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N. Barnwell et al. / Tetrahedron Letters 53 (2012) 1951–1953
moderate diastereoselectivity in comparison with
a-methylben-
zylamine. In both these literature cases, condensation of the ketone
with phenylglycinol gave a mixture of imine and oxazolidine. In
our case, as illustrated in Scheme 1, complete reaction of ketone
2 with (R)-(À)-phenylglycinol was attained by stirring an equimo-
lar mixture of the two components at 50 °C in toluene in the pres-
ence of 4 Å molecular sieves for 12 h. Analysis by 1H NMR
spectroscopy indicated that oxazolidine 4 had been formed as a
50:50 mixture of diastereomers, along with 5% of imine 3c. The
Strecker reaction was attempted upon this mixture in a variety
of solvents. In most cases, mixtures of silylated and non-silylated
products 6 and 5, in varying diastereomer ratios, were obtained
(Scheme 2). However, we were delighted to observe that in tolu-
ene, exclusive formation of 6 took place at 20 °C, albeit at modest
conversion (60% after 24 h) and stereoselectivity (80:20). We
therefore surveyed a range of metal salt additives, and found that
the addition of 10 mol % magnesium bromide diethyl etherate pro-
moted complete conversion in 18 h at À40 °C into a 90:10 mixture
of aminonitrile diastereomers. Accordingly, we were able to isolate
the major diastereomer [which was eventually assigned as (R,R)-6,
vide infra] in a 54% overall yield and excellent purity by crystalliza-
Scheme 3. Summary of route. Reagents and conditions: (a) (R)-(À)-phenylglycinol,
4 Å MS, toluene, 50 °C, 12 h; Me3SiCN, Me3SiOSO2CF3, MgBr2.OEt2, toluene, À40 °C,
18 h; recrystallization from i-hexane–toluene, 54%; (b) HCl, CH2Cl2, À40 °C, 15 min;
H2O (1 equiv), 12 h, 95%; (c) ClCO2Me, LiH, THF, 40 °C, 48 h, 86%; (d) NH3 (7 M),
MeOH, lW, 150 W, 1 h, 100%; (e) HBr (48% aq), AcOH, reflux, 4 h, 62%.
i
tion from hexane–toluene.
The fragility and sterically hindered nature of 6 limited the op-
tions for elaborating this compound to a hydantoin. However, chlo-
rosulfonyl isocyanate10 successfully engaged the amine at À50 °C
in toluene, and following acid-promoted cyclization, hydantoin 7
was isolated in a 30% yield after silica gel chromatography. In the
light of the modest selectivity and conversion observed in this di-
rect process, we sought an alternative method of constructing the
hydantoin, and found that the addition of a single molar equivalent
of water to a solution of 6 saturated with hydrogen chloride affor-
ded lactone 8 (Scheme 3) quantitatively, as a highly crystalline so-
Figure 1. Strecker reaction conformations and nucleophile trajectories.
lid. This proved to be
intermediate.
a much more robust yet tractable
The successful synthesis of lactone 8 also allowed assignment of
the relative stereochemistry. Observation of a positive nOe be-
tween the methyl and N-benzyl protons confirmed that the stereo-
chemistry at the quaternary stereocenter is (R). This can be
accounted for by kinetic control in the Strecker reaction, assuming
coordination of the TMS group to the hydroxy, and activation of the
imine by intramolecular hydrogen bonding. Comparison of the two
A1,3 strain-minimized conformations (Fig. 1) suggests that nucleo-
philic attack upon B, leading to the minor diastereomer, is disfa-
vored by the additional steric encumbrance of the sulfur
eclipsing the benzylic proton.
It is plausible that a stabilizing hydrogen bonding interaction
with sulfur in A is, at least in part, responsible for the favorability
of this pathway. We evaluated the relative contributions by carry-
ing out the analogous Strecker reaction on benzyloxyacetone. Were
hydrogen bonding the dominant effect, the superior ability of oxy-
gen compared to sulfur in this regard should enhance stereoselec-
tivity. On the other hand, the smaller size of the former should lead
to poorer selectivity were that factor to be critical. In the event,
Figure 2. Structure of amide 10 and oxazolidinone 11.
only a 65:35 ratio of diastereomers was obtained, suggesting that
the principal factor is steric. We confirmed that the diastereoselec-
tivity is kinetic and not thermodynamic in origin by re-subjecting
the single diastereomer 6 to the reaction conditions, and did not
observe any erosion of the stereochemical integrity of the amino-
nitrile stereocenter.
The secondary amine 8 was reacted with lithium hydride and
methyl chloroformate to deliver carbamate 9 (Scheme 3). Ring
opening with ammonia took place at room temperature to give
amide 10 (Fig. 2), accompanied by approximately 10% of hydantoin
7. By conducting this reaction in a sealed microwave reactor, we
were able to drive this reaction to deliver 7 with complete conver-
sion, as shown in Scheme 3. We did not observe the formation of
oxazolidinone 11 (which would arise from attack of the hydroxy
group upon the carbamate), consistent with literature reports on
related systems.11 The hydantoin 7 was in turn subjected to reflux-
ing HBr in acetic acid for four hours to afford the target compound
1 in a 62% unoptimized yield.
In summary, and as illustrated in Scheme 3, we have developed
a stereocontrolled route to a chiral 5,5-disubstituted hydantoin
from (benzylthio)acetone using (R)-(À)-phenylglycinol as the
source of asymmetric induction in a diastereoselective Strecker
reaction. Under optimal reaction conditions, unprecedented levels
of stereocontrol derived from the use of phenylglycinol in this con-
text were observed. The phenylglycinol functionality was further
exploited in manipulation of the aminonitrile Strecker product 6
through to the target hydantoin 1 via a short, efficient sequence,
involving crystalline intermediates.
Scheme 2. Strecker reaction of 4 and direct conversion into hydantoin 7. Reagents
and conditions: (a) Me3SiCN, Me3SiOSO2CF3, MgBr2.OEt2, toluene, À40 °C, 18 h;
recrystallization from ihexane–toluene, 54%; (b) ClSO2NCO, CH2Cl2, À50 °C, 2 h; HCl
(aq), reflux, 2 h, 30%.
Barnwell, Neil
