Three-component Ag-catalyzed enantioselective vinylogous mannich and aza-diels - Alder reactions with alkyl-substituted aldehydes

Article abstract of DOI:10.1021/ja807243t

Efficient protocols for three-component catalytic enantioselective vinylogous Mannich (VM) reactions of alkyl-substituted aldimines (including those bearing heteroatom-containing substituents) and readily available siloxyfurans are presented. High efficiency and stereoselectivity is achieved through the use of o-thiomethyl-p-methoxyaniline-derived aldimines. Reactions, performed under an atmosphere of air and in undistilled THF, can be promoted in the presence of as little as 1 mol % of easily accessible amino acid-based chiral ligands and commercially available AgOAc. The desired products are obtained in 44 to 92% yield, and in up to >98:<2 diastereomer and >99:<1 enantiomer ratio (>98% ee). Removal of the N-activating group is performed through a one-vessel oxidation/hydrolysis operation, which proceeds via a stable aza-quinone (characterized by X-ray crystallography). Evidence is presented indicating that reactions with chiral nonracemic aldehydes are subject to catalyst control: both substrate enantiomers react to afford the desired product diastereomers in high stereoselectivity. Aryl- and alkynyl-substituted o-thiomethyl-p-methoxyaniline-derived aldimines undergo Ag-catalyzed enantioselective VM reactions more efficiently and with higher selectivity than the corresponding o-anisidyl substrates. Additionally, Ag-catalyzed aza-Diels-Alder reactions of the alkyl-substituted aldimines bearing the structurally modified N-aryl unit afford enantiomerically enriched (up to 95% ee) products in up to 88% yield.

Full text of DOI:10.1021/ja807243t

Published on Web 11/21/2008
Three-Component Ag-Catalyzed Enantioselective Vinylogous
Mannich and Aza-Diels-Alder Reactions with
Alkyl-Substituted Aldehydes
Hiroki Mandai, Kyoko Mandai, Marc L. Snapper,* and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College Chestnut Hill,
Massachusetts 02467
Received September 12, 2008; E-mail: amir.hoveyda@bc.edu
Abstract: Efficient protocols for three-component catalytic enantioselective vinylogous Mannich (VM)
reactions of alkyl-substituted aldimines (including those bearing heteroatom-containing substituents) and
readily available siloxyfurans are presented. High efficiency and stereoselectivity is achieved through the
use of o-thiomethyl-p-methoxyaniline-derived aldimines. Reactions, performed under an atmosphere of air
and in undistilled THF, can be promoted in the presence of as little as 1 mol % of easily accessible amino
acid-based chiral ligands and commercially available AgOAc. The desired products are obtained in 44 to
92% yield, and in up to >98:<2 diastereomer and >99:<1 enantiomer ratio (>98% ee). Removal of the
N-activating group is performed through a one-vessel oxidation/hydrolysis operation, which proceeds via
a stable aza-quinone (characterized by X-ray crystallography). Evidence is presented indicating that reactions
with chiral nonracemic aldehydes are subject to catalyst control: both substrate enantiomers react to afford
the desired product diastereomers in high stereoselectivity. Aryl- and alkynyl-substituted o-thiomethyl-p-
methoxyaniline-derived aldimines undergo Ag-catalyzed enantioselective VM reactions more efficiently and
with higher selectivity than the corresponding o-anisidyl substrates. Additionally, Ag-catalyzed aza-
Diels-Alder reactions of the alkyl-substituted aldimines bearing the structurally modified N-aryl unit afford
enantiomerically enriched (up to 95% ee) products in up to 88% yield.
reactions of aryl-substituted aldimines.5 The desired products
Introduction
can be obtained in excellent diastereo- (typically >99:<1 dr)
Mannich reactions rank among the most versatile class of
transformations in organic chemistry. Development of efficient
and practical catalytic enantioselective variants of such reactions
stands as a critical goal in chemical synthesis.1,2 One set of
Mannich-type processes involves additions of siloxyfurans to
aldimines; as illustrated in Scheme 1, highly diastereo- and
enantioselective versions of such processes generate small
organic molecules that can be functionalized in a number of
ways. We recently outlined an efficient and selective protocol
for Ag-catalyzed3,4 enantioselective vinylogous Mannich (VM)
and enantioselectivity (typically >95:<5 er) by transformations
that often require as little as 1 mol % of a readily available
phosphine ligand and commercially available Ag salt; transfor-
mations do not require distilled solvents or inert atmosphere
conditions.5 In an earlier investigation, also represented in
Scheme 1, we utilized the above Ag-based chiral complexes to
effect enantioselective aza-Diels-Alder reactions6 with the
Danishefsky diene.7 Transformations in the above two classes
of Ag-catalyzed reactions involve nonenolizable aryl-substituted
aldimines. In the case of protocols disclosed by other labora-
tories, catalytic enantioselective VM and aza-Diels-Alder
reactions with aldimines derived from alkyl-substituted alde-
hydes are either not included or are limited to two examples or
less.8-10 Enantioselective VM processes involving this limited
set of substrates are effected with diminished efficiency and
diastereoselectivity than those of the more common aryl-
substituted aldimines.
(1) For a recent review of Mannich reactions involving aldimines, see:
(a) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102–112. For select recent
reports of catalytic enantioselective Mannich reactions (not VM)
involving aldimines, see: (b) Hamada, T.; Manabe, K.; Kobayashi, S.
J. Am. Chem. Soc. 2004, 126, 7768–7769. (c) Matsunaga, S.; Yoshida,
T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 8777–8785. (d) Hamashima, Y.; Sasamoto, N.; Hotta, D.;
Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005,
44, 1525–1529. (e) Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed.
2005, 44, 3600–3603. (f) Song, J.; Wang, Y.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 6048–6049. (g) Chi, Y.; Gellman, S. H. J. Am. Chem.
Soc. 2006, 128, 6804–6805. (h) Chen, Z.; Yakura, K.; Matsunaga, S.;
Shibasaki, M. Org. Lett. 2008, 10, 3239–3242.
Herein, we describe the development of a protocol for
efficient three-component Ag-catalyzed enantioselective VM
(4) For a review of Ag-catalyzed enantioselective reactions, see: Naodovic,
M.; Yamamoto, H. Chem. ReV. 2008, 108, 3132–3148.
(5) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2006, 45, 7230–7233.
(2) For an overview regarding applications of Mannich reactions to the
preparation of biologically active molecules and target-oriented
synthesis, see:(a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem.,
Int. Ed. 1998, 37, 1044–1070. (b) Bur, S. K.; Martin, S. F. Tetrahedron
2001, 57, 3221–3242.
(6) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 4018–4019.
(3) For an overview of utility of chiral Ag-based phosphine complexes
in enantioselective reactions, see: Yanagisawa, A.; Arai, T. Chem.
Commun. 2008, 1165–1172.
(7) (a) Kerwin, J. F., Jr.; Danishefsky, S. J. Tetrahedron Lett. 1982, 23,
3739–3742. (b) Danishefsky, S. J.; DeNinno, M. P. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 15–23.
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A R T I C L E S
Mandai et al.
Scheme 1. Previously Reported Ag-Catalyzed Enantioselective Vinylogous Mannich and Aza-Diels-Alder Reactions of Aryl-Substituted
Aldimines
reactions of the more demanding alkyl-substituted aldimines, a
class of substrates that cannot be readily isolated and purified
and are typically prone to decomposition. Use of an N-aryl unit
bearing an o-thiomethyl and a p-methoxy substituent is critical
for efficient access to alkyl-substituted aldimines (vs o-anisidyl
in Scheme 1), which are prepared and used in situ through
diastereo- and enantioselective three-component processes (up
to >98:<2 dr and >99:<1 er). We illustrate that alkyl-
substituted aldimines can be used in Ag-catalyzed three-
component enantioselective aza-Diels-Alder reactions as well.
spectrum of the unpurified mixture indicates the presence of a
substantial amount of byproducts, pointing to the relative instability
of the in situ-generated imine.
In search of a more robust substrate, we examined the reaction
of the aldimine derived from 3a and methyl-substituted anisidine
1b (entry 2, Table 1). We surmised that the presence of a methyl
group ortho to the CdN bond11 might provide sufficient steric
hindrance to discourage formation of the aminal (i.e., addition of
aniline to aldimine), a byproduct detected in the reaction with
o-anisidine 1a. As illustrated in entry 2 of Table 1, treatment of
the aldimine derived from 1b to the above conditions results in
<2% conversion. Based on the hypothesis that a more electrophilic
imine might be induced to undergo efficient catalytic enantiose-
lective VM, we turned to the electronically activated p-nitro-
substituted aldimine derived from 1c and 3a; we have recently
demonstrated that use of 1c leads to efficient, diastereo- and
enantioselective VM reactions of R-ketoimine esters.12 As shown
in entry 3 of Table 1, however, the process involving aniline 1c
and aldehyde 3a results in <2% conversion to the desired VM
product.
Results and Discussion
I. Development of Ag-Catalyzed Enantioselective VM of
Alkyl-Substituted Aldimines. a. Examination of various N-aryl
groups. We began by examining the reaction of the aldimine
derived from cyclohexylcarboxaldehyde 3a and aniline 1a (Table
1), a substrate that bears the previously and commonly utilized
o-anisidine N-aryl group, with the commercially available (unpu-
rified) siloxyfuran 2. Chiral ligand 4a, formerly demonstrated to
be effective in promoting Mannich-type processes,5,6 was used.
As the data in entry 1 of Table 1 indicate, with 5 mol % 4a and
AgOAc in THF at -78 °C, there is complete aldimine consumption
and unsaturated γ-lactone 5 is obtained in 95:5 dr and 94:6 er (88%
ee), but in only 44% yield. Examination of the 400 MHz 1H NMR
To determine whether the inefficiency in cases involving
anilines 1b and 1c is due to ineffective aldimine generation,
substrate decomposition and/or lack of substrate reactivity, we
(10) For catalytic enantioselective Mannich-type reactions (not VM or aza-
Diels-Alder) that include reactions of alkyl-substituted aldimines, see:
(a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 8180–8186. (b) List, B. J. Am. Chem. Soc. 2000, 122, 9336–
9337. (c) Gonza´lez, A. S.; Arraya´s, R. G.; Carretero, J. C. Org. Lett.
2006, 8, 2977–2980. (d) Notz, W.; Tanaka, F.; Watanabe, S.;
Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F.,
III. J. Org. Chem. 2003, 68, 9624–9634. (e) Salter, M. M.; Kobayashi,
J.; Shimizu, Y.; Kobayashi, S. Org. Lett. 2006, 8, 3533–3536. (f)
Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Tetrahedron Lett. 2006,
47, 3985–3989. (g) Trost, B. M.; Jaratjaroonphong, J.; Reutrakaul, V.
J. Am. Chem. Soc. 2006, 128, 2778–2779. (h) Song, J.; Shih, H.-W.;
Deng, L. Org. Lett. 2007, 9, 603–606. (i) Marianacci, O.; Micheletti,
G.; Bernardi, L.; Fini, F.; Fochi, M.; Pettersen, D.; Sgarzani, V.; Ricci,
A. Chem.-Eur. J. 2007, 13, 8338–8351.
(8) For disclosures regarding catalytic enantioselective VM reactions that
include examples of alkyl-substituted aldimines, see: With i-Pr- and
Cy-substituted aldimines: (a) Akiyama, T.; Honma, Y.; Itoh, J.;
Fuchibe, K. AdV. Synth. Catal. 2008, 350, 399–402. With two closely
related n-alkyl-substituted aldimines: (b) Yamaguchi, A.; Matsunaga,
S.; Shibasaki, M. Org. Lett. 2008, 10, 2319–2322. Only aryl-substituted
aldimines: (c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 11804–11805.
(9) For reports on catalytic enantioselective aza-Diels-Alder reactions that
include examples with alkyl-substituted aldimines, see: With only Cy-
substituted aldimines: (a) Kobayashi, S.; Komiyama, S.; Ishitani, H.
Angew. Chem., Int. Ed. 1998, 37, 979–981. With i-Pr- and Cy-
substituted aldimines: (b) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew.
Chem., Int. Ed. 2006, 45, 4796–4798. With 2-propyl-substituted
aldimine: (c) Shang, D.; Xin, J.; Liu, Y.; Zhou, X.; Liu, X.; Feng, X.
J. Org. Chem. 2008, 73, 630–637. For a related catalytic enantiose-
lective aza-Diels-Alder protocol, see: (d) Sunde´n, H.; Ibrahem, I.;
Eriksson, L.; Co´rdova, A. Angew. Chem., Int. Ed. 2005, 44, 4877–
4880.
(11) For use of a related N-arylimine in Zr-catalyzed Mannich reactions
with silylketene acetals, see: Ishitani, H.; Ueno, M.; Kobayashi, S.
J. Am. Chem. Soc. 1997, 119, 7153–7154.
(12) Wieland, L. C.; Vieira, E. V.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. in press.
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A R T I C L E S
Table 1. Examination of Various N-Aryl Groups in Three-Component Enantioselective VM Reaction Involving an Aliphatic Aldehydea
a Reactions performed under an atmosphere of air. b Conversions and diastereomer ratio (dr) values were determined by analysis of 400 MHz 1H
NMR spectra of unpurified products (based on disappearance of 3a). c Yields of isolated and purified products. d Enantiomer ratio (er) values were
determined by HPLC analysis; see the Supporting Information for details.
performed the studies summarized in Table 2. We thus find that,
whereas imine formation is relatively efficient with o-anisidine
1a and o-methyl-substituted 1b (42 and 61% conv, respectively;
entries 1-2), the mixture that contains aldehyde 3a and aniline
1c (entry 3) consists of unidentifiable side products (minimal
aldimine detected). These observations imply that the electroni-
cally activated aldimine derived from 3a and 1c is unstable.
In light of the above findings, and based on the assumption
that the corresponding electron rich aldimine is less electrophilic
and thus less prone to decomposition, we prepared and examined
the reaction of the aldimine derived from 3a and 2,4-
dimethoxyaniline 1d (entry 4, Table 1). As illustrated in entry
4 of Table 1, >98% conversion is achieved and 6 is isolated in
81% yield, an outcome significantly superior to that obtained
when 1a is used (entry 1) but with equally high diastereo- (96:4
dr) and enantioselectivity (94:6 er, 88% ee). As the data in entry
4 of Table 2 indicate, with aniline 1d, imine formation is more
efficient than when 1a or 1b are used (83% conv vs 42% and
61% conv, respectively).
the structure of the N-aryl group. Within this context, we chose
to examine an N-aryl unit that bears a S-based metal-coordinat-
ing group. We reasoned that a more effective association of
the “softer” chelating heteroatom with the late transition metal
may lead to a more organized transition state structure and
improved enantiodifferentiation. As illustrated in entry 5 of
Table 1, when o-thiomethylaniline 1e is used to prepare the
aldimine derived from 3a, the desired product (7) is isolated as
a 98.5:1.5 mixture of enantiomers (97% ee), which is a higher
degree of enantiopurity than observed with the corresponding
O-substituted N-aryl group 1a (entry 1, 94:6 er); the diastereo-
selectivity of the process is improved as well, with the product
now obtained as a single diastereomer (>98:<2 dr). Since
rendering the N-aryl group more electron rich leads to more
efficient VM reactions in the case of methoxy-substituted N-aryl
groups (i.e., entry 1 vs 4 in Tables 1-2), we prepared the
aldimine derived from S-substituted aniline 1f. As shown in
entry 6 of Table 1, Ag-catalyzed enantioselective VM with the
cyclohexyl-substituted aldimine derived from the o-thiomethyl-
p-methoxyaniline (1f) proceeds to >98% conversion, affording
8a in 90% yield after chromatography, >98:<2 diastereose-
lectivity and as a single enantiomer (>99:<1 er, >98% ee).
The stereochemical identity of 8a has been determined by X-ray
With a relatively effective catalytic enantioselective VM
reaction in hand (entry 4, Table 1), we turned to determining
whether product enantiopurity (96:4 dr, 88% ee in entries 1 and
4, Table 1) might be improved through further adjustment of
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A R T I C L E S
Mandai et al.
Table 2. Examination of the Relative Facility of Aldimine
Table 3. Ag-Catalyzed Three-Component Enantioselective VM
Formationa
Reactions of Alkyl-Substituted Aldimines with Siloxyfuran 2a
a Reactions performed under an atmosphere of air with 1.0 equiv of
aldehyde and aniline in the presence of 2.0 equiv of siloxyfuran 2;
>98% conversion in all cases (based on disappearance of aldehyde),
except for entry 6 (93% conv). b Yields of isolated purified products.
c Diastereomer ratio (dr) values were determined by analysis of 400
a Reactions run under an atmosphere of air. b Conversion determined by
1
analysis of 400 MHz H NMR spectra of the unpurified reaction mixtures
(based on disappearance of 3a). c Complex mixture of products formed.
MHz H NMR spectra of the unpurified reaction mixtures. d Enantiomer
1
ratio (er) values were determined by HPLC analysis; see the Supporting
Information for details. e Reaction performed with 30 mol % catalyst at
-30 °C.
Scheme 2. Products from Catalytic Enantioselective VM Reactions
of Heteroatom-Bearing Aldiminesa
Figure 1. X-ray structure of product 8a.
structure analysis (Figure 1). As indicated by the data sum-
marized in entries 5-6 of Table 2, similar to anilines 1a and
1d (entries 1 and 4, Table 2), aldimine formation is more
efficient in the case of S-substituted aldimines that bear a more
electron rich N-aryl unit (90% conv in 10 min).
a Reactions performed under identical conditions as shown in Table 3.
b. Ag-Catalyzed Enantioselective VM with Alkyl-Substituted
Aldimines. Aniline 1f can be used in three-component enanti-
oselective VM reactions involving an assortment of alkyl-
substituted aldehydes and commercially available siloxyfuran
2; transformations are promoted in the presence of chiral amino
acid-based phosphine ligands 4a and 4b and commercially
available AgOAc (Table 3). Reactions proceed to >98%
conversion and afford a single diastereomer (>98:<2) with in
situ-generated aldimines that bear an R-branched (entries 1-4),
a ꢀ-branched (entry 5), as well as an n-alkyl substituent (entries
7-8). Ag-catalyzed VM with t-Bu-substituted 3e (entry 6, Table
3) requires 30 mol % loading and elevated temperature (-30
vs -78 °C), affording 8e in 50% yield. In all cases involving
the t-Leu-bearing phophine 4a (entries 1 and 3-8, Table 3),
products 8a-g are obtained as a single enantiomer (>99:<1
er, >98% ee); only when the less expensive Val-containing 4b
is used (entry 2 of Table 3), is any of the minor enantiomer of
8a detected by HPLC analysis (98.5:1.5 er, 97% ee).
As the three examples in Scheme 2 illustrate, the three-
component Ag-catalyzed enantioselective VM process can be
performed with heteroatom-containing aldimines, synthetically
versatile imines scarcely examined in this context.13 Products
8h-j are obtained in moderate yields after purification (44-56%);
these lower yields might be the result of adventitious intramo-
lecular addition of the hydroxyl group of the intermediate
(13) To the best of our knowledge, there is only one reported example of
a catalytic enantioselective Mannich reaction that involves a hetero-
atom-containing imine (benzyloxy acetaldehyde-derived imine); see
ref 10b.
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Vinylogous Mannich and Aza-Diels-Alder Reactions
A R T I C L E S
Scheme 3. Ag-Catalyzed Enantioselective VM Reactions with Me-Substituted Siloxyfurans
hemiamanal to the proximal ester unit (in the case of 8h) or the
relative instability of highly electrophilic aldimines and their
precursor aldehydes (with 8i and 8j). Nonetheless, reactions
represented in Scheme 2 proceed with the same diastereo- and
enantioselectivity as observed with unfunctionalized alkyl-
substituted aldehydes (Table 3).
that both substrate enantiomers react readily with the same chiral
catalyst isomer to afford the two possible diastereomers with
high selectivity. There are, however, it is in cases where the
stereogenic center is proximal to the imine that the substrate
enantiomers can exhibit substantially different reactivity and
selectivity patterns, as the neighboring stereogenic center can
have a significant influence on the transformation. That is, one
substrate enantiomer might undergo reaction more readily and
selectively than the other (substrate control); in such instances,
the catalytic reaction can be utilized to carry out kinetic
resolution.15 Alternatively, both imine enantiomers might react
readily, such that the stereochemical outcome of the reaction is
dictated by the identity of the chiral catalyst (catalyst control),
allowing access to either diastereomer selectively.
To address the above questions, the studies summarized in
Table 4 were performed. As illustrated in entry 1, when
enantiomerically enriched S-1316 is used, 14 is obtained in 68%
yield and with high diastereoselectivity (>98:<2 dr) as a single
enantiomer (>99:<1 er, >98% ee). Precisely the same outcome
is observed, as shown in entry 2 of Table 4, with enantiomeri-
cally enriched R-13: 15 is isolated in 75% yield as a single
isomer. Use of rac-13 leads to the formation of products 14
and 15 with no detectable contamination from any of the
alternative stereoisomers. The above studies demonstrate that
effective catalyst control is operative in Ag-catalyzed enanti-
oselective VM reactions and efficient control of stereochemistry
can be achieved by the appropriate choice of the chiral catalyst.
Ag-catalyzed enantioselective VM reactions can be performed
with various substituted siloxyfurans. Transformations proceed
with similar efficiency as observed with reactions of unsubsti-
tuted 2 and with exceptional diastereoselectivity (Scheme 3).
The degree and sense of enantiodifferentiation, however,
consistent to that previously observed with the related reactions
with aryl-substituted aldimines,5 depend on the identity of the
Si-based nucleophile. Whereas reaction with 4-methyl-substi-
tuted siloxyfuran 9 results in the formation of anti-10 in >99:
<1 er, in the case of 3-methyl-substituted 11, it is syn-12 that
is isolated as the exclusive diastereomer in 87.5:12.5 er (75%
ee). Although 4a promotes the reaction of 9 with aldimine
prepared from 3a and 1f with high diastereo- and enantiose-
lectivity (Scheme 3), the optimal chiral ligand required for VM
of 11, identified through screening studies, is one that bears a
t-Bu-Thr moiety (vs t-Leu).14 When 4a is used to promote the
reaction of the aldimine derived from 3a and 1f with 11, syn-
12 is obtained in >99:<1 dr but only in 61:39 er (22% ee).
Although the mechanistic rationale for the change in the identity
of the chiral ligand is unclear, working models proposed
previously5 for reactions of aryl-substituted aldimines, which
undergo Ag-catalyzed enantioselective VM with similar reactiv-
ity and selectivity trends, can be applied to the present cases.
c. Catalyst vs Substrate Control in Ag-Catalyzed Enanti-
oselective VM Reactions of Chiral Alkyl-Substituted Aldimines.
With an efficient protocol for catalytic enantioselective VM of
alkyl-substituted aldimines, particularly those containing a
heteroatom, in hand, we addressed the issue of catalyst versus
substrate control in three-component transformations involving
chiral aldehydes. Such considerations address the possibility of
whether the catalytic enantioselective method can be used in a
setting where the substrate is chiral and nonracemic. In cases
where the stereogenic center is relatively remote from the CdN
bond (i.e., at the ꢀ or γ carbons of the aldimine), it is likely
d. Practicality of the Catalytic Protocol. One of the hallmarks
of Ag-catalyzed reactions is the simplicity of the procedures:
reactions are performed in undistilled THF, with undistilled
additive (i-PrOH) and in an atmosphere of air. Aniline 1f is
(15) For a case involving an enantioselective conjugate addition of an
enantiomerically enriched enone with a stereogenic center R to the
reacting site, where use of an amino acid-based chiral phosphine
catalyst results in enhancement of selectivity, see: (a) Cesati, R. R.;
de Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 96–101.
For an example where an enantioselective alkylation of an enantio-
merically enriched allylic phosphate promoted by amino acid-based
catalyst proceeds readily and selectively with only one of the substrate
enantiomers, see: (b) Kacprzynski, M. A.; Hoveyda, A. H. J. Am.
Chem. Soc. 2004, 126, 10676–10681.
(16) See the Supporting Information for details regarding the preparation
and enantiomeric purity of chiral non-racemic aldehydes used in this
study. The selectivity values shown in Table 4 are corrected.
(14) See the Supporting Information for details of ligand screening
studies.
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A R T I C L E S
Mandai et al.
Table 4. Ag-Catalyzed Three-Component Enantioselective VM Reactions of Chiral Alkyl-Substituted Aldimines with Siloxyfuran 2a
a Reactions performed in an atmosphere of air with 1.0 equiv of aldehyde and aniline and with 2.0 equiv of siloxyfuran 2; >98% conversion in all
cases (based on disappearance of aldehyde). b Yields of isolated purified products. c Diastereomeric ratios were determined by analysis of 400 MHz 1H
NMR spectra of the unpurified reaction mixtures. d Enantiomer ratio (er) values were determined by HPLC analysis; see the Supporting Information for
details.
prepared from easily accessible, as well as commercially
available (Aldrich), 2-amino-6-methoxybenzothiazole through
a simple basic hydrolysis/alkylation process, which proceeds
in 67-82% yield.17
chiral ligand and AgOAc, affording the desired products with
nearly identical efficiency and enantioselectivity.19 The case
depicted in eq 2 is illustrative.
The enantioselective protocol is amenable to gram scale
preparation of products. As illustrated in eq 1, such reactions
proceed with nearly identical efficiency, as well as diastereo-
and enantioselectivity, as illustrated previously.
e. Removal of the N-Activating Group; Characterization of
the Corresponding Intermediate. The S-containing N-activating
group can be removed through a one-vessel operation that
involves oxidation mediated by cerric ammonium nitrate
Although the studies detailed above involve transformations
promoted by 5 mol % catalyst loading,18 the catalytic reactions
proceed to >98% conversion in the presence of 1 mol % of the
(18) For accuracy in measuring small amounts of chiral ligand and Ag
salt, transformations were performed in the presence of 5 mol %
catalyst.
(19) Although the gram scale reaction shown in eq 1 was performed with
5 mol % catalyst, previous studies involving related Mannich-type
processes indicate that lower catalyst loadings can be readily extended
to larger scale transformations; for example, see ref 5.
(17) McDonald, F. E.; Burova, S. A.; Huffmann, L. G., Jr. Synthesis 2000,
970–974.
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Vinylogous Mannich and Aza-Diels-Alder Reactions
A R T I C L E S
Scheme 4. Oxidative Removal of the N-Activating Group and
Isolation of the Intermediate
5) and alkynyl-substituted (entry 3, Table 5) substrates. As
comparison of transformations in entries 1 and 3 with those
in entries 2 and 4 of Table 5 indicate, VM with o-thiomethyl-
p-methoxyaniline-derived imines are more efficient (>98%
vs 86% yield for phenyl-substituted and 89% vs 70% for
alkynyl-substituted aldimines, respectively). Whereas reac-
tions in all cases proceed with high diastereoselectivity,
processes involving the S-containing N-aryl group are more
selective (>99:<1 vs 98:2 er and >99:<1 er vs 96.5:3.5 er,
respectively). The above observations underline the special
utility of the new N-activating group in allowing for
exceptionally efficient and selective enantioselective VM
reactions with a range of substrates.21
b. Ag-Catalyzed Enantioselective Aza-Diels-Alder Reac-
tions of Alkyl-Substituted Aldimines and the Danishefsky
Diene. o-Thiomethyl-p-methoxy aniline 1f can be used
efficiently in enantioselective three-component aza-Diels-Alder
reactions with a range of alkyl-substituted aldehydes; ex-
amples are illustrated in Table 6. As the transformations in
entries 1-2 (Table 6) indicate, cycloadditions can be
performed in the presence of Val-containing chiral ligand
4b with similar efficiency and selectivity as observed with
t-Leu-bearing 4a.
Cycloadditions are effective with aldimines bearing an n-alkyl
substituent (entry 3, Table 6), as well as those that carry
heteroatom-containing functional groups (entries 4-5, Table 6);
as observed with the related enantioselective VM reactions (see
Scheme 2), however, catalytic aza-Diels-Alder processes with
the latter class of substrates afford dihydropiperidines in lower
yields.
Two additional points regarding the observations in Table 6
merit mention: (1) Ag-catalyzed cycloaddition with i-Bu-
substituted aldimine derived from o-methoxyaniline 1a and
aldehyde 3d (under identical conditions as shown in Table 6)
affords the desired dihydropiperidine in only 16% yield (98:2
er), since the reaction mixture contains unidentified byproducts.
(2) Transformations performed at lower temperature are equally
selective but significantly less efficient. As an example, the
reaction shown in entry 1 of Table 6 results in only ∼30% yield
of 27d under otherwise identical conditions (>98% consumption
of aldimine; >99:<1 er).
(CAN) followed by hydrolytic workup. The example in
Scheme 4, leading to formation of enantiomerically pure
amine 16 in 84% yield is a case in point. An attribute of the
new N-activating group is that, in contrast to the formerly
reported o-anisidyl groups, the derived aza-quinone, oxidation
product (17) that is hydrolyzed to obtain the unmasked amine
(e.g., 16), can be isolated and purified. As also shown in
Scheme 4, subjection of 8a with 2.4 equiv of CAN for 10
min at 0 °C results in the formation of 17 in 78% yield after
silica gel chromatography. The identity of aza-quinone 17
has been ascertained by X-ray crystallography (Scheme 4).
That the initial oxidation product, an electrophilic entity that
can be functionalized in a variety of manners, can be easily
isolated and purified,20 suggests that derivatives previously
inaccessible through the use of o-anisidyl imines are now
Conclusions
We present a reasonably general method for catalytic enan-
tioselective vinylogous Mannich-type reactions that involve
alkyl-substituted aldimines. The three-component Ag-catalyzed
process is performed through a practical procedure (undistilled
solvent, in an atmosphere of air) and proceeds efficiently
(44%-92% yield) and with exceptional diastereo- (>98:<2 dr)
and enantioselectivity (95:5 er to >99:<1 er).
within reach.
(21) As illustrated by the examples below, enantioselective VM reactions
with aldimines derived from R,ꢀ-unsaturated aldehydes proceed to
>98% conversion and in high diastereo- and enantioselectivity but
in low yields. Control experiments point to product instability.
II. Effectiveness of the S-Containing N-Aryl Group in Other
Ag-Catalyzed Enantioselective Mannich-Type Reactions. a. Ag-
Catalyzed Enantioselective Mannich Reactions with Aryl- and
Alkynyl-Substituted Aldimines. The efficiency and high de-
grees of enantiodifferentiation in catalytic enantioselective
VM reactions described above are not limited to alkyl-
substituted aldimines. As the examples in Table 5 demon-
strate, the utility of the S-containing N-aryl group extends
to related catalytic transformations with aryl- (entry 1, Table
(20) For a related oxidation process, see: Momiyama, N.; Yamamoto, Y.;
Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 1190–1195.
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J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008 17967

A R T I C L E S
Mandai et al.
Table 5. Ag-Catalyzed Enantioselective VM Reactions of Isolable Aldimines with Siloxyfuran 2a
a Reactions performed under an atmosphere of air with 1.0 equiv of isolable imine in the presence of 2.0 equiv of siloxyfuran 2. b See Table 3. c See
Table 3. d See Table 3.
Table 6. Ag-Catalyzed Asymmetric Aza-Diels-Alder Reactions of
The present studies furnish an illustration of the utility of
aniline-derived aldimines as effective substrates for catalytic
Alkyl-Substituted Aldimines with Danishefsky Dienea
enantioselective C-C bond forming reactions. Conversion of
the enantiomerically enriched products obtained requires re-
moval of N-aryl groups through oxidative protocols; such
procedures can be more demanding than simple hydrolyses
required for functionalization of products obtained from reac-
tions of other classes of imine substrates (e.g., acid labile
phosphinoylimines).8b,10f,g N-aryl-derived imines, however, offer
entry
aldehyde
ligand product yield (%)b
erc
ee (%)c
an advantage: electronic tuning and modification of the coor-
dinating heteroatom (in addition to N of the CdN bond)
involved in bidentate chelation with the transition metal can be
used to increase aldimine stability as well as elevate reaction
efficiency and selectivity. We thus demonstrate that catalytic
enantioselective VM and aza-Diels-Alder reactions of one of
the more challenging sets of substrates, namely alkyl-substituted
aldimines, can be performed with exceptional efficiency and
enantioselectivity when substrates carry an N,S-based bidentate
chelating structure (vs N,O) and an electron donating p-methoxy
1
2
3
4
5
i-BuCHO (3d)
i-BuCHO (3d)
Ph(CH2)2CHO (3f)
MeO2C(CH2)2CHO (3h) 4a
BnOCH2CHO (3i) 4a
4a
4b
4a
27d
27d
27f
27h
27i
88
85
88
53
66
96:4
96:4
96.5:3.5
95:5
92
92
93
90
95
97.5:2.5
a Reactions performed in an atmosphere of air with 1.0 equiv of
aldehyde and aniline in the presence of 2.0 equiv of diene 26; >98%
conversion in all cases. b Yields of the isolated purified products.
c Enantiomer ratio (er) values were determined by HPLC analysis; see the
Supporting Information for details.
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Vinylogous Mannich and Aza-Diels-Alder Reactions
A R T I C L E S
unit. The availability of a S-based chelating group likely allows
for a more effective association of the substrate with the Ag-
based chiral catalyst and the presence of the electron donating
p-methoxy unit gives rise to aldimines that are less prone to
decomposition.
Design of new chiral amino acid-based ligands and cata-
lysts22 that promote efficient and selective additions to CdN
bonds, development of other catalytic enantioselective processes
involving aldimines and ketoimines derived from structurally
optimized anilines and their application to synthesis of biologi-
cally active molecules are the focus of ongoing studies.
(22) For other related examples of catalytic enantioselective additions
promoted by this class of amino acid-based chiral ligands, see: (a)
Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 1996, 35, 1668–1671.
(b) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.;
Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
1999, 121, 4284–4285. (c) Porter, J. R.; Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 984–985. (d)
Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 10409–10410. (e) Deng, H.; Isler, M. P.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2002, 41,
1009–1012. (f) Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Org.
Lett. 2003, 5, 3273–3275. (g) Akullian, L. C.; Snapper, M. L.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4244–4247. (h)
Hoveyda, A. H.; Hird, A. W.; Kacprzynski, M. A. Chem. Commun.
2004, 1779–1785. (i) Wieland, L. C.; Deng, H.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 15453–15456. (j)
Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2006, 128, 6532–6533. (k) Fu, P.; Snapper, M. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2008, 130, 5530–5541. (l) Friel, D. K.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 9942–9951.
Acknowledgment. Financial support was provided by the NIH
(GM-57212) and the Yamada Foundation (postdoctoral fellowship
to H. M.). We thank L. C. Wieland (Boston College) and Dr. J.
Kung (Boston College and Chungbuk National University, S.
Korea) for many helpful discussions. Mass spectrometry facilities
at Boston College are supported by the NSF (DBI-0619576).
Supporting Information Available: Experimental procedures
and spectral data for substrates and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA807243T
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