Enantioselective synthesis of the C8-C20 segment of curvicollide C

Article abstract of DOI:10.1021/ol702092h

The enantioselective synthesis of the C8-C20 fragment of curvicollide C has been accomplished. A catalytic asymmetric Claisen rearrangement (CAC), a diastereoselective methyl cupration of an alkynoate, and a Julia-Kocienski olefination served as key C/C-connecting transformations.

Full text of DOI:10.1021/ol702092h

ORGANIC
LETTERS
2007
Vol. 9, No. 24
4979-4982
Enantioselective Synthesis of the
C8 C20 Segment of Curvicollide C
−
Marleen Ko1rner and Martin Hiersemann*
Fachbereich Chemie, UniVersita¨t Dortmund, D-44227 Dortmund, Germany
martin.hiersemann@uni-dortmund.de
Received August 24, 2007
ABSTRACT
The enantioselective synthesis of the C8−C20 fragment of curvicollide C has been accomplished. A catalytic asymmetric Claisen rearrangement
(CAC), a diastereoselective methyl cupration of an alkynoate, and a Julia−Kocienski olefination served as key C/C-connecting transformations.
The curvicollides A-C (CA-C, 1-3) are antifungal polyketides
that have been isolated in small amounts from a fermentation
mixture of Podospora curVicolla (Figure 1).1 The myco-
The relative configuration of the lactone ring in CA (1)
was deduced from NOESY data. NMR proton coupling
constants are consistent with the assigned relative configu-
ration and the E-configuration of the two disubstituted double
bonds. The relative configuration of CB (2) and CC (3) was
assigned in analogy to CA (1) based on the similarity of the
NMR data. The relative configuration of the remaining ster-
eogenic carbon atoms, as well as the absolute configuration
of the curvicollides (1-3), has not yet been established.
The curvicollides possess several synthetically challenging
structural features, including the two conjugated diene
moieties and the two vicinal non-heteroatom-substituted
stereogenic carbon atoms C9 and C10. In this letter, we report
a convergent enantioselective synthesis of the C8-C20
segment 4 of curvicollide C (3).2
Figure 1. Reported constitution and relative configuration of
curvicollides A (1), B (2), and C (3).
Our synthetic strategy was designed to assemble the
segments with known and unknown relative configuration
in a highly convergent manner (Figure 2). Therefore, the
C1-C7 fragment was first disconnected. The resulting
building block 4 features the (16R)-configuration, arbitrarily
parasitic fungus was originally isolated from a sclerotium
of Aspergillus flaVus that had been buried in an Illinois
cornfield for 3 years.
(1) Che, Y.; Gloer, J. B.; Wicklow, D. T. Org. Lett. 2004, 6, 1249-
1252.
(2) For a preliminary account on the synthesis of the C8-C12 segment
of CC (3), see: Ko¨rner, M.; Hiersemann, M. Synlett 2006, 121-123.
10.1021/ol702092h CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/25/2007

Scheme 1. Sequence of CAC and K-Selectride Reduction
Provides the R-Hydroxy Ester 11
Treatment of the R-hydroxy ester 11 with DDQ9 removed
the benzyl protecting group and induced lactonization to
provide the crystalline δ-lactone 12. A crystal structure
analysis of 12 confirmed the original assignment of the
relative configuration of 11.10
Having established a scalable access to the crucial central
building block 11, the synthesis of the C8-C14 segment 16
was completed as depicted in Scheme 2. Thus, the R-hydroxy
Figure 2. Retrosynthetic analysis of curvicollide C (3).
selected and easily reversible. Utilizing an olefination
transform to disconnect the C14/C15 double bond afforded
the sulfone 7 and the aldehyde 5. The C15-C20 building
block 7 was further simplified to the known alcohol 8,3 easily
available in both enantiomeric forms.4 The molecular com-
plexity of 5 is obviously caused by the two vicinal stereo-
genic carbon atoms C9 and C10. In need of a synthetic
strategy that enables the construction of the two pivotal
stereogenic carbon atoms in a highly diastereo- and enan-
tioselective fashion, we considered the R-keto ester 6 as
suitable building block. 6 represents a γ,δ-unsaturated
carbonyl compound, in principle, accessible by a catalytic
asymmetric Claisen rearrangement (CAC).5
Scheme 2. Synthesis of the C8-C14 Segment
The enantioselective synthesis of the C8-C12 fragment
rests on only two stereodifferentiating transformations start-
ing from an achiral substrate (Scheme 1). CAC of the known
allyl vinyl ether (Z,Z)-92 in the presence of 7.5 mol% of
6
[Cu{(S,S)-tert-Bu-box}](H2O)2(SbF6)2 (10) provided the
R-keto ester 6, essentially as an enantio- and diastereomeri-
cally pure compound.7 The relative and absolute configura-
tion was assigned based on the well-established stereochem-
ical course of the CAC.5 Subsequent reduction of the R-keto
ester 6 employing K[(s-Bu)3BH]8 provided the R-hydroxy
ester 11 as a single diastereomer based on NMR analysis.
(3) For (R)-8, see: Goldstein, S. W.; Overman, L. E.; Rabinowitz, M.
H. J. Org. Chem. 1992, 57, 1179-1190. Details for the preparation of (R)-8
are reported in the Supporting Information.
(4) For (S)-8, see: Fuganti, C.; Grasselli, P.; Servi, S.; Zirotti, C.
Tetrahedron Lett. 1982, 23, 4269-4272. Details for the preparation of (S)-8
are reported in the Supporting Information.
(5) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem.,
Int. Ed. 2001, 40, 4700-4703. (b) Abraham, L.; Ko¨rner, M.; Schwab, P.;
Hiersemann, M. AdV. Synth. Catal. 2004, 346, 1281-1294.
(6) Evans, D. A.; Miller, S. J.; Lectka, T.; Matt, P. v. J. Am. Chem. Soc.
1999, 121, 7559-7573.
ester 11 was first protected as a TBS ether and then converted
into the aldehyde 13 by a redox sequence.11,12 The R-chiral
aldehyde 13 was sufficiently stable to be purified and
characterized. One-carbon homologation of 13 was ac-
(7) The yield of the CAC is dependent on an appropriate work-up
procedure. See the Supporting Information for details.
4980
Org. Lett., Vol. 9, No. 24, 2007

complished by chloromethylenation13 and a subsequent
Fritsch-Buttenberg-Wiechell14 rearrangement to afford the
alkyne 14.15 The double bond was then cleaved chemose-
lectively by ozonolysis followed by a reductive workup16 to
provide a primary alcohol which was protected as a TBS
ether. The trisubstituted C12/C13 double bond was estab-
lished next. For this purpose, the terminal triple bond was
lithiated and treated with isopropyl chloroformate to provide
the alkynoate 15.
5-thiol (PT-SH) as the nucleophile and a subsequent Mo-
(VI)-catalyzed oxidation21 of the intermediate sulfide. Uti-
lizing the robust and reliable procedure reported by
Kocienski,22 the sulfone 7 was deprotonated with potassium
bis(trimethylsilyl)amide (KHMDS) and treated with the crude
aldehyde 5 to afford the (12E,14E)-configured diene 4.23 The
R,â-unsaturated aldehyde 5 had been prepared from the R,â-
unsaturated ester 16 by a two-step redox sequence and was
used without further purification.24
Subsequent methylcupration of 15 in the presence of
superstoichiometric amounts of copper(I) bromide and me-
thylmagnesium bromide provided the E-configured R,â-
unsaturated ester 16.17-19 In accordance with a report by
Williams,19 we found that the presence of the sterically
demanding isopropyl ester and the bulky TBS protecting
group at C11 in combination with a slow warming process
prior to protic quench was essential for a very high E/Z
diastereoselectivity. The synthesis of the sulfone 7 and the
fragment coupling to provide the C8-C20 building block 4
is outlined in Scheme 3.
At this point, we had established an enantioselective
synthetic access to the C8-C20 building block 4 featuring
a longest linear sequence of 14 steps from the allyl vinyl
ether (Z,Z)-9 with an overall yield of 28%. To substantiate
the feasibility of our synthetic strategy toward CC (3), we
set out to prepare the γ-lactone in 17 from the protected diol
4 in the presence of the potentially sensitive diene moiety
(Scheme 3). Relying on a more conventional, stepwise line
of events, we first chemoselectively cleaved the primary TBS
ether in 4 to afford a primary alcohol which was oxidized
to the corresponding carboxylic acid by a two-step proce-
dure.12,25 Subsequent treatment of the acid with HF in
pyridine26 without an excess of pyridine deprotected the
secondary alcohol and induced lactonization to afford the
desired C8-C20 segment 17 of CC (3).
Scheme 3. Synthesis of the C8-C20 Segment
In summary, we have demonstrated the utility of the
catalytic asymmetric Claisen rearrangement (CAC) in natural
product synthesis.27 The CAC provides scalable access to
the R-keto ester 6 as a single stereoisomer, thereby paving
the way for an efficient synthetic approach to the C8-C20
building block 4. Further work aimed at the completion of
the synthesis and, thereby, the elucidation of the relative and
absolute configuration of curvicollide C (3) is well underway
and will be reported in due course.
(15) The Ohira-Bestmann procedure failed to provide the desired alkyne
14; see: (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) Mu¨ller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.
(16) Witkop, B.; Patrick, J. B. J. Am. Chem. Soc. 1952, 74, 3855-
3860.
(17) NOE studies on both double bond isomers support the assignment
of the double bond configuration. See the Supporting Information for details.
(18) (a) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969,
91, 1851-1852. (b) Siddall, J. B.; Biskup, M.; Fried, J. H. J. Am. Chem.
Soc. 1969, 91, 1853-1854. For a mechanistic study, see: (c) Nilsson, K.;
Andersson, T.; Ullenius, C.; Gerold, A.; Krause, N. Chem.sEur. J. 1998,
4, 2051-2058.
(19) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3,
2721-2724.
(20) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380-
2382.
(21) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140-1142.
The known alcohol 83 was converted into the sulfone 7
by a Mitsunobu reaction20 employing 1-phenyl-1H-tetrazole-
(22) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26-28. (b) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563-2585.
3
(8) Brown, C. A. J. Am. Chem. Soc. 1973, 95, 4100-4102.
(9) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885-888.
(10) Ko¨rner, M.; Schu¨rmann, M.; Preut, H.; Hiersemann, M. Acta
Crystallogr. 2007, E63, o3012.
(11) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190-
6191.
(23) The JHH-based configurational analysis and NOE studies support
the assignment of the E-configuration to the newly generated C13/C14
double bond. See the Supporting Information for details.
(24) For MnO2-mediated oxidation, see: Gritter, R. J.; Wallace, T. J. J.
Org. Chem. 1959, 24, 1051-1056.
(25) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091-2096.
(12) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(13) Seyferth, D.; Grim, S. O.; Read, T. O. J. Am. Chem. Soc. 1961, 83,
1617-1620.
(26) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. J. Org.
Chem. 1979, 44, 4011-4013.
(27) For previous applications, see: (a) Pollex, A.; Hiersemann, M. Org.
Lett. 2005, 7, 5705-5708. (b) Wang, Q.; Millet, A.; Hiersemann, M. Synlett
2007, 1683-1686.
(14) Knorr, R. Chem. ReV. 2004, 104, 3795-3850.
Org. Lett., Vol. 9, No. 24, 2007
4981

Acknowledgment. Financial support for this research was
obtained from the DFG and the University of Dortmund
(UDO). We are grateful to Susanne Knauf (UDO) for skillful
technical assistance. We thank Professor James B. Gloer
(University of Iowa) for providing a proton NMR spectrum
of curvicollide C.
Supporting Information Available: Experimental details
and copies of NMR spectra for all compounds including the
preparation of 8, (Z,Z)-9, and 10. Details of the determination
of enantioselectivities by HPLC. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL702092H
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Org. Lett., Vol. 9, No. 24, 2007