Asymmetric synthesis of β-amino alcohols by reductive cross-coupling of benzylideneamine with planar chiral benzaldehydes

Article abstract of DOI:10.1021/ol0255256

(equation presented) Samarium iodide mediated reductive cross-coupling of N-tosyl benzylideneamine with benzaldehydes or the corresponding chromium complexes gave syn-β-amino alcohol derivatives. A dynamic kinetic resolution of a configurationally equilibrated reactive species occurred in the cross-coupling with planar chiral benzaldehyde chromium complexes.

Full text of DOI:10.1021/ol0255256

ORGANIC
LETTERS
2002
Vol. 4, No. 5
835-838
Asymmetric Synthesis of â-Amino
Alcohols by Reductive Cross-Coupling
of Benzylideneamine with Planar Chiral
Benzaldehydes
,†,‡
Yoshie Tanaka,† Nobukazu Taniguchi,† and Motokazu Uemura*
Department of Chemistry, Faculty of Integrated Arts and Sciences, Osaka Prefecture
UniVersity, Sakai, Osaka 599-8531, Japan, and Research Institute for AdVanced
Sciences and Technology, Osaka Prefecture UniVersity, Sakai, Osaka 599-8570, Japan
uemura@ms.cias.osakafu-u.ac.jp
Received January 8, 2002
ABSTRACT
Samarium iodide mediated reductive cross-coupling of N-tosyl benzylideneamine with benzaldehydes or the corresponding chromium complexes
gave syn-â-amino alcohol derivatives. A dynamic kinetic resolution of a configurationally equilibrated reactive species occurred in the cross-
coupling with planar chiral benzaldehyde chromium complexes.
Enantiomerically pure â-amino alcohols have played sig-
nificant roles as chiral ligands or auxiliaries in asymmetric
reactions1 and are important key synthetic intermediates for
biologically active natural products.2 When not available by
direct reduction of amino acids, â-amino alcohols are often
prepared by indirect routes involving various permutations
of stepwise bond construction with asymmetric induction.3
Usually, nucleophilic addition reactions to chiral R-amino
carbonyls, hydroxy imines, or hydroxyoximes are employed
for stereoselective synthesis of optically active â-amino
alcohols.4 New synthetic strategy for the preparation of
enantiopure â-amino alcohols is still in high demand.
(3) Selected recent C-C bond construction approach for â-amino
alcohols: (a) Matsuda, F.; Kawatsura, M.; Dekura, F.; Shirahama, H. J.
Chem. Soc., Perkin Trans. 1 1999, 2371. (b) Petasis, N. A.; Zavialov, I. A.
J. Am. Chem. Soc. 1998, 120, 11798. (c) Trost, B. M.; Lee, C. B. J. Am.
Chem. Soc. 1998, 120, 6818. (d) Kobayashi, S.; Furuta, F.; Hayashi, T.;
Nishijima, M.; Hanada, K. J. Am. Chem. Soc. 1998, 120, 908. (e) Barrett,
A.; G. M.; Seefeld, M. A.; White, A. J. P.; Williams, D. J. Org. Chem.
1996, 61, 2667. (f) Enders, D.; Reinhold: U. Angew. Chem., Int. Ed. Engl.
1995, 34, 1219. (g) Friestad, G. K.; Massari, S. E. Org. Lett. 2000, 2, 4237.
(h) Friestad, G. K. Org. Lett. 1999, 1, 1499. (i) Tomoyasu, T.; Tomooka,
K.; Nakai T. Synlett 1998, 1147.
(4) Representative examples: (a) Enders, D.; Reinhold, U. Tetrahe-
dron: Asymmetry 1997, 8, 1895. (b) Denmark, S. E.; Nicaise, O. J.-C. J.
Chem. Soc., Chem. Commun. 1996, 999. (c) Denmark, S. E.; Stiff, C. M.
J. Org. Chem. 2000, 65, 5875. (d) Cogan, D. A.; Ellman, J. A. J. Am. Chem.
Soc. 1999, 121, 268. (e) Kobayashi, S.; Sugita, K.; Oyamada, H. Synlett
1999, 138. (f) Davies, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555. (g) Reetz, M. T. Angew. Chem., Int.
Ed. Engl. 1991, 30, 1531. (h) Reetz, M. T.; Schmitz, A. Tetrahedron Lett.
1999, 40, 2737.
† Faculty of Integrated Arts and Sciences.
‡ Research Institute for Advanced Sciences and Technology.
(1) For representative reviews: (a) Bergmeier, S. C. Tetrahedron 2000,
56, 2561. (b) Ager, D.; J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96,
835. (c) Reetz, M. T. Chem. ReV. 1999, 99, 1121. (d) Reetz, M. T. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1531. (e) Bloch, R. Chem. ReV. 1998, 98,
1407. (f) ComprehensiVe Asymmetric Catalyst; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999. (g) Ojima, I. Catalytic
Asymmetric Synthesis, 2nd ed.; VCH: New York, 2000. (h) Noyori, R.
Asymmetric Catalysis via Chiral Metal Complexes. In Asymmetric Catalysis
in Organic Synthesis; John Wiley and Sons: Chichester, 1994.
(2) Representative bioactive naturally occurring amino alcohols: (a)
Kolter, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38, 1532. (b)
Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750.
(c) Carbohydrate Mimics; Chapleur, Y., Ed.; Wiley-VCH: Weinheim, 1998.
(d) Hauser, F. M.; Ellenberger, S. R. Chem. ReV. 1986, 86, 35. (e) Nicolaou,
K. C.; Mitchell, H. J.; van Delft, F. L.; Rubsam. F.; Rodriguez, R. M. Angew.
Chem., Int. Ed. Engl. 1998, 37, 1871.
10.1021/ol0255256 CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/14/2002

Scheme 2a
Figure 1. Carbon-carbon disconnection for â-amino alcohols.
Reductive cross-coupling between aldehydes and aldimines
seems to be the most direct way for the preparation of
â-amino alcohols (Figure 1), but many problems preclude
an efficient cross-coupling in this procedure. Construction
of both stereogenic centers with asymmetric induction should
be required in a single synthetic transformation involving
addition to both CdN and CdO bonds. For an efficient
cross-coupling between two substrates, it is apparently
significant for either substrate to be more easily reduced to
the corresponding radical or ionic species and the generated
reactive species to couple with the other substrate prior to a
homo-coupling. Only a few examples are reported of an
intermolecular reductive cross-coupling between carbonyls
and imines giving â-amino alcohols.5 However, â-amino
alcohols were obtained as a diastereomeric mixture of
racemic anti- and syn-isomers in these methods. As part of
our exploration of the asymmetric synthesis utilizing planar
chiral transition metal-coordinated molecules, we have
investigated the reductive cross-coupling giving optically
active â-amino alcohols.
a Reagent and conditions: (1) SmI2, THF, 0 °C to rt; (2) Ac2O,
pyr; (3) in case of chromium complex: hν-air.
For further extension of the versatility of this type of
reductive cross-coupling giving optically active â-amino
alcohols, we studied other combinations between alidimines
and aldehydes. Samarium iodide mediated cross-coupling of
N-methanesulfonyl benzylideneamine (4a) with benzalde-
hydes 5 was initially studied, and the results are summarized
in Table 1. Although the cross-coupling â-amino alcohol
Table 1. Cross-Coupling of Benzylideneamines 4 with
Benzaldehydes 5 or Chromium Complexes 6
entry
imine
aldehyde
yield 7 (%)
syn/anti
1a
2a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
5a
5b
5c
6a
6b
6c
5a
5b
5c
5d
6a
6b
6c
6d
77
70
93
78
63
89
81
74
76
52
73
60
33
38c
54/46
50/50
50/50
67/33
60/40
67/33
70/30
80/20
70/30
87/13
97/3
3a
We recently reported that the reductive cross-coupling of
N-tosyl ferrocenylideneamine (1) with planar chiral ferrocen-
ecarboxaldehydes 2 in the presence of samarium iodide gave
enantiomerically pure anti â-amino alcohol derivatives 3 in
good yields (Scheme 1).6 It was found that an electron-
4a
5a
6a
7
8
9
10
11b
12b
13b
14b
Scheme 1. Cross-Coupling of N-Tosyl Ferrocenylideneamine
95/5
97/3
97/3
with Planar Chiral Ferrocenecarboxaldehydes
a Isolated as N-mesyl amino alcohols without acetylation. b Homo-
coupling 1,2-diols were obtained in 1-5% yields. c Yield of cross-coupling
was 60% before photo-oxidation.
derivatives 7 were obtained in good yields without formation
of homo-coupling products, the diastereoselectivity of anti-
and syn-â-amino alcohols was extremely low (entries 1-3).
The corresponding benzaldehyde tricarbonylchromium com-
plexes 6 were also coupled with the imine 4a, and the
diastereoselectivity increased slightly (entries 4-6). The
nitrogen substituent of electron-withdrawing benzylidene-
amine was next changed to an N-tosyl group directed toward
high diastereoselectivity. Fortunately, the diastereoselectivi-
ties of the cross-coupling products in the combination
between N-tosyl benzylideneamine (4b) and benzaldehydes
increased appreciably (entries 7-10). Among the ortho-
substituted benzaldehydes studied, o-chlorobenzaldehyde
(5d) resulted with higher diastereoselectivity in 52% yield
withdrawing sulfonyl group such as the N-substituent of the
aldimine was essential for the achievement of efficient cross-
coupling without homo-coupling.
(5) An intermolecular cross-coupling between carbonyls and imines for
synthesis of â-amino alcohols: (a) Roskamp, E. J.; Pedersen, S. F. J. Am.
Chem. Soc. 1987, 109, 6551. (b) Shono, T.; Kise, N.; Fujimoto, T.
Tetrahedron Lett. 1991, 32, 525 (c) Shono, T.; Kise, N.; Kunimi, N.;
Nomura, R. Chem. Lett. 1991, 2191. (d) Shono, T.; Kise, N.; Fujimoto, T.;
Yamanami, A.; Nomura, R. J. Org. Chem. 1994, 59, 1730. (e) Machrouhi,
H.; Namy, J.-L. Tetrahedron Lett. 1999, 40, 1315. (f) Hanamoto, T.; Inanaga,
J. Tetrahedron Lett.1991, 32, 3555.
(6) Taniguchi, N.; Uemura, M. J. Am. Chem. Soc. 2000, 122, 8301.
836
Org. Lett., Vol. 4, No. 5, 2002

Scheme 3
Table 2. Cross-Coupling of â-N-Tosyl Naphthylimines 8 with
Benzaldehydes 5 or Chromium Complexes 6
entry
aldehyde
yield 9 (%)
syn/anti
1
2
3
4
5
6
5a
5b
5c
6a
6b
6c
83
89
76
67
74
89
65/35
78/22
74/26
94/6
83/17
78/22
(entry 10). Therefore, a coordination of more electron-
withdrawing Cr(CO)3 fragment to the arene ring would be
expected to increase the diastereoselectivity. As expected,
the cross-coupling of benzaldehyde chromium complex (6a)
with N-tosyl benzylideneamine (4b) gave â-amino alcohol
derivative 7 (X ) p-Ts, R ) H) with high diastereoselectivity
in 73% overall yield after acetylation and subsequent
demetalation (entry 11). The increase of diastereoselectivity
by tricarbonylchromium complexation would be attributed
to a stereoelectronic effect of the tricarbonylchromium
fragment.7
good yield, while the corresponding R-naphthylimine gave
no cross-coupling product under the same conditions. The
major isomers of the obtained â-amino alcohols were also
syn-isomers. Similarly, the corresponding tricarbonylchro-
mium complexes of benzaldehyde increased syn-diastereo-
selectivity in the cross-coupling with the imine 8.
We next turned our attention to the preparation of optically
active â-amino alcohol derivatives by using planar chiral
benzaldehyde chromium complexes (Scheme 4). The planar
Interestingly, the major â-amino alcohol 7 obtained in this
combination was found to be a syn-isomer.8 The formation
of syn-amino alcohol in this combination is in sharp contrast
to the samarium iodide mediated reductive cross-coupling
between N-tosyl ferrocenylideneamine (1) and ferrocenecar-
boxaldehydes, in which the anti-amino alcohols were ex-
clusively obtained as shown in Scheme 1.9 Similarly, ortho-
substituted benzaldehyde chromium complexes were coupled
with N-tosyl benzylideneamine (4b) to produce the corre-
sponding syn-amino alcohols along with formation of small
amount (1-5%) of homo-coupling 1,2-diols derived from
benzaldehyde chromium complexes under the same condi-
tions (entries 12-14). Unfortunately, samarium iodide medi-
ated cross-coupling of 4b with ferrocenecarboxaldehyde
instead of the benzaldehyde chromium complexes gave a
homo-coupling 1,2-diol in 95% yield without formation of
the expected â-amino alcohol. However, N-methanesulfonyl
analogue 4a was coupled with ferrocenecarboxaldehyde to
give the corresponding â-amino alcohol as a diastereomeric
mixture in only 15% yield.10 Thus, the electronic factor of
both substrates would be significant for the achievement of
cross-coupling giving â-amino alcohols in high yield.
The cross-coupling of N-tosyl naphthylimines with ben-
zaldehydes was also examined (Scheme 3, Table 2). â-Naph-
thylimine 8 was coupled with benzaldehydes 5 to give a
diastereomeric mixture of â-amino alcohol derivatives 9 in
Scheme 4. Enantiopure â-Amiono Alcohol by Reductive
Cross-Coupling
(7) The coordination of a tricarbonylchromium fragment to the arene
ring was found to also increase the diastereoselectivity in the asymmetric
allylboration of aromatic aldehydes: Roush, W. R.; Park, J. C. J. Org. Chem.
1990, 55, 1143.
(8) Authentic stereodefined anti-N-tosyl-2-amino-1,2-diphenylethyl al-
cohol derivative was prepared by the following literature procedure: (a)
Davis, F. A.; Hague, M. S.; Przeslawski, R. M. J. Org. Chem. 1989, 54,
2021. (b) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1141. The corresponding syn-â-amino alcohol: (c)
Reetz, M. T.; Drewes, M. W.; Lennick, K.; Schmitz, A.; Holdgru¨n, X.
Tetrahedron: Asymmetry 1990, 1, 375.
chiral (+)-(1S)-o-methylbenzaldehyde chromium complex
(10)11 (>99% ee) was coupled with 4b to give a chromium-
complexed (1S,2R)-â-amino alcohol derivative 11 ([R]19
D
+49.0; >99% ee).12 Exposure of 11 to sunlight gave a
chromium-free (R,R)13-syn-â-amino alcohol derivative 12
(9) Similarly, the cross-coupling of N-tosyl ferrocenylideneamine (1) with
benzaldehydes or the corresponding chromium complexes gave exclusively
anti-â-amino alcohols under the same conditions: unpublished results.
(10) A homo-coupling 1,2-diol was in 80% yield as a major product.
(11) Enantiomerically pure chromium complexes were obtained by optical
resolution of diastereomers derived from L-valinol: Bromley, L. A.; Davies,
S. G.; Goodfellow, C. L. Tetrahedron: Asymmetry 1991, 2, 139.
Org. Lett., Vol. 4, No. 5, 2002
837

of samarium iodide. A reaction mechanism has been
postulated to rationalize the observed syn-stereoselectivity
(Figure 2). The generated reactive species from the imine
4b would be rapidly equilibrated at the newly created
stereogenic center between 14a and 14b. The planar chiral
ortho-substituted benzaldehyde chromium complex could
exclusively intercept either configurational species depending
on the planar chirality. Taking into account the following
transition states 15 and 16, the samarium metal could
coordinate with both nitrogen and carbonyl oxygen atoms.
Furthermore, it is well-known that the carbonyl oxygen of
ortho-substituted benzaldehyde chromium complexes exists
preferentially in an anti-conformation with the ortho-
substituent as the result of a stereoelectronic effect in both
solid and solution state.14 Therefore, (+)-planar chiral
benzaldehyde chromium complex 10 reacts with the inter-
mediate 14a to give the syn-â-amino alcohol derivative 11
through the transition state 15 with minimal steric hindrance.
The corresponding antipode (-)-ent-10 reacted with 14b
giving the antipode amino alcohol derivative via the transition
state 16. However, the anti-â-amino alcohols were obtained
in the cross-coupling between N-tosyl ferrocenylideneamine
(1) and aldehydes through the transition state with a dipole-
dipole repulsion between the nitrogen and carbonyl oxygen
atoms. The formation of the stereochemically different
â-amino alcohols in both combinations might be attributed
to an electronic character between two the aldimines 1 and
4b, although the precise reaction mechanism is not clear at
the present time. We are now investigating asymmetric
reaction utilizing the optically pure â-amino alcohols as a
chiral ligand or auxiliary and elucidation of plausible reaction
mechanism.
Figure 2. Proposed reaction mechanism.
([R]23 -26.6).12 On the other hand, an antipode (-)-o-
D
methylbenzaldehyde chromium complex ent-10 produced
(+)-(S,S)-syn-â-amino alcohol ent-12 ([R]23 +26.6) under
D
the same reaction sequence. In this way, both enantiomers
of syn-â-amino alcohol were stereoselectively prepared by
the coupling of benzylideneamine with the planar chiral
benzaldehyde chromium complex. Similarly, the cross-
coupling of N-tosyl â-naphthylimine 8 with planar chiral
benzaldehyde chromium complexes 10 and ent-10 gave both
enantiomers of the corresponding syn-â-amino alcohol
derivatives 13 and ent-13, respectively, depending on the
planar chirality. Thus, a configurationally equilibrated reac-
tive species generated from the imines 4b or 8 by the
reduction with samarium iodide underwent a dynamic kinetic
resolution in the cross-coupling with the planar chiral
benzaldehyde chromium complexes in analogy with the
cross-coupling6 of N-tosyl ferrocenylideneamine with the
planar chiral ferrocenecarboxaldehydes.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research from a Ministry
of Education, Science, Sports and Culture.
In this way, the cross-coupling of N-tosyl benzylidene-
amine (4b) with benzaldehydes or their chromium complexes
gave predominantly syn-â-amino alcohols in the presence
Supporting Information Available: Experimental pro-
cedures and characterization data of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Optical purities of 11 and chromium-free 12 were determined by
chiral HPLC. For racemic 11: chiralcel OD-H, hexane/2-propanol (9/1),
flow rate 0.5 mL/min, 40 °C, retention time 33.1 and 36.0 min. For racemic
12: chiralcel OJ-H, hexane/2-propanol (9/1), flow rate 0.5 mL/min, 40 °C,
retention time 20.4 and 25.0 min.
(13) The absolute configuration of the syn-coupling product 12 was
determined as (R,R)-configuration by comparison of the optical rotation
sign of authentic syn-â-amino alcohol derived from (R)-2-phenylglycine
according to ref 8c.
OL0255256
(14) (a) Solladie´-Cavallo, A. AdVances in Metal-Organic Chemistry;
Liebeskind, L. S., Ed.; JAI Press: Greenwich, CT, 1989; Vol. 1, p 99. (b)
Davies, S. G.; McCarthy, T. D. ComprehensiVe Oragnometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford,
1995; Vol. 12, p 1039.
838
Org. Lett., Vol. 4, No. 5, 2002