Hydrogen bond directed highly regioselective palladium-catalyzed allylic substitution

Article abstract of DOI:10.1021/ja028426w

The palladium-catalyzed allylic substitution of 5-vinyloxazolidinones and derivatives was investigated. Unusual and high regioselectivity for the branched product was observed. The regioselectivity was influenced by the type of substrate, the solvents, an

Full text of DOI:10.1021/ja028426w

Published on Web 04/05/2003
Hydrogen Bond Directed Highly Regioselective
Palladium-Catalyzed Allylic Substitution
Gregory R. Cook,* Hui Yu, S. Sankaranarayanan, and P. Sathya Shanker
Contribution from the Department of Chemistry, North Dakota State UniVersity,
Fargo, North Dakota 58105-5516
Received September 5, 2002; E-mail: Gregory.Cook@ndsu.nodak.edu
Abstract: The palladium-catalyzed allylic substitution of 5-vinyloxazolidinones and derivatives was
investigated. Unusual and high regioselectivity for the branched product was observed. The regioselectivity
was influenced by the type of substrate, the solvents, and the nucleophile. Imide-type nucleophiles were
found to be directed to the internal carbon (branched:linear, 75:25 to >98:2), whereas sulfonamides, amines,
and malonates added only to the terminal carbon of the allyl complex. Relatively nonpolar solvents such
as toluene and THF favored the branched product (97:3 and 95:5, respectively). Acetonitrile and
dichloromethane afforded lower regioselectivity (50:50 and 67:33, respectively), and the use of the protic
solvent ethanol resulted in reversal of the regioselectivity (12:88). The directing group on the substrate
was important. Amides afforded almost complete formation of the branched product, and carbamates gave
a 50:50 mixture of regioisomers with phthalimide as the nucleophile. Evidence for direction of the nucleophile
via hydrogen bonding was obtained by replacing the hydrogen of the amide with a methyl, resulting in the
production of only the normal linear product.
Introduction
Scheme 1
The palladium-catalyzed allylic substitution reaction has
1
emerged as a powerful methodology in organic synthesis.
Stereoselective variants have focused primarily on enantiose-
lective processes that utilize chiral ligands and achiral sub-
2
strates. Thus, in the past decade there has been a colossal
development of new chiral catalysts for asymmetric allylic
substitution. Of great significance in these substitution reactions
is the problem of regiocontrol, particularly as many of the
asymmetric reactions rely on a regiospecific addition to a
pseudo-meso Pd-allyl complex for enantioselectivity. If the
substrate is unsymmetrical, the issue of regiocontrol becomes
even more complex. As shown in Scheme 1, a monosubstituted
π-allylmetal complex can react with a nucleophile to afford
either the linear (3) or the branched (4) product. Both sterics
and electronics play a role in determining the outcome of the
reaction, and the choice of metal exerts a significant influence.
For palladium complexes, the sterics overwhelmingly favor
In the past few years, there has been intense interest in
reversing the preferred regioselectivity in the Pd-catalyzed allylic
substitution to favor branched products. Substituents on the allyl
substrate that can coordinate to the Pd have been demonstrated
5
6
7
to alter the regioselectivity. A few electronically and sterically
1,2
addition of the nucleophile to the less hindered allyl terminus;
biased ligands have also been shown to change the regioselec-
tivity to favor 4. The Trost ligands, in particular, offer very
high regioselectivity for sterically unencumbered substrates that
can fit in the chiral pocket. Other metal-allyl complexes (Ir,8
3
however, normally a mixture is obtained. It has also been shown
by both experiment and density functional calculations that polar
substituents (Z) in the allylic position strongly favor the linear
product to give a 1,4-relationship between the polar group and
4
the nucleophile.
(
3) For additive and ligand effects to obtain greater selectivity for the linear
product, see: (a) Kawatsura, M.; Uozumi, Y.; Hayashi, T. Chem. Commun.
1998, 217. (b) van Haaren, R. J.; Oevering, H.; Coussens, B. B.; van
Strijdonck, G. P. F.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M. Eur. J. Inorg. Chem. 1999, 1237. (c) Sj o¨ gren, M. P. T.; Hannson,
S.; Åkermark, B. Organometallics 1994, 13, 1963. (d) Åkermark, B.;
Zetterberg, K.; Hansson, S.; Krakenberger, B. J. Organomet. Chem. 1987,
335, 133.
(
1) For recent reviews: (a) Godleski, S. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
4
, p 585. (b) Hegedus, L. In Organometallics in Synthesis; Schlosser, M.,
Ed.; Wiley: New York, 1994; pp 385-459. (c) Palladium Reagents and
Catalysis; Tsuji, J., Ed.; Wiley: New York, 1995.
(2) For reviews on asymmetric palladium-catalyzed allylic substitutions, see:
(a) Reiser, O. Angew. Chem., Int. Ed. Engl. 1993, 32, 547. (b) Trost, B.
(4) (a) Szab o´ , K. J. Chem. Soc. ReV. 2001, 30, 136. (b) Johasson, C.; Kritikos,
M.; B a¨ ckvall, J.-E.; Szab o´ , K. Chem.-Eur. J. 2000, 6, 432. (c) Macs a´ ri, I.;
Hupe, E.; Szab o´ , K. J. Org. Chem. 1999, 64, 9547. (d) Szab o´ , K. Chem.-
Eur. J. 1997, 3, 592.
M.; VanVranken, D. L. Chem. ReV. 1996, 96, 395. (c) Frost, C. G.; Howarth,
J.; Williams, J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089. (d) Consiglio,
G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257.
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J. AM. CHEM. SOC. 2003, 125, 5115-5120
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A R T I C L E S
Cook et al.
Rh, Mo, Ru,11 W ) generally afford the branched substitution
products 4 preferentially. This change in the regioselectivity
with most metals other than palladium reflects the change in
the metal-allyl structure toward the enyl complex 2 where
electronic control of the selectivity predominates. The control
of the Pd-catalyzed allylic substitution reaction to favor branched
products remains an arduous challenge. Thus, new paradigms
for directing regioselectivity are required.
9
10
12
Scheme 2
During the course of our investigation of the dynamic
diastereoselective allylic substitution reaction of 5-vinyloxazo-
lidinones with nitrogen nucleophiles (phthalimide), unusually
high regioselectivity favoring addition to the internal allyl carbon
13
was encountered. The optimized reaction is described in
Scheme 2. A mixture of oxazolidinone diastereomers 5, readily
obtained from L-phenylalanine, was treated with a Pd catalyst
in the presence of phthalimide. A catalytic amount of potassium
phthalimide was introduced to facilitate reduction of the Pd(II)
precatalyst to the Pd(0) catalyst. Extremely high selectivity for
the branched (1,2-diamine) product 6 was obtained (95:5). The
application of chiral ligands (BINAP) with the chiral substrate
provided the best diastereo- and regioselectivity. Interestingly,
1
6
was obtained as a single diastereomer ( H NMR), and the
chirality of the ligand had no influence on the stereoinduction.
The same syn-diastereomer was produced whether the (R) or
the (S) ligand was employed. However, a pronounced matched
and mismatched effect was observed on the regioselectivity ((R)-
BINAP, 95:5; (S)-BINAP, 75:25).
Scheme 3
The high levels of regioselectivity for the branched product
observed in the allylic substitution of 5-vinyloxazolidinones are
extremely rare among palladium-catalyzed allylic substitution
(
5) (a) Krafft, M. E.; Sugiura, M.; Abboud, K. A. J. Am. Chem. Soc. 2001,
1
23, 9174. (b) Itami, K.; Koike, T.; Yoshida, J.-I. J. Am. Chem. Soc. 2001,
23, 6957. (c) Ma, S.; Zhao, S. J. Am. Chem. Soc. 2001, 123, 5578. (d)
1
Krafft, M. E.; Wilson, A. M.; Fu, Z.; Procter, M. J.; Dasse, O. A. J. Org.
Chem. 1998, 63, 1748. (e) Farthing, C. N.; Kocovsky, P. J. Am. Chem.
Soc. 1998, 120, 6661. (f) Krafft, M. E.; Fu, Z.; Procter, M. J.; Wilson, A.
M.; Dasse, O. A.; Hirosawa, C. Pure Appl. Chem. 1998, 70, 1083.
6) (a) Pr e´ t oˆ t, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323. (b)
Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew. Chem., Int. Ed. Engl.
(
1
997, 36, 2108. (c) Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Williams, J.
M. J. Org. Lett. 1999, 1, 1969.
(
7) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545. (b)
Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am. Chem.
Soc. 2000, 122, 5968. (c) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999,
1
21, 10727. (d) Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Am. Chem.
Soc. 1998, 120, 1681. (e) Hayashi, T.; Kawatsura, M.; Uozumi, Y. Chem.
Commun. 1997, 561. (f) Trost, B. M.; Krische, M. J.; Radinov, R.; Zanoni,
G. J. Am. Chem. Soc. 1996, 118, 6297. (g) Hayashi, T.; Kishi, K.;
Yamamoro, A.; Ho, Y. Tetrahedron Lett. 1990, 31, 1743.
8) (a) Takeuchi, R.; Tanabe, K. Angew. Chem., Int. Ed. 2000, 39, 1975. (b)
Takeuchi, R.; Shiga, N. Org. Lett. 1999, 1, 265. (c) Bartels, B.; Helmchen,
G. Chem. Commun. 1999, 741. (d) Fuji, K.; Kinoshita, N.; Tanaka, K.;
Kawabata, T. Chem. Commun. 1999, 2289. (e) Takeuchi, R.; Kashio, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 263.
(
(
9) (a) Evans, P. A.; Kennedy, L. J. J. Am. Chem. Soc. 2001, 123, 1234. (b)
Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609. (c) Evans,
P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122, 5012. (d) Fagnou, K.;
Lautens, M. Org. Lett. 2000, 2, 2319. (e) Evans, P. A.; Kennedy, L. J.
Org. Lett. 2000, 2, 2213. (f) Evans, P. A.; Robinson, J. E.; Nelson, J. D.
J. Am. Chem. Soc. 1999, 121, 6761. (g) Evans, P. A.; Robinson, J. E. Org.
Lett. 1999, 1, 1929. (h) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998,
3
9, 1725. (i) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120,
581.
reactions, and this result prompted us to investigate the origin
of the unusual selectivity. Because the reaction presumably
proceeds through a zwitterionic complex, we hypothesized that
the amide moiety may be somehow directing the nucleophile
5
(
10) (a) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256. (b) Belda,
O.; Kaiser, N.-F.; Bremberg, U.; Larhed, M.; Hallberg, A.; Moberg, C. J.
Org. Chem. 2000, 65, 5868. (c) Glorius, G.; Pfaltz, A. Org. Lett. 1999, 1,
1
41. (d) Trost, B. M.; Hildbrand, S.; Dogra, K. J. Am. Chem. Soc. 1999,
21, 10416. (e) Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104. (f) Trost,
1
(Scheme 3). As the amide is the only base in the reaction to
B. M.; Lautens, M. J. Am. Chem. Soc. 1987, 109, 1469.
(
11) Zhang, S.; Mitsudo, T.; Kondo, T.; Watanabe, Y. J. Organomet. Chem.
deprotonate the nucleophile, we envisioned a “proximity effect”
might be operative. That is, once the nucleophile is deprotonated,
it reacts at the nearest electrophilic carbon (8 f 9 f 6) before
it diffuses away from the complex to react at the less substituted
allyl carbon (8 f 9 f 7). Another hypothesis is that after proton
1
993, 450, 197.
(
12) (a) Lloyd-Jones, G. C.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1995, 34,
4
62. (b) Trost, B. M.; Tometzki, G. B.; Hung, M. H. J. Am. Chem. Soc.
987, 109, 9, 2176.
1
(
13) Cook, G. R.; Shanker, P. S.; Pararajasingham, K. Angew. Chem., Int. Ed.
1
999, 38, 110.
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Palladium-Catalyzed Allylic Substitution
A R T I C L E S
transfer from the imide to the amide, the nucleophile forms a
Table 1. Effect of Substrate on Regioselectivity
hydrogen bonded complex (10) and is delivered to the internal
carbon in a diastereo- and regioselective fashion.1
4,15
A third
possibility is that the imide nucleophile reacts with the allyl
substrate on the unsubstituted terminus at oxygen rather than
nitrogen, perhaps through a concerted deprotonation/addition
process (11 f 12). The resulting O-allylated intermediate 12
could subsequently undergo a [3,3]-sigmatropic rearrangement
to afford 6.16 To delineate these possibilities, a rigorous
examination of the influence of substrate, solvent, and nucleo-
phile on the regioselectivity was carried out. To exclude effects
of the catalyst, the catalyst/ligand system was not varied. In
this article, we present the results of our study, which clearly
demonstrates that hydrogen bonding to the substrate amide was
responsible for the observed regioselectivity.
Results and Discussion
To test the theories described above, we have carried out
extensive experiments. The basicity of the amide (substrate),
the polarity of the solvent, and the pKa of the nucleophile should
all play a role in the regioselectivity if the amide moiety is
intimately involved as a directing group. Thus, we have
examined the reaction with a variety of substrates, nucleophiles,
and solvents. We have also prepared O-allylated compounds
such as 12 via an independent route to probe the possibility of
concerted [3,3]-rearrangement.
We first examined the influence of the substrate amide moiety
on the regioselectivity, and the results are summarized in Table
1. In the reaction of 5-vinyloxazolidinones with a palladium(0)
catalyst, carbon dioxide is evolved after the oxidative insertion.
It is not clear whether this carboxylate group departs before,
during, or after the step in which the nucleophile adds. To see
whether the carboxylate exerts any control on the regioselec-
tivity, the oxazoline 13, lacking the oxazolidinone carbonyl, was
employed in the reaction. The same level of selectivity was
found, suggesting that the oxazolidinone substrate underwent
decarboxylation prior to the addition of the nucleophile and the
CO2 moiety was not involved in the regioselective addition step.
Next, we investigated carbonate 14, which would generate a
base external to the π-allyl complex (methoxide or methyl
carbonate). While the selectivity decreased slightly, it was still
remarkably high (91:9), and this result disfavors a simple base
proximity effect. Electron-withdrawing or -donating groups on
the benzoyl (15 and 16) exhibited little change. Interestingly,
when the benzoyl group was replaced with carbamoyl groups
a
Determined by H NMR. b Combined yield of 6 and 7.
1
Table 2. Effect of Solvent on Regioselectivitya
ligand
(tol-BINAP)
regioselectivity
(6a:7a)b
yield
(%)c
entry
solvent
1
2
3
4
5
6
7
8
9
toluene
THF
CH2Cl2
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
97:3
95:5
81
98
95
88
85
95
98
92
90
67:33
50:50
12:88
83:17
78:22
33:67
22:78
CH CN
3
EtOH
toluene
THF
CH2Cl2
CH3CN
a
Reactions were carried out with substrate 5 with phthalimide employed
as the nucleophile. b Determined by 1H NMR. c Combined yield of 6
(BOC, 17 or Cbz, 18), a 1:1 ratio of regioisomers was obtained.
and 7.
This implies that hydrogen bonding is important to control
regioselectivity as the carbamates would be weaker hydrogen
bond donors than the amide moieties.
The results of the solvent effects are summarized in Table 2.
The highest regioselectivity (97:3, 6a:7a) was obtained when
the reaction was carried out in toluene (entry 1). When
methylene chloride was used, the selectivity dropped to 2:1
The solvent played an important role in the regioselectivity
of the allylic substitution of 5 with phthalimide nucleophile.
(entry 3), and acetonitrile afforded a 1:1 mixture (entry 4). These
(
14) Hydrogen bonding has been implicated in the asymmetric allylic substitution
with ligands possessing pendant hydroxyl groups: (a) Hayashi, T.;
Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K. J. Am. Chem.
Soc. 1989, 111, 6301. (b) Yamazaki, A.; Morimoto, T.; Achiwa, K.
Tetrahedron: Asymmetry 1993, 4, 2287.
results strongly suggest that hydrogen bonding is important, as
the strength of a hydrogen bond would vary in accordance with
the solvent polarity. That is, in the relatively nonpolar solvent
toluene, hydrogen bonding would be strongest, thus affording
more of the branched product. As the solvent polarity increases,
less direction to the internal allyl carbon is observed, corre-
17
(
15) Hydrogen bonding has been suggested in the allylic substitution of vinyl
epoxides: Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am.
Chem. Soc. 2000, 122, 5968.
(
16) For reviews of the Claisen rearrangement, see: (a) Wipf, P. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991;
Vol. 5, pp 827-873. (b) Blechert, S. Synthesis 1989, 71. (c) Ziegler, F. E.
Chem. ReV. 1988, 88, 1423.
(17) The trend in the solvents observed can be correlated with their E
values. Catal a´ n, J. J. Org. Chem. 1997, 62, 8231.
N(30)
t
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A R T I C L E S
Cook et al.
Table 3. Effect of Nucleophile on Regioselectivity
a
Determined by H NMR. Combined yield of 35 and 36. c When carried out in ethanol, the regioselectivity was completely reversed (5:95). Only the
1
b
d
e
diallylated product (38 or 39) was obtained. The regioisomer ratio is for branched and linear isomers. A mixture of mono- and diallylated products was
obtained. Mono-:diallylated ) 17:1. The regioisomer ratio is for branched and linear isomers. The yield reflects the total yield of both products.
sponding with a weaker hydrogen bond between the nucleophile
and the substrate. When the protic solvent, ethanol, was
employed in the reaction, the regioselectivity reversed to favor
the linear isomer 7a (entry 5). In protic media, hydrogen bonding
to the substrate is disrupted due to hydrogen bonding with the
solvent. As demonstrated in entries 6-9, the same trend was
observed when the mismatched (S)-tol-BINAP ligand was
employed. The solvent effects observed in this reaction are
consistent with a mechanism where hydrogen bonding is
intimately involved.
A diverse set of nucleophiles has been surveyed in the allylic
substitution of 5 with very intriguing results (Table 3). All
nucleophiles were examined with the same set of conditions
using THF as the solvent. Imides performed well in the allylic
substitution. Not surprisingly, naphthalimide 19 provided the
same level of selectivity as phthalimide (95:5, 35:36). Succin-
imide 20 gave a higher level of the branched product (97:3),
while the six-membered ring imides 21 and 22 proved not as
effective (83:17 and 75:25, respectively). Other imide-like
nucleophiles also showed high regioselectivity for the branched
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Palladium-Catalyzed Allylic Substitution
A R T I C L E S
isomer. The hydantoin 23 was identical to phthalimide (95:5),
and phthalazinone 24 was revealed to be superior to all other
nucleophiles (>98:2). Interestingly, when the reaction with 24
was carried out in ethanol, complete reversal of regioselectivity
was again observed (5:95). Comparison of structurally similar
amide 25 with sulfonamide 26 revealed markedly different
results. The amide afforded a greater amount of the branched
isomer (88:12), while the sulfonamide provided the linear
regioisomer as the sole product (0:100). Indeed, the simple
benzyl sulfonamide 27 also yielded only the linear isomer. In
addition, amines 28-31 and carbon nucleophiles 32-34 only
delivered the linear regioisomers, demonstrating the same
profound nucleophile effect in the allylic substitution of 5. These
data do not support the proximity effect as outlined in Scheme
Scheme 4
3
, as most of these nucleophiles (except amines) require
deprotonation prior to addition and should show at least some
formation of the branched product. Again, hydrogen bond
direction is in concert with these results. The geometry of the
nucleophile-substrate complex should be an important factor.
This would explain the slight difference in regioselectivity
between the five- and six-membered ring imides. Further, the
sulfonamide bears a tetrahedral sulfur atom, which greatly
distorts the geometry as compared to the planar carbonyl of
the imides, and this is reflected in only addition through the
non-hydrogen bonded complex. Although the dicarbonyl carbon
nucleophiles could potentially hydrogen bond to the substrate
amide, it is likely that the greater reactivity of the carbanion
versus the nitrogen anion of the imide precludes the formation
of the hydrogen bonded complex.
Scheme 5
Although all of the data strongly suggest that hydrogen
bonding direction is responsible for the high branched regiose-
lectivity observed, an O-allylation-[3,3]-rearrangement pathway
could not be ruled out. Thus, we have investigated the possibility
of a concerted rearrangement of an intermediate like 12 (Scheme
3
) prepared via an alternative route. As shown in Scheme 4,
the allylic alcohols 41a,b were coupled with chlorophthalazine
2 to afford the O-allyl phthalazine derivatives 43. When 43a
R ) Ph) was subjected to the reaction conditions identical to
those of the allylic substitution reaction of 5 with 24, the same
98:2 mixture of the branched (35f) and linear (36f) regioiso-
mers was obtained. This could result from either a concerted
3,3]-rearrangement or a stepwise ionization to form the π-allyl
directed addition, we prepared the allylic carbonate substrate
6 where the H on the amide was replaced with a methyl group
Scheme 5). This would preclude any hydrogen bonding with
the incoming nucleophiles. Treatment of 46 with phthalimide
under the Pd(0)-catalyzed conditions afforded the linear allylic
substitution product 47 as the sole regioisomer.
4
(
4
(
>
[
Conclusions
palladium intermediate and addition of the phthalazinone
nucleophile. To establish whether the rearrangement was
concerted or stepwise, the N-BOC-substituted 43b was exam-
ined. A 50:50 mixture of regioisomers (44 and 45) was obtained.
This was the same result as that obtained by the allylic
substitution of the N-BOC derivative of 5 with phthalazinone.
Consequently, the reaction of 43b with the Pd(0) catalyst must
proceed by a stepwise mechanism: ionization to generate a
π-allyl complex followed by hydrogen bond directed nucleo-
philic addition. This is consistent with what is known about
the Pd(0)-catalyzed Claisen and Cope rearrangements. There-
fore, it can be concluded that if 12 is formed in the reaction, it
simply reionizes to the π-allyl palladium complex.
The lack of evidence for a concerted rearrangement and the
large solvent, substrate, and nucleophile effects on the regiose-
lectivity greatly favor a mechanism of hydrogen bond directed
addition of the nucleophile. To garner further support for this
The results summarized herein shed light on one of the many
factors that control selectivity in the palladium-catalyzed allylic
substitution reaction. Although hydrogen bonding has been
suggested previously to direct the introduction of nucleophiles
onto an allyl palladium substrate, this article presents for the
first time clear evidence for such a directing effect. The
regioselectivity was influenced by the type of substrate, the
solvents, and the nucleophile. Imide-type nucleophiles were
found to be directed to the internal carbon, whereas sulfona-
mides, amines, and malonates added only to the terminal carbon
of the allyl complex. Relatively nonpolar solvents such as
toluene and THF favored the branched product. Acetonitrile and
dichloromethane afforded lower regioselectivity, and the use
of the protic solvent ethanol resulted in reversal of the
regioselectivity. The directing group on the substrate was
important. Amides afforded almost complete formation of the
branched product, and carbamates gave a 50:50 mixture of
regioisomers. Evidence for direction of the nucleophile via
18
(18) Lutz, R. P. Chem. ReV. 1984, 84, 206.
J. AM. CHEM. SOC.
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A R T I C L E S
Cook et al.
hydrogen bonding was obtained by replacing the hydrogen of
the amide with a methyl, resulting in the production of only
the normal linear product.
Supporting Information Available: Experimental details and
characterization data, including NMR spectra, for compounds
6b-e, 7b-e, 35a,b, 36a-m, 37-40, and 43a,b (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We are grateful to the National Science
Foundation (NSF CHE9875013) and the National Institutes of
Health (GM58470-01, RR15566-01) for generous support of
this work.
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