Diastereoselective Diels-Alder reactions of N-sulfonyl-1-aza-1,3-butadienes with optically active enol ethers: An asymmetric variant of the 1-azadiene Diels-Alder reaction

Article abstract of DOI:10.1021/ja0571646

The first detailed study of a room-temperature asymmetric Diels-Alder reaction of N-sulfonyl-1-aza-1,3-butadienes is reported enlisting a series of 19 enol ethers bearing chiral auxiliaries, with many providing highly diastereoselective (endo and facial diastereoselection) reactions, largely the result of an exquisitely organized [4+2] cycloaddition transition state. Three new, readily accessible, and previously unexplored auxiliaries rationally emerged from the studies and provide remarkable selectivities (two of these give 49:1 endo:exo and 48:1 facial selectivity) that promise to be useful in systems beyond those detailed.

Full text of DOI:10.1021/ja0571646

Published on Web 02/07/2006
Diastereoselective Diels-Alder Reactions of
N-Sulfonyl-1-aza-1,3-butadienes with Optically Active Enol
Ethers: An Asymmetric Variant of the 1-Azadiene Diels-Alder
Reaction
Ryan C. Clark, Steven S. Pfeiffer, and Dale L. Boger*
Contribution from the Department of Chemistry and the Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received October 20, 2005; E-mail: boger@scripps.edu
Abstract: The first detailed study of a room-temperature asymmetric Diels-Alder reaction of N-sulfonyl-
1-aza-1,3-butadienes is reported enlisting a series of 19 enol ethers bearing chiral auxiliaries, with many
providing highly diastereoselective (endo and facial diastereoselection) reactions, largely the result of an
exquisitely organized [4+2] cycloaddition transition state. Three new, readily accessible, and previously
unexplored auxiliaries rationally emerged from the studies and provide remarkable selectivities (two of
these give 49:1 endo:exo and 48:1 facial selectivity) that promise to be useful in systems beyond those
detailed.
Introduction
In a series of studies, we introduced and have explored the
4π participation of electron-deficient N-sulfonyl-1-aza-1,3-
butadienes in intermolecular Diels-Alder reactions with electron-
rich dienophiles.1 The complementary N1 substitution of an R,â-
unsaturated imine with an electron-withdrawing substituent
(-SO2R) accentuates the inherent electron-deficient nature of
the 1-aza-1,3-butadiene, accelerating its participation in [4+2]
cycloaddition reactions with electron-rich dienophiles in LU-
MOdiene-controlled Diels-Alder reactions. Further, a bulky
electron-withdrawing N1 substituent decelerates competitive 1,2-
imine addition relative to [4+2] cycloaddition and stabilizes
the [4+2] cycloaddition product (deactivated enamine) to the
reaction conditions while enhancing the electron-deficient
character of the diene. Based on theses features, the N-sulfonyl-
1-aza-1,3-butadienes that were explored were found to partici-
pate in regiospecific and diastereoselective inverse electron
demand Diels-Alder reactions with characteristics of a con-
certed [4+2] cycloaddition reaction (Figure 1).2
Figure 1. N-Sulfonyl-1-azadiene Diels-Alder reaction.
providing the further benefit of a transition-state anomeric effect.
A bonus of the N-sulfonyl-1-aza-1,3-butadienes was that they
proved to be stable imine derivatives capable of simple isolation
and purification (SiO2 or Florisil chromatography), resistant to
tautomerization to the corresponding stabilized enamine, and
still remarkably reactive in prototypical [4+2] cycloadditions
that were found to proceed under unusually mild conditions
(25-100 °C). The utility of these reactions has been exploited
in the total synthesis of several natural products, including
streptonigrone,3 fredricamycin A,4 nothapodytine B and (-)-
mappicine,5 (+)-camptothecin,6 and (-)-piericidin A1.7
Throughout the course of these studies, we have periodically
examined approaches to conducting asymmetric variants of this
[4+2] cycloaddition reaction. To date, we have not been
successful in identifying Lewis acid catalysts (chiral or achiral)
that can accelerate the [4+2] cycloaddition; rather they promote
the nonproductive consumption of the reacting partners. By
Moreover, the reactions exhibited an unusually high endo
diastereoselectivity (g20:1) that could be attributed to a [4+2]
cycloaddition transition state which benefits not only from a
conventional stabilizing secondary orbital interaction but also
from one in which the nitrogen lone pair and the C-O σ bond
of an enol ether dienophile lie trans periplanar to one another,
(1) (a) Boger, D. L.; Kasper, A. M. J. Am. Chem. Soc. 1989, 111, 1517. (b)
Boger, D. L.; Corbett, W. L.; Wiggins, J. M. J. Org. Chem. 1990, 55,
2999. (c) Boger, D. L.; Curran, T. T. J. Org. Chem. 1990, 55, 5439. (d)
Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem.
Soc. 1991, 113, 1713. (e) Boger, D. L.; Corbett, W. L. J. Org. Chem. 1993,
58, 2068.
(2) (a) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in
Organic Synthesis; Academic: San Diego, 1987. (b) Boger, D. L.
Tetrahedron 1983, 39, 2869. (c) Boger, D. L. Chem. ReV. 1986, 86, 781.
(d) Boger, D. L. Chemtracts: Org. Chem. 1996, 9, 149.
(3) Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc. 1993, 115,
10733.
(4) Boger, D. L.; Hu¨ter, O.; Mbiya, K.; Zhang, M. J. Am. Chem. Soc. 1995,
117, 11839.
(5) Boger, D. L.; Hong, J. J. Am. Chem. Soc. 1998, 120, 1218.
(6) Boger, D. L.; Blagg, B. S. J. Tetrahedron 2002, 58, 6343.
(7) Schnermann, M. J.; Boger, D. L. J. Am. Chem. Soc. 2005, 127, 15704.
9
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J. AM. CHEM. SOC. 2006, 128, 2587-2593
2587

A R T I C L E S
Clark et al.
Scheme 1
lectivities in the Lewis acid-catalyzed reactions of a series of
chiral enol ethers with nitroalkenes,11 and Pettus has extended
their use in uncatalyzed cycloaddition reactions with o-quinone
methides (Figure 2).12
Dienophile Preparation. Several methods were enlisted for
the preparation of the vinyl ethers examined (Scheme 1).
Typically, they were prepared from ethyl vinyl ether by Hg-
(OAc)2-catalyzed exchange with the alcohol corresponding to
the desired vinyl ether (method A).13 A variant of this approach
utilizes mercury(II) trifluoroacetate, although few examples of
its use in transetherification reactions have been detailed (method
B).14 Dujardin developed a two-step procedure for vinyl ether
formation involving acid-catalyzed mixed acetal formation from
the chiral alcohol and ethyl vinyl ether, followed by a TMSOTf-
promoted elimination to the desired vinyl ether (method C).15
More recently, Ishii reported an iridium-catalyzed transetheri-
fication ([Ir(cod)Cl]2),16 and Schlaf reported analogous reactions
catalyzed by palladium (Pd(DPP)(OCOCF3)2).17 In our hands,
their effectiveness was found to be substrate dependent.
Survey of Dienophile Chiral Auxiliaries. Initially, 18
optically active enol ethers were examined with the prototypical
N-sulfonyl-1-aza-1,3-butadiene 1 (Figure 3 and Table 1). The
distribution of cycloaddition products and their quantitation were
determined by 1H NMR of the reaction mixtures which typically
displayed distinguishable signals for each of the four possible
products. Thus, the initial assignments and the quantitation were
made by examination and integration of the C2-H and C5-H
1H NMR signals of the cycloadducts. The C5-H splitting was
diagnostic of endo (ddd, J ) 8.3, 5.1, 1.6 Hz) versus exo (dt,
J ) 8.3, 1.8 Hz) addition, and both the C5-H and C2-H
integrations were used for the quantitations. Representative of
this, the results with dienophile 6a are illustrated in Figure 4,
where C5-H of the two endo adducts are each observed as a
clear ddd (5.40 and 5.26 ppm, J ) 1.6, 5.1, 8.3 Hz), whereas
Figure 2. Cycloadditions of optically active enol ethers.
contrast and largely as the result of the exquisitely organized
[4+2] cycloaddition transition state, we have found and herein
detail that their reactions with enol ether dienophiles bearing
chiral auxiliaries provide highly diastereoselective (endo and
facial diastereoselection) Diels-Alder cycloadditions. Three
new, readily accessible, and previously unexplored auxiliaries,
which rationally emerged from these studies, proved highly
selective (>20:1 endo and >20:1 facial selectivity) and promise
to be useful in systems beyond those that we detail.
At the onset of the studies, we explored enol ethers bearing
chiral auxiliaries that have been disclosed in preceding cycload-
dition reactions. Posner has shown that modest to good
diastereomeric excesses are observed when chiral vinyl ethers
derived from benzylic secondary alcohols undergo [4+2]
cycloadditions with 3-sulfinyl- and 3-sulfonyl-2-pyrones both
in the presence and in the absence of a Lewis acid catalyst.8
Dujardin utilized chiral enol ethers derived from mandelate or
pantalactone to prepare enantiopure hexose derivatives and
â-benzamido aldehydes via their reaction with â,γ-unsaturated
R-keto esters.9,10 Denmark has observed excellent diastereose-
Figure 3. Survey of optically active enol ethers.
9
2588 J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006

Diels−Alder Reactions of N-Sulfonyl-1-aza-1,3-butadienes
A R T I C L E S
Table 1. Results of Survey of Optically Active Enol Ethers
ratio of diastereomersb
time major adduct
total
endo facial
endo:exo selectivity
dienophile
(h) (% conversion)a conv (%) endo
exo
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
60
60
60
60
72
60
60
60
60
48
60
60
60
60
60
60
60
48
2b (52)c
3b (72)
4b (49)
5b (63)
6b (48)
7b (71)
8b (53)
9b (71)
10b (85)
11b (12)c
12b (41)
13b (55)
14b (12)
15b (27)
16b (32)
17b (54)d
18b (59)d
19b (96)d
(82)e
97 54:40
94 77:19
63 78:18
80 79:14
64 75:14
91 78:18
69 77:15
88 81:19
98 86:10
31 37:18
55 75:25
86 62:19
18 69:31
45 83:9
38 85:9
68 80:14
65 91:5
g98 96:2
-
:
:
:
:
:
:
:
:
:
:
:
:
:
:
:
:
:
3:3
4:-
4:-
7:-
11:-
4:-
8:-
16:1
19:1
24:1
13:1
8:1
1.4:1
4:1
4:1
6:1
5:1
4:1
5:1
4:1
9:1
2:1
3:1
3:1
2:1
11:1
9:1
6:1
18:1
48:1
-
24:1
12:1
-:- >25:1
4:-
29:16
24:1
1:1
-:- >25:1
13:6 4:1
-:- >25:1
8:-
6:-
6:-
4:-
2:-
12:1
16:1
16:1
24:1
49:1
Figure 5. Dienophile series 3-9.
of the superb endo diastereoselectivity (8:1 vs 19:1). Replacing
the aryl ring with a saturated alkyl group (2a) or a larger
naphthyl ring (9a) did not significantly impact the endo
diastereoselection, and the latter did not improve the cycload-
dition facial selectivity. Within this series, the amount of the
major diastereomer approached the respectable level of 80% of
the product for each of the dienophiles, with the enhanced facial
selectivity of the larger alkyl derivatives being offset by a larger
proportion of exo adduct(s). As such, and because of their
enhanced rates of reactions, 3a and 9a emerge as the most useful
dienophiles in this series (Figure 5).
:
-
ethyl vinyl 46
ether
>25:1
a Reactions performed at room temperature, 0.3 M with respect to diene
in toluene. Major adduct % conversion based on integration of major product
C2-H versus minor diastereomer C2-H’s and diene C2-H. Some
hydrolysis of diene ocassionally observed (<5%). b Ratios based on 1H
NMR integration of C2-H of products unless otherwise noted. Endo and
exo compounds assigned on the basis of 1H NMR splitting patterns. Some
peaks could not be located due to overlap, small size, or low conversion.
c Integration based on C5-H. d Anhydrous CHCl3 as solvent, 1 M with
respect to diene. e Yield from ref 1c.
Several enol ethers, 10-13a, bearing chiral six-membered
rings were examined, inspired by the work of Denmark and
Swindell (10-12a)19-21 or Posner (13a).8 Whereas the most
hindered of these (11a and 12a) exhibited poor reactivities, poor
endo diastereoselectivities (12a) and/or modest to poor facial
selectivities, 13a and especially 10a exhibited good chemical
reactivity (% conversions), outstanding (10a, 24:1) or modest
(13a, 4:1) endo diastereoselectivity, and good (10a, 9:1) or
modest (13a, 3:1) facial selectivity. Of these, the dienophile
10a proved most satisfactory, providing conversions that slightly
exceed 85% for the major diastereomer in a reaction that
provides superb conversions (98%) with exceptional endo
diastereoselectivity (24:1) and excellent facial selectivity (9:1)
(Figure 6).
1
Figure 4. Diagnostic cycloadduct H NMR signals.
The study of the most interesting and useful series, 14-19,
began with an examination of enol ethers derived from
R-hydroxy esters and lactones, inspired by the studies of
Dujardin.9 Thus, the mandelate-derived enol ether 14a, analo-
the minor exo adduct was observed as a dt (5.32 ppm, J ) 1.8,
8.3 Hz), and both the structure and the relative and absolute
stereochemistries of the major product were established by a
single-crystal X-ray structure determination.18 The diagnostic
(8) Posner, G. H.; Wettlaufer, D. G. Tetrahedron Lett. 1986, 27, 667.
(9) (a) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron Lett. 1996, 37, 4007.
(b) Dujardin, G.; Rossignol, S.; Brown, E. Synthesis 1998, 763. (c) Gong,
J.; Bonfand, E.; Brown, E.; Dujardin, G.; Michelet, V.; Geneˆt, J.
Tetrahedron Lett. 2003, 44, 2141. (d) Gaulon, C.; Dhal, R.; Chapin, T.;
Maisonneuve, V.; Dujardin, G. J. Org. Chem. 2003, 68, 4338.
(10) Gizecki, P.; Dhal, R.; Poulard, C.; Gosselin, P.; Dujardin, G. J. Org. Chem.
2004, 37, 4007.
(11) Review: Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137.
(12) Pettus, T. R. R.; Selenski, C. J. Org. Chem. 2004, 69, 9196.
(13) Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79, 2828.
(14) Tan, D. S.; Schreiber, S. L. Tetrahedron Lett. 2000, 41, 9509.
(15) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron Lett. 1995, 36, 1653.
(16) Okimoto, Y.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2002, 124, 1590.
(17) Bosch, M.; Schlaf, M. J. Org. Chem. 2003, 68, 5225.
(18) Atomic coordinates for the major cycloadducts derived from the reaction
of 1 with 3a (3b, CCDC286828), 6a (6b, CCDC286829), 12a (12b,
CCDC286826), 17a (17b, CCDC286830), and 19a (19b, CCDC286827,
(S)-enantiomer) and for the major cycloadduct from the reaction of 21a
with 19a (21b, CCDC287011, (S)-enantiomer) have been deposited with
the Cambridge Crystallographic Data Center.
(19) Denmark, S. E.; Schnute, M. E. J. Org. Chem. 1991, 56, 6738.
(20) Denmark, S. E.; Thorarensen, A. J. Org. Chem. 1996, 61, 6727.
(21) Swindell, C. S.; Tao, M. J. Org. Chem. 1993, 58, 5889.
1
C5-H coupling in the H NMR spectra arises from the well-
defined conformations of the endo (diaxial substituents) versus
exo (axial -OR*, equatorial -CO2Et) cycloadducts and the
resulting C5-H/C4-H coupling constants of ca. 5 Hz (C4-
Heq) versus ca. 2 Hz (C4-Hax). In an analogous fashion, the
structures of the major products derived from 3 and 6 (repre-
sentative of 2-9), 12, and 17 and 19 (representative of 14-
19) were established by X-ray.18
Clear trends emerged in the examination of the series 2-9a,
inspired by the Posner studies, where the role of the aryl ring
was probed with 2 versus 3 and the size of the dienophile alkyl
substituent was systematically increased with 3-6. As the size
of the alkyl group was increased (3af6a), the facial selectivity
of the cycloaddition increased modestly (6:1 vs 4:1), but it did
so at the expense of the rate of the reaction and with an erosion
9
J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006 2589

A R T I C L E S
Clark et al.
Scheme 2
Figure 6. Dienophile series 10-13.
preparation of 18a was conducted from ethyl vinyl ether and
(+)-(R)-2-hydroxy-γ-butyrolactone (both enantiomers are com-
mercially available) utilizing Dujardin’s two-step protocol15
(20%) or Ishii’s [Ir(cod)Cl]2-catalyzed16 alcohol exchange
(20%), whereas the Hg(II)-catalyzed reactions led only to side
product formation. This difficulty in the preparation of 18a (low
conversions), coupled with its propensity to undergo competitive
lactone ring-opening reactions (hydrolysis, esterification) in
subsequent transformations, led to the examination and prefer-
ential use of the corresponding lactam 19a. The preparation of
19a, which eventually proved straightforward, also provided
unexpected initial observations (Scheme 2). (-)-(S)-3-Hydroxy-
2-pyrrolidinone, which is commercially available or readily
prepared from (-)-(S)-4-amino-2-hydroxybutanoic acid (HMDS,
TMSCl, xylenes, 94%)23 and is readily available in both
enantiomeric forms,24 could be cleanly converted to 19a using
ethyl vinyl ether and Dujardin’s two-step protocol, but unex-
pectedly it provided racemic product. Presumably, this arises
through TMSOTf/Et3N silylation of the amide (O-silyl imidate
formation) and subsequent racemization.25 Although the iridium
and Hg(OAc)2-catalyzed exchange with ethyl vinyl ether did
not cleanly provide 19a, the reaction catalyzed by Hg(O2CCF3)2
in the presence of Et3N effectively provides 19a (66%) without
evidence of competitive racemization.25 Significantly, 19a
provides beautiful, large white prisms upon recrystallization
from EtOAc-hexanes, providing a convenient stage and manner
Figure 7. Dienophile series 14-19.
gous to those explored by Dujardin,22 exhibited superb endo
diastereoselection but poor facial selectivity (2:1) and low
conversions, whereas Dujardin’s pantalactone-derived enol ether
17a9 maintained the excellent endo diastereoselection (16:1) and
exhibited a substantially improved facial selectivity (6:1). As
was observed with the preceding hindered enol ethers (e.g., 6a),
the reactivity of 17a was modest and likely contributed to the
erosion of the endo diastereoselection. Consequently, we
examined 18a with removal of the gem-dimethyl substitution
of 17a, which has not been previously explored, and found that
it was more reactive, exquisitely endo diastereoselective (24:
1), and remarkably facial selective (18:1). The lactate-derived
enol ethers 15a and 16a were subsequently examined to define
the importance of cyclic structure of 18a and were found to be
both less reactive and less selective than 18a. Finally, the
corresponding lactam 19a, which proved both synthetically more
accessible and more stable to subsequent transformations, was
examined and found to exhibit a higher reactivity and an even
greater level of endo (49:1) and facial (48:1) diastereoselection
than 18a (Figure 7). Thus, it is from these latter studies that
two of the new and most impressive auxiliaries (18a and 19a)
rationally emerged, exhibiting remarkable endo (>20:1) and
facial (>20:1) selectivities for the [4+2] cycloaddition reactions
with 1 which promise to be useful in systems beyond those
that we detail.
for ensuring its chemical and optical purity (for (S)-19a, [R]25
D
-78 (c 0.77, CHCl3)).25
Cycloaddition Model. We have suggested that the excep-
tional endo diastereoselection observed with the N-sulfonyl-1-
aza-1,3-butadienes results from not only a conventional stabi-
lizing secondary orbital interaction but also a transition-state
anomeric effect in which the nitrogen lone pair and the C-O σ
bond of the dienophile enol ether lie trans periplanar to one
another in the endo boat transition state.1 Regardless of the origin
of stabilization for an anomeric effect (n-σ* stabilization or
avoidance of electrostatic repulsion),26 the endo boat transition
state embodies its trans periplanar lone pair/C-O bond arrange-
ment, whereas the exo boat transition state places them proximal
and gauche to one another. We have suggested that it is the
(23) Sarairi, D.; Maurey, G. Bull. Soc. Chim. Fr. 1987, 297.
(24) Perhaps the most expedient approach to either enantiomer of 3-hydroxy-
2-pyrrolidinone is Amano PS-C lipase-mediated alcoholysis of racemic
3-acetoxy-2-pyrrolidinone (>99% ee of either enantiomer at 50% conver-
sion, er ) 1057): Kamal, A.; Ramana, K. V.; Ramana, A. V.; Babu, A. H.
Tetrahedron: Asymmetry 2003, 14, 2587.
Preparation of 18a and 19a. The preparation of 18a and
19a deserves a more detailed discussion as a result of their
utility. Although we have not yet examined this in depth, the
(25) The two enantiomers of 19a are readily separable by chiral phase HPLC:
2 × 25 cm Chiralcel OD, 10% i-PrOH/hexanes, 1 mL/min, tR ) 15.3 (3R)
and 17.0 (3S) min, R ) 1.11.
(22) (a) Prapansiri, V.; Thornton, E. R. Tetrahedron Lett. 1991, 32, 3147. (b)
Dujardin, G.; Molato, S.; Brown, E. Tetrahedron: Asymmetry 1993, 4,
193.
(26) Juarist, E.; Cuervas, G. Tetrahedron 1992, 48, 5019.
9
2590 J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006

Diels−Alder Reactions of N-Sulfonyl-1-aza-1,3-butadienes
A R T I C L E S
Figure 8. Transition-state model (S-enantiomer depicted).
superimposition of this transition-state anomeric effect on top
of the conventional stabilizing secondary orbital interaction that
provides the exceptional endo diastereoselection.1 Any erosion
of this endo diastereoselectivity with 2-19a is derived from
destabilizing steric interactions present in the endo transition
state, which then result in a slower rate of reaction.
Houk has shown computationally and experimentally that
vinyl ethers prefer to react in inverse electron demand Diels-
Alder and 1,3-dipolar cycloadditions through an s-trans con-
formation (Figure 8, â ) 180°), even though their ground-state
conformation is typically s-cis (â ) 0°).27 Enlisting the s-trans
conformation, the cycloadditions provide products consistent
with reaction through a conformation in which R is ap-
proximately 60°, providing the transition state illustrated in
Figure 8, with the dienophile H oriented toward the diene and
with its large group oriented away from the diene. When the
dienophile approaches the diene in this s-trans conformation,
the chiral auxiliary comes into proximity of the sterically
demanding and electronegative sp3 sulfonyl moiety, requiring
that the sulfonyl phenyl group orient itself on the diene face
opposite the approaching dienophile. This places the electro-
negative sulfonyl oxygens on the same diene face as the
approaching dienophile, accounting for the observation that the
electronegative ester, lactone, or lactam carbonyls of 14-19,
although sterically undemanding, are similarly directed away
from the sulfonyl group and behave as the most effective RL.
Notably, the X-ray crystal structures of the cycloadducts,18 albeit
being ground-state structures of the reaction products, embody
each of these features (Figure 8).
Figure 9. Temperature dependence.
Figure 10. Concentration dependence.
As anticipated, the reactions exhibit a pronounced dependence
on the concentration, with satisfactory rates observed at 25 °C
at reactant concentrations g0.5 M (Figure 10).
Reaction Parameters. A series of reaction parameters were
examined to identify those that might significantly impact the
cycloaddition. As anticipated, increasing the reaction temper-
ature lowers the reaction diastereoselectivity. However, the
N-sulfonyl-1-aza-1,3-butadienes typically possess an intrinsic
reactivity that permits their use at 25 °C. Nonetheless, the
reaction of 1 with 19a was examined at a range of reaction
temperatures, and both the endo selectivity and the facial
diastereoselectivity of the cycloaddition diminished as the
reaction temperature increased. However, the detected changes
were very small and almost within the limits of error of the
detection method (NMR) (Figure 9). The more sterically
hindered pantalactone-derived dienophile 17a, which reacts more
slowly with 1, exhibited a more discernible trend with varying
reaction temperature. Thus, as the reaction temperature was
increased to drive the sluggish reaction to completion, the endo
diastereoselection dropped more significantly than the endo
facial selectivity (Figure 9).
Consistent with expectations for a concerted [4+2] cycload-
dition reaction, the rate of the reaction of diene 1 with dienophile
19a as well as the diastereoselectivity exhibited little solvent
dependency (Figure 11). In fact, slightly faster rates of reaction
were observed as the solvent polarity decreased, not increased,
consistent with little or no charge buildup in the transition state
of the reaction. Moreover, the slight rate enhancement as the
solvent polarity decreases is consistent with the nonpolar solvent
enhancement of a preferential cycloaddition transition state
involving the s-trans versus s-cis enol ether conformation.27 Of
all the solvents explored, CHCl3 consistently provided the
cleanest reactions, proceeding at good rates with outstanding
diastereoselectivities, accommodating a range of substrate
solubilities.
N-Sulfonyl Substituent: Impact on Reactivity and Dias-
tereoselectivity. Although the reactivity of the N-phenylsulfonyl
azadiene 1 is excellent at 25 °C and its reaction diastereose-
lectivity with 19a is outstanding, alternative sulfonyl substituents
were examined in efforts to establish their impact and potential
(27) Liu, J.; Niwayama, Y. Y.; You, Y.; Houk, K. N. J. Org. Chem. 1998, 63,
1064.
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A R T I C L E S
Clark et al.
Scheme 3
Figure 11. Solvent effects.
Figure 12. Sulfonyl substituent.
importance. Moreover, in addition to a predictable impact that
their electron-withdrawing properties might have on reactivity
or that their steric size might have on the facial diastereoselec-
tivity, the additional methods available for their deprotective
removal (e.g., 21a/H+ or 22a and 23a/RS-)28,29 further extend
the scope of the N-sulfonyl-1-aza-1,3-butadiene Diels-Alder
reactions. Thus, dienes 20-25a were prepared by direct
condensation of ethyl trans-4-oxo-2-butenoate with the corre-
sponding sulfonamide (0.6 equiv of TiCl4, 2.3 equiv of Et3N,
CH2Cl2, -15 to 0 °C, 60-85%), and their reaction with 19a
was compared alongside diene 1. Represented in Figure 12 are
conversions at a single time point under conditions that were
suitable to distinguish among all seven dienes. Consistent with
expectations, both 20a and 21a, bearing aliphatic sulfonyl
substituents, were slightly less reactive than the phenylsulfonyl
diene 1. Notably, the reactivity and reaction diastereoselectivity
(>20:1 endo:exo; >20:1 facial selectivity) of 20a and 21a were
comparable, suggesting that the size of the sulfonyl substitutent
has little impact on the reaction, consistent with the transition-
state model (Figure 8). The addition of electron-withdrawing
phenyl substituents (22-25a) predictably and significantly
increases the diene reactivity. This smooth, predicable, and
tunable reactivity of the substituted phenylsulfonyl derivatives
allows the extension of these studies to 1-aza-1,3-butadienes
that might possess an intrinsic lower reactivity. Each of the
dienes exhibited a cycloaddition diastereoselectivity with 19a
that was not distinguishable from that of 1 (>20:1 endo, >20:1
facial selectivity).
Cycloadduct Transformations. Catalytic hydrogenation of
the cycloadduct double bond, followed by acid-catalyzed (TFA)
removal of the chiral auxiliary in the presence of water or an
alcohol, cleanly provides the 2-alkoxy or 2-hydroxy derivatives,
and this is illustrated in Scheme 3 with 17b, 19b, and 21b.
Limited attempts to remove (exchange) the auxiliary without
prior reduction (or reaction) of the double bond led to
preferential and additional alkoxy addition at C5, providing the
2,5-dialkoxy derivative. Unlike the lactam 19b, reactions of the
cycloadducts 17b and 18b bearing the lactone auxiliaries were
often precluded by preferential ring-opening reactions of the
reactive five-membered lactones, and this was more significant
with 18b than with 17b. Finally, reduction of cycloadduct 22b
(H2, Pd(OH)2/C, EtOH), followed by acid treatment of the
resulting amine, led to cyclization to the unique tricyclic
heterocycle 36 in superb conversions.
Dienophile N-Substitution. With the emergence of 19a,
bearing a chiral cyclic amide auxiliary, as the most effective
dienophile for use with the N-sulfonyl-1-azadienes, it became
important to establish the role of the free NH of the secondary
amide. Although comparison of 18a (the corresponding lactone)
with 19a suggested little role for the amide free NH, the latter
did exhibit a greater endo diastereoselectivity (49 vs 24:1) and
(28) Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62, 8604.
(29) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
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2592 J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006

Diels−Alder Reactions of N-Sulfonyl-1-aza-1,3-butadienes
A R T I C L E S
a significantly better endo facial selectivity (48 vs 18:1).
Moreover, and on occasion, competitive dimerization addition
of the amide NH of 19a or its cycloadducts with the N-sulfonyl-
1-aza-1,3-butadiene or dienophile enol ether was observed in
the slower reactions when one of the reaction partners was
enlisted in larger excesses at higher reaction concentrations or
at increased reaction temperatures. As a consequence, we
examined the corresponding N-methyl derivative 37a, possessing
a cyclic tertiary amide, as the chiral auxiliary which lacks the
free NH of 19a. Thus, N-methylation of 19a (1.0 equiv of NaH,
1.5 equiv of MeI, THF, 25 °C, 8 h, 95%) cleanly provided 37a
([R]25D -49 (c 0.58, CHCl3, >99% ee). Enol ether 37a reacted
with the prototypical N-sulfonyl-1-azabutadiene 1 to provide
37b, with an endo diastereoeselectivity (49:1) and endo facial
selectivity (48:1) that were indistinguishable from those of 19a
(Figure 13). Thus, the free NH of 19a does not contribute to
the diastereoselectivity of its cycloaddition reactions, and the
behavior of 37a along with the transition-state model in Figure
8 suggests that a wide range of amide substitutions might be
accommodated. Moreover, 37a proved much more soluble than
19a in the more nonpolar solvents (toluene), where it exhibited
a comparable or perhaps slightly enhanced reactivity, and, unlike
19a, it is not susceptible to competitive dimerization reactions
entailing reactions of the free NH.
Figure 13. Dienophile N-substitution.
provided remarkable selectivities (for 19a and 37a, 49:1 endo
and 48:1 facial diastereoselectivity) for an uncatalyzed Diels-
Alder reaction that proceeds at room temperature. Additional
uses of the new vinyl ether auxiliaries and applications of the
azadiene Diels-Alder reaction are in progress and will be
reported in due course.
Conclusion
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (CA 42056) and
the Skaggs Institute for Chemical Biology. R.C.C. is a Skaggs
Fellow.
A systematic examination of the [4+2] cycloaddition of
N-sulfonyl-1-aza-1,3-butadienes with enol ethers bearing chiral
auxiliaries led to the delineation and optimization of factors that
influence the facial selectivity of the Diels-Alder reaction while
maintaining the intrinsically superb endo diastereoselectivity.
The emerging transition-state model of the [4+2] cycloaddition
(Figure 8) led to the examination of three readily available but
previously unexplored auxiliaries (18a, 19a, and 37a) that
Supporting Information Available: Full experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA0571646
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