Diastereoselective Synthesis of Substituted Tetrahydropyrans by Copper(II)–Bisphosphine-Catalyzed Olefin Migration and Prins Cyclization

Abstract

We developed a copper(II) triflate–bisphosphine complex catalyzed olefin migration and Prins cyclization which lead to the synthesis of substituted tetrahydropyran derivatives. The protocol is convenient and a variety of substituted tetrahydropyrans were obtained in good to excellent yields with excellent diastereoselectivities.

Substituted tetrahydropyran structural motifs are ubiquitous in numerous bioactive natural products.¹ The importance of this heterocycle is also well recognized in medicinal chemistry.² Compounds containing this ring system are widely utilized as pharmaceutical agents and molecular probes.³ Recently, in the context of our nonpep-tide ligand design and synthesis work, we have demonstrated that the tetrahydropyran ring oxygen can be used to mimic the carbonyl oxygen of a peptide bond.⁴ Over the years, a lot of effort has been devoted to the synthesis of stereochemically defined and substituted tetrahydropyran derivatives.⁵ Among these, hetero-Diels–Alder reactions,⁶ Prins cyclizations,⁷ oxy-Michael reactions,⁸ Petasis–Ferrier rearrangements,⁹ and Maitland–Japp reactions¹⁰ are widely used for the synthesis of functionalized tetrahydropyrans containing multiple stereocenters. We recently reported a highly diastereoselective synthesis of diand trisubstituted tetrahydropyrans via a tandem olefin migration and Prins cyclization process.¹¹ For example, the reaction of 5-methylhex-5-en-1-ol with a variety of aliphatic, electron-rich, and electron-poor aromatic aldehydes proceeded efficiently in the presence of a catalytic amount of copper(II) triflate–bisphosphine complex. This protocol is an improvement over previously reported platinum(II) triflate catalyzed cyclizations¹² in both lowering reaction temperature and broadening substrate scope.

In an earlier paper, Hosomi et al. utilized a combination of platinum(II) chloride (0.5 mol%) and silver(I) triflate (1 mol%) catalyst system at 100 °C with 5-methylhex-5-en-1-ol (1) and a number of aldehydes to affect cyclization resulting in 2,3-disubstituted tetrahydropyrans.¹² As shown in Table 1, reaction with benzaldehyde (2) gave trans product trans-3 in 77% yield along with the cis-diastereomer cis-3 and other unidentified products (entry 1). Electron-poor aromatic aldehydes 4-fluorobenzaldehyde (4), 4-nitrobenzaldehyde (6), and 4-cyanobenzaldehyde (8) also resulted in good yields (75–85%) of the trans products trans-5, trans-7, and trans-9, respectively, along with some (7–17%) cis product (entries 2–4). However, reaction with electron-rich p-anisaldehyde (10) gave a complex mixture with <37% yield of the desired trans product trans-11 (entry 5). Reaction with aliphatic aldehydes, octanal (12) and cyclohexanecarbaldehyde (14) gave slightly lower yields 65% and 59% in comparison to electron-poor aromatic aldehydes, but better diastereoselectivity with no detectable cis isomers (entries 6 and 7).

Table 1.

Earlier Work by Hosomi et al.¹²

Entry	Aldehyde	R	Product	Yield (%)	dr
1	2	Ph	3	77	9:1
2	4	4-FC6H4	5	75	4.4:1
3	6	4-O2NC6H4	7	77	11:1
4	8	4-NCC6H4	9	85	11:1
5	10	4-MeOC6H4	11	<37	-a
6	12	(CH2)6Me	13	65	>20:l
7	14	Cy	15	59	>20:l

^a Not determined.

As shown in Table 2, synthesis of trisubstituted tetrahydropyrans was also explored with the platinum(II) chlo-ride/silver(I) triflate catalyst system.¹² Reactions with 1-, 2-, and 3-methylalkenols 16, 20, and 24 gave 6-, 5-, and 4-methyltetrahydropyrans, respectively. Use of 6-methylhept-6-en-2-ol (16) under the standard reaction conditions gave 17–19 in excellent yields (>84%) and diastereoselectivities (>15:1 dr) (entries 1–3). Reactions with 2,5-dimethylhex-5-en-1-ol (20) under standard conditions lead to Prins cyclization giving 21–23 in excellent yields (>80%), but result in lower diastereoselectivities (from 99:1 to 4:1 dr, entries 4–6). However, reactions with 3,5-dimethylhex-5-en-1-ol (24) resulted in substituted tetrahydropyrans 25–27 with excellent diastereoselectivity (19:1), but lower yields than the unsubstituted analogues (entries 7–9).

Table 2.

Earlier Work by Hosomi et al. with Substituted Alkenols¹²

Entry	Alkenol	R1	R2	R3	Aldehyde	R4	Product	Yield (%)	dr
1	16	Me	H	H	2	Ph	17	85	19:1
2	16	Me	H	H	8	4-NCC6H4	18	90	16:1
3	16	Me	H	H	12	(CH2)6Me	19	84	24:1
4	20	H	Me	H	2	Ph	21	82	4:1
5	20	H	Me	H	8	4-NCC6H4	22	84	20:1
6	20	H	Me	H	12	(CH2)6Me	23	80	4:1
7	24	H	H	Me	2	Ph	25	56	20:1
8	24	H	H	Me	8	4-NCC6H4	26	68	20:1
9	24	H	H	Me	12	(CH2)6Me	27	65	19:1

In an effort to probe the reaction mechanism, reactions of 5-methylhex-4-en-1-ol (28) and benzaldehyde (2) were used (Scheme 1). This reaction afforded major product trans-3 in high yield (79%) and a small amount (12%) of the cis-3 product. This result has provided some evidence that the reaction with either substrate likely involved similar intermediates or transition states.

Scheme 1.

Earlier work by Hosomi et al.¹²

As shown in Table 3, similar reactions were reported previously by Loh et al. wherein 6-methylhept-5-en-2-ol (29) and an appropriate aldehyde in the presence of indium(III) triflate afforded substituted tetrahydropyrans.¹³ It was proposed that the reaction proceeded through a (3,5) oxonium-ene-type cyclization. However, there is evidence that the reaction proceeds in a stepwise manner via an intermediate carbocation.¹⁴

Table 3.

Earlier Work by Loh et al.¹³

Entry	Aldehyde	R	Product	Yield (%)	dr
1	2	Ph	17	77	12:1
2	8	4-NCC6H4	18	86	13:1
3	30	(E)-CH=CHPh	31	89	9:1
4	32	(CH2)7Me	33	87	20:1

Further studies on the olefin isomerization from 1 and 28 without the presence of an aldehyde were carried out. As shown in Scheme 2, the reaction of 5-methylhex-5-en-1-ol (1) in the presence of platinum(II) chloride/silver(I) triflate catalytic system provided a cyclized product 2,2-dimethyltetrahydro-2H-pyran (34). It was found that 34 was often a byproduct of the reaction, lowering the yield of the desired tetrahydropyran. In fact, this reaction was previously reported as a synthetic method for the synthesis of tetrahydropyrans and tetrahydrofurans.¹⁵

Scheme 2.

Side product found by Hosomi et al.¹²

As shown in Scheme 3, reaction of 5-methylhex-5-en-1-ol (1) with benzaldehyde (2) utilizing the same platinum(II) chloride and silver(I) triflate catalyst at room temperature afforded acetal 35 exclusively albeit in low yield (14%). It was found that reaction of this acetal 35 under the typical reaction conditions with an elevated temperature gave the expected cyclized product 3.

Scheme 3.

Reaction involving an acetal¹²

While this reaction did proceed well for electron-poor aromatic or aliphatic aldehydes, improvement was needed both in reaction temperature and substrate scope. Also, platinum(II) was implicated in the olefin migration process. In light of this precedence, we planned to explore this transformation with relatively inexpensive metal–ligand complexes. Towards this objective, we examined a variety of Lewis acids and Lewis acid–ligand complexes to catalyze these reactions. For initial studies, we utilized 5-methylhex-5-en-1-ol (1) with benzyloxyacetaldehyde (47) and bisphosphine ligands shown in Figure 1. First, we examined various metal triflates typically used for Prins-type cyclizations¹⁶ at 100 °C. This led to the identification of copper(II) triflate as the best ligand-free Lewis acid. However, copper(II) triflate by itself turned out to be unsatisfactory at lower temperatures. Subsequently, we examined copper(II) triflate–bisphosphine complex catalyzed reactions and found that 1,2-bis(diphenylphosphino)ethylene (L1) and 1,2-bis(diphenylphosphino)benzene (L2) were effective ligands at 40 °C.^11a Further exploration led to the development of 1-(diphenylphosphino)-2-[(diphenylphosphino)methyl]benzene (L3) which allowed the reaction to proceed at room temperature.^11b Reactions with benzaldehyde (2) and electron-poor aromatic aldehydes gave good yields and excellent diastereoselectivity with ligands L1 and L2, however electron-rich aromatic aldehydes resulted in much lower yields. This prompted us to explore the development of the phosphine ligand L3 with a varied bite angle that also possesses a σ-donor ability through an electron-neutral triarylphosphine.¹⁷

Figure 1.

Ligands found to be effective with copper(II) triflate

As shown in Table 4, the use of benzaldehyde (2) and 5-methylhex-5-en-1-ol (1) provided an excellent yield of trans-tetrahydropyran 3 (92% with L1) and high diastereo-selectivity. While the copper(II) triflate–L3-catalyzed reaction with electron-poor 4-nitrobenzaldehyde (6) showed similar results as those with ligand L2, the reaction yield was significantly better with ligand L1 (entries 3–5). As can be seen, the reaction of 1 with electron-rich p-anisaldehyde (10) in the presence of copper(II) triflate–L3 complex proceeded at 23 °C to provide 11 in 69% yield with excellent diastereoselectivity (dr >20:1); the corresponding reactions with ligands L1 and L2 were less satisfactory and were very slow at room temperature. These reactions were all carried out at 40 °C for two hours (entries 6–8). Reaction of electron-rich o-anisaldehyde (36) with copper(II) triflate–L3 complex provided tetrahydropyran 37 in 34% yield at 23 °C for 24 hours. The corresponding reaction with L1 and L2 provided lower yields of 37 (entries 9–11). Reaction of piperonal (38) using copper(II) triflate–L3 complex provided tetrahydropyran 39 in 46% yield and the corresponding reaction using L1 or L2 ligands afforded 39 in lower yields (entries 12–14). The copper(II) triflate–L3 catalyzed reaction with trans-cinnamaldehyde (30) proceeded with improved yield and excellent diastereoselectivitity, providing tetrahydropyran 40 in 74% yield and dr >20:1. In the case of anthracene-9-carbaldehyde (41), good yield and good diastereoselectivity were observed with L1 and L2. Thiophene-2-carbaldehyde (43) is also a suitable substrate for this reaction, providing excellent yields and diastereoselectivities (entries 20, 21). The reaction with isovaleralde-hyde (45) utilizing L3 also provided improved yields over L1 and L2 with comparable diastereoselectivity (entries 22–24). Reactions of benzyloxyacetaldehyde (47) with L1 and L2 gave pyran 48 with good yield and excellent diastereoselectivity (>20:1). Similarly, while tosyloxyacetaldehyde 49 also afforded good yield of 50, the diastereomeric ratio was reduced with L1 (dr 16:1) and L2 (dr 13:1, entries 25–28).

Table 4.

Copper(II) Triflate–L1–L3 Catalyzed Reactions with Alde-hydes

Entry	Aldehyde	R	Product	Liganda	Yield (%)	dr
1	2	Ph	3	L1	92	>20:l
2				L2	52	>20:l
3	6	4-O2NC6H4	7	L1	80	>20:l
4				L2	62	>20:l
5				L3	63	11:1
6	10	4-MeOC6H4	11	L1	42	>20:l
7				L2	20	>20:l
8				L3	69	>20:l
9	36	2-MeOC6H4	37	L1	22	>20:l
10				L2	27	>20:l
11				L3	34	>20:l
12	38	3,4-(OCH2O)C6H3	39	L1	36	>20:l
13				L2	29	>20:l
14				L3	46	>20:l
15	30	(E)-CH=CHPh	40	L1	59	>20:l
16				L2	53	>20:l
17				L3	74	>20:l
18	41	9-anthryl	42	L1	59	16:1
19				L2	50	24:1
20	43	2-thienyl	44	L1	84	>20:l
21				L2	82	>20:l
22	45	i-Bu	46	L1	59	>20:l
23				L2	62	>20:l
24				L3	70	16:1
25	47	CH2OBn	48	L1	67	>20:l
26				L2	57	>20:l
27	49	CH2OTs	50	L1	67	16:1
28				L2	67	13:1

^a Reaction temperature: 40 °C for L1 and L2, 23 °C for L3.

We then examined reactions with 1-substituted 5-methylhex-5-en-1-ols. As shown in Table 5, substituted alkenols provided the expected 2,3,6-trisubstituted tetrahydropyrans, however product yields were lower. Reactions with trans-cinnamaldehyde (30) utilizing either copper(II) triflate–L1 or copper(II) triflate–L3 resulted in good yields and excellent diastereoselectivity. Reaction of methyl-substituted alkenol 16 with trans-cinnamaldehyde (30) catalyzed by copper(II) triflate–L1 led to the desired tetrahydropyran 31 in 64% yield and excellent diastereoselectivity [19:1 dr (¹H NMR), entry 1]. The use of the bulkier isopropyl-substituted alkenol 51 catalyzed by copper(II) triflate–L3 gave the desired trisubstituted tetrahydropyran 52 with good yield and excellent diastereoselectivity (entry 2). The copper(II) triflate–L3 catalyzed reaction between tert-butyl-substituted alkenol 53 with trans-cinnamaldehyde (30) was a significant improvement over the similar copper(II) triflate–L1 catalyzed system (48% vs 28% yield, entries 3 and 4). Phenyl-substituted alkenol 59 also reacted with trans-cinnamaldehyde (30) to give the tetrahydropyran 60 in moderate yield (entry 7). While both allyl 55 and benzyl 57 substitutions were tolerated, their reactions with trans-cinnamaldehyde (30) proceeded with slightly lower yields (entries 5, 6). Reaction of the methyl-substituted alkenol 16 with p-anisaldehyde (10) maintained the high yield and diastereoselectivity previously observed with an unsubstituted alkenol. Use of isopropyl-substituted alkenol 51 with p-anisaldehyde (10) catalyzed by copper(II) triflate–L3 led to the desired product 62 in 59% yield with excellent diastereoselectivity (entry 9). Unlike with trans-cinnamaldehyde, reactions with allyl- 55 and benzyl-substituted alkenols 57 with p-anisaldehyde (10) maintained good yield and diastereoselectivity (entries 10, 11).

Table 5.

Reactions with Substituted Alkenols

Entry	Alkenol	R1	Aldehyde	R2	Ligand	Product	Yield (%)	dr
1	16	Me	30	(E)-CH=CHPh	L1	31	64	19:1
2	51	i-Pr	30	(E)-CH=CHPh	L3	52	56	>20:l
3	53	t-Bu	30	(E)-CH=CHPh	L1	54	28	13:1
4	53	t-Bu	30	(E)-CH=CHPh	L3	54	48	>20:l
5	55	allyl	30	(E)-CH=CHPh	L3	56	34	18:1
6	57	Bn	30	(E)-CH=CHPh	L3	58	34	>20:l
7	59	Ph	30	(E)-CH=CHPh	L3	60	48	>20:l
8	16	Me	10	4-MeOC6H4	L3	61	56	>20:l
9	51	i-Pr	10	4-MeOC6H4	L3	62	59	>20:l
10	55	allyl	10	4-MeOC6H4	L3	63	46	>20:l
11	57	Bn	10	4-MeOC6H4	L3	64	61	>20:l

Reaction of methyl-substituted alkenol 16 with benzyloxyacetaldehyde (47) utilizing reaction conditions with either L1 or L3 ligand and copper(II) triflate led to a mixture of expected tetrahydropyran 65 along with a small amount of the eight-member cyclic ether 66 (3,4,7,8-tetra-hydro-2H-oxocin) (Scheme 4). Presumably, this was formed by a direct nucleophilic attack by the olefin onto the oxocarbenium ion 67 leading to the oxygen-stabilized tertiary carbocation 68, followed by elimination. The formation of eight-membered ring was observed as a minor product for reactions with benzyloxyacetaldehyde (47) or tosyloxyacetaldehyde (49) with all alkenol substrates shown in Table 5. Further studies on this interesting ring formation are currently being explored.

Scheme 4.

Formation of an oxocin byproduct

As shown in Table 6, reactions with 2,5-dimethylhex-5-en-1-ol (20) and 3,5-dimethylhex-5-en-1-ol (24) with our standard conditions using copper(II) triflate and L3 resulted in lower yields. The reaction of methyl alkenol 20 and p-anisaldehyde (10) provided the desired trisubstituted tetrahydropyran 69 in 49% yield, but with lower diastereoselectivity (methyl diastereomer 6:1). Similar results were obtained by Hosomi et al.¹² Similar results were also observed when trans-cinnamaldehyde (30) was used to give tetrahydropyran 70. Again, there was a drop in yield when methyl alkenol 20 was reacted with 4-nitrobenzaldehyde (6) as previously shown in Table 4. When 3,5-dimethylhex-5-en-1-ol (24) was used as the substrate, the drop in reaction yield was even more dramatic. Reaction with either p-anisaldehyde (10) or trans-cinnamaldehyde (30) resulted in formation of tetrahydropyrans 72 and 73, respectively, in less than 20% yield. In all of these reactions, along with formation of the desired tetrahydropyrans, cyclization of the alkenol also resulted in substituted 2,2-dimethyltetrahydropyran as shown in Scheme 2. Un-reacted aldehyde was also recovered. Reaction yield based on recovered aldehyde (limiting reagent) is typically >85%.

Table 6.

Reactions with Dimethylhex-5-en-1-ols

Entry	Alkenol	R1	R2	Aldehyde	R3	Product	Yield (%)	dr
1	20	Me	H	10	4-MeOC6H4	69	49	6:1
2	20	Me	H	30	(E)-CH=CHPh	70	43	4:1
3	20	Me	H	6	4-O2NC6H4	71	29	6:1
4	24	H	Me	10	4-MeOC6H4	72	12	20:1
5	24	H	Me	30	(E)-CH=CHPh	73	13	20:1

The stereochemical outcome of the olefin migration and Prins cyclization reactions which lead to trans-2,3-disubstituted tetrahydropyran derivatives can be rationalized based upon the Zimmerman–Traxler¹⁸ transition-state models (Scheme 5). The copper(II) triflate based Lewis acid catalyzed reaction could lead to the formation of an oxocarbenium ion 74.¹⁹ Subsequent olefin migration followed by cyclization may proceed through either favored transition state 76 or disfavored transition state 75. Proton abstraction β to the carbocation would give rise to trans-2,3- and cis-2,3-tetrahydropyrans 78 and 77, respectively.^20,21 The transition state 76 is favored due to the lack of developing pseudo-1,3-diaxial interactions, as is seen in 75. Consistent with the primary alkenol cyclizations, the secondary alkenol cyclization also provided a 2,3,6-trans,trans-tetrahydropyran 78 as the major isomer. Stereochemistry of the trisubstituted tetrahydropyran products shown in Table 6 can similarly be explained via the same Zimmerman–Traxler transition-state model. This also accounts for the lower diastereoselectivity in reactions with 2,5-dimethylhex-5-en-1-ol (20).

Scheme 5.

Zimmerman–Traxler transition states

Interestingly, the addition of water or the attempted elimination of water (CaCl₂, MgSO₄, and 4 Å MS) resulted in the cessation of this reaction.²² However, the reaction did proceed once a catalytic amount of triflic acid was added. Thus, it appears that a protic acid is possibly required for the olefin rearrangement step.²³

Stereochemical models for reactions of 2,5-dimethylhex-5-en-1-ol (20) and 3,5-dimethylhex-5-en-1-ol (24) with various aldehydes are shown in Scheme 6. As can be seen, for reactions with 2,5-dimethylhex-5-en-1-ol (20), the major product 83 would form through transition state 81, which shows all equatorial substituents. The minor diastereomer 82 would form through transition state 80, which shows unfavorable 1,3-diaxial interaction between substituents. Similarly, for reactions with 3,5-dimethylhex-5-en-1-ol (24), transition state 86 would be favored over 85, providing product 88 as the major diastereomer.

Scheme 6.

Stereochemical models for alkenols 20 and 24

In an effort to further gain insight, reaction of 5-methylhex-5-en-1-ol (1) with salicylaldehyde was explored. As shown in Scheme 7, under standard conditions utilizing the copper(II) triflate–L2 at 40 °C gave bicyclic product 91 in 55% yield as a single diastereomer (by ¹H NMR). Presumably, the product 91 resulted from the nucleophilic attack of salicylaldehyde phenol to the tertiary carbocation intermediate formed by olefin migration. The formation of tricyclic product 91 was previously observed by Inoue and co-workers.²⁴

Scheme 7.

Reaction of alkenol 1 with salicylaldehyde

As shown, the trans-isomer was the major product and often the only isomer observable by NMR analysis. The reaction of 5-methylhex-5-en-1-ol (1) with tosyloxyacetaldehyde (49) was found to provide chromatographically separable diastereomers 50a (trans-major) and 50b (cis-minor). The stereochemical assignment of these compounds was carried out by ¹H NMR NOESY experiments (Figure 2). The observed NOESY between H_a–H_d, H_b–H_c, H_c–H_f, and H_d–H_e for compound 50a is consistent with the assigned trans stereochemistry. Similarly, the observed NOESY between H_b–H_c, H_c–H_d, H_c–H_f, and H_d–H_f supported the assigned cis stereochemistry for compound 50b.

Figure 2.

NOE of tetrahydropyran 50

Rychnovski and co-workers have shown that the condensation of alcohols with aldehydes in attempted 6-(2,5)-Prins reactions undergoes partial or complete racemization via an oxonia-Cope process.²⁵ To examine whether our catalytic system can undergo such stereoisomerization or not, we have carried out olefin migration and Prins cyclization using enantioenriched alcohol 92. This was prepared by Corey–Bakshi–Shibata reduction²⁶ of the corresponding ketone in 89% ee. As shown in Scheme 8, reaction of alcohol 92 with benzyloxyacetaldehyde (47) provided 93, with good diastereoselectively (dr >20:1) and 59% yield. The trans-isomer 93 was obtained in 89% ee, which indicated that the cyclization resulted in no loss of optical activity.^11a This indicates that the present cyclization pathway does not involve a [3,3]-sigmatropic rearrangement.

Scheme 8.

Experiment with optically enriched alkenol

In conclusion, we have developed a mild copper(II) triflate–bisphosphine-catalyzed reaction involving an appropriate alkenol and an aldehyde to provide a variety of substituted tetrahydropyrans. Both electron-rich and electron-deficient aromatic aldehydes were tolerated under our reaction conditions. The reaction proceeded via a tandem olefin migration and Prins cyclization to provide tetrahydropyran derivatives in good to excellent yields and excellent trans diastereoselectivity. This copper(II) triflate and bisphosphine ligand combination has not been previously employed in such synthesis of substituted tetrahydropyrans. Mechanistic explorations and further applications are in progress in our laboratory.

Chemicals and reagents were purchased from commercial suppliers and used without further purification. L3 was prepared as reported.^11b Anhydrous CH₂Cl₂ was distilled from CaH₂. All other solvents were reagent grade. All moisture-sensitive reactions were carried out in oven-dried glassware under argon. All new compounds were isolated as colorless oils except 71. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker Avance ARX-400, a Bruker DRX-500, or a Bruker Avance III-800 spectrometer. Chemical shifts are given in ppm and are referenced against the diluting solvent. For chloroform-d: ¹³C triplet = 77.00 and ¹H singlet = 7.26 ppm. For methanol-d₄: ¹³C septuplet = 49.05 and ¹H quintuplet = 3.31 ppm.

(2S*,3S*,6R*)-3-Isopropenyl-6-methyl-2-[(E)-styryl]tetra-hydro-2H-pyran (31); Typical Procedure Using Ligands L1 and L2

To a suspension of Cu(OTf)₂ (33 mg, 0.092 mmol, 15 mol%) in CH₂Cl₂ (4 mL) was added bis(diphenylphosphino)ethylene (L1; 36 mg, 0.092 mmol, 15 mol%) under an argon atmosphere. This was stirred at r.t. for 1 h to form completely the L1–Cu(OTf)₂ complex. To this was added a soln of 6-methylhept-6-en-2-ol (16; 98 mg, 0.766 mmol, 1.25 equiv) and trans-cinnamaldehyde (30; 77 μL,0.613 mmol, 1 equiv) in CH₂Cl₂ (4 mL) via cannula. The flask was fitted with a reflux condenser and heated to 40 °C for 2 h. Upon cooling the reaction was diluted with CH₂Cl₂ (10 mL) and washed with aq NaHCO₃ (10 mL) and brine (10 mL). The organic layer was dried (Na₂SO₄) and concentrated. The crude product was purified by column chromatography (10% EtOAc–hexanes) to provide tetrahydropyran 31 (95 mg, 64%).

¹H NMR (500 MHz, CDCl₃): δ = 7.42–7.38 (m, 2 H), 7.35–7.30 (m, 2 H), 7.27–7.21 (m, 1 H), 6.64 (d, J = 15.9 Hz, 1 H), 6.21 (dd, J = 16.0, 6.7 Hz, 1 H), 4.80 (s, 2 H), 3.96 (ddd, J = 10.0, 6.7, 1.2 Hz, 1 H), 3.62 (ddd, J = 11.4, 6.3, 2.0 Hz, 1 H), 2.11 (ddd, J = 11.8, 10.1,3.8 Hz, 1 H), 1.95–1.81 (m, 1 H), 1.79–1.65 (m, 5 H), 1.50–1.36 (m, 1 H), 1.29 (d, J = 6.1 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 146.29, 137.14, 131.24, 129.07, 128.35, 127.33, 126.54, 112.13, 80.94, 77.25, 77.00, 76.93, 76.75,73.67, 49.71, 33.37, 29.98, 22.05, 20.88.

MS (EI): m/z = 131, 227, 242 [M⁺].

MS (CI): m/z = 133, 138, 225, 243 [M + H].

(2S*,3R*,5R*)-3-Isopropenyl-2-(4-methoxyphenyl)-5-methyltetrahydro-2H-pyran (69); Typical Procedure for Ligand L3

To a suspension of Cu(OTf)₂ (34 mg, 0.094 mmol, 15 mol%) in CH₂Cl₂ (5 mL) was added 1-(diphenylphosphino)-2-[(diphenylphosphino)methyl]benzene (L3; 43 mg, 0.094 mmol, 15 mol%) under an argon atmosphere. This was stirred at r.t. for 1 h to form completely the L3–Cu(OTf)₂ complex. To this was added a soln of 2,5-dimethylhex-5-en-1-ol (20; 100 mg, 0.78 mmol, 1.25 equiv) and p-anisaldehyde (10; 76 μL, 0.62 mmol, 1 equiv) in CH₂Cl₂ (5 mL) via cannula. The reaction was stirred at r.t. for 18 h. Upon completion the reaction was diluted with CH₂Cl₂ (10 mL) and washed with aq NaHCO₃ (10 mL) and brine (10 mL). The organic layer was dried (Na₂SO₄) and concentrated. The crude product was purified by column chromatography (10% EtOAc–hexanes) to provide tetrahydropyran 69 (76 mg, 49%); dr ~7:1 (¹H NMR).

¹H NMR (400 MHz, CDCl₃): δ = 7.23 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 4.62 (d, J = 10.2 Hz, 2 H), 4.07 (d, J = 10.0 Hz, 1 H), 3.99 (ddd, J = 11.1, 4.3, 2.4 Hz, 1 H), 3.78 (s, 3 H), 3.16 (t, J = 11.0 Hz, 1 H), 2.63–2.55 (m, ~0.14 H, methyl diastereomer), 2.38 (ddd, J = 12.0, 10.0, 3.3 Hz, 1 H), 1.91 (m, 2 H), 1.45 (s, 3 H), 1.35 (q, J = 12.2 Hz, 1 H), 1.26 (d, J = 7.0 Hz, ~0.42 H methyl diastereomer), 0.87 (d, J = 6.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 158.93, 146.20, 133.18, 128.39(2 C), 113.35 (2 C), 111.82, 83.44, 74.99, 55.07, 53.33, 50.30,39.12, 31.18, 21.28, 17.00.

MS (EI): m/z = 121, 161, 246 [M⁺].

MS (CI): m/z = 121, 139, 247 [M + H].

trans-3-Isopropenyl-2-(2-methoxyphenyl)tetrahydro-2H-pyran (37)

Following the typical procedure using 5-methylhex-5-en-1-ol (1; 143 mg, 1.25 mmol) and 2-anisaldehyde (36; 136 mg, 1 mmol) with L3 gave 37 (79 mg, 34%).

¹H NMR (500 MHz, CDCl₃): δ = 7.42 (dd, J = 7.5, 1.8 Hz, 1 H), 7.25 (td, J = 8.3, 1.8 Hz, 1 H), 6.98 (t, J = 7.4 Hz, 1 H), 6.86 (d, J = 8.2 Hz, 1 H), 4.84 (d, J = 10.2 Hz, 1 H), 4.54 (d, J = 7.9 Hz, 2 H), 4.16–4.08 (m, 1 H), 3.83 (s, 3 H), 3.65 (td, J = 11.8, 2.2 Hz, 1 H), 2.52 (td, J = 10.7, 3.5 Hz, 1 H), 1.97–1.67 (m, 4 H), 1.59 (s, 3 H).

¹³C (125 MHz, CDCl₃): δ = 156.72, 146.22, 129.58, 128.51, 127.89, 120.66, 111.64, 110.50, 68.97, 55.33, 50.22, 30.31, 26.43, 20.42.

MS (EI): m/z = 124, 232 [M⁺].

MS (CI): m/z = 125, 233 [M + H].

trans-3-Isopropenyl-2-[3,4-(methylenedioxy)phenyl]tetra-hydro-2H-pyran (39)

Following the typical procedure using 5-methylhex-5-en-1-ol (1; 143 mg, 1.25 mmol) and piperonal (38; 150 mg, 1 mmol) with L3 gave 39 (111 mg, 46%).

¹H NMR (500 MHz, CDCl₃): δ = 6.87 (s, 1 H), 6.84–6.56 (m, 2 H), 5.94 (d, J = 3.4 Hz, 2 H), 4.67 (d, J = 15.2 Hz, 2 H), 4.12 (d, J = 9.9 Hz, 2 H), 3.60 (td, J = 11.8, 2.1 Hz, 1 H), 2.32 (ddd, J = 11.6, 9.6, 3.7 Hz, 1 H), 2.01–1.62 (m, 4 H), 1.51 (s, 3 H).

¹³C (125 MHz, CDCl₃): δ = 147.37, 146.88, 146.27, 135.24, 120.96, 112.05, 107.76, 107.62, 100.83, 84.18, 68.85, 50.56, 30.25, 26.29, 21.42.

MS (EI): m/z = 124, 246 [M⁺].

MS (CI): m/z = 125, 247 [M + H].

(2S*,3S*,6S*)-3-Isopropenyl-6-isopropyl-2-[(E)-styryl]tetra-hydro-2H-pyran (52)

Following the typical procedure using 2,7-dimethyloct-7-en-3-ol (51; 112 mg, 0.725 mmol, 1.25 equiv) and trans-cinnamaldehyde (30; 73 μL, 0.58 mmol, 1 equiv) with L3 gave 52 (88 mg, 56%).

¹H NMR (500 MHz, CDCl₃): δ = 7.41 (dd, J = 7.7, 1.6 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.24 (t, J = 7.3 Hz, 1 H), 6.66 (d, J = 15.9 Hz, 1 H), 6.25 (dd, J = 15.9, 5.9 Hz, 1 H), 4.81 (s, 2 H), 3.94 (ddd, J = 10.1, 5.9, 1.5 Hz, 1 H), 3.16 (ddd, J = 11.2, 6.5, 2.1 Hz, 1 H), 2.08 (ddd, J = 12.3, 10.1, 3.8 Hz, 1 H), 1.89 (dd, J = 13.2, 3.5 Hz, 1 H), 1.84–1.76 (m, 2 H), 1.74 (s, 3 H), 1.68 (dd, J = 12.5, 3.9 Hz, 1 H), 1.38 (tdd, J = 12.8, 11.1, 3.9 Hz, 1 H), 1.04 (d, J = 6.8 Hz, 3 H),0.97 (d, J = 6.9 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 146.50, 137.39, 130.24, 129.45, 128.38, 127.20, 126.48, 112.02, 82.66, 80.47, 50.16, 33.17, 30.17, 27.93, 20.90, 18.96, 18.38.

(2S*,3S*,6S*)-6-tert-Butyl-3-(prop-1-en-2-yl)-2-styryltetra-hydro-2H-pyran (54)

Following the typical procedure using 2,2,7-trimethyloct-7-en-3-ol (53; 113 mg, 0.667 mmol, 1.25 equiv) and trans-cinnamaldehyde (30; 66 μL, 0.533 mmol, 1 equiv) with L3 gave 54 (72 mg, 48%).

¹H NMR (400 MHz, CDCl₃): δ = 7.43–7.36 (m, 2 H), 7.33–7.29 (t, J = 8.5, 6.8 Hz, 8 H), 7.23 (m, J = 7.3 Hz, 3 H), 6.68–6.63 (dd, J = 16.0, 1.5 Hz, 1 H), 6.28–6.23 (dd, J = 15.9, 5.2 Hz, 1 H), 4.81 (d, J = 6.1 Hz, 2 H), 3.95–3.91 (ddd, J = 10.1, 5.2, 1.6 Hz, 1 H), 3.08–3.04 (dd, J = 11.2, 1.8 Hz, 1 H), 2.04–1.96 (m, 1 H), 1.93–1.83 (m, 1 H), 1.74 (s, 3 H), 1.73–1.62 (m, 2 H), 1.41 (m, 1 H), 0.97 (s, 9 H).

¹³C NMR (101 MHz, CDCl₃): δ = 146.55, 137.48, 129.73, 129.28, 128.33, 127.03, 126.36, 111.87, 85.15, 80.08, 50.17, 34.17, 30.38, 26.14, 25.34, 20.90.

MS (EI): m/z = 96, 133, 154, 269, 284 [M⁺].

MS (CI): m/z = 133, 267, 285 [M + H].

(2S*,3S*,6S*)-6-Allyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-2H-pyran (56)

Following the typical procedure using 8-methylnona-1,8-dien-4-ol (55; 68 mg, 0.44 mmol, 1.25 equiv) and trans-cinnamaldehyde (30; 44 μL, 0.35 mmol, 1 equiv) with L3 gave 56 (32 mg, 34%).

¹H NMR (500 MHz, CDCl₃): δ = 7.41 (d, J = 7.3 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.25 (t, J = 7.3 Hz, 1 H), 6.66 (d, J = 15.9 Hz, 1 H), 6.23 (dd, J = 15.9, 6.3 Hz, 1 H), 5.93 (ddt, J = 17.1, 10.3, 7.0 Hz, 1 H), 5.21–5.04 (m, 2 H), 4.82 (s, 2 H), 3.97 (ddd, J = 9.9, 6.3, 1.4 Hz, 1 H), 3.52 (dtd, J = 11.1, 6.4, 2.1 Hz, 1 H), 2.53–2.42 (m, 1 H), 2.36–2.25 (m, 1 H), 2.12 (ddd, J = 12.1, 10.2, 3.7 Hz, 1 H), 1.94–1.83 (m, 1 H), 1.83–1.76 (m, 1 H), 1.74 (s, 3 H), 1.69 (td, J = 13.0, 4.1 Hz, 1 H), 1.41 (tdd, J = 12.9, 11.1, 4.0 Hz, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 146.26, 137.20, 134.95, 130.90, 129.04, 128.38, 127.32, 126.53, 116.69, 112.18, 109.73, 80.77, 77.13, 49.92, 40.81, 30.98, 29.91, 20.89.

MS (EI): m/z = 105, 131, 284 [M⁺].

MS (CI): m/z = 123, 197, 269 [M + H].

(2S*,3S*,6S*)-6-Benzyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-2H-pyran (58)

Following the typical procedure using 6-methyl-1-phenylhept-6-en-2-ol (57; 100 mg, 0.49 mmol, 1.25 equiv) and trans-cinnamalde-hyde (30; 49 μL, 0.39 mmol, 1 equiv) with L3 gave 58 (42 mg, 34%).

¹H NMR (500 MHz, CDCl₃): δ = 7.44 (d, J = 7.5 Hz, 2 H), 7.40–7.23 (m, 6 H), 6.71 (d, J = 15.9 Hz, 1 H), 6.28 (dd, J = 16.0, 6.0 Hz, 1 H), 4.84 (s, 2 H), 4.01 (dd, J = 9.8, 6.0 Hz, 1 H), 3.71 (dt, J = 10.5, 5.5 Hz, 1 H), 3.13 (dd, J = 13.4, 5.9 Hz, 1 H), 2.79 (dd, J = 13.4, 7.1 Hz, 1 H), 2.16 (ddd, J = 12.1, 10.3, 3.8 Hz, 1 H), 1.92–1.77 (m, 1 H), 1.75 (s, 3 H), 1.68–1.40 (m, 4 H), 1.16 (qd, J = 12.8, 5.0 Hz, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 146.24, 138.72, 137.27, 130.84, 129.57 (2 C), 129.03, 128.44 (2 C), 128.22 (2 C), 127.36, 126.54 (2C), 126.16, 112.25, 80.65, 78.55, 71.54, 49.93, 42.96, 30.85, 20.91.

MS (EI): m/z = 91, 117, 131, 188, 303, 318 [M⁺].

MS (CI): m/z = 107, 117, 301, 319 [M + H].

(2S*,3S*,6S*)-6-Phenyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-2H-pyran (60)

Following the typical procedure using 5-methyl-1-phenylhex-5-en-1-ol (59; 138 mg, 0.735 mmol, 1.25 equiv) and trans-cinnamalde-hyde (30; 74 μL, 0.588 mmol, 1 equiv) with L3 gave 60 (85 mg, 48%).

¹H NMR (400 MHz, CDCl₃): δ = 7.52–7.20 (m, 10 H), 6.74–6.71 (dd, J = 15.9 Hz, 1 H), 6.34–6.28 (dd, J = 15.9, 6.2 Hz, 1 H), 4.88 (s, 2 H), 4.57–4.54 (dd, J = 11.4, 2.1 Hz, 1 H), 4.17 (dd, J = 9.6, 6.4 Hz, 1 H), 2.29–2.20 (ddd, J = 13.6, 10.0, 3.7 Hz, 1 H), 2.00 (m, 2H), 1.95–1.84 (m, 1 H), 1.80 (s, 3 H), 1.78–1.66 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 146.11, 142.97, 137.17, 130.87, 128.93, 128.36, 128.24, 127.29, 126.49, 125.97, 125.88, 112.33, 81.10, 79.57, 49.76, 33.86, 30.37, 20.94.

MS (EI): m/z = 104, 133, 286, 304 [M⁺].

MS (CI): m/z = 133, 173, 227, 287, 305 [M + H].

(2R*,3S*,6R*)-3-Isopropenyl-2-(4-methoxyphenyl)-6-methyltetrahydro-2H-pyran (61)

Following the typical procedure using 6-methylhept-6-en-2-ol (16; 54 mg, 0.49 mmol, 1.25 equiv) and p-anisaldehyde (10; 41 μL, 0.34 mmol, 1 equiv) with L3 gave 61 (47 mg, 56%).

¹H NMR (500 MHz, CDCl₃): δ = 7.27 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 2 H), 4.65 (d, J = 13.3 Hz, 2 H), 4.23 (d, J = 10.0 Hz, 1 H), 3.81 (s, 3 H), 3.67 (dtt, J = 12.3, 6.1, 3.1 Hz, 1 H), 2.29 (ddd, J = 11.9, 9.9, 3.8 Hz, 1 H), 1.97–1.88 (m, 1 H), 1.84–1.71 (m, 2 H), 1.52–1.43 (m, 1 H), 1.48 (s, 3 H), 1.27 (d, J = 6.2 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 158.94, 146.57, 133.78, 128.56, 113.44, 111.82, 83.67, 74.31, 55.17, 50.13, 33.65, 30.50, 22.18, 21.44.

MS (EI): m/z = 136, 246 [M⁺].

MS (CI): m/z = 139, 247 [M + H].

(2R*,3S*,6S*)-3-Isopropenyl-6-isopropyl-2-(4-methoxyphenyl)tetrahydro-2H-pyran (62)

Following the typical procedure using 2,7-dimethyloct-7-en-3-ol (51; 65 mg, 0.419 mmol, 1.25 equiv) and p-anisaldehyde (10; 41 μL, 0.335 mmol, 1 equiv) with L3 gave 62 (54 mg, 59%).

¹H NMR (400 MHz, CDCl₃): δ = 7.25–7.23 (d, J = 2.0 Hz, 2 H), 6.84–6.82 (d, J = 2.0 Hz, 2 H), 4.64–4.60 (d, J = 17.3 Hz, 2 H), 4.19–4.16 (d, J = 9.9 Hz, 1 H), 3.79 (s, 3 H), 3.25–3.12 (dd, J = 11.3, 5.8 Hz, 1 H), 2.22–2.16 (t, J = 10.7 Hz, 1 H), 1.95–1.89 (m, 1 H), 1.77–1.70 (m, 4 H), 1.45 (s, 3 H), 0.94 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 158.67, 146.69, 134.23, 128.33, 113.15, 111.61, 83.39, 82.82, 55.05, 50.72, 32.83, 30.43, 27.37, 21.47, 18.69, 17.96.

MS (EI): m/z = 137, 274 [M⁺].

MS (CI): m/z = 137, 167, 275 [M + H].

(2R*,3S*,6S*)-6-Allyl-2-(4-methoxyphenyl)-3-(prop-1-en-2-yl)tetrahydro-2H-pyran (63)

Following the typical procedure using 8-methylnona-1,8-dien-4-ol (55; 100 mg, 0.65 mmol, 1.25 equiv) and p-anisaldehyde (10; 63 μL, 0.52 mmol, 1 equiv) with L3 gave 63 (65 mg, 46%).

¹H NMR (400 MHz, CDCl₃): δ = 7.26–7.24 (d, J = 8.6 Hz, 2 H), 6.86–6.84 (d, J = 8.6 Hz, 2 H), 5.97–5.85 (m, 1 H), 5.15–4.99 (m, 2 H), 4.65–4.61 (d, J = 14.2 Hz, 2 H), 4.22–4.19 (d, J = 10.4, 3.4 Hz, 1 H), 3.79 (s, 3 H), 3.57–3.52 (m, 1 H), 2.43–2.38 (m, 1 H), 2.31–2.23 (m, 2 H), 1.92–1.89 (m, 1 H), 1.82–1.70 (m, 2 H), 1.46 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 158.83, 146.45, 134.93, 133.71, 128.43, 116.53, 113.28, 111.80, 83.58, 77.57, 55.07, 50.32, 40.76, 30.93, 30.27, 21.42.

(2R*,3S*,6S*)-6-Benzyl-2-(4-methoxyphenyl)-3-(prop-1-en-2-yl)tetrahydro-2H-pyran (64)

Following the typical procedure using 6-methyl-1-phenylhept-6-en-2-ol (57; 100 mg, 0.49 mmol, 1.25 equiv) and p-anisaldehyde (10; 47 μL, 0.39 mmol, 1 equiv) with L3 gave 64 (76 mg, 61%).

¹H NMR (500 MHz, CDCl₃): δ = 7.41–7.18 (m, 7 H), 6.88 (d, J = 8.6 Hz, 2 H), 4.65 (d, J = 21.2 Hz, 2 H), 4.26 (d, J = 10.0 Hz, 1 H), 3.83 (s, 3 H), 3.74 (m, 1 H), 3.07 (dd, J = 13.5, 5.1 Hz, 1 H), 2.76 (dd, J = 13.4, 7.7 Hz, 1 H), 2.34–2.20 (m, 1 H), 1.90 (m, 2 H), 1.83–1.50 (m, 3 H), 1.47 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 158.91, 146.48, 138.67, 133.81, 129.60 (2 C), 128.48 (2 C), 128.13 (2 C), 126.05, 113.35 (2 C), 111.85, 83.70, 78.99, 55.14, 50.41, 42.93, 30.74, 30.27, 21.47.

MS (EI): m/z = 91, 117, 136, 188, 231, 322 [M⁺].

MS (CI): m/z = 121, 137, 215, 305, 323 [M + H].

(2R*,3S*,6R*)-2-(Benzyloxymethyl)-3-isopropenyl-6-methyltetrahydro-2H-pyran (65) and 8-(Benzyloxymethyl)-2,6-dimethyl-3,4,7,8-tetrahydro-2H-oxocin (66)

Following the typical procedure using 6-methylhept-6-en-2-ol (16; 105 mg, 0.82 mmol, 1.25 equiv) and benzyloxyacetaldehyde (47; 92 μL, 0.66 mmol, 1 equiv) with L1 gave 65 (94 mg, 55%) and less-polar oxocin 66 (19 mg, 11%).

Tetrahydropyran 65

¹H NMR (500 MHz, CDCl₃): δ = 7.42–7.28 (m, 5 H), 4.79–4.73 (m, 2 H), 4.60 (dd, J = 15.35, 12.35 Hz, 2 H), 3.63–3.56 (m, 2 H), 3.53 (ddd, J = 11.1, 6.2, 2.0 Hz, 1 H), 3.47 (dd, J = 11.1, 6.9 Hz, 1 H),2.11 (ddd, J = 11.9, 10.0, 3.9 Hz, 1 H), 1.81–1.77 (m, 1 H), 1.69 (s, 3 H), 1.68–1.57 (m, 2 H), 1.42–1.31 (m, 1 H), 1.27 (d, J = 6.2 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 146.61, 138.60, 128.21 (2 C), 127.68 (2 C), 127.36, 111.92, 79.56, 73.73, 73.34, 71.86, 45.66, 33.27, 30.12, 22.05, 20.13.

MS (EI): m/z = 91, 107, 139, 260 [M⁺].

MS (CI): m/z = 91, 111, 261 [M + H].

Oxocin 66

¹H NMR (500 MHz, CDCl₃): δ = 7.42–7.29 (m, 5 H), 5.49–5.42 (m, 1 H), 4.62 (q, J = 12.0 Hz, 2 H), 3.62–3.50 (m, 3 H), 3.49–3.40 (m, 1 H), 2.53–2.41 (m, 2 H), 2.00 (dd, J = 13.9, 1.4 Hz, 1 H), 1.98–1.91 (m, 1 H), 1.81 (s, 3 H), 1.70–1.59 (m, 1 H), 1.53 (dddd, J = 13.7,12.5, 4.8, 3.5 Hz, 1 H), 1.17 (d, J = 6.3 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 138.55, 135.30, 128.30 (2 C), 127.59 (2 C), 127.47, 124.99, 79.18, 75.52, 74.03, 73.28, 38.11, 36.99, 25.37, 24.27, 22.21.

MS (EI): m/z = 91, 107, 139, 260 [M⁺].

MS (CI): m/z = 91, 111, 153, 261 [M + H].

(2R*,3S*,5S*)-2-(4-Methoxyphenyl)-5-methyl-3-(prop-1-en-2-yl)tetrahydro-2H-pyran (69)

Following the typical procedure using 2,5-dimethylhex-5-en-1-ol (20; 100 mg, 0.78 mmol, 1.25 equiv) and p-anisaldehyde (10; 76 μL, 0.62 mmol, 1 equiv) with L3 gave 69 (76 mg, 49%).

¹H NMR (400 MHz, CDCl₃): δ = 7.23 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 4.62 (d, J = 10.2 Hz, 2 H), 4.07 (d, J = 10.0 Hz, 1 H), 3.99 (ddd, J = 11.1, 4.3, 2.4 Hz, 1 H), 3.78 (s, 3 H), 3.16 (t, J = 11.0 Hz, 1 H), 2.63–2.55 (m, ~0.14 H, methyl diastereomer), 2.38 (ddd, J = 12.0, 10.0, 3.3 Hz, 1 H), 1.91 (m, 2 H), 1.45 (s, 3 H), 1.35 (q, J = 12.2 Hz, 1 H), 1.26 (d, J = 7.0 Hz, ~0.42 H methyl diastereomer), 0.87 (d, J = 6.4 Hz, 3 H); dr ~7:1.

¹³C NMR (101 MHz, CDCl₃): δ = 158.93, 146.20, 133.18, 128.39 (2 C), 113.35 (2 C), 111.82, 83.44, 74.99, 55.07, 53.33, 50.30, 39.12, 31.18, 21.28, 17.00.

MS (EI): m/z = 68, 95, 112, 121, 135, 161, 246 [M⁺].

MS (CI): m/z = 121, 139, 247 [M + H].

(2S*,3S*,5S*)-5-Methyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-2H-pyran (70)

Following the typical procedure using 2,5-dimethylhex-5-en-1-ol (20; 100 mg, 0.78 mmol, 1.25 equiv) and trans-cinnamaldehyde (30; 79 μL, 0.62 mmol, 1 equiv) with L3 gave 70 (65 mg, 43%).

¹H NMR (400 MHz, CDCl₃): δ = 7.37 (d, J = 7.2 Hz, 2 H), 7.29 (t, J = 7.4 Hz, 2 H), 7.21 (t, J = 7.2 Hz, 1 H), 6.62 (d, J = 16.1 Hz, 1 H), 6.18 (dd, J = 16.0, 6.3 Hz, 1 H), 4.79 (d, J = 1.5 Hz, 2 H), 3.98 (ddd, J = 11.2, 4.2, 2.3 Hz, 1 H), 3.82 (ddd, J = 10.3, 6.4, 1.3 Hz, 1 H), 3.11 (t, J = 11.1 Hz, 1 H), 2.17 (ddd, J = 12.3, 10.0, 3.3 Hz, 1 H), 1.90–1.74 (m, 2 H), 1.71 (s, 3 H), 1.29 (q, J = 12.1 Hz, 1 H), 0.86 (d, J = 6.4 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 145.98, 137.04, 131.06, 128.72, 128.33 (2 C), 127.30, 126.40 (2 C), 112.10, 80.35, 74.33, 50.14, 38.65, 30.98, 20.76, 16.98.

MS (EI): m/z = 68, 95, 112, 131, 227, 242 [M⁺].

MS (CI): m/z = 139, 243 [M + H].

(2R*,3S*,5S*)-5-Methyl-2-(4-nitrophenyl)-3-(prop-1-en-2-yl)tetrahydro-2H-pyran (71)

Following the typical procedure using 2,5-dimethylhex-5-en-1-ol (20; 100 mg, 0.78 mmol, 1.25 equiv) and 4-nitrobenzaldehyde (6; 94 mg, 0.62 mmol, 1 equiv) with L3 gave 71 (48 mg, 29%). Colorless solid; mp 58–60 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.15 (d, J = 8.6 Hz, 2 H), 7.46 (d, J = 8.6 Hz, 2 H), 4.65 (s, 1 H), 4.55 (s, 1 H), 4.21 (d, J = 10.0 Hz, 1 H), 4.02 (ddd, J = 11.3, 4.3, 2.4 Hz, 1 H), 3.17 (t, J = 11.0 Hz, 1 H), 2.26 (ddd, J = 12.1, 10.1, 3.2 Hz, 1 H), 1.97–1.88 (m, 2 H), 1.45 (s, 3 H), 1.43–1.30 (m, 1 H), 1.26 (d, J = 6.9 Hz, ~0.5 H, methyl diastereomer), 0.89 (d, J = 6.4 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 148.44, 147.23, 144.81, 127.95 (2 C), 123.12 (2 C), 112.89, 82.70, 74.74, 51.19, 38.63, 30.98, 21.34, 16.89.

MS (EI): m/z = 68, 95, 112, 246, 262 [M⁺].

MS (CI): m/z = 112, 262 [M + H].

(2R*,3S*,4S*)-2-(4-Methoxyphenyl)-4-methyl-3-(prop-1-en-2-yl)tetrahydro-2H-pyran (72)

Following the typical procedure using 3,5-dimethylhex-5-en-1-ol (24; 118 mg, 0.918 mmol, 1.25 equiv) and p-anisaldehyde (10; 89 μL, 0.734 mmol, 1 equiv) with L3 gave 72 (22 mg, 12%).

¹H NMR (400 MHz, CDCl₃): δ = 7.23–7.18 (d, J = 8 Hz, 2 H), 6.83–6.79 (d, J = 8 Hz, 2 H), 4.66 (s, 1 H), 4.56 (s, 1 H), 4.14–4.04 (m, 2 H), 3.78 (s, 3 H), 3.66–3.57 (td, J = 12.1, 2.3 Hz, 1 H), 1.92–1.89 (t, J = 10.3 Hz, 1 H), 1.79 (m, 1 H), 1.73–1.59 (m, 2 H), 1.56–1.46 (m, 1 H), 1.43 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 158.83, 144.00, 133.46, 128.33, 113.90, 113.26, 83.42, 77.14, 68.37, 58.10, 55.07, 34.46, 33.89, 19.81.

MS (EI): m/z = 85, 112, 135, 161, 246 [M⁺].

MS (CI): m/z = 121, 139, 247 [M + H].

(2S*,3S*,4S*)-4-Methyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-2H-pyran (73)

Following the typical procedure using 3,5-dimethylhex-5-en-1-ol (24; 122 mg, 0.950 mmol, 1.25 equiv) and trans-cinnamaldehyde (30; 95 μL, 0.757 mmol, 1 equiv) with L3 gave 62 (24 mg, 13%).

¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.19 (m, 5 H), 6.62–6.52 (dd, J = 15.9 Hz, 1 H), 6.20–6.13 (dd, J = 16.0, 6.3 Hz, 1 H), 4.84–4.78 (d, J = 24.0 Hz, 2 H), 4.10–4.06 (dd, J = 11.4, 4.4 Hz, 1 H), 3.86–3.81 (m, 1 H), 3.64–3.55 (m, 1 H), 1.76–1.69 (m, 2 H), 1.69–1.59 (m, 5 H), 1.41 (m, 1 H), 0.89 (d, J = 5.0 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 143.76, 137.11, 130.73, 128.98, 128.33, 127.26, 126.40, 126.17, 80.25, 77.14, 67.87, 57.72, 34.29, 33.10, 19.66.

MS (EI): m/z = 67, 82, 112, 131, 227, 242 [M⁺].

MS (CI): m/z = 139, 225, 243 [M + H].

Biographies

Arun K. Ghosh

was born and raised in Calcutta, India. He received his B.S. in chemistry (1979) and M.S. in chemistry (1981) from the University of Calcutta and Indian Institute of Technology, Kanpur respectively. He received his Ph.D. in organic chemistry in 1985 at the University of Pittsburgh. He then pursued postdoctoral research with Professor E.J. Corey at Harvard University (1985–1988). He was a research fellow at Merck Research Laboratories and in 1994, he joined University of Illinois, Chicago as Assistant Professor, eventually becoming Professor of chemistry in 1998. In 2005, he moved to Purdue University, with a joint appointment in the Department of Chemistry and the Department of Medicinal Chemistry and Molecular Pharmacology. He became the Ian P. Rothwell Distinguished Professor in 2009. His research interests include diverse areas of organic, bioorganic, and medicinal chemistry with particular emphasis on organic synthesis and protein-structure-based drug design.

Jorden Kass

was born in Toledo, Ohio (USA) in 1984. He received his B.S. in chemistry in 2006 from Eastern Kentucky University. He taught at Lehman College (spring 2007). In fall 2007, he began his graduate studies at Purdue University. Subsequently, he joined Professor Ghosh’s research group for his thesis work. He was awarded the Fredrick N. Andrews Fellowship from 2007–2009 followed by a Purdue Research Foundation Fellowship at Purdue University (2009–2011). His thesis work has focused on the development of asymmetric multicomponent reactions and total synthesis. He plans to defend his thesis work in fall 2012.

Daniel R. Nicponski

was born in 1984 in Medina, New York (USA). He received his B.S. in chemistry in 2006 from the University at Buffalo in Buffalo, New York. He is presently studying for his Ph.D. degree in organic chemistry at Purdue University. His research work has focused on the development of novel, asymmetric carbon–carbon bond forming reactions, and on the synthesis of reaction-tailored, phosphine-based ligands.

Chad Keyes

was born in West Lafayette, Indiana (USA). He received his BS in chemistry from Ball State University. Chad was an intern during the summer of 2008 at Dow Agrosciences. Upon completion of his B.S., he moved to Purdue University in the spring of 2010 to further pursue his graduate studies in organic chemistry with Professor Arun Ghosh. He was awarded the Ross Fellowship in 2008 at Purdue University. Currently, his thesis work is focused on asymmetric catalysis and synthesis of natural products.