serines,6 we chose to follow a procedure similar to that of
Avenoza et al. because of the high yields and enantio-
selectivity.7
The synthesis was initiated (Scheme 1) with methacrylic
acid 1, which was transformed into the Weinreb amide 2
the minor isomer was easily removed by column chroma-
tography. The methyl ester 6 was saponified with potassium
hydroxide and the azide reduced with palladium on carbon
to give completely unprotected R-methyl-D-serine 7 in a
quantitative yield over the two steps. The zwitterion 7 was
then protected with Boc-anhydride to give Boc-R-methyl-
D-serine 8.
Previously, we reported the synthesis of lanthionine
building blocks from serine derivatives by iodination of the
side chain and displacement of the iodine with the appropriate
thiol.10 This route was unsuccessful utilizing Boc-R-Me-D-
Ser-OMe 10 (Scheme 2). Iodination and bromination with
Scheme 1. Synthesis of Boc-R-Me-D-Serine-â-lactonea
Scheme 2. Attempted Synthesis of
Boc-R-Me-D-Cys(PMB)-OHa
a Reaction conditions: (a) (i) SOCl2, CH2Cl2; (ii) CH3ONHCH3‚
HCl, pyridine (94% overall). (b) Modified â-AD mix, 91%, >94%
ee.9 (c) (i) LiOH, H2O/MeOH; (ii) AcCl, MeOH, reflux (94%
overall). (d) SOCl2, CCl4, reflux, 88%. (e) NaN3, DMF, 50 °C,
72%. The reactions (c-e) followed the methodology reported in
ref 7. (f) (i) KOH, MeOH/H2O; (ii) H2/Pd-C, MeOH (quantitative
overall). (g) Boc2O, 10% aqueous Na2CO3, dioxane, quantitative.
(h) DIAD, PPh3, THF, 67%.
via displacement of the acid chloride with N,O-dimethyl-
hydroxylamine hydrochloride. This substrate was chosen for
the Sharpless asymmetric dihydroxylation on the basis of
previous reports of high enantioselectivity from Avenoza et
al.7 A modified â-AD mix8 that calls for a 5-fold increase
of (DHQD)2-PHAL and K2OsO2(OH)4 as compared to the
original mix was employed to obtain diol 3. The diol was
then saponified with lithium hydroxide and esterified with
acidic methanol to form methyl ester 4. The cyclic sulfite 5
was formed by refluxing the diol with thionyl chloride. The
cyclic sulfite was then selectively opened with sodium azide
at the tertiary carbon to give the azido alcohol 6.9 The
regioselectivity of the attack of the azide at the tertiary carbon
compared to the secondary carbon was found to be 4:1, and
a Reaction conditions: (a) PPh3, I2, imidazole, CH2Cl2. (b) PPh3,
Br2, imidazole, CH2Cl2. (c) MsCl, TEA, THF, 67%. (d) PMBSH,
Cs2CO3, DMF. (e) PPh3, DEAD, THF, 85%. (f) PMBSH, BF3‚OEt2,
CH2Cl2, 25%.
triphenylphosphine and iodine or bromine gave no evidence
of formation of product 11 or 12. With methanesulfonyl
chloride and triethylamine, the side chain alcohol was
mesylated to form compound 13, but this leaving group could
not be displaced with 4-methoxy-R-toluenethiol to give Boc-
R-Me-D-Cys(PMB)-OMe 14. The added steric hindrance
from the R-methyl group prevents displacement at the
methylene carbon. We also attempted to ring open the
R-methyl aziridine carboxylic acid methyl ester 15, which
was formed from Boc-R-Me-D-Ser-OMe 10 with triphenyl-
phosphine and diethyl azodicarboxylate (DEAD). The open-
ing of the aziridine gave low yields of the cysteine derivative
14 consistent with previous results.
(6) This list of references provides examples and is by no means
complete: (a) Seebach, D.; Aebi, J. D. Tetrahedron Lett. 1984, 25, 2545-
2548. (b) Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi,
T. Tetrahedron Lett. 1988, 29, 235-238. (c) Colson, P. J.; Hegedus, L. S.
J. Org. Chem. 1993, 58, 5918-5924. (d) Fukuyama, T.; Xu, L. J. Am.
Chem. Soc. 1993, 115, 8449-8450. (e) Zembower, D. E.; Gilbert, J. A.;
Ames, M. M. J. Med. Chem. 1993, 36, 305-313. (f) Wipf, P.; Venkatraman,
S.; Miller, C. P. Tetrahedron Lett. 1995, 36, 3639-3642.
(7) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.; Sucunza,
D.; Zurbano, M. M. Tetrahedron: Asymmetry 2001, 12, 949-957.
(8) Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett. 1993, 34, 2079-
2082.
The above results led us to explore the formation of Boc-
R-Me-D-serine-â-lactone 9, an analogue of the Vederas
(9) Enantiomeric excess of azido alcohol 6 was determined to be greater
than 94% by formation of Mosher’s ester and subsequent 1H NMR analysis.
For comparison, the enantiomer of 6 was also transformed into Mosher’s
(10) Rew, Y.; Malkmus, S.; Svenssen, C.; Yaksh, T. L.; Chung, N. N.;
Schiller, P. W.; Cassel, J. A.; DeHaven, R.; Goodman, M. J. Med. Chem.
2002, 45, 3746-3754.
1
ester and analyzed by H NMR (Supporting Information).
1036
Org. Lett., Vol. 5, No. 7, 2003