Enantioselective Synthesis of (+)-Crocacin C. An Example of A Highly Challenging Mismatched Double Asymmetric δ-Stannylcrotylboration Reaction

Abstract

A concise, enantioselective synthesis of (+)-crocacin C is described, featuring a highly diastereoselective mismatched double asymmetric δ-stannylcrotylboration of the stereochemically demanding chiral aldehyde 9 with the bifunctional crotylborane reagent (S)-E-10. The total synthesis of (+)-crocacin C was accomplished in seven steps (longest linear sequence) starting from commercially available precursors.

The crocacins A–D are a family of natural products isolated from Chondromyces crocatus and Chondromyces pediulatus (Figure 1).¹ Crocacins A, B, and D are dipeptides of glycine and a 6-aminohexenoic or a 6-aminohexadienoic acid with a polyketide-derived acyl residue connected to the nitrogen atom, while crocacin C is a primary amide of the acyl polyketide fragment. Initial biological studies revealed that the crocacins display antifungal and cytotoxic activities. Compared to crocacins A–C, only crocacin D exhibited potent activity against Saccharomyces cerevisiae with a MIC of 1.4 ng/mL, which indicates that the dipeptide moiety of the crocacins is crucial for their biological properties.¹ Recent crystallographic data suggest that the crocacins are a new class of inhibitors of the cytochrome bc₁ complex.²

Figure 1.

Structures of crocacins A–D.

A characteristic structural feature of crocacin C is the anti,anti-dipropionate stereotriad (highlighted in yellow in Figure 2). It is evident that a mismatched double asymmetric crotylation reaction of an aldehyde substrate, such as 2, with a chiral crotylmetal reagent would be a direct, logical approach to this structural motif.^{3, 4}

Figure 2.

Attempted mismatched double asymmetric crotylboration reactions of aldehyde 2 with reagents 5 and 6 for synthesis of the anti,anti-stereotriad of crocacin C.^4f

However, an attempted^5f mismatched double asymmetric crotylboration of aldehyde 2 with crotylboronate 5 provided a 1:4 diastereomeric mixture in 60% yield, favoring the undesired 3,4-anti-4,5-syn-stereotriad 4 (Figure 2). Attempted crotylboration of aldehyde 2 using Brown’s crotylborane reagent 6 gave a 1:3 mixture of diastereomers, again favoring the undesired diastereomer 4. Owing to the inability to directly access this requisite anti,anti-stereotriad (e.g., 3), the central theme of multiple approaches developed for the synthesis of crocacin C^{5, 6} utilize indirect methods⁷ to prepare the anti,anti-stereotriad with high diastereoselectivity. Strategies involving aldol reactions,^{5a, 5e–g} epoxide ring-opening reactions,^5b–d, or the desymmetrization of meso cyclic precursors^{5i, 6d} have been adopted to access the anti,anti-stereotriad units of crocacin C precursors.

We recently described⁸ highly diastereoselective syntheses of anti,anti-stereotriads using mismatched double asymmetric δ-stannylcrotylboration reactions of chiral aldehydes with crotylborane reagent (S)-E-10⁹ (Figure 3). Because it has been reported that reagents such as 5 and 6 are incapable of overriding the intrinsic diastereofacial preference of aldehyde 2 (Figure 2), we were intrigued whether our new reagent (S)-E-10 could be adopted for synthesis of the anti,anti-stereotriad unit in 7. Furthermore, the vinylstannane unit in 7 can be used in subsequent C–C bond forming reactions, for example, Stille¹⁰ coupling with vinyl iodide 8.^5a We chose crocacin C as the target molecule for this study because it can be converted into other members of the crocacin family using a Cu-catalyzed coupling reaction as demonstrated by Dias and coworkers.¹¹

Figure 3.

Crocacin C, retrosynthetic analysis.

Starting from acyl oxazolidinone 11, aldehyde 9 was obtained in four steps according to known procedures (Scheme 1).¹² Addition of aldehyde 9 to the crotylborane reagent (S)-E-10, generated from the enantioselective and enantioconvergent hydroboration of racemic allenylstannane (±)-16¹³ with (^dIpc)₂BH, at −78 °C followed by warming the reaction mixture to ambient temperature for a 24 h reaction period provided the targeted anti,anti-stereotriad 15 in 61% yield and with >15:1 diastereoselectivity.

Scheme 1.

Total Synthesis of (+)–Crocacin C (1)

Methylation of the secondary alcohol of 15 with Me₃O·BF₄ and Proton Sponge provided methyl ether 7^5a in 88% yield. A Pd(0)-catalyzed Stille coupling^5a,10 of vinylstannane 7 with vinyl iodide 8^5a gave (+)-crocacin C (1) in seven steps (longest linear sequence) and in 21% overall yield from 11 without any protecting group manipulations. The spectroscopic data (¹H NMR, ¹³C NMR, [α]_D) of synthetic (+)-crocacin C were in excellent agreement with the data previously reported for the natural product.^{1, 5}

The intrinsic diastereofacial preference of aldehyde 9 was assessed by using an anti-crotylboration reaction with the achiral pinacol (E)-crotylboronate 17 (Scheme 2). This reaction provided an 18:1 mixture of 3,4-anti-4,5-syn-stereotriad 18 and anti, anti-stereotriad 19 in 77% yield, with 18 as the major product (as expected^3,14). In contrast, the mismatched double asymmetric δ-stannylcrotylboration of aldehyde 9 with (S)-E-10 provided the anti,anti-stereotriad 15 with >15:1 diastereoselectivity. No other crotylation diastereomers were observed in the reaction mixture. Protodestannylation of 15 under acidic conditions (TsOH·H₂O) provided alcohol 19 in 87% yield, which matched the minor isomer obtained from crotylboration of 9 with achiral crotylboronate 17.

Scheme 2.

Crotylboration Studies of Aldehyde 9

The mismatched double asymmetric δ-stannylcrotylboration of 9 with (S)-E-10 thus represents yet another case⁸ where a significant intrinsic diastereofacial barrier, as presented by chiral aldehyde 9, is overridden by the chiral reagent (S)-E-10. The free energy contribution of reagent (S)-E-10 (i.e., the enantioselectivity of the reagent expressed in energetic terms) necessary to override the 18:1 intrinsic diastereofacial preference of 9 and to generate homoallylic alcohol 15 with >15:1 mismatched diastereoselectivity is ≥3.3 kcal/mol (reaction at 23 °C). The exceptional enantioselectivity of (S)-E-10 defines a new standard of excellence that all future methodological studies on enantioselective crotylboration or crotylmetal-carbonyl addition reactions should be judged against.

In conclusion, the total synthesis of (+)-crocacin C (1) was completed in seven steps (longest linear sequence), which represents the shortest synthesis of 1 reported to date. Most importantly, the mismatched double asymmetric δ-stannylcrotylboration of aldehyde 9, with a signficant 18:1 intrinsic diastereofacial preference, was achieved with exceptional selectivity (>15:1) by using the crotylborane reagent (S)-E-10. The vinylstannane unit in the derived anti, anti-stereotriad 15 facilitates the subsequent Stille reaction that was used to complete this short synthesis of crocacin C. Other applications of reagent (S)-E-10 in the synthesis of biologically active natural products will be reported in due course.