Enantioselective synthesis of (+)-crocacin C. An example of a highly challenging mismatched double asymmetric δ-stannylcrotylboration reaction

Article abstract of DOI:10.1021/ol300476f

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

Full text of DOI:10.1021/ol300476f

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1880–1883
Enantioselective Synthesis of
(þ)-Crocacin C. An Example of a
Highly Challenging Mismatched Double
Asymmetric δ-Stannylcrotylboration
Reaction
Ming Chen and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
roush@scripps.edu
Received February 25, 2012
ABSTRACT
A concise, enantioselective synthesis of (þ)-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 (þ)-crocacin C was accomplished in seven steps (longest linear sequence) starting from commercially available precursors.
The crocacins AꢀD are a family of natural products
isolated from Chondromyces crocatus and Chondromyces
pediulatus (Figure 1).1 Crocacins A, B, and D are dipep-
tides of glycine and a 6-aminohexenoic or a 6-aminohex-
adienoic 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 anti-
fungal and cytotoxic activities. Compared to crocacins
AꢀC, 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 crystallo-
graphic data suggest that the crocacins are a new class of
inhibitors of the cytochrome bc1 complex.2
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 asym-
metric 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
However, an attempted5f mismatched double asym-
metric 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.
(3) Reviews of reactions of carbonyl compounds with crotylmetal
reagents: (a) Roush, W. R. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, p 1. (b) Yamamoto, Y.;
Asao, N. Chem. Rev. 1993, 93, 2207. (c) Denmark, S. E.; Almstead, N. G.
In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
2000; p 299. (d) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763. (e)
Lachance, H.; Hall, D. G. Org. React. 2008, 73, 1.
(1) (a) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot.
1994, 47, 881. (b) Jansen, R.; Washausen, P.; Kunze, B.; Reichenbach,
H.; Hofle, G. Eur. J. Org. Chem. 1999, 1085.
(2) Crowley, P. J.; Berry, E. A.; Cromarti, T.; Daldal, F.; Godfrey,
C. R. A.; Lee, D.-W.; Phillips, J. E.; Taylor, A.; Viner, R. Bioorg. Med.
Chem. 2008, 16, 10345.
(4) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
r
10.1021/ol300476f
Published on Web 03/12/2012
2012 American Chemical Society

Figure 2. Attempted mismatched double asymmetric crotyl-
boration reactions of aldehyde 2 with reagents 5 and 6 for
synthesis of the anti,anti-stereotriad of crocacin C.5f
Figure 1. Structures of crocacins AꢀD.
whether our new reagent (S)-E-10 could be adopted for
synthesis of the anti,anti-stereotriad unit in 7. Further-
more, the vinylstannane unit in 7 can be used in subsequent
CꢀC bond forming reactions, for example, Stille10 cou-
pling 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
co-workers.11
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 C5,6
utilize indirect methods7 to prepare the anti,anti-stereotriad
with high diastereoselectivity. Strategies involving aldol
reactions,5a,eꢀh epoxide ring-opening reactions,5bꢀd or the
desymmetrization of meso cyclic precursors5i,6d have been
adopted to access the anti,anti-stereotriad units of crocacin
C precursors.
We recently described8 highly diastereoselective synthe-
ses 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
(5) For total syntheses of crocacin C, see: (a) Feutrill, J. T.; Lilly,
M. J; Rizzacasa, M. A. Org. Lett. 2000, 2, 3365. (b) Chakraborty, T. K.;
Jayaprakash, S. Tetrahedron Lett. 2001, 42, 497. (c) Chakraborty, T. K.;
Jayaprakash, S.; Laxman, P. Tetrahedron 2001, 57, 9461. (d) Dias, L. C.;
de Oliveira, L. G. Org. Lett. 2001, 3, 3951. (e) Sirasani, G.; Paul, T.;
Andrade, R. B. J. Org. Chem. 2008, 73, 6386. (f) Sirasani, G.; Paul, T.;
Andrade, R. B. Bioorg. Med. Chem. 2008, 18, 3648. (g) Gillis, E. P.;
Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084. (h) Feutrill, J. T.;
Lilly, M. J.; White, J. M.; Rizzacasa, M. A. Tetrahedron 2008, 64, 4880.
(i) Candy, M.; Audran, G.; Bienayme, H.; Bressy, C.; Pons, J.-M. J. Org.
Chem. 2010, 75, 1354.
(6) For formal syntheses of crocacin C, see: (a) Gurjar, M. K.;
Khaladkar, T. P.; Borhade, R. G.; Murugan, A. Tetrahedron Lett. 2003,
44, 5183. (b) Raghavan, S.; Reddy, S. R. Tetrahedron Lett. 2004, 45,
Figure 3. Crocacin C, retrosynthetic analysis.
€
5593. (c) Besev, M.; Brehm, C.; Furstner, A. Collect. Czech. Chem.
Commun. 2005, 70, 1696. (d) Yadav, J. S.; Reddy, P. V.; Chandraiah, L.
Tetrahedron Lett. 2007, 48, 145. (e) Yadav, J. S.; Reddy, M. S.; Rao,
P. P.; Prasad, A. R. Synlett 2007, 2049.
(7) For reviews of methods commonly used to synthesize the anti, anti
dipropionate stereotriad: (a) Hoffmann, R. W. Angew. Chem., Int. Ed.
Engl. 1987, 26, 489. (b) Hoffmann, R. W.; Dahmann, G.; Andersen,
M. W. Synthesis 1994, 629.
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
(8) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2012, 134, 3925.
(9) (a) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2011, 133, 5744.
For synthetic applications of reagent (S)-E-10, see: (b) Sun, H.; Abbott,
J. R.; Roush, W. R. Org. Lett. 2011, 13, 2734. (c) Yin, M.; Roush, W. R.
Tetrahedron 2011, 67, 10274. (d) Chen, M.; Roush, W. R. Org. Lett.
2012, 14, 426.
(10) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
(11) Dias, L. C.; de Oliveira, L. G.; Vilcachagua, J. D.; Nigsch, F.
J. Org. Chem. 2005, 70, 2225.
Org. Lett., Vol. 14, No. 7, 2012
1881

Scheme 1. Total Synthesis of (þ)ꢀCrocacin C (1)
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 2. Crotylboration Studies of Aldehyde 9
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 (þ)-crocacin C
(1) in seven steps (longest linear sequence) and in 21%
overall yield from 11 without any protecting group manip-
ulations. The spectroscopic data (1H NMR, 13C NMR,
[R]D) of synthetic (þ)-crocacin C were in excellent agree-
ment 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 expected3,14). In contrast,
the mismatched double asymmetric δ-stannylcrotylbora-
tion 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 condi-
tions (TsOH•H2O) provided alcohol 19 in 87% yield,
which matched the minor isomer obtained from crotyl-
boration of 9 with achiral crotylboronate 17.
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 ex-
pressed in energetic terms) necessary to override the 18:1
intrinsic diastereofacial preference of 9 and to generate
homoallylic alcohol 15 with >15:1 mismatched diaster-
eoselectivity is g3.3 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 crotylmetalꢀ
carbonyl addition reactions should be judged against.
In conclusion, the total synthesis of (þ)-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 asym-
metric δ-stannylcrotylboration of aldehyde 9, with a sign-
ficant 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 sub-
sequent Stille reaction that was used to complete this short
synthesis of crocacin C. Other applications of reagent
The mismatched double asymmetric δ-stannylcrotyl-
boration of 9 with (S)-E-10 thus represents yet another
case8 where a significant intrinsic diastereofacial barrier, as
(12) Evans, D. A.; Miller, S. J.; Ennis, M. D. J. Org. Chem. 1993, 58,
471.
(13) Racemic allenylstannane (()-16 is prepared in two steps from
commercially available (()-3-butyn-2-ol using the route described for
(M)-16 and (P)-16. See: (a) Marshall, J. A.; Lu, Z.-H.; Johns, B. A.
J. Org. Chem. 1998, 63, 817. (b) Marshall, J. A.; Chobanian, H. Org.
Synth. 2005, 82, 43.
(14) Hoffmann, R. W.; Weidmann, U. Chem. Ber. 1985, 118, 3966.
1882
Org. Lett., Vol. 14, No. 7, 2012

(S)-E-10 in the synthesis of biologically active natural
products will be reported in due course.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support provided by the Na-
tional Institutes of Health (GM038436) and Eli Lilly (for a
predoctoral fellowship to M.C.) is gratefully acknowledged.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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