Preparation of Chiral
R
-Oxy-[2H1]methyllithiums
A R T I C L E S
Scheme 1. Preparation of (R)- and
(S)-Dimethylphenylsilyl-[2H1]methanola
Figure 1. Enantiomers of chiral methyllithiums.
nicely supported by numerous calculations at different levels.10
Hoppe et al.’s findings that carbamates with a shielded carbonyl
group are metalated highly enantioselectively using (-)-
sparteine/s-BuLi had a tremendous influence on the application
of R-oxyanions.11 Beak et al. demonstrated the potential of
chiral, nonracemic R-aminoorganolithiums easily accessed by
deprotonation of Boc-protected amines with (-)-sparteine/
BuLi.12 R-Heteroatom-substituted carbanions react with a wide
variety of electrophiles, preferentially in a retentive course.
Up to now only chiral, nonracemic secondary alkyllithiums
with an R-heteroatom have been prepared, but never primary
ones of type 1 with two isotopes of hydrogen, for which we
propose the term chiral methyllithiums (Figure 1). It was
selected in analogy to the term chiral methyl group first
mentioned by Cornforth13 and Arigoni et al.14 in their preparation
of chiral acetic acid. Our direct synthesis of chiral methanol
intrigued us to attack this unsolved challenge.15
a
(a) s-BuLi/TMEDA/-78 °C; (b) borylation with 3; (c) LiAlD4 or
LiBEt3D; (d) H2O2/NaHCO3/H2O/THF/50 °C.
Results and Discussion
dimethylphenylsilyl-[2H1]methanol.15 The key steps are given
for the sake of clarity (Scheme 1). Thus, carbamate 2 was
prepared from homochiral (S,S)-bis(1-phenylethyl)amine and
(dimethylphenylsilyl)methanol [easily available from com-
mercial (chloromethyl)dimethylphenylsilane], metalated with
s-BuLi/TMEDA, and borylated with borate 3 (or the one derived
from (+)-pinane-2,3-diol) to give boronates 4 and 5. Each
diastereomer was reduced with LiBEt3D under inversion of
configuration to a deuterated (dimethylphenylsilyl)methylbo-
ronate 6, which in turn was oxidized (H2O2/THF/NaHCO3) to
give dimethylphenylsilyl-[2H1]methanol 7 (ee 99%). The seem-
ingly simple switch from the dimethylphenylsilyl to the tribu-
tylstannyl substituent forced us to reshape the synthesis
because of the reduced acidity of hydrogens R to tin compared
to silicon.
Additionally, we had to access the corresponding carbamate
by a different route, because (chloromethyl)tributylstannane is
not commercially available. To this end, carbamate 9 was
prepared from methanol and (S,S)-bis(1-phenylethyl)amine (8)
(Scheme 2). Metalation with s-BuLi/TMEDA and quenching
with Bu3SnCl furnished an inseparable mixture of diastereomeric
stannanes 11a/b (ratio by 1H NMR: 2.2:1) in 75% yield,
containing at best 15% of stannylmethyl carbamate 10. This
result reflects the higher acidity of the secondary benzylic
hydrogens R to nitrogen compared to the primary ones R to
oxygen. To overcome this side reaction, the 1-phenylethyl
groups were replaced by isopropyl groups. Metalation and
stannylation of methyl N,N-diisopropylcarbamate gave the
(tributylstannyl)methyl carbamate in about 50% yield as already
found by Boche et al.18 Alternatively, it was prepared by a one-
pot procedure. Tributylstannyllithium19 generated from hexabu-
tylditin and n-BuLi was added to paraformaldehyde, and the
lithium stannylmethoxide 13 was esterified with N,N-diisopro-
As we envisaged to prepare chiral methyllithiums with various
heteroatoms, the starting material of choice would be the chirally
deuterated (tributylstannyl)methanol. It could be converted easily
to the requisite precursors, which are amenable to tin lithium
exchange to give chiral methyllithiums. We anticipated a lower
barrier of inversion compared to the ones with an alkyl group
in place of a hydrogen isotope. However, we were hoping that
at least the oxymethyllithiums would be configurationally stable
at (very) low temperatures, an assumption based on theoretical
calculations.10 Here, we present our results on the generation
of the chiral (diisopropoxyphosphinyl)oxy- and (N,N-diisopro-
pylcarbamoyl)oxy-substituted methyllithiums and the determi-
nation of their microscopic and macroscopic configurational
stabilities, respectively.
Preparation of (R)- and (S)-Tributylstannyl-[2H1]methanol.
The preparation and the enantioselective reduction of acylstan-
nanes are well-known reactions.16 Unfortunately, this sequence
cannot be extended to tributylformylstannane, which has been
postulated as an unstable intermediate of the hydrolysis of (R-
chloro-R-ethoxymethyl)tributylstannane.17 Therefore, we re-
sorted to the method developed for the preparation of chiral
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J.; Schleyer, P. v. R. J. Org. Chem. 1981, 46, 4108-4110. (b) Schleyer, P.
v. R.; Clark, T.; Kos, A. J.; Spitznagel, G. W.; Rohde, C.; Arad, D.; Houk,
K. N.; Rondan, N. G. J. Am. Chem. Soc. 1984, 106, 6467-6475. (c) Boche,
G.; Opel, A.; Marsch, M.; Harms, K.; Haller, F.; Lohrenz, J. C. W.;
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Organometallic Chemisty 5; Springer: Berlin, 2003; pp 61-137.
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Organolithiums in EnantioselectiVe Synthesis; Hodgson, D. M., Ed.; Topics
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(13) Cornforth, J. W.; Redmond, J. W.; Eggerer, H.; Buckel, W.; Gutschow, C.
Nature 1969, 221, 1212-1213.
(14) Lu¨thy, J.; Retey, J.; Arigoni, D. Nature 1969, 221, 1213-1215.
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