0 Hz, 2H), 1.99 – 1.98 (m, 2H), 1.37 – 1.31 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H), 0.36 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) 209.8, 172.0, 138.6, 133.7 (2C), 129.0, 127.7 (2C), 91.5, 82.9, 51.7, 38.2, 31.0, 29.8, 22.4, 13.9, −2.28, −2.32; IR (thin film) 2958, 2921, 2860, 1940, 1744, 1434, 1368, 1168; HRMS (ES+) C₁₈H₂₇O₂Si [M+H ] Calculated: 303.1780; Found: 303.1755.

3-(2-(Dimethyl(phenyl)silyl)vinylidene)heptan-1-ol (25)

A 25 mL round bottom flask was charged with lithium aluminum hydride (4.1 mL of a 1 M solution in Et₂O, 4.02 mmol) and THF (4 mL). The resulting mixture was cooled to 0 °C and a solution of ester 51 (810.5 mg, 2.68 mmol) in THF (4.7 mL) was added dropwise. The solution was stirred for 1 h at rt. The reaction mixture was cooled to 0 °C (ice bath), diluted with Et₂O (30 mL) and quenched very slowly with water (2 mL). The phases were separated, the organic phase was washed with brine (10 mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification of the crude residue by silica gel chromatography using 30% Et₂O/hexanes afforded compound 25 (541 mg, 74%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.56 – 7.54 (m, 2H), 7.38 – 7.36 (m, 3H), 5.15 – 5.14 (m, 1H), 3.67 – 3.65 (m, 2H), 2.19 – 2.17 (m, 3H), 1.94 – 1.92 (m, 2H), 1.38 – 1.34 (m, 4H), 0.90 (m, 3H), 0.37 – 0.36 (m, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 209.0, 138.4, 133.6 (2C), 129.0, 127.7 (2C), 93.8, 82.8, 60.8, 34.9, 31.4, 29.9, 22.4, 13.9, −2.2, −2.3; IR (thin film) 3342, 2962, 2933, 2844, 1945, 1458, 1453, 1381, 1242; HRMS (ES+) C₁₇H₂₅OSi [M−H⁺] Calculated: 273.1675; Found: 273.1653.

N-(but-2-yn-1-yl)-N-(3-(2-(dimethyl(phenyl)silyl)vinylidene)heptyl)-4-methyl benzenesulfonamide (40)

Following the general procedure for preparation of allene-yne via Mitsunobu reaction, alcohol 25 (54.8 mg, 0.2 mmol) in THF (1.5 mL) was reacted with triphenylphosphine (63 mg, 0.24 mmol), N-(but-2-yn-1-yl)-4-methylbenzenesulfonamide³⁰30c (54 mg, 0.24 mmol) and NaHCO₃ (48 μL, 0.24 mmol) for 2.5 h. Purification of the crude residue by silica gel chromatography using 5% Et₂O/hexanes afforded compound 40 (46.7 mg, 49%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃) δ 7.74 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 5.0 Hz, 2H), 7.39 – 7.37 (m, 3H), 7.29 (d, J = 7.4 Hz, 2H), 5.15 – 5.14 (m, 1H), 4.09 (d, J = 2.6 Hz, 2H), 3.24 (t, J = 8.0 Hz, 2H), 2.44 (s, 3H), 2.22 – 2.20 (m, 2H), 1.96 – 1.95 (m, 2H), 1.56 (t, J = 2.3 Hz, 3H), 1.38 – 1.35 (m, 5H), 0.92 (t, J = 7.0 Hz, 3H), 0.37 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 208.9, 143.0, 138.5, 136.0, 133.6 (2C), 129.2 (2C), 129.0, 127.7 (2C), 127.6 (2C), 94.1, 82.9, 81.4, 71.7, 44.9, 37.0, 31.3, 29.8 (2C), 22.4, 21.4, 13.9, 3.2, −2.2, −2.3; IR (thin film) 3395, 3064, 2954, 2860, 2165, 1669, 1593, 1438, 1361, 1254, 1160; HRMS (ES+) C₂₈H₃₆NO₂SSi [M−H⁺] Calculated: 478.2236; Found: 478.2238.

5-Butyl-8-methyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (41)

Following the General Procedure for the [Rh(CO)₂Cl]₂ Catalyzed Cyclocarbonylation Reaction, allene-yne 40 (33.5 mg, 0.07 mmol) and [Rh(CO)₂Cl]₂ (2.7 mg, 0.007 mmol) were reacted in toluene (2.3 mL) for 6 h. Purification of the crude residue by silica gel chromatography using 65% Et₂O/hexanes afforded compound 41 (25.1 mg, 96%) as a colorless oil. ¹H NMR (700 MHz, CDCl₃) δ 7.58 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.45 (s, 2H), 3.57 (t, J = 14.0 Hz, 2H), 2.70 (s, 2H), 2.54 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H), 2.00 (t, J = 7.4 Hz, 2H), 1.82 (s, 3H), 1.27 – 1.24 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 203.9, 161.5, 143.5, 138.6, 137.0, 136.1, 131.1, 129.4 (2C), 127.0 (2C), 47.9, 45.4, 39.2, 37.0, 32.6, 30.0, 22.6, 21.5, 14.0, 8.2; IR (thin film) 2954, 2929, 2856, 1703, 1462, 1352, 1160; HRMS (ES+) C₂₁H₂₈NO₃S [M+H⁺] Calculated: 374.1790; Found: 374.1806.

6-Methyl-2-tosyl-2,3,4,5-tetrahydrocyclopenta[c]azepin-7(1H)-one (48)

To a solution of cyclocarbonylation product 35e (30 mg, 0.067 mmol) in CH₂Cl₂ (0.1 mL) were added 4 Å molecular sieves (12 mg, activated by heating at 170 °C under vacuum for 12 h) and (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) (14 μl, 0.1 mmol). The resulting mixture was stirred at rt for 15 h. The solution was diluted with Et₂O (3 mL), filtered on a Celite plug, rinsed with Et₂O (10 mL) and concentrated under reduced pressure. Purification of the crude residue using a Biotage normal phase automated purification system (4 g SNAP column, gradient of 50 – 70% Et₂O/hexanes) afforded compound 48 (14 mg, 66%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.84 (s, 1H), 3.66 (m, 2H), 3.04 (s, 2H), 2.65 (t, J = 6.2 Hz, 2H), 2.43 (s, 3H), 1.91 – 1.86 (m, 2H), 1.73 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 203.9, 163.7, 144.3, 139.5, 135.4, 130.1 (2C), 126.9 (2C), 121.3, 116.1, 49.3, 40.9, 30.1, 24.4, 21.6, 8.5; IR (thin film) 2921, 2860, 1683, 1634, 1589, 1450, 1344, 1303, 1164, 1095; HRMS (ES+) C₁₇H₂₀NO₃S [M+H⁺] Calculated: 318.1164; Found: 318.1162.