A general asymmetric synthesis of syn- and anti-beta-substituted cysteine and serine derivatives.

Article abstract of DOI:10.1021/jo011172x

A stereodivergent synthetic route has been developed to make the optically pure anti- and syn-beta-substituted cysteine and serine derivatives. In this approach, the key intermediates, > 94% enantiomerically pure cyclic sulfates 3 and aziridines 7, were prepared from alpha,beta-unsaturated esters 1, employing the Sharpless asymmetric dihydroxylation. The high regio- and stereoselective ring-opening reactions of cyclic sulfates and aziridines provided enantiomerically pure beta-substituted cysteine and serine derivatives.

Full text of DOI:10.1021/jo011172x

3514
J . Org. Chem. 2002, 67, 3514-3517
A Gen er a l Asym m etr ic Syn th esis of syn -
a n d a n ti-â-Su bstitu ted Cystein e a n d Ser in e
Der iva tives
Chiyi Xiong, Wei Wang, and Victor J . Hruby*
Department of Chemistry, University of Arizona,
Tucson, Arizona 85721
hruby@u.arizona.edu
Received December 21, 2001
Abstr a ct: A stereodivergent synthetic route has been de-
veloped to make the optically pure anti- and syn-â-sub-
stituted cysteine and serine derivatives. In this approach,
the key intermediates, >94% enantiomerically pure cyclic
sulfates 3 and aziridines 7, were prepared from R,â-unsatur-
ated esters 1, employing the Sharpless asymmetric dihy-
droxylation. The high regio- and stereoselective ring-opening
reactions of cyclic sulfates and aziridines provided enantio-
merically pure â-substituted cysteine and serine derivatives.
F igu r e 1. â-Turn in R-MSH peptide and proposed â-turn
A complete understanding of the stereochemical re-
quirements of side chain groups important in peptide
ligand-receptor/acceptor interactions plays a crucial role
in the rational design of bioactive peptides and their
nonpeptide mimetics. This approach can be realized by
incorporation of conformationally constrained novel amino
acids into a peptide or nonpeptide template.1 Among
novel amino acids, â-substituted cysteines and serines
can play a unique function in peptide conformational
constraints. â-Substituted cysteines, when introduced
into the peptide chain, can constrain the backbone
conformation through the formation of a disulfide bridge,
as well as preserve the respective side chains, which are
important for molecular recognition.2 â-Substituted cys-
teines and serines also can be used as building blocks
for dipeptide â-turn mimetics (Figure 1).3
mimetics.
c[D-Pen-Gly-Phe-D-Pen]-OH),5a andmelanotropin analogues.5b
Introduction of appropriate â-substituted cysteines into
a peptide sequence will preserve the appropriate side
chain orientation and restrict the C-S-S-C dihedral
angle. Hence, there is a need for efficient, stereospecific
synthetic approaches toward these molecules.
Although the synthesis of â-hydroxy amino acids has
been well documented,6 there appears to be no general
stereospecific methodology directed at the synthesis of
â-substituted cysteines. Goodman and co-workers re-
ported the synthesis of R,â-dimethylcysteines and serines,7
but only the anti isomers were accessible with high ee.
Recently, we reported the enantioselective synthesis of
â-phenylcysteine, â-phenyltryptophan, and â-phenylserine
through the ring-opening reaction of 3-phenylaziridine-
2-carboxylic ester.8 We now have further developed this
strategy in the first general asymmetric synthesis of all
four isomers of â-substituted cysteines and serines.
Substituted R,â-unsaturated benzyl esters were the
starting points of the synthesis. R,â-Unsaturated benzyl
esters 1 (Scheme 1) were subjected to Sharpless asym-
metric dihydroxylation in the presence of (DHQ)2PHAL
(AD-mix-R) and methanesulfonamide. The reaction pro-
As part of our R-MSH (melanocyte-stimulating hor-
mones) program, we have identified the core sequence
of R-MSH peptides His-(D/L)Phe-Arg-Trp and found a
â-turn that includes the Phe and Arg residues.4
A
conformationally constrained bicyclic dipeptide mimetic
scaffold (Figure 1) can exist as up to 32 different isomers
with different backbone geometries and side chain ori-
entations, which can provide specific insights into the
bioactive conformation. Furthermore, cysteine and its
â-substituted derivative residues are present in many
peptide/protein sequences having important bioactivities,
including DPDPE, a cyclic enkephalin analogue (H-Tyr-
(5) (a) Mosberg, H. I.; Hurst, R.; Hruby, V. J .; Gee, K.; Yamamura,
H. I.; Galligan, J . J .; Burks, T. F. Proc. Natl. Acad. Sci. U.S.A. 1983,
80, 5871-5874. (b) Hruby, V. J .; Wilkes, B. C.; Cody, W. L.; Sawyer,
T. K.; Hadley, M. E. Pept. Protein Rev. 1984, 3, 1-64.
(6) (a) For a review, see Genet, J .-P. Pure Appl. Chem. 1996, 68,
593-596. (b) Shao, H.; Goodman, M. J . Org. Chem. 1996, 61, 2582-
2583. (c) Laib, T.; Chastanet, J .; Zhu, J . J . Org. Chem. 1998, 63, 1709-
1713. (d) Horikawa, M.; Busch-Petersen, J .; Corey, E. J . Tetrahedron
Lett. 1999, 40, 3843-3846. (e) Panek, J . S.; Masse, C. E. Angew. Chem.,
Intl. Ed. 1999, 38, 1093-1095. (f) Davis, F. A.; Srirajan, V.; Fanelli,
D. L.; Portonovo, P. J . Org. Chem. 2000, 65, 7663-7666. (g) Lubell,
W. D.; J amison, T. F.; Rapoport, H. J . Org. Chem. 1990, 55, 3511-
3522. (h) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1989, 54, 1866-
1875.
* To whom correspondence should be addressed. Phone: (520) 621-
6332. Fax: (520) 621-8407.
(1) Hruby, V. J .; Li, G.; Haskell-Luevano, C.; Shenderovich, M.
Biopolymers, Peptide Science 1997, 43, 219-260.
(2) (a) Hruby, V. J . Life Sci. 1982, 31, 189-199. (b) Kessler, H.
Angew. Chem., Intl. Ed. Engl. 1982, 21, 512-523.
(3) (a) Nagai, U.; Sato, K. Tetrahedron Lett. 1985, 26, 647-650. (b)
Estiarte, M. A.; Rubiralta, M.; Diez, A. J . Org. Chem. 2000, 65, 6992-
6999. (c) Qiu, W.; Gu, X.; Soloshonok, V. A.; Carducci, M. D.; Hruby,
V. J . Tetrahedron Lett. 2001, 42, 145-148. (d) Hanessian, S.; Mc-
Naughton-Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997,
53, 12789-12854.
(4) Hruby, V. J .; Wilkes, B. C.; Hadley, M. E.; Al-Obeidi, F.; Sawyer,
T. K.; Staples, D. J .; deVaux, A. E.; Dym, O.; Castrucci, A. M. L.; Hintz,
M. E.; Riehm, J . P.; Rao, R. J . Med. Chem. 1987, 30, 2126-2130.
(7) Shao, H.; Rueter, J . K.; Goodman, M. J . Org. Chem. 1998, 63,
5240-5244.
(8) Xiong, C.; Wang, W.; Cai, C.; Hruby, V. J . J . Org. Chem. 2002,
67, 1399-1402.
10.1021/jo011172x CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/22/2002

Notes
J . Org. Chem., Vol. 67, No. 10, 2002 3515
Sch em e 1. Syn th esis of a n ti-â-Su bstitu ted Ser in e a n d Cystein e Der iva tives
ceeded smoothly to yield (2R,3S)-diol 2 in high yield and
excellent optical purity (>94% ee).9 The vicinal diol 2 was
then converted to the cyclic sulfite as a mixture of
diastereomers in a 1:1 ratio,10 and the cyclic sulfite was
further oxidized to the cyclic sulfate 3 with RuO4 (NaIO4/
catalytic RuCl3) in acetonitrile and water. Ring-opening
with PPh3 in THF and water to provide the (2R,3S)-â-
alkyl-substituted serine derivatives 6a and 6b. By switch-
ing the Sharpless chiral catalytic ligand to (DHQD)2PHAL
(AD-mix-â), the other anti isomer could be made available
by the same methodologies.
Subsequent aziridine formations were accomplished by
the Staudinger reaction.12 Regioisomers 4c and 5c lead
to the same chiral product 7c, since the hydroxy group
serves as a leaving group in the aziridine formation.
Treatment of 3-phenylaziridine-2-carboxylic ester 7c with
4-methoxybenzylthiol in dichloromethane in the presence
of BF3‚Et2O followed by amino group protection resulted
in (3S,3S)-NR-Βïc-protected â-phenyl cysteine derivative
12 in 67% yield. This ring-opening process occurred
without activating the aziridine ring and was a ste-
reospecific SN2 reaction at the benzylic C-3 position. The
â-phenyl serine derivative was obtained when substrate
7c was stirred at 70 °C with acetic acid for 2 h. The ring
opening proceeded with complete inversion of configura-
tion at C-3 position to give the (2S,3S)-product 13 in 88%
yield.8 The dominant influence of the phenyl group was
demonstrated by the fact that both sulfur and oxygen
reagents gave exclusively C-3 attacks to provide the
R-amino acid derivatives (Scheme 1).
-
reaction of cyclic sulfate 3 in an SN2 fashion with N3
was generally carried out for 2 h at room temperature.
Acidic hydrolysis provided azido esters 4 and 5. In the
case of 3a and 3b, nucleophilic substitution by NaN3
happened exclusively at the R-position of cyclic sulfite 3
with clean inversion of chirality. Since there is competi-
tion of reaction sites between the benzylic and the
R-position in the case of 3c, nucleophilic substitution by
NaN3 gave regioisomers 5c and 4c in a 6:1 â/R ratio,11
1
as determined by H NMR. Reductions of azido esters
4a and 4b were accomplished under neutral conditions
(9) (a) Berrisford, D. J .; Bolm, C.; Sharpless, K. B. Angew. Chem.,
Intl. Ed. Engl. 1995, 34, 1059-1070. (b) Sharpless, K. B.; Amberg,
W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J .; J eong, K. S.; Kwong,
H. L.; Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X. L. J . Org. Chem.
1992, 57, 2768-2771. (c) Amberg, W.; Bennani, Y. L.; Chadha, R. K.;
Crispino, G. A.; Davis, W. D.; Hartung, J .; J eong, K.-S.; Ogino, Y.;
Shibata, T.; Sharpless, K. B. J . Org. Chem. 1993, 58, 844-849. (d)
Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
94, 2483-2547. (e) The enantiomeric excess was evaluated to be >94%
after conversion to products 7a , 7b, and 12, and the limits of the
detection were determined by measurement of the signal-to-noise ratio
in NMR spectra.
(11) (a) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538-
7539. (b) Koskinen, A. M. P.; Karvinen, E. K.; Siirila, J . P. J . Chem.
Soc. Chem. Commun. 1994, 21-22.
(12) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron
1981, 37, 437-472.
(10) (a) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1990, 31,
4317-4320. (b) Lohray, B. B. Synthesis 1992, 11, 1035-1052. (c) Byun,
H. S.; He, L.; Bittman, R. Tetrahedron 2000, 56, 7051-7091.

3516 J . Org. Chem., Vol. 67, No. 10, 2002
Sch em e 2. Retr osyn th esis of syn P r od u cts
Notes
Sch em e 3. P r ep a r a tion of syn -â-P r op yl Cystein e a n d Ser in e Der iva tives
Although the regioselective ring opening of aziridines
with sulfur nucleophiles in the case of â-unsubstituted
or R,â-dimethyl aziridine-2-carboxylate has been docu-
mented,7,13 there are only limited examples of results on
more general C-3-substituted aziridine 2-carboxylates.
Since nonactivated alkyl-substituted aziridines did not
react using previously reported ring-opening reaction
conditions,14 aziridines 9 bearing electron-withdrawing
groups such as Cbz (benzyloxycarbonyl) on the nitrogen
were used. In the case of 9a , a sulfur nucleophile with
the aid of boron trifluoride etherate gave an exclusive
C-3 attack to provide the â-propyl cysteine 10a in 65%
yield. The regiochemistry was confirmed by 1H NMR
analysis: the signal for the proton R to the ester group
was a doublet and doublet; thus, the amido group was
in the R-position. However, the 3-isopropyl aziridine
2-carboxylate 9b provided a 2:1 mixture of products of
C-3 and C-2 attack. It was obvious that the steric bulk
presented by 3-substitution has great influence on the
regioselectivity of the aziridine ring-opening reaction. The
behavior of related â,â-disubstituted aziridine-2-carboxy-
lates is under investigation.
fundamental weakness of the Sharpless AD reaction was
revealed when route A was examined: we found that this
reaction is not sufficiently stereoselective to be syntheti-
cally useful when (Z)-alkenes are used as substrates. The
highest ee so far observed is ca. 80% with (Z)-alkenes.15
In route B, manipulating the configuration of the R-posi-
tion seemed to be a practical way to provide the syn
isomer through the formation of a syn-azido alcohol and
a syn-aziridine.
To make the syn product, we first used LiBr to ring
open the sulfate 3a , followed by a second SN2 nucleo-
philic substitution at the R-position with NaN3 in acetone
-
and water or with NaN3 and 50 mol % n-Bu4+HSO4 in
CH2Cl2 to obtain the desired stereochemistry at the
R-position. However, the NMR spectrum of the crude
product showed it to be a mixture of the epoxide and C-2
diastereomers. We solved this problem by adding NaN3
(2.0 equiv) in DMSO at room temperature to the bromide
14, and this reaction condition led to smooth SN2 dis-
placement of the bromide by the azide to provide the syn-
azido alcohol 15 in good yield (Scheme 3). The stereo-
chemistry of the product was confirmed by comparing 1H
NMR spectra with that of the anti product. In general,
any system that has a potentially nucleophilic substitu-
ent group situated properly for backside displacement of
There are several possibilities to consider for asym-
metric synthesis of the syn isomers of â-substituted
serine and cysteine derivatives (Scheme 2). However, a
(13) Shao, H.; Goodman, M. J . Org. Chem. 1995, 60, 790-791.
(14) (a) Legters, J .; Willems, J . G. H.; Thijs, L.; Zwaneburg, B. Recl.
Trav. Chim. Pays-Bas 1992, 111, 59-68. (b) Mulzer, J .; Becker, R.;
Brunner, E. J . Am. Chem. Soc. 1989, 111, 7500-7504.
(15) (a) Wang, L.; Sharpless, K. B. J . Am. Chem. Soc. 1992, 114,
7568-7570. (b) Fuji, K.; Tanaka, K.; Miyamoto, H. Tetrahedron Lett.
1992, 33, 4021-4024. (c) Hanessian, S.; Meffre, P.; Girard, M.;
Beaudoin, S.; Sanceau, J .-V.; Bennani, Y. J . Org. Chem. 1993, 58, 1991

Notes
J . Org. Chem., Vol. 67, No. 10, 2002 3517
8b, and 18 indicated that enantiopure materials were
produced from the Sharpless asymmetric dihydroxylation
and in subsequent transformations. Hence, aziridine 7a ,
serine derivative 6a , and cysteine derivative 10a are
presumed to be of >94% enantiomeric purity; aziridine
7b, serine derivative 6b, and cysteine derivatives 10b
and 11b are presumed to be of >97% enantiomeric purity,
and aziridine 16, serine derivative 20, and cysteine
derivative 19 are presumed to be of >94% enantiomeric
purity.
The transformation of phenyl-substituted aziridine 7c
to the Mosher amide failed because of the concomitant
ring-opening reaction. The enantiomeric purity of aziri-
dine 7c was determined to be >96% by evaluation of 12,
which is the ring-opening reaction product of 7c.17
In summary, a general and practical new pathway to
the synthesis of both anti- and syn-â-substituted serine
and cysteine derivatives has been developed. A key step
involving regio- and stereoselective ring-opening reac-
tions of cyclic sulfate 3 and aziridines 9 and 17 has been
thoroughly investigated. Incorporation of the amino acids
into biologically active R-MSH peptides and peptidomi-
metics, biological evaluation, and structure-biological
activity relationship studies of the bioactive peptides and
peptidomimetics are in progress.
F igu r e 2. Coupling constants of syn- and anti-aziridines 9a
and 17 in 1H NMR.
a leaving group at another carbon atom of the molecule
can be expected to display neighboring-group participa-
tion. There will always be competition between direct SN2
displacement by an external nucleophile and neighbor-
ing-group participation of an internal nucleophile. The
extent of the rate enhancement will depend on how
effectively the groups act as nucleophiles in different
solvents and the ease with which the molecular geometry
required for participation can be achieved.7 Alcohol 15
was subjected to the reaction conditions previously
described to provide the syn-â-propylserine ester 20 or
syn-â-propyl aziridine 16. Figure 2 shows the coupling
1
pattern in the H NMR spectra of trans-aziridine 9a and
cis-aziridine 17. The coupling constants between Ha and
Hb and those between H′a and H′b confirmed that the
desired stereochemistry was formed.16 Aziridine 16 was
converted to the syn-â-propylcysteine derivative 19
(Scheme 3) using reaction conditions described in Scheme
1 for the preparation of 10a .
Ack n ow led gm en t. This work was supported by US
Public Health Service (DK 17420) and the National
Institute of Drug Abuse (DA 13449). We thank Professor
Dominic V. McGrath for use of his group’s polarimeter.
The configurational integrity of both the syn- and anti-
alkylsubstituted aziridine series 7a , 7b, and 16 was
evaluated after conversion to the corresponding diaster-
eomeric amide (1*R)- and (1*S)-8a , 8b, and 18 as shown
in Schemes 1 and 3. Aziridines 7a , 7b, and 16 were
coupled with (R)- and (S)-Mosher’s agents, respectively,
to give amides, which were directly examined in 19F NMR
spectroscopy using CFCl3 as the internal reference
(-178.00 ppm). Measurements of the diastereomeric
trifluoromethyl singlets at -70.32 and -71.12 ppm for
8a , -71.30 and -70.23 ppm for 8b, and -71.33 and
-71.07 ppm for 18 demonstrated amides 8a , 8b, and 18
to be of >94%, >97%, and >94% diasteromeric excesses,
respectively. The high diasteromeric purity of amides 8a ,
Note Ad d ed After ASAP P ostin g. All experimental
details were removed from the version posted March 22,
2002, and transferred to Supporting Information. The
new version was posted April 16, 2002.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra and experimental details for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O011172X
(17) Specifically, the deprotection of Boc in 12 and its enantiomer
gave a free amine, which was coupled with (S)-(-)-R-methoxyl-R-
trifluoromethyl phenylacetic chloride (Mosher’s agent) to afford the
amides. Measurement of the diastereomeric methyl singlets at 3.35
and 3.28 ppm in proton NMR spectroscopy in CDCl3 demonstrated the
amides to be of >96% diastereomeric excess (the limits of detection
were determined by measurement of the signal-to-noise ratio in NMR
spectra; in each case, the signal-to-noise ratio was 90:1 and the minor
product peak was not observed). Hence, amino acid 12 and its
enantiomer are all presumed to be of a >96% enantiomeric excess.
(16) (a) Bottini, A. T.; VanEtten, R. L.; Davidson, A. J . J . Am. Chem.
Soc. 1965, 87, 755-757. (b) Lwowski, W.; McConaghy, J . S., J r. J . Am.
Chem. Soc. 1967, 89, 2357-2364. (c) Nagel, D. L.; Woller, P. B.;
Cromwell, N. H. J . Org. Chem. 1971, 36, 3911-3917. (d) Cardillo, G.;
Gentilucci, L.; Tolomelli, A.; Tomasini, C. J . Org. Chem. 1998, 63,
3458-3462.