Synthesis of the apratoxin 2,4-disubstituted thiazoline via an intramolecular aza-Wittig reaction

Article abstract of DOI:10.1021/ol0342148

(Matrix presented) In developing a synthetic entry to the thiazoline-containing domain of the apratoxin natural products, we converted vicinal azido-thiolesters into 2,4-disubstituted thiazolines via sequential one-pot Staudinger reduction/aza-Wittig reac

Full text of DOI:10.1021/ol0342148

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1281-1283
Synthesis of the Apratoxin
2,4-Disubstituted Thiazoline via an
Intramolecular Aza-Wittig Reaction
Jiehao Chen and Craig J. Forsyth*
Department of Chemistry, UniVersity of Minnesota, 207 Pleasant St. S.E.,
Minneapolis, Minnesota 55455
forsyth@chem.umn.edu
Received February 5, 2003
ABSTRACT
In developing a synthetic entry to the thiazoline-containing domain of the apratoxin natural products, we converted vicinal azido-thiolesters
into 2,4-disubstituted thiazolines via sequential one-pot Staudinger reduction/aza−Wittig reaction. This method of de novo thiazoline formation
provides a mild and versatile process that is particularly well suited to acid-sensitive substrates.
Thiazoline moieties occur in a variety of natural and
nonnatural products.1 Prominent recent examples include the
apratoxins (1-3), which were isolated from the marine
cyanobacterium Lyngbya majuscula Harvey ex Gomont and
characterized by Moore, Paul, and co-workers (Figure 1).2
The novel structures of the apratoxins, wherein ester and
2,4-disubstituted thiazoline moieties join ketide and peptide
domains, are accompanied by potent levels of cytotoxicity.
However, the molecular basis of their biological action is
unknown.
In developing a synthetic entry to the apratoxin natural
products,3 we needed a method for the de novo synthesis of
2,4-disubstituted thiazoline moieties that contain acid-sensi-
tive functionality. For this, the use of vicinal azido thiolesters
for sequential one-pot Staudinger reduction/intramolecular
aza-Wittig (S-AW) process was found to provide the target
thiazolines under neutral conditions and without complica-
tions. The details and utility of this nondehydrative process
for thiazoline synthesis are summarized herein.
(1) (a) Roy, R. S.; Gehring, A. M.; Milne, J. C.; Belshaw, P. J.; Walsh,
C. T. Nat. Prod. Rep. 1999, 16, 249. (b) Wipf, P. Chem. ReV. 1995, 95,
2115.
(2) (a) Luesch, H.; Yoshida, W. A.; Moore, R. E.; Paul, V. J.; Corbett,
T. H. J. Am. Chem. Soc. 2001, 123, 5418. (b) Luesch, H.; Yoshida, W. A.;
Moore, R. E.; Paul, V. J.; Corbett, T. H. Bioorg. Med. Chem. 2002, 10,
1973.
(3) (a) Chen, J.; Forsyth, C. J. Abstracts of Papers, 34th Great Lakes
Regional Meeting of the American Chemical Society, Minneapolis, MN,
June 2-5, 2002; American Chemical Society: Washington, DC, 2002; GEN
ORG 274. (b) Chen, J.; Forsyth, C. J. Abstracts of Papers, 225th National
Meeting of the American Chemical Society, New Orleans, LA, March 23-
27, 2003; American Chemical Society: Washington, DC, 2003; ORG 208.
Figure 1. Structures of the Apratoxins.
10.1021/ol0342148 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/28/2003

Central to the designed total synthesis of the apratoxins
is the formation of the 2,4-disubstituted thiazoline moiety.
Several methods have been developed for the construction
of this type of structural motif.4 These include the direct
thermal intramolecular cyclization of thiolesters derived from
vicinal amino thiols,5 TiCl4-induced dehydration of amides
derived from vicinal amino thiols,6 condensation of nitriles
with 2-aminothiols,7 addition of aminothiols to imidate
esters,8 combination of a thiolamide with ethyl bromopyru-
vate,8 sulfurization of oxazolines,9 cyclization of a serine-
derived thiolamide with10 or without11 the use of Burgess’
reagent, phosphine-induced annulation of thiolamides and
2-alkynoates,12 and an intramolecular aza-Wittig reaction of
a thiolester.13 Due to its simplicity and directness, the
application of Fukuyama’s acid-induced cyclization of an
R-amino thiolester5 was explored first for the synthesis of
apratoxins’ thiazoline.
This provided two major diastereomeric products 7, both
of which contained the anticipated thiazoline unit. However,
both diastereomers unexpectedly also had incorporated a
tetrahydropyran.
This likely results from acid-induced â-elimination to form
a trisubstituted alkene and hetero-Michael addition of the
residual hydroxyl moiety resulting from TES ether cleavage.
The â-elimination process is clearly related to the reported
acid-catalyzed dehydration of apratoxin A to form (E)-34,35-
dehydroapratoxin A in CDCl3.2 To prevent unwanted dehy-
dration, several thiol esters with different amino and hydroxyl
protecting groups were investigated under the Fukuyama
acid-induced cyclization conditions. But none of those
examined were fruitful. Hence, a key synthetic challenge en
route to the total synthesis of the apratoxins was under-
scored: installation and maintenance of the 2-(â-hydroxy)-
thiazoline.
Thiol ester 6, in which the amine was engaged in a tert-
butyl carbamate, was prepared from carboxylic acid 4 and
the thiol 5 (Scheme 1).14 Compound 4 represents the
Thus, an alternative process for mild thiazoline formation
that would avoid the observed propensity of dehydration/
elimination to give a 2-alkenyl-substituted thiazoline was
sought. This requirement, in conjunction with the basic
synthetic strategy toward the apratoxins, led to the identifica-
tion of a uniquely mild process for de novo thiazoline
formation. The neutral reaction conditions involved in
phosphinimine generation from an azide via Staudinger
reduction and the opportunity for subsequent intramolecular
aza-Wittig reaction under the same anhydrous reaction
conditions15 prompted the exploration of vicinal azido
thiolesters for mild thiazoline formation in the apratoxin
system (Scheme 2). This concept was found to have
Scheme 1. Dehydrative Thiazoline/Tetrahydropyran Formation
Scheme 2. Staudinger Reduction/Intramolecular Aza-Wittig
Process for Nondehydrative Thiazoline Formation
polyketide domain of apratoxins A and B, and 5 is an N-
and C-blocked version of the modified cysteine moiety of
the apratoxins. Following the Fukuyama protocol,5 exposure
of 6 to TFA in CH2Cl2 to cleave the carbamate moiety
followed by removal of solvent and excess TFA gave a
residue that was heated at reflux in benzene.
precedence in the generation of pyranoside-fused thiazolines
as protected forms of vicinal amino-thiols.13
The S-AW process has also been applied to the synthesis
of cyclic imines and an oxazoline.16 However, the acid
sensitivity of the apratoxins’ 2-(â-hydroxy)-thiazoline moiety
presented an unprecedented challenge for convergent thia-
zoline synthesis under mild, nondehydrative conditions.
Several thiolester-azides related to the modified cysteine
moiety of the apratoxins were prepared (Scheme 3). Selective
(4) (a) Wipf, P.; Venkatraman, S. Synlett 1997, 1. (b) Kedrowski, B.;
Heathcock, C. H. Heterocycles 2002, 58, 601.
(5) Fukuyama, T.; Xu, L. J. Am. Chem. Soc. 1993, 115, 8449.
(6) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1992, 57, 5566.
(7) Ehrler, J.; Farooq, S. Synlett 1994, 702.
(8) (a) Inamli, K.; Shiba, T. Bull. Chem. Soc. Jpn. 1986, 115, 8449. (b)
Pattenden, G.; Thom, S. M. J. Chem. Soc., Perkin Trans. 1 1993, 1629.
(9) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267.
(10) Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397.
(11) Zarantonello, P.; Leslie, C. P.; Ferritto, R.; Kazmierski, W. M.
Bioorg. Med. Chem. Lett. 2002, 12, 561.
(15) For reviews on the Staudinger/aza-Wittig process, see: (a) Molina,
P.; Vilaplana, M. J. Synthesis 1994, 1197. (b) Eguchi, E.; Matsushita, Y.;
Yamashita, K. Org. Prep. Proced. 1992, 24, 209.
(16) Mulzer, J.; Meier, A.; Buschmann, J.; Luger, P. Synthesis 1996,
123.
(12) Liu, B.; Davis, R.; Joshi, B.; Reynolds, D. W. J. Org. Chem. 2002,
67, 4595 and references therein.
(13) Brossmer, R.; Mack, H. Tetrahedron Lett. 1981, 22, 933.
(14) Details of the preparation of 4-12d will be reported in due course.
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Table 1. Thiazoline Formation from Azido-Thiolestersa
Scheme 3. Staudinger/Aza-Wittig Formation of
2,4-Disubstiuted Thiazolines
saponification of thiolacetate 8 gave thiol 9, which was
esterified with several different carboxylic acids to provide
thiolesters 10. PMB ether cleavage with DDQ17 followed
by azide formation using diphenylphosphoryl azide (DPPA)
under Mitsunobu conditions18 provided vicinal azido thiol-
esters 11a-d (Table 1) from 10.
Thiazoline formation was accomplished by treatment of
simple thiolacetate 11a with Ph3P in anhydrous THF at 50
°C, which produced 12a in excellent yield. More complicated
thiolesters 11b-d were also converted smoothly into the
corresponding thiazolines (Table 1). Thiazolines 12c and 12d
(entries 3 and 4) were obtained in good yield without any
detectable epimerization of the 2-substiutents’ R-stereogenic
centers or at the 4-position of the thiazolines. Entries 3 and
4 also demonstrate the utility of this method for the formation
of thiazolines that contain acid-sensitive functionality. Silyl
ethers and a tert-butylcarbamate were successfully main-
tained throughout the S-AW process. The ability to affect
thiazoline formation from an azido-thiolester in the presence
of an N-Boc-containing substrate (11c) via orthogonal
activation of a nitrogen-containing functionality may be
particularly useful. Entry 4 demonstrates thiazoline formation
in an acid-sensitive substrate related to the apratoxins without
dehydration to a 2-alkenyl-substituted thiazoline or cleavage
a Under standard conditions: Ph3P, THF, 50 °C, reaction time. Yields
are of isolated, chromatographed, and homogeneous products.
of a TES ether. This latter result supports the application of
the S-AW process to thiazoline formation in the context of
a total synthesis of the apratoxins. Progress toward this goal
will be reported in due course.
Acknowledgment. This work was supported by a gener-
ous unrestricted Bristol-Myers Squibb Grant in Synthetic
Organic Chemistry (C.J.F.).
Supporting Information Available: Experimental pro-
cedures and characterization data for the synthesis of 11d
and 12d. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(18) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 1977.
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