Unified Total Syntheses of Fawcettimine Class Alkaloids: Fawcettimine, Fawcettidine, Lycoflexine, and Lycoposerramine B

Abstract

The total syntheses of the lycopodium alkaloids: fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B have been accomplished through an efficient, unified, and stereocontrolled strategy, which relies on a Diels-Alder reaction to construct the cis-fused 6,5-carbocycles with one all-carbon quaternary center. Access to the enantioselective syntheses of both antipodes of those alkaloids can be achieved by kinetic resolution of the earliest intermediate via a Sharpless asymmetric dihydroxylation (Sharpless AD). Compared to existing approaches to these alkaloids, our synthetic route possesses superior stereocontrol over the C-4 and C-15 stereogenic centers as well as allowing for more functional variation on the 6-membered ring.

INTRODUCTION

The Lycopodium alkaloids continue to attract attention within the chemical community due to their fascinating structures, biogenesis, and range of interesting biological activities, especially the demonstrated capacity of these substances to inhibit acetylcholinesterase.^1,2 The fawcettimine subclass, with more than eighty members isolated thus far, features a cis-fused 6,5-carbocyclic ring core connected to an azonine ring containing an all-carbon quaternary center (Figure 1). The first member of this class, fawcettimine (1), was isolated in 1959 by Burnell from Lycopodium fawcetti, collected in the Blue Mountain Range of Jamaica.^3a This alkaloid has inspired significant interest from the synthetic community, resulting in five total syntheses (two racemic,^4,5 three enantioselective^6,7) and two formal⁸ syntheses. From the same plant, these workers also isolated fawcettidine (2).^3b Plausibly, 2 is biosynthesized from 1 by dehydration.⁹ The biogenetic dehydration of fawcettimine (1) to fawcettidine (2) seems to have been overlooked by the laboratories who have studied the total synthesis¹⁰ of these alkaloids as interrogation of this transformation has not been heretofore reported. Lycoflexine (3) was isolated in 1973 by Ayer and coworkers from Lycopodium clavatum var. inflexum.^3c This alkaloid contains two adjacent all-carbon quaternary centers. A biomimetic conversion of 1 to 3 via a Mannich reaction was also reported by Ayer, which serves as the key step in two recently reported total syntheses of (+)-3.^6b,11

Figure 1.

Structures of representative fawcettimine class alkaloids.

Lycoposerramine B (4), the first lycopodium alkaloid known to contain an oxime functionality, was isolated in 2005 by Takayama and coworkers from Lycopodium serratum.^12a The biosynthesis of 4 from 1 was proposed, which requires the inversion of the C-4 stereogenic center. However, this inversion was found to be difficult,^12a which is consistent with the observation made by Heathcock’s group in their landmark fawcettimine synthesis, that the S-configuration at C-4 was thermodynamically more stable than its epimer.⁵ A 10:1 mixture in favor of the S-epimer was also observed by Toste’s group in their (+)-fawcettimine synthesis.^6a The difficulty in controlling the formation of the uncommon R-configuration at C-4 may in part, account for the single reported total synthesis of (+)-4.⁷

Lobscurinol (5) and epilobscurinol (6) were isolated in 1989 by Ayer and Kasitu from Lycopodium obscurum.^3d They are two isomeric alkaloids and both contain an enone moiety. Lycopoclavamine A (7) was isolated in 2011 by Takayama and coworkers from Lycopodium clavatum. This alkaloid contains a β-oriented methyl group at C-15, which differs from other fawcettimine class members.^12b To date, no total synthesis nor synthetic approach to alkaloids 5–7 has been reported.

Inspired by the fascinating and challenging structural diversities demonstrated by the fawcettimine class alkaloids, we embarked on their total syntheses, with the aim that a general strategy could be developed to address many of the family members. Herein we report our syntheses of 1–4 via an efficient, unified, and stereocontrolled strategy.

RESULTS AND DISCUSSION

Retrosynthetic Analysis

From a strategic vantage, the critical challenge in contemplating the synthesis of this class alkaloids and many other members, is the formation of the cis-fused 6,5-carbocyclic core with one all-carbon quaternary center. To date, the most frequently employed strategy has relied upon exploiting the existing methyl group of 5-methylcyclohex-2-enones to control the trans-addition of reagents (diene for Inubushi’s synthesis⁴ and nucleophiles for others^5,6,8,10a,11) in setting the C-7 stereogenic center (Scheme 1, A).¹³ Starting with enantiomerically pure 5-methylcyclohex-2-enones, enantiospecific syntheses have been realized.^6,8,10a,11 Apparently, this strategy will not be suitable for the synthesis of (−)-lycopoclavamine A (7), which contains an unusual β-oriented methyl group at C-15. Very recently, the Mukai group reported an alternative strategy, which utilized a Pauson-Khand reaction to set the C-7 stereogenic center (Scheme 1, B). These workers also utilized the additional stereocontrol garnered at C-4 to construct lycoposerramine B, although their synthesis is quite lengthy, requiring more than twenty-six steps from commercially available materials.⁷

Scheme 1.

A. Strategies employed by Inubushi, Heathcock, Toste, Liu & Chau, Jung, Yang, Dake, and Ramharter; B. Strategy employed by Mukai.

Given the fact that most of the fawcettimine class alkaloids are structurally related, a unified synthetic strategy¹⁴ with inherent flexibility to access several members of this family constitutes the current state-of-art in natural products synthesis. In light of the common variations encountered on the 6-membered carbocycles (hexanone or hexenone, etc.), we envisioned that a highly stereoselective Diels-Alder reaction could be utilized to construct this ring. Scheme 2 summarizes our synthetic plan. Fawcettimine (1), fawcettidine (2), and lycoflexine (3) can be derived from the same intermediate diketo amine 8,¹⁵ which in turn can be obtained from nosylate 9 with the inversion of the C-4 stereogenic center. With the azonine cis-fused to the 5-membered ring, 9 was also envisioned to serve as the synthetic progenitor for lycoposerramine B (4). By disconnecting the azonine ring of 9 and reconnecting to form a 5-membered ring, 9 was envisioned to be derived from 10, in which the ladder-like cis-fused 6,5,6 rings suggest a Diels-Alder reaction (D-A) between enone 11 and diene 12¹⁶. Enone 11 can be obtained from ketal 13, which is a known compound.¹⁷ It is worthy of note that by employing the enantiomerically pure form of 13, the enantiospecific syntheses of 1–4 can also be achieved (vide infra).

Scheme 2.

Our synthetic plan for 1–4.

Synthesis of 9

Our racemic syntheses of 1–4 commenced with the known ketal 13, which could be synthesized in one step from commercially available isoprene (14) and cyclopentenone ethylene ketal (15) via an ionic Diels-Alder reaction (D-A) (Scheme 3).¹⁷ Oxidative cleavage of the alkene moiety on 13 was effected under Yang’s conditions¹⁸ and afforded keto-aldehyde 16 in 75% yield. In comparison, the Lemieux-Johnson reagent (OsO₄ and NaIO₄)¹⁹ or ozonolysis gave very low yield of the desired product. From 16, the selective intra-molecular aldol condensation/dehydration²⁰ process was achieved by treatment of 16 with KOH in refluxing H₂O for 15 h. Enone 11 was thus obtained in 79% yield, which set the stage for the key Diels-Alder reaction.

Scheme 3.

Synthesis of enone 11.a

^aReagents and conditions: (a) 1.0 mol% RuCl₃·H₂O, NaIO₄, ClCH₂CH₂Cl /H₂O (v/v 5:4), rt, 3h, 75%; (b) KOH, H₂O, reflux, 15h, 79%.

However, it is well-documented that enones like 11, which lack a second activating group, are poor dienophiles for intermolecular Diels-Alder reactions.²¹ In particular, this potential hurdle was exacerbated in our case by the fact that: 1) enone 11 can be sensitive to Lewis or Brønsted acid-catalyzed conditions because of the labile ketal moiety and, 2) enone 11 is deactivated by β-alkyl substitution, both electronically and sterically.

Despite the fact that there was no literature precedent for a D-A reaction between a β-alkyl substituted enone and a 1-siloxy substituted diene, the reaction of enone 11 with diene 17 was chosen as a model to investigate the planned Diels-Alder reaction (Table 1). As anticipated, Lewis acids such as ZnCl₂ or EtAlCl₂ failed to yield any desired product. Both 11 and 17 were found to be unstable at these conditions (entry 1,2). We then focused our attention on thermal conditions. Although no reaction took place in toluene at 110 °C, a 15% (75% brsm) yield of D-A adduct 21 was isolated by heating diene 17 and enone 11 in xylene at 170 °C for 4 days (entry 3, 4). The yield could be improved to 30% (67% brsm) by heating 11 and 17 in the absence of solvent at 190 °C for 3 days (entry 5). To our delight, the reaction time could be dramatically shortened and the yield could be further improved by performing the reaction in a microwave reactor (entry 7).²² However, higher temperature or longer reaction time resulted in lower yield of 21, presumably due to the decomposition of starting materials or D-A adduct (entry 6, 8).

Table 1.

Diels-Alder reaction between enone 11 and dienes.

entry	diene (equiv.)	solvent	T (°C)	time	prodt.	yield (%)a,b
1c	17 (6.0)	CH2Cl2	0	3h	21	0
2d	17 (2.0)	CH2Cl2	–78	1h	21	0
3	17 (2.4)	PhMe	110	10h	21	n.r.
4e	17 (10.0)	xylene	170	4d	21	15(75)
5e	17 (10.0)	–	190	3d	21	30(67)
6e	17 (10.0)	–	240	10h	21	9
7e,f	17 (10.0)	–	190	9h	21	48(69)
8e,f	17 (10.0)	–	200	16h	21	37(55)
9e,f	12 (10.0)	–	195	6h	10	35(76)
10e,f	12 (6.0)	–	185	9h	10	56(65)
11e,f,g	12 (2.5)	–	180	9h	10	74(92)
12e,f,g	12 (2.0)	–	180	10h	10	58(89)
13e,f	18 (6.0)	–	190	4h	22	0
14e,f	19 (6.0)	–	190	4h	23	0
15e,f,h	20 (6.0)	–	190	4h	24	22

^aYield of isolated product.

^bYield in parenthesis is based on recovered 11.

^c25 mol% ZnCl₂ was added.

^d2.5 equiv. EtAlCl₂ was added.

^eReaction was performed in a sealed tube.

^fReaction was performed in a microwave reactor.

^gReaction was performed with >1.0 g of 11.

^hExcess K₂CO₃ in MeOH was added to quench the reaction.

Under these microwave-assisted conditions, diene 12 and enone 11 gave the desired adduct 10, which held its key position in our synthetic route (entry 9–12). Further optimization showed that on gram-scale, the amount of 12 could be reduced to 2.5 equivalents, which provided adduct 10 in 74% yield (92% brsm, dr=1.0 (endo):0.4 (exo)) (entry 11).

Compared to 1-siloxy butadiene 17 and 12, 1-acetoxy butadiene 18 gave no desired adduct 22 (entry 13). The polymerization of 18 was found to be a significant problem. 1,1-Disubstitured butadienes, such as 19²³ and 20²³ were also tested under these microwave-assisted D-A conditions. Although no adduct 23 was formed when diene 20 was employed, it was interesting to find that diene 20 did furnish the desired enone 24 (with basic workup after D-A), albeit the yield was low (22%). To the best of our knowledge, this represents the first example of a Diels-Alder reaction between a 1,1-disiloxy butadiene and a β-alkyl-substituted enone.

The Diels-Alder adduct 10, containing all but one carbon atom of the fawcettimine, fawcettidine, and lycoposerramine B skeletons, was converted to enone 24 in 95% yield by successive treatment of 10 with TBAF and Dess-Martin periodinane²⁴ (Scheme 4). This one-pot enone formation together with the preceding highly selective Diels-Alder reaction should be very useful for the syntheses of lobscurinol (5), epilobscurinol (6) (Figure 1, vide supra), and other enone-containing alkaloids such as magellanine^25a and magellaninone^25b.

Scheme 4.

Synthesis of diol 31.a

^aReagents and conditions: (a) TBAF, CH₂Cl₂, rt, 12h; then NaHCO₃, Dess-Martin periodinane, rt, 6h, 95% for one-pot; (b) LiHMDS, NCCO₂Me, Et₂O, −78 °C to rt, overnight, 60% (94% brsm); (c) NaBH₄, MeOH/CH₂Cl₂ (v/v 1:1), −42 °C, 5h; then acetone, 1M HCl, 5h, 80% for one-pot; (d) m-CPBA, NaHCO₃, CH₂Cl₂, rt, 24h, 92%; (e) MsCl, pyridine, rt, overnight, 97%; (f) 5 mol% Pd/C, 5 mol% Rh/Al₂O₃, H₂, 80 psi, 24h; then DBU, H₂, 80 psi, 12h, 93% for one-pot; (g) LiAlH₄, THF, reflux, overnight; (h) Ac₂O, cat. DMAP, pyridine, rt, 24h; (i) 5 mol% [t-Bu₂Sn(OH)Cl]₂, MeOH/THF (v/v 1:1), rt, 30h, 85% for 3 steps (≥95% brsm).

From enone 24, homologation²⁶ and selective reduction of the newly formed β-keto ester 25 under Ward’s conditions²⁷ gave, after acid work up, the β-hydroxy ester 26. Although 26 is a keto enone, the Baeyer-Villiger oxidation²⁸ was found to be highly selective and only the desired lactone 27 was isolated in 92% yield.

Installation of the correct relative stereochemistry at C-15 (fawcettimine numbering) was tackled next. We envisioned that by increasing the steric hindrance of the convex face of the cis-fused 6,5-carbocycles, hydrogenation could only take place from the more accessible concave face and set the required stereogenic center at C-15 for the syntheses of 1–4. To this end, the hydroxyl group of 27 was mesylated to increase its steric bulk and facilitate its later removal. Pleasingly, the sequence of hydrogenation of the enone group on 28, elimination of the mesylate and hydrogenation of the incipient α, β-unsaturated ester could be conducted in one-pot to afford the desired lactone 29 as a single diastereomer in 93% yield.²⁹ The correct stereochemistry at C-15 was confirmed by NOESY data.

It is worth noting that direct hydrogenation of β-keto ester 25 afforded the corresponding reduction product with a dr 1:1 at C-15. Apparently, devoid of the steric hindrance exerted by the mesylate on 28, the facial selectivity of the enone reduction was significantly eroded. However, this non-selective reduction has an inherent advantage over existing fawcettimine class alkaloids syntheses in that the unusual β-oriented methyl group at C-15 can now be accessed, and is potentially applicable to the synthesis of (−)-lycopoclavamine A (7) (Figure 1, vide supra). Efforts to control the facial selectivity of this reduction to give diastereomer are worthy of further pursuit.

Lactone 29 obtained above was fully reduced to the corresponding tetraol and then peracylated to give tetraacetate 30. Selective removal of the two primary acetyl groups on 30 was accomplished by using Otera’s catalyst³⁰, with diol 31 isolated in 85% yield over this three-step sequence. The by-products of this highly selective deacetylation could be readily recovered and recycled, which increased the yield of deacetylation product to ≥95% (brsm).

With diol 31 in hand, the hurdle remaining for the synthesis of fawcettimine (1) was the formation of the 9-membered azonine ring.³¹ Guided by the elegant synthesis of (−)-strychnine by the Fukuyama group³² as well as our own experience with the synthesis of FR900482,³³ we decided to employ a double (inter- then intra-molecular) Fukuyama-Mitsunobu reaction to construct the medium-ring N-heterocycle. To this end, diol 31 was subjected to extensive screening of reaction parameters (Table 2). The effect of solvent was first examined and it was found that the reaction performed best in a dipolar aprotic solvent, such as DMSO or acetonitrile (entry 1–6). Compared to 40% DEAD solution, pure DEAD or DIAD gave lower yields of 32 (entry 7–9). No reaction took place when other phosphines were used instead of the Ph₃P (entry 10–13). Finally, the relative ratio of each reagent to diol 31 was adjusted and it was found that the combination of 4 equiv. NsNH₂, 6 equiv. Ph₃P and 6 equiv. 40% DEAD was optimal (entry 6, 14–18).

Table 2.

Double Fukuyama-Mitsunobu reaction to form azonine 32.

Entry	Reagent (equiv.)	Solvent	Yield (%)a
1	NsNH2 (4), Ph3P (6), 40% DEAD (6)	THF	24
2	NsNH2 (4), Ph3P (6), 40% DEAD (6)	CH2Cl2	20
3	NsNH2 (4), Ph3P (6), 40% DEAD (6)	CH3CN	36
4	NsNH2 (4), Ph3P (6), 40% DEAD (6)	DMF	33
5b	NsNH2 (4), Ph3P (6), 40% DEAD (6)	py.	25
6	NsNH2 (4), Ph3P (6), 40% DEAD (6)	DMSO	38
7	NsNH2 (4), Ph3P (6), DEAD (6)	DMSO	16
8	NsNH2 (4), Ph3P (6), DIAD (6)	DMSO	28
9	NsNH2 (4), Ph3P (6), DIAD (6)	CH3CN	19
10	NsNH2 (4), (n-Bu)3P (6), 40% DEAD (6)	DMSO	n.r.
11	NsNH2 (4), (Me2N)3P (6), 40% DEAD (6)	DMSO	n.r.
12c	NsNH2 (4), Diphos (6), 40% DEAD (6)	DMSO	n.r.
13d	NsNH2 (4), (n-Bu)3P (6), ADDP (6)	DMSO	n.r.
14	NsNH2 (4), Ph3P (10), 40% DEAD (10)	DMSO	26
15	NsNH2 (6), Ph3P (6), 40% DEAD (6)	DMSO	23
16	NsNH2 (4), Ph3P (5), 40% DEAD (5)	DMSO	26
17	NsNH2 (3), Ph3P (6), 40% DEAD (6)	DMSO	20
18	NsNH2 (2), Ph3P (4), 40% DEAD (4)	DMSO	16

^aYield was determined by ¹H NMR.

^bDiol 31 was partially recovered.

^cDiphos = ethylenebis(diphenylphosphine).

^dADDP = 1,1’-(azodicarbonyl) dipiperidine.

Although pyridine (py.) was not identified as a suitable solvent from above solvent screening, it was noticed that fewer by-products were formed in this solvent (entry 5). We were thus intrigued by the possible beneficial effect of pyridine as a co-solvent and conducted another survey for solvent combinations (Table 3). It is also worthy of note that because azonine 32 co-eluted with NsNH₂ upon column chromatography, an in-situ deacylation procedure was conducted after the double Fukuyama-Mitsunobu reaction to obviate isolation and purification problems. Even though a favorable effect was not observed when pyridine was added to DMSO (entry 1–4), we were pleased to find that addition of pyridine to acetonitrile as the co-solvent improved the yield of azonine significantly (entry 5–8). The best result was achieved when a 5:1 (v/v) combination of acetonitrile and pyridine was used as the solvent, with azonine 9 isolated in 50% yield for this one-pot procedure (entry 7).

Table 3.

One-pot synthesis of 9 from 31.

entry	solvent (v/v)	yield (%)a
1	DMSO	38
2	DMSO/py. (1:1)	30
3	DMSO/py. (3:1)	35
4	DMSO/py. (6:1)	25
5	CH3CN/py. (1:1)	27
6	CH3CN/py. (3:1)	48
7	CH3CN/py. (5:1)	50
8	CH3CN/py. (6:1)	47

^aYield of isolated product.

Synthesis of Fawcettimine, Fawcettidine, Lycoflexine, and Lycoposerramine B

Azonine 9 served as the common intermediate for our syntheses of 1–4 (Scheme 5). From 9, the synthesis of fawcettimine (1) proved to be straightforward. Dess-Martin oxidation of 9 provided diketone 33, which upon treatment with PhSH under basic conditions followed by acidic workup afforded (±)-fawcettimine (1) as its HBr salt. The inversion of the C-4 stereogenic center apparently occurs when the free amine resulting from nosyl group removal is treated with HBr rendering the HBr salt of the natural alkaloid. In this way, we were able to realize complete stereocontrol over the C-4 stereogenic center.

Scheme 5.

Synthesis of (±)-1–4.a

^aReagents and conditions: (a) Dess-Martin periodinane, NaHCO₃, CH₂Cl₂, rt, 6h, 90%; (b) PhSH, 1M KOH, CH₃CN, reflux, 8h, 92%; (c) (CO₂H)₂, AcOH, 160 °C, 12h, 80%; (d) PhSH, 1M KOH, CH₃CN, reflux, 8h; then HCO₂H, 37% HCHO (aq.), reflux, overnight, 91% for one-pot; (e) PhSH, 1M KOH, CH₃CN, reflux, 8h; then MeOH, 37% HCHO (aq.), NaBH₃CN, rt, overnight, 90% for one-pot; (f) (COCl)₂, DMSO, CH₂Cl₂, −78 °C, 1h; then Et₃N, −78 °C to rt, 2h; (g) Et₂NH, NH₂OH·HCl, EtOH, rt, 24h, 40% for two steps

Next, the biomimetic dehydration of (±)-fawcettimine (1) to (±)-fawcettidine (2) was investigated. Although this transformation was reported to be realized through the agency of POCl₃-pyridine,³⁴ the yield and experimental details for this transformation were not reported and we decided to investigate alternative conditions. To our delight, we found that this dehydration took place when (±)-1 was treated with excess oxalic acid in AcOH at 160 °C for 12 hours,³⁵ which afforded (±)-fawcettidine (2) in 80% yield. From diketone 33, a one-pot nosyl group deprotection/Mannich reaction afforded (±)-lycoflexine (3) in 91% yield.

Azonine 9, with the nine-membered N-heterocycle cis-fused to the 5-membered ring, was readily converted to (±)-lycoposerramine B (4). Removal of the nosyl group of 9 followed by in-situ reductive amination generated tertiary amine 34 in 90% yield. Subsequent Swern oxidation³⁶ and selective oxime formation under Takayama’s conditions,^12a afforded (±)-lycoposerramine B (4) in 40% overall yield from 34. All of the spectral data obtained for the synthetic natural alkaloids were fully consistent with those reported.^{5,6,7,10a,11,12a}

Enantiospecific Syntheses

While the protocols just detailed provided the racemic natural products, we recognized that the enantiospecific syntheses of these substances could be achieved by employing enantiomerically pure (+)-13 (Scheme 6). Despite the fact that 13 is the intermediate for the synthesis of epijasmonate and some analogues, which possess pleasant olfactory properties and are widely used by the fragrance industry,¹⁷ the asymmetric synthesis of enantiomerically pure 13 has not been reported. After a considerable amount of experimentation, we were pleased to find that (+)-13 in high enantiomeric purity could be obtained through kinetic resolution of racemic 13. Thus, when (±)-13 was subjected to Sharpless asymmetric dihydroxylation (Sharpless AD) conditions,³⁷ a very effective kinetic resolution took place and provided (+)-13 in 36% yield and greater than 99.8% ee, from which the naturally configured (+)-alkaloids can be synthesized.³⁸ On the other hand, the diol (−)-36 obtained was cleaved to afford keto aldehyde (−)-16 in 52% ee, which can be deployed for the synthesis of the corresponding (−)-antipodes.

Scheme 6.

Kinetic resolution of (±)-13.a

^aReagents and conditions: (a) AD-mix-β, MeSO₂NH₂, K₂CO₃, t-BuOH/H₂O (v/v 1:1), 0–4 °C, 7h; (b) NaIO₄, THF/H₂O (v/v 4:3), rt, 3h, 90%.

With (+)-13 of high enantiomeric purity in hand, the enantiospecific syntheses of epijasmonate and its analogues can also be realized.¹⁷ Compared to AD-mix-β, kinetic resolution of (±)-13 by AD-mix-α should provide the corresponding enantiomer, (−)-13. Thus, this kinetic resolution is readily adaptable to applications in the enantiospecific syntheses of the jasmonoid fragrances.³⁹

CONCLUSIONS

The efficient total syntheses of fawcettimine, lycoflexine, fawcettidine, and lycoposerramine B have been accomplished through an efficient, unified, and stereocontrolled strategy that required sixteen, sixteen, seventeen, and seventeen steps, respectively, from commercially available materials. The key transformations involve: (1) a Diels-Alder reaction between enone 11 and 1-siloxy diene 12 to construct the cis-fused 6,5-carbocycles 10 with one allcarbon quaternary center and, (2) a double Fukuyama-Mitsunobu reaction to form the azonine ring. Access to the enantiospecific syntheses of these alkaloids can be achieved by kinetic resolution of the earliest intermediate (13) via Sharpless asymmetric dihydroxylation technology which can be conducted on multi-gram scale. We have further demonstrated that the putative biomimetic conversion of fawcettimine to fawcettidine can be realized and significantly, we have accomplished the most concise synthesis of lycoposerramine B thus far recorded. Compared to existing approaches to these alkaloids, our unified synthetic route possesses better stereocontrol over the C-4 and C-15 stereogenic centers as well as allowing for more variation in the 6-membered ring. The application of this strategic approach to the stereocontrolled synthesis of other Lycopodium alkaloid family members is currently under investigation.

EXPERIMENTAL SECTION

General Experimental Methods

All reactions were performed in single-neck round bottom flasks fitted with rubber septa under positive pressure of argon with magnetic stirring, unless otherwise noted. Solvents were dried by passage through columns of activated alumina. LiClO₄ (ACS grade) was heated in oven (120 °C) for three days before use. All other reagents were prepared by known literature procedures or used as obtained from commercial sources without further purification, unless otherwise indicated. Reaction progress was monitored by thin-layer chromatography (TLC) carried out on 0.25 mm coated commercial silica gel plates impregnated with a fluorescent indicator (254 nm) visualized by UV light and/or submersion in standard TLC stains (KMnO₄, vanillin, anisaldehyde, etc.) followed by heating on a hot plate (~200 °C, 15 s). Flash column chromatography was performed on silica gel (230–400 mesh), unless otherwise indicated. ¹H and ¹³C NMR spectra were obtained from 300 MHz or 400 MHz spectrometers. The chemical shifts are given in parts per million (ppm) relative to TMS at δ 0.00 ppm or to residual CDCl₃ δ 7.27 ppm for proton spectra and relative to CDCl₃ at δ 77.23 ppm for carbon spectra, unless otherwise noted. IR spectra were recorded on a FT-IR spectrophotometer using NaCl plates. High-resolution mass spectra were obtained using a TOF spectrometer using simultaneous electrospray (ESI) and atmospheric pressure chemical ionization (APCI). Excess (ee) values were measured on a GC or HPLC device. Optical rotations were recorded on a polarimeter at a wavelength of 589 nm. Melting points were measured on a capillary melting point apparatus and are uncorrected. Unless otherwise noted, all compounds are racemates although they are drawn as a single enantiomers in the natural series.

(3a'R,7a'S)-5'-Methyl-2',3',3a',4',7',7a'-hexahydrospiro[[1,3]dioxolane-2,1'-indene] 13.¹⁷

Following the procedure described by Hailes,¹⁷ to an oven dried 500 mL round-bottomed flask with reflux condenser was added LiClO₄ (136.18 g, 1.28 mol) and Et₂O (320 mL). After stirring at room temperature for 1.5 h, isoprene (14) (32 mL, 320 mmol, 4.0 equiv.), 2-cyclopenten-1-one ethylene ketal (15) (9.46 mL, 80 mmol, 1.0 equiv.) and camphorsulfonic acid solution (0.5 M in THF, 0.37 mL, 0.23 mol%) were added. The resulting solution was stirred for additional 50 minutes before NEt₃ (0.40 mL) was added. Cold water (200 mL) was then added cautiously and the organic layer was separated. The aqueous layer was extracted with Et₂O (2 × 200 mL). The combined organic layer was dried over anhydrous MgSO₄, filtered and concentrated at reduced pressure (~15 mmHg, rotavap water bath temp. 0–5 °C). The crude obtained was purified by flash column chromatography (hexanes/EtOAc 50:1) to afford title compound (14.76 g, 95%) as a colorless oil (R_f = 0.57, hexanes/EtOAc 10:1). ¹H NMR (300 MHz, CDCl₃): δ 5.36–5.40 (m, 1H), 3.80–3.96 (m, 4H), 2.26–2.37 (m, 1H), 1.66–2.18 (m, 8H), 1.64 (S, 3H), 1.39–1.52 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 132.2, 119.8, 119.2, 64.9, 64.0, 41.4, 35.0, 34.0, 31.9, 27.1, 24.1, 22.3.

2-((6S,7R)-7-(2-Oxopropyl)-1,4-dioxaspiro[4.4]nonan-6-yl)acetaldehyde 16

To a 2000-mL three-neck round-bottomed flask equipped with mechanical stirrer, 13 (5.06 g, 26.05 mmol, 1.0 equiv.), and RuCl₃·xH₂O (0.054 g, 0.26 mmol, 1.0 mol%) were dissolved in ClCH₂CH₂Cl (130 mL) and H₂O (104 mL). The resulting mixture was stirred vigorously at room temperature. NaIO₄ (11.142 g, 52.09 mmol, 2.0 equiv.) was then added in portions over 5 minutes. After 3 hours at room temperature, sat. Na₂S₂O₃ (50 mL) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layer was dried over anhydrous MgSO₄. After filtration and concentration, the crude obtained was purified by flash column chromatography (hexanes/EtOAc, 2:1) to afford title compound (4.42 g, 75%) as a colorless oil. (R_f = 0.23, hexanes/EtOAc 2:1). IR (thin film): 3413, 2956, 2888, 1716, 1413, 1358, 1289, 1121 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 9.70 (dd, J = 2.7, 1.5 Hz, 1H), 3.73–3.91 (m, 4H), 2.60–2.74 (m, 2H), 2.30–2.48 (m, 3H), 2.16–2.24 (m, 1H), 2.10 (s, 3H), 1.71–2.02 (m, 3H), 1.23–1.36 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 208.1, 202.2, 117.7, 65.0, 64.5, 45.4, 43.7, 39.7, 34.6, 34.2, 30.4, 27.7; HRMS (ESI) calcd. for C₁₂H₁₉O₄ [M+H]⁺ 227.1278 found 227.1276.

Kinetic resolution of (±)-13

To a 500-mL round-bottomed flask, (±)-13 (1.94 g, 10 mmol, 1.0 equiv.), methanesulfonamide (0.951 g, 10 mmol, 1.0 equiv.), and K₂CO₃ (4.146 g, 30 mmol, 3 equiv.) were dissolved in t- BuOH/H₂O (v/v 1:1, 100 mL). The mixture was stirred at 0 °C and then AD-mix-β (1.41g/mmol, 14.1 g) was added in one portion. After stirring at 0–4 °C for 7 hours, sat. Na₂S₂O₃ (50 mL) was added. The mixture was extracted with hexanes (2 × 100 mL). The combined hexanes extract layer was washed successively with H₂O (4 × 50 mL) and brine (40 mL), dried over anhydrous Na₂SO₄. After filtration and concentration at reduced pressure (~15 mmHg, rotavap water bath temp. 0–5 °C), the crude (+)-13 was obtained, which also contains a little (−)-36. All of the aqueous layers were combined and added NaCl until saturation. The aqueous layer was then extracted with CHCl₃ (3 × 50 mL). The combined CHCl₃ extract layer was dried over anhydrous Na₂SO₄. After filtration and concentration, the crude (−)-36 was obtained. The crude (+)-13 was purified by flash column chromatography (hexanes/EtOAc, 50:1) to afford (+)-13 (0.67 g, 36%) as a colorless oil. [α]_D = +12.4°(c 16.23, CHCl₃), > 99.8% ee. After eluting (+)-13, crude (−)-36 was loaded to the same column and chromatographed (THF/hexanes/EtOAc 1:1:1) to yield (−)-36 (1.104 g, 60%) as a colorless oil. Analytical data for (−)-36: IR (film): 3424, 2940, 1438, 1329, 1208, 1153, 1120, 1044, 1014 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 3.73–4.04 (m, 5H), 2.19–2.39 (m, 2H), 1.54–1.96 (m, 8H), 1.32–1.46 (m, 2H), 1.24 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 118.7, 72.3, 71.7, 65.2, 64.2, 46.0, 40.1, 35.7, 32.7, 28.0, 27.6, 27.3; HRMS (ESI) calcd. for C₁₂H₂₀NaO₄ [M+Na]⁺ 251.1254 found 251.1250.

The absolute stereochemistry of (+)-13 was determined by converting (+)-13 to 5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one and comparing its optical rotation with the product obtained from Corey’s CBS catalyzed Diels-Alder reaction.

(3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one from (+)-13

Following the procedure described by Hailes,¹ to a 25-mL round-bottomed flask, (+)-13 (95.0% ee, 0.157 g, 0.81 mmol, 1.0 equiv.) was dissolved in MeOH (ACS grade, 4 mL) at 0 °C. aq. HCl solution (2.7 M, 0.25 mL) was added drop by drop. The resulting mixture was stirred at 0 °C for 2 hours before sat. NaHCO₃ (8mL) was added. The mixture was extracted with hexanes (3 × 15 mL). The combined organic layer was dried over anhydrous MgSO₄, filtered and concentrated at reduced pressure (~15 mmHg, rotavap water bath temp. 0–5 °C). The crude obtained was purified by flash column chromatography (hexanes/Et₂O, 15:1) to afford title compound (0.092 g, 76%, 92.3% ee) as a colorless oil. [α]_D = +21.5°(c 3.57, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ 5.31 (br s, 1H), 2.44–2.55 (m, 1H), 1.93–2.39 (m, 8H), 1.72–1.81 (m, 1H), 1.61 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 220.0, 132.5, 118.9, 46.8, 34.4, 33.0, 31.0, 26.7, 24.1, 21.9. [α]_D = +12.4° (c 16.23, CHCl₃), >99.8% ee. GC conditions: Column: Chiraldex B-DM (Cat. No. 77023), Adv. Separation Technologies, Inc. Oven: 130 °C; Carrier: Helium, head pressure 15 psi; Detection: FID 250 °C

(3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one from Corey’s CBS catalyzed Diels-Alder reaction

To a 25-mL flame dried round-bottomed flask, toluene (1.0 mL) and (S)-(−)-O-tolyl-CBS-oxazaborolidine solution (0.5 M in toluene, 0.80 mL, 0.4 mmol, 20 mol%) were added and the solution was stirred and cooled to −25 °C. (CF₃SO₂)₂NH (0.20 M in CH₂Cl₂, freshly prepared, 1.80 mL, 0.36 mmol, 18 mol%) was then added dropwise. After 10 minutes at −25 °C, 2-cyclopenten-1-one (168 µL, 2 mmol, 1.0 equiv.) and isoprene (1.0 mL, 10 mmol, 5 equiv.) were added. The reaction mixture was stirred for 3 days at −25 °C before NEt₃ (56 µL) was added to quench. The mixture was then warmed to room temperature and concentrated at reduced pressure (~15 mmHg, rotavap water bath temp. 0–10 °C). The crude obtained was purified by flash column chromatography (hexanes/EtOAc, 10:1) to afford title compound (0.157 g, 52%) as a colorless oil. The absolute stereochemistry of title compound was assigned as shown according to the model proposed by Corey’s group.² [α]_D = + 9.8°(c 8.32, CHCl₃), 73.5% ee. GC conditions: Column: Chiraldex B-DM (Cat. No. 77023), Adv. Separation Technologies, Inc. Oven: 130 °C; Carrier: Helium, head pressure 15 psi; Detection: FID 250 °C.

Compound (−)-16 from (−)-36

To a 25-mL round-bottomed flask, (−)-36 (0.129 g, 0.70 mmol, 1.0 equiv.) was dissolved in THF (ACS grade, 4 mL) and H₂O (3 mL). The mixture was stirred vigorously at room temperature and then NaIO₄ (0.225 g, 1.05 mmol, 1.5 equiv.) was added in one portion. After 2 hours, sat. Na₂S₂O₃ (5 mL) was added to quench the reaction. The mixture was extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (5 mL) and dried over anhydrous MgSO₄. After filtration and concentration, the residue was purified by flash column chromatography (hexanes/EtOAc, 2:1) to afford title compound (0.144 g, 90%) as a colorless oil. [α]_D = −11.3° (c 3.38, CHCl₃), 52% ee.

1-((3a'S,6a'S)-3',3a',6',6a'-Tetrahydro-2'H-spiro[[1,3]dioxolane-2,1'-pentalen]-4'-yl)ethanone 11

To a 1000-mL round-bottomed flask equipped with reflux condenser, was added keto aldehyde 16 (3.30 g, 58.86 mmol, 1.0 equiv.) and H₂O (740 mL). The mixture was stirred at room temperature and oxygen was carefully removed under reduced pressure (~15 mmHg) for 20 minutes. The flask was refilled with Ar and the vacuo-Ar cycle was repeated for three times. Solid KOH (3.30 g, 51.2 mmol, 3.5 equiv.) was quickly added and the vacuo-Ar cycle was repeated for another two times. The resulting pale yellow solution was gently refluxed for 15 hours, cooled to room temperature, and extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄. After filtration and concentration, the crude obtained was purified by flash column chromatography (hexanes/EtOAc, 4:1) to afford title compound (2.44 g, 79%) as a yellow oil. (R_f = 0.17, hexanes/EtOAc 4:1). IR (thin film): 2960, 2883, 1708, 1666, 1619, 1435, 1373, 1107 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 6.61–6.62 (m, 1H), 3.77–4.00 (m, 4H), 3.45–3.55 (m, 1H), 2.48–2.78 (m, 3H), 2.28 (s, 3H), 1.90–2.11 (m, 1H), 1.51–1.70 (m, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 196.6, 147.5, 144.1, 118.5, 65.1, 64.2, 47.2, 47.1, 35.2, 33.6, 28.4, 27.3; HRMS (ESI) calcd. for C₁₂H₁₇O₃ [M+H]⁺ 209.1172 found 209.1176.

1-((3aS,3bR,7aS,8aS)-4-((Trimethylsilyl)oxy)-3,3a,3b,4,7,7a,8,8a-octahydro-2H-spiro[cyclopenta[a]indene-1,2'-[1,3]dioxolane]-3b-yl)ethanone 21

To a 10-mL CEM Discover reaction vessel with magnetic stirring bar, enone 11 (0.208 g, 1.0 mmol, 1.0 equiv.) and diene 17 (1.423 g, 10.0 mmol, 10.0 equiv.) were added. The vessel was flushed with Ar, capped and put in the microwave reactor. The mixture was heated to 190 °C and kept at this temperature with high speed stirring for 9 hours. After cooling to room temperature, the pale yellow solution was transferred to a 25-mL round-bottomed flask by pipette. A short-path distillation head was attached and the volatiles (contain diene 17 and crotonaldehyde) were removed (~100 °C/4 mmHg for 0.5 hour). The residue was purified by flash column chromatography (hexanes/EtOAc, 7:1 to 2:1) to afford recovered 11 (0.062 g, 30%) and title compound (0.168 g, 48%, 69% brsm) as a pale yellow oil (inseparable diastereomers, d.r. 1:0.6; R_f = 0.21, hexanes /EtOAc 6:1). IR (thin film): 3029, 2957, 2883, 1697, 1426, 1350, 1251, 1222, 1093 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 5.70–5.77 (m, 0.67H), 5.58–5.68 (m, 1.5H), 5.39–5.45 (m, 0.94H), 4.34 (app d, J = 5.1 Hz, 0.57H), 4.13–4.19 (m, 1H), 3.84–3.98 (m, 6H), 3.01 (dt, J = 8.7, 6.9 Hz, 0.97H), 2.82 (q, J = 8.7 Hz, 0.6H), 2.35–2.61 (m, 4.7H), 2.14 (s, 2.6H), 2.11 (s, 1.6H), 1.98–2.08 (m, 0.74H), 1.59–1.96 (m, 8H), 1.41 (td, J = 13.2, 10.8 Hz, 1.2H), 1.01–1.19 (m, 1.7H), 0.18 (s, 7.5H), 0.16 (s, 4.8H); ¹³C NMR (75 MHz, CDCl₃): δ 211.3, 210.0, 129.6, 128.6, 127.9, 125.9, 118.4, 118.2, 70.2, 66.5, 65.2, 65.1, 64.9, 64.40, 64.35, 49.2, 48.5, 46.84, 46.78, 36.4, 36.0, 35.5, 33.9, 32.4, 31.85, 31.81, 28.2, 27.1, 26.2, 26.0, 0.6, 0.4; HRMS (ESI) calcd. for C₁₉H₃₀NaO₄Si [M+Na]⁺ 373.1806 found 373.1803.

(E)-Trimethyl((3-methylbuta-1,3-dien-1-yl)oxy)silane 12.¹⁶

Following the procedure described by Duhamel,¹⁶ to a 500-mL 2 necked round-bottomed flask equipped with reflux condenser and glass stopper was added ZnCl₂ (0.30 g, 2.2 mmol, 0.8 mol%). The condenser was connected to vacuum and the flask was heated by flame until all the solid ZnCl₂ melted. After cooling to room temperature, the flask was charged with Ar. Et₂O (60 mL), 3-methylcrotonaldehyde (24 mL, 250 mmol, 1.0 equiv.), NEt₃ (40 mL, 287.5 mmol, 1.15 equiv.), and TMSCl (34.9 mL, 275 mmol, 1.10 equiv.) were added. The suspension was stirred at gentle reflux for 25 hours. After cooling to room temperature, hexanes (200 mL) were added and the triethylamine hydrochloride precipitate was removed by filtering over sintered glass funnel under reduced pressure and washed with hexanes (50 mL). The filtrate was concentrated by rotavap and the residue was distilled under reduced pressure (55–65 °C/20 mmHg) to give title compound (30.96 g, 79%, E:Z = 1.0:0.11) as a colorless oil. ¹H NMR (300 MHz, CDCl₃, E isomer): δ 6.53 (dt, J = 12.3, 0.6 Hz, 1H), 5.79 (dd, J = 12.3, 0.6 Hz, 1H), 4.66–4.76 (m, 2H), 1.81 (dd, J = 1.2, 0.6 Hz, 3H), 0.22 (s, 9H); ¹³C NMR (75 MHz, CDCl₃, E isomer): δ 142.0, 140.2, 116.3, 111.7, 18.2, 0.6.

1-((3aS,3bR,7aR,8aS)-6-Methyl-4-((trimethylsilyl)oxy)-3,3a,3b,4,7,7a,8,8a-octahydro-2H-spiro[cyclopenta[a]indene-1,2'-[1,3]dioxolane]-3b-yl)ethanone 10

To a 10-mL CEM Discover reaction vessel with magnetic stirring bar, diene 12 (2.08 g, 13.28 mmol, 2.5 equiv.) and enone 11 (1.11 g, 5.31 mmol, 1.0 equiv.) were added. The vessel was flushed with Ar, sealed and put in microwave reactor. The mixture was heated to 180 °C and kept at this temperature with high speed stirring for 9 hours. After cooling to room temperature, the pale yellow solution was transferred to a 25-mL round-bottomed flask by pipette. A short-path distillation head was attached and the volatiles were removed (~100 °C/4 mmHg for 0.5 hour). The residue was purified by flash column chromatography (hexanes/EtOAc, 7:1 to 2:1) to afford recovered 11 (0.21 g, 19%) and title compound (1.44 g, dr 1:0.4, 74%, 92% brsm) as inseparable diastereomers. IR (thin film): 2957, 1696, 1350, 1251, 1096, 1065 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, major diastereomer): δ 5.07 (s, 1H), 4.09 (t, J = 1.8 Hz, 1H), 3.75–3.91(m, 4H), 2.92 (td, J = 8.4, 8.0 Hz, 1H), 2.23–2.52 (m, 3H), 2.06(s, 3H), 1.72–1.88 (m, 2H), 1.60–1.70 (m, 3H), 1.56 (app d, J = 1.8 Hz, 3H), 1.26–1.38 (m, 1H), 0.96–1.10 (m, 1H), 0.12(s, 9H); ¹³C NMR (75 MHz, CDCl₃, major diastereomer): δ 211.3, 135.6, 123.1, 118.3, 70.9, 67.5, 65.1, 64.8, 64.3, 46.77, 46.75, 36.8, 35.4, 32.4, 31.8, 26.1, 23.2, 0.4; HRMS (ESI) calcd. for C₂₀H₃₂NaO₄Si [M+Na]⁺ 387.1962 found 387.1963.

(3aS,3bS,7aR,8aS)-3b-Acetyl-6-methyl-3,3a,7,7a,8,8a-hexahydro-2H-spiro[cyclopenta[a]indene-1,2'-[1,3]dioxolan]-4(3bH)-one 24

To a solution of 10 (1.556 g, 4.27 mmol, 1.0 equiv.) in CH₂Cl₂ (ACS grade, 43 mL) was added TBAF (1.228 g, 4.70 mmol, 1.1 equiv.). The reaction was stirred at room temperature for 12 hours and NaHCO₃ (1.434g, 17.07 mmol, 4.0 equiv.) was added. Dess-Martin periodinane (2.534 g, 5.98 mmol, 1.4 equiv.) was then added in portions over 5 minutes. The suspension was stirred for 6 hours then quenched with sat. Na₂S₂O₃ (10 mL) and sat. NaHCO₃ (20 mL). After stirring for another 6 hours, the organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc, 4:1) to afford title compound (1.18 g, 95%, R_f = 0.28, hexanes/EtOAc 4:1) as a white solid. m.p. = 111–113 °C; IR (thin film): 2959, 2888, 1702, 1658, 1355, 1197, 1094 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 5.81–5.83 (m, 1H), 3.80–3.91 (m, 4H), 3.64 (q, J = 8.7 Hz, 1H), 2.73–2.92 (m, 2H), 2.39 (t, J = 9.9 Hz, 1H), 2.15 (d, J = 19.2 Hz, 1H), 2.03 (s, 3H), 1.87 (s, 3H), 1.81 (td, J = 6.0, 1.5 Hz, 1H), 1.67–1.76 (m, 2H), 1.53–1.65 (m, 1H), 1.38 (td, J = 13.2, 10.5 Hz, 1H), 0.99–1.11 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 204.4, 196.1, 161.5, 124.7, 118.0, 73.9, 65.2, 64.5, 46.7, 46.6, 37.2, 35.7, 32.0, 30.2, 27.7, 25.2, 24.7; HRMS (ESI) calcd. for C₁₇H₂₃O₄ [M+H]⁺ 291.1591 found 291.1595.

Compound 24 from Diels-Alder reaction between 20 and 11

To a 10-mL CEM Discover reaction vessel with magnetic stirring bar, diene 20²³ (0.733 g, 3.0 mmol, 6.0 equiv.) and enone 11 (0.104 g, 0.5 mmol, 1.0 equiv.) were added. The vessel was flushed with Ar, sealed and put in microwave reactor. The mixture was heated to 190 °C and kept at this temperature with high speed stirring for 4 hours. After cooling to room temperature, the brown solution was transferred to round-bottomed flask by pipette with the aid of MeOH (10 mL). K₂CO₃ (0.70 g) was added and the mixture was stirred at room temperature overnight. EtOAc (20 mL) was added and the mixture was washed with brine (2×10 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc, 4:1) to afford title compound (0.032 g, 22%).

Methyl 3-((3aS,3bS,7aR,8aS)-6-methyl-4-oxo-3,3a,3b,4,7,7a,8,8a-octahydro-2H-spiro[cyclopenta[a]indene-1,2'-[1,3]dioxolane]-3b-yl)-3-oxopropanoate 25

To a stirred solution of 24 (0.6663 g, 2.295 mmol, 1.0 equiv.) in Et₂O (23 mL) at −78 °C (dry ice/acetone bath) was added solid LiHMDS (0.4608 g, 2.754 mmol, 1.2 equiv.). The solution was stirred at −78 °C for 40 minutes before cooling bath was removed. The flask was allowed to warm to room temperature over 20 minutes and then cooled down to −78 °C. Methyl cyanoformate (0.22 mL, 2.754 mmol, 1.2 equiv.) was added and the solution was allowed to warm to room temperature on its own overnight. Sat. NaHCO₃ (12 mL) was then added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc, 7:1 to give 24 then 1:1 to give 25) to afford recovered 24 (0.2392 g, 36%) and title compound (0.4814 g, 60%, 94% brsm) as a colorless oil (contains ~8% enol ester forms, R_f = 0.14, hexanes/EtOAc 4:1). IR (thin film): 2955, 2888, 1746, 1703, 1658, 1437, 1321, 1236, 1152, 1017 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 12.37 (s, 0.08H), 5.84 (s, 1H), 5.05 (s, 0.08H), 3.79–3.90 (m, 6.3H), 3.77 (s, 0.76H), 3.50–3.70 (m, 4.9), 3.44 (d, J = 2.4 Hz, 2H), 2.64–3.02 (m, 3.1H), 2.06–2.55 (m, 3.5H), 2.04 (s, 0.84H), 1.98 (s, 0.49H), 1.34–1.88 (m, 13H), 0.96–1.12 (m, 1.8H); ¹³C NMR (75 MHz, CDCl₃, β-keto ester form): δ 198.9, 195.4, 167.7, 162.1, 124.8, 117.7, 73.7, 65.1, 64.5, 52.4, 47.3, 46.8, 46.3, 37.1, 35.8, 31.8, 30.1, 25.1, 24.8; HRMS (ESI) calcd. for C₁₉H₂₅O₆ [M+H]⁺ 349.1646 found 349.1644.

(R)-Methyl 3-hydroxy-3-((3aS,3bS,7aR,8aS)-6-methyl-1,4-dioxo-1,2,3,3a,3b,4,7,7a,8,8a-decahydrocyclopenta[a]inden-3b-yl)propanoate 26

To a stirred solution of β-keto ester 25 (0.214 g, 0.613 mmol, 1.0 equiv.) in CH₂Cl₂ (4 mL) and MeOH (4 mL) at −42 °C (dry ice/CH₃CN bath) was added NaBH₄ (0.214 g, 5.66 mmol, 9.2 equiv.). The solution was stirred at −42 °C for 4.5 hours. TLC showed complete consumption of 25. Acetone (4 mL) was added to quench the additional NaBH₄. The reaction was allowed to warm to room temperature over 3 hours and 1 M HCl (6 mL) was added to adjust the pH to 1.0 (pH paper). The mixture was stirred at room temperature overnight and then extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with sat. NaHCO₃ (10 mL) and brine (10 mL), dried over anhydrous Na₂SO₄. After filtration and concentration, the residue obtained was purified by flash column chromatography (hexanes/EtOAc, 2:1) to afford title compound (0.150 g, 80%) as a colorless oil (inseparable diastereomers, dr 1:0.14; R_f = 0.28, hexanes/EtOAc 1:1). IR (thin film): 3470, 2953, 1735, 1653, 1437, 1173, 1116 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, major diastereomer): δ 5.79 (s, 1H), 4.12 (br d, J = 10.8 Hz, 1H), 3.62 (s, 3H), 3.37–3.46 (m, 2H), 2.71–2.79 (m, 1H), 2.51–2.62 (m, 2H), 2.33–2.46 (m, 2H), 2.15–2.24 (m, 3H), 2.03–2.14 (m, 1H), 1.87–1.99 (m, 5H), 1.63–1.77 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, major diastereomer): δ 221.5, 201.1, 173.4, 159.9, 125.2, 68.3, 61.4, 52.1, 47.9, 45.1, 40.0, 38.2, 36.4, 32.9, 31.5, 24.7, 23.4; HRMS (ESI) calcd. for C₁₇H₂₃O₅ [M+H]⁺ 307.1540 found 307.1542.

(R)-Methyl 3-hydroxy-3-((4aR,4bS,8aS,9aS)-7-methyl-2,5-dioxo-2,3,4,4a,4b,5,8,8a,9,9a-decahydroindeno[2,1-b]pyran-4b-yl)propanoate 27

(Note: open flask reaction) To a 100-mL round-bottomed flask equipped with reflux condenser, β-hydroxy ester 26 (0.595 g, 1.94 mmol, 1.0 equiv.) was dissolved in CH₂Cl₂ (ACS grade, 20 mL). NaHCO₃ (0.978 g, 11.64 mmol, 6 equiv.) was added and the reaction was cooled to 0 °C (ice-water bath). m-CPBA (77%, 0.739 g, 3.30 mmol, 1.7 equiv.) was then added in portions over 5 minutes and the reaction was allowed to warm to room temperature on its own. After 24 hours, sat. Na₂S₂O₃ (6 mL) was added to quench the reaction. Sat. Na₂CO₃ (14 mL) was added and the mixture was extracted EtOAc (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc, 1:1 to 1:2) to afford title compound (0.575 g, 92%) as a colorless oil (inseparable diastereomers, dr 1:0.14; R_f = 0.12, hexanes/EtOAc 1:1). IR (thin film): 3383, 1736, 1648, 1437, 1071 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, major diastereomer): δ 5.82 (s, 1H), 4.78–4.51 (m, 1H), 4.11 (br d, J = 10.8 Hz, 1H), 3.58 (s, 3H), 2.99–3.08 (m, 1H), 2.92 (td, J = 9.6, 5.4 Hz, 1H), 2.01–2.60 (m, 9H), 1.89 (s, 3H), 1.78–1.87 (m, 2H); ¹³C NMR (75 MHz, CDCl₃, major diastereomer): δ 201.0, 172.8, 172.4, 160.9, 125.7, 80.0, 68.5, 59.8, 52.1, 42.5, 38.0, 34.9, 31.8, 30.4, 24.8, 20.0; HRMS (ESI) calcd. for C₁₇H₂₃O₆ [M+H]⁺ 323.1489 found 323.1488.

(R)-Methyl 3-((4aR,4bS,8aS,9aS)-7-methyl-2,5-dioxo-2,3,4,4a,4b,5,8,8a,9,9a-decahydroindeno[2,1-b]pyran-4b-yl)-3-((methylsulfonyl)oxy)propanoate 28

To a stirred solution of 27 (0.410 g, 1.27 mmol, 1.0 equiv.) in pyridine (13 mL) at 0 °C (ice-water bath) was added MsCl (0.40 mL, 5.09 mmol, 4 equiv.). The solution was allowed to warm to room temperature on its own overnight. Sat. NaHCO₃ (15 mL) was then added carefully and the mixture was extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (15 mL) and dried over anhydrous Na₂SO₄. After filtration and concentration, the residue obtained was purified by flash column chromatography (hexanes/EtOAc, 2:1) to afford title compound (0.494 g, 97%) as a colorless oil (inseparable diastereomers, dr 1:0.18; R_f = 0.19, hexanes/EtOAc 2:1). IR (thin film): 2954, 1738, 1654, 1437, 1339, 1249, 1172, 1131, 1021 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, major diastereomer): δ 5.81 (s, 1H), 5.27 (dd, J = 8.4, 3.0 Hz, 1H), 4.54 (td, J = 8.4, 3.3 Hz, 1H), 3.61 (s, 3H), 3.19 (dt, J = 13.2, 6.6 Hz, 1H), 3.01 (s, 3H), 2.94–2.96 (m, 1H), 2.80–2.88 (m, 1H), 2.63–2.72 (m, 1H), 2.55 (dt, J = 16.8, 3 Hz, 1H), 1.97–2.29 (m, 4H), 1.93 (s, 3H), 1.67–1.88 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, major diastereomer): δ 197.8, 171.8, 170.8, 161.8, 124.2, 79.0, 76.6, 60.5, 52.5, 41.2, 39.3, 37.0, 36.8, 35.3, 30.5, 30.4, 24.8, 20.5; HRMS (ESI) calcd. for C₁₈H₂₄NaO₈S [M+Na]⁺ 423.1084 found 423.1076.

Methyl 3-((4aR,4bS,7R,8aS,9aS)-7-methyl-2,5-dioxododecahydroindeno[2,1-b]pyran-4b-yl)propanoate 29

To a 100-mL hydrogenation vessel, 28 (0.494 g, 1.23 mmol, 1.0 equiv.) was dissolved in EtOAc (ACS grade, 13 mL). 5 wt. % Pd/C (0.494 g) and 5 wt. % Rh/Al₂O₃ (0.494 g) were added and the vessel was sealed. H₂ (80 psi) was filled and then released. This process was repeated twice and the vessel was refilled with H₂ (80 psi). After stirring at room temperature for 1 day, H₂ was released and TLC showed complete consumption of 28. DBU (0.28 mL, 1.85 mmol, 1.5 equiv.) was then added and the vessel was resealed, refilled with H₂ (80 psi). The reaction was stirred at room temperature for another 12 hours and then filtered over Büchner funnel at reduced pressure and washed with EtOAc. The filtrate was concentrated and the residue obtained was purified by flash column chromatography (hexanes/EtOAc, 2:1) to afford title compound (0.353 g, 93%) as a white solid (R_f = 0.16, hexanes/EtOAc 2:1). m.p. = 78–80 °C; IR (thin film): 2955, 1737, 1699, 1437, 1248, 1191, 1132, 1033 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 4.65 (td, J = 7.8, 3.0 Hz, 1H), 3.63 (s, 3H), 3.20 (dt, J = 13.2, 6.9 Hz, 1H), 2.60 (dt, J = 16.5, 3.0 Hz, 1H), 2.43–2.53 (m, 1H), 2.24–2.35 (m, 4H), 1.99–2.19 (m, 2H), 1.67–1.96 (m, 7H), 1.49 (qd, J = 13.3, 3.3 Hz, 1H), 1.02 (d, J = 6.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 213.6, 173.1, 172.6, 80.0, 60.2, 52.1, 47.0, 43.6, 38.9, 36.5, 31.9, 30.4, 30.1, 29.9, 27.5, 22.4, 19.6; HRMS (ESI) calcd. for C₁₇H₂₅O₅ [M+H]⁺ 309.1697 found 309.1698.

(2S,3R,3aS,6R,7aS)-3,3a-Bis(3-acetoxypropyl)-6-methyloctahydro-1H-indene-2,4-diyl diacetate 30

To a 50-mL oven dried round-bottomed flask equipped with reflux condenser, 29 (0.204 g, 0.66 mmol, 1.0 equiv.) was dissolved in THF (14 mL) and stirred at room temperature. LiAlH₄ (0.075 g, 1.98 mmol, 3 equiv.) was added in one portion and the mixture was heated at reflux overnight. After cooling to room temperature the reaction was quenched by successive addition of H₂O (75 µL), 15% NaOH (75 µL), and H₂O (225 µL). The resulting slurry was stirred for another 4 hours and then filtered over Büchner funnel at reduced pressure, washed with EtOAc. After concentration, the crude tetraol obtained was used in the next step without further purification.

To a stirred solution of the tetraol obtained from above (0.66 mmol, theoretical, 1.0 equiv.) in pyridine (7 mL) were added one crystal of DMAP and Ac₂O (0.50 mL, 5.30 mmol, 8 equiv.). The reaction was stirred at room temperature for 1 day and then quenched with sat. NaHCO₃ (10 mL). The mixture was extracted with EtOAc (3 × 10 mL), washed with brine (10 mL), and dried over anhydrous Na₂SO₄. After filtration and concentration, the crude obtained was used in the next step directly without further purification. An analytic sample was purified by flash column chromatography (hexanes/EtOAc, 2:1) to afford title compound as a colorless oil (inseparable diastereomers, dr 9:1; R_f = 0.14, hexanes/EtOAc 4:1). IR (thin film): 2956, 1737, 1458, 1370, 1239, 1024 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, major diastereomer): δ 5.17 (app t, J = 4.2 Hz, 1H), 4.63 (dd, J = 11.4, 3.9 Hz, 1H), 3.86–4.05 (m, 4H), 2.24–2.32 (m, 1H), 1.982 (s, 3H), 1.961 (s, 3H), 1.957 (s, 3H), 1.948 (s, 3H), 1.79–1.87 (m, 1H), 1.22–1.76 (m, 13H), 1.04–1.16 (m, 2H), 0.84 (d, J = 6.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃, major diastereomer): δ 171.2, 171.1, 170.9, 170.4, 81.5, 75.7, 65.3, 64.6, 53.3, 46.5, 39.9, 36.4, 36.3, 33.2, 28.1, 27.0, 24.8, 24.2, 22.7, 22.0, 21.40, 21.36, 21.2, 21.1; HRMS (ESI) calcd. for C₂₄H₄₂NO₈ [M+NH₄]⁺ 472.2905 found 472.2900.

(2S,3R,3aS,6R,7aS)-3,3a-Bis(3-hydroxypropyl)-6-methyloctahydro-1H-indene-2,4-diyl diacetate 31

To a stirred solution of 30 (0.66 mmol, theoretical, 1.0 equiv.) obtained above in MeOH (ACS grade, 3.3 mL) and THF (ACS grade, 3.3 mL) was added Otera’s catalyst³⁰ ([t-Bu₂Sn(OH)Cl]₂) (0.019 g, 33 µmol, 5 mol%). The reaction was stirred at room temperature for 30 hours and NEt₃ (50 µL) was added to quench the reaction. After concentration, the residue was purified by flash column chromatography (hexanes/EtOAc/THF, 1:2:0.5) to afford recovered materials (0.052 g, contains mono- or tri- acetate, which could be recycled by reacetylation to 30) and 31 (0.208 g, 85% for 3 steps, ≥ 95% brsm) as a colorless oil (inseparable diasteromers, dr 9:1; R_f = 0.07, hexanes/EtOAc 1:2). IR (thin film): 3386, 2951, 2871, 1734, 1457, 1375, 1242, 1052, 1023 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, major diastereomer): δ 5.24 (t, J = 4.5 Hz, 1H), 4.70 (app dd, J = 12.0, 4.2 Hz, 1H), 3.47–3.74 (m, 4H), 2.71 (br s, 2H), 2.31–2.40 (m, 1H), 2.007 (s, 3H), 2.004 (s, 3H), 1.76–1.94 (m, 2H), 1.32–1.74 (m, 12H), 1.08–1.25 (m, 2H), 0.87 (d, J = 6.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃, major diastereomer): δ 171.4, 170.9, 81.7, 76.2, 63.6, 62.6, 53.3, 46.7, 40.1, 36.6, 36.2, 33.2, 32.2, 28.8, 27.1, 24.1, 22.5, 22.1, 21.55, 21.52; HRMS (ESI) calcd. for C₂₀H₃₈NO₆ [M+NH₄]⁺ 388.2694 found 388.2696.

(7aR,8S,9aS,11R,13aS)-11-Methyl-4-((2-nitrophenyl)sulfonyl)tetradecahydro-1H-indeno[1,7a-e]azonine-8,13-diyl diacetate 32

To a stirred solution of 31 (0.0039 g, 10.5 µmol, 1.0 equiv.), 2-nitrobenzenesulfonamide (0.0085 g, 42 µmol, 4.0 equiv.), and Ph₃P (0.0165 g, 63 µmol, 6.0 equiv.) in DMSO (1.0 mL) at room temperature was added DEAD (40 wt. % in toluene, 29 µL, 63 µmol, 6.0 equiv.). The reaction was stirred at room temperature for 1 day then H₂O (8 mL) was added. The mixture was extracted with EtOAc (3 × 3 mL). The combined organic layer was washed with H₂O (3 mL) and brine (3 mL), then dried over anhydrous Na₂SO₄. After filtration and concentration, the residue obtained was added Et₂O (2 mL). The white precipitate was removed by filtering through a filter funnel with a cotton plug and washed with Et₂O (3 mL). The filtrate was concentrated and the crude obtained was purified by preparative TLC (hexanes/EtOAc 1:1) to give title compound (0.0021 g, 38%; R_f = 0.24, hexanes/EtOAc 1:1) as a white solid. IR (thin film): 2925, 2854, 1730, 1546, 1458, 1374, 1248, 1166, 1028 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.90–7.94 (m, 1H), 7.65–7.72 (m, 2H), 7.56–7.59 (m, 1H), 5.30–5.39 (m, 1H), 4.86–4.93 (m, 1H), 3.42–3.62 (m, 2H), 2.85–3.04 (m, 2H), 1.07–2.24 (m, 23H), 0.90 (d, J = 6.6 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 171.0, 170.6, 133.6, 131.8, 131.5, 130.8, 124.1, 75.9, 75.8, 50.7, 50.4, 46.04, 45.96, 42.5, 36.2, 33.6, 32.2, 30.0, 28.9, 26.9, 24.8, 24.1, 22.1, 21.7, 21.4, 17.0; HRMS (ESI) calcd. for C₂₆H₃₆N₂NaO₈S [M+Na]⁺ 559.2085 found 559.2093.

(7aR,8S,9aS,11R,13aS)-11-Methyl-4-((2-nitrophenyl)sulfonyl)tetradecahydro-1H-indeno[1,7a-e]azonine-8,13-diol 9

To a stirred solution of 31 (0.0876 g, 236 µmol, 1.0 equiv.), 2-nitrobenzenesulfonamide (0.191 g, 0.94 mmol, 4.0 equiv.), and Ph₃P (0.372 g, 1.42 mmol, 6.0 equiv.) in CH₃CN (20 mL) and pyridine (4 mL) at room temperature was added DEAD (40 wt. % in toluene, 0.65 mL, 1.42 mmol, 6.0 equiv.) over 10 minutes. After 24 hours at room temperature, MeOH (24 mL) and K₂CO₃ (0.326 g, 10.0 equiv.) were added. A reflux condenser was connected and the suspension was stirred with gentle reflux overnight. After cooling to room temperature, the stirring bar was removed and the solution was concentrated. The residue was partitioned between EtOAc (15 mL) and brine (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. To the residue, EtOH (3 mL) was added and the resulting NsNH₂ precipitate was removed by filtering over a filter funnel with a cotton plug and washed with EtOH (3 × 3 mL). The filtrate was concentrated and the residue obtained was purified by flash column chromatography (hexanes/EtOAc, 1:1 to 1:2) to afford title compound (0.054 g, 50%; R_f = 0.07, hexanes/EtOAc 1:2) as a white solid contaminated with trace amount of Ph₃PO. An analytic sample was further purified by preparative TLC (hexanes/EtOAc 1:2). IR (thin film): 3385, 2925, 1545, 1373, 1343, 1164 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ7.91–7.96 (m, 1H), 7.64–7.72 (m, 2H), 7.56–7.62 (m, 1H), 4.62 (dt, J = 8.4, 6.0 Hz, 1H), 3.67–3.78 (m, 1H), 3.47–3.55 (m, 2H), 3.13 (ddd, J = 14.8, 9.6, 4.8 Hz, 1H), 2.95 (dt, J = 13.2, 4.0 Hz, 1H), 1.51–2.31 (m, 16H), 1.22–1.31 (m, 2H), 1.06–1.14 (m, 1H), 0.92 (d, J = 6.4, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 133.5, 132.1, 131.4, 130.9, 124.1, 74.1, 73.0, 51.8, 50.8, 48.0, 46.4, 42.5, 40.4, 36.9, 32.8, 29.5, 27.4, 24.6, 24.5, 22.3, 16.5; HRMS (ESI) calcd. for C₂₂H₃₃N₂O₅S [M+H]⁺ 453.2059 found 453.2061.

(7aR,9aS,11R,13aS)-11-Methyl-4-((2-nitrophenyl)sulfonyl)decahydro-1H-indeno[1,7a-e]azonine-8,13(2H,9H)-dione 33

To a stirred solution of 9 (0.022 g, 49 µmol, 1.0 equiv.) in CH₂Cl₂ (ACS grade, 2 mL) were added NaHCO₃ (0.033 g, 0.39 mmol, 8.0 equiv.) and Dess-Martin periodinane (0.084 g, 0.20 mmol, 4.0 equiv.). The suspension was stirred at room temperature for 6 hours then sat. Na₂S₂O₃ (3 mL) and sat. NaHCO₃ (3 mL) were added. After stirring for additional 1 hour, the mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layer was washed with brine (5 mL) and dried over anhydrous Na₂SO₄. After filtration and concentration, the residue obtained was purified by flash column chromatography (hexanes/EtOAc, 1:1) to afford title compound (0.0195 g, 90%) as a white solid. m.p. = 232–235 °C (decompd.); IR (thin film): 2924, 1737, 1700, 1544, 1439, 1373, 1347, 1168, 1128 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.92 (dd, J = 5.7, 2.0 Hz, 1H), 7.66–7.74 (m, 2H), 7.59 (dd, J = 5.4, 2.0 Hz, 1H), 3.63 (td, J = 12.8, 4.8 Hz, 1H), 3.52 (ddd, J = 15.2, 6.0, 4.0 Hz, 1H), 2.91–2.99 (m, 2H), 2.82 (dt, J = 13.6, 4.0 Hz, 1H), 2.60–2.66 (m, 1H), 1.60–2.41 (m, 13H), 1.48–1.54 (m, 1H), 1.23–1.34 (m, 1H), 1.09 (d, J = 6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 218.7, 214.0, 148.9, 134.0, 131.6, 131.1, 130.9, 124.2, 60.3, 50.1, 49.4, 46.8, 45.5, 42.4, 39.6, 31.2, 30.2, 29.7, 25.0, 22.5, 22.1, 20.9; HRMS (ESI) calcd. for C₂₂H₂₉N₂O₆S [M+H]⁺ 449.1741 found 449.1735.

(±)-Fawcettimine 1

To a 10-mL round-bottomed flask equipped with reflux condenser, 33 (0.0127 g, 30 µmol, 1.0 equiv.) was dissolved in CH₃CN (3 mL). KOH (1.0 M, 300 µmol, 0.30 mL, 10 equiv.) and PhSH (15 µL, 150 µmol, 5 equiv.) were added. The reaction was stirred at gentle reflux for 6 hours then cooled to room temperature. EtOAc (8 mL) was added and the mixture was extracted with 1 M HCl (3 × 4 mL). The combined aqueous layer was added solid Na₂CO₃ until saturation. The resulting mixture was extracted with 3% MeOH in CHCl₃ (3 × 5 mL). The combined organic layer was dried over anhydrous Na₂SO₄. After filtration and concentration, the residue obtained was dissolved in CH₂Cl₂ and added HBr (0.1 M in H₂O, 0.30 mL, 30 µmol). After standing at room temperature overnight, all of the volatiles were removed under vacuum. To the solid obtained, a minimum amount of Et₂O was added, rinsed and removed by pipette. The (±)-fawcettimine hydrobromide salt remained was dissolved in CH₂Cl₂ and dried over anhydrous K₂CO₃ overnight. After filtration and concentration, (±)-fawcettimine (0.0073 g, 92%) was obtained as a pale yellow foam (R_f = 0.35, n-BuOH/AcOH/H₂O 7:2:2). IR (thin film): 3287, 2923, 2856, 1735, 1637, 1458, 1340, 1264, 1144, 1100, 1056 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.76–3.85 (m, 1H), 3.58–3.70 (br, 1H), 3.40 (td, J = 14.2, 4.0 Hz, 1H), 3.03 (dd, J = 14.4, 4.8 Hz, 1H), 2.81–2.86 (m, 1H), 2.60 (dd, J = 18.0, 13.6 Hz, 1H), 1.82–2.35 (m, 11H), 1.37–1.76 (m, 5H), 1.00 (d, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 218.2, 59.9, 54.7, 50.6, 48.1, 43.4, 42.5, 41.6, 34.8, 31.8, 29.9, 27.6, 26.6, 23.9, 21.8, 20.9; HRMS (ESI) calcd. for C₁₆H₂₆NO₂ [M+H]⁺ 264.1958 found 264.1962. Analytical data for (±)-fawcettimine hydrobromide: ¹H NMR (400 MHz, CDCl₃): δ 10.01 (br s, 1H), 5.80 (s, 1H), 4.18 (br s, 1H), 3.51–3.64 (m, 1H), 3.21 (br d, J = 11.2 Hz, 1H), 3.02 (br s, 1H), 2.81 (d, J = 12.4 Hz, 1H), 2.60 (dd, J = 16.8, 12.4 Hz, 1H), 1.82–2.46 (m, 12H), 1.75 (br d, J = 14.0 Hz, 1H), 1.64 (d, J = 12.8 Hz, 1H), 1.48 (td, J = 13.4, 4.8 Hz, 1H), 1.05 (d, J = 6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 216.2, 96.3, 59.2, 56.0, 51.6, 47.7, 43.3, 41.2, 40.3, 33.5, 31.4, 26.8, 24.2, 24.0, 21.6, 19.2.

(±)-Fawcettidine 2

To a 10-mL round-bottomed flask equipped with reflux condenser, fawcettimine (0.0054 g, 20 µmol, 1.0 equiv.) and oxalic acid (0.0540 g, 0.6 mmol, 29.0 equiv.) were dissolved in AcOH (2 mL). Oxygen was carefully removed through a freeze-pump-thaw cycles for 3 times. The flask was refilled with Ar and the reaction was stirred at 160 °C for 12 hours. After cooling to room temperature, n-heptane was added and all the volatiles were removed under vacuum. To the residue, aq. 5% NH₃·H₂O solution (5 mL) was added and the resulting mixture was extracted with 3% MeOH in CHCl₃ (4 × 4 mL). The combined organic layer was dried over anhydrous Na₂SO₄. After filtration and concentration, the crude obtained was purified by flash column chromatography (basic alumina, hexanes/EtOAc, 2:1 then 3% MeOH in CHCl₃) to afford title compound (0.0040 g, 80%) as a white foam (R_f = 0.24, MeOH/CHCl₃ 5:95). IR (thin film): 2924, 2848, 1737, 1662, 1549, 1447, 1328, 1302, 1253, 1216, 1193, 1169, 1149, 1105, 1030 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 5.69 (d, J = 4.8 Hz, 1H), 2.97–3.15 (m, 4H), 2.74 (ddd, J = 16.8, 7.6, 1.6 Hz, 1H), 2.22–2.36 (m, 2H), 2.05–2.20 (m, 3H), 1.82–2.00 (m, 2H), 1.54–1.79 (m, 3H), 1.21–1.41 (m, 4H), 1.06 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 219.1, 146.2, 127.4, 60.6, 56.5, 52.2, 46.4, 44.3, 39.4, 37.5, 34.4, 31.6, 29.4, 28.0, 24.1, 21.1; HRMS (ESI) calcd. for C₁₆H₂₄NO [M+H]⁺ 246.1852 found 246.1855.

(±)-Lycoflexine 3

To a 10-mL round-bottomed flask equipped with reflux condenser, 33 (0.0024 g, 5.3 µmol, 1.0 equiv.) was dissolved in CH₃CN (2 mL). KOH (1.0 M, 42 µmol, 42 µL, 8.0 equiv.) and PhSH (2.7 µL, 26 µmol, 5.0 equiv.) were added. The reaction was stirred at gentle reflux for 8 hours then cooled to room temperature. H₂O (1 mL), HCO₂H (16 µL, 424 µmol, 80 equiv.), and 37% HCHO (aq., 34 µL, 424 µmol, 80 equiv.) were added. The resulting mixture was stirred at gentle reflux overnight before all of the volatiles were removed at vacuum. The residue was dissolved in EtOAc (10 mL) and extracted with 1 M HCl (3 × 4 mL). The combined aqueous layer was added solid Na₂CO₃ until saturation. The mixture was then extracted with 3% MeOH in CHCl₃ (3 × 4 mL) and the combined organic layer was dried over anhydrous Na₂SO₄. After filtration and concentration, the residue was purified by flash column chromatography (basic alumina, hexanes/EtOAc, 1:2 then 3% MeOH in CHCl₃) to afford title compound (0.0013 g, 91%) as a white solid (R_f = 0.23, n-BuOH/AcOH/H₂O 7:2:2). IR (thin film): 2924, 2853, 1727, 1699, 1456, 1352, 1208, 1174, 1127, 1063 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.19 (ddd, J = 14.4, 2.8, 1.2 Hz, 1H), 3.13 (ddd, J = 13.6, 8.0, 4.0 Hz, 1H), 2.94–3.02 (m, 1H), 2.78–2.91 (m, 2H), 2.61–2.72 (m, 2H), 2.19–2.42 (m, 6H), 2.06–2.17 (m, 2H), 1.91–2.01 (m, 2H), 1.71–1.89 (m, 3H), 1.56–1.64 (m, 1H), 1.31–1.36 (m, 1H), 1.04 (d, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 218.6, 214.1, 60.8, 58.7, 56.9, 53.8, 53.5, 46.9, 40.5, 40.3, 36.4, 31.5, 29.5, 28.2, 26.3, 22.6, 19.6; HRMS (ESI) calcd. for C₁₇H₂₆NO₂ [M+H]⁺ 276.1958 found 276.1962.

(7aR,8S,9aS,11R,13aS)-4,11-Dimethyltetradecahydro-1H-indeno[1,7a-e]azonine-8,13-diol 34

To a 25-mL round-bottomed flask equipped with reflux condenser, 9 (0.0310 g, 69 µmol, 1.0 equiv.) was dissolved in CH₃CN (ACS grade, 4 mL). KOH (1.0 M, 0.55 mmol, 0.55 mL, 8 equiv.) and PhSH (35 µL, 0.35 mmol, 5 equiv.) were added. The reaction was stirred at gentle reflux for 8 hours then cooled to room temperature. MeOH (ACS grade, 4 mL), aq. HCHO (37%, 154 µL, 2.07 mmol, 30 equiv.), and NaBH₃CN (0.013 g, 0.21 mmol, 3 equiv.) were added. After stirring at room temperature overnight, aq. HCl (1.0 M, 2.0 mL) was added and the mixture was extracted with 1M HCl (3 × 3 mL). The combined aqueous layer was added solid Na₂CO₃ until saturation. The resulting mixture was extracted with 5% MeOH in CHCl₃ (4 × 4 mL) and the combined organic layer was dried over anhydrous Na₂SO₄. After filtration and concentration, the residue was purified by flash column chromatography (basic alumina, 3% MeOH in CHCl₃) to afford title compound (0.0175 g, 90%) as a white solid. IR (thin film): 3356, 2925, 2869, 1721, 1660, 1455, 1376, 1273, 1107, 1066 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 4.58–4.66 (m, 1H), 3.59–3.66 (m, 1H), 2.51–2.76 (m, 3H), 2.17–2.47 (m, 6H), 1.81–2.14 (m, 5H), 1.11–1.74 (m, 12H), 0.93 (d, J = 6.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 74.4, 73.8, 55.8, 51.9, 48.0, 46.8, 43.3, 39.4, 37.6, 33.0, 28.4, 27.5, 26.7, 25.8, 22.4, 19.6; HRMS (ESI) calcd. for C₁₇H₃₂NO₂ [M+H]⁺ 282.2428 found 282.2434.

(7aR,9aS,11R,13aS)-4,11-Dimethyldecahydro-1H-indeno[1,7a-e]azonine-8,13(2H,9H)-dione 35

To a 15-mL flame dried round-bottomed flask, CH₂Cl₂ (1.0 mL) was added and the flask was cooled to −78 °C (dry ice/acetone bath). (COCl)₂ (13 µL, 152 µmol, 10.0 equiv.) and DMSO (21.6 µL, 304 µmol, 20.0 equiv.) were added. The mixture was stirred at −78 °C for 30 minutes before 34 (4.3 mg, 15.2 µmol, 1.0 equiv.) in 1.0 mL CH₂Cl₂ was added via syringe. The resulting mixture was stirred at −78 °C for 1 hour and then NEt₃ (85 µL, 608 µmol, 40.0 equiv.) was added. After another 20 minutes, the reaction was allowed to warm to room temperature and stirred at room temperature for 2 hours. Brine (4 mL) was added and the resulting mixture was extracted with 3% MeOH in CHCl₃ (3 × 4 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrate to afford crude 35, which was used immediately in next step without further purification. An analytic sample was purified by flash column chromatography (3% MeOH in CH₂Cl₂) to give title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 2.90 (d, J = 5.2 Hz, 1H), 2.49–2.62 (m, 2H), 2.04–2.45 (m, 12H), 1.72–1.99 (m, 5H), 1.31–1.52 (m, 3H), 1.12–1.20 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 220.4, 214.4, 60.9, 55.0, 50.4, 49.0, 46.9, 44.5, 42.8, 39.6, 31.3, 30.4, 28.3, 25.5, 22.7, 22.6, 21.9; HRMS (ESI) calcd. for C₁₇H₂₈NO₂ [M+H]⁺ 278.2115 found 278.2110.

(±)-Lycoposerramine B 4

Following the procedure described by Harayama and Takayama,^12a to a solution of crude 35 (15.2 µmol, theoretical) obtained above in EtOH (1.5 mL) was added Et₂NH (7.9 µL, 76 µmol, 5.0 equiv.). The mixture was stirred at room temperature for 3 hours then NH₂OH·HCl (0.2 M in EtOH, 83.5 µL, 1.1 equiv.) was added dropwise via syringe. After stirring at room temperature for additional 24 hours, the reaction was quenched with chilled sat. NaHCO₃ (3 mL) and extracted with 5% MeOH in CHCl₃ (4 × 5 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was chromatographed (10% MeOH in CHCl₃) to afford crude titled compound. The crude was rechromatographed (NH₃·H₂O/MeOH/CHCl₃ 0.05/5/95) to afford title compound (1.8 mg, 40%) as a colorless oil. IR (thin film): 2918, 2849, 1702, 1451, 1369, 1268, 1210, 1139, 1076 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.18 (d, J = 3.2 Hz, 1H), 2.66 (app td, J = 13.6, 3.6 Hz, 1H), 2.55 (ddd, J = 18.8, 9.2, 0.8 Hz, 1H), 2.38–2.45 (m, 1H), 2.18–2.36 (m, 8H), 1.96–2.16 (m, 4H), 1.55–1.80 (m, 5H), 1.43–1.50 (m, 1H), 1.15–1.40 (m, 3H), 1.04 (d, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 214.0, 169.8, 61.9, 55.2, 48.7, 47.0, 44.5, 43.1, 31.8, 30.1, 29.9, 28.9, 27.7, 25.7, 25.6, 22.6, 21.6; HRMS (ESI) calcd. for C₁₇H₂₉N₂O₂ [M+H]⁺ 293.2224 found 293.2226.