Aryne acyl-alkylation in the general and convergent synthesis of benzannulated macrolactone natural products: An enantioselective synthesis of (-)-curvularin

Article abstract of DOI:10.1021/ol100335y

(Figure Presented) A general approach for the synthesis of benzannulated macrolactone natural products utilizing an ary ne acyl-alkylation reaction is described. Toward this end, the total syntheses of the natural products (-)-curvularin, curvulin, and (-

Full text of DOI:10.1021/ol100335y

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1612-1614
Aryne Acyl-Alkylation in the General
and Convergent Synthesis of
Benzannulated Macrolactone Natural
Products: An Enantioselective Synthesis
of (-)-Curvularin
Pamela M. Tadross, Scott C. Virgil, and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
stoltz@caltech.edu
Received February 9, 2010
ABSTRACT
A general approach for the synthesis of benzannulated macrolactone natural products utilizing an aryne acyl-alkylation reaction is described.
Toward this end, the total syntheses of the natural products (-)-curvularin, curvulin, and (-)-diplodialide C are reported. Furthermore, the
aryne insertion technology has enabled the rapid conversion of simple diplodialide natural products to curvularin, thereby connecting these
two biosynthetically distinct classes of compounds via synthetic methods.
Benzannulated macrolactones are an ever-growing class of
natural products with potential therapeutic and agrochemical
applications (e.g., 1-3) (Scheme 1).1 As part of our ongoing
research in aryne methodology, we targeted these natural
products using an acyl-alkylation reaction between an aryne
and a ꢀ-ketolactone.2 We chose as our initial target (-)-
curvularin (1),3,4 a polyketide natural product isolated from
several species of the mold CurVularia and recently shown
to be an inhibitor of human-inducible nitric oxide synthase
expression.5 By applying this retrosynthetic disconnection
to curvularin, we recognized that the ꢀ-ketolactone fragment
mapped onto the carbon framework of the diplodialide
natural products (4-7), revealing an unusual synthetic (i.e.,
nonbiomimetic) link between the two natural product fami-
lies. Thus, the development of a general synthesis of
benzannulated macrolactones via ring-expansive aryne inser-
tion chemistry from the diminutive macrolactone would
provide access to these valuable natural products and various
synthetic analogues for biological evaluation.
(1) (a) Macrolide Antibiotics: Chemistry, Biology, and Practice, 2nd
ed.; Omura, S., Ed.; Academic Press: San Diego, 2002. Xestodecalactone
A: (b) Edrada, R. A.; Heubes, M.; Brauers, G.; Wray, V.; Berg, A.; Grafe,
U.; Wohlfarth, M.; Muhlbacher, J.; Schaumann, K.; Sudarsono; Bringmann,
G.; Proksch, P. J. Nat. Prod. 2002, 65, 1598–1604. Citreofuran: (c) Lai,
S.; Shizuri, Y.; Yamamura, S.; Kawai, K.; Terada, Y.; Furukawa, H.
Tetrahedron Lett. 1989, 30, 2241–2244.
(-)-Curvularin possesses a 12-membered lactone fused
to a resorcinol aromatic ring, which we disconnected by an
(2) (a) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340–
5341. (b) Ebner, D. C.; Tambar, U. K.; Stoltz, B. M. Org. Synth. 2009, 86,
161–171.
(4) For previous total syntheses, see: (a) Gerlach, H. HelV. Chim. Acta
1977, 60, 3039–3044. (b) Bracher, F.; Schulte, B. Nat. Prod. Lett. 1995, 7,
65–68. (c) Bracher, F.; Schulte, B. Liebigs Ann./Recueil 1997, 1979–1982.
(d) Mohapatra, D. K.; Rahaman, H.; Pal, R.; Gurjar, M. K. Synlett 2008,
1801–1804.
(3) For isolation, see: (a) Musgrave, O. C. J. Chem. Soc. 1956, 4301–
4305. (b) Musgrave, O. C. J. Chem. Soc. 1957, 1104–1108. (c) Birch, A. J.;
Musgrave, O. C.; Richards, R. W.; Smith, H. J. Chem. Soc. 1959, 3146–
(5) Yao, Y.; Hausding, M.; Erkel, G.; Anke, T.; Forstermann, U.;
Kleinert, H. Mol. Pharmacol. 2003, 63, 383–391.
3152
.
10.1021/ol100335y  2010 American Chemical Society
Published on Web 03/02/2010

Scheme 1
.
Aryne Acyl-Alkylation as a General Strategy toward
Scheme 3
.
RCM of Silyl Ether 13 and Synthesis of
(-)-Diplodialide C (6)
the Synthesis of Benzannulated Macrolactone Natural Products
acyl-alkylation between resorcinylic aryne 8 and 10-
membered ꢀ-ketolactone 96 (Scheme 2). This formal C-C
bond insertion into ꢀ-ketolactone 9 forms two new C-C
bonds in a single step. Furthermore, ꢀ-ketolactones, such as
9, represent a substrate class that had not previously been
investigated in aryne acyl-alkylation reactions and would be
amenable to the preparation of other members of this class
of natural products. ꢀ-Ketolactone 9 could be accessed in
turn by ring-closing metathesis (RCM) of linear R,ω-diene
10.
catalysts.8 However, conversion of the allylic alcohol to the
silyl ether (13) led to significantly improved reactivity. We
were intrigued to find that treatment of silyl ether 13 with
Grubbs’ second-generation catalyst (15) in refluxing benzene
resulted in the formation of a single diastereomer having the
cis olefin geometry (anti-Z-14) in 44% yield.9 The relative
stereochemistry of lactone anti-Z-14 was determined by
conversion to (-)-diplodialide C6c,8,10 (6) by desilylation and
hydrogenation. While the resolution of the diastereomers of
silyl ether 13 by RCM was notable, the moderate yield
hindered our efforts. To our delight, use of the sterically less
encumbered Grubbs-Hoveyda third-generation catalyst11 16
led to the formation of a mixture of diastereomers and olefin
isomers of lactone 14 in 77% yield.
Scheme 2. Retrosynthetic Analysis of (-)-Curvularin
With this key RCM result in hand, we sought to streamline
this process by developing a one-pot silylation-RCM-
desilylation procedure beginning with allylic alcohol 12.
Gratifyingly, silylation with HMDS followed by RCM with
Grubbs-Hoveyda third-generation catalyst (16) and acidic
hydrolysis of the trimethylsilyl group generated ꢀ-hydroxy-
lactone 17 as the expected mixture of diastereomers and
olefin isomers (Scheme 4). This mixture was then readily
convertedtoꢀ-ketolactone9byhydrogenationandDess-Martin
oxidation. Interestingly, ꢀ-ketolactone 9 has been shown
previously to be an intermediate in the total syntheses of
the diplodialide family of natural products (Scheme 1).6
We began the forward synthesis by targeting ꢀ-ketolactone
9. Aldol reaction of known acetate 117 with acrolein provided
ꢀ-hydroxyester 12 as a 1:1 mixture of diastereomers (Scheme
3). Initial attempts to generate 10-membered ring products
by RCM proved challenging. Unfortunately, ꢀ-hydroxyester
12 was a poor substrate for RCM with a number of different
(8) In our hands, ꢀ-hydroxyester 12 was not a suitable substrate for RCM
with multiple catalysts. However, for RCM of 12, see: Sharma, G. V. M.;
Reddy, K. L. Tetrahedron: Asymmetry 2006, 17, 3197–3202.
(6) For previous syntheses of ꢀ-ketolactone 9, see: (a) Anand, R. V.;
Baktharaman, S.; Singh, V. K. J. Org. Chem. 2003, 68, 3356–3359. (b)
Ishida, T.; Wada, K. J. Chem. Soc., Perkin Trans. 1 1979, 323–327. (c)
Wakamatsu, T.; Akasaka, K.; Ban, Y. J. Org. Chem. 1979, 44, 2008–2012.
(d) Ishida, T.; Wada, K. J. Chem. Soc., Chem. Commun. 1977, 337–338.
(7) Acetate 11 was prepared by nucleophilic opening of (S)-propylene
oxide with a butenyl Grignard reagent in the presence of a copper catalyst,
followed by acetylation. See: Lin, W.; Zercher, C. K. J. Org. Chem. 2007,
72, 4390–4395.
(9) To our knowledge, only two other examples of a resolution of
diastereomers by RCM using an achiral catalyst are known: (a) Bajwa, N.;
Jennings, M. P. Tetrahedron Lett. 2008, 49, 390–393. (b) Magauer, T.;
Martin, H. J.; Mulzer, J. Angew. Chem., Int. Ed. 2009, 48, 6032–6036.
(10) For previous total syntheses, see: Wakamatsu, T.; Akasaka, K.; Ban,
Y. Tetrahedron Lett. 1977, 32, 2755–2758
.
(11) (a) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs,
R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592. (b) Stewart, I. C.; Douglas,
C. J.; Grubbs, R. H. Org. Lett. 2008, 10, 441–444.
Org. Lett., Vol. 12, No. 7, 2010
1613

pleased to find that treatment of aryne precursor 20 and
ꢀ-ketolactone 9 with CsF resulted in formation of benzan-
nulated macrolactone 24, albeit in lower yield than macro-
cycle 19 (Scheme 6). Finally, hydrogenolysis of the benzyl
groups4a produced (-)-curvularin (1) in 8% overall yield
and in only six steps from acetate 11.
Scheme 4. Synthesis of ꢀ-Ketolactone 9
Scheme 6. Completion of (-)-Curvularin
Preliminary acyl-alkylation studies showed that ꢀ-keto-
lactone 9 reacted competently with unsubstituted silyl aryl
triflate 18,12 producing macrolactone 19 in 61% yield
(Scheme 5). Furthermore, in the insertion reaction between
silyl aryl triflate 2013 and ethyl acetoacetate (21), arene 22
was produced in 58% yield as a single isomer. The
regiochemistry of this product was confirmed by debenzy-
lation of arene 22 to yield the natural product curvulin14,15
(23).
In conclusion, we have successfully completed syntheses
of the natural products (-)-curvularin (1), (-)-diplodialide
C (6), and curvulin (23). A unique resolution of diastereomers
by RCM allowed for the preparation of (-)-diplodialide C
from a mixture of diastereomeric dienes. Application of the
aryne acyl-alkyation en route to curvularin resulted in a
general synthesis that we anticipate will be applicable to a
number of related natural and non-natural analogues. Fur-
thermore, the aryne insertion technology has enabled the
formal conversion of the diplodialide natural products to
curvularin, two biosynthetically distinct classes of com-
pounds. The utilization of these methods in additional
complex settings is currently underway in our laboratories.
Scheme 5
.
Model Acyl-Alkylation Studies and Synthesis of
Curvulin (23)
Acknowledgment. We thank The Gordon and Betty
Moore Foundation, Abbott, Amgen, Boehringer-Ingelheim,
Bristol-Myers Squibb, Merck, Sigma-Aldrich, The California
HIV/AIDS Research Program (fellowship to P.M.T.), and
Caltech for generous funding.
Encouraged by these results, we turned our attention to
the key aryne acyl-alkylation toward curvularin. We were
(12) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–
1214.
(13) Silyl aryl triflate 20 was prepared in five steps from phloroglucinol:
Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org.
Lett. 2010, 12, DOI: 10.1021/ol1000796.
Supporting Information Available: Experimental details
and spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) For isolation, see: Coombe, R. G.; Jacobs, J. J.; Watson, T. R. Aust.
J. Chem. 1968, 21, 783–788
.
(15) For total synthesis, see: Bracher, F.; Krauss, J. Nat. Prod. Lett.
1998, 12, 31–34
.
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