Total synthesis of khafrefungin using highly stereoselective vinylogous Mukaiyama aldol reaction

Article abstract of DOI:10.1021/ol0630191

(Chemical Equation Presented) A convergent total synthesis of khafrefungin was accomplished on the basis of (1) the highly stereoselective TiCl ₄-mediated vinylogous Mukaiyama aldol reaction using vinylketene silyl N,O-acetal and (2) syn-select

Full text of DOI:10.1021/ol0630191

ORGANIC
LETTERS
2007
Vol. 9, No. 5
849-852
Total Synthesis of Khafrefungin Using
Highly Stereoselective Vinylogous
Mukaiyama Aldol Reaction
Shin-ichi Shirokawa, Mariko Shinoyama, Isao Ooi, Seijiro Hosokawa,
Atsuo Nakazaki, and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo UniVersity of Science (RIKADAI),
2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
kobayash@rs.noda.tus.ac.jp
Received December 14, 2006
ABSTRACT
A convergent total synthesis of khafrefungin was accomplished on the basis of (1) the highly stereoselective TiCl4-mediated vinylogous
Mukaiyama aldol reaction using vinylketene silyl N,O-acetal and (2) syn-selective aldol reaction of enal 5a and ethyl ketone 6 followed by
anti-dehydration under Mitsunobu conditions.
We recently reported a highly stereoselective vinylogous
Mukaiyama aldol reaction of vinylketene silyl N,O-acetal
1, which also provides a unique and remarkable entry to a
remote asymmetric induction (Scheme 1).1,2 From a synthetic
polyketide natural products.3 In order to demonstrate the
usefulness of our methodology, we investigated the total
synthesis of khafrefungin (2) (Figure 1). In the polyketide
Scheme 1. Remote Asymmetric Induction
Figure 1. Structure of khafrefungin (2).
moiety of khafrefungin, we can recognize two sets of the
vinylogous Mukaiyama aldol adducts.
Khafrefungin (2) is an antifungal agent isolated from the
fermentation culture MF6020 by a Merck group in 1997.4 It
has been shown to inhibit inositol phosphorylceramide (IPC)
point of view, this method can directly afford the δ-hydroxy-
R,γ-dimethyl-R,â-unsaturated carbonyl unit that is seen in
(2) For general reviews, including vinylogous aldol reaction of silyl dienol
ethers to aldehyde, see: (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu,
G. Chem. ReV. 2000, 100, 1929. (b) Rassu, G.; Zanardi, F.; Battistini, L.;
Casiraghi, G. Chem. Soc. ReV. 2000, 29, 109. (c) Denmark, S. E.; Heemstra,
J. R.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (d) Kalesse,
M. Top. Curr. Chem. 2005, 244, 43.
(1) Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki,
A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604.
10.1021/ol0630191 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/09/2007

synthase, which catalyzes the fungal specific step in Sac-
charomyces cereVisiae and pathogenic fungi such as Cryp-
tococcus neoformans and Candida albicans in picomolar and
nanomolar concentrations and causes ceramide accumula-
tion.5 Distinct from other sphingolipid inhibitors such as
viridiofungin A, myriocin, and australifungin, khafrefungin
does not impair sphingolipid synthesis in mammals. A
convergent total synthesis of khafrefungin and its derivatives
has been achieved by Kobayashi and co-workers on the basis
of their excellent catalytic and enantioselective aldol reac-
tion.6
vinylketene silyl N,O-acetal 1b and ethyl ketone 6 from
propionaldehyde (8) and ent-1b, respectively.
The synthesis of enal 5a (Scheme 3) commenced with the
Scheme 3. Synthesis of C7-C22 Fragment
Our retrosynthetic analysis of khafrefungin (2) is outlined
in Scheme 2. Khafrefungin was divided into two fragments,
Scheme 2. Retrosynthetic Analysis
protection of commercially available methyl (R)-â-hydroxy-
isobutyrate (9) as a benzyl ether. The benzyl ether was then
subjected to a reduction using lithium aluminum hydride and
tosylation of the resulting alcohol. The Ni-catalyzed cross-
coupling reaction of tosylate 10 with a Grignard reagent using
Kambe’s protocol7 provided the benzyl ether in excellent
yield, and the benzyl group was cleanly removed by exposure
to boron trichloride to obtain chiral alcohol 11. The primary
alcohol 11 was oxidized to give aldehyde 7 using the standard
Swern conditions.8 According to the established protocol,
the vinylogous Mukaiyama aldol reaction of chiral aldehyde
7 with the vinylketene silyl N,O-acetal 1b using TiCl4, which
proceeded in the matched manifold, afforded the correspond-
the polyketide acid part 3 and the aldonic acid part 4. We
planned to couple these parts by Mitsunobu esterification.
Alcohol 4 (aldonic acid part) could be prepared from
L-xylose. Polyketide acid 3 could be assembled via the aldol
condensation of enal 5a and ethyl ketone 6 and dehydration.
We envisioned that both enal 5a and ethyl ketone 6 could
be stereoselectively prepared by the vinylogous Mukaiyama
aldol reaction. According to the above retrosynthetic analysis,
enal 5a could be accessed from chiral aldehyde 7 and the
(5) Reviews: (a) Kolter, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999,
38, 1532. See also: (b) Mandala, S. M.; Harris, G. H. Methods Enzymol.
2000, 311, 335-348. (c) Dickson, R. C. Annu. ReV. Biochem. 1998, 67,
27. (d) Other IPC inhibitors: Nagiec, M. M.; Nagiec, E. E.; Baltisberger,
J. A.; Wells, G. B.; Lester, R. L.; Dickson, R. C. J. Biol. Chem. 1997, 272,
9809. (e) Mandala, R. A.; Thornton, R. A.; Milligan, J.; Rosenbach, M.;
Garcia-Calvo, M.; Bull, H. G.; Harris, G.; Abruzzo, G. K.; Flattery, A. M.;
Gill, C. J.; Bartizal, K.; Dreikorn, S.; Kurtz, M. B. J. Biol. Chem. 1998,
273, 14942.
(6) (a) Wakabayashi, T.; Mori, K.; Kobayashi, S. J. Am. Chem. Soc.
2001, 123, 1372. (b) Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda,
S.; Hanada, K. J. Org. Chem. 2001, 66, 5580. (c) Nakamura, M.; Mori, Y.;
Okuyama, k.; Tanikawa, K.; Yasuda, S.; Hanada, K.; Kobayashi, S. Org.
Biomol. Chem. 2003, 1, 3362.
(7) (a) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J.
Am. Chem. Soc. 2002, 124, 4222. (b) Terao, J.; Kambe, N. Bull. Chem.
Soc. Jpn. 2006, 5, 663.
(3) For synthetic application of this methodology, see: (a) Hosokawa,
S.; Ogura, T.; Togashi, H.; Tatsuta, K. Tetrahedron Lett. 2005, 46, 333.
(b) Hosokawa, S.; Yokota, K.; Imamura, K.; Suzuki, Y.; Kawarasaki, M.;
Tatsuta, K. Tetrahedron Lett. 2006, 47, 5415. (c) Nakamura, T.; Shirokawa,
S.; Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2006, 8, 677. (d)
Hosokawa, S.; Kuroda, S.; Imamura, K.; Tatsuta, K. Tetrahedron Lett. 2006,
47, 6183.
(4) Mandala, S. M.; Thornton, R. A.; Rosenbach, M.; Milligan, J.; Garcia-
Calvo, M.; Bull, H. G.; Kurtz, M. B. J. Biol. Chem. 1997, 272, 32709.
(8) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
850
Org. Lett., Vol. 9, No. 5, 2007

ing C(10)-C(11) anti-aldol adduct 12 in 98% yield with
>20:1 diastereoselectivity.
Scheme 5. Fragment Assembly Aldol Reaction
The secondary hydroxyl group of the aldol adduct 12 was
protected as the tert-butyldimethylsilyl (TBS) ether by the
reaction with tert-butyldimethylsilyl trifluoromethanesulfonate
(TBSOTf) and diisopropylethylamine (DIPEA). The p-
methoxybenzyl (PMB) ether 13b was provided by reaction
with PMB trichloroacetimidate and a catalytic amount of
trifluoromethanesulfonic acid.9 Reductive removal of the
chiral auxiliary in 13a and 13b using DIBAL produced the
aldehyde 5a and 5b, respectively. The stereochemistry of
5b (thus 12) was confirmed by comparison of the spectral
data with those reported by Kobayashi.6a
The C(1)-C(6) ethyl ketone 6 was synthesized starting
from propionaldehyde (8) as summarized in Scheme 4. The
The aldonic acid part 4 was prepared from L-xylose
(Scheme 6). Thus, the allyl glycosidation of L-xylose was
Scheme 4. Synthesis of C1-C6 Fragment
Scheme 6. Synthesis of Aldonic Acid Part
vinylogous Mukaiyama aldol reaction of propionaldehyde
with the vinylketene silyl N,O-acetal ent-1b using TiCl4
afforded the corresponding anti-aldol adduct 14 in 91% yield
with high diastereomeric ratio (>20:1 dr). Reductive removal
of the chiral auxiliary, followed by the protection of the
resulting primary alcohol as a TBS ether, and Dess-Martin
oxidation of the secondary alcohol provided ethyl ketone 6.10
Aldol condensation of ethyl ketone 6 and enal 5a was
accomplished by using TiCl4 and DIPEA in CH2Cl2 at -78
°C to afford syn-aldol adduct 16 in 86% yield (Scheme 5).11
We then attempted an anti-dehydration of 16. However, most
of the typical anti-dehydration methods (MsCl/DMAP/Py,
MsCl/Et3N/CH2Cl2, TFAA/2,6-lutidine/CH2Cl2 followed by
HCl/acetone, and SOCl2/Py/CH2Cl2) were unsuccessful. In
contrast, the desired dienone 17 was obtained in 96% yield
under Mitsunobu conditions (DIAD and tributylphosphine
in THF at -30 °C).12 Dienone 17 was converted to acid 3
in 91% yield for the three steps by selective cleavage of the
primary TBS ether followed by MnO2 oxidation and NaClO2
oxidation.13
carried out by treatment with allyl alcohol, and the remaining
hydroxyl groups were protected with the PMB group.
Deprotection of the allyl group was successfully performed
with PdCl2 in CHCl3/H2O under an O2 atmosphere to give
the hemiacetal, which on subsequent reduction with sodium
borohydride in MeOH provided the diol in 62% yield for
the four steps.14 The resulting diol was protected selectively
as its TBS ether to give secondary alcohol 4.
With both segments in hand, we next carried out an
esterification of the secondary alcohol 4 with the unsaturated
acid 3 under Mitsunobu conditions to afford the desired ester
20 in 86% yield (Scheme 7). The primary TBS ether was
selectively deprotected with AcOH/THF/H2O, and the result-
ant primary alcohol was oxidized to a carboxylic acid 21 by
a two-step sequence [(i) Dess-Martin oxidation; (ii) NaClO2
oxidation]. Finally, deprotection of the secondary TBS ether
and three PMB ethers with 25% TFA/CH2Cl2 completed the
total synthesis of khafrefungin (2). The spectroscopic data
(9) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139.
(10) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(11) Evans, D. A.; Rieger, J. C.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047.
(12) Mitsunobu, O. Synthesis 1981, 1.
(13) Bal, B. S.; Chiders, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
(14) (a) Mereyala, H. B.; Guntha, S. Tetrahedron Lett. 1993, 34, 6929.
(b) Mereyala, H. B.; Lingannagura, S. R. Tetrahedron 1997, 53, 17501.
Org. Lett., Vol. 9, No. 5, 2007
851

quence included (i) construction of the C(1)-C(5) and C(7)-
C(11) δ-hydroxy-R,γ-dimethyl-R,â-unsaturated carbonyl unit
using the vinylogous Mukaiyama aldol reaction and (ii) syn-
selective aldol condensation and anti-dehydration under
Mitsunobu conditions.
Scheme 7. Completion of the Total Synthesis
Acknowledgment. We thank Prof. Shu Kobayashi (The
University of Tokyo) for helpful suggestions. We thank
Kaneka Corp. for providing methyl (R)-â-hydroxyiso-
butyrate. This research was supported in part by a Grant-
in-Aid for Scientific Research (B) (KAKENHI No.18390010)
from the Japan Society for the Promotion of Science.
Supporting Information Available: Experimental details
and spectroscopic data for compounds 2-4, 5a, 6, 12, 14,
17, and 20. This material is available free of charge via the
Internet at http://pubs.acs.org.
(1H NMR, 13C NMR, IR, HRMS, optical rotaiton) were in
all respects identical to the data reported by Kobayashi and
co-workers.6a
In summary, we were able to achieve a convergent
synthesis of khafrefungin. Key transformations in the se-
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Org. Lett., Vol. 9, No. 5, 2007