Enantioselective synthesis of (-)-basiliskamide a

Article abstract of DOI:10.1021/ol300282e

Basiliskamide A is an antifungal polyketide natural product isolated by Andersen and co-workers from a Bacillus laterosporus isolate, PNG-276. A nine-step enantioselective synthesis of (-)-basiliskamide A is reported, starting from commercially available

Full text of DOI:10.1021/ol300282e

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1556–1559
Enantioselective Synthesis of
(À)-Basiliskamide A
Ming Chen and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
roush@scripps.edu
Received February 4, 2012
ABSTRACT
Basiliskamide A is an antifungal polyketide natural product isolated by Andersen and co-workers from a Bacillus laterosporus isolate, PNG-276. A
nine-step enantioselective synthesis of (À)-basiliskamide A is reported, starting from commercially available β-hydroxy ester 7. The synthesis
features a highly diastereoselective mismatched double asymmetric δ-stannylallylboration reaction of aldehyde 5 with the bifunctional
allylborane reagent 4.
Basiliskamide A (1) is a polyketide natural product
isolated by Andersen and co-workers from a Bacillus
laterosporus isolate, PNG-276.1 The structure of 1 was
established by extensive NMR experiments and by com-
parison of its spectroscopic properties to that for the
known one-carbon homologation analogue YM-47522
(Figure 1). The relative and absolute configuration assign-
ments for basiliskamide A were subsequently verified by
chemical synthesis.2
Basiliskamide A (1) displays biological activity against
C. albicans and A. fumigatus with MIC values of 1.0 and
2.5 μg/mL, respectively. Intriguingly, in spite of the close
structural similarities between basiliskamide A (1) and
YM-47522 (Figure 1), the biological activity profile of
YM-47522 is quite different, with MIC values against C.
albicans and A. fumigatus of 25 and >50 μg/mL, respec-
Figure 1. Structures of basiliskamide A and YM-47522.
tively. Furthermore, studies with seven fresh clinical iso-
lates of C. albicans indicated that basiliskamide A has
activity comparable to the oxo polyene macrolide antibiotic
amphotericin B, with both compounds having identical
MICs (0.5 μg/mL) against each of the seven clinical isolates.
More importantly, basiliskamide A displayed only minimal
cytotoxicity against human diploid fibroblast cells at a
concentration of 100 μg/mL, while amphotericin B de-
stroyed all the cells at the same concentration.1
This interesting biological profile has inspired the devel-
opment of several total syntheses of basiliskamide A (1).2
The shortest of the three current syntheses requires 14
(1) Barsby, T.; Kelly, M. T.; Andersen, R. J. J. Nat. Prod. 2002, 65,
1447.
(2) (a) Lipomi, D. J.; Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6,
3533. (b) Dias, L. C.; Gonc-alves, C. C. S. Adv. Synth. Catal. 2008, 350,
1017. (c) Dias, L. C.; Gonc-alves, C. C. S. J. Braz. Chem. Soc. 2010, 21,
2012. (d) Yadav, J. S.; Rao, P. P; Reddy, M. S.; Prasad, A. R. Tetra-
hedron Lett. 2008, 49, 5427.
r
10.1021/ol300282e
Published on Web 02/28/2012
2012 American Chemical Society

linear steps (16 steps total) from commercially available
starting materials. Several steps in each synthesis are
devoted to protecting group manipulations or to reduction
or oxidation reactions needed to adjust the oxidation state
of increasingly advanced intermediates. Each of the re-
ported syntheses of 1 also utilized a Stille coupling of vinyl
iodide intermediates, which were prepared via Takai ole-
fination of appropriate aldehyde precursors.2,3a,3b One
drawback associated with Takai olefination is that a
mixture of E/Z olefin isomers is often obtained, with the
ratio of thetwo isomersdepending on structuralfeaturesof
the aldehyde substrate.2,3cÀ3e With the goals to develop an
efficient synthesis of 1, to demonstrate the synthetic utility
of the highly diastereoselective mismatched double asym-
metric δ-stannylallylboration reaction of reagent 4,4À6 and
between the known vinyl iodide 28 and vinylstannane 3.
The δ-stannyl-homoallylic alcohol moiety embedded in
vinylstannane 3 provides a perfect platform to explore the
mismatched double asymmetric δ-stannylallylboration re-
action of aldehyde 5withourrecentlydisclosedallylborane
reagent 4.4 Aldehyde 5 would be obtained from the known
homoallylic alcohol 6,9 which in turn would be prepared
from the commercially available β-hydroxy ester (S)-7
according to published procedures.
Homoallylic alcohol 6 was synthesized in three steps
according to known procedures, starting from β-hydroxy
ester (S)-7 (Scheme 2).9 Hydrogenation of the olefin unit in
6 under standard conditions (Pd/C, H2, MeOH-EtOAc)
provided, unexpectedly, the deprotected diol 9 in 92%
yield (Scheme 1).10 When EtOAc was used as the reaction
solvent, alcohol 8 with the primary TBS ether intact was
obtained in 63% yield; however, a significant amount of
the ketone byproduct 10 (23%) was also obtained. After a
brief screening of reaction conditions, the formation of
ketone 10 was minimized by adding NaHCO3 to the
hydrogenation reaction and by shortening the reaction
time. Under optimized conditions, alcohol 8 was obtained
in 81% yield from alcohol 6.
Scheme 1. Optimization of Hydrogenation of Alcohol 6
Figure 2. Retrosynthetic analysis of basiliskamide A (1).
ultimately to use this synthesis to gain further insight into
the structureÀactivity relationships of these natural pro-
ducts, we have developed and report herein a nine-step,
enantio- and highly diastereoselective synthesis of (À)-
basiliskamide A (1).
As summarized in Figure 2, we envisioned that basilisk-
amide A (1) could be assembled via a Stille coupling7
Acylation of alcohol 8 with (E)-cinnamoyl chloride (11)
provided ester 12 in 63% yield (92% based on recovered
starting material, Scheme 2). Deprotection of the primary
TBS ether of ester 12 proved to be challenging (see
Table 1). When this deprotection was attempted using
TsOH in a THFÀMeOH solvent mixture, a 1:1 mixture
of alcohol 13 and the acyl transfer isomer 14 were obtained
(Table 1, entry 1). Treatment of 12 with TBAF in THF
again provided a 1:1 mixture of alcohols 13 and 14
(3) (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408. (b) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
For recent examples, see: (c) Palimkar, S. S.; Uenishi, J. Org. Lett. 2010,
12, 4160. (d) Li, P.; Li, J.; Arikan, F.; Ahlbrecht, W.; Dieckmann, M.;
Menche, D. J. Org. Chem. 2010, 75, 2429. (e) Crimmins, M. T.; Haley,
M. W.; O’Bryan, E. A. Org. Lett. 2011, 13, 4712.
(4) (a) Chen, M.; Ess, D. H.; Roush, W. R. J. Am. Chem. Soc. 2010,
132, 7881. (b) Stewart, P.; Chen, M.; Roush, W. R.; Ess, D. Org. Lett.
2011, 13, 1478.
(5) 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.
(6) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(7) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50.
(8) (a) Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709. (b) Buynak,
J. D.; Vogeti, L.; Chen, H. Org. Lett. 2001, 3, 2953.
(9) (a) Roush, W. R.; Palkowitz, A. D.; Palmer, M. J. J. Org. Chem.
1987, 52, 316. (b) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am.
Chem. Soc. 1990, 112, 6348.
(10) (a) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron Lett. 2000, 41,
5711. (b) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57, 2109.
(c) Ikawa, T.; Sajiki, H.; Hirota, K. Tetrahedron 2004, 60, 6189. (d)
Espeel, P. E. R.; Piens, K.; Callewaert, N.; Van Der Eycken, J. Synlett
2008, 2321.
Org. Lett., Vol. 14, No. 6, 2012
1557

Scheme 2. Total Synthesis of Basiliskamide A (1)
δ-stannylallylboration of aldehyde 5 with allylborane
4, prepared as described previously,4a gave homoallylic
alcohol 3 with >50:1 diastereoselectivity and in 71%
overall yield from 13. Protodestannylation of 3 under
Table 1. Optimization of the Deprotection of TBS Ether 12
acidic conditions (TsOH H2O) provided alcohol 17 in
3
82% yield, which matched the minor product obtained
from allylboration of aldehyde 5 with allylboronate 15
(Scheme 3).
entry
conditions
13:14a
yield of 13b (%)
1
2
3
4
TsOH, THF/MeOH, rt, 8 h
TBAF, THF, rt, 8 h
1:1
1:1
1:1
9:1
43
47
41
79
Scheme 3. Allylboration Studies of Aldehyde 5
TBAF/HOAc, THF, rt, 8 h
TASF, DMF/H2O, rt, 8 h
a Based on 1H NMR analysis of the crude reaction mixture. b Yield of
isolated desired alcohol 13.
(Table 1, entry 2). Similar results were also obtained when
TBAF buffered with HOAc was used (Table 1, entry 3).
However, when 12 was treated with TASF in a DMFÀ
H2O mixture,11 a 9:1 mixture of 13 and 14 was generated,
from which alcohol 13 was obtained in 79% yield after
chromatographic purification (Table 1, entry 4).
Oxidation of primary alcohol 13 with the DessÀ
Martin periodinane reagent12 provided aldehyde 5,
which was used directly in the subsequent reaction.
The intrinsic diasteofacial selectivity of 5 was accessed
by subjecting 5 to an allylboration reaction with the
achiral pinacol allylboronate 15 (Scheme 3). This reac-
tion provided a 3.5:1 mixture of homoallylic alcohol
16 and 17, favoring the expected Felkin adduct 16.
On the other hand, the mismatched double asymmetric
Finally, Pd-catalyzed Stille coupling7 of vinylstannane 3
with vinyl iodide 28 provided (À)-basiliskamide A (1) in
68% yield. The spectroscopic data (1H NMR, 13C NMR,
[R]D) of synthetic (À)-basiliskamide A were in excellent
agreement with the data previously reported for the nat-
ural product.1,2
(11) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(12) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
In conclusion, the enantioselective total synthesis of (À)-
basiliskamide A was completed in nine steps (longest linear
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Org. Lett., Vol. 14, No. 6, 2012

sequence, 10 steps total) from commercially available
starting materials. The brevity of this synthesis was
facilitated by the mismatched double asymmetric
δ-stannylallylboration reaction of aldehyde 5 with allyl-
borane 44a that provided homoallylic alcohol 3 with
outstanding stereochemical control (>50:1). The vinyl-
stannane unit in 3 was used directly in a Stille
coupling reaction to complete the total synthesis of
(À)-basiliskamide A. Application of this methodology
to the synthesis of other related polyketide natural pro-
ducts will be reported in due course.
Acknowledgment. Financial support provided by the
National Institutes of Health (GM038436) and Eli Lilly
(for a predoctoral fellowship to M.C.) is gratefully
acknowledged.
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.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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