method to prepare them from a common chiral intermediate.
Thus we envisioned a new synthesis using desymmetrization7
of meso serinol to generate the monoacetate. As shown in
Scheme 1, serinol is prochiral and, if the aziridine ring could
and/or enantioselectivity. When triethylamine was added to
the PPL catalyzed reaction of N-Ts-aziridine 1a, the reaction
rate increased but the selectivity was not changed even when
the reaction was run at 0 °C (runs 1-3, Table 1). When the
Scheme 1. Prochirality of Serinol and Transformation to
Table 1. PPL-Catalyzed Desymmetrizations of N-Protected
Serinola
Aziridine
VA (mL/ PPL (mg/ time yield
be closed selectively, each enantiomer of the corresponding
aziridine would be obtained. Once the acetate is obtained
stereoselectively, it could be easily transformed to both
aziridine enantiomers after a few steps by using well-known
synthetic methods. Desymmetrization reactions with serinol
analogues with PPL (pig pancreatic lipase) have been
reported.8 PPL is among the least expensive lipases and can
be used in organic solvents. Thus, we decided to use PPL
for the desymmetrization reaction.
run
1
PG
mmol)
mmol)
(h)
(%)a
erb
Ts 1a
20
20
20
20
20
20
10
20
10
10
20
20
300
300
300
300
300
100
100
300
100
300
300
300
3
81 90/10
2d Ts 1a
3c,d Ts 1a
1.5 83 91/09
4.5 80 89/11
4
5
6
7
8
9
10
11
Mesityl-SO2 1b
Fmoc 1c
Fmoc 1c
Fmoc 1c
Cbz 1d
5
75 70/30
3.5 90 99/01
8 91 99/01
9.5 90 99/01
1.5 85 99/01e
Cbz 1d
Boc 1e
3
86 99/01e
First, the PPL-catalyzed desymmetrization of N-Ts-
protected serinol with vinyl acetate was investigated (Scheme
2). The starting material could be easily prepared from
1.5 83 99/01e
Tr 1f
11 d
6 d
55 50/50
73 50/50
12d Tr 1f
a Isolated yield. b Enatiomeric ratios were determined by chiral HPLC
analysis (Chiralcel OD) of the monoacetate. c The reaction was run at 0
°C. d 1 equiv of NEt3 was used. e Analyzed by chiral HPLC after reacting
Mosher reagent with the corresponding monoacetates.
Scheme 2. Desymmetrization of N-Ts-serinol 1a with PPL
bulkier 2,4,6-mesitylsulfonyl-protected substrate 1b was used,
the enantioselectivity was decreased (run 4, Table 1).
Similarly, when the trityl protecting group was employed,
the reaction was extremely slow and racemic product was
obtained (runs 11 and 12). The lipase-catalyzed reaction was
then investigated with use of carbamate protecting groups.
In all cases (Boc,8a Fmoc and Cbz8c), excellent enantio-
selectivites and high yields were obtained. Changes in the
reactant ratios modify the reaction rate but have no effect
on enantiomeric excess or yield. To determine the enantio-
meric ratio of the monoacetates, authentic samples were
prepared for each racemic product and the racemates were
characterized by chiral HPLC analysis (Chiralcel OD col-
umn). In those cases where the racemic compounds (rac-
2d, rac-2e) could not be separated by a chiral OD column,
they were analyzed after esterifying the monoacetate with
Mosher’s reagent.
racemic serine or directly from commercially available
serinol. The desymmetrization reaction of N-Ts-serinol was
carried out with PPL (300 mg/mmol substrate) and vinyl
acetate (20 mL/mmol substrate) as acetylating agent and
solvent at room temperature. Although N-Ts-serinol 1a was
only partially soluble in vinyl acetate, it was smoothly
consumed in 3 h to give the desired monoacetate product in
good yield (81%) and enantiomeric ratio (90/10). Recrys-
tallization of the product in EtOAc-hexane yields a single
enantiomer in 60% yield, which was analyzed by chiral
HPLC. The use of THF as a solvent gave a homogeneous
reaction solution but did not provide an advantage in terms
of reactivity or stereoselectivity.
There are several reports regarding the enhancement of
selectivity and reactivity of the lipase reaction by the use of
additives.9 Triethylamine is the most commomly used
additive9 and generally shows an increase in reaction rate
Conversion of the monoacetates to the corresponding
aziridines was then investigated (Scheme 3). All attempts
to convert the N-Fmoc protected monoacetate 2c to aziridine
were unsuccessful; deprotection of the Fmoc group under
ring-closing conditions (PPh3/DIAD or mesylation followed
by NaH) occurred instead. In contrast, both 2d and 2e were
smoothly converted to the desired aziridines. Compound 2d
was the preferred intermediate because of its chromophore
and because of concerns about product stability under the
acidic conditions required for Boc deprotection of 2e.
(7) For a review of enantioselective enzymatic desymmetrizations in
organic synthesis, see: Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem.
ReV. 2005, 105, 313.
(8) (a) Neri. C.; Williams, J. M. J. AdV. Synth. Catal. 2003, 345, 835.
(b) Terradas, F.; Teston-Henry, M.; Fitzpatrick, P. A.; Klibanov, A. M. J.
Am. Chem. Soc. 1993, 115, 390. (c) Wang, Y.-F.; Lalonde, J. J.; Momongan,
M.; Bergbreiter, D. E.; Wong, C.-H. J. Am. Chem. Soc. 1998, 110, 7200.
(9) For a review of enhancement of selectivity and reactivity of lipase
by additives, see: Theil, F. Tetrahedron 2000, 56, 2905.
216
Org. Lett., Vol. 9, No. 2, 2007