Total Synthesis of (+)-Cystothiazole A

Article abstract of DOI:10.1021/ol035600s

(Equation presented) The total synthesis of cystothiazole A is described. Key steps of the synthesis include an Evans asymmetric catalytic aldol reaction, which established the required C₄-C₅ stereochemistry. The [2,4′]-bis(thiazole)

Full text of DOI:10.1021/ol035600s

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4163-4165
Total Synthesis of (+)-Cystothiazole A
Patrick L. DeRoy and Andre´ B. Charette*
De´partement de chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received August 25, 2003
ABSTRACT
The total synthesis of cystothiazole A is described. Key steps of the synthesis include an Evans asymmetric catalytic aldol reaction, which
established the required C −C stereochemistry. The [2,4′]-bis(thiazole) was obtained applying our methodology of electrophilic activation of
4
5
amide. Semistabilized Wittig reaction between the phosphonium salt 3 and the aldehyde 2 afforded 1 in nine linear steps and 38% overall
yield.
In 1998, Sakagami1 and co-workers isolated from the myxo-
bacterium Cystobacter fuscus a bis(thiazole)-type antibiotic
called cystothiazole A.
also discovered to possess an in vitro cytotoxicity against
human tumor cells: colon carcinoma HCT-116 and Leu-
kaemia K 562 with an IC50 value of, respectively, 130 and
110 ng/mL. The structure of (+)-cystothiazole A (1) was
determined by NMR methods (1H, 13C, HETCOR, HMBC),
with the E geometry of the trisubstituted double bond at C2
being determined by difference NOE data (H-2/3-OMe). Its
absolute chemistry was confirmed by the total syntheses of
Williams in 20014a and Akita and co-workers in 2002.5
Our interest in the total synthesis of (+)-cystothiazole A
originated not only because of its interesting biological
activity but also because of its [2,4′]-bis(thiazole) unit. In
1998, we reported an efficient method to synthesize thiazo-
line moieties,6 and since then we have applied this methodol-
ogy to the total synthesis of curacin A and B.7 Herein, we
report the total synthesis of (+)-cystothiazole A, extending
our methodology to obtain the [2,4′]-bis(thiazole) unit.
This natural product was highly active against a wide range
of fungi, including Candida albicans (AJ-5682, MIC 0.4 µg/
mL), with no effect on bacterial growth. Although this com-
pound was structurally similar to the known antibiotic myxo-
thiazol,2 cystothiazole A was more active against fungi and
less cytotoxic. Its antifungal activity appeared to result from
the inhibition of submitochondrial NADH oxidation.1,3 It was
(3) Clough, J. M. Nat. Prod. Rep. 1993, 565.
(4) (a) Williams, D. R.; Samarjit, S.; Clark, M. P. J. Org. Chem. 2001,
66, 8463. For synthtic application see: (b) Williams, D. R.; Lowder, P. D.;
Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett. 1997, 38, 331. (c) Freeman, D.
J.; Pattenden, G. Tetrahedron Lett. 1998, 39, 3251. (d) Pattenden, G.;
Thompson, T. Chem. Commun. 2001, 8, 717. (e) Yokokawa, F.; Sameshima,
H.; Shioiri, T. Tetrahedron Lett. 2001, 42, 4171.
(1) Ojika, M.; Suzuki, Y.; Tsukamoto, A.; Sakagami, Y.; Fudou, R.;
Yoshimura, T.; Yamanaka, S. J. Antibiot. 1998, 51, 275.
(2) (a) Gerth, K.; Irschik, H.; Reichenbach, H.; Trowitzsch, W. J. Antibiot.
1980, 33, 1474. (b) Trowitzsh, W.; Reifenstahl, G.; Wray, W.; Gerth, K. J.
Antibiot. 1980, 33, 1480.
(5) Akita, H.; Kato, K.; Nishimura, A.; Yamamoto, Y. Tetrahedron Lett.
2002, 43, 643.
(6) Charette, A. B.; Chua, P. J. Org. Chem. 1998, 63, 908.
(7) Charette, A. B.; DeRoy, P. L.; Berthelette, C.; Lacombe, P.; Sametz,
G. Manuscript in preparation.
10.1021/ol035600s CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/02/2003

Scheme 1
Scheme 2
Our retrosynthetic strategy of 1 is illustrated in Scheme 1
and involves a catalytic asymmetric synthesis of the â-meth-
oxyacrylate system, and the application of our electrophilic
amide activation methodology for constructing the [2,4′]-
bis(thiazole) moiety. Thus, 1 would be synthesized by Wittig-
type reaction of an aldehyde 2 with a phosphonium salt 3.8
The C4-C5 vicinal stereogenic centers would be introduced
by an Evans catalytic asymmetric aldol reaction between
silylketene acetal 4 and (benzyloxy)acetaldehyde 5.9 The
latter process would then be followed by an activation of
amide 7 and treatment with L-cysteine hydrochloride 6, and
an oxidation step would be used to obtain the bis(thiazole)
unit.
Synthesis of (+)-2 began with the formation of the (Z)-
silylketene thioacetal 4 (Scheme 2).10 The [Cu((R,R)-Ph-
pybox)](SbF6)2 (9)-catalyzed aldol reaction between benzy-
loxyacetaldehyde 5 and (Z)-silylketene acetal 4 smoothly
afforded the syn aldol adduct (-)-10 ([R]25D -42.4° (c 0.55,
CH2Cl2)) in excellent diastereoselectivity (97.5:2.5 syn:anti
homologated, using methyldiazoacetate13 12 in the presence
of SnCl2 to obtain the â-ketoester (-)-13 (85%, 2 steps, ratio
10.5:1 (-)-13:enol form determined by H NMR).
1
1
ratio determined by H NMR) with >98% ee for the syn
The (E)-â-methoxyacrylate (+)-14 was prepared via
deprotonation of â-ketoester (-)-13 in hexamethylphosphoric
triamide (HMPA) as a solvent, followed by the methylation
using dimethyl sulfate.4a,14 Cleavage of the benzyl group was
then achieved using Pearlman’s catalyst to form the primary
alcohol (+)-15 in a good yield. The reaction had to be
monitored to prevent hydrogenation of the E double bond.
This side reaction was observed when the reaction was left
more than 30 min under a hydrogen atmosphere. Dess-
Martin periodinane oxidation of (+)-15 afforded the desired
isomer. The hydroxyl functionality was methylated, using
the Meerwein11 reagent in the presence of a proton sponge
as a base, to afford (-)-11 (95%).
The thioester was reduced in the corresponding aldehyde
using triethylsilane as a source of hydride in the presence of
10% palladium on carbon.12 The crude aldehyde was then
(8) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Victor, J. C. J. Am. Chem.
Soc. 2000, 122, 10033.
(9) (a) Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem.
Soc. 1996, 118, 5814. (b) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.;
Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 687.
(10) For a general procedure of the Z or E silylketene acetal see: Evans,
D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Connell, B. T. J.
Am. Chem. Soc. 1999, 121, 669.
(11) (a) Meerwein, H.; Laasch, P.; Mersch, R.; Spille, J. Chem. Ber.
1956, 89, 203. (b) Pettit, G. R.; Singh, S. B.; Herald, D. L.; Lloyd-Williams,
P.; Kantoci, D.; Burkett, D. D.; Barkoczy, J.; Hogan, F.; Wardlaw, T. R. J.
Org. Chem. 1994, 59, 6287.
25
25
aldehyde (+)-2 ([R]D +105.0 (c 0.46, CHCl3); lit.5 [R]D
(13) (a) The methyldiazoacetate was prepared as described in: Womack,
E. B.; Nelson, A. B. Organic Syntheses; Wiley: New York, 1955; Collect.
Vol. III, p. 392. (b) For synthetic application, see: Yajura, T.; Ueki, A.;
Kitamura, T.; Tanaka, K.; Nameki, M.; Ikeda, M. Tetrahedron 1999, 55,
7461. (c) Yakura, T.; Yuamada, S.; Azuma, M.; Ueki, A.; Ikeda, M.
Synthesis 1998, 7, 973. (d) Yakura, T.; Ueki, A.; Kitamura, T.; Tanaka,
K.; Nameki, M.; Ikeda, M. Tetrahedron 1999, 55, 7461. (e) Phukan, P.;
Mohan, J. M.; Sudalai, A. J. Chem. Soc., Perkin Trans. 1 1999, 24, 3685.
(14) Backhaus, D. Tetrahedron Lett. 2000, 41, 2087.
(12) For synthetic application see: (a) Tokuyama, H.; Yokoshima, S.;
Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002, 8, 1121. (b) Fukuyama,
T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 19, 7050. (c) Kanda, Y.;
Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451.
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Org. Lett., Vol. 5, No. 22, 2003

+104.7 (c 0.55, CHCl3)) in 99% yield. The spectral proper-
ties were identical to those reported.14
Scheme 3
The right-hand side of the cystothiazole containing the
[2,4′]-bis(thiazole) moiety was prepared using methodology
that we developed for the preparation of thiazoline via an
electrophilic activation of amide using triflic anhydride
(Tf2O).6 The isopropylamide 1615 was activated with Tf2O
in the presence of pyridine to afford a pyridinium salt
intermediate.16 Addition of L-cysteine‚HCl afforded the
thiazoline (+)-17 in 90% yield. Oxidation of the thiazoline
ring using bromotrichloromethane4 (BrCCl3) in the presence
of 2 equiv of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave
the first thiazole ring 717 (99%). The ester functionality was
then transformed into the corresponding N-methylamide 18
(92%), using a solution of 2.5 M methylamine in methanol.
Amide 18 was treated with Tf2O and pyridine followed by
addition of L-cysteine‚HCl.18 The corresponding crude thi-
azoline was then oxidized using BrCCl3/DBU to afford the
bis(thiazole) 1917 in 69% yield over two steps. The ester
functionality was reduced with lithium aluminum hydride
(LiAlH4) to obtain the corresponding alcohol 20 (93%). This
primary alcohol 20 was mesylated, and addition of tribu-
tylphosphine (Bu3P) afforded a solution in DMF of the
phosphonium salt 3. The reaction conditions developed by
Evans in the total synthesis of phorboxazole B19 were used
to obtain a E double bond using a similar semistabilized
Wittig reagent. This methodology uses a tributylphosphonium
salt and an aldehyde in the presence of DBU at room
temperature and gave a good mixture of (E/Z) isomers (21:1
to 27:1). When we mixed the phosphonium salt 3 with the
aldehyde 2 followed by the addition of DBU, we obtained a
mixture of (+)-(E)-1/(+)-(Z)-1 ) 1.8:1 in 66% yield.
In summary, a convergent total synthesis of 1 was ac-
complished employing a Wittig-type olefination between 2
and 3 as the final step. The [2,4′]-bis(thiazole) moiety was
successfully synthesized using electrophilic activation of an
amide followed by condensation with an aminothiol salt.
Finally we have synthesized (+)-cystothiazole A in nine
linear steps and 38% overall yield.
When the Wittig was run at 0 °C, we obtained a mixture
of E/Z isomers in a ratio of 6.9:1. Both isomers were
separated by HPLC to afford pure (+)-1. The physical data
of synthetic (+)-1 were identical with those reported for the
natural product (+)-1 (exptl [R]D25 +104.0 (c 0.21, CHCl3);
Acknowledgment. This work was supported by NSERC
and the Universite´ de Montre´al.
25
lit. [R]D +109 (c 0.24, CHCl3)).1
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS) and
HPLC traces for isomers or enantioselectivity. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) Alfred, E. L.; Huwitz, M. D. J. Org. Chem. 1965, 30, 2376.
(16) Charette, A. B.; Grenon, M. Can. J. Chem. 2001, 79, 1694.
(17) NMR spectra are identical to those reported: see ref 4a.
(18) Thiazoline prepared from 18 was not purified since it partially
oxidized on silica gel.
(19) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Victor, J. C. J. Am. Chem.
Soc. 2000, 122, 10033.
OL035600S
Org. Lett., Vol. 5, No. 22, 2003
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