Asymmetric synthesis of anti- and syn-β-amino alcohols by reductive cross-coupling of transition metal-coordinated planar chiral arylaldehydes with aldimines

Article abstract of DOI:10.1021/jo0205412

Samarium iodide-mediated cross-coupling of N-tosyl ferrocenylideneamine with planar chiral ferrocenecarboxaldehydes or benzaldehyde chromium complexes gave diastereoselectively the corresponding anti-β-amino alcohol derivatives in good yields, while N-tosyl benzylideneamine produced syn-β-amino alcohols by coupling with planar chiral arylaldehydes. Dynamic kinetic resolution of a configurationally equilibrated reactive species generated from achiral N-tosyl ferrocenilideneamine and benzylideneamine by reduction with samarium iodide was observed in the cross-coupling with planar chiral arylaldehydes giving both antipodes of β-amino alcohols depending on the planar chirality. The obtained anti-β-amino alcohol with the ferrocene ring was utilized as a chiral ligand for catalytic asymmetric reduction of acetophenone.

Full text of DOI:10.1021/jo0205412

Asym m etr ic Syn th esis of a n ti- a n d syn -â-Am in o Alcoh ols by
Red u ctive Cr oss-Cou p lin g of Tr a n sition Meta l-Coor d in a ted P la n a r
Ch ir a l Ar yla ld eh yd es w ith Ald im in es
†
†
†
,†,§
Yoshie Tanaka, Nobukazu Taniguchi, Takayuki Kimura, and Motokazu Uemura*
Department of Chemistry, Faculty of Integrated Arts and Sciences, Osaka Prefecture University,
Sakai, Osaka 599-8531, J apan, and Research Institute for Advanced Science and Technology,
Osaka Prefecture University, Sakai, Osaka 599-8570, J apan
uemura@ms.cias.osakafu-u.ac.jp
Received August 14, 2002
Samarium iodide-mediated cross-coupling of N-tosyl ferrocenylideneamine with planar chiral
ferrocenecarboxaldehydes or benzaldehyde chromium complexes gave diastereoselectively the
corresponding anti-â-amino alcohol derivatives in good yields, while N-tosyl benzylideneamine
produced syn-â-amino alcohols by coupling with planar chiral arylaldehydes. Dynamic kinetic
resolution of a configurationally equilibrated reactive species generated from achiral N-tosyl
ferrocenilideneamine and benzylideneamine by reduction with samarium iodide was observed in
the cross-coupling with planar chiral arylaldehydes giving both antipodes of â-amino alcohols
depending on the planar chirality. The obtained anti-â-amino alcohol with the ferrocene ring was
utilized as a chiral ligand for catalytic asymmetric reduction of acetophenone.
In tr od u ction
pinacol coupling, is the most direct method for the
preparation of â-diols or diamines. Although this reaction
can be achieved in high yield by lanthanoid metals or
Enantiomerically pure â-diols, diamines, and amino
alcohols have found widespread use as chiral ligands or
auxiliaries in asymmetric reactions, and are also im-
portant as key synthetic intermediates for biologically
5
low-valent transition metals, highly diastereoselective
1
formation of â-diols or diamines is problematic under
6
conventional reductive coupling. The utilization of some
2
active natural products. While optically pure â-diols have
modified reducing agents in catalytic or stoichiometric
reaction has been developed for the achievement of high
been conveniently prepared by catalytic asymmetric
dihydroxylation of the olefins with high optical purity,3
the generally accepted method for the preparation of
chiral diamines involves an optical resolution of racemic
compounds with certain chiral carboxylic acids. A reduc-
tive coupling of carbonyl or imine compounds, homo-
7
diastereoselectivity for the pinacol coupling. However,
only moderate enantioselectivity of â-diols was achieved
by pinacol coupling of aldehydes in the presence of a
4
8
9
chiral source. We have recently reported that enantio-
merically pure â-diols and diamines could be easily
prepared by the reductive homo-coupling of planar chiral
tricarbonylchromium complexes of benzaldehydes and
†
Department of Chemistry, Faculty of Integrated Arts and Sciences.
Research Institute for Advanced Science and Technology.
§
(
1) For representative reviews: (a) Bergmeier, S. C. Tetrahedron
2
1
000, 56, 2561. (b) Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev.
996, 96, 835. (c) Reetz, M. T. Chem. Rev. 1999, 99, 1121. (d) Reetz,
(5) For reviews: (a) Imamoto, T. Lanthanoids in Organic Synthesis;
Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Academic Press:
London, UK, 1994. (b) Molander, G. A. Chem. Rev. 1992, 92, 29. (c)
Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307. (d) Sonder-
quist, J . A. Aldrichim. Acta 1991, 24, 15. (e) Kagan, H. B.; Namy, J .
L. Tetrahedron 1986, 42, 6573. (f) Dushin, R. G. In Comprehensive
Organometallic Chemistry II; Wilkinsons, G., Stone, P. G. A., Abel, E.
W., Eds.; Pergamon Press: Oxford, UK, 1995; Vol. 12, p 1071.
(6) (a) Namy, J . L.; Souppe, J .; Kagan, H. B. Tetrahedron Lett. 1983,
24, 765. (b) Souppe, J .; Danon, L.; Namy, J . L.; Kagan, H. B. J .
Organomet. Chem. 1983, 250, 227.
(7) Some representative dl selective pinacol coupling: (a) Handa,
Y.; Inanaga J . Tetrahedron Lett. 1987, 28, 5717. (b) Szymoniak, J .;
Besan c¸ on, J .; Mo ¨ı se, C. Tetrahedron 1992, 48, 3867. (c) Suzuki, H.;
Manabe, H.; Enokiya, R.; Hanazaki, Y. Chem. Lett. 1986, 1339. (d)
Raubenheimer, H. G.; Seebach, D. Chimica 1986, 40, 12. (e) Clerici,
A.; Clerici, L.; Porta, O. Tetrahedron Lett. 1996, 37, 3035. (f) Gans a¨ uer,
A. J . Chem. Soc., Chem. Soc. 1997, 457. Gans a¨ uer, A. Synlett 1997,
363. (g) Wallace, T. W.; Wardell, I.; Li, K.-D.; Leeming, P.; Redhouse,
A. D.; Challand, S. R. J . Chem. Soc., Perkin Trans. 1 1995, 2293. (h)
Hirao, T.; Hasegawa, T.; Muguruma, Y.; Ikeda, I. J . Org. Chem. 1996,
61, 366. (i) Nomura, R.; Matsuno, T.; Endo, T. J . Am. Chem. Soc. 1996,
118, 11666. (j) Barden, M. C.; Schwartz, J . J . Am. Chem. Soc. 1996,
118, 5484 and references therein.
M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531. (e) Bloch, R. Chem.
Rev. 1998, 98, 1407. (f) J acobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.
Comprehensive Asymmetric Catalyst; Springer-Verlag: Berlin, Ger-
many, 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; J ohn
Wiley and Sons: Chichester, UK, 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,
Germany, 1998. (d) Hauser, F. M.; Ellenberger, S. R. Chem. Rev. 1986,
6, 35. (e) Nicolaou, K. C.; Mitchell, H. J .; van Delft, F. L.; Rubsam.
F.; Rodriguez, R. M. Angew. Chem., Int. Ed. 1998, 37, 1871.
3) (a) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem.
8
(
Rev. 1994, 94, 2483. (b) Becker, H.; King, S. B.; Taniguchi, M.;
Vanhessche, K. P. M.; Sharpless, K. B. J . Org. Chem. 1995, 60, 3940
and references therein.
(4) (a) Saigo, K.; Kubota, N.; Takebayashi, S.; Hasegawa, M. Bull.
Chem. Soc. J pn. 1986, 99, 931. (b) Corey, E. J .; Imwinkelried, R.; Pikul,
S.; Xiang, Y. B. J . Am. Chem. Soc. 1989, 111, 5493. (c) Pikul, S.; Corey,
E. J . Org. Synth. 1992, 71, 22.
1
0.1021/jo0205412 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/28/2002
J . Org. Chem. 2002, 67, 9227-9237
9227

Tanaka et al.
TABLE 1. Cr oss-Cou p lin g of F er r ocen eca r boxa ld eh yd e
1
w ith F er r ocen ylid en ea m in e 2
F IGURE 1. Carbon-carbon connection for â-amino alcohols.
benzaldimines, and the related planar chiral transition
metal coordinated molecules with samarium iodide. On
the other hand, â-amino alcohols are often prepared by
direct reduction of amino acids. Indirect routes involving
various permutations of stepwise bond construction with
asymmetric induction also have been utilized for prepa-
ration of â-amino alcohols.10 Usually, nucleophilic addi-
tion reactions to the chiral R-amino carbonyls, hydroxy
imines, or hydroxyoximes are used for the stereoselective
synthesis of optically active â-amino alcohols.11 However,
as the stereogenic R-carbon of R-amino carbonyl com-
pounds is labile, the optical purity was sometimes
decreased. Therefore, new synthetic strategy for the
preparation of enantiopure â-amino alcohols is still highly
demanded. Recently, syn-â-amino alcohols were prepared
by catalytic asymmetric Mannich-type reaction from
R-hydroxyacetone, aldehydes, and aniline in the presence
of (S)-proline with high optical purity.12 Reductive cross-
coupling between aldehydes and aldimines seems to be
the most direct route for the preparation of â-amino
alcohols (Figure 1), but many problems preclude an
efficient cross-coupling in this procedure. Thus, the homo-
coupling of both substrates giving â-diols or diamines
should be suppressed for the preparation of â-amino
alcohols. Furthermore, construction of both stereogenic
centers with asymmetric induction should be required
in a single synthetic transformation involving addition
to both CdN and CdO bonds. Only a few examples of
4a yield (%)
entry
1b
imine 2
3 yield (%)
5 yield (%)
2a
2b
2c
2d
2e
2f
2g
2g
2h
0
0
0
0
0
95
96
96
98
0
0
95
0
0
0
0
e
0
b
2
3
4
5
6
7
8
9
c
c
92
92
88
trace
trace
54
d
a
28
94f
trace
a
Obtained as a 1:1 diastereomeric mixture. b Obtained as the
c
hydrolysis product of 2 in >98% yield. Recovered 2 in 90-98%
yield. d Carried out in 15% HMPA. The CdN reduction product
e
f
was obtained in 50% yield. Ratio of anti and syn isomers: 9/1.
an intermolecular cross-coupling of carbonyls with imines
have been reported. However, this cross-coupling af-
13
forded a diastereomeric mixture of anti- and syn-â-amino
alcohols as racemic compounds. As part of our exploration
of asymmetric synthesis utilizing the planar chiral
transition metal-coordinated molecules, we have inves-
tigated the reductive cross-coupling of aldehydes with
aldimines directed toward the synthesis of optically active
â-amino alcohols.
(8) Formation of 1,2-diols with moderate enantioselectivity by the
pinacol coupling in the presence of a chiral source. (a) Seebach, D.;
Daum, H. J . Am. Chem. Soc. 1971, 93, 2795. (b) Seebach, D.; Oei, H.
A.; Daum, H. Chem. Ber. 1977, 110, 2316. (c) Matsubara, S.; Hash-
imoto, Y.; Okano, T.; Utimoto, K. Synlett 1999, 1411. (d) Bandini, M.;
Cozzi, G.; Morganti, S.; Umani-Ronchi, A. Tetrahedron Lett. 1999, 40,
Resu lts a n d Discu ssion
1
997.
9) (a) Taniguchi, N.; Uemura, M. Tetrahedron 1998, 54, 12775. (b)
Taniguchi, N.; Kaneta, N.; Uemura, M. J . Org. Chem. 1996, 61, 6088.
c) Tanuguchi, N.; Uemura, M. Synlett 1997, 51. (d) Taniguchi, N.;
Uemura, M. Tetrahedron Lett. 1998, 39, 5385.
10) Selected recent C-C bond construction approach for â-amino
(
Sa m a r iu m Iod id e-Med ia ted Cr oss-Cou p lin g of
F er r ocen ylid en ea m in es w ith Ald eh yd es. To achieve
an efficient cross-coupling between aldehydes and ald-
imines, it is apparently significant for either substrate
to be more easily reduced to the corresponding reactive
species which reacts with another substrate without
homo-coupling. We initially studied the cross-coupling of
ferrocenylideneamine with arylaldehydes directed toward
the synthesis of optically enriched â-amino alcohols, and
the reaction results are summarized in Table 1. Treat-
ment of a mixture of ferrocenecarboxaldehyde (1) and
N-alkyl ferrocenylideneamines 2a , 2b or hydrazone
derivatives 2d , 2e with samarium iodide in THF gave
homo-coupling â-diol 4 as a diastereomeric mixture along
(
(
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,
9
08. (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.
(11) Representative examples: (a) Enders, D.; Reinhold, U. Tetra-
hedron: 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. (i) Shimizu, M.; Tsukamoto, K.;
Fujisawa, T. Tetrahedron Lett. 1997, 38, 5193. (j) Hoffman, R. V.;
Maslouh, N.; Cervantes-Lee, F. J . Org. Chem. 2002, 67, 1045.
(13) 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. (g)
Guijarro, D.; Yus, M. Tetrahedron 1993, 49, 7761.
(12) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J . J . Am. Chem.
Soc. 2002, 124, 827.
9
228 J . Org. Chem., Vol. 67, No. 26, 2002

Asymmetric Synthesis of anti- and syn-â-Amino Alcohol
SCHEME 1a
TABLE 2. Cr oss-Cou p lin g of P la n a r Ch ir a l N-Tosyl
F er r ocen ylid en ea m in e a n d F er r ocen eca r boxa ld eh yd es
a
Reagent and conditions: (1) t-BuLi, ether; (2) electrophile (RX);
(3) p-TsOH, CH2Cl2, H2O.
with recovered ferrocenylideneamine or its hydrolyzed
ferrocenecarboxaldehyde depending on the structure of
ferrocenylimine (entries 1, 2, 4, and 5). With N-phenyl
ferrocenylideneamine (2c), two corresponding homo-
coupling products, 1,2-diol 4 and diamine 5, were ob-
tained as a diastereomeric mixture, respectively (entry
aldehyde 7
9 yield
(%)
3
). However, it was fortunately found that electron-
(% ee)a
b
entry
1
imine 8
[R]D (CHCl3)
% ee 9
withdrawing N-sulfonyl ferrocenylideneamine was criti-
cal for the effective cross-coupling with ferrocenecarbox-
aldehyde (1). Thus, the reductive cross-coupling of
N-arylsulfonyl ferrocenylideneamines 2f, 2g with fer-
rocenecarboxaldehyde (1) gave anti-â-amino alcohol 3 as
a single diastereomer (entries 6 and 7) without any
formation of the corresponding homo-coupling products
and the stereoisomer of the â-amino alcohol. With N-
methanesulfonyl ferrocenylideneamine (2h ), the corre-
sponding anti-amino alcohol was obtained as the major
diastereomer along with a small amount of syn-amino
alcohol (entry 9). Interestingly, the â-amino alcohol
derivatives obtained in this reductive cross-coupling were
anti diastereomers, while the homo-pinacol coupling of
the planar chiral ferrocenecarboxaldehydes gave exclu-
sively syn-â-diols.9 The formation of the anti-â-amino
alcohols in the cross-coupling is also in contrast to the
7a (95)
7a
7b (95)
7c (97)
7d (96)
7e
7e
7e
7e
8a
8b
8b
8c
8d
8a
8b
8c
8d
92
93
90
93
0
91
96
95
0
+99.7 (c 0.83)
+36.8 (c 0.44)
-9.7 (c 0.40)
+1.8 (c 0.52)
95
95
95
97
c
2
3
4
5
6
7
8
9
+90.3 (c 0.84)
-16.8 (c 0.63)
+3.8 (c 0.30)
92
94
97
a
Enantiomeric excess was determined by HPLC with Chiralpak
AS (eluted with haxane/2-propanol (9/1), 1.0 mL/min). Enantio-
meric excess was determined by HPLC with Chiralcel OD-H
(eluted with haxane/2-propanol (9/1), 0.5 mL/min). Value of
b
c
deiodination compound obtained from the cross-coupling product.
We initially studied the samarium iodide-mediated
cross-coupling of a combination between the planar chiral
N-tosyl R-substituted ferrocenylideneamines 8 and fer-
rocenecarboxaldehydes 7 (Table 2). (+)-(R)-R-Methylfer-
rocenecarboxaldehyde (7a ) was coupled with (R)-N-tosyl
R-methylferrocenylideneamine (8a ) to give anti-â-amino
alcohol 9a in 92% yield (entry 1). The stereochemistry of
the anti-coupling product 9a was determined as (1R,2S)-
configuration by X-ray crystallography.16 Similarly, the
cross-coupling of R-halogenated ferrocenyl compounds
produced the corresponding anti-â-amino alcohols with-
out reduction of the halogen atom in good yields. How-
ever, N-tosyl 2-trimethylsilyferrocenylideneamine (8d )
gave no cross-coupling product probably due to steric
hindrance (entries 5 and 9). The â-amino alcohol deriva-
tives 9b and 9e obtained by the cross-coupling with (+)-
(S)-N-tosyl R-iodoferrocenylideneamine (8b) gave (+)-
3
predominant formation of syn diastereomers in NbCl -
mediated cross-coupling between aldehydes and ald-
imines.1 In the presence of HMPA, the â-amino alcohol
was obtained as a 1:1 diastereomeric mixture in only 28%
yield along with formation of homo-coupling â-diol and
CdN double bond reduction product (entry 8).
3a
Since â-amino alcohols could be obtained by the reduc-
tive cross-coupling between N-sulfonyl ferrocenylidene-
amines and ferrocenecarboxaldehyde in good yield, we
next turned our attention to the preparation of optically
active â-amino alcohols utilizing planar chiral ferrocenyl
compounds.14 Enantiomerically active R-substituted fer-
rocenecarboxaldehydes 7 as starting materials were
prepared by the literature method.15 Treatment of fer-
(
1R,2S)-â-amino alcohol 9g ([R]26
with n-BuLi in 96% yield. Furthermore, an antipode (-)-
R)-R-iodoferrocenecarboxaldehyde (ent-7b)17 was coupled
with 8b to give anti-â-amino alcohol 10 as a single
diastereomer (Scheme 2). The stereochemistry of 10 was
D
+40.8) by deiodination
rocenecarboxaldehyde dimethyl acetal with (-)-(S)-1,2,4-
butanetriol followed by methylation with MeI and NaH
gave the chiral acetal of ferrocenecarboxaldehyde 6.
Diastereoselective lithiation of 6 with t-BuLi followed by
trapping of electrophiles afforded optically active R-sub-
stituted ferrocenecarboxaldehydes 7 with high optical
purity (Scheme 1). The corresponding planar chiral
N-tosyl ferrocenylideneamines 8 were obtained by treat-
ment of the chiral ferrocenecarboxaldehydes 7 with
(
(
16) Crystallographic data for the structures reported in this paper
have been deposited with Cambridge Crystallographic Data Center
as supplementary publication no. CCDC-189226 for 9a . Crystal data
3 2
for 9a : empirical formula C31H33NO SFe , M ) 611.36, orthorhombic,
space group P2
914(2) Å , Z ) 4, D
1
2
1
2
c
1
, a ) 13.489 Å, b ) 30.253 Å, c ) 7.141 Å, V )
) 1.393 g/cm , F000 ) 1272.00, Mo KR (λ ) 0.71069
p-TsNH
2
in the presence of molecular sieves 4A and a
3
3
2
catalytic amount of p-TsOH in good yields.
Å), no. of reflections measured 3812, least-square refinement using
1
733 reflections with I > 3.00σ(I), R ) 0.050, R
17) Antipode (R)-2-iodoferrocenecarboxaldehyde ent-7b was pre-
pared from 6 by diastereoselective lithiation followed by quenching
with Me SiCl, and then repeated lithiation and subsequent introduc-
tion of iodine and finally desilylation; (i) t-BuLi (ii) Me SiCl (iii) t-BuLi,
(iv) I(CH I, (v) n-Bu NF, (vi) aq HCl.
w
) 0.044.
(
(
14) Preliminary report; Taniguchi, N.; Uemura, M. J . Am. Chem.
Soc. 2000, 122, 8301.
15) Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H. B.
J . Org. Chem. 1997, 62, 6733.
3
(
3
2
)
2
4
J . Org. Chem, Vol. 67, No. 26, 2002 9229

Tanaka et al.
SCHEME 2
TABLE 3. Cr oss-Cou p lin g of Ach ir a l N-Tosyl
F er r ocen ylid en ea m in e 2g w ith P la n a r Ch ir a l
F er r ocen eca r boxa ld eh yd es
SCHEME 3
a
entry
aldehyde 7
yield (%)
[R]D (CHCl3)
% ee 13
1
2
3
4
7a
7b
7c
7d
92
94
91
91
-22.8 (c 0.88)
-43.4 (c 0.94)
-39.4 (c 0.50)
-38.3 (c 0.27)
93
94
93
94
determined by X-ray crystallography,18 and the generated
stereogenic centers were also confirmed by comparison
with authentic compound. Thus, spectra data including
an optical rotation of the deiodinated â-amino alcohol
derived from 10 were identical with that of 9g obtained
by deiodination of 9b. In this way, the absolute configu-
rations at the generated chiral centers of anti-â-amino
alcohols in the cross-coupling with the planar chiral
N-tosyl ferrocenylideneamines 8 were only governed by
the planar chirality of ferrocenylimine 8, regardless of
the planar chirality of ferrocenecarboxaldehydes.
a
Enantiomeric excess was determined by HPLC with Chiralcel
OD-H (eluted with haxane/2-propanol (9/1), 0.5 mL/min).
TABLE 4. Cr oss-Cou p lin g of 2g w ith Ben za ld eh yd es or
Cor r esp on d in g Tr ica r bon ylch r om iu m Com p lexes
Similarly, the planar chiral (+)-(S)-N-tosyl R-iodofer-
rocenylideneamine (8b) was coupled with benzaldehyde.
Thus, the cross-coupling of 8b with o-methoxybenzalde-
hyde (11c) gave the corresponding anti-â-amino alcohol
1
1a
11b
11c
14a
14b
14c
derivative 12 ([R]27
yield (%)
95
92
94
94
94
96
D
-47.8) as a single diastereomer after
deiodination and subsequent acetylation (Scheme 3). The
absolute configuration of 12 was determined as the
desired â-amino alcohols in good yields. These results
would be attributed to the steric effect. However, the
reaction of o-bromobenzaldehyde chromium complex with
(
1S,2S)-configuration by comparison of the optical rota-
tion with a stereochemically defined authentic compound
vide infra), and was also governed by the planar chirality
(
2
g resulted in a complex mixture.
of the ferrocenylimine 8. However, the corresponding
tricarbonylchromium complex of o-methoxybenzaldehyde
We next examined the absolute configuration at the
stereogenic centers of the â-amino alcohols obtained by
cross-coupling of achiral ferrocenylimine 2g with planar
chiral ferrocenecarboxaldehydes and benzaldehyde chro-
mium complexes. The samarium iodide-mediated cross-
coupling of 2g with (+)-(S)-R-iodoferrocenecarboxalde-
1
4c gave homo-coupling â-diol in 80% yield without
formation of the expected cross-coupling â-amino alcohol
by the reaction with 8b probably due to steric hindrance.
We next studied the cross-coupling with achiral N-tosyl
ferrocenylideneamine. The samarium iodide-mediated
cross-coupling of 2g with planar chiral ferrocenecarbox-
aldehydes 7 gave similarly anti-â-amino alcohol deriva-
tives in good yields without formation of diastereomers
2
6
hyde (7b) gave (-)-(1S,2R)-amino alcohol ent-9g ([R]
40.5) after deiodination by treatment with n-BuLi
Scheme 4). The obtained â-amino alcohol was an optical
D
-
(
antipode with anti-â-amino alcohol 9g obtained by the
cross-coupling of the planar chiral (S)-N-tosyl R-iodofer-
rocenylideneamine (8b) with ferrocenecarboxaldehyde as
discussed above. On the other hand, the corresponding
(
Table 3). In this combination, R-trimethylsilylferro-
cenecarboxaldehyde (7d ) fortunately gave the expected
anti-â-amino alcohol by cross-coupling with 2g (entry 4).
Similarly, benzaldehydes and the corresponding tri-
carbonylchromium complexes were coupled with achiral
ferrocenylideneamine 2g to afford anti-â-amino alcohols
2
8
ent-7b afforded the (+)-(1R,2S)-â-amino alcohol 9g ([R]
40.8) by the same reaction sequence. Similarly, the
D
+
planar chiral benzaldehyde chromium complexes afforded
both enantiomers of anti-â-amino alcohols depending on
the planar chirality (Scheme 5). Thus, (+)-(S)-o-meth-
oxybenzaldehyde chromium complex (17b)19 gave (+)-
anti-â-amino alcohol derivative 18b without formation
1
5 without formation of stereoisomers in good yields
(Table 4). While the planar chiral R-substituted ferroce-
nylideneamine resulted in no cross-coupling products
with a benzaldehyde chromium complex as mentioned
above, achiral N-tosyl ferrocenylideneamine (2g) gave the
(
19) Optically pure o-methoxy and methylbenzaldehyde chromium
(
18) Crystal data for ent-10: no. CCDC-189227, empirical formula
SFe , M ) 835.10, monoclinic, space group P2 /a, a )
c
1.903 Å, b ) 21.818 Å, c ) 12.204 Å, V ) 3000.8 Å , Z ) 4, D )
complexes were obtained by separation of diastereomers derived from
L-valinol with column chromatography according to the literature
method: (a) Davies, S. G.; Goodfellow, C. L. J . Chem. Soc., Perkin
Trans. 1 1989, 192. (b) Davies, S. G.; Goodfellow, C. L. J . Chem. Soc.,
Perkin Trans. 1 1990, 393. (c) Bromley, L. A.; Davies, S. G.; Goodfellow,
C. L. Tetrahedron: Asymmetry 1991, 2, 139.
C
1
1
29
H
27NO
3
2
I
2
1
3
3
.848 g/cm , F000 ) 1624.00, Mo KR (λ ) 0.71069 Å), no. of reflections
measured 7408, least-square refinement using 5741 reflections with I
0.00σ(I), R ) 0.145, R ) 0.190.
>
w
9
230 J . Org. Chem., Vol. 67, No. 26, 2002

Asymmetric Synthesis of anti- and syn-â-Amino Alcohol
SCHEME 4a
a
Reagent and conditions: (1) SmI2, 2g, THF; (2) n-BuLi, THF
then H2O.
SCHEME 5
F IGURE 2. CD spectra.
SCHEME 6
TABLE 5. Red u ction P oten tia lsa
1
11a
14a
2a
2c
-2.34
-2.04
-1.70
-2.42
-2.02
2
g
2h
29a
29b
31
-1.80
-1.74
-1.56
-1.50
-1.44
of any stereoisomers in good yield. The absolute config-
uration of 18b was determined by X-ray crystallogra-
phy.20 The corresponding (R)-(-)-o-methoxybenzaldehyde
chromium complex (ent-17b) produced (-)-anti-â-amino
alcohol derivative ent-18b under the same conditions.
Also, optically pure o-methylbenzaldehyde chromium
complexes, 17a and ent-17a gave the corresponding anti-
â-amino alcohols 18a and ent-18a , respectively, under the
same reaction sequence. Surprisingly, optical rotation of
o-methyl-substituted anti-â-amino alcohol derivatives
a
Potential in volts vs Ag/Ag+ with a glassy carbon working
electrode, a platinum flag counter electrode in MeCN using
tetrabutylammonium perchlorate (0.05 M) as a supporting elec-
trolyte, and a sweep rate of 50 mV s
-
1
.
dependent on using the planar chirality of ferrocene-
carboxaldehydes and benzaldehyde chromium complexes
in the coupling reaction.
Also, aliphatic aldehydes in analogy with arylaldehydes
gave the expected â-amino alcohols by samarium idodide-
mediated cross-coupling with N-tosyl ferrocenylidene-
amine (2g) under the same conditions in good yields
without formation of homo-coupling products (Scheme 6).
However, the obtained cross-coupling products 19 were
a 1:1 diastereomeric mixture of anti- and syn-amino
alcohols.
1
3
8a and ent-18a was almost zero in CHCl solution,
despite using the optically active arene chromium com-
plexes as the starting material. However, CD spectra of
the â-amino alcohol derivatives supported that both 18a
and ent-18a are optically active compounds (Figure 2).
Thus, the o-methyl-substituted anti-â-amino alcohols,
1
8a and ent-18a , have the same behavior with the
optically active â-amino alcohols, 18b and ent-18b, with
o-methoxy substituent in the CD spectra. In conclusion,
the absolute configuration at the R,R′-positions of anti-
â-amino alcohols in the combination between achiral
ferrocenylimine 2g and planar chiral arylaldehyde was
Rea ction Mech a n ism of Cr oss-Cou p lin g w ith
N-Tosyl F er r ocen ylid en ea m in es
A reaction mechanism has been postulated to rational-
ize the observed stereoselectivity of the cross-coupling of
N-tosyl ferrocenylideneamines with arylaldehydes. An
efficient achievement of the cross-coupling between fer-
rocenecarboxaldehyde 1 and N-arylsulfonyl ferrocenyliden-
imines 2f, 2g would be attributed to different reduction
potentials between both substrates (Table 5). The redox
properties of these compounds were examined by cyclic
(
20) Crystal data for 18b: no. CCDC-189228. empirical formula
SFe, M ) 547.45, monoclinic, space group P2 , a ) 12.781
) 1.324
C
28
H
29NO
5
1
3
Å, b ) 10.519 Å, c ) 20.434 Å, V ) 2746(1) Å , Z ) 4, D
c
3
g/cm , F000 ) 1144.00, Mo KR (λ ) 0.71069 Å), no. of reflections
measured 13161, least-square refinement using 8292 reflections with
w
I > 0.00σ(I), R ) 0.085, R ) 0.077.
J . Org. Chem, Vol. 67, No. 26, 2002 9231

Tanaka et al.
voltammetry. The voltammograms of all compounds
exhibited clear reduction waves but no apparent oxida-
tion waves. Therefore, the differences between these
compounds were compared by the potentials at which
they began to be reduced. Electron-withdrawing N-
sulfonyl ferrocenylideneamines 2g and 2h were found to
be more easily reduced than the corresponding ferrocene-
carboxaldehyde 1. We next studied whether the reactive
intermediated species generated from N-sulfonyl imine
is a radical or ionic species. Reduction of N-tosyl imine
2
2 3
g with SmI in the presence of CH OD in THF gave a
deuterium-incorporated CdN reduction product in good
yield. The incorporation of deuterium in the reduction
product shows that the reactive intermediate species
would be the ionic species. Thus, single-electron reduction
of the sulfonyl ferrocenylideneimine generates a ketyl
radical intermediate, which would be further reduced to
a dianion species.
In the cross-coupling with the planar chiral N-tosyl
R-substituted ferrocenylideneamines, samarium iodide
attacks the anti-oriented CdN double bond to the R
substituent21 from the exo-side to generate dianion
intermediate 21, which is configurationally stable against
epimerization (Figure 3).22 No epimerization between 21
and 22 would be attributed to an interaction of the
p-orbital of R-carbon with the d-orbital of the iron metal,
resulting in the formation of an exo-cyclic double bond
character 23. Taking into account the following transition
states 24a and 24b, the N-tosyl group is oriented anti23
to the carbonyl oxygen of arylaldehydes due to dipole-
dipole repulsion. The carbonyl oxygen of the planar chiral
ferrocenecarboxaldehydes is also known to exist prefer-
F IGURE 3. Proposed reaction mechanism of cross-coupling
with planar chiral N-tosyl ferrocenylideneamine.
entially in the anti conformation21 to the ortho substitu-
ent. When the planar chiral arylaldehydes 7 were coupled
with a dianion intermediate, the transition state 24a
caused a severe steric interaction between the FeCp ring
of ferrocenecarboxaldehyde and ferrocenylimine because
of the same planar chirality of both substrates. Therefore,
the anti-oriented carbonyl oxygen in transition state 24a
would be isomerized to the alternative syn-oriented
transition state 24b, giving the anti-â-amino alcohols 9.
In the case of cross-coupling with optical antipode ent-7,
the sterically stable anti-oriented transition state 25 is
preferred for anti-â-amino alcohol formation.
On the other hand, the reactive species generated from
achiral ferrocenylideneamine 2g rapidly equilibrates at
the stereogenic center due to a lack of the R-substituent
on the Cp ring (Figure 4). The planar chiral R-substituted
ferrocenecarboxaldehyde could intercept either configu-
rated species among the equilibrated carbanions depend-
ing on the planar chirality of arylaldehydes. Thus, the
anti-oriented carbonyl of the planar chiral ferrocenecar-
(21) Predominant anti conformation of the CdO or CdN double bond
to the ortho substituents of ferrocenyl compounds was proposed by
diastereoselective nucleophilic addition to the double bond. For a review
see: Ferrocenes; Togni, A., Hayashi, T., Eds.; VCH: Weinheim,
Germany, 1995.
F IGURE 4. Proposed reaction mechanism of cross-coupling
with achiral N-tosyl ferrocenylideneamine.
(
22) R-Ferrocenyl lithium derivatives have similar stereochemical
character for the electrophilic quenching depending on the R-position
in the presence or absence of an ortho substituent on the Cp ring.
Ireland, T.; Perea, J . J . A.; Knochel, P. Angew. Chem., Int. Ed. 1999,
boxaldehydes 7 is attacked via transition state 27 giving
a single anti-amino alcohol 16. On the other hand, ent-7
gave the antipode anti-â-amino alcohol, ent-16, via the
transition state 28. In the cross-coupling of the achiral
ferrocenylideneamine with planar chiral arylaldehydes,
dynamic kinetic resolution takes place among the equili-
brating R-ferrocenyl carbanion configuration.
3
8, 1457.
23) A mechanism of acyclic selection in intermolecular radical
reactions and intramolecular radical cyclization. (a) Smadja, W. Synlett
(
1
1
6
994, 1. (b) Bobo, S.; Storch de Gracia, I.; Chiara, J . S. Synlett 1999,
551. (c) Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J . Org. Chem. 1998,
3, 5877.
9
232 J . Org. Chem., Vol. 67, No. 26, 2002

Asymmetric Synthesis of anti- and syn-â-Amino Alcohol
TABLE 6. Cr oss-Cou p lin g of Ben zylid en ea m in e 29 w ith
Ben za ld eh yd e or th e Cor r esp on d in g Ch r om iu m
Com p lexes
TABLE 7. Cr oss-Cou p lin g of â-Na p h th ylim in e 31
a
entry
aldehyde
yield 32 (%)
syn/anti
1
2
3
4
5
6
11a
11b
11c
14a
14b
14c
83
89
76
67
74
89
65/35
78/22
74/26
94/6
83/17
78/22
entry
imine
aldehyde
30 (yield, %)
syn/ anti
diastereoselectivity by the tricarbonylchromium com-
plexation would be attributed to a stereoelectronic effect
of the tricarbonylchromium fragment.25
a
1
2
3
4
5
6
29a
29a
29a
29a
29a
29a
29b
29b
29b
29b
29b
29b
29b
29b
11a
11b
11c
14a
14b
14c
11a
11b
11c
11d
14a
14b
14c
14d
30a (77)
30b (70)
30c (93)
30a (78)
30b (63)
30c (89)
30d (81)
30e (74)
30f (76)
30g (52)
30d (73)
30e (60)
30f (33)
54/46
50/50
50/50
67/33
60/40
67/33
70/30
80/20
70/30
87/13
97/3
a
a
a
Interestingly, the major â-amino alcohol 30 obtained
a
26
in this combination was found to be a syn isomer. The
a
predominant formation of the syn-â-amino alcohol in this
combination is in sharp contrast to the reductive cross-
coupling of N-tosyl ferrocenylideneamine with arylalde-
hydes giving the anti-â-amino alcohols as mentioned
above. Similarly, ortho-substituted benzaldehyde chro-
mium complexes were coupled with N-tosyl benzylidene-
amine (29b) to produce the corresponding syn-amino
alcohols along with formation of a small amount (1-5%)
of homo-coupling â-diols derived from benzaldehyde
chromium complexes under the same conditions (entries
7
8
9
1
1
1
1
1
0
1
2
3
4
b
b
b
b
95/5
97/3
97/3
c
30g (38)
a
b
Isolated as amino alcohols without acetylation. Homocou-
c
pling 1,2-diols were obtained in 1-5% yields. Yield of cross-
coupling was 60% before photooxidation.
1
2-14). However, the cross-coupling of ferrocenecarbox-
aldehyde with 29b gave a homo-coupling â-diol in 95%
yield without formation of the expected â-amino alcohol,
while the cross-coupling of N-tosyl ferrocenylideneamines
with ferrocenecarboxaldehydes proceeded in good yields
as mentioned above. The electronic factor of aldehydes
and imines seems to be also significant for an efficient
achievement of the cross-coupling giving â-amino alco-
hols. Therefore, an electron-donating methoxy group was
introduced on the arene ring of N-tosyl benzylideneamine
Cr oss-Cou p lin g
Ald eh yd es
of Ben zylid en ea m in es
w ith
For further extension of the reductive cross-coupling
giving optically active â-amino alcohols, we next studied
2
4
the cross-coupling with benzylideneamines. N-Sulfonyl
benzylideneamines 29a and 29b would be expected to
give â-amino alcohols in the cross-coupling with arylal-
dehydes by judging of the reduction potentials (Table 5).
Indeed, the cross-coupling of N-methanesulfonyl ben-
zylideneamine (29a ) with benzaldehyde 11 gave the
corresponding â-amino alcohol derivatives 30 in good
yields without formation of homo-coupling products
(29b) for the reductive cross-coupling. As expected,
N-tosyl 3,4,5-trimethoxybenzylideneamine was coupled
with ferrocenecarboxaldehyde to give a 1:1 diastereomeric
mixture of the corresponding â-amino alcohols, albeit in
3
0% yield.
(Table 6). However, the diastereoselectivity of anti- and
Furthermore, the cross-coupling of N-tosyl naphthyl-
syn-â-amino alcohols was extremely low (entries 1-3).
The corresponding benzaldehyde tricarbonylchromium
complexes 14 were also coupled with the imine 29a with
a slight increase of the diastereoselectivity (entries 4-6).
With N-tosyl benzylideneamine (29b), the diastereose-
lectivity of the cross-coupling products increased ap-
preciably (entries 7-10). Among the ortho-substituted
benzaldehydes studied, o-chlorobenzaldehyde (10d ) re-
sulted with higher diastereoselectivity in 52% yield (entry
imines with benzaldehydes was examined (Table 7).
â-Naphthylimine 31 was coupled with benzaldehydes 11
to give a diastereomeric mixture of â-amino alcohol
derivatives 32 in good yields. The major isomers of the
obtained â-amino alcohols were also syn isomers. Simi-
larly, the corresponding tricarbonylchromium complexes
of benzaldehyde increased syn diastereoselectivity in the
(25) The coordination of a tricarbonylchromium fragment to the
1
0). The cross-coupling of benzaldehyde chromium com-
arene ring was found to also increase the diastereoselectivity in the
asymmetric allyboration of aromatic aldehydes: Roush, W. R.; Park,
J . C. J . Org. Chem. 1990, 55, 1143.
plex (14a ) with N-tosyl benzylideneamine (29b) gave
â-amino alcohol derivative 30d with high diastereose-
lectivity in 73% overall yield after acetylation and
subsequent demetalation (entry 11). The increase of
(26) Authentic N-tosyl-2-amino-1,2-diphenylethyl alcohol 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.
1
987, 26, 1141. The corresponding syn-â-amino alcohol: (c) Reetz, M.
(
24) A preliminary report: Tanaka, Y.; Taniguchi, N.; Uemura, M.
T.; Drewes, M. W.; Lennick, K.; Schmitz, A.; Holdgr u¨ n, X. Tetrahe-
dron: Asymmetry 1990, 1, 375.
Org. Lett. 2002, 4, 835.
J . Org. Chem, Vol. 67, No. 26, 2002 9233

Tanaka et al.
SCHEME 7a
F IGURE 5.
A reaction mechanism of the cross-coupling of N-tosyl
aldimines 29b or 31 with planar chiral benzaldehyde
chromium complexes has been postulated to rationalize
the observed syn stereoselectivity (Figure 5). The reactive
species generated from the imines would be rapidly
equilibrated at the newly created stereogenic center as
well as achiral N-tosyl ferrocenylideneamine 2g. The
planar chiral ortho-substituted benzaldehyde chromium
complex is oriented anti of the carbonyl oxygen to the
ortho substituents.28 The transition state giving the syn-
amino alcohols is proposed as the coordination structure
of the samarium with both nitrogen and carbonyl oxygen
atoms 36 or 37 via dynamic kinetic resolution of the
generated reactive species depending on the planar
chirality of benzaldehyde chromium complexes. As shown
in Figures 3 and 4, the transition states of the cross-
coupling with N-tosyl ferrocenylideneamines were pro-
posed as the dipole-dipole repulsion intermediate be-
cross-coupling with â-naphthylimine 31. However, the
corresponding R-naphthylimine gave no cross-coupling
â-amino alcohol product under the same conditions.
We next turned our attention to the preparation of
optically active â-amino alcohol derivatives by using
planar chiral benzaldehyde chromium complexes (Scheme
III
tween N-Sm and carbonyl oxygen groups. An alternative
transition state might be proposed in the cross-coupling
with N-tosyl benzylideneamine from the following results.
The reaction of benzylideneamine 29b with aliphatic
aldehydes was different from the cross-coupling of N-tosyl
ferrocenylideneamine with aliphatic aldehydes. Thus,
N-tosyl benzylideneamine (29b) gave a complex mixture
by reaction with aliphatic aldehydes, while the ferroce-
nylideneamine afforded the expected â-amino alcohols by
coupling with both aromatic and aliphatic aldehydes in
good yields as shown above. These results indicate that
in the cross-coupling of 29b with arylaldehydes, both
ketyl radical species generated from the imine and
arylaldehydes might be coupled via a coordination struc-
ture 38 with the samarium metal without stepwise
reaction. On the other hand, in the combination between
N-tosyl ferrocenylideneamine and aldehydes, the dianion
species would be initially generated from the imine and
the generated reactive species reacts with aldehydes to
give the â-amino alcohols. Further elucidation of the
reaction mechanism is necessary for an explanation of
the stereochemically distinguished cross-coupling be-
tween N-tosyl ferrocenylideneamine and benzylideneam-
ine.
7
). Enantiomerically pure (+)-(1S)-o-methylbenzaldehyde
chromium complex (17b) was coupled with 29b to give a
chromium-complexed (+)-(1S,2R)-â-amino alcohol deriva-
tive 33 (>99% ee). Exposure of 33 to sunlight gave a
2
7
chromium-free (-)-(R,R) -â-amino alcohol derivative 34.
On the other hand, an antipode (-)-o-methylbenzalde-
hyde chromium complex (ent-17b) produced (+)-(S,S)-â-
amino alcohol ent-34 under the same reaction sequence.
In this way, both enantiomers of syn-â-amino alcohol
could be prepared by the coupling of N-tosyl benzyli-
deneamine with the planar chiral benzaldehyde chro-
mium complexes. Similarly, the cross-coupling of N-tosyl
â-naphthylimine 31 with the planar chiral benzaldehyde
chromium complexes 17b and ent-17b gave both enan-
tiomers of the corresponding syn-â-amino alcohol deriva-
tives 35 and ent-35, respectively, depending on the planar
chirality. Thus, configurationally equilibrated reactive
species generated from N-tosyl imines 29b or 31 obvi-
ously underwent a dynamic kinetic resolution in the
cross-coupling with the planar chiral benzaldehyde chro-
mium complexes, in analogy with the cross-coupling of
achiral N-tosyl ferrocenylideneamine 2g with planar
chiral arylaldehydes as shown in Schemes 4 and 5.
(
28) (a) Solladi e´ -Cavallo, A. Advances in Metal-Organic Chemistry;
(
27) The absolute configuration of the syn-coupling product 34 was
Liebeskind, L. S., Ed.; J AI 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, UK, 1995; Vol. 12, p 1039.
determined as the (R,R)-configuration by comparison of the optical
rotation sign of authentic syn-â-amino alcohol derived from (R)-2-
phenylglycine according to ref 26c.
9
234 J . Org. Chem., Vol. 67, No. 26, 2002

Asymmetric Synthesis of anti- and syn-â-Amino Alcohol
SCHEME 8
TABLE 8. Asym m etr ic CBS Red u ction of
Acetop h en on ea
b
entry
ligand 40
yield (%)
% ee (configuration)
1
2
3
4
5
40a
40b
40c
40d
40e
83
62
77
78
73
91 (S)
66 (S)
90 (S)
90 (S)
90 (S)
a
Enanriomeric purity of chiral â-amino alcohols used in this
b
study was ∼95% ee. Enantiomeric excess was determined by
HPLC with Chiralcel OD-H (eluted with hexane/2-propanol (9/1),
0
.5 mL/min).
Ap p lica tion to Asym m etr ic Rea ction
species from achiral N-tosyl ferrocenylidenamine and
benzylideneamine was observed by the coupling with
planar chiral arylaldehydes. High catalytic asymmetric
reduction of acetophenone was achieved by using chiral
oxazaborolidine derived from anti-â-amino alcohols with
ferrocene rings as a chiral ligand.
Having established a general method for the prepara-
tion of optically active â-amino alcohol derivatives, we
explored the possibility of asymmetric reaction as a chiral
ligand. At first, the catalytic efficiency of these new chiral
ferrocenyl ligands was studied for CBS reduction29 of
ketones. The chiral â-amino alcohols 39 were prepared
by reductive elimination of the N-tosyl group of 9 with
lithium naphthalide in good yields (Scheme 8). These
chiral anti-â-amino alcohols 39 were converted to B-
methyl or phenyl oxazaborolidines 40 by treatment with
methylboronic acid or phenylboronic acid under dehy-
drating conditions.
Exp er im en ta l Section
All manipulations involving organometallics were carried
out under an atmosphere of nitrogen or argon with inert gas/
vacuum double-manifold techniques. All melting points were
determined on a Yanagimoto MPJ -2 micro melting point
apparatus and are uncorrected. NMR spectra were recorded
The effect of the substituent R on the borane of 40 was
initially studied in catalytic asymmetric reduction of
acetophenone. The reduction was carried out in the
presence of 5 mol % of B-substituted oxazaborolidine 40
and equivalent borane in THF at room temperature.
B-Phenyl-substituted oxazaborolidine 40b resulted in
lower yield and enantioselectivity than the corresponding
B-methyl-substituted ligand 40a due to the steric effect.
We next examined the steric effect of the substituent on
the Cp ring. It is obvious from Table 8 that the methyl
substituent on the ferrocene ring has no significant effect
for the asymmetric induction of reduction of acetophe-
none. The oxazaborolidine 40a without a methyl sub-
stituent has enough steric effect for direction of the
substrate approach based on the cis conformation of both
ferrocene rings. Thus, asymmetric reduction of acetophe-
none was achieved by using chiral oxazaborolidine 40a
with high optical purity.
In conclusion, we have demonstrated asymmetric
synthesis of â-amino alcohols by samarium iodide-medi-
ated cross-coupling of the planar chiral arylaldehydes
with arylaldimines. The diastereoselectivity of anti- and
syn-â-amino alcohols was governed by the nature of
arylaldimines used. N-Tosyl ferrocenylidenamines gave
anti-â-amino alcohols by coupling with arylaldehydes,
while benzylideneamines afforded syn-â-amino alcohols.
Also, dynamic kinetic resolution of the generated reactive
3
in CDCl solvent with tetramethylsilane as an internal refer-
ence. Optical rotations were measured on a J ASCO DIP-370
automatic polarimeter at 589 nm (sodium D line) using a 0.5-
dm cell. Reductive potentials were measured with a Poten-
tiostat/Galvanostat (Hokuto Denko HA-501G) and a Function
Generater (Hokuto Denko HB-105). Diethyl ether and tet-
rahydrofuran were distilled from sodium/benzophenone ketyl
immediately before use. Methylene chloride was distilled over
P
2
O
5
before use.
P r ep a r a tion of (S)-N-Tosyl R-Iod ofer r ocen ylid en ea m -
in e (8b). A mixture of (S)-R-iodoferrocenecarboxaldehyde (7b)
100 mg, 0.3 mmol), p-tosyl sulfonamide (55 mg, 0.3 mmol), a
(
catalytic amount of p-TsOH (5 mg), and MS 4A (1 g) in ether
(5 mL) was stirred for 14 h at room temperature. After
filtration, the mixture was extracted with ether. The extract
was washed with saturated aqueous NaHCO
over MgSO , and evaporated under reduced pressure. The
3
and brine, dried
4
residue was purified by silica gel chromatography (hexane/
ether, 1/1) to give N-tosyl benzylideneamine 8b (105 mg, 71%)
1
as a red oil. H NMR (270 MHz, CDCl
3
) δ 2.43 (3H, s), 4.20
(5H, s), 4.80-4.82 (1H, m), 4.92-4.94 (1H, m), 5.04-5.05 (1H,
m), 7.34 (2H, d, J ) 8.2 Hz), 7.88 (2H, d, J ) 8.2 Hz), 9.13 (s,
2
6
1H); [R]
D
3
+1400 (c 0.09, CHCl ).
Cr oss-Cou p lin g of P la n a r Ch ir a l Ar yla ld eh yd es w ith
N-Tosyl Ar yla ld im in es. A typical procedure for the prepara-
tion of 9a is as follows: To a solution of 7a (107.0 mg, 0.47
mmol) and 8a (167.0 mg, 0.43 mmol) in dry THF (1.0 mL) was
added a solution of SmI (0.10 M, 21.5 mL, 2.15 mmol) in THF
2
at 0 °C, and the solution was stirred at the same temperature
for 30 min under argon atmosphere. The reaction mixture was
4
quenched with saturated aqueous NH Cl and the resulting
(
29) Some representative references; (a) Itsuno, S.; Sakurai, Y.; Ito,
mixture was filtered through a Celite pad. The filtrate was
extracted with ether. The extract was washed with brine, dried
K.; Hirao, A.; Nakahama, S. Bull. Chem. Soc. J pn. 1987, 60, 395. (b)
Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc. 1987, 109,
551. (c) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh,
V. K. J . Am. Chem. Soc. 1987, 109, 7925. (d) Wallbaum, S.; Martens,
J . Tetrahedron: Asymmetry 1992, 3, 1475. (e) Lin, G.-Q.; Li, Y.-M.;
Chan, A. S. C. Principles and Applications of Asymmetric Synthesis;
Wiley and Sons: New York, 2001; p 367.
over MgSO
residue was purified by column chromatography on silica gel
eluted with Et O/hexane) to give 245.7 mg (92%) of 9a . Yellow
crystals; mp 159-160 °C dec; H NMR (270 MHz, CDCl
4
, and evaporated under reduced pressure. The
5
(
2
1
3
) δ
1.24 (3H, s), 1.30 (3H, s), 2.05 (1H, d, J ) 4.6 Hz), 2.49 (3H,
J . Org. Chem, Vol. 67, No. 26, 2002 9235

Tanaka et al.
1
-
s), 3.73 (1H, s), 3.79 (1H, s), 3.86 (1H, t, J ) 5.0 Hz), 3.95 (5H,
s), 3.98-3.99 (2H, m), 4.00 (5H, s), 4.07-4.14 (2H, m), 4.43
3270, 1600, 1310, 1140 cm- . HRMS (FAB ) calcd for C15
16
H -
NO S 290.0851, found 290.0855.
The coupling products 30 derived from N-tosyl benzylidene-
amine (29b) with benzaldehydes or the corresponding chro-
mium complexes were isolated as acetate derivatives. 30d :
colorless amorphous; H NMR (300 MHz, CDCl
3
(1H, t, J ) 5.9 Hz), 5.49 (1H, d, J ) 5.0 Hz), 7.45 (2H, d, J )
8
.2 Hz), 7.97 (2H, d, J ) 8.2 Hz); 13C NMR (67 MHz, CDCl
δ 13.2, 13.7, 21.6, 57.5, 65.9, 66.1, 66.3, 68.0, 68.8, 69.0, 69.1,
9.3, 70.8, 72.6, 82.8, 84.2, 84.8, 127.3, 129.9, 137.9, 143.9.
Anal. Calcd for C31 SFe : C, 60.90; H, 5.44; N, 2.29.
3
)
6
1
3
) for the syn
H
33NO
3
2
isomer, δ 2.03 (3H, s), 2.31 (3H, s), 4.68 (1H, t, J ) 7.3 Hz),
2
2
Found: C, 60.70; H, 5.18; N, 2.40; [R]
enantiomeric purity was determined by HPLC with Chiralcel
D
+99.7 (c 0.80, CHCl
3
);
1
5
.57 (1H, br), 5.89 (1H, d, J ) 7.3 Hz), 6.88-7.53 (14H, m); H
NMR (300 MHz, CDCl ) for the anti isomer, δ 1.97 (3H, s),
.32 (3H, s), 4.81 (1H, dd, J ) 9.0, 4.5 Hz), 5.35 (1H, br), 5.91
1H, d, J ) 4.5 Hz), 6.88-7.53 (14H, m); IR (Nujol) 3300, 1730,
3
OD-H (eluted with hexane/2-propanol (9/1), 0.5 mL/min); 95%
ee.
2
(
1
0: 93%; yellow crystals; mp 177-178 °C; 1H NMR (270
MHz, CDCl ) δ 2.35 (1H, d, J ) 3.0 Hz), 2.48 (3H, s), 3.38-
.39 (1H, m), 4.03 (5H, s), 4.05 (5H, s), 4.07-4.29 (6H, m), 4.64
1H, br), 5.53 (1H, d, J ) 5.9 Hz), 7.42 (2H, d, J ) 8.2 Hz),
-1
+
24
1600, 1320, 1240, 1160 cm . HRMS (FAB ) calcd for C23H -
3
NO
4
S 410.1427, found 410.1427.
1
3
32a : colorless amorphous; H NMR (300 MHz, CDCl ) for
3
the syn isomer, δ 2.14 (3H, s), 2.71 (1H, br), 4.60 (1H, t, J )
6.2 Hz), 4.88 (1H, d, J ) 6.2 Hz), 5.77 (1H, t, J ) 6.2 Hz),
(
8
4
7
.08 (2H, d, J ) 8.2 Hz); 13C NMR (67 MHz, CDCl
) δ 21.7,
3
1
4.9, 45.8, 56.8, 65.3, 68.0, 69.1, 70.8, 71.3, 71.6, 73.5, 74.3,
5.9, 81.0, 87.5, 127.6, 129.8, 137.2, 143.7. Anal. Calcd for
6.81-7.82 (16H, m); H NMR (300 MHz, CDCl ) for the anti
3
isomer, δ 2.10 (3H, s), 2.55 (1H, br), 4.70 (1H, dd, J ) 7.5, 3.9
C
29
H
27NO
3
SFe
2
I
2
: C, 41.71; H, 3.26; N, 1.68. Found: C, 41.68;
Hz), 5.08 (1H, d, J ) 3.9 Hz), 5.94 (1H, d, J ) 7.5 Hz), 6.81-
2
5
-1
H, 3.30; N, 1.61. [R]
D
+5.0 (c 0.76, CHCl
3
).
7.82 (16H, m); IR (Nujol) 3450, 3240, 1590, 1320, 1150 cm .
1
-
1
3a : yellow crystals; mp 145-146 °C; H NMR (270 MHz,
3
HRMS (FAB ) calcd for C25H22NO S 416.1321, found 416.1329.
Com p ou n d 33 (67%): yellow amorphous; 1H NMR (300
MHz, CDCl ) δ 1.80 (3H, s), 2.12 (3H, s), 2.29 (3H, s), 4.60
(1H, dd, J ) 9.4, 6.5 Hz), 4.76 (1H, d, J ) 6.2 Hz), 5.09 (1H,
t, J ) 6.2 Hz), 5.40 (1H, t, J ) 6.2 Hz), 5.72 (1H, d, J ) 6.2
Hz), 5.92 (1H, t, J ) 6.5 Hz), 6.04 (1H, d, J ) 9.4 Hz), 6.76-
7.65 (9H, m); IR (Nujol) 3250, 1960, 1870, 1740, 1600, 1330,
CDCl
J ) 7.5 Hz), 3.83 (1H, br), 3.93 (5H, s), 3.95-3.98 (3H, br),
.05-4.06 (1H, br), 4.07 (5H, s), 4.12-4.22 (1H, m), 4.45 (1H,
br), 5.27 (1H, d, J ) 7.5 Hz), 7.38 (2H, d, J ) 8.2 Hz), 7.91
3
) δ 1.69 (3H, s), 2.00 (1H, br), 2.46 (3H, s), 3.60 (2H, d,
3
4
1
3
(
5
8
2H, d, J ) 8.2 Hz); C NMR (67 MHz, CDCl
3
) δ 13.5, 21.6,
8.0, 65.3, 65.5, 66.0, 67.0, 67.7, 68.7, 68.8, 69.0, 69.8, 70.8,
2.7, 85.1, 86.6, 127.1, 129.5, 138.3, 143.3. Anal. Calcd for
SFe : C, 60.32; H, 5.23; N, 2.34. Found: C, 60.19;
H, 5.21; N, 2.30. [R]
-
1
1230, 1160 cm ; HRMS (FAB) calcd for C27H25NO SCr
7
559.0757, found 559.0762; [R]19 +49.0 (c 0.10, CHCl ). A
C
30
H
31NO
3
2
D
3
2
2
D
-22.8 (c 0.88, CHCl
3
).
solution of the chromium-complexed â-amino alcohol derivative
33 (56 mg, 0.10 mmol) in ether (5 mL) was exposed to sunlight
at 0 °C for 30 min, and the mixture was filtered and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel (eluted with ether/hexane) to give
Cr oss-Cou p lin g of Ach ir a l F er r ocen ylid en ea m in e 2g
w ith Ben za ld eh yd e a n d th e Cor r esp on d in g Ch r om iu m
Com p lexes. A typical procedure for the preparation of 18b
is as follows: To a solution of (S)-(+)-tricarbonyl(o-methoxy-
benzaldehyde)chromium (17b) (>99% ee) (100.0 mg, 0.27
mmol) and 2g (100 mg, 0.27 mmol) in THF (1.0 mL) was added
(R,R)-syn-amino alcohol 34 (39 mg, 90%) as a colorless solid:
H NMR (270 MHz, CDCl ) δ 1.96 (3H, s), 2.02 (3H, s), 2.33
1
3
a solution of SmI
2
(0.10 M, 13.5 mL, 1.35 mmol) at 0 °C, and
(3H, s), 4.70 (1H, t, J ) 7.1 Hz), 5.31 (1H, d, J ) 7.1 Hz), 6.05
(1H, dt, J ) 7.1 Hz), 6.89-7.39 (13H, m); IR (Nujol) 3180, 1720,
the mixture was stirred for 30 min. Usual workup gave the
coupling product which was used for acetylation without
purification. A solution of the obtained crude product in
pyridine (2 mL), acetic anhydride (1 mL), and 4-dimethylami-
nopyridine (10.0 mg) was stirred at room temperature for 1 h
under argon. The reaction mixture was quenched with satu-
-
1
1600, 1340, 1240, 1160 cm ; HRMS (FAB-OAc) calcd for
C
CHCl
22
H
22NO
2
S 364.1372, found 364.1372; [R]23
3
). The diastereomeric ratio of the syn and anti isomers
D
-26.6 (c 0.12,
1
was determined by H NMR of the crude product without
purification at each step. The protons of CH(NTs)-CH(OAc)-
for the syn isomer appeared usually at higher field than those
of the corresponding protons of the anti isomer. 34: for the
anti isomer 4.72 (1H, dd, J ) 8.4, 4.6 Hz, -CH(NTs)-CH-
(OAc)-), 6.11 (1H, d, J ) 4.6 Hz, -CH(NTs)-CH(OAc)-). The
enantiomeric purity of 33 was determined by chiral HPLC with
Chiralcel OD-H (eluted with hexane/2-propanol (9/1), 0.5 mL/
min) and the ee of 34 was determined with Chiralcel OJ -H
rated aqueous NH
with ether. The reaction mixture was extracted with ether,
and the extract was washed with aqueous 6 N HCl, H O,
saturated aqueous NaHCO , and brine, dried over MgSO , and
evaporated under reduced pressure. The residue was purified
by column chromatography on silica gel (eluted with Et O/
hexane; 1/1) to give 140.5 mg (94%) of 18b: mp 154-155 °C;
4
Cl and the resulting mixture was extracted
2
3
4
2
1
H NMR (270 MHz, CDCl
1H, br), 3.79 (3H, s), 3.96 (1H, br), 4.04 (1H, br), 4.09 (1H,
br), 4.15 (5H, s), 4.61 (1H, dd, J ) 4.0, 7.6 Hz), 5.21 (1H, d, J
7.6 Hz), 6.07 (1H, d, J ) 4.0 Hz), 6.66 (1H, t, J ) 7.9 Hz),
.68 (1H, d, J ) 7.2 Hz), 6.74 (1H, J ) 7.9 Hz), 7.13 (1H, t, J
7.2 Hz), 7.30 (2H, d, J ) 8.2 Hz), 7.80 (2H, d, J ) 8.2 Hz);
3
) δ 2.00 (3H, s), 2.43 (3H, s), 3.60
(eluted with hexane/2-propanol (9/1), 0.5 mL/min).
35: yellow amorphous; H NMR (300 MHz, CDCl
1
(
3
) δ 1.80
(3H, s), 2.11 (3H, s), 2.14 (3H, s), 4.73 (1H, d, J ) 6.2 Hz),
4.77 (1H, t, J ) 7.7 Hz), 5.14 (1H, t, J ) 6.2 Hz), 5.40 (1H, t,
J ) 6.2 Hz), 5.55 (1H, d, J ) 7.7 Hz), 5.76 (1H, t, J ) 6.2 Hz),
6.04 (1H, d, J ) 7.7 Hz), 6.88 (2H, d, J ) 7.3 Hz), 7.05 (1H, d,
J ) 8.8 Hz), 7.37-7.72 (8H, m); IR (Nujol) 3230, 1950, 1870,
)
6
)
1
3
C NMR (67 MHz, CDCl ) δ 21.1, 21.6, 55.4, 55.5, 65.9, 66.9,
3
-
1
6
1
1
7.7, 68.7, 69.1, 71.7, 86.2, 110.0, 120.1, 125.2, 126.8, 126.9,
28.7, 129.5, 138.2, 143.1, 155.6, 169.2; IR (Nujol) 3250, 1740,
1730, 1600, 1330, 1220, 1160 cm ; HRMS calcd for C31
NO
27
H -
SCr 609.0914, found 609.0915; [R]22
7
D
3
-31.1 (c 0.1, CHCl );
600, 1320, 1230, 1160 cm-1. Anal. Calcd for C28
H29NO SFe:
5
99% ee. HPLC conditions: Chiralcel OD, hexane/2-propanol
(9/1), flow rate 0.5 mL/min, 40 °C, retention time 50.6 min.
C, 61.43; H, 5.34; N, 2.56. Found: C, 61.25; H, 5.35; N, 2.45.
2
7
[R]
D
+66.7 (c 0.15, CHCl
3
).
Deiod on a tion of th e Cr oss-Cou p lin g P r od u cts 9b, 10,
a n d en t-16 w ith n -Bu Li. A typical procedure is as follows:
To a solution of â-amino alcohol 9b (100.0 mg, 0.12 mmol) in
THF (5.0 mL) was added n-BuLi (1.6 M, 0.3 mL, 0.48 mmol)
in hexane at 0 °C, and the solution was stirred at the same
temperature for 1 h under argon atmosphere. The reaction
mixture was quenched with saturated aqueous NH
extracted with ether. The extract was washed with brine, dried
over MgSO , and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel
(eluted with Et O/hexane) to give 70.6 mg (95%) of 9g: yellow
The cross-coupling products 30 derived from N-mesyl ben-
zylideneamine (29a ) with benzaldehydes or the corresponding
chromium complexes were isolated as alcohol derivatives.
1
3
0a : H NMR (300 MHz, CDCl
3
) for the syn isomer, δ 2.32
(
(
(
1H, d, J ) 3.3 Hz), 2.39 (3H, s), 4.65 (1H, t, J ) 5.6 Hz), 4.94
1H, dd, J ) 5.6, 3.3 Hz), 5.32 (1H, d, J ) 5.6 Hz), 7.03-7.11
4
Cl and
1
4H, m), 7.27-7.34 (6H, m); H NMR (300 MHz, CDCl
3
)for the
anti isomer, δ 2.28 (1H, d, J ) 4.4 Hz), 2.56 (3H, s), 4.73 (1H,
4
dd, J ) 8.1, 4.4 Hz), 5.13 (1H, t, J ) 4.4 Hz), 5.15 (1H, d, J )
8
.1 Hz), 7.05-7.11 (4H, m), 7.22-7.29 (6H, m); IR (Nujol) 3460,
236 J . Org. Chem., Vol. 67, No. 26, 2002
2
9

Asymmetric Synthesis of anti- and syn-â-Amino Alcohol
1
crystals; mp 146-147 °C dec; H NMR (270 MHz, CDCl
3
) δ
mL) and evaporated under reduced pressure. After carrying
out this operation three times, the residue was dissolved in
THF (4 mL). To the above solution was added a borane (1.0 M
in THF, 0.83 mL, 0.83 mmol), and the reaction mixture was
stirred for 15 min at room temperature. A solution of aceto-
phenone (100 mg, 0.83 mmol) in THF (1 mL) was added to
the above solution at room temperature with a syringe over
10 min, and stirring was continued for 1 h. After being
quenched with MeOH (4 mL) and 1 M aqueous HCl (4 mL),
the reaction mixture was extracted with ether. The organic
2
.14 (1H, br), 3.69 (1H, s), 2.47 (3H, s), 3.66 (1H, s), 3.81 (2H,
s), 3.97-4.01 (3H, m), 4.03 (5H, s), 4.06 (5H, s), 4.27-4.33 (3H,
m), 5.08 (1H, d, J ) 7.9 Hz), 7.41 (2H, d, J ) 8.2 Hz), 7.92
1
3
(
2H, d, J ) 8.2 Hz); C NMR (67 MHz, CDCl ) δ 21.6, 59.1,
3
6
5.9, 66.4, 67.4, 67.5, 67.6, 67.7, 67.8, 67.9, 68.5, 68.8, 72.6,
4.9, 87.6, 127.2, 129.8, 138.1, 143.7. Anal. Calcd for C29
SFe : C, 59.71; H, 5.01; N, 2.40. Found: C, 59.67; H, 5.04;
N, 2.34. [R]
8
29
H -
NO
3
2
2
6
D
3
+40.8 (c 0.61, CHCl ).
Desu lfon yla tion of 9. A typical procedure is as follows: A
mixture of Li metal (29.0 mg, 4.25 mmol) and naphthalene
4
layer was washed with brine, dried over MgSO , and evapo-
(
4.0 mg, 0.03 mmol) in dry THF (5.0 mL) was stirred for 2 h
at -78 °C under argon atmosphere. A solution of amino alcohol
g (100.0 mg, 0.17 mmol) in dry THF (3.0 mL) was added to
a lithium naphthalenide solution at -78 °C with stirring for
h. The reaction mixture was quenched with MeOH and
extracted with ether. The extract was washed with brine, dried
over MgSO , and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel
eluted with ethyl acetate/hexane) to give 67.5 mg (92%) of
rated under reduced pressure. The residue was purified by
column chromatography to give R-phenyl ethyl alcohol. The
enantiomeric purity and absolute configuration were deter-
mined by chiral HPLC with chiralcel OD-H with comparison
of authentic optically active and racemic compounds. HPLC
conditions: hexane/2-propanol 9/1, column temperature 40 °C,
flow rate 0.5 mL/min, (S)-(+)-isomer 12.3 min, (R)-(-)-isomer
13.1 min.
9
2
4
(
1
2
desulfonylated amino alcohol 39 (R ) R ) H): yellow
Ack n ow led gm en t. This work was financially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sports and Culture.
We gratefully thank Dr. M. Satoh for measurement of
the reduction potential.
1
crystals; mp 157-158 °C; H NMR (270 MHz, CDCl
3
) δ 1.87
(
1H, br), 3.69 (1H, d, J ) 5.0 Hz), 3.96 (1H, s), 4.04 (1H, s),
4
5
6
.08-4.10 (8H, m), 4.11 (5H, s), 4.15 (5H, s), 4.23 (1H, d, J )
13
.0 Hz); C NMR (67 MHz, CDCl
7.5, 67.6, 67.7, 68.2, 68.3, 68.4, 68.6, 74.5, 89.6, 90.5. Anal.
23NOFe : C, 61.58; H, 5.40; N, 3.26. Found: C,
1.51; H, 5.42; N, 3.23. [R]
Ca ta lytic Asym m etr ic Red u ction of Acetop h en on e.
After a solution of methylboronic acid (0.05 mmol) and chiral
3
) δ 56.6, 65.1, 65.4, 67.3,
Calcd for C22
6
H
2
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the reductive cross-coupling, as well as spectral data
for new compounds and X-ray analysis of 9a , ent-10, and 18b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2
3
D
3
-24.0 (c 0.20, CHCl ).
1
2
â-amino alcohol 39 (R ) R ) H) (0.042 mmol) in toluene (20
mL) was refluxed for 2 h, the reaction mixture was reduced
by vacuum pump. The residue was dissolved in dry toluene (2
J O0205412
J . Org. Chem, Vol. 67, No. 26, 2002 9237