Catalytic diastereoselective petasis reactions

Article abstract of DOI:10.1002/anie.201103271

Multicomponent Petasis reactions: The first diastereoselective Petasis reaction catalyzed by chiral biphenols that enables the synthesis of syn and anti β-amino alcohols in pure form has been developed. The reaction exploits a multicomponent approach that

Full text of DOI:10.1002/anie.201103271

Communications
DOI: 10.1002/anie.201103271
Multicomponent Reactions
Catalytic Diastereoselective Petasis Reactions**
Giovanni Muncipinto, Philip N. Moquist, Stuart L. Schreiber, and Scott E. Schaus*
The Petasis boronic acid Mannich reaction is a versatile
multicomponent reaction of boronic acids, amines, and
aldehydes that generates highly functionalized a-amino
acids and b-amino alcohols.[1] When enantiopure a-hydroxy
aldehyde derivatives are used as the carbonyl component in
the reaction, enantiopure b-amino alcohols are produced with
exclusively anti diastereoselectivity.[2] This motif has proven
useful in the synthesis of stereodefined, biologically active
molecules including sialic acids,[3] iminocyclitols,[4] and pyrrol-
izidine alkaloids.[5] The characteristic of the diastereoselective
boronic acid Mannich reaction that makes it valuable, namely
its predictable sense of anti diastereoselectivity, is also its
Scheme 1. a) Catalytic enantioselective Petasis reaction and b) a DOS
library synthesis utilizing the diastereoselective Petasis reaction.
M.S.=molecular sieves.
limitation because syn b-amino alcohols are unattainable
under these conditions [Eq. (1)].[6] Previous attempts to
catalysis would be applicable to the diastereoselective var-
iant.[8,9] An immediate application of this methodology is a
synthetic route to the full matrix of stereoisomeric products of
a pathway conceived for use in small-molecule screening
(Scheme 1b).[10] This type of library development continues to
represent a substantial challenge given current limitations in
synthetic methodology. The synthesis of compounds having
stereogenic carbon centers in diversity-oriented synthesis
(DOS) appears to be useful based on one study showing a
correlation between compounds with intermediate stereo-
chemical complexity and improved binding selectivity.[11] In
addition, stereochemistry-based structure–activity relation-
ships (SSAR) can provide important clues that facilitate
optimization and modification studies following the discovery
of a small-molecule lead.[12]
obtain syn b-amino alcohols through the Petasis reaction
have been unsuccessful and underscore the difficulty in
overriding the intrinsic selectivity of the reaction.[7] Herein,
we report the first diastereoselective Petasis reaction cata-
lyzed by chiral biphenols that enables the synthesis of anti and
syn b-amino alcohols in pure form.
This collaborative project was undertaken with the goal of
developing a catalyst-controlled diastereoselective Petasis
reaction. We recently developed the first enantioselective
Petasis reaction between alkenyl boronates, secondary
amines, and ethyl glyoxylates catalyzed by chiral biphenols
(Scheme 1a) and anticipated this type of ligand-exchange
Initial development of the syn-selective Petasis reaction
focused on (S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-ol 5a,
l-phenylalanine methyl ester 6a, and (E)-diethyl styrylboro-
nate 7a—a modified reaction from our previous library
synthesis.[10] The uncatalyzed reaction of these components
produced exclusively the anti b-amino alcohol 8 (Table 1,
entry 1). Catalysts (S)-VAPOL 1, (S)-H8-BINOLs 2a and 2b,
(S)-BINOLs 3a and 3b were tested in the reaction, and
although syn b-amino alcohol 8 was observed in the product
mixture, these catalysts primarily gave the anti diastereomer
(Table 1, entries 2–6). A breakthrough occurred with catalyst
(S)-3,3’-Br2-BINOL 4, which produced the syn diastereomer 8
as the major product in 4:1 d.r. (Table 1, entry 7). Attempts to
optimize the diastereoselectivity through solvent effects
(Table 1, entries 9–11) and boronate ligation were unsuccess-
ful (Table 1, entries 12 and 13); however, an increase in
syn selectivity to 5.5:1 d.r. was found with the addition of
molecular sieves (4 ꢀ; Table 1, entry 8). In addition, the two
diastereomers were separable on normal-phase chromatog-
raphy allowing for isolation of the syn product in 54% yield.
This result shows for the first time that it is possible to
overcome the inherent selectivity of the diastereomeric
[*] Dr. P. N. Moquist, Prof. Dr. S. E. Schaus
Department of Chemistry, Center for Chemical Methodology and
Library Development at Boston University (CMLD-BU)
Life Science and Engineering Building, Boston University
24 Cummington Street, Boston, MA 02215 (USA)
E-mail: seschaus@bu.edu
Dr. G. Muncipinto, Prof. Dr. S. L. Schreiber
Broad Institute of Harvard and MIT, Howard Hughes Medical
Institute, Department of Chemistry and Chemical Biology
Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
[**] This research was supported by the NIH (R01 GM078240, S.E.S.
and P.N.M.). The NIGMS-sponsored Center of Excellence in
Chemical Methodology and Library Development (P50-GM069721,
S.L.S and G.M.) enabled this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103271.
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Angew. Chem. Int. Ed. 2011, 50, 8172 –8175

Table 1: Diastereoselective Petasis reaction.[a]
With optimized conditions in hand, we explored the scope
of the syn-selective reaction. In all cases, the uncatalyzed
reaction gave only the anti b-amino alcohol. Alkene addition
with boronate 7a formed primarily the syn diastereomer with
lactol 5b and l-phenylalanine-derived amines 6a and 6b
(Table 2, entries 1 and 2). The Cbz-protected amino lactol 5c
was also successful, thus indicating high functional group
tolerance in the reaction (Table 2, entries 3 and 4). Isolation
of the pure syn b-amino alcohols 9–12 was possible in these
reactions in yields up to 80%. Aryl addition was also possible
in the reaction using 4-methoxyphenylboronate 7d, which
afforded the syn product with amino ester 6a (Table 2,
entries 5–7). However, the use of amino acetal 6b in the
aryl addition reaction led to poor diastereoselectivity and the
products were inseparable by chromatography on silica gel
(Table 2, entries 8–10). Alkynylboronate 7e in combination
with lactol 5a and amine 6a afforded the syn product in
Entry
Catalyst
Boronate
Solvent
Yield [%][b]
d.r.
syn/anti[c]
1
2
3
4
5
6
7
8
–
1
2a
2b
3a
3b
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(R)-4
rac-4
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7a
7a
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
toluene
CH2Cl2
THF
24
69
73
66
41
81
70
68 (54)
67
57
anti only
1:10
1:6
1:8
1:4
Table 2: Diastereoselective Petasis reaction[a]
2:3
4:1
5.5:1[d]
1:1
9
10
11
12
13
14
15
1:3
n.d.
1:1.5
n.d.
anti only
1:9
<5
48
<5
86
PhCF3
PhCF3
PhCF3
PhCF3
84
[a] Reactions were run with 0.4 mmol of boronate, 0.2 mmol of lactol,
0.2 mmol of amine, and 20 mol% of catalyst in organic solvent (0.2m)
for 24 h under Ar, and subsequently purified by flash chromatography on
silica gel. [b] Yield of diastereomeric mixture upon isolation. Yield in
parenthesis is the yield of the isolated syn diastereomer (>20:1 d.r.).
1
[c] Determined by H NMR spectroscopy. [d] Run with molecular sieves
(4 ꢀ). n.d=not determined.
Entry Lactol Amine Boronate Product Yield [%][b] d.r.
syn/anti[c]
1
2
3
4
5
6
7
8
5b
5b
5c
5c
5a
5b
5c
5a
5b
5c
5a
5a
5b
5c
5a
6a
6b
6a
6b
6a
6a
6a
6b
6b
6b
6a
6c
6c
6c
6d
7a
7a
7a
7a
7d
7d
7d
7d
7d
7d
7e
7a
7a
7a
7a
9
95 (80)
96 (84)
84 (56)
77 (45)
62 (n.d.)
75 (n.d.)
73 (n.d.)
65 (n.d.)
70 (n.d.)
71 (n.d.)
77 (62)
70 (45)
71 (40)
69 (33)
61 (n.d.)
5.5:1
7:1
2:1
1.5:1
5:1
4:1
2:1
1:1
1:10
1:4
5:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Petasis reaction and obtain syn b-amino alcohols in their pure
form. The ability of the catalyst to control the diastereo-
selectivity from > 99:1 d.r. (anti as major product) to 5.5:1 d.r.
(syn as major product) represents remarkable kinetic control
of the reaction. Interestingly, the enantiomers of the catalysts
form a matched and a mismatched relationship with other
components of the reaction. When enantiomeric catalyst (R)-
4 was used in the reaction the anti product was formed
exclusively in 86% yield (Table 1, entry 14), while the racemic
catalyst (Æ )-4 gave the anti product in 9:1 d.r. (Table 1,
entry 15). Therefore, the S-configured catalysts give mis-
matched selectivity and form the syn product, while the R-
configured catalysts are matched and reinforce the anti path-
way.
9
10
11
12
13
14
15
2:1
1.5:1
1:1
1:3
[a] Reactions were run with 0.2 mmol of boronate, 0.1 mmol of lactol,
0.1 mmol of amine, 20 mol% of catalyst, and M.S. (4 ꢀ) in PhCF3 (0.2m)
for 16–60 h under Ar, and subsequently purified by flash chromatography
on silica gel. [b] Yield of the diastereomeric mixture upon isolation. Yield
in parenthesis is the yield of the isolated syn diastereomer (>20:1 d.r.).
[c] Determined by H NMR spectroscopy. The anti products were
synthesized using the matched catalyst (R)-4 and the same reaction
conditions. Cbz=benzyloxycarbonyl.
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Table 3: Diastereoselective Petasis reaction with l- and d-amines.[a]
5:1 d.r. with 62% yield of the pure syn diastereomer
(Table 2, entry 11).
Next, the achiral amino ester 6c and d-amino
ester 6d were tested under the catalyzed conditions.
The reaction of amine 6c, alkenylboronate 7a, and
lactol 5a gave the syn diastereomer with 2:1 d.r. in
70% yield (Table 2, entry 12). Changing the aldehyde
component afforded the syn product in 1.5:1 d.r. with
lactol 6b and 1:1 d.r. with lactol 6c (Table 2, entries 13
and 14). The reaction with d-phenylalanine methyl
ester 6d, boronate 7a, lactol 5a, and (S)-4 formed
primarily the anti product 23 in 3:1 d.r. (Table 2,
entry 15). Attempts to optimize the reaction through
the use of other biphenol catalysts failed to generate
better diastereoselectivity.[13] These results dramati-
cally demonstrate the influence of the amine stereo-
genic center as a third element of diastereocontrol. It
becomes apparent that the d-amine is a matched pair
with (S)-lactol and reinforces the anti selectivity of the
reaction, while the l-amine has matched selectivity
with the S-configured catalyst to form the syn prod-
uct.
Owing to the significance of the amino acid
configuration on product diastereoselectivity, we
compared the catalyzed reaction of boronate 7a and
lactol 5a with the various d- and l-amino acid
derivatives. Whereas the l-phenylglycine amino
ester 6e gave the syn product in 2:1 d.r., the d
enantiomer 6i produced the anti product in 20:1 d.r.
(Table 3, entries 1 and 6). Similar results appeared in
the reaction with enantiomers of leucine-derived 6 f
and 6j and valine-derived amino esters 6g and 6k
(Table 3, entries 2, 7, 3 and 8, respectively), in which
the l-amine provides the syn product and the d-
amine provides anti product. The size of the substitu-
Entry l-Amine
Yield [%][b] d.r.
syn/
Entry d-Amine
Yield [%][b] d.r.
syn/
anti[c]
anti[c]
1
2
3
4
55 (n.d.) 2:1
6
7
8
9
57 (n.d.) 1:20
71 (n.d.) 1:2
68 (n.d.) 1:6
74 (n.d.) 1:10
80 (56)
7.5:1
65 (n.d.) 2.5:1
72 (48)
94 (80)
2:1
6:1
5
10
83 (38)
4:1
[a] Reactions were run with 0.2 mmol of boronate, 0.1 mmol of lactol, 0.1 mmol of
amine, 20 mol% of catalyst, and M.S. (4 ꢀ) in PhCF3 (0.2m) for 16–60 h under Ar,
and subsequently purified by flash chromatography on silica gel. [b] Yield of
diastereomeric mixture upon isolation. Yield in parenthesis is the yield of only the
isolated syn diastereomer. [c] Determined by 1H NMR spectroscopy. The anti prod-
ucts were synthesized using the matched catalyst (R)-4 and the same reaction
conditions.
ents also affects the selectivity of the reaction, with smaller
groups affording higher quantities of syn product. Interest-
ingly, the d-phenylalanine dimethyl acetal 6m gave the
syn product in 4:1 d.r. under the catalyzed conditions and
was isolated as the pure syn diastereomer in 38% yield
(Table 3, entry 10). Therefore, phenylalanine dimethyl acetals
6b and 6m are able to form the full matrix of stereoisomeric
products in the library.
As an extension of this methodology, glycolaldehyde
dimer 34 was used in the reaction to synthesize primary b-
amino alcohols. The uncatalyzed reaction of amine 6e,
boronate 7a, and glycolaldehyde 34 produced a 4:1 mixture
of the (S,S)-amino alcohol 35 and (S,R)-amino alcohol 36
(Scheme 2). Use of 20 mol% of (S)-4 gave > 20:1 d.r. of (S,S)-
amino alcohol 35. This result indicates that both the catalyst
and amine direct the boronate addition to the form of the S-
stereogenic center of the amino alcohol. The R-configured
catalyst (R)-4 produced the opposite diastereomers 36 in
10:1 d.r. and easily overcomes the inherent selectivity of the
amine component. These results are further evidence of the
matched selectivity of catalyst (S)-4 with l-amino acids and
catalyst (R)-4 with d-amino acids.
Scheme 2. Catalytic Petasis reaction using glycolaldehyde.
the anti diastereoselective Petasis reaction involves an a-
hydroxy-directed boronate addition to the imine, and pro-
ceeds through a Felkin–Anh-type transition state.[14] Unsur-
prisingly, the use of 3-phenylpropanal and (S)-2-methoxy-3-
phenylpropanal in the catalyzed reaction gave only trace
amounts of product (< 1% yield). This outcome indicates that
the boronate coordination to the a-hydroxy group remains
Next, we undertook a preliminary mechanistic investiga-
tion of the catalyzed reaction. The stereochemical model for
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undergo a single-ligand exchange with the catalyst as
1
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appears the boronate undergoes both ligand exchange with
the catalyst and coordination with the a-hydroxy aldehyde
during the course of the reaction. This type of activation is in
line with the current mechanistic model of the diastereose-
lective Petasis reaction, as well as previous models for
catalytic activation of boronates with chiral diols.[8,9]
Because this reaction relies on three stereocontrolling
elements, it can be classified as a catalytic triple-diastereo-
selective reaction. Although catalytic reactions involving
double diastereoselectivity are well studied, catalyzed reac-
tions involving three elements of diastereocontrol are rare. To
this end, the research groups of Masamune and Kishi have
pioneered and produced elegant studies in this area.[15]
However, because these initial reports have not investigated
all enantiomers of the three stereocontrolling elements, this is
the first report for which all enantiomers of the components
have been examined. What we learned from this reaction can
be simplified into a few generalized rules. 1) The uncatalyzed
reaction maintains exclusively anti diastereoselectivity
regardless of the amine, lactol, or boronate components.
2) Although the amine is unable to overcome the diastereo-
control of the lactol, the structure and configuration of the
amine play a large role in the diastereoselectivity of the
catalyzed reaction. 3) The matched combination of an l-
amine and S-configured catalyst usually produces predom-
inantly the syn diastereomers. 4) In general, the matched
combination of d-amine and (S)-lactol using the catalyst-
promoted conditions leads to the anti b-amino alcohol with
the exception of amino acetal 6m, a characteristic of this
particular reaction we are continuing to explore.
In conclusion, we have reported the first diastereoselec-
tive Petasis reaction of boronates, a-hydroxy aldehydes, and
amines to produce syn b-amino alcohols. In many cases the
syn product can be obtained in isomerically pure form for
further elaboration. Furthermore, the full matrix of stereo-
isomers for use in library synthesis was achieved using
phenylalanine methyl acetal, and we believe other amines
will be successful at this task. Although these preliminary
results indicate that a number of challenges have yet to be
met, this study represents a substantial improvement in the
utility and scope of the reaction. Our current efforts are
focused on the improvement of this catalyst system and
further investigations are ongoing to understand the mecha-
nism and activity of this reaction.
Received: May 12, 2011
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Published online: July 12, 2011
Keywords: asymmetric catalysis · boronic acids ·
.
multicomponent reactions · organocatalysis · Petasis reaction
[1] a) N. A. Petasis, I. Akritopoulou, Tetrahedron Lett. 1993, 34,
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Angew. Chem. Int. Ed. 2011, 50, 8172 –8175
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