Novel stereospecific dehydration of β-hydroxy-α-amino acids using Martin's sulfurane

Article abstract of DOI:10.1016/S0040-4039(02)02179-2

The stereospecific dehydration of threo-N-acyl-β-hydroxy-α-amino acid derivatives was performed using Martin's sulfurane to give (Z)-α,β-dehydroamino acids, while erythro-N-acyl-β-hydroxy-α-amino acid amides were converted to 4,5-trans-oxazolines using an

Full text of DOI:10.1016/S0040-4039(02)02179-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8679–8682
Novel stereospecific dehydration of b-hydroxy-a-amino acids
using Martin’s sulfurane
Fumiaki Yokokawa† and Takayuki Shioiri*,‡
Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 26 August 2002; revised 24 September 2002; accepted 27 September 2002
Abstract—The stereospecific dehydration of threo-N-acyl-b-hydroxy-a-amino acid derivatives was performed using Martin’s
sulfurane to give (Z)-a,b-dehydroamino acids, while erythro-N-acyl-b-hydroxy-a-amino acid amides were converted to 4,5-trans-
oxazolines using analogous reaction conditions. © 2002 Elsevier Science Ltd. All rights reserved.
In the preceding communication,1 we described the
novel effective dehydrative elimination of N-acyl
threonine ester using Martin’s sulfurane (diphenyl
bis(1,1,1,3,3,3-hexafluoro-2-phenyl-2-propyl)sulfurane)2
to provide the (Z)-Abu (2-amino-2-butenoic acid) moi-
ety during the total synthesis of somamide A. We have
further investigated the general aspects for the dehydra-
tive reactions of b-hydroxy-a-amino acids using Mar-
tin’s sulfurane. In this paper, we describe the
stereospecific elimination of the threo-b-hydroxy-a-
amino acid derivatives 1 to the dehydroamino acid
derivatives 3 as well as the cyclodehydration to the
4,5-trans-oxazolines
4 from the erythro-N-acyl-b-
hydroxy-a-amino acid amides 2 (Scheme 1).
As shown in Table 1, we initially attempted the dehy-
dration of Boc-(S)-Phe-(S)-Thr-OAllyl (5) using
(diethylamino)sulfur trifluoride (DAST, Et2N-SF3) with
pyridine or triethylamine based on the Shanzer’s
conditions3 to afford Boc-(S)-Phe-(Z)-Abu-OAllyl (6)
in moderate yield (entries 1 and 2). In this reaction, the
elimination of the intermediate ROSF2NEt2 derivative
is likely to be sluggish with pyridine or triethylamine.
Next, we applied two-step procedures that require
DAST-Et3N followed by exposure to 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) to give 6 in higher yield
(entry 3). It is noteworthy that the one-pot reaction of
5 using Martin’s sulfurane without base smoothly
occurred to produce 6 in 86% yield (entry 4). The
dehydration of the threonine amide derivative 7 slug-
gishly proceeded even in the two-step protocol using
DAST to give Boc-(S)-Phe-(Z)-Abu-(S)-Ala-OMe (8)4
in 19% yield (entry 5). In contrast, the one-pot dehydra-
tion using Martin’s sulfurane smoothly afforded 8 in
80% yield (entry 6). The other b-hydroxy-a-amino acid
derivatives including threo-phenylthreonine, serine, and
b-hydroxyvaline effectively underwent the dehydration
to give the a,b-dehydroamino acid derivatives using
Martin’s sulfurane in good to excellent yields (entries
7–10). The noteworthy feature is that the reactions with
Martin’s sulfurane proceeded at room temperature for
1 h.
Scheme 1.
Keywords: stereospecific dehydration; b-hydroxy-a-amino acid; Mar-
tin’s sulfurane; dehydroamino acid; 4,5-trans-oxazoline.
* Corresponding author. Tel./fax: +81-52-832-1555; e-mail: shioiri@
ccmfs.meijo-u.ac.jp
† Present address: Tsukuba Research Institute, Novartis Pharma
K.K., Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
‡ Present address: Graduate School of Environmental and Human
Sciences, Meijo University, Shiogamaguchi, Tempaku, Nagoya 468-
8502, Japan.
Remarkably, the threonine-thiazole moiety 17 was also
smoothly eliminated to give the Thr-Abu-Thz fragment
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02179-2

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F. Yokokawa, T. Shioiri / Tetrahedron Letters 43 (2002) 8679–8682
Table 1. Dehydrative elimination of the N-acyl-b-hydroxy-a-amino acid esters or amides
Scheme 2.
185 of micrococcin P1 using this one-pot method
E (20, 35%) and Z (21, 56%) isomers in the Abu
residues (Scheme 3).
(Scheme 2).6
Unfortunately, the treatment of the N-acyl allo-
threonine ester 19 with Martin’s sulfurane did not lead
to the stereospecific elimination, but gave a mixture of
Interestingly, we observed that the allo-threonine
residues in the peptide sequences could be converted to
the corresponding 4,5-trans-oxazolines without compet-

F. Yokokawa, T. Shioiri / Tetrahedron Letters 43 (2002) 8679–8682
8681
The plausible mechanism for the stereospecificity in this
dehydrative reaction is shown in Scheme 5. The
stereospecific formation of the (Z)-dehydroamino acids
3 from the threo-hydroxy amino acid derivatives 1 will
proceed through the formation of the Martin’s sul-
furane intermediates 30a followed by trans E2 elimina-
tion from the antiperiplanar conformation, while these
threo substrates did not undergo cyclization to the
cis-oxazolines 4a due to the less favorable formation of
the sterically crowded intermediates 30b.
Similarly, the (E)-isomer 3a would be a product
expected to be formed from the erythro substrates 2b if
a trans E2 elimination occurs as in the case of the
reaction of 19 with Martin’s sulfurane (Scheme 3). The
(Z)-isomer 21 formed in this reaction might arise from
isomerization of the thermodynamically less favored
(E)-isomer 20.9 On the other hand, the N-allo-
threonine amides 2a will predominantly undergo
cyclization to give the sterically favored trans-oxazoli-
nes 4 through the intramolecular SN2 attack of the
amide carbonyl groups, because of the lower acidity of
the a-proton in the allo-threonine residues.
Scheme 3.
ing formation of the Abu moiety under the one-pot
Martin’s sulfurane dehydrative conditions.7 As shown
in Table 2, this novel cyclodehydration protocol is
suitable for the various allo-threonine-containing pep-
tides (entries 1, 2). Especially, cyclodehydration of the
cyclic peptide 26 using Martin’s sulfurane provided the
biologically active marine natural product, cis,cis-cer-
atospongamide (27)8 in 81% yield (entry 3).
Furthermore, one of the noteworthy stereospecific fea-
ture of the method was well demonstrated by treatment
of Boc-(S)-Phe-(S)-aThr-(S)-Thr-OMe (28) with Mar-
tin’s sulfurane, causing the oxazoline formation at the
aThr site and the dehydrative elimination at the Thr
site to give the oxazoline-Abu product 29 in excellent
yield (Scheme 4).
In summary, we have demonstrated that Martin’s sul-
furane is a useful reagent for the dehydrative elimina-
tion of threo-b-hydroxy-a-amino acid derivatives and
cyclodehydration of erythro-N-acyl b-hydroxy-a-amino
amides to 4,5-trans-oxazolines. Since Martin’s sul-
furane is a mild and neutral dehydrative agent, this
one-pot protocol would be compatible with a wide
Table 2. Cyclodehydration of the erythro-N-acylthreonine amides with Martin’s sulfurane
Scheme 4.

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F. Yokokawa, T. Shioiri / Tetrahedron Letters 43 (2002) 8679–8682
Scheme 5.
range of functional groups and applicable to the syn-
thesis of natural products.
4. Shin, C.; Yonezawa, Y.; Ikeda, M. Bull. Chem. Soc. Jpn.
1986, 59, 3573–3579.
5. Nakamura, Y.; Shin, C.; Umemura, K.; Yoshimura, J.
Chem. Lett. 1992, 1005–1008.
Acknowledgements
6. Ciufolini et al. performed the synthesis of the Abu-thiazole
fragment in a two-step procedure through tosylation of
threonine hydroxy group and DBU mediated elimination.
See: Ciufolini, M. A.; Shen, Y.-C. Org. Lett. 1999, 1,
1843–1846.
7. For the cyclodehydration of b-hydroxy amides to oxazoli-
nes, see: Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.;
Williams, D. R. Org. Lett. 2000, 2, 1165–1168, and refer-
ences cited therein.
This work was financially supported in part by Grant-
in-Aids from the Uehara Memorial Foundation (to
F.Y.), the Fujisawa Foundation (to F.Y.), and the
Ministry of Education, Science, Sports and Culture,
Japan.
8. (a) Yokokawa, F.; Sameshima, H.; Shioiri, T. Synlett
2001, 986–988; (b) Yokokawa, F.; Sameshima, H.; In, Y.;
Minoura, K.; Ishida, T.; Shioiri, T. Tetrahedron 2002, 58,
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9. (a) Srinivasan, A.; Stephenson, R. W.; Olsen, R. K. J. Org.
Chem. 1977, 42, 2256–2260; (b) Nitz, T. J.; Holt, E. M.;
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