Total synthesis of (±)-mycothiazole and formal enantioselective approach

Article abstract of DOI:10.1021/ol047603q

(Chemical Equation Presented) A total synthesis of (±)-mycothiazole and a formal enantioselective approach have been achieved from 2,4-dibromothiazole. A chain extension of a homoallylic alcohol proceeding through an unsaturated sultone intermediate, generated by ring-closing metathesis, was used as a key step for the elaboration of the conjugated (Z)-dienol moiety.

Full text of DOI:10.1021/ol047603q

ORGANIC
LETTERS
2005
Vol. 7, No. 2
339-342
Total Synthesis of (±)-Mycothiazole and
Formal Enantioselective Approach
Alexandre Le Flohic, Christophe Meyer,* and Janine Cossy*
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
christophe.meyer@espci.fr; janine.cossy@espci.fr
Received November 22, 2004
ABSTRACT
A total synthesis of (±)-mycothiazole and a formal enantioselective approach have been achieved from 2,4-dibromothiazole. A chain extension
of a homoallylic alcohol proceeding through an unsaturated sultone intermediate, generated by ring-closing metathesis, was used as a key
step for the elaboration of the conjugated (Z)-dienol moiety.
Over the past few years, natural products of marine origin
have continued to be of interest due to their wide spectrum
of biological and pharmacological properties. Mycothiazole
was first isolated in 1988 from the marine sponge Spongia
mycofijiensis collected from the Vanuatu islands.1 Its pres-
ence was also detected recently in the extracts of another
marine sponge of the genus Dactylospongia.2 Mycothiazole
was found to exhibit an antihelminthic activity in vitro.
Moreover, screening assays by the National Cancer Institute
(NCI) in the United States indicated that mycothiazole
exhibits a rather selective toxicity against a small cell lung
cancer line.3 The structure of mycothiazole was established
after extensive NMR analysis and confirmed by exhaustive
interpretation of a HREIMS spectrum (Figure 1).4
between two acyclic polyunsaturated side chains. The C2
side chain includes a nitrogen substituent at C13 (methyl
carbamate), a conjugated diene moiety consisting of a (Z)-
disubstituted double bond (C9-C10) and a methylene group
(C11-C20), a quaternary carbon at C6, adjacent to the
thiazole, substituted by a gem-dimethyl group and a second-
ary alcohol at C7 that consitutes the unique stereocenter of
mycothiazole. The C4 substituent is a hexadienyl chain
containing a (E)-disubstituted double bond (C15-C16) and
a terminal olefin (C18-C19). To date, a single total synthesis
of mycothiazole has been achieved, which enabled the
assignment of the (R) absolute configuration of the natural
product,5 although some discreapancies were observed
between the optical rotation of the synthetic sample and the
natural product due to the lability of the latter upon storage.
Synthetic approaches toward two subunits containing the 2,4-
disubstituted thiazole6 or the conjugated (Z)-diene7 have also
been reported.
(1) Crews, P.; Kakou, Y.; Quin˜oa`, E. J. Am. Chem. Soc. 1988, 110,
4365-4368.
(2) Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.;
Gomez-Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775-778.
(3) The results of the National Cancer Institute Human Tumor Cell Line
Screen mean graph can be consulted on the Internet at http://dtp.nci.nih.gov
(NCS number 647640).
Figure 1. Structure of (-)-mycothiazole.
(4) The atom numbering has been chosen so that the positions of the
thiazole ring (C2/C4/C5) may be designated in the classical fashion.
(5) (a) Sugiyama, H.; Yokokawa, F.; Shioiri, T. Org. Lett. 2000, 2, 2149-
2152. (b) Sugiyama, H.; Yokokawa, F.; Shioiri, T. Tetrahedron 2003, 59,
6579-6593.
The most unique structural feature of this natural product
is a 2,4-disubstituted thiazole ring, which is imbedded
10.1021/ol047603q CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/30/2004

We have previously described that secondary homoallylic
alcohols of type A could be converted to sultones of type B
by reaction with allylsulfonyl chloride and subsequent ring-
closing metathesis of the intermediate sulfonates.8,9 Sultones
of type B could be sequentially deprotonated at the R-position
of the sulfonyl group and first alkylated with halides (R′X)
and then with the carbenoid ICH2MgCl,10 which led after
â-elimination and loss of sulfur dioxide to the conjugated
(Z)-dienols of type C (Scheme 1).
Our synthesis of mycothiazole began with the chemose-
lective substitution of the bromine at C2 in 2,4-dibromothia-
zole 1 by treatment with prenylmagnesium chloride in THF,
which reacted with complete allylic transposition12 and
afforded the 2,4-disubstituted thiazole 2 (87%). The terminal
olefin in compound 3 was subjected to a dihydroxylation
(cat. OsO4, NMO, t-BuOH/H2O), and the resulting interme-
diate 1,2-diol underwent an oxidative cleavage with NaIO4
in THF/H2O to afford the aldehyde 3 (88%). This compound
was treated with allylmagnesium bromide, and the resulting
secondary alcohol 4 (87%) was protected as a tert-butyldi-
methylsilyl ether (TBSOTf, 2,6-lutidine, 0 °C) to produce
compound 5 (95%). As various attempts to introduce the
side chain at C4 by direct formation of the C4-C14 bond
turned out to be unsuccessful,13 it was envisaged at first to
homologate the substituted 4-bromothiazole 5 at C4 and then
create the C14-C15 bond. Thus, the substituted 4-
bromothiazole 5 underwent lithium-bromine exchange
with tert-butyllithium in ether at -78 °C, and subsequent
formylation with DMF provided the aldehyde 6 (85%). After
reduction (DIBAL-H, Et2O, -78 °C), the resulting alcohol
7 (95%) was converted to the bromide 8 (97%) by treatment
with PPh3 and CBr4 in the presence of 2,6-lutidine in
acetonitrile. With the aim of elaborating the unsaturated side
chain of mycothiazole at C4 in a single operation, the
bromide 8 was subjected to a Stille coupling with (E)-1-
tributylstannylpenta-1,4-diene14 catalyzed by PdCl2(MeCN)2
in NMP,5 and the 1,4-diene 9 was obtained in 95% yield.
Subsequent deprotection of the hydroxyl group at C7 with
TBAF in THF at 50 °C finally afforded the homoallylic
alcohol 10 (94%) (Scheme 3).
Scheme 1. Synthesis of Conjugated (Z)-Dienols from
Homoallylic Alcohols
Herein, we would like to report the use of this strategy in
the synthesis of (()-mycothiazole, which contains a conju-
gated (Z)-dienol subunit of type C.
In our retrosynthetic analysis, the introduction of the
methyl carbamate at C13 was envisaged by a Schmidt
reaction applied to the carboxylic acid of type D. The key
stage will be the elaboration of the conjugated (Z)-dienol
moiety in compound D from the corresponding homoallylic
alcohol derivative of type E by using the chain extension
methodology outlined above. The introduction of the side
chain at C4 in compound E should be achieved from the
substituted 4-bromothiazole of type F. In this latter com-
pound, the secondary homoallylic alcohol functionality at
C7 would be generated by allylation of an intermediate
aldehyde whose preparation was envisaged from the readily
available 2,4-dibromothiazole 111 (Scheme 2).
Following our synthetic plan, the elaboration of the
conjugated (Z)-dienol moiety of mycothiazole by chain
extension of the homoallylic alcohol 10 required at first the
preparation of the key intermediate unsaturated sultone 12.
At first, the sterically hindered secondary alcohol 10 was
treated with allylsulfonyl chloride in THF provided that
DMAP was used as the base. The intermediate sulfonate 11
was isolated but not purified and underwent ring-closing
metathesis by treatment with Grubbs’ second generation
catalyst (Grubbs II) in benzene at 70 °C. Under these
Scheme 2. Retrosynthetic Analysis of Mycothiazole
(6) Serra, G.; Mahler, G.; Manta, E. Heterocycles 1998, 48, 2035-2048.
(7) Rodriguez-Conesa, S.; Candal, P.; Jime´nez, C.; Rodriguez, J.
Tetrahedron Lett. 2001, 42, 6699-6702.
(8) Le Flohic, A.; Meyer, C.; Cossy, J.; Galland, J.-C.; Desmurs, J.-R.
Synlett 2003, 667-670.
(9) (a) Karsch, S.; Schwab, P.; Metz, P. Syntlett 2002, 2019-2022. (b)
Karsch, S.; Freitag, D.; Schwab, P.; Metz, P. Synthesis 2004, 1696-1712.
(10) (a) Plietker, B.; Metz, P. Tetrahedron Lett. 1998, 39, 7827-7830.
(b) Plietker, B.; Seng, D.; Fro¨hlich, R.; Metz, P. Eur. J. Org. Chem. 2001,
3669-3676.
(11) Reynaud, P.; Robba, M.; Moreau, R. C. Bull. Soc. Chim. Fr. 1962,
1735-1738.
(12) Florio, S.; Epifani, E.; Ingrosso, G. Tetrahedron 1984, 40, 4527-
4533.
(13) No satisfactory conditions were found in order to couple an
organometallic species generated at C4 from the substituted 4-bromothiazole
5 with allylic electrophiles incorporating the C14-C19 side chain.
(14) (E)-1-Tributylstannylpenta-1,4-diene was prepared in four steps
(26% overall yield) from trimethylsilylacetylene by allylation (EtMgBr then
AllylBr, cat. CuBr‚SMe2, THF) and hydroalumination (Dibal-H, hexanes/
Et2O) and subsequent iodinolysis (I2, THF), desilylation (MeONa/MeOH),
and lithium-iodine exchange (t-BuLi, Et2O, -78 °C) followed by stan-
nylation (Bu3SnCl, rt).
340
Org. Lett., Vol. 7, No. 2, 2005

Scheme 3. Preparation of Homoallylic Alcohol 10
Scheme 4. Total Synthesis of (()-Mycothiazole
conditions, the unsaturated sultone 12 was obtained in 70%
yield (2 steps from the alcohol 10). Addition of LiHMDS to
a mixture of sultone 12 and 1,1-dimethoxy-3-iodopropane15
in the presence of HMPA in THF at -78 °C cleanly afforded
the monoalkylated sultone 13 (76%) as a 1/1 mixture of
diastereomers. The crucial step of our synthetic plan could
be investigated next. Thus, sultone 13 was efficiently
deprotonated with n-butyllithium in THF at -78 °C, and
subsequent addition of the carbenoid ICH2MgCl (generated
from CH2I2 and i-PrMgCl, THF, -80 °C) led to the
conjugated (Z)-dienol 14 in 60% yield (Scheme 4).8
Having successfully accomplished the key transformation
of our synthesis, only functional groups manipulations were
required in order to complete the total synthesis of myco-
thiazole. Hydrolysis of the dimethyl acetal in compound 14
(PPTS, THF/H2O, 50 °C) quantitatively afforded aldehyde
15, which was not purified but directly oxidized chemose-
lectively by NaClO2 in the presence of amylene and excess
NaH2PO4 in t-BuOH/H2O.16 The resulting carboxylic acid
16, which turned out to be an extremely sensitive compound,
was directly extracted from the reaction mixture and im-
mediately treated with diphenylphosphoryl azide (DPPA) and
Et3N in toluene. After formation of the acyl azide 17, the
reaction mixture was heated at reflux in order to induce the
Curtius rearrangement to the corresponding isocyanate 18.
As the latter was not readily converted to mycothiazole when
MeOH was added to the reaction mixture at reflux, we
initially thought that it had probably accidentally hydrolyzed
to the amine 19. However, the compound obtained after
purification by preparative TLC on silica gel did not react
with ClCO2Me in the presence of Et3N. This result suggested
that we had isolated the rather robust isocyanate 18, and
therefore the reaction mixture was treated with an excess of
MeOH. Under these conditions, a smooth methanolysis took
place,17 which produced mycothiazole 1 in 33% overall yield
from the dimethyl acetal 14 (4 steps) (Scheme 4). The NMR
data of this compound were in agreement with those
described in the literature.5
As mycothiazole contains a single stereocenter at C7, a
formal enantioselective approach of this natural product has
(17) The reaction between ClCO2Me and MeOH may have generated
traces of HCl, which can catalyze the methanolysis of isocyanates, see:
Khoukhi, M.; Vaultier, M.; Banalil, A.; Carboni, B. Synthesis 1996, 483-
487.
(15) Clive, D. L. J.; Chua Paul, C.; Wang, Z. J. Org. Chem. 1997, 62,
7028-7032.
(16) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175-1176.
Org. Lett., Vol. 7, No. 2, 2005
341

also been investigated with the preparation of the optically
active alcohol (R)-4. Thus, addition of the chiral allylic
borane I [generated from allylmagnesium bromide and
(+)-chlorodiisopinocampheyl borane ((+)-DIPCl)]18 to al-
dehyde 3 in Et2O at -78 °C led to the corresponding
secondary homoallylic alcohol (R)-4 (70%) with low optical
purity (ee ) 54%).19 Although this result probably could
have been optimized by modifying the reaction conditions,
an enantioselective allyltitanation of aldehyde 3 with the
allyltitanium complex (S,S)-II [generated from allylmagne-
sium chloride and the corresponding ((S,S)-TADDOL)-
CpTiCl complex]20 in THF/Et2O at -78 °C afforded (R)-4
in much better yield and enantiomeric excess19 (82% yield,
ee ) 99%) (Scheme 5).
the known face-selectivities of the chiral allylating reagents
and particularly the allyltitanium complex II, which displays
an extremely high face-selectivity regardless of the nature
of the aldehydes.20
In summary, we have achieved a total synthesis of
(()-mycothiazole in 18 steps from 2,4-dibromothiazole with
an overall yield of 5%. The side chain at C2 was created in
a stepwise fashion by using a chemoselective prenylation,
an aldehyde allylation, a chain extension of a homoallylic
alcohol to a conjugated (Z)-dienol, proceeding through an
intermediate unsaturated sultone, and a Curtius rearrange-
ment. The installation of the side chain at C4 was based on
a one-carbon homologation followed by a Stille coupling.
A formal enantioselective approach has also been demon-
strated with the preparation of the secondary homoallylic
alcohol 4 in high enantiomeric purity (ee ) 99%).
Acknowledgment. A.L.F. thanks the CNRS and Rhodia
for a grant, and financial support from Rhodia is gratefully
acknowledged.
Scheme 5. Preparation of Homoallylic Alcohol (R)-4
Supporting Information Available: Experimental pro-
cedures and characterization data for key intermediate
compounds 4, (R)-4, 9, 12, 13, 14, and mycothiazole and
1
copies of their H NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL047603Q
(18) Jadhav, P. K.; Bhat, K. S.; Perumal, T.; Brown, H. C. J. Org. Chem.
1986, 51, 432-439.
(19) Determined by chiral HPLC analysis: chiral OD-H column; eluent,
hexane; elution rate, 1 mL/min; detection, 230-260 nm; retention times,
(S)-enantiomer 48.4 min, (R)-enantiomer 55.5 min.
(20) (a) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit,
P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321-2336. (b) Cossy,
J.; BouzBouz, S.; Pradaux, F.; Willis, C.; Bellosta, V. Synlett 2002, 1595-
1606.
The (R) configuration of the homoallylic alcohol 4
obtained from these reactions was attributed on the basis of
342
Org. Lett., Vol. 7, No. 2, 2005