Efficient total synthesis of khafrefungin: Convergent approach using Suzuki coupling under thallium-free conditions toward multigram-scale synthesis

Article abstract of DOI:10.1055/s-2002-22726

An efficient and practical synthetic route to khafrefungin, an antifungal agent, has been developed based on successive coupling of three components, 3, 4, and then 2. A key step of the synthesis is the Suzuki coupling of 2 and 10, in which the use of tox

Full text of DOI:10.1055/s-2002-22726

LETTER
601
Efficient Total Synthesis of Khafrefungin: Convergent Approach Using
Suzuki Coupling under Thallium-free Conditions Toward Multigram-scale
Synthesis
E
fficient Tota
l
Syn
u
thesis of
K
h
i
afrefun
c
gin hiro Mori, Masayuki Nakamura, Takeshi Wakabayashi, Kouhei Mori, Sh Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, CREST, Japan Science and Technology Corporation (JST), Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)56840634; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Received 25 December 2001
ever, synthesis of fragment 2 needs the most multiple
Abstract: An efficient and practical synthetic route to khafrefun-
transformations among the three fragments. It is more ef-
gin, an antifungal agent, has been developed based on successive
ficient that 3 is connected with 4 by esterification first,
coupling of three components, 3, 4, and then 2. A key step of the
followed by Suzuki coupling with 2.4 Another drawback
synthesis is the Suzuki coupling of 2 and 10, in which the use of tox-
ic thallium ethoxide has been avoided, and the coupling adduct (11) of the previous convergent synthesis is the use of a thalli-
was obtained in multigram-scale quantities.
um reagent as a base in the Suzuki coupling.
Key words: khafrefungin, total synthesis, antifungal agents, Suzu-
ki coupling, multigram-scale synthesis
Khafrefungin (1) is a novel antifungal agent isolated from
the fermentation culture MF6020 by a Merck group in
1997 (Figure).1 It has been shown to inhibit IPC (inositol
phosphorylceramide) synthase, which catalyzes the fun-
gal specific step, in Saccharomyces cerevisiae and patho-
genic fungi. Unlike other inhibitors that inhibit the
corresponding enzyme in fungi and mammals to the same
extent, khafrefungin does not impair sphingolipid synthe-
sis of mammals.2 Although the Merck group revealed the
plane structure of khafrefungin, the stereochemistry of
khafrefungin had been unknown until we disclosed the
relative and absolute configuration of khafrefungin.
Figure Khafrefungin (1)
We have already completed the first total synthesis and
developed a convergent route to khafrefungin.3 In order to
Scheme 1 Retrosynthetic analysis for the synthesis of 1.
synthesize various derivatives of khafrefungin, more effi-
cient strategies, which tolerates multigram-scale prepara-
tion is necessary. We now report here an efficient
synthesis of khafrefungin under thallium-free conditions.
Our convergent synthetic strategy of khafrefungin is
shown in Scheme 1. Khafrefungin is divided into three
fragments; alkyne 2, alkenyliodide 3, and protected alco-
hol 4 (aldonic acid part). In the previous report, 2 was con-
nected with 3 using Suzuki coupling, followed by
esterification with 4 to convert to khafrefungin (1). How-
Scheme 2 Synthesis of chiral alcohol 9.
Synlett 2002, No. 4, 29 03 2002. Article Identifier:
First, we developed an alternative synthetic pathway to 9,
which is a key intermediate for the preparation of 2
(Scheme 2). Benzylation of commercially available meth-
yl (R)-(–)-3-hydroxy-2-methylpropionate (7) followed by
1437-2096,E;2002,0,04,0601,0603,ftx,en;Y25701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

602
Y. Mori et al.
LETTER
reduction using lithium aluminium hydride and tosylation In addition, it was revealed that the Suzuki coupling reac-
gave 8 (96%, 3 steps). Benzyl ether 8 was alkylated and tion of alkenyliodide 3 with alkyne 2 also proceeded
the benzyl group was deprotected to give 9. Chiral alcohol smoothly under thallium-free conditions. As highlighted
9 was converted to alkyne 2 according to the reported pro- in Scheme 4, the Suzuki coupling reaction of 3 with 2 suc-
cedure.3 The synthesis has been achieved in multigram- cessfully provided the desired product 12. After reduction
scale quantities, and we have also completed the synthe- with DIBAL, the resulting alcohol was oxidized to the
ses of the other two units (3 and 4) in multigram-scale corresponding aldehyde, which was treated with sodium
quantities.5 The coupling reaction of 3 with 4 was then in- chlorite9 to afford the carboxylic acid in 73% yield for two
vestigated (Scheme 3). Ester 3 was converted to the car- steps. The Keck esterification reaction of the carboxylic
boxylic acid, which was treated with alcohol 4 under acid with alcohol 4 furnished ester 11 in 69%.
Keck’s esterification conditions6 to afford the coupling
adduct (10). We next examined the Suzuki coupling reac-
tion of 10 with alkyne 2 (Table). In the previous synthesis,
catecholborane and thallium ethoxide7 were used as re-
agents for the Suzuki coupling reaction. Thallium ethox-
ide is not suitable for large-scale synthesis and analogous
derivatization due to its high toxicity. We tested several
conditions, and found that one-pot procedure with 9-
BBN, PdCl2(dppf), and K3PO4 gave 11 in better yield
(76%, Table, entry 4). In a larger-scale reaction, the yield
was improved to 84% (Scheme 3).8 After purification by
column chromatography (silica gel), no regioisomer of 11
was observed by NMR analysis. It is noted that multi-
gram-preparation of 11 has been successfully achieved
based on the novel synthetic strategy.
Scheme 4 Synthesis of 11.
The completion of the synthesis of khafrefungin from 11
is shown in Scheme 5.3 Deprotection of the two silyl
groups with 1 M aqueous hydrochloric acid in THF gave
the corresponding diol in 84% yield. Oxidation of the diol
was successfully performed using Dess–Martin
periodinane10 to afford the ketoaldehyde, which was treat-
ed with sodium chlorite to furnish the ketocarboxylic acid.
Finally, the four PMB groups were removed with BCl3 to
afford khafrefungin in 57% yield.
Scheme 5 Synthesis of khafrefungin (1).
In conclusion, we have developed efficient and practical
synthetic routes to khafrefungin and its analogues. The
synthesis is based on successive coupling reactions of 3
and 4, and then 2. Multigram-scale synthesis of the three
fragments has been accomplished. A key step in this syn-
thesis is the Suzuki coupling of 2 and 10. The use of toxic
thallium ethoxide has been avoided to attain multigram-
scale preparation of the coupling product (11). Our con-
tinued effort toward exploration of structure activity rela-
tionships of khafrefungin will be reported in due course.
Scheme 3 Synthesis of 11.
Table Suzuki Coupling Reaction
Acknowledgement
Entry Borane
Temp. Pd
Base
Yield
(%)
This work was partially supported by CREST, Japan Science and
Technology Corporation (JST), and a Grant-in-Aid for Scientific
Research from Japan Society of the Promotion of Science (JSPS).
TW thanks the JSPS fellowship for Japanese Junior Scientists.
1
2
3
4
catecholborane 50 °C
Pd(PPh3)4
Pd(PPh3)4
TlOEt
42 (33)a
catecholborane 50 °C
catecholborane r.t.
Na2CO3 27 (53)a
PdCl2(dppf) K3PO4 50
PdCl2(dppf) K3PO4 76
9-BBN
r.t.
a Recovered 10 (%).
Synlett 2002, No. 4, 601–603 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Total Synthesis of Khafrefungin
603
(6) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394.
(7) Uenishi, J.; Beau, J. M.; Armstrong, R. W.; Kishi, Y. J. Am.
Chem. Soc. 1987, 109, 4756.
References
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(5) Multigram-scale synthesis of alkyne 2, alkenyliodide 3, and
alcohol 4: Alkyne 2 (5.2 g) was synthesized from methyl
(R)-(–)-3-hydroxy-2-methylpropionate (10 mL) according
to the literature (14 steps).3b In the present synthesis, chiral
alcohol 9 was synthesized by the procedure shown in
Scheme 2. Alkenyliodide 3 (18.2 g) was prepared from
diethyl methylmalonate (40 mL) according to the literature
(9 steps).3b Alcohol 4 (5.5 g) was synthesized from D-
arabinose (4.7 g) according to the literature (5 steps).3a
(8) Suzuki coupling reaction of alkyne 2 with alkenyliodide 10:
To a stirred solution of alkyne 2 (1.09 g, 2.82 mmol) in THF
(18 mL) was added 9-BBN (6.00 mmol, 0.5 M solution in
THF) at 0 °C. The reaction mixture was stirred for 12 h at
room temperature. Alkenyliodide 10 (2.76 g, 2.34 mmol) in
THF (10 mL), H2O (10 mL), K3PO4 (2.50 g, 11.8 mmol), and
PdCl2(dppf) (0.38 g, 0.47 mmol) were added subsequently,
and the mixture was stirred for 30 min at 70 °C. After the
mixture was cooled to room temperature, saturated aqueous
NaHCO3 was added and the organic layer was extracted with
EtOAc. The organic layer was washed with brine, dried, and
concentrated. Purification by silica gel chromatography
(EtOAc–hexane, 1:6) gave the coupled product 11 (2.93 g,
84%) as a colorless oil.
(9) Bal, B. S.; Childers, W. E. Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091.
(10) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
Synlett 2002, No. 4, 601–603 ISSN 0936-5214 © Thieme Stuttgart · New York