Enantioselective synthesis of syn - And anti -1,3-aminoalcohols via β-aminoketones and subsequent reduction/dynamic kinetic asymmetric transformation

Article abstract of DOI:10.1021/ja107857v

β-Aminoketones obtained from imines in an organocatalytic Mannich reaction were transformed to enantio- and diastereomerically pure 1,3-aminoalcohols with two stereogenic centers via a combined reduction/dynamic kinetic asymmetric transformation. Both syn and anti diastereomers were obtained in high yield, dr, and ee.

Full text of DOI:10.1021/ja107857v

Published on Web 10/13/2010
Enantioselective Synthesis of syn- and anti-1,3-Aminoalcohols via
ꢀ-Aminoketones and Subsequent Reduction/Dynamic Kinetic Asymmetric
Transformation
Renaud Millet, Annika M. Tra¨ff, Michiel L. Petrus, and Jan-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity, SE-106 91 Stockholm, Sweden
Received September 1, 2010; E-mail: jeb@organ.su.se
using sodium borohydride or hydrogenation with catalyst 3 led to
poor diastereoselectivty in favor of the anti diastereomer (dr ) 2:1
and 2.8:1, respectively). Similar reduction by L-selectride showed
a selectivity for the syn diastereomer, but again, the diastereomeric
ratio was low (dr ) 1:3). The enantiomeric and diastereomeric
excess of 1,3-aminoalcohols therefore had to be introduced through
a second asymmetric transformation. Taking advantage of the high
Abstract: ꢀ-Aminoketones obtained from imines in an organo-
catalytic Mannich reaction were transformed to enantio- and
diastereomerically pure 1,3-aminoalcohols with two stereogenic
centers via a combined reduction/dynamic kinetic asymmetric
transformation. Both syn and anti diastereomers were obtained
in high yield, dr, and ee.
enantioselectivity shown by lipases in transesterification reactions
of secondary alcohols would give an amplification of the second
Acyclic chiral 1,3-aminoalcohols with two stereogenic centers
are structural motifs in many natural products and biologically active
compounds.1 They are also useful building blocks in asymmetric
synthesis.2 Various methods for their preparation have been
developed, but most of these methods are based on diastereose-
lective reduction,3 and only a few describe enantioselective
preparations. There is therefore a demand for new and efficient
methods for the enantio- and diastereoselective preparation of
acyclic 1,3-aminoalcohols.
During the past decade, the combination of metal catalysis and
enzymatic resolution has emerged as a powerful tool for the
synthesis of enantiopure esters and amides via dynamic kinetic
resolution (DKR).4 Although enzymatic kinetic resolution of
racemic mixtures is a useful tool for obtaining enantiopure
compounds, it is limited by a theoretical yield of 50%. To overcome
this problem, the slow-reacting enantiomer can be converted into
the other one by a racemization catalyst, allowing a yield of 100%
to be obtained via DKR. The same approach has been employed
to form diastereo- and enantiomerically pure 1,3-diols via a dynamic
kinetic asymmetric transformation (DYKAT).5
stereocenter. However, the ketone first had to be reduced to the
corresponding alcohol. The Shvo complex 39 can act as a dual
catalyst for both reduction of the ketone and epimerization of the
alcohol, and thus, a one-pot procedure for transforming the ketone
to the enantiomerically pure aminoalcohol derivative via DYKAT
could be realized.10,11
The reaction conditions for the reduction/DYKAT were opti-
mized. CALB was chosen as a suitable lipase because of its
thermostability, wide substrate scope, and high enantioselectivity
for secondary alcohols. N-Boc-protected ꢀ-aminoketone (S)-1a was
used as a standard substrate, and the previously described p-
chlorophenyl acetate (PCPA) was employed as the acyl donor.12
Table 1. Combined Reduction/DKR of (S)-1aa
entry
equiv of PCPAb
T (°C)
conv. (%)c
drc
ee (%)d
Herein we report our strategy based on a two-step procedure
combining organo-, organometallic, and enzymatic catalysis (Scheme
1).6 The enantiopure ꢀ-aminoketones 1, which were available via
organocatalysis, were subjected to reduction and subsequent
DYKAT to give enantio- and diastereomerically pure 1,3-aminoac-
etates 2.
1
2
3
1.2
1.2
1.2
2.5
2.5
3.5
70
80
90
90
90
90
70
67
72
89
79
99 (92)
>95:5
>95:5
>95:5
>95:5
>95:5
98:2g
>99
>99
>99
>99
>99
>99
4
5e
6f
a The reactions were run on a 0.25 mmol scale under hydrogen for
20 h followed by argon for 24 h. Unless otherwise noted, 10 mg of
immobilized CALB was employed. b PCPA ) p-chlorophenyl acetate.
c Determined by 1H NMR spectroscopy. The isolated yield of pure
acetate is given in parentheses. d Determined by HPLC. e Reaction was
run under hydrogen for 48 h. f Using 20 mg of CALB. g Determined by
HPLC on pure acetate.
Scheme 1. Two-Step Synthesis of Protected 1,3-Aminoalcohols
The first parameter to be investigated was the temperature (Table
1, entries 1-3). Neither the conversion, dr, nor ee changed with
increasing temperature. However, the syn/anti ratio of the inter-
mediate alcohol 4a proved to be highly temperature-dependent and
first showed a 1:1 ratio at 90 °C. This indicates that a temperature
of 90 °C is required for an efficient epimerization. The next
parameters to be changed were the amounts of the acyl donor and
the catalysts. Increasing the amount of the acyl donor PCPA to 2.5
ꢀ-Aminoketones 1 were synthesized through an enantioselective
proline-catalyzed Mannich reaction.7 A wide range of electron-
rich and electron-deficient ꢀ-aminoketones 1 were obtained in >98%
ee in moderate to good yields.8 It was shown that reduction of 1a
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15182 J. AM. CHEM. SOC. 2010, 132, 15182–15184
10.1021/ja107857v  2010 American Chemical Society

C O M M U N I C A T I O N S
equiv gave a higher conversion (Table 1, entry 4), while increasing
the loading of the Shvo catalyst 3 from 2 to 4 mol % did not lead
to any notable improvement. However, when the amount of CALB
was doubled and the amount of PCPA was further increased to 3.5
equiv, the reaction reached full conversion after 48 h, and (2R,4S)-
2a was isolated in 92% yield with a dr of 98:2 and an ee of >99%
(entry 6).
Hydrogen gas was required in the first step of the process for
the reduction of the ketone. However, it was not necessary in the
epimerization of the alcohol and not even desirable. In fact, the
epimerization rate decreased when hydrogen gas was present during
the whole reaction (Table 1, entry 5). The atmosphere was therefore
changed from hydrogen to argon after 20 h, and this procedure
gave the best results for the coupled reduction/DKR process.13
The results using the optimized reduction/DKR conditions
indicate that CALB has a very high selectivity for the R configu-
ration of the alcohol in the diastereomeric alcohols. To measure
the pseudo-E value, a kinetic asymmetric transformation (KAT)
of a 50:50 mixture of (2R,4S)-4a and (2S,4S)-4a as well as of a
50:50 mixture of (2R,4R)-4a and (2S,4R)-4a were carried out
(Scheme 2).
Scheme 2. Determination of the Pseudo-E Value
Figure 1. Reaction scope of γ-aminaoalcohol synthesis.
tively, in high yields and high ee, and the more bulky naphthyl
derivative afforded (2R,4S)-2e in high yield and 99% ee with a dr
of >97:3.14 Finally, to our delight, the 2-furyl derivative was
obtained in good yield with high enantio- and diastereoselectivity.
Scheme 3. Deprotection of N-Boc-aminoacetate
Enzymatic resolution (KAT) of a 50:50 mixture of (2R,4S)-4a
and (2S,4S)-4a led to the formation of (2R,4S)-2a with an anti/syn
ratio of >99.5:0.5 at 36% conversion. At this conversion, the anti/
syn ratio of the starting material 4a had changed from 50:50 to
20:80. This gave a pseudo-E value of >200 (350) for this kinetic
asymmetric transformation (eq 1 in Scheme 2). CALB also showed
a high selectivity for the other pair of diastereomers. At 48%
conversion, the aminoacetate (2R,4R)-2a had been formed in a syn/
anti ratio of >99.5:0.5, and the syn/anti ratio of the starting material
changed from 50:50 to 3:97 (eq 2 in Scheme 2). Thus, the pseudo-E
value was >200 (700).
To investigate the scope of the process, a wide range of imines
were subjected to the proline-catalyzed Mannich reaction, and the
aminoketones obtained were then subjected to the optimized
DYKAT conditions. The 1,3-aminoacetates were obtained in dr’s
up to >98:2 and ee’s of >99%, and both (S)- and (R)-aminoketones
were tolerated, providing access to both (2R,4S)- and (2R,4R)-
aminoacetates (Figure 1). It is interesting to note that the high
selectivity of the DYKAT reaction completely overrides the inherent
diastereoselectivity to give either the syn- or anti-1,3-aminoacetate
in good to high yield and high ee. The phenyl derivative as well as
electron-rich p-methoxy and electron-deficient p-chloro derivatives
were transformed to enantiomerically pure aminoacetates 2a, 2b,
and 2c, respectively, of either syn or anti form. Also, p- and m-tolyl
derivatives were converted to (2R,4S)-2d and (2R,4S)-2e, respec-
The N-Boc-protected aminoacetate was easily deprotected in two
steps with retained enantiomeric and diastereomeric excess (Scheme
3). Hydrolysis of the acetate in the presence of K2CO3 in MeOH/
water yielded (2R,4S)-4a in 85% yield with a >97:3 anti/syn ratio
and >99% ee. The Boc group was cleaved off in the presence of
trifluoroacetic acid in dichloromethane, yielding the free aminoal-
cohol (2R,4S)-5a in quantitative yield. The stereochemical assign-
ment of the aminoalcohol was confirmed by transformation into
its cyclic carbamate (4R,6S)-6a.
In conclusion, we have developed an efficient procedure for
enantio- and diastereoselective synthesis of N-Boc-protected 1,3-
aminoacetates via an organocatalytic Mannich reaction and a
subsequent highly enantioselective tandem reduction/DYKAT. The
procedure illustrates the combination of organo-, organometallic,
and enzymatic catalysis. The two diastereomers (2R,4S) and (2R,4R)
were obtained in high ee and high diastereoselectivity. Hydrolysis
of the acetate as well as of the tert-butylcarbamate was carried out
without any loss of enantio- or diastereoselectivity.
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C O M M U N I C A T I O N S
Kinetic Resolutions. In Asymmetric Organic Synthesis with Enzymes; Gotor,
V., Alfonso, I., Garcia-Urdiales, E., Eds.; Wiley-VCH: Weinheim, Germany,
2008; pp 89-113. (c) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord.
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Acknowledgment. Financial support from the Swedish Research
Council, the Berzelii Center EXSELENT, INTENANT, and the
Knut and Alice Wallenberg Foundation is gratefully acknowledged.
R.M. thanks the Swiss National Science Foundation for financial
support.
(5) Edin, M.; Steinreiber, J.; Ba¨ckvall, J.-E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5761.
(6) For a related combination of organocatalysis and enzymatic catalysis, see:
Baer, K.; Krausser, M.; Burda, E.; Hummel, W.; Berkessel, A.; Gro¨ger,
H. Angew. Chem., Int. Ed. 2009, 48, 9355.
(7) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609.
(8) See the Supporting Information.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) (a) Blum, Y.; Czarkie, D.; Stein, Z.; Shvo, Y. Organometallics 1985, 4,
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