Asymmetric total synthesis of (-)-mycothiazole.

Article abstract of DOI:10.1021/ol000128l

[structure: see text] In this Letter we describe the first total synthesis of mycothiazole, a polyketide thiazole from a marine sponge. Key steps include our CMD oxidation for the conversion of thiazolidine 11 to thiazole 12 and the Nagao acetate aldol re

Full text of DOI:10.1021/ol000128l

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2149-2152
Asymmetric Total Synthesis of
(−)-Mycothiazole
Hideyuki Sugiyama, Fumiaki Yokokawa,* and Takayuki Shioiri*
Faculty of Pharmaceutical Sciences, Nagoya City UniVersity, Tanabe-dori,
Mizuho-ku, Nagoya 467-8603, Japan
yokokawa@phar.nagoya-cu.ac.jp
Received May 15, 2000
ABSTRACT
In this Letter we describe the first total synthesis of mycothiazole, a polyketide thiazole from a marine sponge. Key steps include our CMD
oxidation for the conversion of thiazolidine 11 to thiazole 12 and the Nagao acetate aldol reaction of 5 with aldehyde 4 to construct the chiral
secondary alcohol. The skipped diene was constructed by the standard Stille coupling, and the conjugated diene was synthesized by lithium-
(I)- and copper(I)-mediated Stille coupling.
Mycothiazole (1) was isolated from Spongia mycofijiensis
collected in Vanuatu by Crews et al.,1 and it exhibited
Scheme 1
anthelmintic activity (in vitro) while high toxicity was
observed in mice. The most unique feature of its structure
is a thiazole ring which is imbedded between two acyclic
polyketide chains. While mycothiazole (1) was the first
example of the 2,4-disubstituted thiazole to be reported, a
few examples such as patellazoles A-C2 and pateamine3
have also been reported. Furthermore, the side chains of 1
contain skipped diene and conjugated diene systems which
consist of exo- and Z-configured olefins. Although 1 has only
one stereogenic center at the secondary alcohol, its config-
uration had not been determined. For the purpose of
elucidation of the absolute configuration and further biologi-
cal activity, we have embarked on the total synthesis of
mycothiazole (1).
Our retrosynthetic approach is shown in Scheme 1. We
disconnected the unstable conjugated diene of 1 to Z-iodide
2 and 1-substituted vinylstannane 3 which could be combined
by Stille coupling.4 The secondary alcohol of 2 could be
constructed by the Nagao acetate aldol reaction using chiral
(1) Crews, P.; Kakou, Y.; Quin˜oa`, E. J. Am. Chem. Soc. 1988, 110,
4365-4368.
1,3-thiazolidine-2-thione 55 with aldehyde 4. The noncon-
jugated diene could be synthesized by iterative Stille coupling
(2) Zabriskie, T. M.; Mayne, C. L.; Ireland, C. M. J. Am. Chem. Soc.
1988, 110, 7919-7920.
(3) Northcote, P. T.; Blunt, J. W.; Munro, M. H. G. Tetrahedron. Lett.
1991, 32, 6411-6414.
using vinylstannanes 7 and 8.
10.1021/ol000128l CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/13/2000

By following this synthetic strategy, we began to synthe-
size thiazole moiety 12.6 We had already developed the
synthesis of thiazolidines from N-protected R-amino alde-
hydes and the cysteine methyl ester which were subsequently
dehydrogenated to thiazoles using chemical manganese
dioxide (CMD);7 these were produced for dry battery
manufacture. Therefore, we applied this methodology to the
synthesis of the core part of 1.
The following synthesis of aldehyde 4 is summarized in
Scheme 3. After reduction of the ester (91% yield), treatment
Scheme 3a
As shown in Scheme 2, protection of the hydroxy function
of methyl hydroxypivalate with tert-butyl diphenylsilyl
Scheme 2a
a (a) DIBAL, Et2O, -78 °C, 30 min, 91%; (b) Ms2O, Et3N,
CH2Cl2, 0 °C, 20 min; LiBr, acetone, rt, 1 h, quantitative; (c) 7,
Pd(CH3CN)2Cl2 (10 mol %), NMP, rt, 10 min, 94%; (d) CBr4, Ph3P,
CH2Cl2, rt, 10 min, 95%; (e) 8, Pd(CH3CN)2Cl2(10 mol %), NMP,
rt, 40 min, 85%; (f) TBAF, THF, 55 °C, 2 h, quantitative; (g)
pyridine‚SO3, DMSO, Et3N, CH2Cl2, rt, 20 min, 95%.
a (a)TBDPSCl, imidazole, DMF, rt, 14 h; (b) DIBAL, Et2O, -78
°C, 30 min; (c) pyridine‚SO3, DMSO, Et3N, CH2Cl2, rt, 20 min;
(d) H-L-Cys-OMe‚HCl, Et3N, toluene, rt, 12 h, 71% in four steps;
(e) CMD, pyridine, benzene, reflux, 12 h, 62%.
chloride (TBDPSCl), followed by reduction of the ester group
and oxidation of the resulting alcohol, gave aldehyde 10,
which was condensed with L-cysteine methyl ester to give
thiazolidine 11 as a diastereomeric mixture (71% yield in
four steps). The initial attempt of CMD oxidation of 11 did
not proceed, and the thiazolidine was slowly hydrolyzed to
aldehyde 10, probably because of the moisture contained in
commercially available CMD.8 Therefore, we activated CMD
by azeotropic removal of H2O with benzene, which oxidized
11 to thiazole 12 in 62% yield. Remarkably, this modified
procedure gave a reproducible yield and was also tolerant
even on a large scale.9
of the resulting alcohol with Ms2O and then LiBr quantita-
tively provided bromide 6. The Stille coupling of 6 with
vinylstannane 7,10 obtained from propargyl alcohol in a single
step, using Pd(CH3CN)2Cl2 as a catalyst in the absence of
phosphine ligand rapidly proceeded to give coupling product
13 in 94% yield. Conversion of 13 to the corresponding allyl
bromide 14 (95% yield) followed by coupling with tri-n-
butylvinylstannane 8 afforded skipped diene 1511 in 85%
yield. After deprotection of the TBDPS ether with TBAF,
oxidation of the resulting alcohol gave aldehyde 4 in
excellent yield.
The introduction of the C2-unit accompanied by the
stereoselective construction of the chiral center was per-
formed by the Nagao acetate aldol reaction of aldehyde 4
with N-acetylthiazolidinethione 5,5 which proceeded smoothly
to give (R)-aldol adduct 17 in a highly diastereoselective
fashion (>10:1 dr by 1H NMR spectrum of the crude
product). The transition state of the reaction is probably 16,
shown in Scheme 4. Major diastereoisomer 17 could be
isolated in a pure state in 75% yield by SiO2 column
chromatography. Confirmation of the stereoconfiguration was
achieved by using a modified Mosher method.12 The removal
(4) Reviews: (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508-524. (b) Mitchell, T. N. Synthesis 1992, 803-815. (c) Farina, V.;
Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652. (d) Duncton,
M. A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235-1246.
(5) (a) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E. J.
Chem. Soc., Chem. Commun. 1985, 1418-1419. (b) Nagao, Y.; Hagiwara,
Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org.
Chem. 1986, 51, 2391-2393.
(6) Other synthetic methods for the thiazole moiety of mycothiazole (1)
have been reported. Serra, G.; Mahler, G.; Mante, E. Heterocycles 1998,
48, 2035-2048.
(7) (a) Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J.
Org. Chem. 1987, 52, 1252-1255. (b) Aoyama, T.; Sonoda, N.; Yamauchi,
M.; Toriyama, K.; Anzai, A.; Ando, A.; Shioiri, T. Synlett 1998, 35-36.
(8) CMD was purchased from Wako Pure Chemical Industries, Ltd.
(9) We obtained 12 in 50% yield on a 30 mmol scale.
13
of the chiral auxiliary with LiOH and H2O2 followed by
(10) (a) Jung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851-
3854. (b) Oddon, G.; Uguen, D. Tetrahedoron Lett. 1988, 39, 1153-1156.
(11) This reaction also gave a trace amount of SN2′-type product which
was the major product in copper-mediated coupling of 14 with vinyl-
magnesium bromide.
(12) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
(13) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141-6144.
(14) (a) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475-1478. (b) Shioiri, T.; Aoyama, T. Encyclopedia of Reagents for
Organic Synthesis, Vol. 7; Paquette, L. A., Ed.; John. Wiley & Sons:
Chichester, 1985; p 5248
(15) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165-7166.
(16) Kamiyama, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675-676.
(17) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183-2192.
2150
Org. Lett., Vol. 2, No. 14, 2000

Scheme 4a
Scheme 5a
a (a) TMSCl, NaI, H2O, CH3CN, rt, 1 h; (b) TsCl, Et3N,
Me3N‚HCl, CH2Cl2, 0 °C, 1 h, 55% in two steps; (c) NaN3, DMF,
rt, 2 h, then, 50 °C, 3 h; (d) Ph3P, H2O, THF, rt, 12 h; ClCO2Me,
Et3N, rt, 4 h, 78% in two steps; (e) Me3SnSnMe3, Pd(CH3CN)2Cl2
(10 mol %), NMP, rt, 4 h, 57%.
conversion of iodide 22 to trimethyltin analogue 3 was
18
achieved with Me3SnSnMe3 in 56% yield.
The construction of mycothiazole is summarized in
Scheme 6. After protection of the secondary alcohol of 17
with TBSOTf, removal of the chiral auxiliary with DIBAL19
gave the aldehyde 23 in 86% yield. Homologation of 23 to
(Z)-vinyl iodide 2 was effected in a completely stereoselec-
tive manner in 82% yield by treatment with Ph3P+CH2I‚I-
under “salt-free” condition developed by Stork.20
a (a) 5, Sn(OTf)2, N-ethylpiperidine, CH2Cl2, -45 to -15 °C, 3
h; 4, -78 °C, 20 min, 75%; (b) LiOH, H2O2, THF/H2O, 0 °C, 15
min; (c) TMSCHN2, MeOH/toluene (3:1), rt, 30 min quantitative
in two steps; (d) (R)-MTPA, DCC, DMAP, CH2Cl2, rt, 16 h, then
35 °C, 20 h, 85%; (e) (S)-MTPA-Cl, DMAP, CH2Cl2, 0 °C to rt,
2.5 h, 81%.
The first attempt to accomplish the final cross-coupling
of 2 to 3 with Pd(CH3CN)2Cl2 was ineffective, and no desired
product was obtained. Instead, 3 was decomposed when the
21
temperature was raised. Alternatively, addition of CdCl2
14
to accelerate the rate of transmetalation gave the coupling
product 24 in only 25% yield. However, CuCl- and LiCl-
mediated Stille coupling modified by Corey22 afforded 24
in 63% yield without the cine (Heck-type) product.23 Finally,
deprotection of the TBS group using TBAF provided (-)-
mycothiazole in 90% yield. Although this material proved
to be identical in all respects (1H and 13C NMR, IR, HRMS)
with natural mycothiazole, there are differences in the [R]D
values between the synthetic and natural products (synthetic,
[R]23 -26.0 (c 0.6, CHCl3); natural, [R]23 -3.8 (c 2.9,
esterification using TMSCHN2 quantitatively afforded
â-hydroxy ester 18. Alcohol 18 was treated with (R)-MTPA,
DCC, and DMAP or (S)-MTPA-Cl15 and DMAP to give the
corresponding MTPA esters 19a and 19b, respectively, in
high yield. As predicted, the configuration of the secondary
1
alcohol was determined to be (R) by analysis of H NMR
spectra.
D
D
CHCl3)). It is possible that contamination with artifacts exists
in natural mycothiazole.24 Using the modified Mosher
analysis, the absolute stereochemistry of the synthetic product
(18) Azizian, H.; Eaborn, C.; Pidcock, A. J. Organomet. Chem. 1981,
215, 49-58
(19) Izawa, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1979, 52, 555-
558.
1
Figure 1. ∆δ (δS - δR) values (ppm) for H NMR.
(20) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
(21) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497-
4513.
(22) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600-7605.
The other required fragment, 1-substituted vinylstannane
3, was synthesized as shown in Scheme 5. Thus, regiose-
lective addition of HI to 3-butyn-1-ol 20 under Ishii
conditions16 followed by Me3N-catalyzed tosylation17 gave
vinyl iodide 21 in 55% yield (two steps). After conversion
of tosylate to the azide with NaN3, reduction with Ph3P
followed by protection with methoxycarbonyl chloride
furnished compound 22 in 78% yield for two steps. Finally,
(23) (a) Farina, V.; Hossain, M. A. Tetrahedron Lett. 1996, 37, 6997-
7000. (b) Crisp, G. T.; Glink, P. T. Tetrahedron. 1994, 50, 3213-3234.
See also ref 22.
(24) The (R)-mycothiazole we synthesized was found to be rather labile.
In fact, when we received the natural mycothiazole from P. Crews’
laboratory (we thank Prof. Crews for sending the natural sample and 1H
NMR spectrum), it was decomposed, and we could not measure its optical
rotation. Thus, the natural sample may have contaminated with decomposed
products such as dehydration products, further oxidation products, or
isomerization products when its optical rotation was measured.
Org. Lett., Vol. 2, No. 14, 2000
2151

Scheme 6a
a (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 30 min, 96%; (b) DIBAL, toluene, -78 °C, 1 h, 86%; (c) Ph3P+CH2I‚I-, NaHMDS, HMPA,
THF, -78 °C, 1 h, 82%; (d) Pd(Ph3P)4 (40 mol %), CuCl (5.0 equiv), LiCl (6.0 equiv), DMSO, rt, 15 h, 63%; (e) TBAF, THF, rt, 2 h, 90%.
can be determined, and (-)-mycothiazole is assigned as (R).
However, due to the disparity in [R]D values, we cannot make
a definitive assignment of the mycothiazole at the present
time.
of this CMD methodology to the thiazole-containing natural
products is underway in our laboratory and will be reported
in due course.25
In summary, we have accomplished the first asymmetric
total synthesis of (-)-mycothiazole. During the course of
the synthesis, we have demonstrated the utilities of the Nagao
acetate aldol reaction and cuprous chloride accelerated Stille
coupling with a 1-substituted vinylstannane and a (Z)-vinyl
iodide. In addition, we have found that azeotropic activation
of CMD allowed the CMD-mediated thiazole synthesis to
be reproducible even on a large scale. Further application
Acknowledgment. This work was financially supported
in part by Grant-in-Aids from the Ministry of Education,
Science, Sports and Culture, Japan.
Supporting Information Available: Experimental pro-
cedures for the preparation of compound 17 and all com-
pounds reported in Scheme 2, 3, 5, and 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Our preliminary work has recently been reported, see: Fujiwara,
H.; Tojiki, K.; Yokokawa, F.; Shioiri, T. Peptide Science 1999; Fujii, N.,
Ed.; The Japanese Peptide Society: Minoh, 2000, pp 9-12.
OL000128L
2152
Org. Lett., Vol. 2, No. 14, 2000