Enantioselective TADMAP-catalyzed carboxyl migration reactions for the synthesis of stereogenic quaternary carbon

Article abstract of DOI:10.1021/ja056150x

The chiral, nucleophilic catalyst TADMAP [1, 3-(2,2,2-triphenyl-1- acetoxyethyl)-4-(dimethylamino)-pyridine] has been prepared from 3-lithio-4-(dimethylamino)pyridine (5) and triphenylacetaldehyde (3), followed by acylation and resolution. TADMAP catalyzes the carboxyl migration of oxazolyl, furanyl, and benzofuranyl enol carbonates with good to excellent levels of enantioselection. The oxazole reactions are especially efficient and are used to prepare chiral lactams (23) and lactones (30) containing a quaternary asymmetric carbon. TADMAP-catalyzed carboxyl migrations in the indole series are relatively slow and proceed with inconsistent enantioselectivity. Modeling studies (B3LYP/6-31G*) have been used in qualitative correlations of catalyst conformation, reactivity, and enantioselectivity.

Full text of DOI:10.1021/ja056150x

Published on Web 12/23/2005
Enantioselective TADMAP-Catalyzed Carboxyl Migration
Reactions for the Synthesis of Stereogenic Quaternary
Carbon
Scott A. Shaw, Pedro Aleman, Justin Christy, Jeff W. Kampf, Porino Va, and
Edwin Vedejs*
Contribution from the Department of Chemistry, UniVersity of Michigan,
Ann Arbor, Michigan 48109
Received September 7, 2005; E-mail: edved@umich.edu
Abstract: The chiral, nucleophilic catalyst TADMAP [1, 3-(2,2,2-triphenyl-1-acetoxyethyl)-4-(dimethylamino)-
pyridine] has been prepared from 3-lithio-4-(dimethylamino)pyridine (5) and triphenylacetaldehyde (3),
followed by acylation and resolution. TADMAP catalyzes the carboxyl migration of oxazolyl, furanyl, and
benzofuranyl enol carbonates with good to excellent levels of enantioselection. The oxazole reactions are
especially efficient and are used to prepare chiral lactams (23) and lactones (30) containing a quaternary
asymmetric carbon. TADMAP-catalyzed carboxyl migrations in the indole series are relatively slow and
proceed with inconsistent enantioselectivity. Modeling studies (B3LYP/6-31G*) have been used in qualitative
correlations of catalyst conformation, reactivity, and enantioselectivity.
Introduction
Chiral DMAP analogues have been particularly attractive
targets, since DMAP itself is highly reactive, easy to handle,
Chiral nucleophilic catalysis is an important category of
organocatalysis and has been demonstrated to mediate a variety
of transformations, including phosphorylation, sulfonylation,
Baylis-Hillman reactions, and ketene addition reactions.1,2
However, nucleophilic catalysis is most often used in acyl
transfer reactions, and a variety of chiral catalysts have been
developed to effect enantioselective variants. Beginning with
Wegler’s original work using alkaloids,3a catalysts have included
chiral trialkylamines,3 4-(dimethylamino)pyridine (DMAP)
derivatives,4-10 synthetic peptides,11,12 amidines,13 nucleophilic
heterocyclic carbenes,14,15 and phosphines.16
(4) (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809. (b) Harper,
L. A. Studies Toward an EnantioselectiVe Nucleophilic Catalyst Based on
Dimethylaminopyridine (DMAP), 2001; Chem. Abstr. 136, 369315. (c)
Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368.
(5) (a) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230. (b) Fu, G. C.
Acc. Chem. Res. 2000, 33, 412. (c) Fu, G. C. Acc. Chem. Res. 2004, 37,
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119, 3169. (b) Kawabata, T.; Yamamoto, K.; Momose, Y.; Yoshida, H.;
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Stragies, R.; Fukaya, T.; Fuji, K. Chirality 2003, 15, 71. (d) Kawabata, T.;
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(b) Spivey, A. C.; Maddaford, A.; Fekner, T.; Redgrave, A. J.; Frampton,
C. S. J. Chem. Soc., Perkin Trans. 1 2000, 3460. (c) Spivey, A. C.; Zhu,
F.; Mitchell, M. B.; Davey, S. G.; Jarvest, R. L. J. Org. Chem. 2003, 68,
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Tetrahedron 2004, 60, 4513.
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I. B. Tetrahedron Lett. 2002, 43, 6001. (b) Priem, G.; Pelotier, B.;
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68, 3844. (c) Pelotier, B.; Priem, G.; Campbell, I. B.; Macdonald, S. J. F.;
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1, 4254.
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(1) For reviews on asymmetric nucleophilic catalysis, see: (a) Spivey, A. C.;
Maddaford, A. Org. Prep. Proced. Int. 2000, 32, 333. (b) Spivey, A. C.;
Andrews, B. I. Angew. Chem., Int. Ed. 2001, 40, 3131. (c) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2001, 49, 3726. (d) Jarvo, E. R.; Miller,
S. J. Tetrahedron 2002, 58, 2481. (e) Taggi, A. E.; Hafez, A. M.; Lectka,
T. Acc. Chem. Res. 2003, 36, 10. (f) France, S.; Guerin, D. J.; Miller, S. J.;
Lectka, T. Chem. ReV. 2003, 103, 2985. (g) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138.
(2) For general reviews on nucleophilic organocatalysis, see: (a) Ho¨fle, G.;
Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569.
(b) Scriven, E. F. V. Chem. Soc. ReV. 1983, 12, 129. (c) Lu, X.; Zhang,
C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (d) Murugan, R.; Scriven, E. F.
V. Aldrichimica Acta 2003, 36, 21. (e) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811. (f) Methot, J. L.; Roush,
W. R. AdV. Synth. Catal. 2004, 346, 1035. (g) Spivey, A. C.; Arseniyadis,
S. Angew. Chem., Int. Ed. 2004, 43, 5436.
(3) (a) Wegler, R. Liebigs Ann. Chem. 1932, 498, 62. (b) Wegler, R. Liebigs
Ann. Chem. 1933, 506, 77. (c) Wegler, R. Liebigs Ann. Chem. 1934, 510,
72. (d) Wegler, W.; Ru¨ber, A. Chem. Ber. 1935, 68, 1055. (e) Bird, C. W.
Tetrahedron 1962, 18, 1. (f) Stegmann, W.; Uebelhart, P.; Heimgartner,
H.; Schmid, H. Tetrahedron Lett. 1978, 19, 3091. (g) Potapov, V. M.;
Dem’yanovich, V. M.; Khlebnikov, V. A.; Korovina, T. G. Zh. Org. Khim.
1988, 24, 759 and references therein. (h) Weidert, P. J.; Geyer, E.; Horner,
L. Liebigs Ann. Chem. 1989, 533. (i) Oriyama, T.; Hori, Y.; Imai, K.; Sasaki,
R. Tetrahedron Lett. 1996, 37, 8543. (j) Sano, T.; Imai, K.; Ohashi, K.;
Oriyama, T. Chem. Lett. 1999, 265. (k) Sano, T.; Miyata, H.; Oriyama, T.
Enantiomer 2000, 5, 119.
(12) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc. 2004, 126, 12212.
(13) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J. Am.
Chem. Soc. 2004, 126, 12226.
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A R T I C L E S
Shaw et al.
Scheme 1. Synthesis of TADMAP (1)
Figure 1. C-3 substituted chiral DMAP derivatives.
and catalytically active for a variety of transformations.2a-d,g
Strategies for making chiral DMAP analogues have included
stereogenic substitution at the C(2) and C(3) positions on the
pyridine ring as well as chirality in the dialkylamino group.
The most successful strategy so far (Fu et al.) utilizes a planar-
chiral DMAP analogue, where the chiral information is com-
municated to the active pyridine ring nitrogen via a ferrocene
group fused to the pyridine core.5 This catalyst is capable of
high enantioselectivity in a variety of transformations.
Work in our laboratory has centered on finding a chiral
DMAP-based catalyst that would be easily accessible as well
as highly enantioselective.4 Design considerations are limited
by the presence of two mirror planes of symmetry in the DMAP
core and by a total of three sites, C(2), C(3), and C(4)-N, where
chiral substituents might be attached. Substitution at C(2) is
problematic, because of the expected decrease in catalytic
reactivity due to steric hindrance,4a,c,17 and the remaining sites
at C(3) and C(4)-N are not ideal because chiral substituents
would have to communicate stereochemical information across
a substantial distance. Nevertheless, important progress has been
made and enantioselective DMAP catalysts have been developed
in both structural categories by Fuji et al. [C(4)-N]6 and Spivey
et al. [C(3)].7a,c,d Several other chiral DMAP catalysts based on
variations of the C(3) or the C(4)-N substituent have also been
disclosed.7b,8-10
With the goal of developing shorter routes to potentially
selective catalysts, we chose to study a new class of chiral C(3)-
substituted pyridine derivatives 1 (Figure 1). Placing the
substitution at C(3) puts it as close to the nucleophilic pyridine
nitrogen as possible without hindering the catalytically active
site. It was hypothesized that the corresponding N-acylpyri-
dinium intermediate 2 would prefer a geometry where the
dialkylamino group is nearly coplanar with the pyridine ring,
thereby maximizing nN f π electron delocalization. The
benzylic substituents would rotate to place the bulky, confor-
mationally degenerate trityl group over one face of the pyridine
ring, thus ensuring that one face of the pyridinium ring is always
“blocked” by a phenyl group. The benzylic hydrogen on the
acylated catalyst 2 would be oriented toward the 4-dialkylamino
group in order to minimize steric interactions. In this conformer,
the acetoxy group creates a chirotopic environment on the
“open” face of the pyridine ring. Retrosynthetically, 1 would
be available from a 3-metallo-4-(dialkylamino)pyridine and a
triarylacetaldehyde. This disconnection provides rapid access
to racemic 1 and has potential for asymmetric synthesis as well
as variation of catalyst substitution.
Results and Discussion
Synthesis of Enantiomerically Pure TADMAP 1. The
synthesis of racemic 1 [“TADMAP”, for 3-(2,2,2-triphenyl-1-
acetoxyethyl)-4-(dimethylamino)pyridine] began with the con-
version of commercially available triphenylacetic acid to
triphenylacetaldehyde 318 using a two-step reduction/oxidation
sequence (LiAlH4, TPAP/NMO; Scheme 1). Pyridinium chlo-
rochromate (PCC) was originally used for the oxidation,18 but
this required chromatography. In contrast, TPAP/NMO gave
crude 3 that could be crystallized to purity on a multigram scale.
Aldehyde 3 was then treated with the aryllithium reagent 5 from
3-bromo-4-(dimethylamino)pyridine 419 and tBuLi, and the
resulting lithium alkoxide 6 was quenched with acetic anhydride
to afford racemic 1 (four steps, 37% overall from triphenylacetic
acid on a gram scale). No chromatography was required until
the final aryllithium coupling reaction.
It was necessary to perform the addition of 5 to 3 under dilute
conditions (∼0.10 M) to avoid precipitation of 5. Reversing
the order of addition and adding 3 to the precipitated 5 produced
a modest yield of 1 on a 200-mg scale (43%), but only 13% on
a 800-mg scale. Even under the former (dilute) conditions, it
was necessary to use 1.5 equiv of 5 to achieve complete
conversion of 3, and it was important to add 5 with vigorous
stirring and careful temperature control at -78 °C to minimize
the formation of byproducts. If the alkoxide 6 was quenched
with water instead of acetic anhydride, the products included
triphenylmethane and trace amounts of aldehyde 8 in addition
to the pyridyl alcohol 7. Evidently, the alkoxide 6 fragments to
give trityllithium and 8 in the latter experiment. Fragmentation
(14) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347.
(15) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905.
(16) (a) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61, 430. (b)
Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813. (c) Vedejs,
E.; MacKay, J. A. Org. Lett. 2001, 3, 535. (d) Vedejs, E.; Daugulis, O.;
MacKay, J. A.; Rozners, E. Synlett 2001, 1499. (e) Vedejs, E.; Rozners,
E. J. Am. Chem. Soc. 2001, 123, 2428. (f) Vedejs, E.; Daugulis, O. J. Am.
Chem. Soc. 2003, 125, 4166. (g) Vedejs, E.; Daugulis, O.; Harper, L. A.;
MacKay, J. A.; Powell, D. R. J. Org. Chem. 2003, 68, 5020.
(17) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34, 2069.
(18) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.; Portonovo, P.
S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org.
Chem. 1997, 62, 2555.
(19) Groziak, M. P.; Melcher, L. M. Heterocycles 1987, 26, 2905.
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TADMAP-Catalyzed Carboxyl Migration Reactions
A R T I C L E S
Table 1. Energy Minima for N-(Phenoxycarbonyl)pyridinium Ion 2a
of the triphenylmethyl group did not occur when the analogous
alkoxide intermediate was generated from 3 and phenyllithium,
suggesting that synergistic electron donation involving both the
alkoxide and the arene ring in 6 is necessary to generate enough
“push” to release the basic trityl anion (pKaMeCN ) 44, pKaDMSO
) 30.6).20
With multigram quantities of racemic catalyst 1 in hand,
resolution of the enantiomers was necessary. Initially, small
quantities of rac-1 were resolved by HPLC over a chiral support,
but this laborious process was not suited to gram-scale synthesis.
Fortunately, enantiomerically pure TADMAP was readily
obtained via classical resolution. Treatment of rac-1 with 0.5
equiv of (-)-camphorsulfonic acid (CSA) in warm toluene
produced the enantiomerically enriched salt 9. After neutraliza-
tion with NaOH, the procedure was repeated on the scalemic
material to give (R)-1 with >99% ee. The (S)-1-enriched mother
liquor of the initial crystallization was treated analogously with
(+)-CSA, producing (S)-1 in >96% ee. Using this procedure,
7.4 g of racemate was resolved to give 0.7 g of (R)-1 (>99%
ee) and 1 g of (S)-1 (98.3% ee), with 4.7 g of scalemic 1
available for further resolution (>85% recovery over the
crystallization sequence).
To better understand the three-dimensional structure of
catalyst 1, the N-carboxylpyridinium salt 2 (Ar ) Ph, R ) Me,
R′ ) OPh) was studied using computational methods. Electron
donation from the C-4 nitrogen into the pyridine ring was
expected to play a major role in conformational bias. Therefore,
DFT (B3LYP/6-31G*) methods were used that take mesomeric
stabilization into account.21 The choice of the N-(phenoxycar-
bonyl)pyridinium environment for computation was made to
address the best results of carboxyl migration experiments to
be discussed later. Three energy minima were located having
nearly equal energies (Table 1). As expected, the trityl group
was oriented over one face of the pyridine ring in the favored
conformers to minimize steric interactions, and the side chain
ethyl backbone was in a staggered conformation. The acetate
adopts the standard secondary ester geometry with the carbonyl
group nearly eclipsing the adjacent benzylic C-H bond and
the dialkylamino group in each minimum is nearly coplanar
with the pyridinium ring.
a Ar ) Ph, R ) Me, R′ ) OPh. b Energy minima located using DFT
computations (B3LYP/6-31G*).
The energy minima have similar geometry, but differ in
conformational details involving the phenoxycarbonyl group.
Thus, both N-CO rotamers were found (Table 1, entry 1 vs
entries 2 and 3), and the phenyl ring of the phenoxycarbonyl
subunit was twisted out of the carbonyl plane. The same
geometry was also found as an energy minimum for the
unsubstituted DMAP-derived cation 10 (Figure 2, θ ) ca. 60°)
and was favored by ∼0.5 kcal/mol over the coplanar structure
(Figure 2, θ ) 0°). The conformational profile for 10 also
showed a small energy maximum where the phenyl ring is
perpendicular to the carbonyl/pyridine plane (θ ) 90°).
Although TADMAP (1) was resolved with CSA, the resulting
crystals were not suitable for X-ray analysis. Dibenzoyl-L-tartaric
acid, on the other hand, was ineffective as a resolving agent,
but crystallization of a 1:1 mixture of resolved (+)-1 and
dibenzoyl-L-tartaric acid gave suitable crystals of the salt 11
(Figure 3). This allowed assignment of the absolute stereo-
Figure 2. N-(Phenoxycarbonyl)-DMAP energy profile (B3LYP/6-31G*).
chemistry as well as the solid state conformation and revealed
good qualitative agreement with features of the computed energy
minima (Table 1), including the coplanar dialkylamino group,
the trityl group extending over one face of the pyridine, and
the relative orientation of the benzylic hydrogen.
Enantioselective Steglich Rearrangement of Oxazolyl
Carbonates. The Steglich rearrangement (Scheme 2)22,23 was
selected for a systematic investigation of carboxyl migration
using catalyst 1. Oxazolyl carbonates 13 are easily synthesized
(20) pKaDMSO: (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. pKaMeCN
:
(b) ChemFiles, Fluka, vol. 3.
(21) WaVefunction, PC SPARTAN PRO, ver 1; Wavefunction, Inc.: Irvine, CA,
1999.
9
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A R T I C L E S
Shaw et al.
ion pair 14 followed by carboxyl migration to give the
C-carboxyl azlactone 15. The rearrangement is high yielding if
Ar ) p-MeOC6H4, but the corresponding reaction with Ar )
Ph affords a significant amount of the undesired C-2 carboxy-
lated isomer 16.22 Fu and Ruble have reported a highly
enantioselective version of the Steglich rearrangement of 13 (R2
) Bn) using a planar-chiral pyridine catalyst.23 Comparisons
with their results were expected to provide a basis for evaluating
1 as a chiral nucleophilic catalyst for synthesis of chiral
quaternary carbon-containing molecules.24
In the initial experiments, the alanine-derived oxazolyl
carbonate 13a23 was treated with 1 mol % of (S)-TADMAP (1)
in CH2Cl2. The rearranged C-carboxylated isomer 15a was
obtained in high yield as the only product, but the ee value was
only 30%. Similar results were obtained with a methoxycarbonyl
analogue 13c in preliminary screens. However, changing the
migrating group to phenoxycarbonyl (13b, R ) Ph) and
lowering the temperature to 0 °C gave a dramatic increase in
selectivity and afforded the C-carboxyl product 15b with 73%
ee. Further improvement to 84-89% ee was observed in toluene
or in ether solvents, and the best result was obtained in tert-
amyl alcohol (91% ee). Decomposition was noted in more polar
solvents such as acetonitrile, so tert-amyl alcohol was used in
subsequent experiments to define the scope of the carboxyl
migration.
A variety of substituted oxazolyl carbonates 13 were treated
with 1 mol % of the enantiomeric TADMAP catalyst (R)-1 using
the optimized tert-amyl alcohol conditions. Excellent yields
(90-99%) and enantiomeric excess (91-95% ee) were observed
for all of the phenoxycarbonyl substrates 13b,d,f,g bearing an
unbranched methylene side chain. However, the benzyloxycar-
bonyl derivative 13e gave lower ee (ent-15e, 71% ee), similar
to the behavior of 13a. Lower enantioselectivity was also
observed with the phenylglycine-derived 13h to afford the
C-carboxylated azlactone product ent-15h (58% ee). Further-
more, the corresponding isopropyl-substituted oxazolyl carbon-
ate derived from valine gave no migration product at all,
apparently due to excessive steric hindrance. These findings
underscore the importance of substrates 13 having unbranched
alkyl substituents R1 for the enantioselective Steglich rearrange-
ment to 15 or ent-15 as well as the critical role of the phen-
oxycarbonyl migrating group.
Figure 3. (a) Structure of TADMAP‚dibenzoyl-L-tartaric acid‚EtOH 11.
(b) 11 from a different perspective with counterion and ethanol atoms
omitted.
Scheme 2. Steglich Rearrangement
The optimized enantioselectivities are comparable to those
reported by Fu and Ruble, although their best results were
obtained with the benzyloxycarbonyl migrating group, as in 13a
and 13e.23 We were curious to know whether the migrating
group would be subject to similar restrictions when the
conversion from 13 to 15 is induced by the structurally unique,
highly nucleophilic chiral phosphine 17,16b,f so the corresponding
carboxyl migration experiments were investigated. Surprisingly,
the carboxyl group was unimportant in this system, and nearly
identical enantioselectivities in the range of 85-92% ee were
(22) (a) Steglich, W.; Ho¨fle, G. Angew. Chem., Int. Ed. Engl. 1968, 7, 61. (b)
Steglich, W.; Ho¨fle, G. Tetrahedron Lett. 1968, 9, 1619. (c) Steglich, W.;
Ho¨fle, G. Chem. Ber. 1969, 102, 883. (d) Steglich, W.; Ho¨fle, G. Chem.
Ber. 1969, 102, 899. (e) Steglich, W.; Ho¨fle, G. Tetradedron Lett. 1970,
11, 4727. (f) Steglich, W.; Ho¨fle, G. Chem. Ber. 1971, 104, 3644.
(23) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532.
(24) For reviews on asymmetric quaternary carbon synthesis, see: (a) Martin,
S. F. Tetrahedron 1980, 36, 419. (b) Fuji, K. Chem. ReV. 1993, 93, 2037.
(c) Corey, E. J.; Guzman-Peres, A. Angew. Chem., Int. Ed. 1998, 37, 389.
(d) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (e)
Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (f)
Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105.
from N-aroylamino acids via azlactones 12, and treatment with
DMAP as a nucleophilic catalyst results in generation of an
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TADMAP-Catalyzed Carboxyl Migration Reactions
A R T I C L E S
Scheme 3
catalyze nucleophilic azlactone cleavage afforded the lactams
23a or 23b (65-70% overall). In the case of 22b, replacing
the nucleophilic Bu3P catalyst with the more basic DMAP or
using excess Et3N without an added nucleophile gave a
byproduct, apparently resulting from phenoxy displacement by
the side chain amine.25 This side reaction was not observed from
22a because the benzyloxycarbonyl subunit is less activated
compared to phenoxycarbonyl, but the same conditions for
lactam formation were used as a precautionary measure. Lactams
23a and 23b were isolated with 92% ee and 91% ee, respec-
tively, evidence that intermediates in the carboxyl migration
retain the absolute configuration of the precursors 22a,b and
do not undergo interconversion of the ester and azlactone
carboxyl groups during conversion to 23.
In a similar sequence (Scheme 4), the protected homoserine
24 was N-aroylated, saponified to the carboxylic acid 25, and
cyclized to the azlactone 26 by treatment with DCC. Subsequent
conversion into the oxazolyl carbonates 27a or 27b was carried
out in the usual way, and carboxyl migration was effected using
10 mol % of the phosphine catalyst 17 with 27a or 1 mol % of
(R)-1 with 27b. The carboxyl migration products 28a (89% ee)
and 28b (91% ee) were obtained in excellent yield and good
enantiomeric purity. Subsequent silyl ether cleavage by treatment
with HF·pyridine resulted in the direct conversion to the lactones
30a and 30b in >85% yield. The intermediate alcohols 29a,b
were not detected in this case, and no additional catalysts were
required for azlactone cleavage. However, use of the acidic
fluoride source was critical as treatment of either 28a or 28b
with the more basic TBAF reagent led to the formation of the
R-amido lactone 31. Presumably, this occurs via a retro-Claisen/
cyclization sequence, but the mechanistic details were not
investigated. In any event, the results of Schemes 3 and 4
suggest a number of potential applications of the enantioselective
carboxyl migration methodology for synthesis of unusual amino
acid derivatives containing a stereogenic quaternary carbon.26
Enantioselective Carboxyl Migration of Furan-Derived
Enol Carbonates. Among the early goals of this program was
to establish a route to chiral quaternary carbon-containing
intermediates of the general structure 33 as part of our effort to
obtain diazonamide A by total synthesis. An approach based
on the Black rearrangement from a benzofuran 32 was therefore
initiated (Scheme 5),27,28 but using chiral nucleophiles in place
of Black’s DMAP catalyst. The mechanism of this reaction is
believed to be closely analogous to that of the Steglich
rearrangement discussed earlier. However, the original structure
of the diazonamide A core (34) proved to be wrong, and a
revised structure 35 has now been defined.29 In principle, 35
might also be accessed via Black rearrangement from benzo-
furan substrate 36 or from the analogous rearrangement of indole
37. Although strategic considerations eventually resulted in a
different solution for the diazonamide quaternary carbon
observed for benzyloxy-, phenoxy-, and methoxycarbonyl
substrates 13a,b,c (see Table S-3 of the Supporting Information
for tabulated results). However, the phosphine catalyst 17 proved
to be substantially less reactive than TADMAP (1), and efficient
substrate conversion required ca. 10 mol % of the catalyst.
The identity of azlactone ent-15a obtained from 13a using
17 was established by comparing NMR data and the sign of
optical rotation with known material.23 A chemical correlation
was then performed to define the configuration of 15b [prepared
from 13b and catalyst (S)-1] by ring opening with benzyl alco-
hol, or the corresponding ring opening of ent-15a with phenol.
Both reactions were conducted under nucleophilic catalysis
conditions (tributylphosphine/benzoic acid), and both gave the
same enantiomer of an amido-malonate diester via alcoholysis
of the azlactone (see Supporting Information for details).
On the basis of the enantioselective carboxyl migrations
briefly summarized above, good results were expected with
oxazole substrates containing additional functionality designed
to allow intramolecular bond formation following the carboxyl
rearrangement step. Thus, the protected ornithine 18 was
converted into the oxazole carbonates 20a and 20b via the
azlactone 19 (Scheme 3). In accordance with the precedents,
the benzyloxycarbonyl derivative 20a rearranged to 21a with
good enantioselectivity (92% ee) upon treatment with 10 mol
% of the chiral phosphine 17. Alternatively, the phenoxycar-
bonyl analogue 20b gave 21b in 91% ee when 1 mol % of
(R)-1 was used as the catalyst.
(25) Structure i for the byproduct is consistent with NMR and IR data.
(26) For reviews R,R-disubstituted amino acids, see: (a) Cativiela, C.; Diaz-
de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517. (b) Cativiela,
C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645. For
an alternative approach to R,R-disubstituted amino acids from azlactones,
see: (c) Trost, B. M.; Chulbom, L. J. Am. Chem. Soc. 2001, 123, 12191.
Deprotection of either of the oxazolyl carbonates 21a or 21b
with trifluoroacetic acid followed by treatment of the intermedi-
ate salts 22a,b with Et3N/Bu3P to neutralize the salt and to
9
J. AM. CHEM. SOC. VOL. 128, NO. 3, 2006 929

A R T I C L E S
Scheme 4
Shaw et al.
migrating group (39b) gave 40b with modest 26-44% ee in a
variety of solvents at room temperature, while the isopropoxy-
carbonyl derivative 39c gave totally racemic 40c. Only a small
improvement was observed for the conversion of 39b to 40b at
-20 °C (52-59% ee in ether, THF, or toluene). Fortunately, a
larger temperature effect was found for 39d, and 40d was
obtained in 86% ee and 92% yield by carrying out the reaction
at -40 °C in dichloromethane. However, improved ee came at
the cost of a significant rate decrease that required the use of
20 mol % of (S)-TADMAP (1) over 18 h. If desired, 95% of
the TADMAP catalyst could be recovered via chromatography,
but the high catalyst loading and long reaction time raised
concerns about potential applications to more hindered substrates
such as 32 or 36. Reactivity problems were also encountered
in preliminary attempts to use chiral phosphine catalysts for
the carboxyl rearrangement from 39 or its analogues.34
After the struggle to optimize the rearrangement from 39 to
40, it was gratifying to find that the enantioselective carboxyl
migration from the 3-alkyl benzofuranyl carbonates 41 to
benzofuranones 42 is quite easy and follows the substrate
preferences observed earlier with the oxazole substrates. This
study was conducted using the enantiomeric TADMAP catalyst
(R)-1 and began with a comparison of the methoxycarbonyl
(41a) and phenoxycarbonyl (41b) migrating groups in dichlo-
romethane. As with the oxazole substrates, the reaction was
more highly selective with the phenoxycarbonyl migrating group
(Table 2, entry 1 vs 2), although the best ee’s were obtained in
ether (entry 4) rather than tert-amyl alcohol (entry 6). Several
other 3-alkyl benzofuranyl carbonates were investigated (entries
7-9) under the same conditions [ether, room temperature, 1
mol % of (R)-1] and afforded the desired C-phenoxycarbonyl
benzofuranones 42c-e in good yield (88-97%) and enantio-
meric excess (92-93% ee). The absolute stereochemistry of
the C-carboxylated isomers 42b-e was assigned on the basis
of analogy with the oxazole studies and with furanone deriva-
tives to be discussed in the next section.
problem,30 the relevant benzofuran and indole rearrangements
have been explored in depth in our laboratory, as described
below. Similar substrates have been studied by Fu and Hills
using their chiral DMAP catalyst with excellent results.31
Simple benzofuranyl enol carbonates 39 and 41 were easily
obtained from the known benzofuranones 38 (Scheme 6),32,33
but the enantioselective carboxyl rearrangement of 3-phenyl
derivative 39 as a model for the hypothetical conversions from
32 to 33 proved to be a challenging problem. Treatment of the
phenoxycarbonyl derivative 39a27 with 1 mol % of (S)-
TADMAP (1) produced the C-carboxylated product 40a at room
temperature, but the reaction was nonselective (2% ee). A variety
of other enol carbonates 39b-e were prepared and the carboxyl
migrations were screened using (S)-1. The ethoxycarbonyl
Table 2. 3-Alkylbenzofuran Enol Carbonate Rearrangements
entry
substrate
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
41a
41b
41b
41b
41b
41b
41c
41d
41e
CH2Cl2
CH2Cl2
THF
NA
97
97
92
89
NA
88
96
97
44
71
87
92
89
70
92
93
93
Et2O
toluene
t-amyl-OH
Et2O
Et2O
Et2O
(27) Black, T. H.; Arrivo, S. M.; Schumm, J. S.; Knobeloch, J. M. J. Org. Chem.
1987, 52, 5425.
a Reaction at room temperature, 4 h.
(28) (a) Studies Toward the Asymmetric Synthesis of Diazonamide A. Wang,
J., Ph.D. Thesis, University of Wisconsin, 1997; Diss. Abs. Int., B 1998,
59, 1121. (b) Vedejs, E.; Wang, J. Org. Lett. 2000, 2, 1031.
(29) (a) Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.; Harran, P. G. Angew.
Chem., Int. Ed. 2001, 40, 4770. (b) Nicolaou, K. C.; Bella, M.; Chen, D.
Y. K.; Huang, X. H.; Ling, T. T.; Snyder, S. A. Angew. Chem., Int. Ed.
2002, 41, 3495. (c) Nicolaou, K. C.; Rao, P. B.; Hao, J. L.; Reddy, M. V.;
Rassias, G.; Huang, X. H.; Chen, D. Y. K.; Snyder, S. A. Angew. Chem.,
Int. Ed. 2003, 42, 1753. (d) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P.
G. Angew. Chem., Int. Ed. 2003, 42, 4961.
The TADMAP-catalyzed carboxyl migration reaction was
extended to monocyclic furanone-derived enol carbonates 44.
(34) The rearrangement of 39b works very well using simple phosphine catalysts
and is complete within 2 h at room temperature with 1 equiv of Et3P or
Bu3P or within 24 h using Et2PPh (see ref 28, p 149). A modestly
enantioselective version of the rearrangement can be effected using the
P-Ph analogue of 16 (32% ee, 84-87% yield after 24 h at room
temperature with ca. 7% of the catalyst in CH2Cl2). However, attempts to
achieve similar rearrangement with more highly substituted enol carbonates
of general structure 32 resulted in low reactivity and formation of the parent
benzofuranone as a side product. This side reaction, superficially corre-
sponding to enolate protonation at the stage of the ion pair, was observed
in nearly all attempts, and little C-carboxylated product was obtained even
with simple phosphines. The side reaction was also dominant in the case
where 10% Et3P was used to catalyze the rearrangement of 39b with Ph
replaced by o-tolyl (Barda, D. A.; Vedejs, E. Unpublished results).
(30) Peris, G.; Vedejs, E. To be published.
(31) (a) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921. (b) A
related acyl migration approach to saturated furanones is reported:
Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 5604.
(32) 38 with R1 ) Me: Piccolo, O.; Filippini, L.; Tinucci, L.; Valoti, E.; Attilio,
C. J. Chem. Res. Synop. 1985, 258.
(33) 38 with R1 ) misc. alkyls: Yoneda, E.; Sugioka, T.; Hirao, K.; Zhang,
S.-W.; Takahashi, S. J. Chem. Soc., Perkin Trans. 1 1998, 477. R ) Ph:
Padwa, A.; Dehm, D.; Oine, T.; Lee, G. A. J. Am. Chem. Soc. 1975, 97,
1837.
9
930 J. AM. CHEM. SOC. VOL. 128, NO. 3, 2006

TADMAP-Catalyzed Carboxyl Migration Reactions
A R T I C L E S
Scheme 5
Scheme 6
Scheme 7
Table 3. 3-Methyl-5-arylfuran Enol Carbonate Rearrangement
entry
substrate
solvent
45:46a
eemajor (%)
1b
2b
3
4
5
44a
44b
44c
44c
44c
44c
44c
44d
44d
44d
44d
44d
CH2Cl2
3:2
3:2
5:1
10:1
11:1
10:1
6:1
1:4
1:4
1:4
1:4
1:4
75
91
82
90c
83
74
91
63
74
90e
83
50
In an attempt to improve regiocontrol, the electronic effect
of the C-5 aryl substituent was varied. The relatively electron-
rich methoxyphenyl derivative 44c produced a better ratio (up
to 11:1) favoring the R-carboxyl isomer 45c (Table 3, entries
3-7). However, the electron-deficient 44d gave a reversed 4:1
ratio favoring the γ-carboxyl product 46d (entries 8-12). After
optimization of solvent for each substrate, good yields and ee
values were obtained for the major product in each example.
The striking electronic effect of donor or acceptor substituents
at C(5) aryl in these reactions is reminiscent of the trends
reported by Steglich and Ho¨fle for the related oxazole rear-
rangements, as already mentioned in connection with Scheme
2.22
CH2Cl2
CH2Cl2
THF
Et2O
6
7
toluene
tert-amyl-OH
CH2Cl2
THF
Et2O
toluene
tert-amyl-OH
8d
9d
10d
11d
12d
a Ratio based on NMR assay; >95% conversion. b 1 mol % of catalyst
1. c 45, 83% yield; 46, 7% yield (80% ee). d reaction complete in 4 h. e 46,
75% yield; 45, 25% yield.
Treatment of the benzyloxy or phenoxy derivatives 44a or 44b
with 1 mol % of TADMAP 1 led to the formation of two
regioisomeric C-alkoxycarbonyl products 45a and 46a or 45b
and 46b, respectively (Table 3, entries 1 and 2; 3:2 45:46).
However, as observed earlier in the azlactone series, the
phenoxycarbonyl group migrated with higher enantioselectivity
(entry 2; 91% ee for 45b), so the phenoxy derivatives were
explored in greater depth.
The absolute stereochemistry of the furanones was probed
in the case of the p-bromophenyl furanone 45e (Scheme 7),
obtained in the usual way (88% ee, 75% yield from 44, using
(R)-1), along with a small amount of isomer 46e. After
crystallization, the major product 45e was analyzed by X-ray
crystallography (anomalous dispersion) and was shown to
possess the (R)-45e absolute stereochemistry. The absolute
configurations of other furanone carboxyl migration products
9
J. AM. CHEM. SOC. VOL. 128, NO. 3, 2006 931

A R T I C L E S
Shaw et al.
Table 4. 3-Alkylindole Enol Carbonate Rearrangement
Scheme 8
entry
substrate
solvent
timea
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
49a
49a
49a
49a
49a
49b
49b
49c
49c
49d
49d
49e
49e
49f
49f
49g
49g
49h
49h
53
CH2Cl2
THF
Et2O
35 d
35 d
35 d
35 d
35 d
8 d
8 d
8 d
8 d
28 d
28 d
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
3 h
23
55
55
45
33
37
2
toluene
tert-amyl-OH
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
tert-amyl-OH
CH2Cl2
THF
CH2Cl2
tert-amyl-OH
tert-amyl-OH
7
18
48
50
2
23
<1
<1
10
5
39
49
65
61
75b
44
78b
(entries 14-18). The best result was obtained with 49h
(trichlorobutoxycarbonyl as the migrating group, 49% ee). No
attempt was made to correlate absolute configuration in view
of the modest ee values, so the configurations as drawn are
tentative and are based on the furan and oxazole analogies.
To provide greater flexibility for optimization in the indole
series at low temperatures, the substrate was modified by the
introduction of an electron-withdrawing nitro group to help
stabilize the intermediate ion pair (Scheme 8). The starting
nitrooxindole 52 was prepared by oxidation of the corresponding
indole36 and was converted into enol carbonate 53. Compared
to the analogous 49h, the carboxyl migration rate upon treatment
with 10 mol % of the catalyst 1 increased by ca. 8-fold at room
temperature. Additionally, the selectivity improved substantially
(entries 20 and 21), and could be further enhanced by lowering
the temperature to 0 °C (entries 22 and 24), leading to the
functionalized C-carboxylated oxindole 54 in 75-78% ee,
>98% yield.
In a final series of experiments, the carboxyl migration
methodology was extended to the N-protected 3-phenylindole
55 as a model substrate corresponding to 37, the indole precursor
that would be needed in a carboxyl migration approach to
diazonamide A as discussed in connection with Scheme 5. Enol
carbonate 55 was obtained in 87% yield by reaction of
3-phenyloxindole with phenyl chloroformate and triethylamine.
Subsequent treatment of 55 with 10 mol % TADMAP, (R)-1,
produced the desired carboxyl migration product 56. The
enantioselectivity in various solvents was good to excellent
(Table 5), but the reaction was slow compared to the N-alkyl-
3-methylindole examples of Table 4 (entries 12-18). Reactivity
was improved for 55 compared to the N-(phenoxycarbonyl)-3-
methyl analogue 49a, probably due to the stabilizing effect of
the 3-phenyl substituent at the stage of the ion pair intermediate,
but several days or more were required for conversion of 55 at
room temperature. Fortunately, the reaction could be conducted
at 35-40 °C with only modest erosion of the enantiomeric
excess (Table 5, entries 3, 5, 7, 9), resulting in good conversion
within 18 h. In the best case (entry 9), using tert-amyl alcohol
53
53
53
53
5 h
24 h
5 h
24 h
a Time required for >95% conversion of 49 or 53. b Reaction at 0 °C;
>98% yield.
were assigned by analogy. This stereochemistry is similar to
that observed for the corresponding methyl substituted azlactone
15b, as expected given the structural similarities.
Enantioselective Carboxyl Migration of 3-Substituted
2-Alkoxycarbonyloxyindoles. Extension of the carboxyl migra-
tion methodology to 2-indolyl enol carbonates proved difficult
and somewhat problematic. Treatment of 49a with 10 mol %
of TADMAP (1) afforded the desired 50 as the sole product
(Table 4, entries 1-5). However, the reaction was very slow,
requiring over a month to reach completion at room temperature.
While the enantioselectivity was in the promising range in the
best solvents (45-55% ee), ee improvement at lower temper-
atures was not an option due to poor reactivity. Evidently, the
enolate subunit of the necessary ion pair intermediate 51 is not
sufficiently stabilized, an effect that can be attributed to the
substituent at indole nitrogen, R ) N-CO2Ph. Although the
inductive effect of amide carbonyl is expected to help stabilize
a simple enolate,35 there is an opposing factor in 51 because
the nitrogen electron pair is potentially part of a delocalized
indole π-system while amide delocalization with R ) N-CO2-
Ph works against aromaticity. According to this rationale,
substrates 49b-e containing relatively electron rich (R ) allyl,
benzyl, p-methoxyphenyl, methyl) substituents at the indole nit-
rogen may be more reactive due to increased stability for 51.
Enol carbonates 49b-e were screened, and improved reactiv-
ity was indeed observed (entries 6-13). However, the enanti-
oselectivities were marginal at best and poor for the most highly
reactive N-methylindole 49e. In an attempt to address this
problem, optimization of the migrating group was investigated
(35) Garst, M. E.; Bonfiglio, J. N.; Grudoski, D. A.; Marks, J. J. Org. Chem.
1980, 45, 2307.
(36) Takase, S.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron 1986, 42, 5879.
9
932 J. AM. CHEM. SOC. VOL. 128, NO. 3, 2006

TADMAP-Catalyzed Carboxyl Migration Reactions
A R T I C L E S
Table 5. 3-Phenylindole Enol Carbonate Rearrangement
entry
solvent
temp (
°
C)
timea (h)
ee (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
THF
THF
Et2O
23
23
40
23
40b
23
40
23
40
96
96
18
96
18
96
18
96
18
73
82
82
90
83
87
74
90
86c
Et2O
toluene
toluene
tert-amyl-OH
tert-amyl-OH
a Time required for >95% conversion of 55. b Sealed tube. c 93% isolated
yield.
as the solvent, the desired oxindole 56 was formed in 93% yield
and 86% ee.
Figure 4. Qualitative models for stereochemical induction.
Compared to the relatively facile, highly enantioselective
phenoxycarbonyl migrations with oxazole, furan, and benzofuran
substrates, the analogous indole enol carbonates are substantially
less reactive, and the enantioselectivity trends in Tables 4 and
5 are somewhat different. Much of the reactivity difference
probably reflects the decreased stability of ion pair 51 compared
to analogous intermediates in the oxazole, furan, and benzofuran
series. Qualitatively, this difference can be appreciated by
comparing the pKa values of the unsubstituted benzofuranone
38 with R1 ) H (pKa ) 11.9) and the corresponding N-
methyloxindole 47 with R1 ) H (pKa ) 15.7),37 adjusted for
the added delocalization by R1 ) Ph (pKa 8.4 for 38 with R1 )
Ph).38
oselectivity. However, the analogous indole structure (62) would
project the N-R substituent toward the acetoxy group of the
catalyst. The added steric requirements of the indole N-R group
may contribute to the decreased reactivity of 49a-d as well as
to the low enantioselectivity observed with 49e. Thus, the faster
rearrangements are observed with the smallest N-R group (Me
> allyl or benzyl; Table 4, entry 12 vs entries 6, 8). However,
there is no simple correlation of reactivity with enantioselectivity
in Table 4. The qualitative model sheds no light on the preferred
geometry for the indole rearrangements and does not address
the detailed differences among the alkoxycarbonyl migrating
groups.
Assuming that the enantioselectivity-determining transition
states for product formation in the more facile oxazole and furan
enol carbonate rearrangements resemble tetrahedral intermedi-
ates leading to the C-carboxylated products, two isomeric
transition structures, 57 or 58, can be considered for substrates,
where R1 has a methylene group connected to the ring (Figure
4). Structure 57 would be formed from the less hindered
phenoxycarbonyl pyridinium salt conformer and should be
favored since it would also have fewer interactions between
the phenoxy and trityl groups. As drawn, these structures
somewhat exaggerate the role of one of the trityl phenyl groups
in blocking the lower face of the pyridine ring,39 but preferred
bonding from the top face is expected. Analogous structures
are plausible in the most highly enantioselective oxazole (59),
furan (60), and benzofuran (61) rearrangements, provided that
Ra corresponds to the eventual carbonyl group in the product,
Rb is the unbranched carbon substituent required for optimum
ee, and Rc is the aromatic substituent (C2 aryl in 59, C5 aryl in
60, and benzo-fused ring in 61). In these examples, the favored
conformer is relatively devoid of unfavorable steric interactions,
and the qualitative models correspond to the sense of enanti-
Summary
TADMAP (1) has been shown to catalyze the carboxyl
migration of oxazolyl, furanyl, and benzofuranyl enol carbonates
with good to excellent levels of enantioselection. In general these
findings compare well in terms of yield, reactivity, and catalyst
loading to the results reported earlier by Fu et al. using their
planar chiral catalyst for similar rearrangements,23,31 although
the enantioselectivities are somewhat lower for the benzofuran
and indole substrates. The oxazole reactions are especially
efficient, and applications in more highly functionalized sub-
strates allow the synthesis of convenient precursors of chiral
lactams and lactones containing a quaternary asymmetric carbon.
The analogous TADMAP-catalyzed indole reactions suffer from
inconsistent enantioselectivity and low reactivity, requiring the
use of 10 mol % of catalyst. Better enantioselection was
observed by Fu et al. for the indoles, although a similar reactivity
problem was encountered. Further studies will be needed to
improve reactivity as well as catalyst accessibility. Even with
the relatively short synthesis, TADMAP is probably not suitable
for applications where 10% catalyst loading is necessary.
However, shorter routes to analogous 3-substituted DMAP
derivatives are easily imagined, and relevant studies are under
way.
(37) Kresge, A. J.; Meng, Q. J. Am. Chem. Soc. 2002, 124, 9189.
(38) Heathcote, D. M.; De Boos, G. A.; Atherton, J. H.; Page, M. I. J. Chem.
Soc., Perkin Trans. 2 1998, 535.
(39) A more more sterically demanding analogue of TADMAP was prepared
with the trityl group replaced by tris(3,5-dimethylphenyl)methyl. Virtually
identical results were obtained using this catalyst in dichloromethane (room
temperature) for the carboxyl migrations of 39b (28% ee) and 41b (73%
ee) compared to TADMAP, while lower enantioselectivities were observed
starting with 13a (12% ee) and 44b (79% ee).
As a final comment, we will briefly note that TADMAP is
only modestly selective as a catalyst for kinetic resolution. In a
preliminary study, the best enantioselectivity, s ) 4.4, was
9
J. AM. CHEM. SOC. VOL. 128, NO. 3, 2006 933

A R T I C L E S
Shaw et al.
observed for the isobutyroylation of 1-naphthyl-1-ethanol at
room temperature. If kinetic resolution had been used as the
exclusive probe for the potential utility of TADMAP as a chiral
nucleophilic catalyst, we may have opted to explore new
catalysts and to bypass the experiments leading to the highly
enantioselective carboxyl migrations reported above.
(CA17918), and by fellowships provided to S.A.S. by the
University of Michigan, Board of Regents, and to P.A. by the
Spanish Ministry of Education and Culture.
Supporting Information Available: Experimental procedures,
characterization, and crystal structures (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the National
Science Foundation and the National Institutes of Health
JA056150X
9
934 J. AM. CHEM. SOC. VOL. 128, NO. 3, 2006