Toward the Asymmetric Synthesis of Cardenolides and Related Steroidal Systems: Syn-Sn2’ of Organometallics with C14–C17 Vinylepoxides

Abstract

In a program aimed at establishing a common sequence of C–C bond-forming reactions for asymmetric construction of tetracyclic triterpenoid natural products and related synthetic systems, effort has been directed toward introducing C17β-substitution by late-stage functionalization of stereodefined ‘steroidal’ D-ring vinylepoxides (spanning C14–C17). It has been found that cyanocuprates participate in syn-Sn2’ reactions that result in products bearing various C17β-substituents and containing a β-OH at C14.

Graphical Abstract

Tetracyclic triterpenoids are a large and structurally diverse class of complex natural products, members of which include steroid hormones, cardenolides, bufadienolides and limonoids, among others (Figure 1A).¹ Their potent and diverse biological activities have attracted the attention of synthetic and medicinal chemists for nearly a century.² While many creative approaches for stereoselective de novo construction of such agents have been reported, today it is more common to resort to semi-synthesis (natural product functionalization) as a means to fuel medicinal investigations in the area.³ This reality is reasoned to be based on inefficiencies of established de novo synthesis strategies (step economy and stereoselectivity) as well as limitations in flexibility. With the understanding that historically significant approaches to triterpenoid synthesis have had a profound impact on organic chemistry as a discipline,^4–6 our efforts have focused on imagining a modern approach that has the potential to be more efficient and flexible than established strategies.⁷ Here, it is revealed that ‘steroidal’ D-ring vinylepoxides (I, Figure 1B) undergo highly stereoselective syn-Sn2’ addition reactions with organometallic nucleophiles that favor the formation of C17β-substituted systems II, in favor of those derived from anti-Sn2’ (III) or Sn2 (IV) mechanisms. Notably, it has been found that cyanocuprates are particularly effective in this regard — an observation that stands in sharp contrast to previously reported reactions of this class of organometallic nucleophiles with stereodefined vinylepoxides.⁸

Figure 1.

Introduction – a strategy for late-stage introduction of a steroidal C17 substituent by reaction of organometallics with D-ring vinylepoxides.

For context, we have been developing an asymmetric step-economical strategy for the synthesis of tetracyclic triterpenoid systems that employs epichlorohydrin as the source of absolute stereochemistry (Figure 2).⁹ Simple three-step conversion to a stereodefined enyne (5) is followed by metallacycle-mediated annulation to generate a substituted hydrindane (6). Subsequent C9–C10 bond formation¹⁰ establishes 9-substituted estranes (7) that can be further advanced to synthetic androstanes (8) through an oxidative dearomatization and group selective alkyl shift from C9 to C10. Unfortunately, this concise and convergent synthesis strategy delivers steroidal products that lack substitution at C17 (7 and 8). While enynes related to 5 that contain a substituted C17 carbon can be employed in this sequence of bond-forming events,¹¹ such enynes currently require many additional chemical steps to prepare.¹² As such, it was reasoned that late stage introduction of varied C17 substituents to species related to 7 or 8 would be strategically beneficial.

Figure 2.

Enantioselective construction of C9-alkyl estranes and androstanes from epichlorohydrin.

It was imagined that steroidal D-ring vinylepoxides spanning C14–C17 may serve as viable electrophiles for stereoselective reactions with organometallic reagents, whereby regioselective C–C bond-formation was reasoned to be possible at C17 via Sn2’ addition. In pursuit of this hypothesis, the substituted estranes 9 and 10 (Figure 3) were converted to the stereodefined vinylepoxides 13 and 14 through a simple five-step sequence: (1) oxidation of the C16 alcohol, (2) base-mediated alkene isomerization that establishes the C8 stereocenter with very high levels of stereoselectivity (no evidence was found for the production of a stereoisomeric product),¹³ (3) formation of an enoltriflate, (4) Pd-catalyzed reduction,¹⁴ and (5) regio- and stereoselective epoxidation of the C14,C15-alkene.¹⁵

Figure 3.

Synthesis of vinylepoxides 13 and 14, and initial efforts to accomplish syn-Sn2’ addition reactions with them.

Initial experiments aimed at accomplishing syn-Sn2’ opening of these stereodefined vinylepoxides explored nucleophiles that have been described as being capable of undergoing related stereoselective processes.¹⁶ Unfortunately, as depicted in Figure 3, attempted conversion of 13 to either 15 or 16 with TMSCN or Et₂Al–CCTMS was unsuccessful. In both cases, the majority of material isolated after chromatography was simply the unreacted starting material. In contrast to these nucleophiles, treatment of 13 with PhLi (−78 to 0 °C) led to efficient and highly stereoselective syn-Sn2’ addition, delivering the C17β-phenyl substituted tetracycle 17 in 74% isolated yield.

While delighted to observe the desired regio- and stereoselective functionalization of 13 by reaction with an organolithium reagent, we aimed to identify less reactive/basic nucleophiles as potentially more functional group tolerant alternatives. Notably, cyanocuprates were conceived as potentially useful in this regard, albeit it was understood that related Sn2’ reactions of such nucleophiles with vinylepoxides are known to proceed in an anti-Sn2’ fashion (Figure 4A).^{8, 17} While we were aware of a report by Marino that formal syn-Sn2’ addition has been observed with reagents originally derived from alkyl iodides (Figure 4B), this observation was reasoned to result from a reaction mechanism proceeding by way of initial Sn2 addition of iodide to the electrophilic epoxide, followed by anti-Sn2’ addition of the organocopper species to the resulting allylic iodide.¹⁸

Figure 4.

Syn-Sn2’ addition reactions of organocopper reagents to steroidal D-ring vinylepoxides. Note: No evidence was found for products derived from anti-Sn2’ addition, or direct nucleophilic addition to C15 (dr ≥ 20:1; rr ≥ 20:1).

Despite a lack of precedent to support generality for the desired regio- and stereoselective syn-Sn2’ reaction of cyanocuprate reagents with vinylepoxides like 13 and 14, effort was directed at investigating the viability of this type of functionalization reaction. As summarized in Figure 4C, it was found that a variety of cyanocuprates, generated from either an organolithium or Grignard reagent, effectively converted 13 and 14 to the substituted products 23 and 24, respectively. In all cases, these products (23a – 23e, and 24a – 24e) were formed with exquisite levels of regio- and stereoselectivity,¹⁹ with C–C bond formation occuring at C17 in an overall syn-Sn2’ fashion (71–96% isolated yields; no evidence was found for the production of regio- or stereoisomeric products). Notably, these products possess a range of substituents at C17 (Me, butyl, 2-propenyl, allyl, t-Bu, s-Bu and 3-furyl), while also containing a stereodefined β-OH group at C14. It is appreciated that cis-fused CD-ring systems that possess a C14β-hydroxy group and a C17β-substituent are common in cardenolide and bufadienolide natural products (Figure 1A). Also of note, such tertiary allylic alcohols are substrates for oxidation reactions that occur with allylic transposition to deliver enones spanning C14–C16 (see Supporting Information). Such a molecular feature has been observed in limonoids and other tetracyclic triterpenoid natural products, and is reasoned to be a useful moiety for additional functionalization.

Overall, efforts focused on establishing a flexible and step-economical asymmetric de novo synthesis of tetracyclic triterpenoids have led to the desire to accomplish a syn-Sn2’ addition reaction of organometallics to ‘steroidal’ D-ring vinylepoxides. Such electrophiles (e.g., 13 and 14) are readily available from stereodefined synthetic estranes, themselves prepared in just a few steps from epichlorohydrin. Of the established nucleophiles known to engage vinylepoxides in syn-Sn2’ addition, we found that only a reactive organolithium (PhLi) was suitable for accomplishing this transformation. In an attempt to identify more functional group tolerant organometallic reagents capable of undergoing such a stereoselective transformation, cyanocuprates were investigated. Despite precedent showing that related organocopper species typically react by anti-Sn2’ addition, our studies reveal that these organometallic reagents, formed from organolithium- or Grignard reagents, indeed undergo syn-Sn2’ addition with vinylepoxides 13 and 14. While further study is required to understand these syn-Sn2’ reactions, the β-face of these vinylepoxides is reasoned to be substantially more accessible than the corresponding α-face. Regardless of the precise mechanism by which these syn-Sn2’ reactions proceed, studies are underway to exploit this unique reactivity to address problems in natural product total synthesis, and to drive chemical efforts aimed at identifying novel compositions of matter that have potentially valuable biological and medicinal properties.