K. Toyama et al. / Tetrahedron Letters 47 (2006) 7163–7166
7165
yield with 99% ee.15 The Swern oxidation of (R)-17
followed by construction of the C-4 side chain using
a-formylethylidenephosphorane and Wittig reagents
provided 4-methoxy tetronic acid analogue 20. The
conversion of 20 to the desired tetronic acid (R)-21
was achieved by use of lithium 1-propanethiolate in
87% yield. We succeeded in the first total synthesis of
chiral tetronic acid (R)-21 from the (R)-alcohol 17 in
40% yield in four steps.
OMe
OMe
OMe
a
b
O
O
OH
O
O
O
S
S
S
(
R
)-4
10 (99%)
11
Scheme 2. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, THF,
À78 °C to rt, 2 h; (b) Ph3P@C(CH3)CHO, THF, reflux, 48 h.
OMe
OMe
OMe
+ RCHO
In summary, we have developed a chemoenzymatic syn-
thesis of (R)-thiolactomycin and its O-analogue having
a chiral quaternary carbon atom at C5. The lipase-
catalyzed kinetic resolution of the thiotetronic acid
derivatives demonstrated good enantioselectivity; both
enantiomers were obtained with high enantiomeric
excess by use of ChirazymeÒ L-2. Chemical transforma-
tion of (R)-alcohol 4 provided chiral (R)-thiolactomycin
(1) in 36% yield in five steps. We hope that this simple
synthesis of (R)-1 will be helpful for the syntheses of
chiral analogues and for solving unidentified bioactive
properties in the future.
R
O
O
O
S
O
O
S
S
R
10
12
13
Scheme 3. Deformylation of 10.
with crotyl tributylstannane. Bromination under neutral
condition, followed by elimination afforded an insepara-
ble mixture of 4-methoxy thiolactomycin 16 in good
yields in an E/Z ratio of 9/1. Standard condition for
the deprotection of the methoxy group using lithium
thiolate led to thiolactomycin (R)-1a in 36% yield in five
steps from chiral thiotetronic acid (R)-4 (see Scheme 4).
Acknowledgments
Asymmetric synthesis of tetronic acid analogue 21 of
thiolactomycin (1) was examined as shown in Scheme
5, because Still and Drewery reported the synthesis of
racemate 21 from the precursor (rac)-17.14 Lipase PS-
D-catalyzed kinetic resolution of the tetronic acid 17
gave the corresponding (S)-acetate in 58% yield with
50% ee along with the recovered (R)-alcohol 17 in 32%
We would like to thank Amano Enzyme Co., Ltd., Mei-
to Sangyo Co., Novo Nordisk, and Roche Molecular
Biochemicals for a generous gift of enzymes. This work
was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science,
Sports, and Culture of Japan.
References and notes
OMe
OMe
OMe
1. Waller, R. F.; Ralph, S. A.; Reed, M. B.; Su, V.; Douglas,
J. D.; Minnikin, D. E.; Cowman, A. F.; Besra, G. S.;
McFadden, G. I. Antimicrob. Agents Chemother. 2003, 47,
297–301.
2. (a) Oishi, H.; Noto, T.; Sasaki, H.; Suzuki, K.; Hayashi,
T.; Okazaki, H.; Ando, K.; Sawada, M. J. Antibiot. 1982,
35, 391–395; (b) Sasaki, H.; Oishi, H.; Hayashi, T.;
Matsuura, I.; Ando, K.; Sawada, M. J. Antibiot. 1982, 35,
396–400.
3. (a) Hayashi, T.; Yamamoto, O.; Sasaki, H.; Kawaguchi,
A.; Okazaki, H. Biochem. Biophys. Res. Commun. 1983,
115, 1108–1113; (b) Heath, R. J.; White, S. W.; Rock, C.
O. Appl. Microbiol. Biotechnol. 2002, 58, 695–703.
4. (a) Omura, S.; Iwai, Y.; Nakagawa, A.; Iwata, R.;
Takahashi, Y.; Shimizu, H.; Tanaka, H. J. Antibiot.
1983, 36, 109–114; (b) Omura, S.; Nakagawa, A.; Iwata,
R.; Hatano, A. J. Antibiot. 1983, 36, 1781–1782.
5. Rapp, C.; Jung, G.; Isselhorst-Scharr, C.; Zaehner, H.
Liebigs Ann. Chem. 1988, 1043–1047.
a
b
O
O
O
S
S
O
S
OH
14 (58%)
Br
15 (82%)
10
OMe
OH
c
d
O
O
S
S
16 (78%)
(R)-1a (99%)
Scheme 4. Reagents and conditions: (a) CH3CH@CHCH2SnBu3,
BF3ÆOEt2, CH2Cl2, À78 °C, 3 h; (b) PPh3, CBr4, CH2Cl2, reflux, 2 h;
(c) DBU, toluene, rt, 24 h; (d) n-C3H7SLi, HMPA, rt, 0.5 h.
OMe
OMe
OMe
c
a
b
O
OH
OH
O
O
O
d
O
O
O
O
6. Dolak, L. A.; Castle, T. M.; Truesdell, S. E.; Sebek, O. K.
J. Antibiot. 1986, 39, 26–31.
(rac)-17
(
R
)-17 (32%)
OMe
18 (84%)
OMe
OH
7. Alli, P. M.; Pinn, M. L.; Jaffee, E. M.; McFadden, J. M.;
Kuhajda, F. P. Oncogene 2005, 24, 39–46, See also Ref. 9d.
8. Synthesis of racemic thiolactomycin (1): Wang, C. L. J.;
Salvino, J. M. Tetrahedron Lett. 1984, 25, 5243–5246.
9. Asymmetric synthesis of 1 by use of chiral pool and chiral
auxiliary approaches: (a) Chambers, M. S.; Thomas, E. J.
J. Chem. Soc., Chem. Commun. 1989, 23–24; (b) Cham-
bers, M. S.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1
1997, 417–431; (c) McFadden, J. M.; Frehywot, G. L.;
e
O
O
O
O
O
O
20 (68%)
(R)-21 (87%)
19 (81%)
Scheme 5. Reagents and conditions: (a) Lipase PS-D, vinyl acetate,
25 °C, 24 h, 99% ee; (b) (COCl)2, DMSO, Et3N, THF, À65 °C to rt,
1 h; (c) Ph3P@C(CH3)CHO, THF, reflux, 48 h; (d) n-BuLi, Ph3PCH3I,
THF, rt, 16 h; (e) n-C3H7SLi, HMPA, rt, 14 h.