Enantioselective total synthesis of spirofungins A and B

Article abstract of DOI:10.1021/ol101961c

Figure Presented. The enantioselective total synthesis of spirofungins A (1) and B (2) is reported in 14 steps over the longest linear sequence. Key steps include the use of thiazolidinethione-mediated aldol reactions to assemble the major fragments and installation of the C1-C6 side chain using a cross metathesis reaction.

Full text of DOI:10.1021/ol101961c

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4416-4419
Enantioselective Total Synthesis of
Spirofungins A and B
Michael T. Crimmins* and Elizabeth A. O’Bryan
Kenan and Caudill Laboratories of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599, United States
crimmins@email.unc.edu
Received August 18, 2010
ABSTRACT
The enantioselective total synthesis of spirofungins A (1) and B (2) is reported in 14 steps over the longest linear sequence. Key steps include
the use of thiazolidinethione-mediated aldol reactions to assemble the major fragments and installation of the C1-C6 side chain using a
cross metathesis reaction.
Spirofungins A (1) and B (2) were isolated in 1998 as
secondary metabolites of Streptomyces Violaceusniger Tu¨
4113 as a 4:1 mixture.1 These spiroketal-containing natural
products differ only in the configuration about the C-15
spirocenter.2 The spirofungins, along with the structurally
related reveromycins,3 possess high antifungal activity
against yeasts, including the human pathogen Candida
albicans. Further biological studies by the Kozmin group
revealed that spirofungin A suppresses the growth of several
human cancer cell lines and selectively inhibits isoleucyl-
tRNA synthetase in vitro.4 The interesting structure and
biological profile of the spirofungins have resulted in two
total syntheses4,5 as well as several approaches to the
spiroketal core.6 Additionally, the Shimizu group has begun
investigating derivatives of both spirofungin A and the
reveromycins.7
Herein, we describe a highly convergent route to (-)-
spirofungin A (1) and (+)-spirofungin B (2) in which a cross
metathesis reaction would be employed to install the C1-C6
side chain 3 in an efficient manner (Scheme 1). The cross
metathesis partner, diene 4 or 5, was envisioned to arise from
the spiroketalization of ketone 6, available via a Horner-
Wadsworth-Emmons olefination, conjugate reduction se-
quence. The ꢀ-ketophosphonate 7, aldehyde 8, and ester 3
would be prepared using chiral auxiliary mediated aldol
reactions developed in our laboratories.8,9
Initial efforts were focused on the synthesis of aldehyde
8. Due to the required anti substitution, this fragment could
not be accessed directly from a thiazolidinethione-mediated
(1) Holtzel, A.; Kempter, C.; Metzger, J. W.; Jung, G.; Groth, I.; Fritz,
T.; Fiedler, H.-P. J. Antibiot. 1998, 51, 699–707.
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1041–1044.
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3141–3144. (b) Shimizu, T.; Kusaka, J.; Ishiyama, H.; Nakata, T. Tetra-
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Lett. 2004, 6, 2587–2590. (d) La Cruz, T. E.; Rychnovsky, S. D. Org. Lett.
2005, 7, 1873–1875.
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Shimizu, S.; Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1409–1413.
(b) Takahashi, H.; Osada, H.; Koshino, H.; Sasaki, M.; Onose, R.;
Nakahoshi, M.; Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1414–
1419. (c) Koshino, H.; Takahashi, H.; Osada, H.; Isono, K. J. Antibiot.
1992, 45, 1420–1427.
(7) Shimizu, T.; Usui, T.; Fujikura, M.; Kawatani, M.; Satoh, T.;
Machida, K.; Kanoh, N.; Woo, J.-T.; Osada, H.; Sodeoka, M. Bioorg. Med.
Chem. Lett. 2008, 18, 3756–3760.
(4) Marjanovic, J.; Kozmin, S. A. Angew. Chem., Int. Ed. 2007, 46,
8854–8857.
(8) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. J.
(5) Shimizu, T.; Satoh, T.; Murakoshi, K.; Sodeoka, M. Org. Lett. 2005,
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10.1021/ol101961c  2010 American Chemical Society
Published on Web 09/10/2010

nal11 gave rise to aldol adduct 10 in 81% yield and >20:1
diastereomeric ratio. Direct displacement of the chiral
auxiliary8 with iso-butyl alcohol provided ester 11 in 98%
yield. The Frater-Seebach alkylation with methyl iodide
proceeded in high diastereoselectivity; however, optimization
was necessary to improve the rate of conversion. After
screening a variety of conditions, it was determined that
adding DMPU resulted in the highest and most consistent
yields.12 The alkylated ester 12 was obtained in 63% yield
and a 10:1 diastereomeric ratio with the optimized conditions.
Protection of 12 as the triethylsilyl ether and reduction of
the ester generated aldehyde 8 in five steps and 44% overall
yield.
Scheme 1. Retrosynthetic Analysis of the Spirofungins
The synthesis of ꢀ-ketophosphonate 7 commenced with
an Evans syn propionate aldol addition11 between N-
propionylthiazolidinethione 13 and known aldehyde 1413 to
deliver secondary alcohol 15 in 88% yield and >20:1
diastereomeric ratio (Scheme 3). The resultant alcohol was
protected as the triethylsilyl ether, and reductive removal of
the thiazolidinethione auxiliary gave rise to aldehyde 16 in
81% yield over the two steps.
A Wittig reaction with stabilized ylide 17 was employed
to homologate the aldehyde to the R,ꢀ-unsaturated ester.
Upon 1,4-reduction with di-iso-butylaluminum hydride me-
diated by MeCu,14 ester 18 was obtained in 83% yield.
Treatment of ester 18 with lithiated dimethyl methylphos-
phonate15 furnished ꢀ-ketophosphonate 7 in 87% yield and
48% overall yield for the six steps.
With both ꢀ-ketophosphonate 7 and aldehyde 8 in hand,
formation of the spiroketal precursor via a modified
Horner-Wadsworth-Emmons olefination16 was next ex-
plored. Treatment of 7 with barium hydroxide followed by
addition of aldehyde 8 formed the desired C13-14 bond.
Conjugate reduction14 of the resultant enone generated ketone
6 in 94% yield. Exposure of the ketone to PPTS in methanol
resulted in facile cleavage of the silyl protecting groups and
spontaneous spiroketalization to provide a 2:1 mixture of
spiroketals 19 (15S-isomer) and 20 (15R-isomer). NOESY
and COSY NMR analysis determined that the major product
corresponded to the spiroketal core of spirofungin A. The
spiroketals were readily separated by flash column chroma-
tography to give 19 and 20 in 56% and 26% yields,
respectively, each of which was carried on separately for
the remaining steps in the synthesis.
propionate aldol reaction (Scheme 2). Instead, aldehyde 8
was prepared via a diastereoselective acetate aldol reaction
Scheme 2. Synthesis of Aldehyde 8
Introduction of the desired oxidation state of C24 was
achieved via a manganese dioxide oxidation employing
sodium cyanide and methanol17 to deliver methyl esters 21
(11) Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L. Synth.
Commun. 1998, 28, 3675–3679.
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6823–6831. (b) Suzuki, T.; Nakada, M. Tetrahedron Lett. 2002, 43, 3263–
3267. (c) Clarke, P. A.; Davie, R. L.; Peace, S. Tetrahedron 2005, 61, 2335–
2351.
followed by a Frater-Seebach alkylation.10 The acetate aldol
reaction between N-acetylthiazolidinethione 99 and 3-bute-
(14) Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T. J.
Org. Chem. 1986, 51, 537–540.
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200. (b) Frater, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40, 1269–
1277.
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M.; Sinisterra, V. J. J. Chem. Soc., Chem. Commun. 1987, 1509–1511.
Org. Lett., Vol. 12, No. 19, 2010
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Scheme 3. Synthesis of Spiroketals 4 and 5
and 22 each in 78% yield. To arrive at the desired cross
metathesis partner, installation of the C6-C8 diene was
accomplished via a sequential cross metathesis/Wittig reac-
tion.18 Treatment of 21 or 22 with methacrolein and Grubbs
second-generation catalyst gave rise to enals 23 and 24 in
74% yield. A methylene Wittig19 olefination introduced the
terminal olefin, providing dienes 4 and 5 in 86% and 75%
yield, respectively.
Scheme 4. Synthesis of Allylic Alcohol 3
Having developed an efficient route to the spiroketal core,
focus was shifted to synthesis and appendage of the C1-C6
side chain. Allylic alcohol 3 could be generated in a sequence
analogous to that used to prepare ꢀ-ketophosphonate 7
(Scheme 4). Beginning with an Evans syn propionate aldol
reaction between N-propionylthiazolidinethione 13 and ac-
rolein gave aldol adduct 25 in 96% yield and excellent
diastereoselectivity. The alcohol was then protected as the
triethylsilyl ether and the auxiliary reductively cleaved to
deliver aldehyde 26 in 92% yield over the two steps. A Wittig
reaction with ylide 17 and removal of the silyl protecting
group furnished allylic alcohol 3 in excellent yield over the
five steps.
previous success of a cross metathesis between a similarly
substituted diene and allylic alcohol from our group,20 we
anticipated the proposed cross metathesis between diene 4
or 5 and allylic alcohol 3 to be selective for the desired E
alkene.21 While the reaction was highly selective, initial
attempts were plagued by low yields and conversion. Several
The major bond-forming event that remained was intro-
duction of the C6-C7 bond via a cross metathesis reaction
of either diene with allylic alcohol 3. On the basis of the
(17) (a) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616–5617. (b) Nyangulu, J. M.; Galka, M. M.; Jadhav, A.; Gai,
Y.; Graham, C. M.; Nelson, K. M.; Cutler, A. J.; Taylor, D. C.; Banowetz,
G. M.; Abrams, S. R. J. Am. Chem. Soc. 2005, 127, 1662–1664.
(18) Paul, T.; Andrade, R. Tetrahedron Lett. 2007, 48, 5367–5370.
(19) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654–1666.
(20) (a) Crimmins, M. T.; Christie, H. S.; Chaudhary, K.; Long, A. J. Am.
Chem. Soc. 2005, 127, 13810–13812. (b) Crimmins, M. T.; Christie, H. S.;
Long, A.; Chaudhary, K. Org. Lett. 2009, 11, 831–834.
(21) Chatterjee, A. K.; Choi, T.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370.
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Org. Lett., Vol. 12, No. 19, 2010

reaction conditions and model substrates were examined to
optimize the key cross metathesis reaction. Ultimately, it was
found that to obtain the highest yields it was necessary to
add the ruthenium catalyst as a solution over several hours.
Under the optimized conditions, the cross metathesis products
27 and 28 were obtained in 83% and 71% yield, respectively,
based on recovered diene. Finally, employing conditions used
by Shimizu,5 hydrolysis of the diester with lithium hydroxide
provided (-)-spirofungin A (1) in 87% yield and (+)-
spirofungin B (2) in 88% yield (Scheme 5).
Scheme 5. Total Synthesis of Spirofungins A and B
In summary, a highly convergent total synthesis of
spirofungins A and B has been completed in 14 steps as the
longest linear sequence from known aldehyde 14. The key
fragments were assembled using the thiazolidinethione-
mediated propionate and acetate aldol reactions developed
in our laboratories. A cross metathesis reaction provided an
efficient strategy for appending the right-hand side chain to
the spiroketal core.
Acknowledgment. Financial support from the National
Institute of General Medical Sciences (GM60567) is grate-
fully acknowledged.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
OL101961C
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