A stereospecific elimination to form dehydroamino acids: Synthesis of the phomopsin tripeptide side chain

Full text of DOI:10.1021/ja991037q

6100
J. Am. Chem. Soc. 1999, 121, 6100-6101
Table 1. Dehydroamino Acids from Tertiary Alcohols
A Stereospecific Elimination to Form Dehydroamino
Acids: Synthesis of the Phomopsin Tripeptide Side
Chain
Michelle M. Stohlmeyer, Hiroko Tanaka, and
Thomas J. Wandless*
Department of Chemistry, Stanford UniVersity
Stanford, California 94305-5080
ReceiVed April 1, 1999
An increasing interest in R,â-dehydroamino acids has devel-
oped in recent years based both on their importance as commodity
chemicals and their presence in biologically active natural
products. Efficient methods for the asymmetric hydrogenation of
R,â-dehydroamino acids allow access to a wide variety of un-
natural amino acids.1 Dehydroamino acids are also found in many
natural products including the antrimycins, tentoxin, and the
phosphatase inhibitors microcystin and nodularin.2 Unsaturated
amino acids introduce elements of conformational rigidity as well
as changes in reactivity due to the presence of an alkene.3 In this
report, we describe an efficient and stereoselective method for
the synthesis of R,â-dehydroamino acids from readily available
â-hydroxyamino acids.
These findings grew out of research directed toward the total
synthesis of phomopsin A, which is a fungal metabolite that binds
to microtubules (Chart 1).4 Our synthetic approach required a
a The (2S,3S) substrate was used providing (E) 3.
ineffective. Others have used these methods to synthesize
dehydroisoleucine, and the most efficient method provided a 3:2
mixture of E and Z isomers.6
Chart 1
Enantiomerically pure â-hydroxy-R-amino acids are readily
accessible using Sharpless’ methods,7 and thus we chose dehydra-
tion as our preferred synthetic strategy. We observed that
treatment of an N-acyl-â-hydroxyamino ester with thionyl chloride
led to formation of cyclic sulfamidites. The diastereomeric
products, arising from two configurations at sulfur, were separated
and isolated. Treatment of either diastereomer with base resulted
in elimination of SO2 to yield the R,â-dehydroamino ester
(Scheme 1). The more oxidized cyclic sulfamidates have previ-
method to stereoselectively prepare (E)-dehydroisoleucine. A
variety of methods exist for the synthesis of dehydroamino acids,
and they have been reviewed recently.3c,5 Some of these ap-
proaches introduce unsaturation using elimination reactions such
as the dehydration of â-hydroxyamino acids as well as N-
chlorination followed by dehydrochlorination. Alternative methods
utilize condensation reactions (e.g., the Horner-Wadsworth-
Emmons reaction of phosphorylglycine esters) to form the double
bond. These methods generally rely on thermodynamic control
to dictate the alkene geometry. If there is no strong thermody-
namic preference or if the desired product is not the thermody-
namically favored isomer, the existing synthetic methods are often
Scheme 1
ously been used as substrates for nucleophilic substitution
reactions.8 Recently, direct nucleophilic ring openings of cyclic
sulfamidites derived from amino alcohols have been reported.9
However, neither cyclic sulfamidites nor sulfamidates have been
directly employed as substrates for elimination reactions.
Tertiary alcohols can be difficult to functionalize and stereo-
selectively eliminate due to steric crowding and a propensity to
undergo E1 elimination reactions. In our hands, tosylation and
mesylation of â-hydroxyisoleucine could only be achieved in low
yields, and subsequent elimination reactions led to complex
mixtures of products. However, Table 1 shows the results for the
* To whom correspondence should be addressed. Telephone: (650) 723-
4005. E-mail: wandless@chem.stanford.edu.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley-
Interscience: New York, 1994; pp 16-28. (b) RajanBabu, T. V.; Ayers, T.
A.; Halliday, G. A.; You, K. K.; Calabrese, J. C. J. Org. Chem. 1997, 62,
6012-6028. (c) Nagel, U.; Albrecht, J. Top. Catal. 1998, 5, 3-23.
(2) (a) Templeton, G. E. Microb. Toxins 1972, 8, 160-192. (b) Rich, D.
H.; Bhatnagar, P.; Mathiaparanam, P.; Grant, J. A.; Tam, J. P. J. Org. Chem.
1978, 43, 296-302. (c) Botes, D. P.; Tuinman, A. A.; Wessels, P. L.; Viljoen,
C. C.; Kruger, H.; Williams, D. H.; Santikarn, S.; Smith, R. J.; Hammond, S.
J. J. Chem. Soc., Perkin Trans. 1 1984, 2311-2318. (d) Valentekovich, R. J.;
Schreiber, S. L. J. Am. Chem. Soc. 1995, 117, 9069-9070.
(6) (a) Shin, C.; Yonezawa, Y.; Ikeda, M. Bull. Chem. Soc. Jpn. 1986, 59,
3573-3579. (b) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht,
A.; Mangold, R.; Meyer R.; Riedl, B. Synthesis 1992, 487-490.
(7) (a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538-
7539. (b) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655-
658. (c) Shao, H.; Goodman, M. J. Org. Chem. 1996, 61, 2582-2583.
(8) (a) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J. Tetrahedron:
Asymmetry 1990, 1, 881-884. (b) Alker, D.; Doyle, K. J.; Harwood: L. M.;
McGregor, A. Tetrahedron: Asymmetry 1990, 1, 877-880.
(3) (a) Hagihara, M.; Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber, S.
L. J. Am. Chem. Soc. 1992, 114, 6568-6570. (b) Jain, R.; Chauhan, V. S.
Biopolymers 1996, 40, 105-119. (c) Humphrey, J. M.; Chamberlin, A. R.
Chem. ReV. 1997, 97, 2243-2266.
(4) Mackay, M. F.; Van Donkelaar, A.; Culvenor, C. C. J. J. Chem. Soc.,
Chem. Commun. 1986, 1219-1221.
(9) Gautun, H. S. H.; Carlsen, P. H. J. Tetrahedron: Asymmetry 1995, 6,
1667-1674.
(5) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1988, 159-172.
10.1021/ja991037q CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/10/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 25, 1999 6101
Table 2. Dehydroamino Acids from Secondary Alcohols
steric and electronic characteristics are tolerated on the nitrogen
atom, and entry 8 demonstrates that this method may be used for
dipeptide substrates. The high degree of stereoselectivity is
especially noteworthy in the case of (E)-dehydrophenylalanine
(entry 9).11 Cyclic sulfamidites may also be effectively used to
synthesize dehydroalanine derivatives.12
We used this method to synthesize the tripeptide side chain of
phomopsin A (Scheme 2). The benzyl ester of â-hydroxyisoleu-
Scheme 2
cine (10) was coupled to N-Boc-dehydroproline (11) to provide
dipeptide 12. Formation of the cyclic sulfamidite was followed
by stereoselective elimination to yield the didehydrodipeptide,
which was subsequently protected with Boc anhydride to provide
13. Transfer hydrogenolysis liberated the free carboxylic acid
without reduction of dehydroproline. The carboxylic acid was then
coupled to dimethyl â-hydroxyaspartate (14), and subsequent
dehydration provided the desired protected tripeptide (15), which
will be further elaborated to phomopsin A.
We have developed an efficient and stereospecific method to
synthesize trisubstituted and tetrasubstituted R,â-dehydroamino
acids from â-hydroxyamino acid derivatives. The requisite
substrates are readily available, and high to moderate yields of
the desired dehydroamino acid derivatives are obtained. Cyclic
sulfamidites provide an effective solution to the problem of
stereoselectively synthesizing R,â-dehydroamino acids.
a The Fmoc group was removed and the amine was obtained. b By
using the two-step procedure the cyclic sulfamidite was isolated, but
the intermediate underwent hydrolysis upon treatment with base.
elimination of tertiary â-hydroxyamino esters to â,â-disubstituted
dehydroamino esters via sulfamidite intermediates. This reaction
is highly stereoselective, which facilitates the synthesis of either
the E or Z isomer of dehydroisoleucine depending upon the
configuration of the initial â-hydroxyamino ester (Table 1, entries
3 and 6). Only products derived from antiperiplanar elimination
have been observed, and molecular modeling of both diastereo-
meric sulfamidite intermediates (Table 1, entry 1) reveals H-CR-
Câ-O bond angles of 150-154°.
Acknowledgment. Support has been provided by the NIH (CA-
77317), the Dreyfus Foundation, the Beckman Foundation, and Pharmacia
& Upjohn. M.M.S. acknowledges the National Science Foundation for a
predoctoral fellowship.
Supporting Information Available: Experimental procedures and
characterization data are provided (PDF). This material is provided free
of charge via the Internet at http://pubs.acs.org.
JA991037Q
This method is also suitable for the elimination of secondary
alcohols, and results using threonine and hydroxyphenylalanine
derivatives are shown in Table 2. Preliminary investigations led
to the development of two experimental methods. Using a two-
step procedure, the intermediate sulfamidites are isolated, purified
by chromatography, and then treated with 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU).10 An alternative procedure is a one-pot
protocol that requires an excess of base. Acyl groups with various
(10) Bases other than DBU have been used for the two-step procedure with
similar success. Tetramethylguanidine, 1,5-diazabicyclo[4,3,0]non-5-ene, and
potassium tert-butoxide efficiently convert sulfamidites to the corresponding
alkenes (data not shown).
(11) Excellent yields of (E)-dehydrophenylalanine derivatives may also be
obtained by treating the intermediate cyclic sulfamidite with RuCl3 and NaIO4
to form the cyclic sulfamidate, which stereoselectively provides the desired
product upon treatment with DBU.
(12) Treatment of Cbz-serine-benzyl ester with thionyl chloride using the
one-step procedure provided 74% yield of the R,â-dehydroamino ester.