enantioselectivity to (-)-sparteine in s-BuLi-mediated depro-
tonation reactions.
produced 8.4 g of diamine (R,R)-4 after distillation, the only
purification required in the sequence.
We were attracted to cyclohexane-derived diamines (e.g.,
TMCDA), which are readily available in both enantiomeric
forms. In particular, recent work from the Alexakis group
has advocated the use of diamines such as (R,R)-2-4 that,
by way of differently functionalized amino groups, possess
stereogenic nitrogen atoms upon complexation to organo-
lithium reagents.7,8 Hence, we evaluated some asymmetric
deprotonation reactions with s-BuLi/diamines (R,R)-2-4, and
herein it is reported that diamine 4 is as effective as (-)-
sparteine for the deprotonation of N-Boc pyrrolidine. We also
describe an efficient multigram scale preparation of diamine
(R,R)-4 (and (S,S)-4) and two synthetic applications of
diamine (S,S)-4 where (+)-sparteine-derived stereochemistry
is needed to obtain the appropriate enantiomer of the product.
Diamines (R,R)-2-4 were prepared using routes that
involved minor changes to those originally described by
Alexakis7 (see Supporting Information). As a representative
example, the synthesis of (R,R)-4 is summarized in Scheme
1. First, (()-trans-cyclohexane-1,2-diamine was resolved
With diamines (R,R)-2-4 in hand, we evaluated them in
different asymmetric deprotonation reactions. First, Beak’s
lithiation-trapping of N-Boc pyrrolidine 7 (f 8) was used
to compare the three ligands. The results are shown in
Scheme 2, together with those obtained with (-)-sparteine,
Scheme 2
Scheme 1
(+)-1,4 and (R,R)-TMCDA.11 The sterically hindered di-
amines (R,R)-2 and (R,R)-3 produced s-BuLi complexes that
were unreactive (low yields with significant amounts of
recovered starting material) and gave racemic adduct 8. In
contrast, moving the sterically hindered t-Bu group in the
ligand one atom further along the N-alkyl chain relative to
(R,R)-3 gave a s-BuLi complex that delivered (S)-8 of 95:5
er in 72% yield. The difference between diamines (R,R)-3
and (R,R)-4 is remarkable. Indeed, this is the first example
of a non-sparteine-like diamine whose s-BuLi complex shows
such high enantioselectivity.
Having established that diamine 4 was the optimal
cyclohexane-derived ligand, asymmetric deprotonation of an
O-alkyl carbamate,1,12 an epoxide,13 and a phosphine borane14
were investigated using s-BuLi/diamine 4 (Scheme 3). A
satisfactory result was obtained with the O-alkyl carbam-
ate: deprotonation of 9, trapping with CO2, and reduction
with BH3 gave alcohol (S)-10 of 84:16 er (84% yield). This
is slightly worse than a previous result using s-BuLi/TMCDA
on a sterically hindered O-alkyl carbamate.12 In contrast, the
enantioselectivity with cyclooctene oxide 11 and phosphine
borane 13 were significantly worse than those obtained with
(-)-sparteine. Apparently, the s-BuLi/diamine 4 complex
using L- and D-tartaric acid to give both salts (R,R)-5 and
(S,S)-5.9 Then, reaction of (R,R)-5 with NaOH(aq)/MeO2CCl
gave a bis-methyl carbamate, which was reduced using
10
LiAlH4 to deliver diamine (R,R)-6. Next, acylation of
diamine (R,R)-6 using t-butylacetyl chloride delivered a crude
bis-amide that was reduced using LiAlH4 to give diamine
(R,R)-4 in 72% yield after purification by Kugelrohr distil-
lation over 4 steps (Scheme 1). The synthesis was readily
achieved on a multigram scale: 10.0 g of salt (R,R)-5
(6) (a) Johansson, M. J.; Schwartz, M.; Amedjkouh, M.; Kann, N.
Tetrahedron: Asymmetry 2004, 15, 3531. (b) Morita, Y.; Tokuyama, H.;
Fukuyama, T. Org. Lett. 2005, 7, 4337. (c) Wilkinson, J. A.; Rossington,
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Int. Ed. 2007, 46, 7491.
(7) (a) Kizirian, J.-C.; Caille, J.-C.; Alexakis, A. Tetrahedron. Lett. 2003,
44, 8893. (b) Kizirian, J.-C.; Cabello, N.; Pinchard, L.; Caille, J.-C.;
Alexakis, A. Tetrahedron 2005, 61, 8939. (c) Cabello, N.; Kizirian, J.-C.;
Gille, S.; Alexakis, A.; Bernardinelli, G.; Pinchard, L.; Caille, J.-C. Eur. J.
Org. Chem. 2005, 4835. (d) Gille, S.; Cabello, N.; Kizirian, J.-C.; Alexakis,
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Tetrahedron: Asymmetry 2007, 18, 2503.
(11) Gallagher, D. J.; Beak, P. J. Org. Chem. 1995, 60, 7092.
(12) Wu¨rthwein, E.-U.; Behrens, K.; Hoppe, D. Chem.-Eur. J. 1999,
5, 3459.
(13) Hodgson, D. M.; Cameron, I. D.; Christlieb, M.; Green, R.; Lee,
G. P.; Robinson, L. A. J. Chem. Soc., Perkin Trans 1 2001, 2161.
(14) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995,
117, 9075.
(8) Hoffmann, R. W.; Klute, W.; Dress, R. K.; Wenzel, A. J. Chem.
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(9) Larrow, J. F.; Jacobsen, E. N. Org. Synth. 1997, 75, 1.
(10) A long reaction time (48 h) for the LiAlH4 reduction ensured that
crude diamine (R,R)-6 was of sufficient purity for subsequent reaction.
1410
Org. Lett., Vol. 10, No. 7, 2008