A direct catalytic asymmetric Mannich-type reaction to syn-amino alcohols

Article abstract of DOI:10.1021/ja028782e

The Mannich reaction is one of the most widely utilized chemical transformations for the construction of nitrogen-containing compounds. With the increasing occurrence of nitrogen in drugs and natural products, highly asymmetric variants of the Mannich rea

Full text of DOI:10.1021/ja028782e

Published on Web 12/13/2002
A Direct Catalytic Asymmetric Mannich-type Reaction to syn-Amino Alcohols
Barry M. Trost* and Lamont R. Terrell
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received October 2, 2002 ; E-mail: bmtrost@stanford.edu
Table 1. Additions to Glyoxalate Iminesa
The Mannich reaction is one of the most widely utilized chemical
transformations for the construction of nitrogen-containing com-
pounds.1 By the sheer nature of this multicomponent reaction,
considerable diversity with as many as two chiral centers could be
generated. With the increasing occurrence of nitrogen in drugs and
natural products, highly asymmetric variants of the Mannich
reaction are desirable.2 Moreover, a catalytic diastereo- and
enantioselective reaction would be the most efficient means of
constructing this class of compounds because the chirality control-
ling element is used in limited quantities. Although the Mannich
reaction has gained increased popularity, only recently have
asymmetric catalytic variants been realized.3 Our interest in the
development of a catalytic asymmetric Mannich-type reaction stems
from our results with the analogous aldol reaction.4 In this
communication, we report the application of our dinuclear zinc
catalyst to a highly asymmetric imine aldol (Mannich-type) reaction
to generate syn 1,2-amino alcohols.
imine 4
R )
yield 5b
(%)
eed 5
(%)
entry
ketone Ar )
C6H5
cat.
drc 5
1e
2af
bf
cf,g
3
4
5
6
H
1a
1a
2a
1a
1a
2a
2a
2a
76
79
92
97
75
59
81
81
6.5:1
8:1
12:1
8.6:1
2:1
7:1
>20:1
8:1
95
>98
>99
98
94
98
C6H5
CH3
4-MeO-C6H4
3-MeO-C6H4
2-MeO-C6H4
2-furyl
CH3
CH3
CH3
CH3
>99
>99
a All reactions are as in eq 1 using a 2:1 ratio of hydroxyketone to imine
using 5 mol % catalyst unless noted otherwise. b See ref 5. c Determined
by 1H NMR spectroscopy on the crude mixture. d Determined by chiral
HPLC on a Chiracel OD or AD column. e 10 mol % catalyst. f 2.5 mol %
catalyst. g Hydroxyketone-to-imine ratio 1.1:1 in the presence of 3.7 mol
% Ph3PS.
Table 2. Additions to Aldiminesa
As previously reported,4 the dinuclear zinc catalyst is generated
by exposing ligands 1-3 to 2 equiv of diethylzinc in THF (Scheme
1). Subjection of glyoxalate imine 4a (R ) H) and hydroxy-
Scheme 1. Generation of Dinuclear Zinc Catalysts
acetophenone to the standard dinuclear zinc catalyst (10 mol %)
gave a high yield of the desired amino alcohol adduct 55 with good
diastereoselectivity favoring the syn adduct (6.5:1) and excellent
enantioselectivity (95%) (eq 1 and Table 1, entry 1).
Optimization of the reaction conditions as well as the substitution
pattern of the nitrogen arene showed that the sterically more
demanding 2-methyl-4-methoxy aniline derivatives gave better
results (eq 1 and Table 1, entries 2-6). With hydroxyacetophenone
a All reactions are as in eq 1 using a 2:1 ratio of hydroxyketone to imine
using 5 mol % catalyst unless noted otherwise. b See ref 5. c Determined
by 1H NMR spectroscopy on the crude mixture. d Determined by chiral
HPLC on a Chiracel OD or AD column. e Hydroxyketone-to-imine ratio
1.1:1 in the presence of 7.5 mol % Ph3AsO. f 5 mmol scale.
The use of more electron-rich aromatic hydroxy ketones required
higher catalyst loads of 5 mol % (no reaction at the 2.5 mol %
load) (entries 3-6). The electron-rich arenes should facilitate the
subsequent Baeyer-Villiger oxidation. Surprisingly, the 4′-methoxy
hydroxy ketone (entry 3) saw a dramatic drop in the diastereo-
selectivity. The syn-to-anti ratio was a mere 2:1. With the methoxy
substituent in the meta-position (entry 4), the diastereoselectivity
was regained (dr ) 7:1, 98% ee) but with some loss of reactivity
(59% yield). With the ortho-substituted methoxy hydroxy ketone
(entry 5), complete diastereo- and enantioselectivity were observed
(dr ) >20:1, >99% ee). In addition, a “near” atom-economical
reaction (1.1 equiv of ketone) is possible with the “zincaphilic”
additive Ph3PS (entry 2c) with no deleterious effect on conversion
or stereocontrol (entry 2a vs 2c). Hetereoaromatic hydroxy ketones
were also found to be applicable in our imine aldol reaction.
2-Hydroxyacetylfuran (entry 6) gave the desired 1,2-amino alcohol
adduct with comparable selectivities as the parent acetophenone
and imine 4b (R ) methyl) (entry 2a), an increase in both the
diastereo- (8:1 vs 6.5:1) and the enantioselectivity (98% vs 95%)
of the resultant amino alcohol was observed with a substantial lower
catalyst load (2.5 mol % vs 10 mol %). The reaction also showed
a dramatic ligand effect. With biphenyl ligand 2 (entry 2b), a further
increase in the dr was observed (12:1 vs 8:1) accompanied by a
yield increase. Thus, biphenyl ligand 2 was adopted as the standard
ligand for the glyoxalate series.
9
338
J. AM. CHEM. SOC. 2003, 125, 338-339
10.1021/ja028782e CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
donor. Moreover, the furan moiety adds another element of diversity
to the amino alcohol scaffold.
nOe studies.7 The absolute stereochemistry was determined by
converting the amino alcohols into their O-methyl mandelate
amides.8 It is noteworthy that the absolute configuration in these
reactions is opposite that observed in the aldol reaction - a result
that may derive from the fact that lone pair coordination in the
case of aldehydes occurs anti to the bulky group but syn in the
case of imines. CAN-promoted oxidative dearylation gave oxa-
zolidinone 9. Regioselective Baeyer-Villiger oxidation with bis-
(trimethylsilyl) peroxide9 as the oxidant gave phenyl ester 10 and
“proof of principle” that the amino alcohols can be utilized as a
synthetic scaffold for the synthesis of R-hydroxy-â-amino acids.
In summary, we have demonstrated the application of our
dinuclear zinc catalyst in the catalytic asymmetric Mannich-type
reaction. Typically, the diastereoselectivity of the reaction was at
least 8:1 with most substrates in the >15:1 range. In all cases, the
enantiomeric excess of the reaction was typically >98%.
Another class of imines investigated was those derived from
aromatic aldehydes. Table 2 and eq 2 summarize the results for a
number of examples. The standard phenyl ligand 1 (5 mol %) with
hydroxyacetophenone and imine 6a (R1 ) 4-methoxyphenyl, R2
) H) (entry 1a) only slightly favored the syn-isomer (1.7:1), but,
encouragingly, both diastereomers had excellent enantioselectivity
(99%). A strong ligand effect was also observed in this aromatic
series. The â-naphthyl ligand 3 (entry 1b) more than doubled the
diastereoselectivity (4.3:1).
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences,
for their generous support of our programs. L.R.T. thanks Pfizer,
Inc., for support of his postdoctoral studies. Mass spectra were
provided by the Mass Spectrometry Regional Center of the
University of California-San Francisco supported by the NIH
Division of Research Resources.
With imine 6b (R1 ) 2-methoxyphenyl, R2 ) H) (entry 2a), a
dramatic increase in diastereoselectivity (>15:1) was observed. The
increased diastereoselectivity can be rationalized through a bidentate
binding model with the ortho-substituted derivative. The two-point
binding of the imine through the nitrogen and methoxy helps rigidify
the dynamic nature of the imine-Lewis acid complex.6 The increased
rigidity should prevent the E/Z isomerization of the carbon-nitrogen
double bond, which may account for the low dr in entry 1a.
With imines 6b and 6c, the ligand effect was negligible (entry
2a vs 2b and entry 3a vs 3b). However, the reaction showed a
significant electronic effect. With para-chlorine imine 6c (R1 )
2-methoxyphenyl, R2 ) Cl) (entry 3a), the reaction saw a dramatic
rate increase with no adverse effect on stereocontrol. Similar to
the glyoxalate series, a near “atom-economical” protocol (1.1 equiv
of ketone) (entry 3a) is realized with the “zincaphilic” additive
Ph3AsO (7.5 mol %) with no change in chemoselectivity. The
reaction at the 5 mmol scale (entry 3a) saw no change in conversion
or stereocontrol. The electron-rich aromatic ketones (entries 4 and
5) showed excellent diastereo- and enantioselectivity with imine
6c, although longer reaction times were needed due to a decrease
in the reaction rate.
Supporting Information Available: Experimental details and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Reviews: (a) Denmark, S. E.; Nicaise, O. J.-C. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Heidelberg, 1999; pp 923-961. (b) Kleinmann, E. F. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
New York, 1991; Vol. 2, Chapter 4.1. (c) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044-1070.
(2) See: (a) Kober, R.; Papadopoulus, K.; Miltz, W.; Enders, D.; Steglich
W.; Reuter, H.; Puff, H. Tetrahedron 1985, 41, 1693. (b) Corey, E. J.;
Decicco, C. P.; Newbold, R. C. Tetrahedron Lett. 1991, 32, 5287. (c)
Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am.
Chem. Soc. 1994, 116, 10520. (d) Enders, D.; Ward, D.; Adam, J.; Raabe,
G. Angew. Chem., Int. Ed. Engl. 1996, 35, 981. (e) Vinkovic, V.; Sunjic,
V. Tetrahedron 1997, 53, 689. (f) Zarghi, A.; Naimi-Jamal, M. R.; Webb,
S. A.; Balalaie, S.; Saidi, M. R.; Ipaktschi, J. Eur. J. Org. Chem. 1998,
197, 7. (g) Palomo, C.; Oiarbide, M.; Gonzalez-Rego, M. C.; Sharma, A.
K.; Garcia, J. M.; Gonzalez, A.; Landa, C.; Linden, A. Angew. Chem.,
Int. Ed. 2000, 39, 1063.
(3) (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 2060. (b) Ishitani, H.; Ueno, M.; Kobayashi, S. J.
Am. Chem. Soc. 1997, 119, 7153. (c) Kobayashi, S.; Ishitani, H.; Ueno,
M. J. Am. Chem. Soc. 1998, 120, 431. (d) Hagiwara, E.; Fujii, A.; Sodeoka,
M. J. Am. Chem. Soc. 1998, 120, 2474. (e) Ferraris, D.; Young, B.;
Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548. For methods
that utilize unmodified ketones, see the following: (f) Yamasaki, S.; Iida,
T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 307. (g) Yamasaki, S.; Iida,
T.; Shibasaki, M. Tetrahedron 1999, 55, 8857. (h) List, B. J. Am. Chem.
Soc. 2000, 122, 9336. (i) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H.
J. J. Am. Chem. Soc. 2002, 124, 827. (j) Cordova, A.; Notz, W.; Zhong,
G.; Betancort, J. M.; Barbas, C. F. J. Am. Chem. Soc. 2002, 124, 1843.
(4) Leading reference: Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122,
12003.
The imine aldol adducts are valuable synthetic intermediates.
Baeyer-Villiger oxidation and oxidative dearylation should give
R-hydroxy-â-amino acids, an increasingly important biological class
of compounds. As such (Scheme 2), subjection of amino alcohol 5
to triphosgene in the presence of i-Pr2EtN gave oxazolidinone 8.
At this point, the relative stereochemistry was established through
Scheme 2. Studies toward R-Hydroxy-â-amino Acids
(5) This compound has been satisfactorily characterized spectroscopically,
and its elemental composition has been established.
(6) (a) McCarty, C. G. In The Chemistry of the Carbon-Nitrogen Double
Bond; Patai, S., Ed.; John Wiley & Sons: New York, 1970; Chapter 9.
(b) Biørgo, J.; Boyd, D. R.; Watson, C. G.; Jennings, W. B. J. Chem.
Soc., Perkin Trans. 2 1974, 757.
(7) In support of our assignment, the relative stereochemistry of oxazolidinones
can also be determined by examination of the J4-5 coupling constants:
Murakami, M.; Ito, H.; Ito, Y. J. Org. Chem. 1993, 58, 6766.
(8) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59, 4202.
(9) Go¨ttlich, R.; Yamakoshi, K.; Sasai, H.; Shibasaki, M. Synlett 1997, 971.
JA028782E
9
J. AM. CHEM. SOC. VOL. 125, NO. 2, 2003 339