Enantioselective total syntheses of marine natural products (+)-cylindricines C, D, E and their diastereomers

Abstract

A seven-step total synthesis of (+)-cylindricine D and epi-cylindricine D is described. The efficiency relies on the highly diastereoselective reductive bis-functionalization of N,O-protected (S)-pyroglutaminol by our recently improved protocol to build the N-α-tert-alkylamine motif, and a telescoped one-step four-reaction protocol to build the fused bicyclic ring system. (+)-Cylindricine C and its 2-epimer were synthesized by essentially the same sequence in eight steps. Acetylation of the latter then delivered (+)-cylindricine E and its 2-epimer, respectively.

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Efficiency is one of the major themes in organic synthesis.¹ In the field of the total synthesis of natural products, the efficiency not only depends on the synthetic strategy employed, but also relies in efficient synthetic methods.² Amides are a class of readily available and highly stable compounds which have long been employed as privileged starting materials and synthetic intermediates in the total synthesis of alkaloids and N-containing medicinal agents. However, as the least reactive class of carboxylic acid derivatives, the direct, chemoselective transformation of amides is challenging. Hence multistep methods have to be employed which dramatically reduced the synthetic efficiency.³ During the last decade, we have developed a series of methods for the direct transformations of amides,⁴ which include an unique reaction for the one-pot conversion of tertiary amides (A) into α-tert-alkylamines (B)^5,6 (reductive di- and bis-alkylation)^4a (Scheme 1a). On the basis of the amide transformation reactions (amide strategy), we have achieved the concise total syntheses of several alkaloids.^4b,d,e

Scheme 1 (a) Our previous work; (b) modification of the amide reductive bis-alkylation reaction towards new targets; (c) the alkaloids of the cylindricine/fasicularin/lepadiformine family.

Cylindricines A–K are a group of eleven tricyclic alkaloids (Scheme 1c, only the structures of 1a–1i shown) isolated from the ascidian Clavelina cylindrica collected from the East Coast of Tasmania.⁷ Cylindricines A, C–I, and K possess a new pyrrolo[2,1-j]quinoline framework, whereas cylindricines B and J share a pyrido[2,1-j]quinoline system. All of them possess a cis-fused 1-azadecalin A/B-ring system. Surprisingly, neither optical rotations nor the absolute configurations of this group of natural products have been described in the literature. Despite of the lack of information on the absolute stereochemistry and of unknown bioactivities (except for toxicity in a brine shrimp assay), the intriguing structures of cylindricines have attracted considerable attention from synthetic community.^8–10 More than twenty research groups including those of Snider,^9a Weinreb,^9b Heathcock,^9c Molander,^10a Kibayashi,^10c,f Trost,^10b Ciufolini,^10d Hsung,^10e,g–i Shibasaki,^10j–l Donohoe,^9e Renaud,^9d Pandey,^10m and Chida/Sato^6c have been engaged in the total syntheses of cylindricines, which resulted in many elegant approaches.^8–10 However, efficient and flexible enantioselective synthetic approaches are still demanding.^8c In connection with our longstanding interest in the divergent total synthesis of alkaloids and their diastereomers,^4b,d,e,11 we decided to explore a concise and flexible approach to (+)-cylindricines C–E (1c, 1d, and 1e), and the results are reported herein.

Because the absolute configurations of the natural cylindricines are unknown, before starting our enantioselective total synthesis, we have to firstly decide the enantiomers to be synthesized. In this regard, it is worth mentioning that several structurally related (to cylindricines) tricyclic alkaloids such as lepadiformine (2)¹² and fasicularin (3)¹³ have been isolated. Although their absolute configurations have not been determined by the phytochemists,^12,13 through the enantioselective total syntheses of lepadiformine (2), Kibayashi¹⁴ and Weinreb¹⁵ have independently arrived at the conclusion that natural lepadiformine is dextrorotatory having (2R,5S,10S,13S) configuration (with the structure shown by 2). Thus, Weinreb has assumed that all the other alkaloids of the cylindricine/fasicularin/lepadiformine family have the same absolute stereochemistry as lepadiformine.^8b On the basis of these considerations, we opted for the putative natural (+)-cylindricines C–E (1c–1e) with the absolute configurations shown in Scheme 1 as our targets.

Our synthetic strategy to (+)-cylindricines C–E (1c–1e) stemmed from the identification of the α-tert-alkylamine motif-bearing prolinol moiety as the key structural feature, and inspired from the diversity of the alkaloids of the cylindricine/fasicularin/lepadiformine family as marked by the generic structure C (Scheme 1). Thus, in the light of the amide reductive bis-alkylation reaction,^4aL-pyroglutamic acid derived lactam (+)-9 was selected as our chiral pool. In line with this strategy, the retrosynthetic analysis of (+)-cylindricine D (1d) is outlined in Scheme 2, which implies the last stage formation of A ring from bicyclic precursor 4, and a later stage formation of B ring from (S)-prolinol derivative 5. The employment of Weinreb amide¹⁶7 would allow for the introduction of different alkyl groups and thus affords the flexibility for the synthesis of different alkaloids bearing either an n-hexyl or an n-butyl side chain and analogues. Ester 8 was envisioned to be accessible in one-pot from chiral lactam (S)-9 by the amide reductive bis-alkylation method that we developed previously.^4a

Scheme 2 Retrosynthetic analysis of (+)-cylindricine D.

To start our investigation, the known (S)-N-benzylpyroglutaminol methyl ether (9)¹⁷ was prepared from commercially available (S)-N-benzylpyroglutaminol [(S)-11] (NaH, MeI, 0 °C) in 90% yield. Successive treatment of a solution of lactam (S)-9 (1.0 equiv.) and DTBMP (1.2 equiv., 2,6-di-tert-butyl-4-methylpyridine) in CH₂Cl₂ with Tf₂O (1.1 equiv.), Grignard reagent 10 (1.0 equiv.), and sodium enolate generated in situ by deprotonation of ethyl acetate (1.5 equiv.) with NaHMDS (1.8 equiv., sodium bis(trimethylsilyl)amide), afforded the desired functionalized prolinol derivative 8 and its diastereomer in 60% yield (dr = 7 : 1) (Scheme 3). Replacement of the Tf₂O/DTBMP combination by Tf₂O/TTBP (2,4,6-tri-tert-butylpyrimidine), an amide activation system that has recently been shown to be versatile for the transformations of both secondary and tertiary amides,¹⁸ resulted in an improvement of the yield from 60% to 75% (dr = 7 : 1). The stereochemistry of the major diastereomer 8 was assumed to be trans in analogy with our previous results,^4a which was confirmed by its ultimate transformation into (+)-cylindricine D (1d) (vide infra). The stereochemical outcome can be understood in terms of the trans-addition of the enolate from the less hindered β-face of the pyrrolidinium ion intermediate.

Scheme 3 Total syntheses of (+)-cylindricine D, 2-epi-cylindricine D, and an intermediate of cylindricines C and E.

Next, we proceeded to the chain elongation of ester. Employing Liotta's method,¹⁹ the Weinreb amide 7 was obtained in excellent yield. Subjection of N-benzylpyrrolidine derivative 7 to catalytic hydrogenolysis in the presence of Pearlman's catalyst [20% Pd(OH)₂/C] and Boc₂O resulted in the switch of N-protecting group from benzyl to Boc (6) in 93% yield. The reaction of Weinreb's amide 6 with alkynyllithium, generated in situ from oct-1-yne (3.0 equiv.) and n-butyllithium (3.0 equiv.), proceeded smoothly to give the desired ynone 5 in almost quantitative yield. Next, partial saturation of the alkynyl group was investigated. After several trials, it was found that in the presence of a catalytic amount of Lindlar catalyst (5% Pd/CaCO₃ poisoned with Pb, 30 mol%), partial hydrogenation of ynone 5 in toluene/1-hexene proceeded smoothly to give the desired (Z)-α,β-enone 17, which after a simple filtration, was exposed to trifluoroacetic acid in methylene chloride (0 °C, 1 h). After removal of CH₂Cl₂ and TFA under reduced pressure, the residue was treated with K₂CO₃ in methanol at 60 °C for 8 hours, which yielded bicyclic alcohol 18 in 83% yield as an inseparable 1 : 1 diastereomeric mixture (the diastereomeric ratio was determined by integrating the peaks at 3.37 and 3.35 ppm of the ¹H NMR spectrum of the mixture). Comparing with the reported excellent diastereoselectivity from the enamine-based S_Ni reaction,^10c the stereochemical outcome of our intramolecular aza-conjugate addition is unexpected. This is attributable to the conformational flexibility of both the pyrrolidine ring and the conjugate addition reaction. Although we were unable to control the formation of the newly formed stereocenter, telescoping four reactions [(1) partial reduction of ynone 5 to the presumed (Z)-enone 17; (2) N-deprotection; (3) O-deprotection; (4) intramolecular aza-conjugate addition] into one step rendered the synthesis highly efficient. Finally, O-mesylation of the diastereomeric mixture 18 and treating the resultant keto mesylate with potassium tert-butoxide in THF produced (+)-cylindricine D (1d) and 2-epi-cylindricine D (2-epi-1d) (dr = 1 : 1) in a combined yield of 80%. The physical {1d: [α]²⁰_D +22.5 (c 0.25, CHCl₃); natural sample:^7b data not reported; synthetic sample: lit.^10e [α]²³_D +21.8 (c 0.57, CHCl₃); 2-epi-1d: [α]²⁵_D +7.4 (c 0.1, CHCl₃)} and spectroscopic data of our synthetic compounds match those reported in the literature.^10e

Having achieved a short total synthesis of (+)-cylindricine D, we proceeded to the syntheses of (+)-cylindricines C and E. For this purpose, the known benzyl ether 12 ¹⁷ was prepared from (S)-N-benzylpyroglutaminol [(S)-11] by exposing to NaH and BnBr at 0 °C, which afforded 12 in 94% yield (Scheme 3). Pleasantly, the Tf₂O/TTBP-promoted one-pot reductive bis-functionalization of 12 with Grignard reagent 10 and sodium enolate generated in situ from ethyl acetate and NaHMDS afforded the desired functionalized prolinol derivative 13 in 80% yield and in excellent diastereoselectivity (dr ≥ 20 : 1) (Scheme 3). The observed higher diastereoselectivity as compares with that obtained from lactam 9 may be due to beneficial steric hindrance of the benzyl group in lactam 12. Amidation of ester 13 [Me(MeO)NH-HCl, ⁱPrMgCl, THF, −20 °C, yield: 96%] followed by 20% Pd(OH)₂/C-catalyzed hydrogenolysis of Weinreb amide 14 in the presence of (Boc)₂O produced selectively O-t-butyl carbamate 15 in 95% yield. Alkynylation of Weinreb amide 15 yielded ynone 16 in 88% yield (Scheme 3). Telescoped one-step Lindlar hydrogenation of ynone 16, cleavage of the N-Boc with trifluoroacetic acid and treating the resultant mixture with K₂CO₃ yielded indolizidinone 20, which was O-tosylated to yield tosylate 21 in 77% yield (from 16, Scheme 4) as an inseparable 1.1 : 1 diastereomeric mixture (the diastereomeric ratio was determined by integrating the peaks at 3.27 and 3.08 ppm of the ¹H NMR spectrum of the mixture). KHMDS-mediated cyclization of 21 in THF at −78 °C afforded diastereomeric mixture 22 (dr = 1.1 : 1) in 94% yield. O-Debenzylation of 22 under acidic conditions (10% Pd/C, H₂, MeOH/H₂O/AcOH, rt, 24 h) proceeded smoothly to afford (+)-cylindricine C (1c) and 2-epi-cylindricine C (2-epi-1c) both in 41% yield. The physical {1c: [α]²⁵_D +56.9 (c 0.25, CHCl₃); natural sample:^7b data not reported; synthetic sample: lit.^10m [α]²²_D +60.2 (c 0.5, CHCl₃); 2-epi-1c: [α]²⁵_D +46.2 (c 1.0, CHCl₃), lit.^10d [α]²⁵_D −39 (c 0.5, CH₂Cl₂)} and spectroscopic data of our synthetic compounds match those reported in the literature.^10m

Scheme 4 Completion of the total syntheses of (+)-cylindricines C, E, and C-2 epimers.

Finally, O-acetylation of 1c (Ac₂O, Et₃N, DMAP, CH₂Cl₂) produced (+)-cylindricine E (1e) in 97% yield. Similarly, O-acetylation of 2-epi-cylindricine C (2-epi-1c) yielded 2-epi-cylindricine E (2-epi-1e) in excellent yield. The physical {1e: [α]²⁵_D +27.5 (c 0.25, CHCl₃), lit.^10m [α]²²_D +28.3 (c 0.15, CHCl₃); 2-epi-1e: [α]²⁵_D +29.1 (c 1.0, CHCl₃)} and spectroscopic data of our synthetic compounds matched those reported in the literature.^9a

Conclusions

To summarize, on the basis of the amide strategy and telescoped one-step four-reaction transformation, we have developed a concise approach to cylindricines C–E. The total synthesis of cylindricine D (1d) was achieved in 7 steps and 20.9% overall yield from the known compound (S)-9 [8 steps, 18.8% overall yield from commercial compound (S)-11]. Similarly, (+)-cylindricine C (1c) was synthesized in 8 steps, 19.1% overall yield from (S)-12 [9 steps, 17.9% overall yield from (S)-11], and (+)-cylindricine E (1e) was synthesized in 9 steps, 18.5% overall yield from (S)-12 [10 steps, 17.4% overall yield from (S)-11]. Thus, we have accomplished one of the shortest and the most efficient total syntheses of (+)-cylindricines C–E so far reported.^8,20 In addition, alongside with cylindricines C–E, their C-2 epimers were obtained concurrently in similar overall yields. Work is on progress towards the total synthesis of other members and analogues of alkaloids of the cylindricine/fasicularin/lepadiformine family.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (21931010) and the National Key R&D Program of China (grant No. 2017YFA0207302).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1qo01408k

‡ These authors contributed equally to this work.

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