The Pauson-Khand Reaction as a New Entry to the Synthesis of Bridged Bicyclic Heterocycles: Application to the Enantioselective Total Synthesis of (−)-Alstonerine

Abstract

The first application of the Pauson-Khand reaction (PKR) to the synthesis of azabridged bicyclic structures is described. Compounds containing azabicyclo[3.3.1]nonane and azabicyclo[3.2.1]octane rings fused to cyclopentenones were efficiently constructed via the PKR of cis-2,6-disubstituted N-acyl piperidine enyne substrates, many of which can be readily prepared from 4-methoxypyridine in a few steps. Moreover, the PKR of cis-2,6-disubstituted piperazine enynes allowed the preparation of diazabicyclo[3.3.1]nonanes fused to cyclopentenones. This new strategy for the synthesis of azabridged bicyclic frameworks was exploited as a key step in a concise, enantioselective total synthesis of the macroline alklaoid (−)-alstonerine.

1. Introduction

The macroline/sarpagine alkaloids comprise a diverse class of biologically active natural products characterized by an azabicyclo[3.3.1]nonane annelated to an indole ring.ⁱ A variety of methods have been devised to access this structural motif, and these include a sequential Pictet-Spengler reaction and Dieckmann condensation,ⁱⁱ ring-closing metathesis,ⁱⁱⁱ phosphine-catalyzed [4+2] annulation/Friedel-Crafts cyclization,^iv and aza Diels-Alder/intramolecular Heck reaction.^v As a representative member of the macroline family of alkaloids, alstonerine (1) has been the subject of a number of synthetic studies culminating in two total syntheses and one formal synthesis.^iv,vi In addition to its challenging structural features, 1 has been reported to exhibit cytotoxic activity against two human lung cancer cell lines.^vii

Within the context of an ongoing interest in the synthesis of complex, biologically active alkaloids, we have been interested in designing novel and general strategies for the facile preparation of the representative members of different alkaloid families.^viii While developing new transition metal-catalyzed cascade reaction sequences,^ix we became interested in examining possible applications of the Pauson-Khand reaction (PKR) toward alkaloid synthesis. The intramolecular version of the PKR has been applied to the syntheses of a few alkaloid natural products,^x but in each case its use has been limited to the preparation of bicyclo[3.3.0]octenones and bicyclo[3.3.0]nonenones.^xi

As is apparent from the retrosynthetic strategy outlined in Scheme 1, we expected to obtain 1 by reduction, elimination, and acylation of the lactone 2, which we envisioined would arise by Baeyer-Villiger oxidation and stereoselective reduction of the enone 3. A key step in the synthesis of 1 would then be the PKR of the enyne 4, which had been previously prepared in our group,ⁱⁱⁱ to give 3. We anticipated that the PKR approach would represent a particularly efficient strategy for the preparation of 1, because the PKR of 4 would result in the formation of three new carbon-carbon bonds and the assembly of two rings in a single step. Notably, the enone 3 contains all of the carbons present in the core of 1.

Scheme 1.

2. Results and Discussion

2.1. Model Studies

Inasmuch as the pivotal PKR to form azabridged bicyclic frameworks lacked precedent, we undertook the synthesis of a number of cis-2,6-disubstituted piperidine enynes that differed in the number of carbons separating the alkene and alkyne moieties from the acylated nitrogen atom. We sought to use these enynes as substrates for PKRs to assemble azabicyclo[3.3.1]nonanes and azabicyclo[3.2.1]octanes. We reasoned that a number of such enynes could be easily prepared from 4-methoxypyridine (5) via slight modification of chemistry we had previously developed that was inspired by the work of Comins.^iii,xii Accordingly, 4-methoxypyridine (5) was treated with the acetylide ion derived from TMS-acetylene in the presence of Cbz-Cl, and following an acidic workup, the enone 6 was isolated in 95% yield (Scheme 2). Compound 6 underwent facile conjugate addition of allyl tributylstannane in the presence of TBS-OTf as a Lewis acid, and treating the intermediate adduct thus obtained in situ with TBAF furnished the enyne 7 in excellent yield and diastereoselectivity. Similarly, reaction of 6 with a vinyl cuprate followed by removal of the silyl group provided the enyne 8 with excellent diastereoselectivity.

Scheme 2.

Alternatively, treatment of 4-methoxypyridine (5) with the zinc reagent derived from 1-trimethylsilyl propargyl bromide in the presence of Cbz-Cl gave enone 9 in 77% yield (Scheme 3). Sequential reaction of 9 with a vinyl cuprate followed by treatment with TBAF gave the enyne 11 with excellent diastereoselectivity.

Scheme 3.

With a series of the requisite cis-2,6-disubstituted piperidines 7, 8, and 11 in hand, the PKR of 7 was investigated utilizing Co₂(CO)₈ and a number of common promoters, including NMO,^xiii BuSMe,^xiv and 4 Å molecular sieves.^xv The conditions that were found to be the most efficient involved reacting 7 with Co₂(CO)₈ to give an intermediate cobalt-complex that was then treated with six equivalents of DMSO and warmed to 65 °C. Using this protocol, the enone 14 was isolated in 89% yield as a single diastereomer (Table 1, entry 1). During the course of optimizing this reaction, we discovered that handling and storage of Co₂(CO)₈ under argon gave the best results. We briefly examined several catalytic variants employing either cobalt or rhodium catalysts, but these conditions failed to provide isolable quantities of the enone 14,^xvi and starting enyne 7 was typically recovered. With the optimized PKR conditions in hand, the enyne 11 was then cyclized to provide 15, again as a single diastereomer (entry 2). On the other hand, the PKR of enyne 8 gave the more strained enone 16 as a mixture (3:1) of diastereomers (entry 3).

Table 1.

Pauson-Khand Reactions of Piperidones

entry	substrate	product	yield (%)
1			89
2			91
3			33 (3:1 dr)

Each of the PKR substrates thus far prepared contained a carbonyl group at C(4) of the piperidine ring, and it was of interest to determine the effect of having an sp³ carbon atom at this position. Toward this end, the enyne 7 was treated with L-Selectride to deliver the alcohol 17, which was protected as the corresponding TBS-ether 18 (Scheme 4).

Scheme 4.

We were also interested in enyne substrates lacking functionality at C(4) such as 23. However, preliminary attempts to deoxygenate either 7 or 17 under a number of standard conditions to give 23 were unavailing. We therefore developed a different strategy for preparing 23 that was based upon previous work in our group.ⁱⁱⁱ In the event, alkylation of the known sulphone 19 with the acetylide derived from TMS-acetylene gave the lactam 20, which was N-acylated to provide 21 (Scheme 5). Reduction of the more electrophilic amide carbonyl group in 21 with DIBAL-H gave an intermediate N,O-acetal that was treated sequentially with allyltrimethylsilane TMS in the presence BF₃.Et₂O and fluoride ion to furnish the desired enyne 23.

Scheme 5.

Bicyclic derivatives of piperazine are commonly found in compounds having useful biological activities, so we were intrigued by the possibility of preparing cyclopentenone rings fused to diazabicyclo[3.3.1]nonanes via a PKR. In order to probe the feasibility of such processes we prepared the piperazine derivatives 30 and 31 using chemistry inspired by Beak.^xvii Accordingly, directed lithiation of the Boc-protected piperazines 24 and 25 followed by transmetalation and alkylation with allyl bromide provided the known allyl piperazines 26 and 27 (Scheme 6).^xviii A second directed lithiation of 26 and 27 followed by formylation of the intermediate carbanions with DMF provided a mixture of aldehyde epimers that underwent equilibration on silica gel to provide solely the cis-products 28 and 29. Subsequent treatment of aldehydes 28 and 29 with the Bestmann-Ohira reagent in methanol containing K₂CO₃ gave the piperazine enynes 30 and 31.

Scheme 6.

We discovered that the substitution at C(4) in 18, 23, 30 and 31 played a role in the diastereoselectivity of the PKR (Table 2). For example, the PKR of the silyl ether 18 gave 34 as a single diastereomer (entry 1), whereas 23, which bears a methylene group at C(4) underwent a PKR to give a mixture (4:1) of diastereomers favoring 35 as the major product (entry 2). The piperazines 30 and 31 underwent clean PKRs to give the enones 36 and 37 as single diastereomers (entry 3).

Table 2.

Pauson-Khand Reactions of Piperidines

entry	substrate	product	yield (%)
1			69
2			74 (4:1 dr)
3			R = Me; 85 R = Bn; 81

2.2. Total Synthesis of (−)-Alstonerine (1)

As outlined in Scheme 1, our plan for the total synthesis of (−)-alstonerine (1) hinged upon the PKR of the enyne 4 to give the azabridged bicyclic cyclopentenone 3. The precedent established in the PKRs of the model substrates described in the previous section strongly suggested that this retrosynthetic plan was sound. The known enyne 4 was first prepared in four steps from L-tryptophan following a procedure previously developed in our group.ⁱⁱⁱ The PKR of 4 proceeded smoothly to give the cyclopentenone 3 in excellent yield as a single diastereomer (Scheme 7). At this juncture, it was necessary to establish the relative stereochemistry of the newly established stereocenter on the cyclopentenone ring, but 3 was not crystalline. However, protection of the indole nitrogen atom with a Boc group gave 38, which was a crystalline compound. The X-ray structure of 38 showed that the hydrogen atom on the newly formed stereocenter was oriented trans to the bridging nitrogen atom, a stereochemical relationship that is identical to that found in (−)-alstonerine (1).

Scheme 7.

With the pentacyclic intermediate 3 readily in hand, the next stage of the synthesis required the ring expansion and oxidation of the cyclopentenone ring to give a δ-lactone ring as found in 2. We had originally envisionied that such a transformation might be induced via a Baeyer-Villiger reaction. Perhaps not unexpectedly in retrospect, initial experiments directed toward conducting a Baeyer-Villiger reaction on 3 gave complicated reaction mixtures. Reasoning competing oxidation of the indole ring in 3 might be a source of difficulty, we also examined the Baeyer-Villiger oxidation of 38 to ascertain whether we might access the unsaturated lactone 41. While the putative oxidation of the indole ring was thus thwarted, the Baeyer-Villiger reaction of 38 was accompanied by unavoidable double bond oxidation to give the epoxy lactone 39 (Scheme 8), a side reaction we knew was well precedented.^xix As a final attempt, we treated 38 with basic hydrogen peroxide, a reagent that has been reported to induce Baeyer-Villiger reactions of strained ketones,^xx but this reaction afforded only the epoxide 40.

Scheme 8.

Since we were unable to obtain the unsaturated lactone 41 by a Baeyer-Villiger reaction of 38, it was necessary to devise an alternate plan for the synthesis of (−)-alstonerine (1); this is outlined in retrosynthetic format in Scheme 9. Namely, we envisioned that the saturated lactone 42 would arise from reduction of the aldehyde 43 followed by lactonization. The aldehyde 43 would in turn be prepared by the oxidative cleavage of the silyl enol ether 44, which in turn would be obtained from either 3 or preferably 38 by stereoselective hydrosilylation of the enone moiety.

Scheme 9.

In order to minimize any interference from the electron rich indole ring, we initiated our studies with the protected indole 38. After some experimentation, we discovered that hydrosilylation of 38 was most efficiently induced by treating 38 with 0.5% platinum divinyltetramethyl disiloxane complex (Karstedt’s catalyst) in the presence of five equivalents of i-Pr₃SiH at elevated temperature to give 45 in excellent yield (Scheme 10).^xxi Less bulky silanes such as TES-H and TBS-H led to the formation of significant amounts of the ketone 46 (20–30%), which could have arisen via two different pathways. Silane dimerization would form molecular hydrogen that could then reduce the enone in the presence of the platinum catalyst to give 46.^xxii Alternatively, hydrolysis of the less stable TES- and TBS-enol ethers 44 (R₃ = Et₃ or t-BuMe₂) would also produce 46. The stereochemistry of the hydrosilylation of 38 was determined by converting the silyl enol ether 45 into the crystalline amino alcohol 47 in four steps [(a) TBAF, THF; (b) NaBH₄, THF; (c) silica gel, 100 °C; (d) H₂, Pd/C, EtOAc] in about 50% overall yield. Inasmuch as the X-ray analysis of 47 confirmed that the relative stereochemistry of 47 was identical to that found in 1, we could further advance our efforts toward the synthesis of 1.

Scheme 10.

Because ozonolysis of 45 under several different conditions gave complex mixtures, we turned to a two-step procedure to induce oxidative cleavage of the silyl enol ether moiety in 45. Rubbottom oxidation of 45 using MCPBA or DMDO under a number of conditions was found to be problematic. Similarly, oxidation of 45 using various protocols involving catalytic quantities of OsO₄ led to low conversions. However, treatment of 45 with stoichiometric amounts of OsO₄ led to complete consumption of 45, and reduction of the intermediate osmate ester using H₂S furnished a mixture of epimeric α-hydroxy ketones 48 (Scheme 11). This mixture of α-hydroxy ketones was treated with Pb(OAc)₄ in the presence of MeOH to give an aldehyde/ester intermediate that was reduced in situ to deliver the hydroxy ester 49. Lactonization of 49 under acidic conditions then gave the lactone 50, which is a protected derivative of 2.

Scheme 11.

Although we had developed an efficient route to access the lactone 50, the use of stoichiometric amounts of osmium and lead reagents inspired us to pursue an oxidative cleavage strategy that was more environmentally benign. The application of Johnson-Lemieux conditions to the oxidative cleavage of silyl enol ethers is rare.^xxiii Consequently, we were gratified to find that reaction of 45 with a catalytic amount of OsO₄ (10%) in the presence of NaIO₄ gave the intermediate aldehyde/ester 51 that underwent facile lactonization upon sequential treatment with NaBH₄ and acid to give 50 (Scheme 12).

Scheme 12.

Having thus developed an improved route to the intermediate lactone 50, it was necessary to convert the δ-lactone into a dihydropyran. Toward this objective, 50 was reduced with DIBAL-H to afford an intermediate lactol that was converted to the dihydropyran 52 by a one step process involving O-mesylation and elimination (Scheme 13). Compound 52 was then transformed into the N,N′-dimethyl derivative 54 by reduction of the Cbz group to a methyl group and removal of the Boc group with LiAlH₄ followed by methylation of the indole nitrogen atom of the 53 thus formed.

Scheme 13.

The final phase of the synthesis of (−)-alstonerine (1) required acetylation of the dihydropyran ring of 54. We therefore examined a number of Friedel-Crafts reaction conditions that had previously been employed to acetylate dihydropyran rings.^xxiv However, treatment of 54 with acetylating agents such as AcCl and Ac₂O in the presence of different Lewis acids (AlCl₃, BF₃•OEt₂, FeCl₃, ZnCl₂) led to mixtures of products (Scheme 14). Competitive acylation at C(5) of the indole ring system was observed as a predominant side reaction, and only small quantities of 1 were obtained. In previous work directed toward the syntheses of heteroyohimboid alkaloids,^xxv we had discovered that dihydropyrans could be readily trichloroacetylated using trichloroacetyl chloride under less forcing conditions and in the absence of Lewis acid catalysis. If 54 could be converted into 55, reduction of the trichloroacetyl group would afford 1. However, treatment of 54 with trichloroacetyl chloride at room temperature led to rapid formation of an intractable mixture of unidentifiable products.

Scheme 14.

This result did not occasion great surprise as we had previously found that those reactions of pentacyclic indolic dihydropyrans having free amines and/or unprotected indoles could be problematic.^xxv Although several attempts to acetylate the protected substrate 52 with AcCl in the presence of Lewis acids were unsuccessful, we discovered that trichloroacetylation of 52 was readily accomplished to give 55 (Scheme 15). Reduction of the trichloroacetyl group using Zn/HOAc gave the protected (−)-alstonerine 56 in good yield over the two steps. This sequence of reactions should prove to be generally useful as a method for the synthesis of C(2)-acylated glycals, a functional motif found widely in biologically active natural products.^xxvi

Scheme 15.

Removal of both of the carbamate protecting groups from 56 proceeded cleanly upon treatment with TMS–I to give 57, which was N,N′-dimethylated 57 by sequential reaction with MeI to methylate the bridging secondary amine followed by NaH and MeI to alkylate the indole nitrogen atom, thereby completing the enantioselective synthesis of (−)-alstonerine (1). The spectral data (¹H and ¹³C NMR) for the synthetic 1 thus obtained were consistent with those previously reported,^vib and the optical rotation was comparable to the value reported in the literature.^via

3. Conclusion

In summary, we have developed the first application of the Pauson-Khand reaction to prepare azabridged bicyclic compounds. A number of cis-2,6-disubstituted piperidine and piperazine enynes were efficiently prepared, and these enynes underwent PKR to give cyclopentenone rings fused to aza- and diazabicyclo[3.n.1]alkanes (n = 2, 3), typically in high yields and high diastereoselectivities. The utility of this new entry to bridged nitrogen heterocycles was highlighted by its application to the concise, enantioselective total synthesis of the macroline indole alkaloid (−)-alstonerine (1). The total synthesis of 1 required only 15 chemical steps from L-tryptophan and proceeded in a 4.4% overall yield. Other key steps in the synthesis entailed a conjugate hydrosilylation of the cyclopentenone and an oxidative cleavage that led to an intermediate δ-lactone. Moreover, a novel, mild two-step protocol to acetylate cyclic enol ethers such as dihydropyrans to give vinylogous esters, a common structural subunit in many natural products, was developed. Further applications of PKR reactions to the syntheses of other biologically active alkaloid natural products are in progress and will be reported in due course.

Experimental

General

Solvents and reagents were reagent grade and used without purification unless otherwise noted. Dichloromethane (CH₂Cl₂) and triethylamine (Et₃N) were distilled from calcium hydride and stored under nitrogen. After opening, Co₂(CO)₈ was handled and stored under argon. Tetrahydrofuran (THF) and diethyl ether (Et₂O) were passed through a column of neutral alumina and stored under argon. Methanol (MeOH) and dimethylformamide (DMF) were passed though a column of molecular sieves and stored under argon. Toluene was passed through a column of Q5 reactant and stored under argon. All reactions were performed in flame-dried glassware under nitrogen or argon. ¹H nuclear magnetic resonance (NMR) spectra were obtained at 500 or 400 MHz. Chemical shifts are reported in parts per million (ppm, δ) and referenced to the solvent. Coupling constants are reported in Hertz (Hz). Spectral splitting patterns are designated as: s, singlet; d, doublet; t, triplet; m, multiplet; comp, complex; br, broad; and bs, broad singlet. Infrared (IR) spectra were obtained using a Perkin-Elmer FTIR 1600 spectrophotometer on sodium chloride plates and reported as wavenumbers (cm⁻¹). Low-resolution chemical ionization mass spectra were obtained on a Finnigan TSQ-70 instrument, and high-resolution measurements were obtained on a VG Analytical ZAB2-E instrument. Analytical thin layer chromatography was preformed using Merck 250 micron 60F-254 silica plates. The plates were visualized with UV light, p-anisaldehyde, and potassium permanganate. Flash column chromatography was performed according to Still’s method using ICN Silitech 32–63 D 60A silica gel.^xxvii

4-Oxo-2-trimethylsilanylethynyl-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (6)

EtMgBr (2.35 mL, 2 M in THF, 4.7 mmol) was added to a solution of TMS-acetylene (508 mg, 5.17 mmol) in THF (4 mL) at −78 °C, and the cooling bath was removed while stirring was continued for 30 min. The solution was added to a solution of 4-methoxypyridine (430 mg, 3.90 mmol) in THF (4 mL) at −78 °C, and the reaction was stirred for 5 min. Upon warming to −20 °C, Cbz-Cl (1.00 g, 5.90 mmol) was added. The reaction was stirred for an additional 20 min, whereupon 10% HCl (6 mL) was added. The cooling bath was removed, and stirring was continued for 10 min. Et₂O (6 mL) was added, and the aqueous layer was extracted with Et₂O (3 × 10 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 678 mg (96%) of 6 as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 7.2 Hz, 1 H), 7.39-7.32 (comp, 5 H), 5.41-5.22 (comp, 4 H), 2.79 (dd, J = 16.4, 6.8 Hz, 1 H), 2.58 (d, J = 16.4 Hz, 1 H), 0.09 (s, 9 H); ¹³C NMR (100 MHz, CDCl₃) δ 191.1, 134.8, 128.8, 128.7, 128.6, 128.1, 107.7, 100.3, 89.5, 69.1, 45.6, 41.2, 38.1, −0.39; IR (neat) 2960, 1732, 1677, 1609, 1329, 1307, 1252, 1213, 1188, 845 cm⁻¹; mass spectrum (CI) m/z 328.1373 [C₁₈H₂₂NO₃Si (M+H) requires 328.1369], 328 (base), 312, 284.

2-Allyl-6-ethynyl-4-oxopiperidine-1-carboxylic acid benzyl ester (7)

TBS-OTf (924 mg, 3.50 mmol) was added to a solution of 6 (950 mg, 2.91 mmol) and allyltributylstannane (1.15 g, 3.50 mmol) in CH₂Cl₂ (15 mL) at −78 °C, and the solution was stirred for 15 min. TBAF (2.90 g, 9.00 mmol) was added, and the cooling bath was removed. After 30 min, NH₄Cl (15 mL) was added. The mixture was extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 830 mg (96%) of 7 as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.20 (comp, 5 H), 5.80-5.40 (comp, 2 H), 5.20-5.00 (comp, 4 H), 4.52 (bs, 1 H), 2.80-2.40 (comp, 6 H), 2.41 (d, J = 2.7 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ 205.4, 154.8, 135.9, 133.9, 128.5, 128.2, 128.0, 118.3, 82.5, 67.9, 53.2, 45.1, 42.9, 42.7, 39.5; IR (neat) 3285, 3067, 3033, 2977, 1693, 1642, 1404, 1322, 1112, 1028, 920, 698 cm⁻¹; mass spectrum (CI) m/z 298.1439 [C₁₉H₂₀NO₃ (M+H) requires 298.1443].

2-Ethynyl-4-oxo-6-vinyl-piperidine-1-carboxylic acid benzyl ester (8)

MeLi (0.94 mL, 1.6 M in Et₂O, 1.5 mmol) was added to a suspension of CuCN (134 mg, 1.5 mmol) in THF (4 mL) at −78 °C. The mixture was cooled to 0 °C, stirred for 1 min, and then recooled to −78 °C. A solution of vinyl magnesium bromide (1.5 mL, 1 M in THF, 1.5 mmol) was added dropwise. The reaction was stirred for 20 min, whereupon a solution of 6 (327 mg, 1 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred for 1 h at −78 °C, at which point the reaction was poured into a vigorously stirred mixture (9:1) of saturated NH₄Cl/NH₄OH. The mixture was stirred 30 min until all the solids has dissolved, and the solution was extracted with Et₂O (3 × 20 mL). The combined organic layers were washed with H₂O (30 mL), brine (30 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 227 mg (64%) of a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.30 (comp, 5 H), 6.07 (ddd, J = 16.8, 10.4, 6.4 Hz, 1 H), 5.49 (bs, 1 H), 5.22-5.10 (comp, 4 H), 4.88 (bs, 1 H), 2.97 (dd, J = 15.6, 7.2 Hz, 1 H), 2.69-2.58 (comp, 3 H), 0.12 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃) δ 205.4, 154.7, 137.6, 136.0, 128.5, 128.2, 128.0, 116.3, 107.7, 104.0, 90.7, 67.9, 54.7, 45.3, 43.2, −0.49; IR (neat) 2959, 1704, 1403, 1309, 1250, 1224, 1054, 844 cm⁻¹; mass spectrum (CI) m/z 356 (M+H) (base), 340, 312, 257, 168. TBAF (400 mg, 1.12 mmol) was added in one portion to a solution of the above oil (200 mg, 0.56 mmol) in THF (5 mL). The reaction was stirred for 30 min and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 83 mg (53%) of 8 as a pale yellow oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 7.40-7.30 (comp, 5 H), 6.07 (ddd, J = 17.0, 10.5, 6.0 Hz, 1 H), 5.42 (dt, J = 7.5, 2.5 Hz, 1 H), 5.18 (d, J = 17.0 Hz, 1 H), 5.17 (s, 2 H), 5.10 (d, J = 9.0 Hz, 1 H), 5.00 (dd, J = 13.0, 6.0 Hz, 1 H), 3.22 (s, 1 H), 2.87 (dd, J = 16.0, 7.0 Hz, 1 H), 2.80 (dd, J = 16.0, 7.0 Hz, 1 H), 2.65 (dd, J = 16.0, 5.5 Hz, 1 H), 2.46 (d, J = 2.4 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ 205.0, 154.8, 137.3, 135.8, 128.5, 128.2, 128.0, 116.7, 82.4, 73.8, 68.0, 54.8, 44.9, 43.2, 42.5; IR (neat) 3285, 2957, 1698, 1403, 1310, 1264, 1310, 1264, 1226, 1113, 1027, 698 cm⁻¹; mass spectrum (CI) m/z 284.1291 [C₁₇H₁₈NO₃ (M+H) requires 284.1287] 284 (base), 266, 240.

4-Oxo-2-(3-trimethylsilanyl-prop-2-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (9)

3-Trimethylsilylpropargyl bromide (2.74 g, 14.4 mmol) was added to a mixture of 4-methoxypyridine (752 mg, 7.2 mmol), Zn dust (1.87 g, 28.8 mmol), and HgCl₂ (30 mg, 0.1 mmol) in THF (50 mL), and the reaction was heated to reflux for 3 h. Upon cooling to room temperature, Cbz-Cl (2.45 g, 14.4 mmol) was added dropwise, and the reaction was stirred for 10 min. The mixture was filtered through a plug of Celite (1 cm) to remove excess Zn dust washing with EtOAc (30 mL). The filtrate was washed with 1 N HCl (2 × 50 mL), brine (50 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (9:1-3:1) to give 1.90 g (77%) of 9 as a yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 7.68 (bs, 1 H), 7.34-7.15 (comp, 5 H), 5.25 (bs, 1 H), 5.20 (s, 2 H), 4.66 (bs, 1 H), 2.69 (d, J = 6.0 Hz, 2 H), 2.50 (d, J = 7.6 Hz, 2 H), 0.09 (s, 9 H); ¹³C NMR (100 MHz, CDCl₃) δ 191.7, 141.0, 134.6, 128.5, 128.1, 127.1, 126.6, 100.9, 88.2, 68.9, 64.7, 51.6, 38.4, 21.9, −0.4; IR (neat) 2959, 2900, 1731, 1672, 1604, 1328, 1296, 1198, 1107, 1016, 847, 760, 698 cm⁻¹; mass spectrum (CI) m/z 342.1528 [C₁₉H₂₄NO₃Si (M+H) requires 342.1525] 342 (base), 326.

4-Oxo-2-(3-trimethylsilanylprop-2-ynyl)-6-vinylpiperidine-1-carboxylic acid benzyl ester (10)

A solution of MeLi (2.88 mmol, 1.8 mL, 1.6 M in hexanes) was slowly added to a suspension of flame dried CuCN (256 mg, 2.88 mmol) at −78 °C. The reaction was warmed to 0 °C for 1 min and then recooled to −78 °C. Vinyl magnesium bromide (2.88 mmol, 2.88 mL, 1 M in THF) was added dropwise over 5 min, and the reaction was stirred for 10 min. A solution of 9 (655 mg, 1.92 mmol) in THF (2 mL) was added, and the mixture which turned a deep orange/red color was stirred at −78 °C for 1.5 h. The reaction was poured into a solution of NH₄Cl/NH₄OH (9:1, 10 mL), and stirred until all the salts dissolved. The aqueous solution was extracted with Et₂O (3 × 10 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 678 mg (96%) of 10 as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 7.40-7.29 (comp, 5 H), 6.02 (ddd, J = 15.5, 10.5, 5.0 Hz, 1 H), 5.19-5.10 (comp, 5 H), 4.60 (dt, J = 7.0, 6.0 Hz, 1 H), 2.79 (dd, J = 16.0, 7.5 Hz, 1 H), 2.71 (dd, J = 16.0, 7.5 Hz, 1 H), 2.63-2.47 (comp, 5 H), 0.12 (s, 9 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 205.2, 154.5, 139.0, 136.1, 127.8, 127.2, 126.9, 115.0, 103.4, 86.8, 66.4, 52.6, 51.0, 41.8, 41.7, 25.9, −0.7; IR (neat) 3089, 3034, 2959, 2900, 1698, 1607, 1403, 1326, 1250, 843 cm⁻¹; mass spectrum (CI) m/z 370.1848 [C₂₁H₂₈NO₃Si (M+H) requires 370.1838].

4-Oxo-2-prop-2-ynyl-6-vinylpiperidine-1-carboxylic acid benzyl ester (11)

TBAF·H₂O (300 mg, 0.900 mmol) was added in one portion to a stirred solution of 10 (300 mg, 0.813 mmol) in THF (5 mL). The reaction was stirred for 5 min and NH₄Cl (5 mL) was added. The mixture was extracted with Et₂O (3 × 5 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 166 mg (69%) of 11 as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 7.40-7.29 (comp, 5 H), 5.99 (ddd, J = 16.0, 10.5, 4.5 Hz, 1 H), 5.19-5.12 (comp, 5 H), 4.61 (dt, J = 6.5 5.0 Hz, 1 H), 2.80 (dd, J = 16.0, 7.0 Hz, 1 H), 2.74 (dd, J = 16.0, 7.0 Hz, 1 H), 2.69 (dt, J = 3.0, 1.0 Hz, 1 H), 2.59 (ddd, J = 19.2, 3.0, 1.5 Hz, 1 H), 2.53-2.46 (comp, 3 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 205.2, 154.5, 138.8, 136.1, 127.8, 127.2, 127.0, 115.2, 80.3, 72.4, 66.4, 52.7, 51.2, 41.7, 41.6, 24.7; IR (neat) 3307, 3035, 2959, 1694, 1407, 1320, 1271, 1114, 1057 cm⁻¹; mass spectrum (CI) m/z 298.1443 [C₁₈H₂₀NO₃ (M+H) requires 298.1443].

Representative Procedure for PKR of cis-2,6-Disubstituted Piperidines

4,10-Dioxo-12-azatricyclo[6.3.1.0^2,6]dodec-2-ene-12-carboxylic acid benzyl ester (14)

Co₂(CO)₈ (45 mg, 0.130 mmol) was added to 7 (35 mg, 0.118 mmol) in THF (1 mL) under an Ar atmosphere. The reaction was stirred for 1 h and complete conversion to the alkyne-Co(CO)₆ complex observed by TLC. DMSO (55 mg, 0.708 mmol) was added, and the reaction was heated to 50 °C for 14 h. Et₂O (3 mL) was added and the reaction was filtered through Celite washing with acetone (5 mL). The combined filtrate and washings were concentrated under reduced pressure to give a dark oil that was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 34 mg (89%) of 14 as a white solid; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 7.60-7.20 (comp, 5 H), 5.98 (s, 1 H), 5.57 (d, J = 7.0 Hz, 1 H), 5.17 (s, 2 H), 4.80 (s, 1 H), 2.96 (dd, J = 16.5, 7.0 Hz, 2 H), 2.84 (dd, J = 11.0, 7.5 Hz, 2 H), 2.54-2.44 (m, 1 H), 2.35 (d, J = 16.5 Hz, 1 H), 2.19 (ddd, J = 13.5, 6.5, 2.0 Hz, 1 H), 1.92 (dd, J = 18.5, 3.0 Hz, 1 H), 1.60 (dt, J = 13.5, 1.0 Hz, 1 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 205.8, 205.5, 175.5, 153.1, 136.1, 127.9, 127.4, 127.0, 126.5, 66.5, 50.2, 48.0, 44.0, 43.7, 41.1, 38.4, 32.8; IR (neat) 3582, 3408, 3063, 2957, 2919, 1694, 1633, 1416, 1096, 913; mass spectrum (CI) m/z 326.1381 [C₁₉H₂₀NO₄ (M+H) requires 326.1392].

4,10-Dioxo-12-azatricyclo[6.3.1.0^2,6]dodec-5-ene-12-carboxylic acid benzyl ester (15)

The PKR of 11 was performed on a scale of 0.17 mmol according to the representative procedure, and the crude product was purified by flash chromatography eluting with EtOAc to give 15 in a 91% yield as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 7.42-7.31 (comp, 5 H), 5.93 (s, 1 H), 5.21 (s, 2 H), 4.94 (dt, J = 8.0, 1.5 Hz, 1 H), 4.85 (t, J = 6.5 Hz, 1 H), 3.15 (dt, J = 6.5, 1.5 Hz, 1 H), 2.83 (d, J = 14.0 Hz, 1 H), 2.74 (dd, J = 15.0, 6.0 Hz, 1 H), 2.68 (dd, J = 16.5, 6.5 Hz, 1 H), 2.54 (dd, J = 17.0, 7.0 Hz, 1 H), 2.41 (dd, J = 19.0, 7.0 Hz, 1 H), 2.28 (t, J = 15.0 Hz, 1 H), 2.10 (dd, J = 19.5, 2.5 Hz, 1 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 205.0, 204.3, 173.5, 153.3, 136.1, 131.7, 127.9, 127.3, 127.0, 66.5, 50.7, 47.4, 44.8, 43.6, 38.7, 36.7, 34.8; IR (neat) 3035, 2963, 2902, 1706, 1626, 1416, 1335, 1264, 1220, 1100, 1028 cm⁻¹; mass spectrum (CI) m/z 326.1392 [C₁₉H₂₀NO₄ (M+H) requires 326.1392].

4,9-Dioxo-11-azatricyclo[5.3.1.0^2,6]undec-2-ene-11-carboxylic acid benzyl ester (16)

The PKR of 8 was performed on a scale of 0.17 mmol according to the representative procedure, and the crude product was purified by flash chromatography eluting with hexanes/EtOAc (3:1-1:1) to give 14 mg (33%) of 16 as a colorless oil as a mixture (3:1) of diastereomers; ¹H NMR (500 MHz, d₆−DMSO, 100 °C) δ 7.42-7.31 (comp, 5 H), 6.09 (s, 1 H), 5.38 (bs, 1 H), 5.20 (s, 2 H), 5.24-5.23 (m, 1 H), 4.62 (t, J = 6.0 Hz, 1 H), 3.49-3.45 (m, 1 H), 2.91 (dd, J = 17.0, 6.0 Hz, 1 H), 2.84-2.79 (comp, 1 H), 2.60 (dd, J = 18.0, 6.0 Hz, 1 H), 2.38 (d, J = 18.0 Hz, 1 H), 2.17 (dd, J = 18.0, 3.0 Hz, 1 H); mass spectrum (CI) m/z 312.1234 [C₁₈H₁₈NO₄ (M+H) requires 312.1236] 312 (base), 268.

2-Allyl-6-ethynyl-4-hydroxypiperidine-1-carboxylic acid benzyl ester (17)

A solution of 7 (750 mg, 2.52 mmol) in THF (20 mL) was cooled to −78 °C and a solution of L-selectride (3.0 mL, 1 M in THF) was added dropwise. The reaction was stirred at −78 °C whereupon sat. NH₄Cl (10 mL) was added. The mixture was extracted with Et₂O (3 × 10 mL) and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1-1:1) to give 524 mg (70%) of 17 as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.29 (comp, 5 H), 5.76 (ddt, J = 16.8, 10.0, 7.2 Hz, 1 H), 5.28-4.96 (comp, 5 H), 4.29-4.22 (m, 1 H), 2.83 (t, J = 7.2 Hz, 2 H), 2.63 (d, J = 2.4 Hz, 1 H), 2.21-1.98 (comp, 3 H), 1.73 (ddd, J = 3.2, 7.2, 14.0, Hz, 1 H); ¹³C NMR (125 MHz, CDCl₃) (rotamers) δ 155.4, 136.4, 135.9, 128.5, 128.0 127.9, 117.4, 85.5, 71.8, 67.5, 64.6, 50.3, 39.5, 38.2, 36.4, 32.6, 29.7; IR (neat) 3447, 3297, 2953, 1684, 1409, 1324, 1087, 1063, 990, 914 cm⁻¹; mass spectrum (CI) m/z 300.1602 [C₁₈H₂₂NO₃ (M+H) requires 300.1600], 300 (base), 258, 256, 238, 214.

2-Allyl-4-(tert-butyldimethylsilanyloxy)-6-ethynylpiperidine-1-carboxylic acid benzyl ester (18)

17 (250 mg, 0.84 mmol) was dissolved in DMF (5 mL) and imidazole (170 mg, 2.5 mmol) and TBS-Cl (151 mg, 1 mmol) were added sequentially. The reaction stirred at room temperature for 12 h and NH₄Cl (5 mL) was added. The mixture was extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layers were washed with H₂O (5 mL), brine (5 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (9:1) to give 268 mg (81%) of 18 as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.29 (comp, 5 H), 5.77 (ddd, J = 17.2, 10.0, 7.2 Hz, 1 H), 5.15 (s, 2 H), 5.07 (d, J = 17.2 Hz, 1 H), 4.97 (d, J = 10.0 Hz, 1 H), 4.26-4.20 (m, 1 H), 4.08 (app p, J = 4.0 Hz, 1 H), 3.73 (dt, J = 6.8, 4.4 Hz, 1 H), 2.92-2.77 (m, 2 H), 2.20 (d, J = 2.4 Hz, 1 H), 2.02-1.67 (comp, 4 H), 0.90 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 155.5, 136.6, 136.5, 128.4, 127.9, 127.8, 116.8, 85.4, 70.6, 67.3, 64.2, 50.7, 39.1, 38.6, 36.6, 33.6, 25.8, 18.1, −4.9, −5.0; IR (neat) 3307, 2953, 2856, 1694, 1640, 1407, 1335, 1312, 1255, 1093, 774 cm⁻¹; mass spectrum (CI) m/z 414.2466 [C₂₄H₃₆NO₃Si (M+H) requires 414.2464] 414 (base), 398, 372, 356, 238.

6-Trimethylsilanylethynylpiperidin-2-one (20)

A solution of TMS-acetylene (3.23 g, 33 mmol) in THF (25 mL) was cooled to −78 °C and nBuLi (13.2 mL, 2.5 M in hexanes, 33 mmol) was added dropwise. The reaction was warmed to 0 °C and stirred for 10 min. The solution was added to a solution of 19 (2.6 g, 10.9 mmol) in THF (25 mL) at −78 °C, and the reaction was stirred for 30 min at −78 °C and 30 min at room temperature. The reaction was quenched with NaHCO₃ (30 mL) and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc to give 1.52 g (71%) of 20 as a white solid: mp = 126–127 °C; ¹H NMR (400 MHz, CDCl₃) δ 5.74 (s, 1 H), 4.26-4.23 (m, 1 H), 2.37-2.33 (comp, 2 H), 2.04-1.95 (comp, 2 H), 1.86-1.70 (comp, 2 H), 0.14 (s, 9 H); ¹³C NMR (100 MHz, CDCl₃) δ 171.2, 104.4, 88.1, 44.9, 31.1, 28.8, 18.8, −0.3; IR (neat) 3190, 3077, 2956, 1687, 1649, 1405, 1309, 1252, 841, 756 cm⁻¹; mass spectrum (CI) m/z 196.1160 [C₁₀H₁₈NOSi (M+H) requires 196.1158] 196 (base), 180.

2-Oxo-6-trimethylsilanylethynylpiperidine-1-carboxylic acid benzyl ester (21)

A solution of 20 (750 mg, 3.85 mmol) in THF (15 mL) was cooled to −78 °C and a solution of nBuLi (1.86 mL, 2.27 M in hexanes, 4.23 mmol) was added dropwise over 5 min. The reaction was stirred for 30 min whereupon Cbz-Cl (1.30 g, 7.70 mmol) was added. The cooling bath was removed, and the reaction was stirred for 15 min. The reaction was quenched with sat. NH₄Cl (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (9:1-3:1) to give 1.02 g (81%) of 21 as a white solid: mp = 70–71 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.29 (comp, 5 H), 5.32-5.24 (comp, 2 H), 5.12-5.10 (m, 1 H), 2.75-1.79 (comp, 6 H), 0.12 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃) δ 170.3, 152.9, 135.1, 128.3, 128.0, 127.7, 103.1, 88.8, 68.4, 48.3, 34.0, 28.5, 17.5, −0.4; IR (neat) 3065, 2959, 2899, 1778, 1738, 1714, 1498, 1455, 1373, 1250, 1134, 1062, 843 cm⁻¹; mass spectrum (CI) m/z 330.1526 [C₁₈H₂₄NO₃Si (M+H) requires 330.1525] 330 (base), 286, 270.

2-Allyl-6-ethynylpiperidine-1-carboxylic acid benzyl ester (23)

A solution of 21 (830 mg, 2.52 mmol) in THF (25 mL) was cooled to −78 °C and a solution of DIBAL-H (3.03 mL, 1 M in toluene, 3.03 mmol) was added slowly dropwise over 5 min. The reaction was stirred at −78 °C for 30 min and MeOH (0.5 mL) was added. The reaction was warmed to room temperature and sat. Rochelle’s salt (25 mL) was added with vigorous stirring. The mixture was extracted with EtOAc (3 × 15 mL) and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The pale yellow oil was dissolved in CH₂Cl₂ (25 mL) and cooled to −78 °C whereupon allyl TMS (1.43 g, 12.6 mmol) and BF₃.Et₂O (1.77 g, 12.6 mmol) were added sequentially. The reaction was stirred for 30 min and warmed to room temperature. NaHCO₃ (15 mL) was added and the mixture stirred for 15 min. The solution was extracted with CH₂Cl₂ (3 × 15 mL) and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure to give a crude oil (506 mg). A portion of the oil (200 mg) was dissolved in THF (10 mL) and TBAF (220 mg, 0.845 mmol) was added. The reaction was stirred at room temperature for 30 min and NH₄Cl (5 mL) was added. The mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (9:1) to give 138 mg (52%) of 23 as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 7.38-7.29 (comp, 5 H), 5.73 (ddd, J = 17.5, 10.0, 7.0 Hz, 1 H), 5.12 (s, 2 H), 5.05 (d, J = 17.5, Hz, 1 H), 5.04-5.02 (m, 1 H), 4.98 (d, J = 10.0 Hz, 1 H), 4.23-4.19 (m, 1 H), 2.99 (d, J = 2.5 Hz, 1 H), 2.56-1.48 (comp, 8 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 154.2, 136.3, 135.5, 127.7, 127.2, 126.9, 116.0, 84.5, 72.4, 66.0, 50.6, 40.9, 36.0, 29.8, 26.0, 14.0; IR (neat) 3294, 3248, 2944, 1697, 1406, 1318, 1267, 1098 cm⁻¹; mass spectrum (CI) m/z 284.1653 [C₁₈H₂₂NO₂ (M+H) requires 284.1651], 284 (base), 242, 198, 176.

2-Allyl-4-methyl-piperazine-1-carboxylic acid tert-butyl ester (26)

Compound 24 (1 g, 4.99 mmol), s-BuLi (20 mL of a 0.6 M solution in n-hexane, 11.98 mmol), TMEDA (1.39 g, 11.98 mmol), CuCN (1.07 g, 11.98 mmol), LiCl (1.02 g, 23.97 mmol), and allyl bromide (1.45 g, 11.98 mmol) in Et₂O (150 mL) were reacted as reported in literature.^xviii Purification via flash chromatography eluting with CH₂Cl₂-MeOH (20:1) yielded 26 (0.997 g, 83%) as a light yellow oil; ¹H NMR (400 MHz, CDCl₃) (rotamers) δ 5.65–5.77 (m, 1 H), 5.03 (d, J = 16.8 Hz, 1 H), 4.96 (d, J = 10.0 Hz, 1 H), 4.05 (bs, 1 H), 3.81 (d, J = 9.6 Hz, 1 H), 2.30 (t, J = 12.4 Hz, 1 H), 2.65 (t, J = 10.8 Hz, 2 H), 2.34–2.47 (m, 2 H), 2.18 (s, 3 H), 1.97 (d, J = 11.2 Hz, 1 H), 1.86 (t, J = 12.0 Hz, 2 H), 1.40 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃) (rotamers) δ 154.7, 135.3, 116.9, 79.4, 77.2, 57.1, 55.0, 50.7, 46.4, 39.1, 34.6, 28.3; IR (neat) 2358, 1698, 1458, 1409, 1365, 1247, 1174, 1106 cm⁻¹; mass spectrum (CI) m/z 241.1919 [C₁₃H₂₅N₂O₂ (M+H) requires 241.1916], 213, 199, 185.

2-Allyl-6-formyl-4-methyl-piperazine-1-carboxylic acid tert-butyl ester (28)

s-BuLi (0.95 mL of a 1.2 M solution in n-hexane, 1.14 mmol) was added to a mixture of 25 (0.210 g, 0.874 mmol) and TMEDA (0.132 g, 1.14 mmol) in Et₂O (20 mL) at −78 °C and the reaction was stirred for 1 hr. DMF (0.96 g, 1.31 mL) was quickly added and reaction was stirred for an additional 1 hr. The reaction was quenched at −78 °C with satd. NH₄Cl, allowed to warm to room temperature, extracted with Et₂O (4 × 10 mL), dried (K₂CO₃), and concentrated. The crude oil was then dissolved in hexanes/EtOAc/NEt₃ (98:2:1, 20 mL) and SiO₂ (1.4 g) was added. The reaction was allowed to stir until the disappearance of the trans- isomer was observed by TLC (eluting with CH₂Cl₂:MeOH, 20:1). The reaction was filtered, concentrated, and the residue purified via flash chromatography eluting with CH₂Cl₂:MeOH (30:1) to give 183 mg (78%) of 28 as a light yellow oil; ¹H NMR (400 MHz, CDCl₃) (rotamers) δ 9.63 (s, 1 H), 5.68–5.79 (m, 1 H), 5.98-5.04 (comp, 2 H), 4.35 (bs, 1 H), 4.00 (bs, 1 H), 3.30 (d, J = 11.6 Hz, 1 H), 2.65 (d, J = 10.8 Hz, 1 H), 2.21–2.28 (m, 2 H), 2.18 (s, 3 H), 2.01 (dd, J = 6.4, 5.2 Hz, 1 H), 1.95 (dd, J = 7.6, 4.0 Hz, 1 H), 1.48 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃) (rotamers) δ 200.4, 154.7, 136.1, 117.1, 79.6, 68.7, 61.2, 54.6, 50.5, 46.5, 39.3, 28.3; IR (neat) 2968, 2790, 1731, 1690, 1455, 1402, 1367, 1331, 1296, 1173, 1049 cm⁻¹; mass spectrum (CI) m/z 269.1867 [C₁₄H₂₅N₂O₃ (M+H) requires 269.1865], 241, 227, 213, 169, 154.

2-Allyl-6-ethynyl-4-methyl-piperazine-1-carboxylic acid tert-butyl ester (30)

To a mixture of 28 (0.480 g, 1.79 mmol), K₂CO₃ (0.742 g, 5.37 mmol) in MeOH (20 mL) at 0 °C was added Bestmann-Ohira reagent (0.688 g, 3.58 mmol). The reaction was warmed to room temperature and stirred under argon for 16 hr. The reaction was concentrated, dissolved in EtOAc (30 mL), washed with brine (1 × 10 mL), satd. NaHCO₃ (2 × 10 mL), brine (1 × 10 mL). The organic layer was dried (MgSO₄), filtered, concentrated, and the residue was purified via flash chromatography eluting with CH₂Cl₂:MeOH (30:1) to give 379 mg (80%) of 30 as a colorless oil; ¹H NMR (400 MHz, CDCl₃) (rotamers) δ 5.74–5.85 (m, 1 H), 5.14 (d, J = 17.2, 1 H), 5.05 (d, J = 10.4, 1 H), 4.85 (bs, 1 H), 4.00–4.04 (m, 1 H), 2.93 (dt, J = 11.6, 2.0 Hz, 1 H), 2.72–2.82 (comp, 2 H), 2.60–2.67 (m, 1 H), 2.28 (s, 3 H), 2.22 (d, J = 2.4 Hz, 2 H), 2.09 (dd, J = 7.2, 4.0 Hz, 1 H), 1.95 (dd, J = 7.2, 4.0, 1 H), 1.45 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃) (rotamers) δ 154.7, 136.4, 117.4, 84.7, 80.6, 70.3, 61.5, 59.5, 56.8, 46.9, 37.0, 28.6; IR (neat) 3295, 2978, 2942, 2802, 1696, 1455, 1390, 1337, 1296, 1249, 1179, 1044 cm⁻¹; mass spectrum (CI) m/z 265.1912 [C₁₅H₂₅N₂O₂ (M+H) requires 265.1916], 249, 237, 223, 209, 165, 154.

2-Allyl-4-benzyl-piperazine-1-carboxylic acid tert-butyl ester (27)

Compound 25 (0.200 g, 0.724 mmol), s-BuLi (1.2 mL of a 1.46 M solution in n-hexane, 1.74 mmol), TMEDA (0.202 g, 1.74 mmol), CuCN (0.156 g, 1.74 mmol), LiCl (0.148 g, 3.48 mmol), and allyl bromide (0.114 g, 0.941 mmol) in Et₂O (24 mL) were reacted as reported in literature.^xviii Purification via flash chromatography eluting with CH₂Cl₂-MeOH (30:1) yielded 27 (0.229 g, 84%) as a light yellow oil; ¹H NMR (400 MHz, CDCl₃) (rotamers) δ 7.35-7.22 (comp, 5 H), 5.74-5.64 (m, 1 H), 5.04-4.93 (comp, 2 H), 4.06 (bs, 1 H), 3.85 (d, J = 11.2 Hz, 1 H), 3.53 (d, J = 13.2 Hz, 1 H), 3.38 (d, J = 13.2 Hz, 1 H), 3.07 (td, J = 12.6, 2.8 Hz, 1 H), 2.76 (d, J =10.8 Hz, 1H), 2.70 (d, J = 11.2 Hz, 1 H), 2.53-2.41 (m, 2 H), 2.07-1.99 (comp, 2 H), 1.45 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃) (rotamers) δ 154.8, 138.4, 135.5, 128.8, 128.2, 127.0, 117.0, 79.4, 62.8, 54.7, 53.2, 34.6, 28.4; IR (neat) 3064, 2975, 2807, 1694, 1455, 1410, 1364, 1174 cm⁻¹; mass spectrum (CI) m/z 317.2229 [C₁₉H₂₉N₂O₂ (M+H) requires 317.2229], 289, 275, 261, 243, 217, 173.

2-Allyl-4-benzyl-6-formyl-piperazine-1-carboxylic acid tert-butyl ester (29)

s-BuLi (0.4 mL of a 1.46 M solution in n-hexane, 0.584 mmol) was added to a mixture of 27 (0.123 g, 0.389 mmol) and TMEDA (0.068 g, 0.584 mmol) in Et₂O (13 mL) at −78 °C and the reaction was stirred for 1 hr. DMF (0.043 g, 0.05 mL) was quickly added and reaction was stirred for an additional 1 hr. The reaction was quenched at −78 °C with satd. NH₄Cl, allowed to warm to room temperature, extracted with Et₂O (4 × 10 mL), dried (K₂CO₃), and concentrated. The crude oil was then dissolved in hexanes/EtOAc/NEt₃ (98:2:1, 13 mL) and SiO₂ (1.0 g) was added. The reaction was allowed to stir until the disappearance of the trans-isomer was observed by TLC (eluting with CH₂Cl₂:MeOH, 20:1). The reaction was filtered, concentrated, and the residue purified via flash chromatography eluting with CH₂Cl₂:MeOH (30:1) to give 0.134 g (81%) of 29 as a light yellow oil; ¹H NMR (400 MHz, CDCl₃) (rotamers) δ 9.61 (s, 1 H), 7.31-7.20 (comp, 5 H), 5.74-5.59 (m, 1 H), 5.03-4.83 (comp, 2 H), 4.46-4.32 (comp, 1 H), 4.02-3.84 (comp, 1 H), 3.55 (t, J = 12.8 Hz, 2 H), 3.37 (d, J = 13.2 Hz, 2 H), 2.77-2.68 (m, 1 H), 2.54-2.42 (m, 1 H), 2.35-2.26 (comp, 2 H), 2.21 (dd, J = 6.4, 4.4 Hz, 1 H), 2.06-1.99 (comp, 2 H), 1.48-1.45 (comp, 9 H); ¹³C NMR (75 MHz, CDCl₃) (rotamers) δ 201.9, 154.7 137.6, 136.3, 135.4, 135.2, 128.8, 128.7, 128.2, 127.2, 127.0, 117.5, 116.9, 80.6, 79.3, 62.7, 62.4, 54.6, 53.3, 53.1, 28.2; IR (neat) 3072, 2966, 2912, 2801, 2707, 1731, 1690, 1455, 1390, 1367, 1249 cm⁻¹; mass spectrum (CI) m/z 345.2179 [C₂₀H₂₉N₂O₃ (M+H) requires 345.2178], 318, 303, 289, 261, 201, 173.

2-Allyl-4-benzyl-6-ethynyl-piperazine-1-carboxylic acid tert-butyl ester (31)

To a mixture of 29 (0.094 g, 0.273 mmol), K₂CO₃ (0.113 g, 0.819 mmol) in MeOH (3 mL) at 0 °C was added Bestmann-Ohira reagent (0.105 g, 0.546 mmol). The reaction was warmed to room temperature and stirred under argon for 16 hr. The reaction was concentrated, dissolved in EtOAc (10 mL), washed with brine (1 × 5 mL), satd. NaHCO₃ (2 × 5 mL), brine (1 × 5 mL). The organic layer was dried (MgSO₄), filtered, concentrated, and the residue was purified via flash chromatography eluting with CH₂Cl₂:MeOH (30:1) to give 0.093 g (76%) of 31 as a colorless oil; ¹H NMR (400 MHz, CDCl₃) (rotamers) δ 7.35-7.23 (comp, 5 H), 5.74-5.64 (m, 1 H), 5.04-4.94 (comp, 2 H), 4.07 (bs, 1 H), 3.84 (bs, 1 H), 3.54 (d, J = 13.2 Hz, 1 H), 3.38 (d, J = 13.2 Hz, 1 H), 3.07 (t, J = 12.4 Hz, 1 H), 2.77 (d, J = 10.8 Hz, 1 H), 2.70 (d, J = 11.6 Hz, 1 H), 2.54-2.42 (m, 2 H), 2.07-2.00 (comp, 2 H), 1.48-1.45 (comp, 9 H); ¹³C NMR (75 MHz, CDCl₃) (rotamers) δ 138.6, 135.7, 129.1, 128.4, 127.2, 117.2, 79.7, 63.1, 55.0, 53.4, 51.6, 34.9, 29.9, 28.6; IR (neat) 3304, 3074, 2975, 2811, 2773, 1697, 1640, 1454, 1399, 1367, 1336, 1302, 1255, 1175 cm⁻¹; mass spectrum (CI) m/z 341.2226 [C₂₁H₂₉N₂O₂ (M+H) requires 341.2229], 325, 313, 299, 285, 240.

10-(tert-Butyldimethylsilanyloxy)-4-oxo-12-azatricyclo[6.3.1.0^2,6]dodec-2-ene-12-carboxylic acid benzyl ester (34)

The PKR of 27 was performed on a scale of 0.29 mmol according to the representative procedure, and the crude product was purified by flash chromatography eluting with hexanes/EtOAc (9:1-3:1) to give 39 in a 69% yield as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 7.37-7.28 (comp, 5 H), 5.87 (d, J = 2.0 Hz, 1 H), 5.17 (d, J = 7.5 Hz, 1 H), 5.10 (s, 2 H), 4.47-4.44 (m, 1 H), 4.30-4.24 (m, 1 H), 4.09-4.05 (m, 1H), 2.40 (dd, J = 18.0, 6.5 Hz, 1 H), 2.28 (comp, 2 H), 2.00 (ddd, J = 13.0, 7.0, 2.0 Hz, 1 H), 1.94 (dd, 18.0, 3.0 Hz, 1 H), 1.71-1.64 (comp, 2 H), 1.53 (dt, J = 12.5, 5.0 Hz, 1 H), 0.85 (s, 9 H), 0.07 (s, 3 H), 0.03 (s, 3 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 205.9, 179.0, 153.2, 136.3, 127.8, 127.2, 126.8, 125.6, 66.0, 62.2, 48.0, 45.4, 41.8, 37.1, 35.3, 35.0, 32.6, 25.0, 16.9, −5.6, −5.7; IR (neat) 2928, 2855, 1713, 1623, 1416, 1322, 1278, 1088, 839 cm⁻¹; mass spectrum (CI) m/z 442.2411 [C₂₅H₃₆NO₄Si (M+H) requires 442.2414] 442 (base), 308.

4-Oxo-12-azatricyclo[6.3.1.0^2,6]dodec-2-ene-12-carboxylic acid benzyl ester (35)

The PKR of 32 was performed on a scale of 0.35 mmol according to the representative procedure, and the crude product was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 40 in a 74% yield as a colorless oil as a mixture (4:1) of diastereomers; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 7.37-7.28 (comp, 5 H), 5.89 (bs, 1 H), 5.11 (s, 2 H), 4.36 (t, J = 4.4 Hz, 1 H), 3.57-3.51 (m, 1 H), 2.53 (dd, J = 18.0, 6.0 Hz, 1 H), 2.50-2.48 (m, 1 H), 2.15 (dd, J = 13.5, 7.5 Hz, 1 H), 2.08-1.52 (comp, 7 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 205.7, 178.1, 153.2, 136.4, 127.8, 127.2, 126.8, 125.8, 65.9, 49.5, 46.6, 43.2, 37.2, 35.5, 27.6, 18.4, 14.1; IR (neat) 2939, 1694, 1621, 1419, 1321, 1085 cm⁻¹; mass spectrum (ESI) m/z 312.1601 [C₁₉H₂₂NO₃ (M+H) requires 312.1600] 334 (base), 312.

10-Methyl-4-oxo-10,12-diaza-tricyclo[6.3.1.0^2,6]dodec-2-ene-12-carboxylic acid tert-butyl ester (36)

The PKR of 30 was performed on a scale of 0.56 mmol according to the representative procedure, and the crude product was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 36 in a 85% yield as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 5.86 (d, J = 2.1 Hz, 1 H), 4.92 (s, 1 H), 4.14 (s, 1 H), 3.99–4.05 (m, 1 H), 2.92 (d, J = 11.2 Hz, 1 H), 2.87 (d, J = 11.6 Hz, 1 H), 2.48 (dd, J = 18.2, 6.5, 1 H), 2.32 (dd, J = 11.5, 3.3 Hz, 1 H), 2.26 (dd, J = 1.8, 1.7 Hz, 1 H), 2.24 (dd, J = 1.8, 1.7 Hz, 1 H), 2.19 (s, 3 H), 2.17 (m, 1 H), 1.79 (dd, J = 18.2, 3.3 Hz, 1 H), 1.87 (m, 1 H), 1.40 (s, 9 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 206.1, 178.6, 152.5, 127.6, 125.4, 79.0, 57.9, 56.4, 57.9, 56.4, 44.6, 42.6, 38.0, 37.6, 27.5; IR (neat) 2973, 2920, 2791, 1696, 1623, 1458, 1407, 1322, 1173, 1046 cm⁻¹; mass spectrum (CI) m/z 293.1866 [C₁₆H₂₅N₂O₃ (M+H) requires 293.1865] 237.

10-Benzyl-4-oxo-10,12-diaza-tricyclo[6.3.1.02,6]dodec-2-ene-12-carboxylic acid tert-butyl ester (37)

The PKR of 31 was performed on a scale of 0.100 mmol according to the representative procedure, and the crude product was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 37 in a 81% yield as a colorless oil; ¹H NMR (400 MHz, CDCl₃) (rotamers) δ 7.35-7.24 (comp, 5 H), 5.93-5.86 (comp, 1 H), 5.07-4.90 (comp, 1 H), 4.29 (s, 1 H), 4.23 (bs, 1 H), 3.51 (d, J = 12.8 Hz, 1 H), 3.46 (d, J = 13.2 Hz, 1 H), 2.95-2.89 (comp, 2 H), 2.67 (dd, J = 12.0, 6.4 Hz, 1 H), 2.50 (dd, J = 8.4, 3.2 Hz, 1 H), 2.41 (d, J = 11.2, 1 H), 2.18-2.12 (m, 1 H), 1.90 (dt, J = 18.4, 2.4 Hz, 1 H), 1.75-1.59 (comp, 2 H), 1.43 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃) (rotamers) δ 208.5, 179.6, 179.0, 153.7, 137.5, 128.7, 128.5, 127.3, 126.4, 80.5, 62.9, 56.7, 55.4, 51.8, 47.6, 43.9, 39.2, 38.7, 28.3; IR (neat) 2967, 2920, 2803, 2768, 1692, 1621, 1451, 1315, 1287, 1246, 1175 cm⁻¹; mass spectrum (CI) m/z 369.2175 [C₂₂H₂₉N₂O₃ (M+H) requires 369.2178] 341, 313.

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-6,13-imino-cyclooct[1,2-b]indole (3)

Co₂(CO)₈ (1.77 g, 5.12 mmol) was added to a solution of 4 (1.88 g, 5.08 mmol) in THF (50 mL). The reaction was stirred for 1 h and complete Co-alkyne complex formation was observed by TLC. DMSO (2.20 g, 27.92 mmol) was added and stirred at 60 °C for 8 h. The reaction was cooled to room temperature and Et₂O (30 mL) was added. The purple Co-precipitate was removed via filteration through silica washing with Et₂O (30 mL) and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1-1:1) to give 1.86 g (92%) of 3 as a colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 10.73 (s, 1 H), 7.39 (d, J = 7.9 Hz, 1 H), 7.35-7.29 (comp, 6 H), 7.07 (dt, 7.2, 1.3 Hz, 1 H), 6.98 (dt, J = 7.9, 1.0 Hz, 1 H), 6.05 (bs, 1 H), 5.64 (d, J = 6.8 Hz, 1 H), 5.50 (bs, 1 H), 5.21-5.09 (comp, 2 H), 3.33 (dd, J = 16.4, 6.9 Hz, 1 H), 2.75 (d, J = 16.4 Hz, 1 H), 2.79-2.68 (comp, 1 H), 2.34 (dd, J = 18.3, 6.4 Hz, 1 H), 2.26 (dq, J = 6.2, 2.4 Hz, 1 H), 1.99 (dd, 18.3, 3.0 Hz, 1 H), 1.76 (dt, J = 12.6, 3.8 Hz, 1 H); ¹³C NMR (125 MHz) δ 205.8, 177.4, 153.4, 136.1, 135.6, 132.3, 127.8, 127.3, 127.0, 126.5, 125.8, 120.6, 118.2, 117.2, 110.8, 105.5, 66.3, 49.3, 47.6, 40.2, 37.1, 34.4, 25.0; IR (neat) 3464, 3052, 2985, 1702, 1623 cm⁻¹; mass spectrum (CI) m/z 399.1710 [C₂₅H₂₃N₂O₃ (M+H) requires 399.1709].

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-cyclooct[1,2-b]indole (38)

(Boc)₂O (327 mg, 1.22 mmol) was added to a solution of 3 (350 mg, 0.88 mmol) and DMAP (134 mg, 0.88 mmol) in CH₃CN/CH₂Cl₂ (20 mL, 3:1), and the reaction was stirred at room temperature for 1 h. Et₂O (20 mL) was added and the reaction was washed with 0.2 M citric acid (2 × 10 mL), sat. NaHCO₃ (10 mL), and brine (10 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 430 mg (99%) of 42 as a white foam; ¹H NMR (500 MHz) δ 8.12 (d, J = 8.2 Hz, 1 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.34-7.28 (comp, 6 H), 7.24 (t, J = 6.7 Hz, 1 H), 6.08 (bs, 1 H), 6.06 (bs, 1 H), 5.66 (d, J = 7.2 Hz, 1 H), 5.15 (s, 2 H), 3.31 (dd, J = 17.1, 7.1 Hz, 1 H), 2.79-2.76 (comp, 2 H), 2.41-2.35 (comp, 1 H), 2.38 (dd, J = 18.4, 6.5 Hz, 1 H), 2.01 (dd, J = 18.5, 3.0 Hz, 1 H), 1.76 (dt, J = 12.7, 4.1 Hz, 1 H), 1.62 (s, 9 H); ¹³C NMR (125 MHz) δ 205.9, 176.8, 153.3, 148.8, 136.0, 135.1, 132.3, 127.8, 127.5, 127.4, 127.1, 126.5, 123.9, 122.4, 117.8, 114.9, 114.1, 84.1, 66.5, 54.1, 48.1, 40.3, 36.2, 33.9, 27.2, 24.6; IR (neat) 3400, 2977, 2929, 1771, 1713, 1626 cm⁻¹; mass spectrum (CI) m/z 499.2211 [C₃₀H₃₁N₂O₅ (M+H) requires 498.2233].

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-7,11-[2,7-dioxabicyclo[4.1.0]heptan-3-one]-cyclooct[1,2-b]indole (39)

Trifluoroacetic anhydride (15 mg, 0.07 mmol) was added to a mixture of 38 (10 mg, 0.02 mmol),urea·H₂O₂ (19 mg, 0.20 mmol), and Na₂HPO₄ (26 mg, 0.18 mmol) in CH₂Cl₂ (1 mL) at 0 °C, and the reaction was stirred for 3 h. The reaction was filtered through a plug of Celite (1 cm), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1-1:1) to give 10 mg (94%) of 39 as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 7.80 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 7.5 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H), 7.37-7.26 (comp, 5 H), 7.23 (t, J = 7.5 Hz, 1 H), 5.88 (bs, 1 H), 5.32 (d, J = 8.0 Hz, 1 H), 5.09 (s, 2 H), 4.37 (bs, 1 H), 3.70 (bs, 1 H), 2.78-2.74 (m, 1 H), 2.62 (dd, J = 18.0, 6.5 Hz, 1 H), 2.32 (d, J = 14.0 Hz, 1 H), 2.09 (dd, J = 13.5, 8.0 Hz, 1 H), 1.97 (dd, J = 18.0, 3.5 Hz, 1 H), 1.70-1.69 (m, 1 H), 1.57 (s, 9 H); ¹³C NMR (125 MHz) δ 205.8, 177.4, 151.9, 148.1, 139.4, 136.2, 128.4, 127.7, 127.1, 126.8, 126.7, 125.7, 124.1, 123.1, 123.3, 121.1, 113.8, 109.2, 83.4, 65.9, 60.6, 54.5, 42.3, 33.3, 27.3, 23.1; IR (neat) 2955, 1791, 1764, 1710, 1632, 1421, 1307, 1252, 1150, 739 cm⁻¹; mass spectrum (CI) m/z 531 (M+H), 463, 319, 243 (base).

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-7,8-epoxycyclopentane-cyclooct[1,2-b]indole (40)

A solution of NaOH (10 μL, 100 mg NaOH/1mL H₂O, 0.024 mmol) and a solution of H₂O₂ (15 μL, 30% in H₂O, 0.1 mmol) were sequentially added to a solution of 38 (10 mg, 0.02 mmol) in THF/MeOH (0.4 mL, 1:1) at −20 °C. The reaction was stirred for 30 min, and the cooling bath was removed. A solution of NaOH (10 μL, 100 mg NaOH/1mL H₂O, 0.024 mmol) was added, and the reaction was stirred for an additional 1 h. The solution was filtered through a plug of Na₂CO₃/silica (1 cm/1 cm) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (9:1-3:1) to give 7.8 mg (78%) of 40 as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 8.12 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 5.5 Hz, 1 H), 7.35-7.25 (comp, 7 H), 5.98 (bs, 1 H), 5.14 (s, 2 H), 4.51 (d, J = 6.5 Hz, 1 H), 3.64 (s, 1 H), 3.16 (dd, J = 17.0, 7.0 Hz, 1 H), 2.92 (d, J = 17.0 Hz, 1 H), 2.44-2.32 (comp, 3 H), 1.82-1.73 (comp, 2 H), 1.62 (s, 9 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 207.1, 153.4, 148.7, 135.9, 135.2, 132.1, 127.8, 127.5, 127.2, 127.0, 124.0, 122.4, 117.8, 114.8, 114.2, 84.1, 69.6, 66.6, 61.3, 47.7, 47.3, 37.6, 35.1, 29.0, 27.2, 22.8; IR (neat) 2977, 2928, 1750, 1730, 1703, 1455, 1417, 1360, 1326, 1156, 1012, 755 cm⁻¹; mass spectrum (CI) m/z 515.2175 [C₃₀H₃₁N₂O₆ (M+H) requires 515.2182].

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-9-triisopropylsiloxycyclopent-8-ene-cyclooct[1,2-b]indole (45)

Solid 38 (1.0 g, 2.0 mmol) was added to a solution of platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (0.50 mL, 0.1 M in xylenes, 0.05 mmol, 2.5 mol%) and ⁱ Pr₃SiH (5 mL, 24 mmol) in toluene (5 mL), and the reaction was heated to 60 °C for 18 h. The reaction was concentrated under reduced pressure, and the residue was purified by flash chromatography (neutral alumina) eluting with hexanes/EtOAc (1:0-9:1) to give 1.32 g (93%) of 45 as a white foam; ¹H NMR (300 MHz, CDCl₃) (rotamers) δ 8.29-8.25 (m, 1 H), 7.42-7.26 (comp, 8 H), 6.03 (s, 0.5 H), 5.93 (s, 0.5 H), 5.22 (s, 1 H), 5.17 (s, 1 H), 4.91 (d, J = 6.6 Hz, 0.5 H), 4.83 (d, J = 6.6 Hz, 1 H), 4.72 (s, 0.5 H), 4.61 (s, 0.5 H), 3.27-3.12 (m, 1 H), 2.78-2.54 (comp, 3 H), 2.08-1.80 (comp, 4 H), 1.76 (s, 4.5 H), 1.61 (s, 4.5 H), 1.29-1.13 (comp, 21 H); ¹³C NMR (75 MHz, CDCl₃) (rotamers) δ 155.7, 155.4, 154.8, 154.7, 149.7, 136.7, 136.5, 135.9, 133.5, 133.2, 128.7, 128.6, 128.3, 128.2, 127.8, 127.7, 127.4, 124.0, 123.9, 122.6, 122.5, 117.7, 117.6, 115.6, 115.3, 114.7, 104.2, 103.8, 83.8, 83.6, 67.1, 66.8, 48.0, 47.8, 47.6, 47.4, 47.3, 47.1, 40.7, 40.6, 31.3, 30.9, 29.9, 28.0, 27.9, 27.6, 27.0, 17.7, 12.3; IR (neat) 2943, 2865, 1731, 1698, 1634, 1455, 1424, 1366, 1325, 1145, 882 cm⁻¹; mass spectrum (CI) m/z 657 (M+H) (base), 601, 556, 405.

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-9-oxycyclopentane-cyclooct[1,2-b]indole (46)

TBAF·3H₂O (158 mg, 0.5 mmol) was added to a solution of 45 (153 mg, 0.25 mmol) in CH₂Cl₂ (10 mL) and the reaction was stirred at room temperature for 3 h. Sat. NH₄Cl (10 mL) was added and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL) and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1-1:1) to give 100 mg (66%) of 46 as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 8.10 (d, J = 8.0 Hz, 1 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.32-7.27 (comp, 6 H), 7.24 (t, J = 7.5 Hz, 1 H), 5.94 (s, 1 H), 5.12 (s, 2 H), 4.64 (d, J = 6.5 Hz, 1 H), 3.14 (dd, J = 16.5, 7.0 Hz, 1 H), 2.74 (d, J = 17.0 Hz, 1 H), 2.50-2.48 (m, 1 H), 2.28 (dd, J = 18.5, 8.0 Hz, 2 H), 2.14-2.08 (comp, 2 H), 1.90 (d, J = 18.0 Hz, 2 H), 1.61 (s, 9 H), 1.54 (td, J = 13.5, 4.5 Hz, 1 H); ¹³C NMR (100 MHz, C₆D₆) δ 215.3, 154.2, 148.8, 136.2, 135.1, 132.4, 127.8, 127.2, 127.0, 126.8, 123.7, 122.2, 117.6, 114.8, 110.7, 83.9, 66.2, 46.9, 44.6, 40.2, 38.4, 29.1, 28.3, 27.9, 27.2, 23.1; IR (neat) 2953, 1731, 1701, 1455, 1423, 1368, 1326, 1147, 1016, 747 cm⁻¹; mass spectrum (CI) m/z 501 (M+H), 400 (base).

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-6,13-imino-9R-hydroxycyclopentane-cyclooct[1,2-b]indole (47)

NaBH₄ (34 mg, 1.0 mmol) was added in one portion to a solution of 46 (200 mg, 0.4 mmol) in THF (10 mL) at room temperature. The reaction stirred for 1 h and sat. NaHCO₃ (5 mL) was added. The reaction was extracted with EtOAc (3 × 5mL) and the combined organic layers were dried and concentrated under reduced pressure. The crude oil was adsorbed on to silica gel (2.0 g) and heated at 80 °C under vacuum (1 mm Hg) for 6 h. The flask was cooled and the silica was washed with EtOAc (5 mL) to which 10% Pd/C (20 mg) was added under an atmosphere of H₂ (1 atm). The reaction stirred for 3 h and was filtered through Celite (1 cm) and concentrated to give 53 mg (45%) of 47 as a white solid. Slow evaporation from CH₂Cl₂/MeOH (2 mL) gave white needles suitable for x-ray: mp = 200–204; ¹H NMR (400 MHz, CD₃OD) δ 7.26 (d, J = 9.5 Hz, 1 H), 7.15 (d, J = 9.5 Hz, 1 H), 6.91 (td, J = 8.5, 1.5 Hz, 1 H), 6.85 (dt, J = 8.5, 1.5 Hz, 1 H), 4.17-4.11 (m, 1 H), 4.01 (s, 1 H), 3.28 (d, J = 7.5 Hz, 1 H), 3.21–3.19 (m, 1 H), 3.09 (dd, J = 19.5, 8.0 Hz, 1 H), 2.46 (d, J = 19.5 Hz, 1 H), 2.02-1.43 (comp, 7 H), 1.17 (dd, J = 18.0, 3.0 Hz, 1 H); ¹³C NMR (100 MHz, CD₃OD) δ 137.6, 135.5, 128.6, 121.7, 119.6, 118.4, 111.8, 108.2, 72.9, 49.7, 45.5, 42.2, 39.4, 35.4, 34.1, 32.3, 30.0; IR (neat) 3394, 2924,1450, 1335, 742 cm⁻¹; mass spectrum (CI) m/z 270 (M+H).

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-8-hydroxy-9-oxycyclopentane-cyclooct[1,2-b]indole (48)

OsO₄ (289 mg, 1.18 mmol) was added in one portion to a solution of 45 (690 mg, 1.12 mmol) in THF (10 mL) at room temperature. The reaction was stirred at room temperature for 12 h, and then H₂S was bubbled through the reaction for 15 min. The thick black precipitate was removed by filtering through Celite (1 cm) washing with THF (30 mL), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1-1:1) to give 480 mg (71%) of a mixture of epimers 48 as a colorless oil; major isomer: ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 8.10 (d, J = 8.0 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.32-7.22 (comp, 7 H), 5.96 (s, 1 H), 5.16-5.09 (comp, 2 H), 4.86 (d, J = 7.0 Hz, 1 H), 3.90 (d, J = 10.5 Hz, 1 H), 3.19 (dd, J = 16.5, 7.0 Hz, 1 H), 2.69 (d, J = 16.5 Hz, 1 H), 2.28 (dd, J = 19.0, 8.0 Hz, 1 H), 2.08-1.98 (comp, 4 H), 1.69-1.65 (m, 1 H), 1.61 (s, 9 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 215.1, 154.3, 148.8, 136.3, 135.1, 132.5, 127.9, 127.8, 127.2, 126.8, 123.7, 122.3, 117.7, 115.1, 114.8, 83.9, 72.9, 66.2, 47.2, 45.1, 40.5, 39.0, 30.7, 27.2, 25.7, 23.2; IR (neat) 3436, 2976, 1729, 1699, 1456, 1424, 1360, 1328, 1153, 754 cm⁻¹; mass spectrum (CI) m/z 517 (M+H), 473, 461, 417.

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-7-hydroxymethyl-11-carboxylic acid methyl ester-cyclooct[1,2-b]indole (49)

Pb(OAc)₄ (640 mg, 1.45 mmol) was added to a solution of 48 (375 mg, 0.722 mmol) in MeOH/benzene (10 mL, 1:1) at 0 °C and the reaction was stirred for 15 min at 0 °C. NaBH₄ (430 mg, 10 mmol) was added in 6 portions over 5 min, and the reaction was stirred at 0 °C for 15 min. NaHCO₃ (20 mL) was added and the solution was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 291 mg (72%) of 49 as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 8.10 (d, J = 8.0 Hz, 1 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.31-7.22 (comp, 7 H), 5.93 (bs, 1 H), 5.08 (s, 2 H), 4.91 (d, J = 7.5 Hz, 1 H), 3.55 (dd, J = 11.0, 5.0 Hz, 1 H), 3.49 (s, 3 H), 3.50-3.46 (m, 1 H), 3.21 (dd, J = 17.5, 8.0 Hz, 1 H), 2.57 (d, J = 17.5 Hz, 1 H), 2.37 (dd, J = 15.5, 7.0 Hz, 1 H), 2.27-2.17 (comp, 2 H), 1.88-1.84 (m, 1 H), 1.76-1.67 (comp, 2 H), 1.60 (s, 9 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 171.6, 154.3, 148.8, 136.4, 134.9, 133.7, 127.7, 127.1, 126.6, 123.6, 122.2, 117.6, 114.7, 83.7, 65.9, 57.6, 50.3, 46.3, 45.3, 36.0, 33.6, 29.6, 27.2, 26.2, 25.0, 23.1; IR (neat) 2931, 1729, 1697, 1454, 1367, 1328, 1155, 1116, 912, 747 cm⁻¹; mass spectrum (CI) m/z 549 (M+H) (base), 493, 449.

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-7,11-[Tetrahydropyran-2-one]-cyclooct[1,2-b]indole (50)

OsO₄ (4 mg, 0.015 mmol) was added to a slurry of NaIO₄ (130 mg, 4 mmol) and 49 (100 mg, 0.152 mmol) in THF/H₂O (1.5 mL, 5:1). The reaction was stirred at room temperature for 48 h and H₂O (5 mL) was added. The solution was extracted with CH₂Cl₂ (3 × 3 mL) and the combined organic layers were concentrated to give a crude black oil. The oil was dissolved in MeOH (5 mL) and NaBH₄ (6 mg, 0.152 mmol) was added. The reaction stirred at room temperature for 30 min and TsOH·H₂O (48 mg, 0.25 mmol) was added and stirred an additional 4 h. Sat. NaHCO₃ (5 mL) was added and the solution was extracted with CH₂Cl₂ (3 × 3 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 43 mg (55%) of 50 as a white foam; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 8.10 (d, J = 8.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.31-7.27 (comp, 6 H), 7.24 (t, J = 7.5 Hz, 1 H), 5.98 (bs, 1 H), 5.11 (s, 2 H), 4.51 (d, J = 7.5 Hz, 1 H), 4.40 (dd, J = 11.5, 5.5 Hz, 1 H), 4.32 (t, J = 11.5 Hz, 1 H), 3.18 (dd, J = 17.0, 7.5 Hz, 1 H), 2.73 (d, J = 17.0 Hz, 1 H), 2.60 (dd, J = 18.0, 7.5 Hz, 1 H), 2.37-2.33 (m, 1 H), 2.16-2.09 (dd, J = 18.0, 2.0 Hz, 1 H), 2.12 (m, 1 H), 1.95-1.86 (comp, 2 H), 1.61 (s, 9 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 168.9, 153.9, 148.7, 136.2, 135.2, 132.4, 127.8, 127.2, 126.9, 125.9, 122.2, 117.6, 114.9, 110.7, 106.4, 83.9, 67.4, 66.2, 47.4, 46.9, 36.8, 33.6, 30.6, 29.9, 27.2, 23.4; IR (neat) 2976, 1731, 1698, 1455, 1423, 1329, 1141, 912, 733 cm⁻¹; mass spectrum (CI) m/z 517 (M+H), 545, 517 (base), 417.

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-7,11-[3,4-dihydro-2H-pyran]-cyclooct[1,2-b]indole (52)

A solution of 50 (235 mg, 0.455 mmol) in toluene (10 mL) was cooled to −78 °C, and a solution of DIBAL-H (0.547 mL, 1 M in toluene, 0.547 mmol) was slowly added dropwise. The reaction was stirred for 1 h at −78 °C and then MeOH (0.5 mL) was added. The reaction was warmed to room temperature and sat. Rochelle’s salt (20 mL) was added. The solution was extracted with EtOAc (3 × 10 mL) and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was dissolved in THF (5 mL) and cooled to 0 °C. Et₃N (340 mg, 3.36 mmol) and MsCl (121 mg, 1.05 mmol) were sequentially added and the reaction was stirred at 0 °C for 30 min. Sat. NH₄Cl (5 mL) was added and the solution was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (9:1) to give 130 mg (61%) of 52 as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 8.10 (d, J = 8.5 Hz, 1 H), 7.45 (d, J = 7.5 Hz, 1 H), 7.32-7.27 (comp, 6 H), 7.23 (t, J = 7.0 Hz, 1 H), 6.30 (d, J = 6.0 Hz, 1 H), 5.93 (bs, 1 H), 5.11 (s, 2 H), 4.61 (t, J = 5.5 Hz, 1 H), 4.55 (d, J = 7.5 Hz, 1 H), 4.00 (dd, J = 11.0, 2.5 Hz, 1 H), 3.76 (t, J = 11.0 Hz, 1 H), 3.15 (dd, J = 17.0, 7.5 Hz, 1 H), 2.75 (d, J = 17.0 Hz, 1 H), 2.12-1.96 (comp, 3 H), 1.79-1.73 (m, 1 H), 1.61 (s, 9 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 153.8, 148.8, 142.8, 136.2, 135.1, 132.5, 127.7, 127.3, 127.2, 126.9, 123.6, 122.2, 117.6, 114.9, 114.8, 103.6, 83.8, 66.2, 63.7, 47.5, 46.5, 37.9, 32.0, 27.2, 26.0, 23.3; IR (neat) 2976, 1729, 1699, 1455, 1422, 1330, 1142, 747 cm⁻¹; mass spectrum (CI) m/z 500 (M+H), 401, 387 (base), 267, 229.

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-methyl-6,13-iminopyrano[3′,4′:5,6]cyclooct[1,2-b]indole (53)

LiAlH₄ (18 mg, 0.48 mmol) was added in one portion to a solution of 52 (60 mg, 0.12 mmol) in THF (5 mL). The reaction was heated to reflux for 1 h and cooled to room temperature. MeOH was added until bubbling ceased (3 drops) and the reaction was filtered through Celite (1 cm) washing with EtOAc (5 mL). The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1-0:1) to give 29 mg (86%) of 53 as a white solid: mp = 174–175 °C; ¹H NMR (400 MHz, C₆D₆) δ 7.61-7.58 (m, 1 H), 7.28-7.24 (comp, 2 H), 7.15-7.11 (m, 1 H), 6.47 (d, J = 6.0 Hz, 1 H), 6.23 (bs, 1 H), 4.48 (dd, J = 11.0, 4.4 Hz, 1 H), 4.42 (d, J = 11.0 Hz, 1 H), 3.91 (d, J = 9.2 Hz, 1 H), 3.29 (s, 1 H), 2.98 (dd, J = 16.8, 7.2 Hz, 1 H), 2.56 (d, J = 6.4 Hz, 1 H), 2.14 (s, 3 H), 2.11 (s, 1 H), 1.99 (td, J = 12.0, 3.6 Hz, 1 H), 1.87-1.79 (comp, 2 H), 1.47 (d, J = 12.0 Hz, 1 H); ¹³C NMR (100 MHz, C₆D₆) δ 144.1, 136.2, 132.0, 128.5, 121.6, 119.7, 118.5, 111.1, 107.2, 105.0, 66.8, 55.5, 54.9, 41.7, 40.8, 35.8, 24.2, 22.8; IR (neat) 3394, 2927, 2360, 1646, 1457, 1244, 1070, 741, 668 cm⁻¹; mass spectrum (CI) m/z 281.1657 [C₁₈H₂₁N₂O (M+H) requires 281.1654].

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7,14-dimethyl-6,13-iminopyrano[3′,4′:5,6]cyclooct[1,2-b]indole (54)

NaH (12 mg, 0.311 mmol) was added to a solution of 53 (29 mg, 0.104 mmol) in DMF (1 mL) at −5°C. The reaction was stirred for 15 min and MeI (22 mg, 0.150 mmol) was added. The reaction was stirred for 1.5 h during which time the temperature had warmed to 5 °C. The reaction was quenched with H₂O/brine (2 mL, 1:1) and extracted with CH₂Cl₂ (4 × 5 mL). The combined organic layers were washed with H₂O (5 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 29 mg (86%) of 54 as a white solid: mp = 192–193 °C; ¹H NMR (400 MHz, C₆D₆) δ 7.66-7.63 (m, 1 H), 7.30-7.28 (comp, 2 H), 7.10-7.07 (m, 1 H), 6.47 (d, J = 6.0 Hz, 1 H), 4.49 (t, J = 5.6 Hz, 1 H), 4.43 (d, J = 11.0 Hz, 1 H), 3.92 (ddd, J = 11.0, 4.0, 1.6 Hz, 1 H), 3.48 (t, J = 3.2 Hz, 1 H), 3.04 (dd, J = 16.4, 6.8 Hz, 1 H), 2.84 (s, 3 H), 2.59 (d, J = 6.8 Hz, 1 H), 2.20 (d, J = 16.4 Hz, 1 H), 2.15 (s, 3 H), 1.99 (dd, J = 12.4, 4.0 Hz, 1 H), 1.93-1.83 (m, 2 H), 1.48 (dt, J = 12.4, 3.2 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ 136.9, 133.3, 126.5, 120.8, 118.8, 117.9, 109.7, 108.7, 106.3, 104.8, 66.6, 55.2, 53.6, 41.8, 40.5, 37.9, 34.7, 23.7, 22.9; IR (neat) 2925, 2360, 2340, 1644, 1467, 1379, 1070, 895, 738, 668 cm⁻¹; mass spectrum (CI) m/z 293.1659 [C₁₉H₂₁N₂O (M-H) requires 293.1654].

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-imino-7,11-[1-(5,6-dihydro-4H-pyran-3-yl)-ethanone]-cyclooct[1,2-b]indole (56)

Trichloroacetyl chloride (0.4 mL, 3.6 mmol) was added to a solution of 52 (170 mg, 0.34 mmol) in pyridine (2 mL), and the reaction was heated to 65 °C for 18 h. The reaction was concentrated under reduced pressure and the residue was dissolved in CH₂Cl₂ (10 mL). The solution was washed with NH₄Cl (2 × 10 mL), filtered through a silica plug (1 cm), and concentrated to give a crude yellow oil. The oil was dissolved in AcOH (2 mL) and added dropwise to a suspension of Zn dust (200 mg, 3.0 mmol) in AcOH (2 mL). The reaction was stirred for 30 min and more Zn dust (200 mg, 3.0 mmol) was added. The reaction was stirred for an additional 15 min, filtered through Celite (1 cm), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 138 mg (75%) of 56 as a colorless oil; ¹H NMR (500 MHz, d₆-DMSO, 100 °C) δ 8.15 (d, J = 8.0 Hz, 1 H), 7.71 (s, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.33-7.23 (comp, 7 H), 5.93 (bs, 1 H), 5.12 (s, 2 H), 4.62 (d, J = 7.5 Hz, 1 H), 4.24 (dd, J = 11.0, 3.0 Hz, 1 H), 3.94 (t, J = 11.5 Hz, 1 H), 3.20 (dd, J = 16.5, 7.5 Hz, 1 H), 2.77 (d, J = 17.0 Hz, 1 H), 2.63 (dt, J = 11.5, 4.5 Hz, 1 H), 2.22-2.18 (m, 1 H), 2.06-2.03 (m, 1 H), 2.04 (s, 3 H), 1.70-1.65 (m, 1 H), 1.60 (s, 9 H); ¹³C NMR (125 MHz, d₆-DMSO, 100 °C) δ 193.9, 156.8, 153.9, 148.8, 136.2, 135.1, 132.7, 127.7, 127.4, 127.3, 126.9, 123.7, 122.3, 119.3, 117.6, 114.8, 110.7, 83.8, 66.2, 64.7, 47.7, 46.0, 35.9, 29.9, 27.2, 25.7, 24.2, 22.3; IR (neat) 2913, 1721, 1691, 1612, 1427, 1318, 1090, 740 cm⁻¹; mass spectrum (CI) m/z 543 (M+H), 488, 444 (base), 400.

1-[(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexahydro-7,14-dimethyl-6,13-imino-7,11-[1-(5,6-dihydro-4H-pyran-3-yl)-ethanone]-cyclooct[1,2-b]indole (57)

Freshly distilled TMS-I (19 mg, 0.093 mmol) was added to a solution of 56 (12 mg, 0.022 mmol) in CH₃CN (1 mL) at 0 °C. The reaction was stirred for 30 min at 0 °C and 15 min at room temperature. Methanolic HCl (1 mL, 1 M) was added and the reaction was concentrated under reduced pressure. The residue was dissolved in aqueous HCl (5 mL, 1 M) and extracted with CH₂Cl₂ (3 × 5 mL). The aqueous layer was basified with 30% NH₄OH dropwise until pH~12 and then extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc/MeOH (9:1) to give 6 mg (78%) of 57 as a white film; ¹H NMR (400 MHz, CDCl₃) δ 7.99 (bs, 1 H), 7.53 (s, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.13 (t, J = 6.8 Hz, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 4.43 (t, J = 11.6 Hz, 1 H), 4.19 (ddd, J = 11.2, 4.0, 1.6 Hz, 1 H), 4.10 (bs, 1 H), 3.44 (d, J = 6.8 Hz, 1 H), 3.22 (dd, J = 16.0, 6.8 Hz, 1 H), 2.74-2.67 (m, 1 H), 2.66 (d, J = 16.4 Hz, 1 H), 2.11-2.06 (m, 1 H), 2.08 (s, 3 H), 1.92-1.70 (comp, 4 H); ¹³C NMR (75 MHz, CDCl₃) δ 195.5, 157.5, 135.6, 135.5, 127.2, 121.5, 121.3, 119.3, 117.7, 111.2, 107.9, 67.4, 48.3, 47.7, 37.4, 32.3, 28.8, 25.0, 23.7; IR (neat) 2921, 1614, 1453, 1321, 1195, 738 cm⁻¹; mass spectrum (CI) m/z 309 (M+H) (base).

(−)-Alstonerine (1)

Methyl iodide (7 mg, 0.05 mmol) was added to 57 (8 mg, 0.0265 mmol) in THF (0.25 mL) and the reaction was stirred at room temperature for 3 h. NaH (3 mg, 0.075 mmol) was added and the reaction was stirred for 30 min. Methyl iodide (10 mg, 0.075 mmol) was added, and the reaction was stirred at room temperature for 3 h. MeOH/EtOAc (1:9, 1 mL) was added and the reaction was filtered through silica gel. The filtrate was concentrated under reduced pressure and the crude residue dissolved in CH₂Cl₂ (5 mL) and washed with NaHCO₃ (5 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1-0:1) to give 6 mg (72%) of 1 as a white film; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.2 Hz, 1 H), 7.07 (t, J = 8.0 Hz, 1 H), 4.39 (t, J = 11.2 Hz, 1 H), 4.15 (ddd, J = 10.8, 4.0, 1.6 Hz, 1 H), 3.86 (t, J = 3.2 Hz, 1 H), 3.63 (s, 3 H), 3.31 (dd, J = 16.4, 6.8 Hz, 1 H), 3.07 (d, J = 6.8 Hz, 1 H), 2.60 (app dt, J = 10.0, 4.4 Hz, 1 H), 2.48 (d, J = 16.4 Hz, 1 H), 2.30 (s, 3 H), 2.11 (ddd, J = 11.2, 4.6, 4.0 Hz, 1 H), 2.07 (s, 3 H), 1.89 (m, 1 H), 1.80 (dd, J = 12.0, 3.6 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ 195.5, 157.4, 137.2, 133.2, 126.5, 121.1, 120.8, 118.7, 117.8, 109.0, 105.9, 67.8, 54.7, 53.8, 41.8, 38.5, 32.4, 29.1, 25.0, 22.9, 22.8; IR (neat) 2895, 2359, 1617, 1468, 1320, 1276, 1192, 911, 741 cm⁻¹; mass spectrum (CI) m/z 337.1914 [C₂₁H₂₅N₂O₂ (M+H) requires 337.1916]; [α]_D²⁵ = −187 (c 0.30, EtOH) {lit.^vi [α]_D²⁵ = −195 in EtOH}.