The importance of iminium geometry control in enamine catalysis: Identification of a new catalyst architecture for aldehyde-aldehyde couplings

Article abstract of DOI:10.1002/anie.200461851

Central to the design of a new organocatalyst system for aldehyde-aldehyde aldol reactions is the necessity of iminium geometry control during the enamine addition step (see scheme). Significant structural variation in both the aldol donor and aldol acceptor are possible while maintaining high reaction efficiency and enantioselectivity. TFA=trifluoroacetic acid.

Full text of DOI:10.1002/anie.200461851

Communications
molecular aldol reaction. Almost three decades later, studies
by the groups of Barbas[3a] and List[3b] revealed that proline
catalysis could be extended to a variety of transformations,
including the direct enantioselective aldol reaction[4] between
ketones and aldehydes. Recently, our group advanced this
proline-catalysis concept to the first example of a direct
enantioselective cross-coupling of aldehyde substrates[5]
(Scheme 1), a powerful yet elusive aldol variant that had
previously only been carried out within the realm of
enzymatic catalysis.
Scheme 1. Proline-catalyzed aldehyde–aldehyde aldol reaction.
As part of an ongoing program to develop organocatalysts
of broad utility to chemical synthesis, we recently initiated
studies towards the identification of simple amines that mimic
aldolase type I enzymes while providing complementary
function or stereoselectivity to known enamine catalysts
(e.g., proline). Herein we describe a mechanism-based
investigation that has established imidazolidinones as effi-
cient catalysts for direct and enantioselective aldehyde–
aldehyde aldol reactions. More importantly, we demonstrate
a new class of enamine catalyst with selectivity parameters
that rival or complement benchmark amino acid catalysts
(Scheme 2).
In 2001, Houk and Bahmanyar reported a computational
study into the transition-state topographies involved in
enamine aldol reactions.[6] Besides providing further insight,
this study described that secondary enamine additions
typically proceed via a late transition state in which the
Organocatalysis
The Importance of Iminium Geometry Control in
Enamine Catalysis: Identification of a New
Catalyst Architecture for Aldehyde–Aldehyde
Couplings**
Ian K. Mangion, Alan B. Northrup, and
David W. C. MacMillan*
In 1971, Hajos and Parrish[1] and Eder, Sauer, and Wiechert[2]
independently described the first examples of enantioselec-
tive proline-catalyzed reactions in the form of an intra-
[*] I. K. Mangion, A. B. Northrup, Prof. D. W. C. MacMillan
Division ofChemistry and Chemical Engineering
California Institute of Technology
1200 E. California Blvd., MC 164-30, Pasadena, CA 91125 (USA)
Fax: (+1)626-795-3658
E-mail: dmacmill@caltech.edu
[**] Financial support was provided by the NIHGMS (R01 GM66142-01)
and kind gifts from Bristol-Myers Squibb, Eli Lilly, and Merck
Research Laboratories. I.K.M. and A.B.N are grateful for NSF
predoctoral fellowships.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Imidazolidinone-catalyzed aldehyde–aldehyde aldol reac-
tion.
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DOI: 10.1002/anie.200461851
Angew. Chem. Int. Ed. 2004, 43, 6722 –6724

Angewandte
Chemie
development of the iminium p bond precedes the formation
of the carbon–carbon bond. On this basis, we hypothesized
that enantiofacial discrimination in enamine additions might
be governed, in part, by the ability of an amine catalyst to
control iminium geometry during the transition state. Given
the success of imidazolidinones as asymmetric catalysts that
confer iminium activation and geometry control,[7] we ration-
alized that amines of type 1 might readily function as
enantioselective enamine-aldol catalysts. This hypothesis
was further substantiated by the computational model
MM3-2, which predicts p-facial differentiation of enamine-
iminiums derived from 1 on the basis of 1) selective formation
of the E iminium isomer during the transition state to avoid
nonbonding interactions with the bulky tert-butyl group, and
2) the benzyl group on the catalyst framework which effec-
tively prevents the Re face of the enamine from participating
in carbonyl addition.
The ability of imidazolidinone 1 to catalyze enantioselec-
tive cross-aldol reactions between non-equivalent aldehydes
was examined next. As highlighted in Table 1, addition of a-
methylenealdehyde donors by means of a syringe pump to a
Table 1: Imidazolidinone-catalyzed direct aldol condensation: reaction
scope.
Entry R1
R2
Product
Yield anti/ ee
[%][a] syn[b] [%][c,d]
1
2
Me
Me
86
90
4:1 94
5:1 95
Initial investigations revealed that the (2S,5S)-5-benzyl-2-
tert-butylimidazolidinone catalyst 1 (10 mol%) does, indeed,
promote the aldol self-coupling of propionaldehyde to
provide the putative aldol adduct 3 in ꢀ 86% yield with
94% ee (Scheme 3). Unexpectedly, the initial aldol dimeriza-
Me
Me
iPr
3
4
c-C6H11
81
61
5:1 97
4:1 93
Me
Ph
5
6
nBu
Bn
iPr
72
80
58
64
84
84
6:1 91
5:1 91
4:1 90
4:1 92
11:1 97
1:4 92
iPr
7
Me
OPiv
OBn
SBn
8
OBn
SBn
Scheme 3. Imidazolidinone-catalyzed aldol reaction: initial results.
9
tion adduct 3 undergoes rapid formation to the hemiacetal
system 4, a self-termination step that fortuitously protects the
product from participation in further aldol processes. To our
delight, methanolysis of this aldol hemiacetal product in situ
allows direct access to the bench-stable b-hydroxy dimethox-
yacetal 5 without loss in enantiopurity or diastereocontrol.
Notably, the observed sense of asymmetric induction is in
accord with the calculated enamine-iminium model MM3-2.
In contrast to the proline variant, this enantioselective
aldehyde coupling is readily accomplished in a wide variety
of solvents,[8] with low dielectric media (e.g., hexane: 90% ee;
dioxane: 94% ee) being generally most efficient. The superior
levels of asymmetric induction and efficiency exhibited by the
amine salt 1 in Et2O to afford the dimethoxy-protected
aldehyde (2R)-5 in 86% yield with 94% ee in one chemical
process prompted us to select these catalytic conditions for
further exploration.
10[e]
OTIPS OTIPS
[a] Absolute and relative stereochemistry assigned by chemical correla-
tion. [b] Determined by chiral GLC or Mosher ester analysis. [c] Enantio-
meric excess ofmajor diastereomer. [d] Performed in dioxane. [e] Et 2NH/
SiO2 in place ofMeOH/Amberlyst-15. TIPS =triisopropylsilyl, Piv=piv-
aloyl.
variety of formyl acceptors effectively prevents homodime-
rization while providing the desired cross-aldol products in
excellent yields (Table 1, entries 1–10, 58–90% yield). Sig-
nificant electronic and structural modification in the acceptor
component can be realized to incorporate a-alkyl, a-aro-
matic, and a-oxy functionality (Table 1, entries 1–7, 90–
97% ee).
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Communications
[6] S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc. 2001, 123, 11273.
[7] a) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am.
Chem. Soc. 2000, 122, 4243; b) J. F. Austin, D. W. C. MacMillan,
J. Am. Chem. Soc. 2002, 124, 1172.
[8] Solvent study for propionaldehyde dimerization with amine 1:
hexane: 89% yield, 3:1 anti/syn, 90% ee; CH2Cl2: 66% yield, 4:1
anti/syn, 93% ee; CHCl3: 42% yield, 4:1 anti/syn, 91% ee;
toluene: 80% yield, 3:1 anti/syn, 87% ee; THF: 22% yield, 2:1
anti/syn, 90% ee; Et2O: 86% yield, 4:1 anti/syn, 94% ee;
dioxane: 92% yield, 4:1 anti/syn, 94% ee.
[9] A. B. Northrup, I. K. Mangion, F. Hettche, D. W. C. MacMillan,
Angew. Chem. 2004, 116, 2204; Angew. Chem. Int. Ed. 2004, 43,
2152.
[10] A. B. Northrup, D. W. C. MacMillan, Science 2004, 305, 1752.
[11] We recently determined that this imidazolidinone-catalyzed
aldol reaction allows enantioselective access to gulose in two
steps.
Whereas it has been documented that a-acyloxy-substi-
tuted aldehydes are inert to proline catalysis,[9] we have found
that these substrates readily participate as electrophilic aldol
partners in the presence of amine 1 (Table 1, entry 7, 58%
yield, 90% ee).
We next examined the capacity of imidazolidinone 1 to
catalyze the homodimerization of a-heterosubstituted alde-
hydes (Table 1). It has been established that proline catalysis
in this venue provides erythrose architecture in one step,[9]
a
transformation that enables the selective production of
mannose, glucose, or allose in only two chemical reactions.[10]
As shown in Table 1, entries 8 and 9, exposure of catalyst 1 to
a-benzyloxy or a-benzylsulfide aldehydes also provides the
erythrose aldol adduct with high levels of enantiocontrol (92–
97% ee). In contrast, a-silyloxy aldehydes provide the
corresponding threose aldehyde product upon hydrolysis of
the corresponding hemiacetal over silica gel (Table 1,
entry 10, 4:1 syn/anti, 92% ee). As such, we anticipate that
the imidazolidinone catalyst will be valuable in the produc-
tion of hexose carbohydrates that are not available through
proline catalysis (e.g. idose, gulose, galactose).[11] More
importantly, this result demonstrates the capacity for orthog-
onal enamine selectivities as a function of amine catalyst
architecture.
In summary, we have documented the first asymmetric
organocatalytic aldol reaction in the presence of imidazolidi-
none catalysts. This method allows enantioselective access to
b-hydroxy dimethoxyacetals, bench-stable adducts that func-
tionally complement the b-hydroxyaldehyde adducts derived
from proline-catalyzed aldol reactions.
Received: September 1, 2004
Keywords: aldehydes · aldol reaction · nitrogen heterocycles ·
.
organocatalysis · synthetic methods
[1] “Asymmetric Synthesis of Optically Active Polycyclic Organic
Compounds”: a) Z. G. Hajos, D. R. Parrish, German Patent
DE2102623, July 29, 1971; b) Z. G. Hajos, D. R. Parrish, J. Org.
Chem. 1974, 39, 1615.
[2] a) “Optically active 1,5-Indanone and 1,6-Naphthalenedione”:
U. Eder, G. Sauer, R. Wiechert (Schering AG), German Patent
DE2014757, Oct. 7, 1971; b) U. Eder, G. Sauer, R. Wiechert,
Angew. Chem. 1971, 83, 492; Angew. Chem. Int. Ed. Engl. 1971,
10, 496.
[3] a) K. Sakthievel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem.
Soc. 2001, 123, 5260; b) W. Notz, B. List, J. Am. Chem. Soc. 2000,
122, 7386.
[4] For examples of metal-mediated direct aldol reactions, see:
a) Y. M. A. Yamada, N. Yoshikawa, H. Sasai, M. Shibasaki,
Angew. Chem. 1997, 109, 1290; Angew. Chem. Int. Ed. Engl.
1997, 36, 1871; b) N. Yoshikawa, N. Kumagai, S. Matsunaga, G.
Moll, T. Oshima, T. Suzuki, M. Shibasaki, J. Am. Chem. Soc.
2001, 123, 2466; d) N. Kumagai, S. Matsunaga, N. Yoshikawa, T.
Oshima, M. Shibasaki, Org. Lett. 2001, 3, 1539; e) B. M. Trost, H.
Ito, J. Am. Chem. Soc. 2000, 122, 12003; f) B. M. Trost, E. R.
Silcoff, H. Ito, Org. Lett. 2001, 3, 2497; g) D. A. Evans, J. S.
Tedrow, J. T. Shaw, C. W. Downey, J. Am. Chem. Soc. 2002, 124,
392.
[5] A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 6798.
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 6722 –6724