Asymmetric De Novo Synthesis of a Cucurbitane Triterpenoid: Total Synthesis of Octanorcucurbitacin B

Abstract

The asymmetric de novo synthesis of a cucurbitane natural product, octanorcucurbitacin B, has been accomplished. Cucurbitanes are a family of structurally complex triterpenoids that characteristically contain three stereodefined quaternary centers at ring fusion carbons positioned about their tetracyclic skeletons (at positions 9, 13 and 14). Taking a diversion from the biosynthetic hypothesis for cucurbitane synthesis, the approach established here provides direct access to the cucurbitane skeleton without having to proceed by way of a lanostane. Using a simple chiral enyne as starting material, a sequence of annulative cross-coupling and intramolecular Heck reaction provides a stereodefined polyunsaturated tetracycle possessing the C9 and C13 quaternary centers. This intermediate was converted to octanorcucurbitacin B through a twelve-step sequence that features hydroxy-directed Simmons–Smith cyclopropanation, regioselective deconjugative alkylation and allylic oxidation.

Graphical Abstract

Cucurbitanes are a structurally diverse family of triterpenoid natural products, members of which are known to possess a variety of medically relevant properties that include antitumor, anti-inflammatory, and anti-HIV activities.¹ Structurally, cucurbitanes are related to lanostanes, euphanes and tirucallanes in that their tetracyclic skeleton contains three stereodefined quaternary centers located at ring fusion carbons (Figure 1A) – a structural feature that renders such targets markedly more challenging to prepare than simple steroidal systems bearing only one (estrane) or two (androstane and pregnane) such quaternary centers. In contrast to the historically significant attention that lanostanes (and related natural products) have received from the synthetic organic chemistry community,² cucurbitanes have been the subject of few reports.³ To our knowledge, no de novo total synthesis of a cucurbitane natural product has ever been accomplished. Unlike lanostanes, euphanes, and tirucallanes that possess quaternary centers at C10, C13 and C14 and maintain a relatively flat polycyclic network, cucurbitanes possess quaternary centers at C9, C13 and C14 and have a cis-fused BC ring system that results in a convex tetracyclic system (Figure 1A). In a program aimed at reimagining the manner in which synthetic chemists address the asymmetric construction of diverse tetracyclic triterpenoid natural products, we initiated efforts directed toward accomplishing the first de novo asymmetric synthesis of a cucurbitane. Here, we describe the success of these efforts and report the asymmetric total synthesis of octanorcucurbitacin B (1), a cucurbitane triterpenoid isolated from the stems of the bitter gourd, Momordica charantia (Figure 1B).⁴ Alongside the typical triad of quaternary centers [C9, C13 and C14; for other examples see endecaphyllacin A (2) and cucurbitacin D (3)], this natural product possesses oxygenation at C3, C7 and C16. These structural features were addressed in just fifteen chemical steps from a simple chiral enyne through a synthesis pathway that showcases the application of a recently developed sequence of stereoselective metallacycle-mediated annulative cross-coupling followed by a stereoselective intramolecular Heck reaction.

Figure 1.

Related tetracyclic terpenoids.

Semisynthesis of cucurbitane derivatives has been reported by derivatizing natural cucurbitane starting materials or by biomimetic cationic rearrangement of a lanostane system.^5,6 Biosynthetically, cucurbitanes are thought to derive from 2,3-oxidosqualene by way of initial conversion to the protosterol cation 4 and subsequent rearrangement to the cationic lanostane system 5 (Figure 2A). Conversion to a cucurbitane skeleton (6) is then thought to occur through methyl shift from C10 to C9, followed by hydride shift from C5 to C10, and loss of a proton from C6. While this type of lanostane-to-cucurbitane rearrangement has been the subject of numerous synthetic studies (Figure 2B),⁷ it is noteworthy to appreciate that the lanostane starting materials for these efforts are neither readily available nor easily accessible by de novo synthesis.

Figure 2.

Biosynthetically inspired approaches to cucurbitane systems based on methyl migration from C10 to C9 — cucurbitanes from lanostanes.

The synthetic design central to this report takes a significant departure from the biosynthetic hypothesis and targets the construction of a cucurbitane system directly without the need for a lanostane-type intermediate. With octanorcucurbitacin B (1) as the target of our studies, a retrosynthetic strategy was imagined that embraced the tetracyclic ketone 11 as a key late-stage intermediate that would require functionalization of the AB-ring system (Figure 3). It was recognized that this complex intermediate that possesses the challenging vicinal quaternary centers at C13 and C14 could be accessed from enone 12. In turn, tetracycle 12 was thought to derive from diene 13 through a process that would establish the requisite C8 stereochemistry and the cis-BC ring-fusion. Diene 13 was recognized as an intermediate that is readily accessible from aryltriflate 14 by way of an intramolecular Heck reaction that establishes the B-ring and the C9 quaternary center.⁸ Notably, the polyunsaturated hydrindane 14 is easily prepared from metallacycle-mediated annulative coupling of TMS-propyne with enyne 15,⁹ itself being the product of bidirectional functionalization of epichlorohydrin (16) with a simple Grignard reagent (17) and the acetylide derived from alkyne 18.

Figure 3.

Retrosynthetic analysis of octanorcucurbitacin B.

As illustrated in Figure 4, synthesis of tetracycle 13 was accomplished by a three-step sequence comprising alkoxide-directed metallacycle-mediated annulative cross-coupling of enyne 15 with TMS-propyne and subsequent protodesilylation to deliver the functionalized hydrindane 14 (49% overall isolated yield) followed by stereoselective intramolecular Heck reaction (Pd₂dba₃, rac-BINAP and i-Pr₂NEt) to establish the C9 quaternary center.⁸ This concise sequence translates stereochemical information from epichlorohydrin to C9 and C13 of the tetracyclic product 13 with exquisite levels of control (no evidence was found for the presence of diastereomeric products). Then, the cis-fused BC-ring system characteristic of cucurbitane compounds was realized by oxidation of the C16 secondary alcohol to the corresponding ketone with the Dess–Martin periodinane¹⁰ followed by base-mediated isomerization of the C8,C14 alkene (DBU, 60 °C). In this way, tetracycle 12 was generated in 74% isolated yield, and no evidence was found for production of the trans-fused isomer that would be epimeric at C8.

Figure 4.

Asymmetric de novo synthesis of a cucurbitacin: Total synthesis of octanorcucurbitacin B.

With the cis-fused BC-ring fusion established, attention was directed toward installation of the C14 quaternary center and realization of the characteristic vicinal quaternary centers observed at the CD-ring fusion of cucurbitane natural products. It was appreciated that simple diastereoselective conjugate addition would be the most straightforward, but previous studies on related substrates that possess additional unsaturation (C8–C9; not shown) have been uniformly unsuccessful in our hands likely owing to the extreme steric congestion around C14. As such, it was not anticipated that related conjugate addition chemistry would be viable with enone 12. Therefore, functionalization at C14 was explored by way of stepwise stereoselective reduction of the C16 ketone of 12 (CeCl₃•7H₂O, NaBH₄, MeOH) and hydroxy-directed Simmons–Smith cyclopropanation.^{11, 3a} Gratifyingly, this sequence of reactions delivered 19 as a single isomer in 75% overall yield.

Oxidation of the C16 alcohol of 19, again by the action of the Dess–Martin periodinane, delivered an intermediate ketone suitably functionalized for a global dissolving metal reduction.¹² In short, treatment with Li⁰ in ammonia resulted in regioselective cleavage of the cyclopropane, reduction of the C16 ketone, and reductive dearomatization of the A-ring to deliver triene 20 as an inconsequential mixture of diastereomers at C16 in 73% yield. Hydrolysis of the enol ether of 20 was then accomplished by treatment with HCl in wet acetone, and subsequent oxidation of the C16 alcohol delivered dione 21 in 84% yield.

With focus now directed toward appropriate functionalization of the A and B rings, acid-mediated isomerization of the C5,C10 alkene (HCl, MeOH, 65 °C) resulted in generation of the conjugated enone with concomitant establishment of the C10 stereocenter, albeit in an unoptimized 38% isolated yield. Methylation by the action of KOt-Bu and MeI then resulted in deconjugative alkylation, generation of the C4 quaternary center and establishment of the C5,C6 alkene present in 22 (97% yield). Notably, no product was found that contained a C5,C10 alkene in this deconjugative alkylation. The product of this sequence (22) was easily crystallized by slow evaporation from hexanes/Et₂O (3:2), and subsequent X-ray diffraction analysis confirmed both the relative and absolute stereochemistry of this advanced intermediate. Finally, chemoselective hydrogenation of the C11,C12 alkene (Pd/C, H₂, MeOH) was followed by allylic oxidation (CrO₃, pyridine, CH₂Cl₂) to generate octanorcucurbitacin B (1).

Overall, a de novo asymmetric synthesis of a cucurbitane natural product has been accomplished. Unlike the biosynthetic hypothesis for cucurbitane synthesis, the synthetic pathway described here is based on direct assembly of the cucurbitane skeleton without requiring rearrangement of a lanostane. The synthesis proceeds in just fifteen steps (0.8% overall yield)¹³ from a simple chiral enyne (15) that is easily prepared from epichlorohydrin (16). This accomplishment demonstrates the value of sequential metallacycle-mediated annulative cross-coupling and stereoselective formation of the “steroidal” C9–C10 bond as an enantioselective entry to the general cucurbitane skeleton. We look forward to exploring key aspects of the chemical approach described here to enable other campaigns in natural product- and function-oriented synthesis. Efforts along these lines will be reported in due course.