Enantioselective (Formal) Aza-diels-alder reactions with non-danishefsky-type dienes

Article abstract of DOI:10.1021/ja104480g

Enantioselective (formal) aza-Diels-Alder reactions between acylhydrazones and non-Danishefsky-type dienes have been developed. The reactions are promoted by a simple and economical chiral silicon Lewis acid and are typically conducted at ambient temperature. Both glyoxylate- and aliphatic aldehyde-derived hydrazones may be employed, as may variously substituted dienes, leading to the synthesis of a diverse array of tetrahydropyridines with good to excellent levels of enantioselectivity.

Full text of DOI:10.1021/ja104480g

Published on Web 07/14/2010
Enantioselective (Formal) Aza-Diels-Alder Reactions with
Non-Danishefsky-Type Dienes
Uttam K. Tambar, Sharon K. Lee, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received May 24, 2010; E-mail: leighton@chem.columbia.edu
Electronic tuning of the hydrazone aryl group was pursued as a
Abstract: Enantioselective (formal) aza-Diels-Alder reactions be-
tween acylhydrazones and non-Danishefsky-type dienes have been
developed. The reactions are promoted by a simple and economical
chiral silicon Lewis acid and are typically conducted at ambient
temperature. Both glyoxylate- and aliphatic aldehyde-derived hy-
drazones may be employed, as may variously substituted dienes,
leading to the synthesis of a diverse array of tetrahydropyridines
with good to excellent levels of enantioselectivity.
means of perturbing the ratio of products. Thus, whereas electron-
poor hydrazone 2b gave a 1:1.5 ratio of products 4b and 5b, electron-
rich hydrazone 2c led to a 1.8:1 ratio of products 4c and 5c (Scheme
2). Interestingly, however, o-methoxybenzoylhydrazone 2d favored
the production of the [4 + 2] product 5d (1:1.8), suggesting that steric
factors might play an important role as well. This led to an examination
of pivaloyl hydrazone 2e, which produced 5e as the exclusive product
in 69% yield. It was subsequently found that the reaction was best
conducted at room temperature in CH2Cl2 with 1.5 equiv of silane 1.
Under these conditions, 5e was isolated in 91% yield and 85% ee.
On any list of important heterocycles, both for natural products
chemistry and medicinal chemistry, piperidines would figure most
prominently. While countless methods may be imagined for the
synthesis of such structures, the diene-imine [4 + 2] cycloaddition
(aza-Diels-Alder, ADA) reaction must surely rank as one of the
more direct and potentially versatile methods.1 Despite this, it is
only recently that the first examples of enantioselective variants of
this reaction have been developed.2 However, the highly enanti-
oselective reactions that have been reported are mostly limited to
the use of Danishefsky-type dienes, significantly limiting the scope
of the reaction. We describe here the development of enantiose-
lective (formal) ADA reactions with non-Danishefsky-type dienes
employing a simple and practical silane Lewis acid.
Scheme 2
We have previously reported the use of silane 13 with acylhy-
drazones in [3 + 2] cycloaddition reactions with electron-rich
alkenes.4 Attempts to divert the reaction course to a [4 + 2] pathway
focused first on cyclopentadiene, but when the complex formed
from the reaction of hydrazone 2a with silane 1 was treated with
cyclopentadiene, pyrazolidine 3 was the exclusive product (Scheme
1). However, when 2,3-dimethyl-1,3-butadiene was employed, a
1:1 mixture of [3 + 2] product 4a and [4 + 2] product 5a was
obtained in 76% yield. We have established that the [3 + 2]
cycloaddition reaction proceeds in a stepwise fashion,4 and these
results may be rationalized using this framework. Thus, initial attack
of the diene on the silane-hydrazone complex results in allyl cation
intermediate 6, which can collapse to give the [3 + 2] product 4a
(path a) or the [4 + 2] product 5a (path b).
A brief survey of the scope of the reaction with respect to the diene
structure was carried out (Table 1). Isoprene and other 2-alkyl-1,3-
butadienes uniformly provide the products in near-quantitative yields
and with good levels of enantioselectivity (entries 1-3). The phenyl-
substituted diene gives a lower ee (entry 4), but this can be reversed
by using toluene as the solvent (entry 5). In contrast, the p-BrC6H4-
substituted diene performs as well as the alkyl-substituted dienes (entry
6). Finally, we have demonstrated a 3.8 mmol (of 2e) scale preparative
reaction with this diene using reduced (1.3 equiv) silane loadings (entry
7). The product was isolated by recrystallization in 70% yield and
98% ee, and the pseudoephedrine was recovered in 93% yield.
Table 1. Enantioselective Diene-Acylhydrazone [4 + 2] Reactions
Scheme 1
entry
R
solvent
yield (%)
ee (%)
1
2
Me
CHCl3
CHCl3
CHCl3
CHCl3
PhCH3
CHCl3
CHCl3
96
99
95
99
66
99
70
85
87
90
-81
95
PhCH2CH2
PMBOCH2CH2
Ph
Ph
p-BrC6H4
p-BrC6H4
3
4a
5
6a
7b
-86
98
a The enantiomeric silane Lewis acid (S,S)-1 was used in this
reaction. b Conditions: 3.8 mmol of 2e, 1.3 equiv of (R,R)-1, and 2.0
equiv of diene. (R,R)-Pseudoephedrine was recovered in 93% yield.
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C O M M U N I C A T I O N S
Aliphatic aldehyde-derived hydrazone 7 is also a successful
substrate, albeit one that requires extended reaction times and/or
elevated temperatures (Scheme 3). Despite the sluggish rate of these
reactions, products 8-10 may be accessed with good to excellent
yields and enantioselectivities. Aromatic aldehyde-derived hydra-
zones have thus far proven unreactive.
without precedent in the long and illustrious history of the
Diels-Alder reaction and its variants.
Reductive cleavage of the N-N bond in the hydrazide
8
products with SmI2 requires prior acylation in a modification
of the Friestad procedure.9 Thus, benzoylation of ent-10a
[prepared as in Scheme 3 using (S,S)-1] followed by reduction
with SmI2 gave 17 in 56% yield (Scheme 5). We also discovered
an interesting alternative when an attempt to methylate the
pivalamide nitrogen of ent-10a unexpectedly delivered 18.
Reduction of 18 with SmI2 proceeded smoothly to give 19 in
70% overall yield.
Scheme 3
Scheme 5
To further expand the scope with respect to the diene structure
and to access more structural and stereochemical complexity in
the products, dienes having the general structures 11 and 12 were
investigated (Scheme 4). While such dienes have been exten-
sively studied in Diels-Alder reactions (and with only two
exceptions5 react to give the regioisomer expected from stereo-
electronic considerations), next to no information is available
regarding the corresponding ADA reactions.6 Reactions of dienes
11a and 11b with the complex formed from 2e and (R,R)-1 led
to 13a and 13b, respectively. The products were formed with
complete regio- and diastereoselectivity and in 83 and 86% ee,
respectively. Interestingly, however, dienes 12a and 12b exhib-
ited reversed regioselectivity, leading to 14a and 14b, respec-
tively, as the major products of reactions that appear to be
governed by the minimization of steric interactions in the initial
C-C bond formation. While the regio- and diastereoselectivities
in these reactions were not as high, the reactions are nevertheless
preparatively useful, as 14a was isolated pure in 61% yield and
97% ee and 14b in 57% yield and 95% ee. Perhaps even more
remarkably, a remote methoxy group reestablished the supremacy
of electronic control in the dihydronaphthalene series, as the
reaction of 12c with the complex formed from 15 and (R,R)-1
produced 16 (7:1 regioselectivity, 9:1 diastereoselectivity), albeit
with reduced enantioselectivity.7 After purification, 16 was
isolated in 66% yield and 77% ee. Either regioisomer (14 or
16) is thus available based solely on variation of a remote
substituent on the diene 12, a phenomenon that appears to be
We have described the development of enantioselective (formal)
ADA reactions with non-Danishefsky-type dienes promoted by a
silicon Lewis acid. Both glyoxylate- and aliphatic aldehyde-derived
hydrazones may be employed, and a reasonably wide scope with
regard to diene structure has been demonstrated as well, giving
access to a diverse array of piperidine derivatives.
Acknowledgment. This work was supported by Grant CHE-
08-09659 from the National Science Foundation. U.K.T is the
recipient of a postdoctoral fellowship (F32 GM077937) from
the NIH/NIGMS, and S.K.L. is a National Science Foundation
Graduate Research Fellow. We thank Prof. Gerard Parkin and
Mr. Aaron Sattler for X-ray structure analyses (see the Sup-
porting Information), and the National Science Foundation
(CHE-06-19638) is thanked for funding to acquire an X-ray
diffractometer.
Supporting Information Available: Experimental procedures,
characterization data, stereochemical proofs, and crystallographic
data (CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
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