Asymmetric petasis reactions catalyzed by chiral biphenols

Article abstract of DOI:10.1021/ja8018934

Chiral biphenols catalyze the enantioselective Petasis reaction of alkenyl boronates, secondary amines, and ethyl glyoxylate. The reaction requires the use of 15 mol % of (S)-VAPOL as the catalyst, alkenyl boronates as nucleophiles, ethyl glyoxylate as the aldehyde component, and 3 A molecular sieves as an additive. The chiral α-amino ester products are obtained in good yields (71-92%) and high enantiomeric ratios (89:11-98:2). Mechanistic investigations indicate single ligand exchange of acyclic boronate with VAPOL and tetracoordinate boronate intermediates. Copyright

Full text of DOI:10.1021/ja8018934

Published on Web 05/07/2008
Asymmetric Petasis Reactions Catalyzed by Chiral Biphenols
Sha Lou† and Scott E. Schaus*
Department of Chemistry, Center for Chemical Methodology and Library DeVelopment at Boston UniVersity, Life
Science and Engineering Building, Boston UniVersity, 24 Cummington Street, Boston, Massachusetts 02215
Received March 13, 2008; E-mail: seschaus@bu.edu
Asymmetric multicomponent reactions efficiently yield chiral
compounds in a single process.1 The Petasis reaction is the
multicomponent condensation of boronic acids with amines and
aldehydes.2 Accessibility of the reagents and the mild reaction
conditions make the method extremely practical. The use of
glyoxylates in the reaction results in the construction of R-amino
acids.2b If the reaction were rendered asymmetric, the process would
be an attractive approach for the synthesis of chiral amino acids.3
Asymmetric approaches have focused on the use of chiral sub-
strates.4 Chiral amines2b,4a,c,d and chiral boronate esters4b have been
used to access enantioenriched R-amino acids. More recently, a
Figure 1. Chiral biphenols.
Table 1. Asymmetric Petasis Reaction Catalyzed by Chiral Diolsa
chiral organic catalyst promoted the asymmetric addition of
boronates to activated quinolines.5 Chiral biphenol-derived diols
(Figure 1) serve as proficient catalysts for asymmetric reactions
involving boronates,6 and we postulated their utility could be
expanded to include multicomponent condensation reactions. Herein
entry
boronate
R
catalyst
% yieldb
erc
we report the development of an asymmetric Petasis reaction
between alkenyl boronates, secondary amines, glyoxylates, and
chiral biphenol catalysts to afford chiral R-amino acids (eq 1).
1
2
3
4
5
6
7
8
6a
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6c
6d
6e
6a
H
80
<5
45
65
51
25
70
60
43
67
77
80
90
81
77
90
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
CH3
Et
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5j
5j
5j
60:40
75:25
70:30
59:41
55:45
70:30
64:36
72:28
85:15
87:13
90:10
95.5:4.5
93:7
9
We initiated our investigation with the reaction of (E)-styrylbor-
onates with dibenzylamine and ethyl glyoxylate (Table 1). In the
absence of any catalyst, the reaction of styrylboronic acid 6a afforded
the racemic R-amino ester 9 in 80% isolated yield at -15 °C (entry
1). In contrast, only trace amount of desired product was formed when
(E)-diisopropyl styrylboronate 6b was subjected to the reaction (entry
2). Addition of 20 mol % (S)-BINOL to the reaction mixture resulted
in a significant rate enhancement and moderate enantioselectivity (er
) 60:40, entry 3). Evaluating other chiral BINOL derivatives and
solvents did not provide a significant improvement in yield or
enantioselectivity with the (S)-3,3′-Br2-BINOL-catalyzed reaction in
toluene affording the product in 65% isolated yield and 3:1 er as the
best result (entry 4). Diminished yields and enantioselectivities were
observed from the use of catalysts that possess large substituents at
the 3,3′-positions (entries 5 and 6). Electron-withdrawing substituents
at these positions resulted in higher yields, but the enantioselectivity
was still low (entry 7). Monosubstituted BINOL derivatives were also
evaluated in the reaction (entries 8-10). Interestingly 3-CF3SO2-
BINOL 5h-catalyzed reaction resulted in higher yield and enantiose-
lectivity (72:28 er). Finally, the use of vaulted biaryl phenols
(S)-VANOL and (S)-VAPOL7 as catalysts afford the chiral R-amino
ester in good yields (>77%) and good er’s (>87:13, entries 11 and
12). We next evaluated the effect of the boronate alcohol ligands on
the enantioselectivity of the reaction. Dimethyl boronate resulted in
higher yields and improved enantioselectivity (entry 13). However,
10
11
12
13
14
15
16
n-Bu
H
5j
57:43
a Reactions were run with 0.15 mmol boronate, 0.10 mmol dibenzylamine,
0.10 mmol glyoxylate, 0.020 mmol catalyst, and 3 Å molecular sieves in
toluene (0.1 M) for 24 h under Ar, followed by flash chromatography on silica
gel. b Isolated yield. c Enantiomeric ratios determined by chiral HPLC analysis.
diethyl and dibutyl boronate gave higher enantioselectivities with
diethyl styrylboronate affording 9 in highest er (95.5:4.5, entry 14).
The reaction of 6a in the presence of 5j resulted in almost no
enantioselectivity but high yields most likely due to a high rate of
uncatalyzed reaction (entry 16).
The optimized reaction conditions for dibenzylamine and ethyl
glyoxylate required 15 mol % of (S)-VAPOL 5j, diethyl boronate,
and 3 Å molecular sieves. Catalyst 5j could be recovered from the
reaction and reused without lost of activity or enantioselectivity. These
conditions proved to be general for a variety of alkenyl boronates
(Table 2). Electron-rich and electron-deficient styrenyl boronates
afforded corresponding R-amino ester in good yields and high er’s
(entries 1-5). Heteroaromatic-substituted alkenyl boronate 14f was
also a good substrate for the reaction (entry 6). Reactions using alkyl-
substituted boronates displayed slower reaction rates, but the selectivi-
ties remained high (entries 7-9). Disubstituted vinyl boronates also
† Current address: Department of Chemistry, Massachusetts Institute of Technol-
ogy, Cambridge, Massachusetts 02139.
9
6922 J. AM. CHEM. SOC. 2008, 130, 6922–6923
10.1021/ja8018934 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Petasis Reaction with Dibenzylamine 7a
Scheme 1
Scheme 2
entry
R1
R2
product
% yieldb
erc
1
2
3
4
5
6
Ph
H
H
H
H
H
H
H
H
15a
15b
15c
15d
15e
15f
15g
15h
15i
81
84
82
80
82
87
76
73
74
78
71
95.5:4.5
96:4
95:5
95:5
95:5
95:5
97:3
95:5
95.5:4.5
95:5
p-CH3O-C6H4
p-Br-C6H4
m-F-C6H4
m-CF3-C6H4
3-C4H3S
C6H11
n-Bu
BnOCH2
Ph
7d
8d
9d
10
11d
H
CH3
CH3
15j
15k
n-Bu
93:7
were also good coupling partners for the reaction. The reaction of
diamine 18 with boronate 6d and ethyl glyoxylate generated
piperazinone 19 in good yield and er (Scheme 1).8
a Reactions were run with 0.25 mmol 14, 0.25 mmol amine, 0.25 mmol
glyoxylate, 0.0375 mmol (S)-5j, and 3 Å molecular sieves in toluene for 36 h
under Ar, followed by flash chromatography on silica gel. b Isolated yield.
c Determined by chiral HPLC analysis. d Reactions were run at 0 °C.
Mechanistic studies using NMR and ESI-MS analysis of reaction
mixtures at room temperature indicated single ligand exchange
consistent with our previous observations.6d Monitoring the reaction
by 11B NMR demonstrated conversion of a trivalent vinyl boronate
to a tetravalent boronate species at 5.4 ppm consistent with previous
observations.9 Also congruous with observations made by Petasis,2a
aminals 20 and 21 were found to be equally reactive in the reaction
to afford 9 in comparable yield and er’s, whereas the use of
(dibenzylamino)methanol 22 resulted in little product formation
(Scheme 2). These observations highlight the possible intermediacy
of an aminal and the importance of the glyoxylate ester functionality.
In summary, we have developed an enantioselective Petasis
reaction catalyzed by chiral biphenols. Mechanistic studies are
ongoing to facilitate expansion of the scope and utility.
Table 3. Asymmetric Petasis Reaction with Boronate 6da
Acknowledgment. This research was supported by a gift from
Amgen Inc. and the NIH (P50 GM067041 and R01 GM078240).
Supporting Information Available: Experimental procedures and
HPLC analysis for compounds 15a-15k, 17a-17j, and 19. This
material is available free of charge via the Internet at http://pubs.acs.org.
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proved equally effective in the reaction (entries 10 and 11). We next
evaluated the scope of secondary amines using the general reaction
conditions (Table 3). Secondary benzyl amines afforded the corre-
sponding R-amino esters in good yield and enantioselectivities (entries
1-6).
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complex amines (entries 4-6). The less nucleophilic ethyl aniline
(entry 7) resulted in slightly lower yield and selectivity. Dially-
lamine proved effective in the reaction (entry 8). Both enantiomers
of allyl R-methylbenzylamine were subjected to the (S)-5j-catalyzed
reaction. The R-derived amine resulted in 9:1 dr with (R,R)-17i as
major product (entry 9). With the (S)-amine, the catalyst still
appeared to control the selectivity (84:16 dr, entry 10). Diamines
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