A concise enantioselective synthesis of (+)-crocacin C is described featuring a

A concise enantioselective synthesis of (+)-crocacin C is described featuring a highly diastereoselective mismatched double asymmetric δ-stannylcrotylboration of the stereochemically demanding Pomalidomide chiral aldehyde 9 with the bifunctional crotylborane reagent (and (Physique 1). against with a MIC of 1 1.4 ng/mL which indicates that this 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 cyclic precursors5i 6 have been adopted to access the anti anti-stereotriad models 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 (Physique 3). Because it has been reported that reagents such as 5 and 6 are incapable of overriding the intrinsic diastereofacial preference of aldehyde 2 (Physique 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 selected 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 Physique 3 Crocacin C retrosynthetic analysis. Starting from acyl oxazolidinone 11 aldehyde 9 was obtained in four actions according to known procedures (Plan 1).12 Addition of aldehyde 9 to the crotylborane reagent (S)-E-10 generated from your enantioselective and enantioconvergent hydroboration of racemic allenylstannane (±)-1613 with (dIpc)2BH at ?78 °C followed by warming the reaction mixture to ambient temperature for any 24 h reaction period provided the targeted anti anti-stereotriad 15 in NES 61% yield and with >15:1 diastereoselectivity. Plan 1 Total Synthesis of (+)-Crocacin C (1) Pomalidomide Methylation of the secondary alcohol of 15 with Me3O·BF4 and Proton Sponge provided methyl ether 75a in 88% yield. A Pd(0)-catalyzed Stille coupling5a 10 of vinylstannane 7 with vinyl iodide 85a gave (+)-crocacin C (1) in seven actions (longest linear sequence) and in 21% overall yield from Pomalidomide 11 without Pomalidomide any protecting group manipulations. The spectroscopic data (1H NMR 13 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 (Plan 2). This reaction provided an 18:1 mixture of 3 4 5 18 and anti anti-stereotriad 19 in 77% yield Pomalidomide with 18 as the major product (as expected3 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 combination. 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. Plan 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 offered by chiral aldehyde 9 is usually 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 usually ≥3.3 kcal/mol (reaction Pomalidomide at 23 °C). The outstanding 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 actions (longest.