A highly efficient and practical method for catalytic Asymmetric Vinylogous Mannich (AVM) reactions

Article abstract of DOI:10.1002/anie.200603496

(Chemical Equation Presented) Very selective but very easy: These are two of the attributes of the asymmetric vinylogous Mannich reactions presented herein. These reactions can be run on a gram scale and in undistilled THF and air (see scheme; TMS = SiMe₃). All that is needed is commercially available AgOAc, a readily available amino acid derived phosphine, and a commercially available or easily prepared (one step) siloxyfuran.

Full text of DOI:10.1002/anie.200603496

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been synthesized and used as chiral building blocks. A
catalytic asymmetric vinylogous Mannich (AVM) process
would constitute a more efficient strategy, one that does not
require pre-existing chirality.[3] As illustrated in Equation (1)
(PG = protecting group), a catalytic AVM involving a siloxy-
furan can deliver synthetically versatile, enantiomerically
enriched products that bear two stereogenic centers
appended to a g-butenolide.
In 1999, Martin and Lopez reported a method (Ti-
catalyzed) for addition of siloxyfurans to 2-aminophenol-
derived imines; reactions proceeded in 40–92% de but in only
up to 54% ee.[4] Terada and co-workers have outlined an
enantioselective (up to 97% ee) protocol for Brønsted acid
catalyzed Friedel–Crafts reactions of N-Boc aldimines with 2-
methoxyfuran. Enantiomerically enriched furan-2-ylamines
may be oxidized to afford alkylamine-substituted g-buteno-
lides [Eq. (1)] by a two-step sequence that generates the
carbinol stereogenic center with moderate diastereoselectiv-
ity (70% de).[5]
Herein we report the first highly diastereo- and enantio-
selective protocol for catalytic AVM reactions. Ag-catalyzed
transformations[6] proceed in > 98% de, in 79 to > 98% ee
and 60–98% isolated yield. The catalytic method is practical:
transformations are carried out in air with undistilled solvent
and undistilled additive, in the presence of 1–15 mol%
commercially available AgOAc (not purified) and an easily
accessible chiral phosphine (three steps, 50% yield). Siloxy-
furans are commercially available and/or readily prepared
(one step, 90% yield).
Asymmetric Catalysis
DOI: 10.1002/anie.200603496
A Highly Efficient and Practical Method for
Catalytic Asymmetric Vinylogous Mannich
(AVM) Reactions**
As the data summarized in entry 1 of Table 1 illustrate, in
the presence of 1 mol% 1a,[6b–d] 1 mol% AgOAc, 1.1 equiv-
alents iPrOH, in undistilled THF and in air, reaction of
aldimine 2a and commercial siloxyfuran 3 affords g-buteno-
lide 4a in > 98% de, 95% ee,[7] and 82% yield. When 1b,
bearing a tLeu (vs. iLeu) unit (entry 2) or ligand 1c,
containing the less expensive Val (entry 3) is used, similar
reactivity and selectivity is observed.[8] The efficient reaction
with 3 is especially noteworthy and was somewhat surprising,
since we had previously established that silylketene acetals do
not participate (< 2% conv.) in this class of catalytic Mannich
reactions.[6d] It is likely that this change in reactivity, in spite of
somewhat lower nucleophilicity of siloxyfurans (vs. ketene
acetals)[9] is the result of reduced steric hinderance at the
reacting carbon. As represented by catalytic AVM in
entries 4–5 (Table 1), one of the chiral phosphines (1a, 1b,
or 1c) can deliver slightly higher efficiency (90% vs. 85%
conv.) and enantioselectivity (97% vs. 93% ee); others are
shown in entries 12–13 and 15–16. Reactions proceed readily
and with high enantioselectivity with electron-rich (entries 4–
5 and 15–16) and electron-poor (entries 6–9 and 14) aryli-
mines. Sterically demanding ortho-substituted aldimines, such
as 2 f (entries 10–11), 2g (entries 12–13), and 2h (entry 14)
Emma L. Carswell, Marc L. Snapper,* and
Amir H. Hoveyda*
Stereoselective vinylogous Mannich reactions[1] are of signifi-
cant utility in organic synthesis.[2] Through diastereoselective
addition of vinylogous enol equivalents to enantiomerically
enriched imines, a,b-unsaturated, d-amino carbonyls have
[*] E. L. Carswell, Prof. M. L. Snapper, Prof. A. H. Hoveyda
Department of Chemistry
Merkert Chemistry Center
Boston College
Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-1442
E-mail: marc.snapper@bc.edu
amir.hoveyda@bc.edu
[**] This work was generously supported by a grant from the United
States NIH (GM-57212). We thank Dr. R. J. Staples and Mr. S. J.
Malcolmson for X-ray determinations; X-ray facilities at Boston
College are supported by Schering-Plough.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Ag-catalyzed AVMwith siloxyfuran 3.
needed for synthetically useful conversions and yields
(5 mol% vs. 1 mol% typically required for 3).
Catalytic AVM of 3-substituted siloxyfuran 7 (Table 3)
proved more complicated, requiring identification of a new
Table 3: Ag-catalyzed AVMreactions with substituted siloxyfuran 7.
Entry
Ar
Ligand
(mol%)
Conv. Yield
de
ee
[%][a]
[%][b]
[%][b]
[%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
a
a
a
b
b
c
d
d
e
f
1a (1)
1b (1)
1c (1)
1a (1)
1b (1)
1a (1)
1a (1)
1c (1)
1a (1)
1a (1)
1b (1)
1a (5)
1b (5)
1a (3)
1a (1)
1b (1)
91
94
85
85
90
>98
94
98
94
96
>98
86
73
89
98
82
82
77
76
85
98
89
86
75
94
94
73
65
60
77
78
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
95
96
92
93
97
91
93
92
93
98
>98
93
94
93
Entry
Ar
Mol%
Conv.
[%][a]
Yield
[%][b]
de
ee
p-MeOC6H4
p-MeOC6H4
p-NO2C6H4
p-ClC6H4
[%][a]
[%][c]
1
2
3
4
Ph
a
b
d
h
10
15
10
10
88
71
93
70
66
82
65
>98
>98
>98
>98
85
88
83
79
p-MeOC6H4
p-ClC6H4
o-BrC6H4
p-ClC6H4
9
m-NO2C6H4
2-naphthyl
2-naphthyl
o-MeC6H4
o-MeC6H4
o-BrC6H4
2-furyl
>98
10
11
12
13
14
15
16
[a]–[c] See Table 1.
f
g
g
h
i
optimal chiral ligand. Catalytic AVM of 7 and 2a with 1a or
1b (5 mol% loading, À788C, 18 h) resulted in diastereose-
lective (> 98% de) but inefficient transformations (25% and
34% conv., respectively); furthermore, enantioselectivity was
disappointingly low (35% and 23% ee, respectively). Exami-
nation of alternative chiral ligands was thus performed,
leading us to discover that 1d, bearing a Thr(tBu) residue,
delivers the AVM product in 79% ee (48% conv.). Subse-
quent optimization led us to establish that at À608C, 8a is
obtained in > 98% de, 85% ee, and 70% yield. Ag-catalyzed
AVM of 7 with electron-rich 2b and electron-poor 2d and 2h
gives 8b, 8d, and 8h in 66–82% isolated yield and 79–88% ee
(entries 2–4, Table 3). Two additional points merit mention:
1) Ligand 1d is ineffective for reactions of 3 or 5. For example,
with 3 mol% 1d (À788C), formation of 6a (entry 1, Table 2)
proceeds to 91% conversion but in < 5% ee. 2) In contrast to
catalytic AVM of 3 (Table 1) and 5 (Table 2), with 3-
substituted 7, it is the syn diastereomer that is formed
exclusively (Table 3). Determination of the absolute stereo-
chemistry of 8[13] indicates that the opposite aldimine enantio-
face undergoes addition.
84
90
2-furyl
i
98
[a] Determined by analysis of 400-MHz 1H NMR spectra. [b] Isolated
yields of purified products. [c] Determined by chiral HPLC analysis; see
the Supporting Information for details.
can be used; higher catalyst loadings, however, may be
required (3–5 vs. 1 mol%). The presence of iPrOH as an
additive is required for high conversions,[10] particularly with
larger-scale processes where adventitious moisture is less
available (H2O is an effective additive[11]).
Reactions of 4-Me-substituted 5, prepared from the
commercially available lactone precursor (TMSOTf, Et3N,
08C; 90% yield; TMS = SiMe3, OTf = OSO2CF3) have been
examined. As the data in Table 2 indicate, with 5 mol% 1a
and AgOAc, 6a–b, 6d, 6h, and 6j are obtained in > 98% de,
64–97% yield, and 83–90% ee.[12] Phosphine 1c, bearing the
less expensive Val moiety, can be used, but products are
obtained in slightly lower selectivities (e.g., 93% conv., 90%
yield, 84% ee for 6a in entry 1). Higher catalyst loadings are
Preliminary mechanistic models are shown in Scheme 1.
The Lewis acidic[14] chiral complex may associate with the
aldimine substrate through bidentate chelation (cf. I,
Scheme 1). In the activated complex, to minimize steric
interactions, the substrate is bound anti to the bulky amino
acid substituent (R). The catalyst-bound imine may react with
the siloxyfuran by an endo-type addition (I)[15] to generate
II.[16] Intramolecular desilylation by the Lewis basic amide
terminus of the chiral ligand delivers III. Product release is
facilitated by iPrOH by desilylation of the amide terminus
Table 2: Ag-catalyzed AVMreactions with substituted siloxyfuran 5.
Entry
Ar
Conv.
[%][a]
Yield
[%][b]
de
ee
[%][a]
[%][c]
À
and protonation of the N Ag bond. Such a pathway should be
1
2
3
4
5
Ph
a
b
d
h
j
92
80
>98
98
85
70
97
64
90
>98
>98
>98
>98
>98
87
83
90
89
88
unfavorable for siloxyfuran 7 because of steric repulsion in
the catalyst-bound imine (V). Thus, in reactions involving 7,
the exo-type mode of addition VI may be favored, leading to 8
(Table 3). Additions of 7 may be more sluggish because of a
transition structure that requires positioning of the imineꢀs
p-MeOC6H4
p-ClC6H4
o-BrC6H4
p-BrC6H4
>98
[a]–[c] See Table 1.
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conv.) than 1a and delivers nearly racemic 4a (À13% ee). The
amide moiety might prolong catalyst longevity by providing
stabilization of cationic Ag complexes (e.g., IV). Moreover,
amide termini can stabilize intermediates (e.g., III,
Scheme 1), which contain a positively charged C terminus.
The lower activity of electron-rich phosphine 12 (entry 5)
points to the importance of a Lewis acidic phosphine·Ag
complex.
Anisidyl groups are removed by a one-pot procedure with
PhI(OAc)2 (commercial, used directly).[18] Synthetically ver-
satile derivatives, such as amine 13 and Cbz amide 14, can be
obtained in > 98% de (Scheme 2). Conversion into enantio-
merically enriched 15 (Scheme 2) illustrates one of several
functionalization possibilities that the butenolide moiety
offers.
Scheme 1. Mechanistic models. Si=trimethylsilyl group.
aryl group and the siloxyfuran in the proximity of the amino
acid substituent (R).[17] The origin of the dependence of
specific catalyst classes for reactions of particular siloxyfurans
(e.g., inefficiency of 1a for AVMs of 7 or of 1d for additions of
5) is unclear.
The above hypotheses suggest that C-terminal amide
Lewis basicity is critical to reactivity and enantioselectivity of
catalytic AVM reactions; this is supported by the data in
Table 4. In contrast to the AVM of 2a and 3 promoted by 1a
(> 98% conv., 94% ee), the ligand bearing a p-trifluorometh-
ylaniline amide (9; entry 2, Table 4) gives 55% conversion
into 4a in 85% ee. Ligand 10 (entry 3), with an n-butylamide
terminus, is equally active (> 98% conv.) but initiates a less
enantioselective AVM (87% vs. 94% ee with 1a). The less
Lewis basic methyl ester of 11 (entry 4) is less effective (70%
Scheme 2. Functionalizations of catalytic AVMproducts. Cbz =benzyl-
oxycarbonyl; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
The present catalytic asymmetric protocol is exceptionally
practical. As shown in Equation (2), Ag-catalyzed AVM and
unmasking of the enantiomerically enriched amine can be
carried out efficiently on a multigram scale with only 1 mol%
catalyst loading.
Table 4: Effect of ligand structure on efficiency of catalytic AVM.
Entry
G
R
Ligand
Conv.
[%][a]
de
ee
[%][a]
[%][b]
Applications to reactions of enolizable aldimines[19] and
mechanistic studies are in progress.
1
2
3
4
5
H
H
H
H
N(H)-p-MeOC6H4
N(H)-p-CF3C6H4
N(H)nBu
OMe
N(H)-p-MeOC6H4
1a
9
10
11
12
>98
55
>98
70
>98
>98
>98
>98
>98
94
85
87
Received: August 26, 2006
Published online: October 16, 2006
À13
OMe
86
82
1
[a] Determined by analysis of 400-MHz H NMR spectra of unpurified
products. [b] Determined by chiral HPLC analysis; see the Supporting
Information for details.
Keywords: asymmetric catalysis · enantioselective synthesis ·
imines · silver · vinylogous Mannich reactions
.
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[17] Pre-association of the amide moiety with the siloxyfuran is also
[1] For reviews on utility of stereoselective vinylogous Mannich
reactions, see: a) G. Casiraghi, F. Zanardi, G. Appendino, G.
Rassu, Chem. Rev. 2000, 100, 1929 – 1972; b) S. F. Martin, Acc.
Chem. Res. 2002, 35, 895 – 904.
feasible; such an interaction would enhance enolsilane nucleo-
philicity and facilitate delivery; see: a) S. E. Denmark, G. L.
Beutner, T. Wynn, M. D. Eastgate, J. Am. Chem. Soc. 2005, 127,
3774 – 3789, and references therein; b) Y. Zhao, J. Rodrigo,
A. H. Hoveyda, M. L. Snapper, Nature 2006, 443, 67 – 70.
[18] a) J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L. Snapper, J.
Am. Chem. Soc. 2001, 123, 10409 – 10410; b) L. C. Akullian,
M. L. Snapper, A. H. Hoveyda, Angew. Chem. 2003, 115, 4376 –
4379; Angew . Chem. Int. Ed. 2003, 42, 4244 – 4247.
[2] For example, see: a) S. F. Martin, S. Liras, J. Am. Chem. Soc.
1993, 115, 10450 – 10451; b) S. Liras, C. L. Lynch, A. M. Fryer,
B. T. Vu, S. F. Martin, J. Am. Chem. Soc. 2001, 123, 5918 – 5924;
c) M. V. Spanedda, M. OurØvitch, B. Crousse, J.-P. BØguØ, D.
Bonnet-Delopn, Tetrahedron Lett. 2004, 45, 5023 – 5025.
[3] For a review of Mannich reactions, see: a) A. Córdova, Acc.
Chem. Res. 2004, 37, 102 – 112; for select recent reports of
catalytic asymmetric Mannich reactions (not AVM), see: b) T.
Hamada, K. Manabe, S. Kobayashi, J. Am. Chem. Soc. 2004, 126,
7768 – 7769; c) S. Matsunaga, T. Yoshida, H. Morimoto, N.
Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 8777 –
8785; d) Y. Hamashima, N. Sasamoto, D. Hotta, H. Somei, N.
Umebayashi, M. Sodeoka, Angew. Chem. 2005, 117, 1549 – 1553;
Angew. Chem. Int. Ed. 2005, 44, 1525 – 1529; e) P. G. Cozzi, E.
Rivalta, Angew. Chem. 2005, 117, 3666 – 3669; Angew. Chem. Int.
Ed. 2005, 44, 3600 – 3603; f) J. Song, Y. Wang, L. Deng, J. Am.
Chem. Soc. 2006, 128, 6048 – 6049; g) Y. Chi, S. H. Gellman, J.
Am. Chem. Soc. 2006, 128, 6804 – 6805.
[19] Preliminary results show that the present procedure is applicable
to AVM of aldimines derived from aliphatic aldehydes.
[4] S. F. Martin, O. D. Lopez, Tetrahedron Lett. 1999, 40, 8949 – 8953.
[5] D. Uraguchi, K. Sorimachi, M. Terada, J. Am. Chem. Soc. 2004,
126, 11804 – 11805.
[6] For related Ag-catalyzed Mannich-type reactions (not AVM),
see: a) D. Ferraris, B. Young, T. Dudding, T. Lectka, J. Am.
Chem. Soc. 1998, 120, 4548 – 4549; b) N. S. Josephsohn, M. L.
Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2003, 125, 4018 –
4019; c) N. S. Josephsohn, M. L. Snapper, A. H. Hoveyda, J. Am.
Chem. Soc. 2004, 126, 3734 – 3735; d) N. S. Josephsohn, E. L.
Carswell, M. L. Snapper, A. H. Hoveyda, Org. Lett. 2005, 7,
2711 – 2713.
[7] For determination of relative and absolute stereochemical
identity of AVM products from reactions of 3, see the Supporting
Information.
[8] See the Supporting Information for all data.
[9] For relative p nucleophilicity of various enol silanes, see: H.
Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66 – 77.
[10] For a similar effect in Cr-catalyzed enantioselective aldol
additions of siloxyfurans to aldehydes, see: S. Onitsuka, Y.
Matsuoka, R. Irie, T. Katsuki, Chem. Lett. 2003, 32, 974 – 975.
[11] For example, when carried out on a 0.5-g (2.4-mmol) scale, AVM
of 2a and 3 proceeds to only 43% conversion (93% ee) in the
absence of iPrOH (> 98% conv., 82% yield, 91% ee with
1.1 equiv of the alcohol additive). Ag-catalyzed AVM to afford
4a proceeds to 97% conversion (87% yield) in 92% ee with
1.1 equivalents H2O (conditions in Table 1).
[12] Relative and absolute stereochemical identity of products
derived from 5 was established through an X-ray crystal
structure of 6j (entry 5, Table 2). See the Supporting Informa-
tion for details.
[13] For relative and absolute stereochemical identity of products
derived from 7, see the Supporting Information.
[14] Preliminary data indicate that the chiral Ag complex likely
serves as a Lewis acid catalyst (vs. Ag enolate). For example,
there is ca. 30% conversion in the presence of 20 mol% of Et3N
(synthesis of 4a with 1 mol% 1a, À788C).
[15] Preference for endo-type (“Diels–Alder”-type) transition states
has been suggested for diastereoselective (non-asymmetric)
vinylogous Mannich reactions; see: S. K. Burr, S. F. Martin,
Org. Lett. 2000, 2, 3445 – 3447.
=
[16] The C N bond of chiral ligands do not undergo addition likely
because of steric hinderance provided by the amino acid
substituent.
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