SN2 reaction of sulfur nucleophiles with hindered sulfamidates: Enantioselective synthesis of α-methylisocysteine

Article abstract of DOI:10.1021/jo051632c

The work described here demonstrates that the five-membered cyclic α-methylisoserine-derived sulfamidate, (R)-1, behaves as an excellent chiral building block for the ring-opening reaction by S2 attack with sulfur nucleophiles at the quaternary carbon. As

Full text of DOI:10.1021/jo051632c

SN2 Reaction of Sulfur Nucleophiles with
Hindered Sulfamidates: Enantioselective
Synthesis of r-Methylisocysteine
Alberto Avenoza,* Jesu´s H. Busto,
Gonzalo Jime´nez-Ose´s, and Jesu´s M. Peregrina*
FIGURE 1. SN2 reaction on cyclic sulfamidate (R)-1.
Departamento de Qu´ımica, UniVersidad de La Rioja, Grupo de
S´ıntesis Qu´ımica de La Rioja, U.A.-C.S.I.C.,
E-26006 Logron˜o, Spain
secondary structures than their natural counterparts, â peptides
have been the subject of extensive investigation. In addition to
the numerous secondary structures that have been identified, â
peptides have also displayed interesting biological properties.
These features have made the field of â-amino acids a matter
of constant interest.6 Particularly attractive are the â- or
R-substituted â-amino acids (â3- or â2-amino acids), because
these substituents favor folded conformations in â peptides.6c,7
For this reason, several approaches have been described to
prepare these amino acids, although very few routes have been
reported for chiral R,R-disubstituted â-amino acids (â2,2-amino
acids).8 Accordingly, the development of practical methods for
the synthesis of â-amino acids bearing a chiral quaternary center
in the R position would be especially important.9
alberto.aVenoza@dq.unirioja.es
ReceiVed August 4, 2005
The work described here demonstrates that the five-
membered cyclic R-methylisoserine-derived sulfamidate, (R)-
1, behaves as an excellent chiral building block for the ring-
opening reaction by SN2 attack with sulfur nucleophiles at
the quaternary carbon. As a synthetic application of this
methodology, and to show that this sulfamidate is a valuable
starting material, the synthesis of two new R-methylisocys-
teine derivatives has been carried out to cover the lack of
R- and â-methylated amino acids that incorporate the cysteine
or isocysteine skeleton. These compounds are two new R,R-
disubstituted â-amino acids (â2,2-amino acids), and the
synthetic routes involve nucleophilic ring opening followed
by acid hydrolysis.
Bearing these facts in mind, we focused our attention on the
five-membered cyclic R-methylisoserine-derived sulfamidate
(R)-1 (Figure 1) as an excellent chiral building block for the
synthesis of R-methylated â-amino acids by nucleophilic ring-
opening reactions. In this sense, we recently communicated a
synthetic approach to a varied collection of â-amino acids,
namely, â2,2-amino acids and unsaturated â-amino acids, by
opening the mentioned sulfamidate with C, N, and O nucleo-
philes.10
Although the synthesis and reactivity of several sulfamidates
have been described in detail, in all cases, these compounds
were monosubstituted or R,â-disubstituted.1,2,11 In contrast, little
is known about hindered sulfamidates.12 On this basis, and
(3) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547. (b) Berrisford, D. J.; Bolm, C.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1059-1070. (c) Johnson, R. A.;
Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH
Publishers: New York, 1993; pp 227-272.
(4) (a) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744-
4745. (b) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135-
6141. (c) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973,
38, 26-31.
(5) (a) Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian,
A. Z.; Huang, X. Chem.sEur. J. 2004, 10, 5581-5606. (b) Nicolaou, K.
C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy, M. V. Angew.
Chem., Int. Ed. 2002, 41, 834-838.
(6) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219-3232. (b) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-
8035. (c) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVersity
2004, 1, 1111-1239. (d) Seebach, D.; Kimmerlin, T.; Sebesta, R.; Campo,
M. A.; Beck A. K. Tetrahedron 2004, 60, 7455-7506. (e) Kimmerlin, T.;
Seebach, D. J. Peptide Res. 2005, 65, 229-260. (f) Enantioselective
Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
(g) Huck, B. R.; Gellman, S. H. J. Org. Chem. 2005, 70, 3353-3362. (h)
Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M. I. Curr.
Med. Chem. 2002, 9, 811-822.
The important roles that cyclic sulfamidates have played in
organic synthesis, as well as the recent developments in their
chemistry, have made the synthesis and reactivity of these
systems the subject of a recent review.1 Moreover, this subject
has already been analyzed in the context of a review of their
analogues: cyclic sulfate derivatives.2 In particular, the five-
membered cyclic sulfamidates have been the most widely
described sulfamidate systems. These compounds have been
extensively used as reactive intermediates in organic synthesis
because most intermolecular ring-opening reactions of cyclic
sulfamidates with nucleophiles proceed by the SN2 pathway with
total inversion at the stereogenic center.1 Furthermore, the most
direct method to obtain five-membered cyclic sulfamidates has
been the use of the â-amino alcohol and sulfuryl chloride,1 a
protocol that involves the catalytic asymmetric dihydroxylation
reaction,3 followed by treatment of the corresponding 1,2-diol
with a Burgess-type reagent.4 This approach has contributed to
the expansion of the chemistry of these compounds.5
(7) (a) Seebach, D.; Abele, S.; Gademann, K.; Guichard, G.; Hintermann,
T.; Jaun, B.; Matthews, J. L.; Schreiber, J. V.; Oberer, L.; Hommel, U.;
Widmer, H. HelV. Chim. Acta 1998, 81, 932-982. (b) Martinek, T. A.;
Fu¨lo¨p, F. Eur. J. Biochem. 2003, 270, 3657-3666. (d) Sandvoss, L. M.;
Carlson, H. A. J. Am. Chem. Soc. 2003, 125, 15855-15862.
(8) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1-15.
On the other hand, since Seebach and co-workers discovered
that short chains of â-amino acids generally form more stable
* To whom correspondence should be addressed. Fax: +34 941 299655.
(1) Mele´ndez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581-2616.
(2) Bittman, R.; Byun, H.-S.; He, L. Tetrahedron 2000, 56, 7051-7091.
(9) Quaternary Stereocenters: Challenges for Organic Synthesis; Baro,
A., Christoffers, J., Eds.; Wiley: New York, 2005.
10.1021/jo051632c CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/13/2006
1692
J. Org. Chem. 2006, 71, 1692-1695

considering that several synthetic reviews of quaternary carbon
centers in a stereoselective fashion have been carried out in
recent years,13 we decided to undertake an in-depth study into
the behavior of the five-membered cyclic sulfamidate (R)-1. In
this compound, the quaternary carbon center is activated for
nucleophilic displacement, and the reactivity with several sulfur
nucleophiles (S nucleophiles) in the SN2 reaction was explored
(Figure 1).
FIGURE 2. Mercapto amino acids and their R- and â-methylated
derivatives.
Significant â-amino acids such as R-methylisocysteine and
S-phenyl-R-methylisocysteine were selected to prove the ap-
plicability of the methodology presented here, that is, the SN2
reaction of cyclic sulfamidate (R)-1, followed by acid hydrolysis,
for the synthesis of â2,2-amino acids as a result of the
significance that some amino acid analogues have attained in
recent years. For example, a large number of studies have
focused on S-phenyl-L-cysteine as a biological marker of human
exposure to benzene.14 Moreover, amino acids bearing a thiol
group appear to be particularly valuable for the generation of
disulfide bridges and, therefore, are capable of generating
restrictions in the peptide backbone.15 â-Methylcysteine has been
used to synthesize glutathione (GSH) analogues, which have
been designed as potential glyoxalase I inhibitors.16 Several
syntheses of R-methylcysteine17 have been reported, and once
again, GSH analogues incorporating both enantiomers of this
amino acid have recently been synthesized.18 Moreover, the total
synthesis of halipeptin A, a potent anti-inflammatory cyclic
depsipeptide that incorporates an R-methylcysteine derivative
unit, was recently achieved by Ma and co-workers.19
synthesized in enantiomerically pure forms by the ring opening
of (2S,3S)-3-methyl-2-aziridinecarboxylic acid.23 Bearing in
mind the crucial role played by the 3-hydroxyl function of
â-phenylisoserine in taxol, the synthesis of analogues containing
the R-thiol function has also been developed.24
In summary, with regard to the R-amino acid cysteine and
the â-amino acid isocysteine, as well as their R- and â-meth-
ylated series (Figure 2), all compounds or derivatives of them
have been previously synthesized in enantiomerically pure
forms, except for R-methylisocysteine. In an effort to cover this
gap, we report here the enantioselective synthesis of this new
â
2,2-amino acid isocysteine derivative. To the best of our
knowledge, only two racemic syntheses of a â2,2-amino acid
incorporating the isocysteine skeleton have been reported in the
literature and these concerned R-methyl-â-phenylisocysteine25
and N-tosyl-R-methylisocysteine derivatives.26
As mentioned above,10 a very short methodology to obtain
enantiomerically pure (R)-1 was used, and this involved using
the recent method reported by Nicolaou and co-workers5 to
synthesize regio- and stereoselective sulfamidates from chiral
1,2-diols using Burgess’ reagent. The nucleophilic ring opening
of sulfamidate (R)-1 was examined using several S nucleophiles
(Table 1). In our procedure, sulfamidate (R)-1 (1.00 equiv) and
the S nucleophile (1.05 or 1.10 equiv, dependent on the method)
were heated in DMF at 50 °C for 1 h, and the sulfamic acid
intermediate was hydrolyzed in an acid medium. The use of
the corresponding method in each case was dependent on the S
nucleophile and on the lability of the functional groups. Indeed,
with sulfur anion derivatives as S nucleophiles, methods A1 or
A2 (absence of base) were selected, while with thiols as S
nucleophiles, DBU was added as a base to deprotonate the SH
group (methods B1 or B2). On the other hand, methods A1 or
B1 (20% H2SO4) were used to hydrolyze the sulfamic acid
intermediate when functional groups that are resistant to acid
hydrolysis are present in the molecule. By contrast, when the
molecule incorporates functional groups that are sensitive to
acid media, methods A2 or B2 (1 M NaH2PO4) were preferred
(Table 1).
As far as isocysteine and its derivatives are concerned, various
syntheses have been reported in the literature,20 and the
replacement of cysteine with this compound in a specific
peptidic sequence generates potent peptide inhibitors of stromely-
sin.21 Moreover, suitably protected isocysteine-based building
blocks have been used to provide convenient access to isocys-
teinyl peptides.22 â-Methylisocysteine derivatives have been
(10) Avenoza, A.; Busto, J. H.; Corzana, F.; Jime´nez-Ose´s, G.; Peregrina,
J. M. Chem. Commun. 2004, 980-981.
(11) (a) Bower, J. F.; Svenda, J.; Williams, A. J.; Charmant, J. P. H.;
Lawrence, R. M.; Szeto, P.; Gallagher, T. Org. Lett. 2004, 6, 4727-4730.
(b) Williams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R. M.; Gallagher,
T. Org. Lett. 2003, 5, 811-814.
(12) Posakony, J. J.; Tewson, T. J. Synthesis 2002, 859-864.
(13) (a) Martin, S. F. Tetrahedron 1980, 36, 419-460. (b) Fuji, K. Chem.
ReV. 1993, 93, 2037-2066. (c) Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388-401. (d) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105-10146. (e) Kimura, M.; Yamazaki, T.;
Kitazume, T.; Kubota, T. Org. Lett. 2004, 6, 4651-4654.
(14) Rooseboom, M.; Vermeulen, N. P.; Durgut, F.; Commandeur, J.
N. Chem. Res. Toxicol. 2002, 15, 1610-1618.
(15) Hruby, V. J.; Al-Obeidi, F.; Kazmierski, W. Biochem. J. 1990, 268,
249-262.
(16) (a) Xie, X.; Creighton, D. J. Biochem. Biophys. Res. Commun. 1991,
177, 252-258. (b) Lucente, G.; Luisi, G.; Pinnen, F. Il Farmaco 1998, 53,
721-735.
(17) (a) Parsons, R. L.; Heathcock, C. H. J. Org. Chem. 1994, 59, 4733-
4734. (b) Boyce, R. J.; Mulqueen, G. C.; Pattenden, G. Tetrahedron Lett.
1994, 35, 5705-5708. (c) Groth, U.; Scho¨llkopf, U. Synthesis 1983, 37-
38. (d) Mulqueen, G. C.; Pattenden, G.; Whiting, D. A. Tetrahedron 1993,
49, 5359-5364. (e) Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron
Lett. 1995, 36, 3639-3642. (f) Shao, H.; Zhu, Q.; Goodman, M. J. Org.
Chem. 1995, 60, 790-791.
(18) Leplawy, T., Jr.; Slomczynska, U.; Leplawy, M. T.; Marshall, G.
R. In Pept., Proc. Eur. Symp. 21st 1990; Giralt, E., Andreu, D., Eds.;
ESCOM Sci.: Leiden, The Netherlands, 1991; p 285.
All of the S nucleophiles used were commercially available.
In a previous study10 we observed that the SN2 reaction
progresses satisfactorily when a simple S nucleophile (sodium
methanethiolate) was used to give compound (S)-16 in 93%
yield. To explore the scope of the hindered sulfamidate (R)-1
in the ring-opening with different S nucleophiles, we initially
(21) Fotouhi, N.; Lugo, A.; Visnick, M.; Lusch, L.; Walsky, R.; Coffey,
J. W.; Hanglow, A. C. J. Biol. Chem. 1994, 269, 30227-30231.
(22) Dose, C.; Seitz, O. Org. Biomol. Chem. 2004, 2, 59-65.
(23) Hata, Y.; Watanabe, M. Tetrahedron 1987, 43, 3881-3888.
(24) Lee, S.-H.; Qi, X.; Yoon, J.; Nakamura, K.; Lee, Y.-S. Tetrahedron
2002, 58, 2777-2782.
(25) Stefanovic, G.; Stojiljkovic, A.; Stefanovic, M. Tetrahedron 1962,
18, 413-418.
(26) Burgaud, B. G. M.; Horwell, D. C.; Padova, A.; Pritchard, M. C.
Tetrahedron 1996, 52, 13035-13050.
(19) Yu, S.; Pan, X.; Lin, X.; Ma, D. Angew. Chem., Int. Ed. 2005, 44,
135-138.
(20) (a) Gustavson, L. M.; Srinivasan, A. Synth. Commun. 1991, 21,
221-225. (b) Pires, R.; Burger, K. Tetrahedron Lett. 1996, 37, 8159-
8160.
J. Org. Chem, Vol. 71, No. 4, 2006 1693

TABLE 1. SN2 Reaction of Cyclic Sulfamidate (R)-1 with Different
S Nucleophiles
2-methyl-2-propanethiolate, and triphenylmethanethiol, sul-
famidate (R)-1 and the S nucleophiles gave compounds (S)-12
(91%) and (S)-13 (86%), respectively, in very good yields. To
the best of our knowledge, these reactions constitute the first
examples of SN2 reactions on quaternary carbons with highly
hindered S nucleophiles.27 The investigation of aromatic thiols
as S nucleophiles was explored using sodium thiophenolate and
two other ortho-substituted aromatic thiols, one of which has a
donor substituent (2-methoxybenzenethiol) and the other an
electron-withdrawing group [2-(trifluoromethyl)benzenethiol].
The opening products (S)-4, (S)-5, and (S)-6, respectively, were
again obtained with excellent yields (94 to 98%). Finally, other
types of S nucleophiles were tested (potassium thioacetate and
ammonium thiocyanate), and these gave compounds (S)-2 and
(S)-3, respectively, in good yields (97 and 84%). It is important
to highlight that, in all of the cases explored for the reaction of
sulfamidate (R)-1 with S nucleophiles, elimination products were
not detected.
The stereochemical assignment of the opening products was
supported by X-ray analysis of the corresponding monocrystals
of compound (S)-2 (Table 1), which were obtained by the slow
evaporation of an ethyl ether/hexane solution.
The enantiomeric purity of the starting material, (R)-1, was
1
determined by H NMR spectroscopy using a europium(III)
chelate as a chiral shift reagent (93% ee). Different chemical
shifts for the methyl carbamate protons were observed when a
0.12 molar ratio of Eu(hfc)3/substrate (hfc ) 3-(heptafluoro-
propyl-hydroxymethylene)-D-camphorate) and a concentration
of 0.1 mmol/mL substrate in deuterated chloroform at 22 °C
were used. Indeed, we prepared a mixture [56.5% (R)-1 + 43.5%
(S)-1] without Eu(hfc)3, and this showed a singlet centered at
3.42 ppm, corresponding to the methyl carbamate, while the
same mixture with Eu(hfc)3 showed two singlets, one centered
at 3.93 ppm (S-isomer) and the other at 3.96 ppm (R-isomer)
as a result of splitting by the action of Eu(hfc)3. In a similar
way, to determine the enantiomeric purity of the opening
products, compound (S)-4 was selected as a reference com-
pound, showing a 93% ee. This compound shows a splitting of
the NH proton at 6.05 and 6.35 ppm when a 0.15 molar ratio
of Eu(hfc)3/substrate and a concentration of 0.1 mmol/mL
substrate in deuterated chloroform at 22 °C were used. In the
selected case, the enantiomeric purity of the corresponding
product was, therefore, similar to that described for starting
material (R)-1. We were unable to determine the enantiomeric
ratio of the opening products using GC-MS with R-, â-, or
γ-DEX chiral capillary columns because the separation of the
two enantiomers could not be achieved after testing several sets
of conditions on different products.
a Method A1: (i) S nucleophile (1.05 equiv), DMF, 50 °C, 1 h; (ii) 20%
H2SO4 (aq)/CH2Cl2 (1:1), rt, 8 h. Method A2: (i) S nucleophile (1.05 equiv),
DMF, 50 °C, 1 h; (ii) 1 M NaH2PO4 (aq)/CH2Cl2 (1:1), 2 h. Method B1:
(i) S nucleophile (1.10 equiv), DBU (1.05 equiv), DMF, 50 °C, 1 h; (ii)
20% H2SO4 (aq)/CH2Cl2 (1:1), rt, 8 h. Method B2: (i) S nucleophile (1.10
equiv), DBU (1.05 equiv), DMF, 50 °C, 1 h; (ii) 1 M NaH2PO4 (aq)/CH2Cl2
(1:1), rt, 2 h. b We have unambiguously determined the absolute configu-
ration of compounds 2, 4, 12, 13, and 15 by derivatization and X-ray
analysis. However, because we have not found scientific evidence of
absolute configurations in the case of other products, we have assumed
that they are the same as those cited above for their parent compounds.
c Measured after column chromatography. d The mixture of compounds 11a
and 11b corresponds to the diastereomers (S,S)-11 and (R,S)-11, which could
not be separated by column chromatography. e Reference 10.
To confirm that the nucleophilic displacement on the qua-
ternary carbon of sulfamidate (R)-1 corresponds to a second-
order process, we developed a kinetic study for the ring-opening
reaction of sulfamidate (R)-1 with potassium thioacetate as the
nucleophile. The rate of this opening reaction was determined
by 1H NMR analysis, with the reaction carried out in an NMR
tube at room temperature in DMF-d7. The initial concentrations
of the reagents (R)-1 and potassium thioacetate were 0.101 M.
attempted the SN2 reaction with primary alkanethiols in which
the chain size increased gradually: 1-butanethiol, 4-sulfanyl-
1-butanol, 1-octanethiol, and 4-(methoxyphenyl)methanethiol to
give compounds (S)-8, (S)-9, (S)-10, and (S)-15, respectively,
in excellent yields (94 to 99%).
Moreover, we did not encounter any problems regarding other
functional groups present in the S nucleophiles, such as alcohols
[see compound (S)-9]. Similarly, when secondary alkanethiols
were used as nucleophiles (sodium 2-propanethiolate, 2-butane-
thiol, and cyclohexanethiol), the SN2 reaction on the quaternary
center of the sulfamidate gave excellent yields (94 to 96%) of
the following products: (S)-7, 11a,b, and (S)-14, respectively.
Surprisingly, in the same opening reactions with highly
hindered reagents, for example, tertiary alkanethiols, sodium
1
The H NMR experiments were monitored every minute over
30 min, at which time the conversion level was 81% (Figure
3).
(27) We have carried out kinetic studies using different concentrations
of Ph3CS- as a nucleophile, showing that this reaction follows a second-
order process (see Supporting Information).
1694 J. Org. Chem., Vol. 71, No. 4, 2006

SCHEME 2. Determination of the Absolute Configuration of
(S)-17a
a (a): (i) AcCl, MeOH, reflux, 10 h; (ii) N-(tosyl)phenylalaninyl chloride,
DIEA, CH2Cl2, 25 °C, 14 h, 88%.
In conclusion, we present a simple methodology to obtain
two new classes of enantipure â2,2-amino acids with a methyl-
containing quaternary carbon center: R-methylisocysteine and
its S-phenyl derivative. The route starts with the ring opening
of a cyclic R-methylisoserine-derived sulfamidate, which be-
haves as an excellent chiral building block for the SN2 reaction
with sulfur nucleophiles.
FIGURE 3. Kinetic study of the opening reaction of sulfamidate (R)-1
with potassium thioacetate.
SCHEME 1a
Experimental Section
Experimental Procedure for the SN2 Reaction of (R)-1 with
4-(Methoxyphenyl)methanethiol. The sulfamidate (R)-1 (1.54 g,
5.45 mmol), DBU (0.88 mL, 5.72 mmol), and 4-(methoxyphenyl)-
methanethiol (0.93 mL, 5.98 mmol) were heated in DMF (20 mL)
at 50 °C for 1 h, until the consumption of the sulfamidate was
observed by TLC and/or GC-MS. The solution was then cooled,
the solvent removed, and the residue dissolved into a mixture of
aqueous 10% H2SO4/CH2Cl2 (1:1), which was stirred for 8 h at
room temperature. The aqueous layer was successively extracted
with EtAcO (2 × 20 mL), dried over Na2SO4, and concentrated,
and the crude product was chromatographed on silica gel (hexane/
a (a): (i) 6 M HCl, reflux, 12 h; (ii) propylene oxide/EtOH (3:1), 70 °C,
2 h, 89%. (b): 12 M HCl, reflux, 12 h, 63% (from 2), 71% (from 12), 88%
(from 13), 91% (from 15).
EtAcO, 7:3) to give 1.97 g of (S)-15 as a colorless oil. Yield: 99%.
1
[R]25 -14.3° (c 1.84, CHCl3). H NMR (CDCl3, 300 MHz): δ
D
We analyzed the experiments by monitoring the disappear-
ance of the signal at 1.89 ppm, corresponding to the quaternary
methyl of (R)-1, and the appearance of the signal at 1.69 ppm,
corresponding to the quaternary methyl of the sulfamic acid
intermediate (S)-2-sul (denoted with circles in Figure 3). The
second-order kinetics were determined from the observed
linearity in the representation of 1/[A] - 1/[A0] versus the
reaction time in minutes.28 As a result, the slope of this plot
gives a second-order rate constant (k) value of 1.399 M-1 min-1
(Figure 3).
Furthermore, we demonstrated the synthetic utility of sul-
famidate (R)-1 as an excellent chiral building block by carrying
out the synthesis of two new â2,2-amino acids, R-methyliso-
cysteine derivatives (S)-17 and (S)-18, by means of an acid
hydrolysis of opening products (S)-4, (S)-2, (S)-12, (S)-13, and
(S)-15 (Scheme 1). In particular, and as a suggestion of the
referees, in the last case we have enlarged the reaction scale by
five times; therefore, we carried out the SN2 reaction of 5.45
mmol of sulfamidate (R)-1 with 4-(methoxyphenyl)methanethiol
to generate the opening product (S)-15, which was hydrolyzed
to R-methylisocysteine hydrochloride (S)-18 with an excellent
yield of 91%.
1.58 (s, 3H), 3.22 (s, 3H), 3.53-3.82 (m, 13H), 5.38 (br t, 1H),
6.81 (d, 2H, J ) 8.5 Hz), 7.18 (d, 2H, J ) 8.5 Hz). 13C NMR
(CDCl3, 300 MHz): δ 20.1, 33.2, 33.8, 48.7, 51.8, 52.2, 55.0, 60.5,
113.7, 128.8, 129.9, 157.2, 158.5, 172.2. ESI+ (m/z): 357.4. Anal.
Calcd. for C16H24N2O5S: C, 53.91; H, 6.79; N, 7.86; S, 9.00.
Found: C, 53.87; H, 6.77; N, 7.83; S, 8.94.
Experimental Procedure for the Synthesis of (S)-r-Methyl-
isocysteine Hydrochloride (S)-18. Compound (S)-15 (1.97 g, 5.50
mmol) was suspended in an aqueous solution of 12 M HCl (10
mL), and the mixture was heated under reflux for 12 h. The solvent
was removed, and the residue was dissolved in H2O. After washing
this solution with EtAcO, it was basified by the dropwise addition
of 10% NaOH. Toluene was then added, and the mixture was
concentrated. This operation was repeated several times until the
disappearance of methoxymethylamine was observed (followed by
1H NMR). An aqueous solution of 6 M HCl was then added to the
mixture, the resulting solution was completely evaporated, and
ethanol was added. This solution was filtered and evaporated to
give 851 mg (4.99 mmol) of (S)-R-methylisocysteine as a hydro-
chloride derivative (S)-18 (white solid). Yield: 91%. [R]25D -10.4°
(c 1.00, H2O). 1H NMR (D2O, 300 MHz): δ 1.60 (s, 3H), 3.30 (d,
1H, J ) 13.6 Hz), 3.45 (d, 1H, J ) 13.6 Hz). 13C NMR (D2O, 300
MHz): δ 24.2, 46.7, 47.9, 176.0. ESI+ (m/z): 172.6. Anal. Calcd.
for C4H10ClNO2S: C, 27.99; H, 5.87; N, 8.16; S, 18.68. Found:
C, 28.06; H, 5.89; N, 8.19; S, 18.75.
Additionally, the absolute configuration of R-methylisocys-
teine derivative (S)-17 was unambiguously determined by the
transformation of the methyl ester derivative of this â2,2-amino
acid, obtained by esterification with acetyl chloride in MeOH,
into the dipeptide 19, a chiral derivative with two stereogenic
centers, whose absolute configuration was found to be (S,S) by
X-ray analysis (Scheme 2).
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (project CTQ2005-06235/BQU and Ramon y Cajal
contract of J.H.B.), Gobierno de La Rioja (project ANGI-2004/
03), and the Universidad de La Rioja (project API-04/02 and
doctoral fellowship of G.J.-O.).
Supporting Information Available: Experimental details,
spectroscopic characterization, as well as crystal structure data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(28) Attempts to represent the data points according to a first-order
process (ln[A0] - ln[A] vs t) gave a poor adjustment (see Supporting
Information). Moreover, we observed that the change of the nucleophile
concentration influences the reaction rate.
JO051632C
J. Org. Chem, Vol. 71, No. 4, 2006 1695