A new approach to asymmetric synthesis of β-amino alcohols by means of α-chirally protected amino alkyllithiums

Article abstract of DOI:10.1055/s-1998-1891

A new, general synthetic approach to enantiopure α-amino ketones and syn-β-amino alcohols is described which employs the doubly chiral N-protected α-amino alkyllithiums generated via Pearson's transmetalative protocol as the key synthetic intermediates.

Full text of DOI:10.1055/s-1998-1891

October 1998
SYNLETT
1147
A New Approach to Asymmetric Synthesis of β-Amino Alcohols by Means of α-Chirally
Protected Amino Alkyllithiums
Takahiro Tomoyasu, Katsuhiko Tomooka, and Takeshi Nakai *
†
‡
‡
†
Nutrition Research Institute, Otsuka Pharmaceutical Factory, Inc., Muya-cho, Naruto, Tokushima 772, Japan
‡
Department of Chemical Technology, Tokyo Institute of Technology, Meguro-ku, Tokyo 152, Japan
Fax: +81-3-5734-2885; e-mail: takeshi@o.cc.titech.ac.jp
Received 1 July 1998
Abstract: A new, general synthetic approach to enantiopure α-amino
ketones and syn-β-amino alcohols is described which employs the
doubly chiral N-protected α-amino alkyllithiums generated via
Pearson’s transmetalative protocol as the key synthetic intermediates.
Enantiopure β-amino alcohols have attracted much interest as key
components of bio-active molecules such as sphingolipids, taxonoids,
protease inhibitors. Such amino alcohols are generally prepared starting
With the chiral stannane in hand, we first carried out the reaction of the
doubly chiral alkyllithium generated from 1b with aldehydes (eq 4).
Thus, 1b was treated with n-BuLi in THF at -78 8 °C for 5 min followed
with enantiopure α-amino acids. The most popular synthetic method
relies on the stereocontrolled addition of organometallic reagents to
1
chiral α-amino aldehydes (route A in eq 1). In principle, on the other
6
by addition of an aldehyde to give the β-amino alcohol 5 in good yield
hand, the addition of chiral α-amino organolithiums to aldehydes should
constitute another general, straightforward route to β-amino alcohols
(route B).
as a mixture of the two diastereomers (Table 1). Particularly notable is
that as expected, the two diastereomers obtained in each entry have the
single identical configuration (S) at the C-2 chiral center and hence they
7
are epimeric to each other at the C-1 chiral center, although the
8
epimeric ratio was moderate or low.
Despite the great potential, route B remains relatively unexplored,
mainly because of the great difficulty of the enantioselective generation
2
of α-amino organolithiums and their configurational instability.
Recently Pearson et al. have reported an interesting protocol for the
highly diastereoselective generation of the chirally protected α-
aminoethyllithium 2a from an α-racemic mixture of organostannane 1a
by virtue of rapid equilibration to the thermodynamically most stable
3
diastereomer (eq 2). However, the applicability of this protocol has
been hampered by the tedious preparation of the organotin precusor of
1a from gem-diiodoethane and by the great difficulty of deprotection of
the chiral oxazolidinone moiety. Herein we wish to describe a new,
general synthetic route to enantiopure α-amino ketones and syn-β-
amino alcohols based on the improvement of Pearson’s protocol.
Next, our effort was directed to the preparation of diastereomerically-
defined β-amino alcohols via an oxidation-reduction sequence on the
epimeric mixture 5 (eq 5). Thus, Dess-Martin oxidation of the epimeric
6
mixture of 5a gave the α-amino ketone 6 which was then reduced with
9,10
L-Selectride to afford syn-5a in >95% de.
While deprotection of the
At the outset, we have successfully developed a new route to the
oxazolidinone moiety has been
protocol, we have now successfully overcome this problem by using
a serious problem in Pearson’s
3
requisite stannane 1 from easily available α-hydroxy stannane 3 via
4
mesylation followed by S 2 reaction with the potassium salt of (S)-4-
N
the Birch condition (Na/NH -THF/t-BuOH). Thus, 6 was subjected to
3
5
phenyl-2-oxazolidinone (4). Obviously, this route is more convenient
the Birch condition followed by reprotection of the liberated primary
and flexible than Pearson’s procedure.

1148
LETTERS
SYNLETT
amine with benzyloxycarbonyl chloride to furnish the Cbz-protected β-
amino alcohol 7 in good yield.
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol 1, pp 459-485. (e) Gawley, R. E.; Rein, K. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol 3, pp 65-83.
6
3.
4.
(a) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem.
Soc., 1993, 115, 2622. (b) Pearson, W. H.; Lindbeck, A. C. J. Am.
Chem. Soc., 1991, 113, 8546.
Tomooka, K.; Igarashi, T.; Watanabe, M.; Nakai, T. Tetrahedron
Lett., 1992, 33, 5795.
5.
6.
(S)-4-Phenyl-2-oxazolidinone (4) was purchased from Aldrich.
1
13
All the compounds were characterized by H, C-NMR. Data for
1
selected products are as follows. syn-5a: H-NMR (CDCl ) δ 0.64
3
(d, J = 6.5 Hz, 3H), 0.88 (t, J =7.4 Hz, 3H), 0.92 (d, J = 6.5 Hz,
3H), 1.18-1.34 (m, 2H), 1.37-1.50 (m, 2H), 1.51-1.65 (m, 1H),
3.28 (dd, J = 6.0, 13.0 Hz, 1H), 3.30 (brs, 1H), 3.45 (ddd, J = 4.0,
5.4, 8.6 Hz, 1H), 4.29 (dd, J = 7.2, 9.0 Hz, 1H), 4.67 (t, J = 9.0 Hz,
13
1H), 4.92 (dd, J = 7.2, 9.0 Hz, 1H), 7.41 (brs, 5H).
C-NMR
(CDCl ) δ 10.1, 22.2, 22.3, 24.2, 27.8, 37. 6, 57.0, 60.5, 70.6,
73.2, 128.0, 129.2, 129.3, 138.7, 160.0. anti-5a: H-NMR
Alternatively and more conveniently, enantiopure α-amino ketone 6 can
be obtained directly from 1 via acylation of the in situ generated α-
amino alkyllithiums with Weinreb amides (eq 6).
3
1
11
(CDCl ) δ 0.56 (t, J = 7.5 Hz, 3H), 0.89 (d, J =6.5 Hz, 3H), 0.90
3
(d, J = 6.5 Hz, 3H), 1.09-1.45 (m, 3H), 1.58-1.71 (m, 1H), 1.91-
2.00 (m, 1H), 3.02 (ddd, J = 1.2, 2.7 11.0 Hz, 1H), 3.64 (dt, J =
1.2, 7.0 Hz, 1H), 4.28 (dd, J = 6.7, 9.0 Hz, 1H), 4.39 (brs, 1H),
4.69 (t, J = 9.0 Hz, 1H), 4.84 (dd, J = 6.7, 9.0 Hz, 1H), 7.34-7.47
13
(m, 5H). C-NMR (CDCl ) δ 9.9, 21.4, 23.7, 24.8, 27.3, 34.3,
3
1
56.2, 63.1, 70.7, 77.1, 127.6, 129.4, 129.5, 138.3, 159.5. 6: H-
NMR (CDCl ) δ 0.45 (d, J = 6.0 Hz, 3H), 0.87 (d, J = 6.0 Hz, 3H),
3
1.06 (t, J = 7.3 Hz, 3H), 1.21-1.36 (m, 3H), 2.46-2.59 (m, 2H),
4.25 (dd, J = 6.0, 8.8, 1H), 4.33 (dd, J = 4.4, 9.2 Hz, 1H), 4.71 (dd,
J = 8.8, 9.0 Hz, 1H), 5.00 (dd, J = 6.0, 9.0 Hz, 1H), 7.38 (brs, 5H).
The synthetic potential of this method is now demonstrated in the
13
C-NMR (CDCl ) δ 7.4, 21.2, 22.3, 24.6, 33.3, 36.8, 59.3, 61.1,
3
context of the asymmetric synthesis of syn-β-amino α-trifluoromethyl
1
6,12
70.7, 127.5, 129.1, 129.2, 139.7, 159.1, 208.9. 7: H-NMR
alcohol 9,
7).
a recently-reported candidate of protease inhibitor (eq
13
(CDCl ) δ 0.92 (t, J = 6.4 Hz, 6H), 0.95 (t, J = 7.4, 3H), 1.20-1.70
3
(m, 5H), 2.22 (brs, 1H), 3.44 (brs, 1H), 3.70 (brs, 1H), 5.01 (brs,
13
1H), 5.08 (s, 2H), 7.26-7.39 (m, 5H). C-NMR (CDCl ) δ 10.0,
3
22.0, 23.1, 24.6, 27.1, 41.7, 52.4, 66.6, 75.3, 127.0, 128.0, 128.5,
1
136.7, 156.9. 8: H-NMR (CDCl ) δ 0.50-2.00 (m, 13H), 4.32
3
(dd, J = 5.6, 8.8, 1H), 4.74 (dt, J = 8.8, 8.9 Hz, 1H), 4.84 (dd, J =
4.3, 9.9 Hz, 1H), 4.98 (dd, J = 5.6, 8.9 Hz, 1H), 7.38 (brs, 5H).
13
C-NMR (CDCl ) δ 25.8, 26.0, 26.2, 31.6, 32.7, 33.6, 56.5, 59.0,
3
71.0, 119.5 (q, J = 279.0 Hz), 127.5, 129.1, 129.4, 138.80,
CF
1
158.6, 190.1 (q, J = 33.8 Hz). 9: H-NMR (CDCl ) δ 0.80-1.80
CF
3
(m, 13H), 3.85-4.05 (m, 2H), 4.20 (brs, 1H), 5.00-5.20 (m, 3H),
13
7.30-7.40 (m, 5H).
C-NMR (CDCl ) δ 25.9, 26.0, 26.3, 32.5,
3
33.4, 33.8, 38.9, 48.0, 67.1, 71.6 (q, J = 29.1 Hz), 124.7 (q, J
= 282.5 Hz), 128.0, 128.3, 128.6, 136.3, 157.0. 10: H-NMR
CF
CF
1
(CDCl ) δ 0.92 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.02
3
(t, J = 7.4, 3H), 1.29-1.39 (m, 1H), 1.48-1.58 (m, 1H), 1.61-1.80
In summary, we have developed an efficient and flexible synthetic route
to enantiopure α-amino ketones and syn-α-amino alcohols via the
chirally protected α-amino alkyllithiums generated by the improved
Pearson protocol. Further work is in progress to expand the synthetic
scope of the present methodology.
(m, 3H), 3.52 (ddd, J = 4.9, 5.9, 8.8 Hz, 1H), 4.07 (ddd, J = 5.7,
13
5.9, 7.0 Hz, 1H), 6.74 (brs, 1H). C-NMR (CDCl ) δ 9.0, 21.7,
3
23.0, 24.7, 27.4, 44.7, 55.7, 84.2, 160.0.
1
7.
8.
The diastereomers of 5 are easily distinguishable by H-NMR
(CDCl ). For instance, the δ value for CHOH, 3.45 for syn-5a and
3
3.64 for anti-5a. The oxidation of the diastereomer mixture of 5a
with Dess-Martin periodinane was found to produce the single
diastereomer of ketone 6, indicating that the two isomers were
epimer at the hydroxy-bearing carbon.
References and Notes
1.
(a) Jurczak, J.; Golebiowski, A. Chem. Rev., 1989, 89, 149. (b)
Tramontini, M. Synthesis, 1982, 605.
The syn selectivity in 1,2-addition reaction can be explained as a
result that the four-membered transition state A is sterically more
less congested than B.
2.
(a) Gawley, R. E.; Zhang, Q. J. Org. Chem., 1995, 60, 5763. (b)
Burchat, A. F.; Chong, J. M.; Park, S. B. Tetrahedron Lett., 1993,
34, 51. (c) Chong, J. M.; Park, S. B. J. Org. Chem., 1992, 57,
2220. (d) Gawley, R. E.; Rein, K. In Comprehensive Organic

October 1998
SYNLETT
1149
9.
The syn stereochemistry of 5a was confirmed on the basis of the
H-NMR spectrum of oxazolidinone 10 derived from 7 via
10. This result suggests that the stereoselective reduction of α-amino
1
ketone can be rationalized by applying the Felkin-Anh model.
treatment with NaH in DMF (62%). The stereoisomer 10 exhibits
11. Nahm, S.; Weinreb, S. M. Tetrahedron Lett., 1981, 22, 3815.
a coupling constant J = 5.9 Hz, indicating the trans relationship
1
ab
12. The relative stereochemistry of syn-9 was confirmed by H-NMR
between H and H : see Dufour, M-N.; Jouin, P.; Poncet, J.,
a
b
spectrum of the corresponding oxazolidinone (J = 4.6 Hz) as
ab
Pantaloni, A.; Castro, B. J. Chem. Soc. Perkin Trans 1, 1986,
1895.
described for syn-5a.
13. Begue, J-P.; Bonnet-Delpon, D; Fischer-Durand, N.; Amour, A.;
Reboud-Ravaux, M. Tetrahedron: Asymmetry, 1994, 5, 1099.