A direct catalytic asymmetric Mannich-type reaction via a dinuclear zinc catalyst: Synthesis of either anti- or syn-α-hydroxy-β-amino ketones

Article abstract of DOI:10.1021/ja057498v

The use of imines bearing a hydrolyzable nitrogen substituent in direct asymmetric Mannich reactions with α-hydroxyketones is developed. Previous work focused on the use of N-arylimines or nonenolizable imines, and the latter with only methoxy-substituted

Full text of DOI:10.1021/ja057498v

Published on Web 02/03/2006
A Direct Catalytic Asymmetric Mannich-type Reaction via a Dinuclear Zinc
Catalyst: Synthesis of Either anti- or syn-r-Hydroxy-â-Amino Ketones
Barry M. Trost,*,† Jaray Jaratjaroonphong,†,‡ and Vichai Reutrakul*,‡
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080, and Department of Chemistry,
Faculty of Science, Mahidol UniVersity, Rama VI Road, Bangkok 10400, Thailand
Received November 2, 2005; E-mail: bmtrost@stanford.edu
Scheme 1. anti- and syn-â-Amino Alcohol Synthesis
The Mannich reaction is one of the most widely utilized chemical
transformations for the construction of â-amino carbonyl com-
pounds and 1,2-amino alcohol derivatives, valuable synthetic
intermediates for the synthesis of drugs and biologically active
compounds.1 Only recently, several groups have reported a direct
catalytic asymmetric Mannich reaction without resorting to preac-
tivation of the pronucleophile using organocatalysts and metal
catalysts,2,3 including our own dinuclear zinc complex 2.3b Most
of the examples reported to date are limited to reaction of
unmodified ketone or hydroxyketone donors with imine acceptors.
In addition, the cleavage of the N-protective group also requires
harsh oxidizing conditions. Shibasaki, recently, reported pioneering
work on the Et2Zn/(S,S)-linked-BINOL catalysis using an easily
removable N-protective diphenylphosphinoyl (Dpp) imine and Boc-
imine, which selectively provided either anti- or syn-â-amino alco-
hols, respectively.3c,d The successful donors are 2′- and 4′-methoxy-
substituted hydroxyacetophenones, and so far, the successful imine
acceptors have been limited to those derived from nonenolizable
aldehydes, most notably, aryl. In this paper, we report the applica-
tion of our dinuclear zinc catalyst to the complementary direct
catalytic asymmetric Mannich-type reaction of R-hydroxyketones
using R-enolizable Dpp-imines4 and Boc-imines,5 which we have
found to be stable at 0 °C at least for several days, to generate
either anti- or syn-â-amino alcohols, respectively (Scheme 1).
We first examined the reaction of Dpp-imine 4a with hydroxy-
ketone 3a (Table 1) using dinuclear zinc catalyst 2a,6 which was
prepared from chiral ligand 1a and 2 equiv of Et2Zn in THF
(Scheme 2). Initially, subjection of the catalyst 2a (3.5 mol %) to
a mixture of 3a (1.4 equiv) and Dpp-imine 4a in the presence of 4
Å MS in THF afforded the desired amino alcohol 5a in reasonable
yield but with poor diastereomeric ratios (dr) (entries 1 and 2).
Changing the sequence of addition by subjection of 3a and then
4a in THF to the suspension of the catalyst 2a and 4 Å MS in
THF and lowering the reaction temperature to -25 °C (entry 3)
led to a significant increase in anti selectivity. Increasing the catalyst
loading to 5 mol % and the amount of ketone to 2.0 equiv and
stirring the reaction at -30 °C (entry 4) gave a high yield of 5a
with high dr and ee (enantiomeric excesses). Increasing the size of
the chiral ligand by switching from 1a (Ar ) Ph) to 1b (Ar )
4-biphenyl) gave comparable yield and ee but with slightly increased
dr (entry 5). On the other hand, using ligand 1c decreased both
yield and dr (entry 6). By lowering the catalyst loading to 3.5 and
2.5 mol % (entries 7 and 8), the desired product 5a was also
obtained in high yield and selectivity. With 2.5 mol % of 2a,
however, a longer reaction time (36 h) was necessary (entry 8).
The optimized reaction conditions (Table 1, entry 7) were
applicable to various aliphatic Dpp-imine 5, and the results are
summarized in Table 2. Increasing the size of the R-substituents
Table 1. Optimization Studiesa
3a
4a
cat. 2
temp
C)
time
(h)
yieldb
(%)
drc
eed (%)
(anti)
entry
(equiv)
(equiv)
(mol %)
(
°
(anti:syn)
1e
2e
3
4
5
6
7
8
1.4
1.4
1.4
2
2
2
1
1
1
1
1
1
1
1
2a (3.5)
2a (3.5)
23 17
-5 17
62
66
62
86
80
75
86
90
1:1
1:1
5:1
5:1
6:1
4:1
5:1
5:1
ND
(-)-67
(-)-96
(-)-94
(+)-96
ND
(-)-94
(-)-92
2a (3.5) -25 14
2a (5.0) -30 36
2bf (5.0) -30 36
2c (5.0) -30 36
2a (3.5) -30 24
2a (2.5) -30 36
2
2
a To a mixture of catalyst 2, ketone 3a, and 4 Å MS in THF was added
imine 4a in THF at the temperature shown in the Table. b Isolated yield.
c Determined by the 1H NMR of the crude mixture. d Determined utilizing
chiral HPLC. e To suspension of 3a, imine 4a, and 4 Å MS in THF was
added the catalyst 2 in THF. f (R,R)-Catalyst 2b was used. ND ) not
determined.
Scheme 2. Generation of Dinuclear Zinc Catalyst
of the Dpp-imines increases the dr and ee. Reacting 3a with imine
4d-f (entries 4-6) derived from primary aldehydes (bearing both
linear and â-branched aliphatic chains) also afforded the anti-amino
alcohols 5d-f, respectively, in good yields and excellent ee with
high diastereoselectivity (dr >4:1).
In an analogous manner, Mannich-type reaction with other
hydroxyketone donors was then investigated to extend the scope
of the reaction (Table 2, entries 7-13). The use of heteroaromatic
hydroxyketone was found to be applicable in our Mannich-type
reaction. With 2-hydroxyacetylfuran 3b and imine 4a, an increase
in both yield and stereoselectivity of the resultant amino alcohol
5g was observed with a higher catalyst load (entries 7 and 8).
Surprisingly, hydroxyketone 3c (entries 9 and 10), the best ketone
donor in Shibasaki’s results,3c,d saw a dramatic drop in both dr and
ee. The hydroxyketones 3d and 3e (entries 11-15) were studied
† Stanford University.
‡ Mahidol University.
9
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J. AM. CHEM. SOC. 2006, 128, 2778-2779
10.1021/ja057498v CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Mannich-type Reaction with Dpp-Iminea
respectively.8 It is noteworthy that our dinuclear zinc catalyst 2
provides the Mannich adducts, anti-5 and syn-7, together with aldol
adduct6 with the same absolute configuration at the R-position. On
the other hand, the stereoselectivity at the â-position of the amino
alcohol derivatives is differentiated. The observed stereoselectivities
(see Scheme 1) can be understood by assuming the following
mechanism. With the more bulky Dpp-imine, anti selectivity
dominates to avoid the steric repulsion between the Dpp group and
the Zn enolate.3d Conversely, to avoid the steric repulsion between
a substituent (R group) of the less sterically demanding Boc-imine
and zinc-enolate, the syn-amino alcohol 7 was observed in this case.
In summary, we have demonstrated the application of our
dinuclear zinc catalyst for the synthesis of either syn- or anti-amino
alcohols. Typically, with aliphatic Dpp-imines, the desired amino
alcohols were obtained with anti selectivity (yield up to 86, dr up
to 6:1, ee up to >99%). On the other hand, syn selectivity was
obtained in the reaction with Boc-imines. Detailed mechanistic
studies of the present reaction and further application of our catalyst
with other hydroxyketone donors and aliphatic Boc-imines are
ongoing.
yieldb
(%)
drc
eed (%)
(anti)
entry
Ar
R
product
(anti:syn)
1
2
3
4
5
Ph
Ph
Ph
Ph
Ph
Ph
3a cyclo-hexyl 4a
3a cyclo-propyl 4b
5a
5b
5c
5d
5e
5f
5g
5g
5h
5h
5i
86
79
83
80
76
71
73
85
65
70
71
74
69
77
74
5:1
5:1
6:1
5:1
4:1
4:1
3:1
4:1
2:1
1:1
3:1
4:1
3:1
4:1
4:1
94
83
>99
96
96
96
83
90
56
57
87
88
(-)-86
(-)-95
(+)-95
3a i-propyl
3a i-butyl
4c
4d
3a PhCH2CH2 4e
3a n-hexyl 4f
3b cyclo-hexyl 4a
3b 4a
2-MeOC6H4 3c cyclo-hexyl 4a
6
7
2-furyl
8e
9
10e
3c
4a
4c
4c
4c
4c
4c
11 1-naphthyl 3d i-propyl
12e
3d
5i
5j
5j
5j
13 2-naphthyl 3e i-propyl
14e
15f
3e
3e
a All reactions were performed using 3.5 mol % of 2a and 2 equiv of 3
in THF at 0.3 M unless noted otherwise. b Isolated yield. c Determined by
the 1H NMR of the crude mixture. d Determined utilizing chiral HPLC.
e With 5 mol % catalyst 2a. f With 5 mol % (R,R)-catalyst 2a.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
(GM-13598) for their generous support. The awards of the Royal
Golden Jubilee Ph.D. Scholarship to J.J. and a Senior Research
Scholar to V.R. by the Thailand Research Fund are also gratefully
acknowledged. We also thank the Higher Education Development
project: PERCH for financial support. Mass spectra were provided
by the Mass Spectrometry Regional Center of the University of
CaliforniasSan Francisco supported by the NIH Division of
Research Resources.
Table 3. Asymmetric Mannich-type Reaction with Boc-Iminea
time
(h)
yieldb
(%)
drc
eed (%)
8b
entry
R
product
(anti:syn)
(anti:syn)
(%)
1
2
cyclo-hexyl 6a
7a
7b
14
19
77
70
1:5
1:3
ND, 94
95, 90
6
5
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.
i-propyl
6b
a All reactions were performed using 5 mol % of 2a and 2 equiv of 3a
in THF at 0.3 M unless noted otherwise. b Isolated yield. c Determined by
the 1H NMR of the crude mixture. d Determined utilizing chiral HPLC.
ND ) not determined.
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. (d) Kobayashi, S.;
Ishitani, H. Chem. ReV. 1999, 99, 1069.
in order to gain insight on the origin of the observed selectivity.
With ketone 3d and 4c using 3.5 mol % catalyst loading, dr was
modest (entry 11). Increasing catalyst loading to 5 mol %, dr was
significantly improved (entry 12). The use of hydroxyketone 3e
and imine 4c in the presence of 5 mol % 2a also provided the
Mannich adduct 5j in high ee (95%) with good anti selectivity (entry
14). Furthermore, the enantiomeric product was smoothly obtained
in comparable yield and dr with completely reversed enantiose-
lectivity when (R,R)-2a was used (entry 15). It is clear from our
results that the methoxy substituent in the ortho-position plays a
significant role in the loss of the yield and selectivity.
Another class of imine investigated was Boc-imine 6 (Table 3).
Surprisingly the syn-â-amino alcohol 7a was selectively obtained
in a ratio of 5 (syn, 94% ee) to 1 (anti) on treatment of imine 6a
with 3a in the presence of 5 mol % of catalyst 2a and 4 Å MS in
THF (entry 1). In this reaction, the undesired product 8a derived
from alkoxide attack on the imine was isolated as a minor product
(6%). The reaction of 3a with acyclic imine 6b also afforded the
syn-7b in good yield and excellent ee. To the best of our knowledge,
this is the first example of a direct catalytic asymmetric Mannich-
type reaction using a Boc-imine derived from an R-enolizable
aldehyde.
(2) A review of the direct Mannich reaction: Co´rdova, A. Acc. Chem. Res.
2004, 37, 102.
(3) For selected examples for metal catalysts, see: (a) Juhl, K.; Gathergood,
N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995. (b) Trost,
B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338. (c) Matsunaga,
S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
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S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365.
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(g) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
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Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842.
(4) Dpp-imine was prepared by treatment of N-(diphenylphosphinoyl)-R-
(p-toluenesulfonyl) alkylamine 9 with saturated aqueous NaHCO3 in
CH2Cl2; see Supporting Information for details. For preparation of 9,
see: Coˆte´, A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5405.
(5) Boc-imine was prepared by treatment of N-(N-tert-butyloxycarbonyl)-R-
(phenylsulfonyl) alkylamine 10 with 1.5 M aqueous K2CO3 in CH2Cl2;
see Supporting Information for details. For preparation of 10, see: Pearson,
W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993, 115,
2622.
(6) Leading reference: Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122,
12003.
(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.; Rulley, S. R. J. Org. Chem. 1994, 59, 4202.
The relative and absolute stereochemistry were established by
converting the amino alcohols into their corresponding 1,3-oxazoli-
din-2-one through NOE studies7 and O-methyl mandelic amides,
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