Asymmetric synthesis of β-amino alcohols by cross-pinacol coupling of planar chiral ferrocenecarboxaldehydes with imines [2]

Full text of DOI:10.1021/ja000479v

J. Am. Chem. Soc. 2000, 122, 8301-8302
8301
Table 1. Cross-Coupling between Ferrocenecarboxaldehyde 1 and
Ferrocenylideneamine 2
Asymmetric Synthesis of â-Amino Alcohols by
Cross-Pinacol Coupling of Planar Chiral
Ferrocenecarboxaldehydes with Imines
Nobukazu Taniguchi and Motokazu Uemura*
Department of Chemistry
Faculty of Integrated Arts and Sciences
Osaka Prefecture UniVersity, Sakai, Osaka 599-8531, Japan
ReceiVed February 8, 2000
Although a pinacol coupling of carbonyl or imine compounds
is the most direct way to synthesize 1,2-diols or diamines, a highly
stereoselective formation of these compounds is problematic.1
Furthermore, the preparation of optically enriched compounds is
not so easy under pinacol coupling conditions.2 In contrast to the
homo-pinacol coupling, the cross-coupling reaction between two
substrates is an even more complicated problem. Only few
examples of an intermolecular cross-coupling of carbonyls with
imines have been reported as a racemic form.3 We now wish to
report enantioselective synthesis of â-amino alcohols by samarium
iodide-mediated cross-coupling of the planar chiral N-sulfonyl
ferrocenylideneamine with carboxaldehydes.
entry
imine 2
3 yield (%)
4 yield (%)
5 yield (%)
1a
2a
3
2a
2b
2c
2d
2e
2f
0
0
95
0
0
96
0
96
95
0
4b
5b
6
0
98
0
92
0
92
88
trace
trace
0
7
2g
0
a Obtained 1 as hydrolysis product of 2 in >98% yield. b Recovered
2 in 90-98% yield.
To achieve an efficient cross-pinacol coupling between two
substrates, it is apparently significant for either substrate to be
more easily reduced to the corresponding ketyl radical or ionic
species, and the generated reactive species to react with another
substrate prior to the homo-coupling. We initially focused on the
effect of the substituent on the nitrogen atom for the cross-coup-
ling between ferrocenecarboxaldehyde and the corresponding aldi-
mines (Table 1). Among various N-substituents studied, it was
fortunately found that an electron-withdrawing N-phenylsulfonyl
ferrocenylideneamine was critical for the effective cross-coupling
with aldehyde 1. Thus, reductive coupling of N-phenylsulfonyl
ferrocenylideneamine 2 (X ) SO2Ar) with 1 gave erythro â-amino
alcohol4 as a single diastereomer (entries 6, 7). In any event, ef-
ficient achievement of cross-coupling between the aldehyde 1 and
N-arylsulfonyl ferrocenylidenimines 2f, 2g would be attributed
to the remarkable different reduction potentials between both
substrates.5
Table 2. Samarium(II)-Mediated Cross-Coupling of Planar Chiral
Ferrocenecarboxaldehydes 6 and Imines 7
aldehydes
% eea
8 Yield
(%)
entry
imines
[R]D (CHCl3)
% ee 8b
1
2
3
4
5
6
6a 95
6b 95
6c 97
6d -
6d -
6d -
7a
7b
7c
7a
7b
7c
92
90
93
91
96
95
+99.7 (c 0.80)
-9.7 (c 0.40)
+1.8 (c 0.52)
+90.3 (c 0.84)
-16.8 (c 0.63)
+3.8 (c 0.30)
95
95
97
92
94
97
We next turned our attention to the preparation of optically
active â-amino alcohols utilizing planar chiral ferrocenyl com-
pounds. (+)-(R)-2-Methylferrocenecarboxaldehyde 6a6 was coupled
with (R)-N-tosyl 2-methylferrocenylideneamine 7a7 to give the
erythro â-amino alcohol 8 (R1 ) R2 ) Me) (Table 2, entry 1).
The stereochemistry at R- and R′-positions was determined as
a Enantiomeric excess was determined by HPLC with Chiralpack
AS (eluted with hexane/2-propanol (9/1), 1.0 mL/min). b Enantiomeric
excess was determined by HPLC with Chiralcel OD (eluted with
hexane/2-propanol (9/1), 0.5 mL/min).
(1) Some representative reviews: Imamoto, T. Lanthanoids in Organic
Synthesis; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Academic
Press: London, 1994. Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96,
307-338. Molander, G. A. Org. React. 1994, 46, 211.
(RR,SR′)-configuration by X-ray crystallography.8 Similarly, the
cross-coupling between other planar chiral ferrocenecarboxalde-
hydes 6b,c and same planar chiral imines 7b,c produced the
corresponding (RR,SR′)-â-amino alcohols 8 (entries 2, 3). Interest-
ingly, â-amino alcohols 8 obtained by the cross-coupling were
erythro isomers, while the homo-pinacol coupling of the planar
chiral ferrocenecarboxaldehydes gave exclusively the threo-diols.9
Deiodination of the cross-coupling product 8 (R1 ) R2 ) I) with
(2) Matsubara, S., Hashimoto, Y., Okano, T.; Utimoto, K. Synlett 1999,
1411-1412. Bandini, M.; Cozzi, G.; Morganti, S.; Umani-Ronchi, A.
Tetrahedron Lett. 1999, 40, 1997-2000.
(3) (a) Roskamp, E. J.; Pedersen, S. F. J. Am. Chem. Soc. 1987, 109, 6551-
6553. (b) Shono, T.; Kise, N.; Fujimoto, T. Tetrahedron Lett. 1991, 32, 525-
528; Shono, T.; Kise, N.; Kunimi, N.; Nomura, R. Chem. Lett. 1991, 2191-
2194. (c) Machrouhi, Namy, J.-L. Tetrahedron Lett. 1999, 40, 1315-1318.
(d) Hanamoto, T.; Inanaga, J. Tetrahedron Lett. 1991, 32, 3555-3556.
(4) The formation of erythro â-amino alcohols is sharp in contrast to the
predominant formation of threo-diastereomers in NbCl3-catalyzed cross-
coupling between aldehydes and imines. see ref 3a.
n-BuLi gave (RR,SR′)-amino alcohol 8 (R1 ) R2 ) H; [R]26
D
+40.8, 95% ee)8 in 96% yield.
(5) Reduction potential by cyclic voltammetric studies; -2.3 V for 1; -2.4
V for 2a; -2.0 V for 2c, -1.8 V for 2g.
(8) The authors have deposited atomic coordinates for the structures 8 (R1
) R2 ) I) and 9a with the Cambridge Crystallographic Data Centre. The
X-ray data can be obtained on request from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(9) (a) Taniguchi, N.; Kaneta, N.; Uemura, M. J. Org. Chem. 1996, 61,
6088-6089. (b) Taniguchi, N.; Uemura Synlett 1997, 51-53. (c) Taniguchi,
N.; Uemura, M. Tetrahedron Lett. 1998, 39, 5385-5388. (d) Taniguchi, N.;
Uemura, M. Tetrahedron 1998, 54, 12775-12788.
(6) The planar chiral ortho-substituted ferrocenecarboxaldehydes 6 were
prepared by diastereoselective lithiation of chiral ferrocenyl acetal according
to the literature procedure. Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.;
Kagan, H. B. J. Org. Chem. 1997, 62, 6733-6745.
(7) Optically active ferrocenylimines 7 were prepared by treatment of the
corresponding planar chiral ferrocenecarboxaldehydes 6 with p-TsSO2NH2 in
the presence of molecular seives 4Å and catalytic amount of p-TsOH in
refluxing toluene in good yields. The optical purities for imines 7 were identical
with those of the corresponding aldehydes 6 by HPLC with Chiralcel OD.
(10) Enantiomeric excess for compounds 8, 9, and 10 was determined by
HPLC with Chiralcel OD.
10.1021/ja000479v CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/11/2000

8302 J. Am. Chem. Soc., Vol. 122, No. 34, 2000
Communications to the Editor
Scheme 1. Coupling of Antipode
(-)-(R)-2-Iodoferrocenecarboxaldehyde ent-6b
Scheme 2. Cross-Coupling of Planar Chiral
Ferrocenecarboxaldehyde 6 with Non-Planar Chiral Imine 2g
Our attention was next focused on the stereochemistry of the
cross-coupling â-amino alcohols obtained by two combinations
between the planar chiral ferrocenyl compounds and nonplanar
chiral ferrocenes. The cross-coupling of nonplanar chiral fer-
rocenecarboxaldehyde 6d with planar chiral N-tosyl 2-substituted
ferrocenylideneamines 7a∼7c gave amino alcohols 8 (R1 ) H,
R2 ) Me, I, Br) as a single detectable cross-coupling product
(Table 2, entries 4-6). Furthermore, the cross-coupling of anti-
pode (-)-(R)-2-iodoferrocenecarboxaldehyde, ent-6b, (95% ee)
Figure 1. Proposed reaction mechanism.
11 and 12 would be attributed to an interaction of p-orbital of
R-carbon with d-orbital of iron metal, resulting in the formation
of an exo-cyclic double bond character. Taking into account the
following transition states 13 and 14, the N-tosyl group is oriented
in anti-orientation14 to the carbonyl oxygen of ferrocenecarbox-
aldehydes due to dipole repulsion. Although the carbonyl oxygen
of ferrocenecarboxaldehydes exists preferentially in anti-confor-
mation12 to the o-substituent, the transition state 13 causes severe
steric interaction between the FeCp ring of aldehyde and the
ferrocenyl imine because of the same planar chirality of both
substrates. Therefore, an alternative syn-oriented transition state
14 is favorable for the cross-coupling, giving the (RR,SR′)-amino
alcohols 8. Thus, the proposed model of the cross-coupling for
erytho-selectivity is different with homo-pinacol coupling of
ferrocenecarboxaldehydes giving threo 1,2-diols via coordination
model of the samarium with two oxygens.9 On the other hand,
the generated dianion species from nonplanar chiral ferroce-
nylideneamine 2g is rapidly equilibrating at the generated
stereogenic center. However, the planar chiral ferrocenecarbox-
aldehyde could intercept either dianion species among the
equilibrated carbanions depending on the planar chirality of
carboxaldehyde. Thus, the anti-oriented carbonyl of ferrocen-
ecarboxaldehyde is attacked via sterically less hindered transition
state 16 giving single erytho amino alcohol. In this way, the cross-
coupling of the nonplanar chiral ferrocenylideneimine with
o-substituted ferrocenecarboxaldehydes occurs through a dynamic
kinetic resolution of an enantiotopic face of the equilibrating
R-ferrocenyl carbanion configuration.
with (S)-ferrocenyl imine 7b gave an amino alcohol 9a ([R]25
D
+5.0, 95% ee) (Scheme 1). The absolute stereochemistry of 9a
was confirmed by X-ray crystallography,8 and the deiodination
product was consistent with â-amino alcohol 8 (R1 ) R2 ) H)
([R]23D +40.8 (CHCl3)) regarding all spectra data including optical
rotation. These results indicate that the absolute stereochemistry
at the R,R′-positions of â-amino alcohols was governed by the
planar chirality of ferrocenylideneamines, regardless of the pre-
sence or absence of a substituent on the ferrocenecarboxaldehyde
ring. In an alternative combination of the cross-coupling of non-
planar chiral N-tosyl ferrocenylideneamine 2g with planar chiral
2-substituted ferrocenecarboxaldehydes, the absolute configuration
of the cross-coupling â-amino alcohols was found to be controlled
by the planar chirality of ferrocenecarboxaldehydes as follows
(Scheme 2). Thus, the coupling of (+)-(S)-2-iodoferrocenecar-
boxaldehyde 6b with 2g gave an amino alcohol 10 (R1 ) I) which
was converted to the deiodinated (SR,RR′)-compound 10 (R1 )
H) with ent-8 (R1 ) R2 ) H). Similarly, the planar chiral ferro-
cenecarboxaldehydes 6 with other substituent gave the correspon-
ding (SR,RR′)-amino alcohols 10 in good yields. On the other hand,
(R)-2-iodoferrocenecarboxaldehyde ent-6b was coupled with non-
planar chiral imine 2g to produce the enantiomeric (RR,SR′)-amino
alcohol 9b (95% ee) under the same conditions (Scheme 1).11
A reaction mechanism has been postulated to rationalize the
observed stereoselectivities of the cross-coupling (Figure 1).
Sulfonyl ferrocenylideneimine generates a dianion species by two
electron reduction. Generation of the dianion intermediate was
supported by reduction of N-tosyl imine 2g with SmI2 in the
presence of CH3OD in THF giving a deuterium-incorporated Cd
N reduction product. In the cross-coupling with planar chiral
N-tosyl 2-substituted ferrocenylideneamines 7, the dianion inter-
mediate 11 generated by an exo-side attack of SmI2 to an anti-
oriented12 CdN double bond to the ortho-substituent is configu-
rationally stable against epimerization.13 No epimerization between
In summary, we have developed the synthesis of enantiomeri-
cally pure â-amino alcohols by cross-coupling of the planar chiral
ferrocenylideneimines with aldehydes.
Acknowledgment. This work was financially supported by a Grant-
in-Aid for Scientific Research from a Ministry of Education, Science,
Sports and Culture. We gratefully thank Dr. M. Satoh for measurement
of the reduction potential.
Supporting Information Available: Experimantal details for the
cross-pinacol coupling as well as spectra data for new compounds (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
JA000479V
(13) R-Ferrocenyllithium 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, 38, 1457-1460.
(14) A mechanism of acyclic selection in intermolecular radical reactions
and intramolecular radical cyclization between carbonyls and imines. (a)
Smadja, W. Synlett 1994, 1-26. (b) Bobo, S.; Storch de Gracia, I.; Chiara, J.
S. Synlett 1999, 1551-1554. (c) Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J.
Org. Chem. 1998, 63, 5877-5882.
(11) The same stereochemical behavior was observed in samarium iodide-
mediated cross-coupling between 2g and planar chiral benzaldehyde tricar-
bonylchromium complexes. N-Phenylsulfonyl benzylideneamine was also
coupled with aldehydes giving â-amino alcohols.
(12) Predominant anti-conformation of the CdO or CdN double bond to
the ortho substituents of ferrocenyl compounds was proposed by diastereo-
selective nucleophilc addition to the double bond. For a review: Ferrocenes;
Togni, A., Hayashi, T., Eds.; VCH: Weinheim, 1995.