Highly enantioselective azadiene diels-alder reactions catalyzed by chiral N-heterocyclic carbenes

Article abstract of DOI:10.1021/ja062707c

Highly enantioselective, N-heterocyclic carbene (NHC)-catalyzed aza-Diels-Alder reactions are described. A novel chiral triazolium salt based on the cis-1,2-aminoindanol platform serves as an efficient precatalyst for the NHC-catalyzed redox generation of

Full text of DOI:10.1021/ja062707c

Published on Web 06/09/2006
Highly Enantioselective Azadiene Diels-Alder Reactions Catalyzed by Chiral
N-Heterocyclic Carbenes
Ming He, Justin R. Struble, and Jeffrey W. Bode*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106-9510
Received April 18, 2006; E-mail: bode@chem.ucsb.edu
Scheme 1. Proposed NHC-Mediated Enolate Generation
Carbon-carbon bond forming processes mediated by N-hetero-
cyclic carbene (NHC) organocatalysts have witnessed recent, im-
pressive progress in the discovery of new reaction manifolds and
the development of asymmetric processes.1,2 Notable advances
include new chiral triazolium catalysts for enantioselective inter-
molecular homodimerization of aryl aldehydes,3 intramolecular
aldehyde-ketone benzoin cyclizations,4 and intramolecular Stetter
reactions.5 Our own efforts have focused on extending the mecha-
nistic pathways available to the key “Breslow intermediate” formed
by the nucleophilic addition of NHC catalysts to aldehydes,6 and
we have reported the application of this strategy to the catalytic
generation of activated carboxylates7,8 and to novel carbon-carbon
bond forming processes that proceed via a formal homoenolate
intermediate.9
In the context of these studies, we recognized that protonation
or trapping of a conjugated Breslow-type intermediate i should lead
to the formation of a catalyst-bound enol or enolate poised for
carbon-carbon bond formation (Scheme 1).10,11 We now report the
first example of such a strategy, namely, the NHC-catalyzed
generation of a highly reactive dienophile that participates in
LUMOdiene-controlled Diels-Alder cyclizations with R,â-unsatur-
ated imines under unprecedentedly mild conditions.12 Furthermore,
we have developed a new triazolium precatalyst that affords the
dihydropyridinone products in >99% ee for a wide range of
substrates (eq 1).
Table 1. Development and Optimization of NHC-Catalyzed
Azadiene Diels-Alder Reactions (Ar ) MeOC6H4)
entry cat. (%)
conditions
3:4a
% conv.b
1
2
3
4
5
6
7
8
5 (15) 10 mol % of DBU, 0.1 M THF
5 (15) 10 mol % of DIPEA, 0.1 M THF
6 (15) 10 mol % of DBU, 0.1 M THF
7 (15) 10 mol % of DBU, 0.1 M THF
7 (15) 10 mol % of DBU, 0.1 M EtOAc
7 (15) 10 mol % of DBU, 0.1 M toluene
>10:1
>10:1
36 (7:1 dr)
13 (2:1 dr)
nr
47
38
1:8
1:5
1:10 44
7 (15) 10 mol % of DIPEA, 0.1 M toluene >1:20c 44
7 (10) 10 mol % of DIPEA, 23 h
0.05 M 10:1 toluene:THF
>1:20c 63
9
8 (10) 10 mol % of DIPEA, 23 h
nr
0.05 M 10:1 toluene:THF
10 9 (10) 10 mol % of DIPEA, 23 h
>1:20c 90% yieldd
0.05 M 10:1 toluene:THF
99.5% ee
An obstacle to the successful implementation of this approach
to the catalytic generation of reactive enolates was the unexpected
reluctance of the postulated Breslow intermediate, or its homoeno-
late resonance structure, to undergo protonation. When imidazolium-
derived NHC catalysts were employed, no protonation at the â-posi-
tion occurred even in protic solvents at elevated temperatures.7b
To address this, triazolium precatalyst 7 was designed and, in con-
junction with a weak tertiary amine base, found to promote the de-
sired protonation reaction, presumably leading to enol iii or enolate
iv (Scheme 1). Efforts to trap these species, however, were frustrated
by high temperatures and the tendency of the nucleophilic carbenes
to react with an added electrophile in preference to the enal.9c
a Product ratios and diastereoselectivities determined by 1H NMR analysis
of unpurified reaction mixtures. b Ratio of lactam products relative to starting
imine. c Lactam 3 was not detected. d Yield of isolated product. DIPEA )
N,N-diisopropylethylamine.
To increase the electrophilicity of the enal, we selected inex-
pensive, commercially available ethyl trans-4-oxo-2-butenoate13
1
as a substrate for NHC-promoted reactions with N-sulfonyl imines.
The reaction of imidazolium-derived carbenes with 1 was fast, but
did not result in protonation at the â-position. Instead, γ-lactams
were formed (Table 1, entries 1 and 2).9c In contrast, hindered tri-
azolium catalyst 7 led to the formation of a new product. Structure
9
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C O M M U N I C A T I O N S
Table 3. Variation of the Enal Substratea
Table 2. Catalytic, Enantioselective Diels-Alder Reactionsa
a See Table 2 for reaction conditions and notes. b An additional 1.0 equiv
portion of the enal was added after 15 h. c Determined by HPLC analysis
on Chiralpak AD (entry 2) and AS (entries 1, 3, 4) columns.
Figure 1. Stereochemical model for endo-Diels-Alder cycloaddition.
R,â-unsaturated imine in the presence of 10 mol % of 9 and 10
mol % of DIPEA at ambient temperature for 23-48 h followed by
removal of the solvent and purification by chromatography. The
only detectable side products were those arising from imine
decomposition (5-25%) and small amounts of enal dimerization
(>5%). No byproducts are formed in the reaction, obviating the
need for an aqueous workup. This process tolerated a full range of
unsaturated imine substrates (Table 2), including both electron-
rich and electron-deficient cinnamaldehyde derivatives, as well as
heterocyclic and aliphatic examples. In all cases, the enantiomeric
excesses were >99%.
Variation in the enal reactant was also possible, and the necessary
substrates were prepared in a single step from the corresponding
phosphonate esters and dimethylglyoxaldehyde acetal.15 The syn-
thetically attractive tert-butyl ester substrate participated in good
yield and enantioselectivity (Table 3, entry 1). Methyl or phenyl
ketones also gave the desired product in >98% ee (entries 2-4).
The formation of dihydropyridinones bears the hallmark of a
LUMOdiene-controlled inverse electron demand Diels-Alder cy-
cloaddition.12 Related, uncatalyzed processes have been described
in detail by Boger,16 Fowler,17 and Hsung.18 In these studies, how-
ever, the reaction of unactivated imines, such as 2, with electron-
rich dienophiles required high pressure (12 kbar) or high temper-
atures, while the NHC-carbene-catalyzed aza-Diels-Alder reaction
proceeds readily at ambient conditions. The exceptional diastereo-
selectivity is rationalized by the high preference for an endo
transition state, and in the NHC-catalyzed system, this reaction
mode is reinforced by the presence of the bulky triazolium moiety
in the active dienophile (Figure 1). The cis-stereoselectivity would
arise from a (Z)-enolate reacting as the dienophile. We have
postulated that protonation of the Breslow intermediate can occur
only in a fully conjugated, extended arrangement that necessarily
leads to the (Z)-enolate or enol structure.7b The model shown in
a Ar ) 4-MeOC6H4. All reactions were performed at 0.05 M for 23-48
h. In all cases, only a single diastereomer was detected in unpurified reaction
mixtures by 1H NMR or HPLC analysis. b Yields of isolated products. c 10
mol % of ent-9 was used as the catalyst. d Determined by HPLC analysis
on Chiralpak AS (entries 1-3, 6), OD (entry 4), or AD (entry 5) columns.
All enantiomeric ratios were >200:1 based on integration of the minor
enantiomer or baseline.
elucidation by single-crystal X-ray analysis revealed this product
to be dihydropyridinone 4, apparently formed by a Diels-Alder-
type reaction of imine 2 and a catalytically generated dienophile.
A screen of solvents and bases optimized the product ratio and
conversion (entries 4-7). Remarkably, the reaction occurs readily
at lower temperatures (-20 °C), although these conditions offered
no significant advantages to catalytic couplings at ambient tem-
perature.
Intrigued by the prospect of developing an enantioselective entry
to these attractive products, we screened known chiral triazolium
salts as catalysts. Disappointingly, the aminoindanol-derived pre-
catalyst 8 described by Rovis was completely inactive in the
reaction.14 A brief survey of triazolium salts possessing more
sterically demanding aryl groups identified mesityl-substituted salt
9 as a highly active catalyst, affording the dihydropyridinone
product in >99% ee, >50:1 cis-diastereoselectivity, and without
forming γ-lactam product 3. The absolute configuration was
determined by X-ray analysis of the product arising from a para-
bromocinnamaldehyde imine (see Supporting Information). Other
protecting groups on the imine nitrogen were viable; the para-
methoxybenzenesulfonyl derivative provided the highest rates and
yields of isolated products by diminishing electrophilic inhibition
of the nucleophilic NHC catalyst.9c
In the optimized protocol, enantiopure dihydropyridinones were
obtained simply by mixing near equimolar amounts of enal and an
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C O M M U N I C A T I O N S
Scheme 2. Postulated Catalytic Cycle
reaction. In addition to the potential of this powerful approach to
the catalytic generation of an exceptionally reactive dienophile, it
is a rare example of a highly enantioselective intermolecular cross-
coupling reaction catalyzed by an NHC organocatalyst.21 The
operationally friendly reaction conditions do not require heating,
cooling, workup, or additional reagents. The chiral dihydropyridi-
none products, which are obtained in good yield and with
remarkable enantioselectivities, are valuable structures for the
synthesis of biologically active molecules.
Acknowledgment. This work was supported by the California
Cancer Research Coordinating Committee and a Camille and Henry
Dreyfus New Faculty Award (to J.W.B.). J.W.B. gratefully
acknowledges Richard and Leslie Anderson and Amgen for
additional support. M.H. is a 2006 J.H. Tokuyama Fellow. A
generous gift of aminoindanol was provided by Donald Gauthier
(Merck Research Laboratories). We thank Keisuke Suzuki and
Hiroshi Takikawa (Tokyo Institute of Technology) for a kind gift
of 8, Guang Wu (UCSB) for X-ray analyses, and Alex Lippert
(UCSB) for helpful discussion.
Figure 1 also rationalizes the observed absolute stereochemistry of
the products. The conformation of the enol-triazolium bond is a
key determinate of the stereochemical outcome, and the origin of
this preference is not immediately clear. Further experimental and
computational investigations are underway and will lead to an
improved understanding of the mechanism and stereochemical
outcome.
Supporting Information Available: Experimental procedures and
characterization data for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
At present, we attribute the need for enals bearing electron-
withdrawing groups only to the increased electrophilicity of these
substrates, which enhances the rate of their reaction with the
nucleophilic catalysts.19 There does not appear to be a mechanistic
limitation requiring extended conjugation in the catalytically
generated dienophile as would be found in enolate 10, a resonance
structure of the Breslow intermediate, or 11, a tautomeric form.
References
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diastereoselective protonation of enolates generated from R,â-epoxyal-
dehydes, see ref 7a.
To test this hypothesis, we briefly explored the generation of
dienophiles from R-chloro aldehyde 13, which is known to undergo
related NHC-catalyzed redox reactions,8 leading to enols or enolates.
In the presence of 10 mol % of 7 and 1.5 equiv of DIPEA, 13
afforded dihydropyridinone product 14 in 40% yield. Thus, although
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the homoenolate to generate 12.
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suggesting an alternative Morita-Baylis-Hillman-like generation
of the enolate.20 Attempts to employ fumarates or other electron-
deficient substrates lacking the aldehyde functionality have so far
been unproductive, disfavoring this mechanistic pathway. A step-
wise conjugate addition-lactamization sequence featuring an
intermediate activated carboxylate would require exclusive reaction
of the s-cis-imine conformer, rendering this mechanism less likely.
Taken together, these considerations, along with our previous
investigations of NHC-catalyzed transformations, support the
catalytic cycle shown in Scheme 2.
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(19) When less electrophilic enals are employed, the NHC catalyst reacts
preferentially with the electrophilic imine. Thus, at the current stage of
development, cinnamaldehyde and related substrates give only imine
decomposition products under these conditions.
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In summary, we have described a new manifold for asymmetric
organocatalysis through the first NHC-catalyzed Diels-Alder
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