Dirhodium tetracarboxylate derived from adamantylglycine as a chiral catalyst for carbenoid reactions

Article abstract of DOI:10.1021/ol060893l

The dirhodium tetracarboxylate, Rh₂(S-PTAD)₄, derived from adamantylglycine, is a very effective chiral catalyst for carbenoid reactions. High asymmetric induction was obtained in Rh₂(S-PTAD) ₄-catalyzed intramo

Full text of DOI:10.1021/ol060893l

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3437-3440
Dirhodium Tetracarboxylate Derived
from Adamantylglycine as a Chiral
Catalyst for Carbenoid Reactions
Ravisekhara P. Reddy, Gene H. Lee, and Huw M. L. Davies*
Department of Chemistry, UniVersity at Buffalo, State UniVersity of New York,
Buffalo, New York 14260-3000
hdaVies@acsu.buffalo.edu
Received April 12, 2006
ABSTRACT
The dirhodium tetracarboxylate, Rh2(S-PTAD)4, derived from adamantylglycine, is a very effective chiral catalyst for carbenoid reactions. High
asymmetric induction was obtained in Rh2(S-PTAD)4-catalyzed intramolecular C H insertion (94% ee), intermolecular cyclopropanation (99%
ee), and intermolecular C H insertion (92% ee).
−
−
Rhodium-catalyzed reactions of diazo compounds have broad
application in organic synthesis.1 In recent years, it has
become recognized that donor/acceptor-substituted diazo
compounds generate carbenoids capable of highly regio- and
stereoselective reactions.2 The most commonly utilized types
of donor/acceptor carbenoids have been derived from either
methyl aryldiazoacetates or methyl vinyldiazoacetates. These
precursors are capable of highly enantioselective transforma-
tions when catalyzed by the dirhodium tetraprolinate Rh2-
(S-DOSP)4 or the bridged variant Rh2(S-biTISP)2.2,3 High
enantioselectivity is maintained with a broad range of
functionality on the donor group, leading to powerful
methods for asymmetric cyclopropanation, [4 + 3] cycload-
dition, C-H insertion, and ylide formation.2 Ironically, the
acceptor group has very stringent requirements for high
asymmetric induction with Rh2(S-DOSP)4, and a methyl ester
is by far the optimum functionality.4 To broaden the scope
of enantioselective reactions of donor/acceptor-substituted
carbenoids, the acceptor group and the chiral catalysts need
to be carefully matched. In this paper, we describe that
Hashimoto’s phthalimido catalyst Rh2(S-PTTL)45 and the new
adamantyl variant Rh2(S-PTAD)4 developed by us are very
effective backup chiral catalysts when Rh2(S-DOSP)4 fails
to give high asymmetric induction (Figure 1).
A common strategy in chiral catalyst design is to use
sterically blocking groups to limit the number of reasonable
orientations of the substrates as they interact with the
(4) Davies, H. M. L.; Bruzinski, P.; Lake, D. H.; Kong, N.; Fall, M. J.
J. Am. Chem. Soc. 1996, 118, 6897.
(5) (a) Takahashi, T.; Tsutsui, H.; Tamura, M.; Kitagaki, S.; Nakajima,
M.; Hashimoto, S. Chem. Commun. 2001, 1604. (b) Kitagaki, S.; Anada,
M.; Kataoka, O.; Matsuno, K.; Umeda, C.; Watanabe, N.; Hashimoto, S. J.
Am. Chem. Soc. 1999, 121, 1417. (c) Hashimoto, S.; Tsutsui, H. I. J. Chem.
2001, 41, 283. (d) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.;
Hashimoto, S. Tetrahedron Lett. 2002, 43, 9561. (e) Tsutsui, H.; Yamaguchi,
Y.; Kitagaki, S.; Nakamura, S.; Anada, M.; Hashimoto, S. Tetrahedron:
Asymmetry 2003, 14, 817. (f) Minami, K.; Saito, H.; Tsutsui, H.; Nambu,
H.; Anada, M.; Hashimoto, S. AdV. Synth. Catal. 2005, 347, 1483.
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; Wiley: New York, 1998.
(2) Davies, H. M. L.; Walji, A. M. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp
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(3) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459.
10.1021/ol060893l CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/15/2006

Figure 1. Chiral dirhodium tetracarboxylates.
catalyst.6 In recent years, the ready accessibility of tert-
leucine has made the tert-butyl group a very popular unit to
incorporate into chiral catalysts, especially as the enantio-
induction is often much improved compared to catalysts
containing smaller groups.7 Hashimoto has successfully used
the tert-butyl group in the carbenoid field in the design of
his rhodium phthalimidocarboxylate catalysts, where in most
instances the tert-butyl derivative Rh2(S-PTTL)4 is far
superior to other catalysts derived from amino acids with
smaller side chains.5 The use of ligands with stereogenic
centers containing larger groups than tert-butyl, such as
adamantyl, have rarely been incorporated into chiral cata-
lysts,8 although large groups away from the stereogenic
centers have been used with good effect.9 We recognized
that our newly developed C-H activation chemistry10 would
allow us enantioselective access to adamantylglycine.11
Therefore, in evaluating the potential of using Rh2(S-PTTL)4
as a backup chiral catalyst for Rh2(S-DOSP)4, we expanded
the study to include the adamantyl catalyst Rh2(S-PTAD)4.
The key step in the synthesis of Rh2(S-PTAD)4 is an
intermolecular C-H functionalization of adamantane by
means of a metal carbenoid-induced C-H insertion. The Rh2-
(S-DOSP)4-catalyzed reactions of donor/acceptor-substituted
carbenoids are particularly effective because highly regiose-
lective and enantioselective C-H functionalization can be
achieved.12 Previous studies have demonstrated that a range
of alkanes can be functionalized,13 and in this paper, we use
this reaction in the synthesis of adamantylglycine. The results
of the Rh2(S-DOSP)4-catalyzed reaction of the vinyldi-
azoacetates 2 with adamantane (1) using hexanes as solvent
are summarized in Table 1. Selective C-H functionalization
Table 1. Optimization of Adamantane C-H Activation
(6) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
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Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336. (c) Glos, M.;
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A.; Reiser, O. Org. Lett. 2001, 3, 4259. (e) Mu¨ller, P.; Bolea, C. HelV.
Chim. Acta 2002, 85, 483. (f) Lim, H.-J.; Sulikowkski, G. A. J. Org. Chem.
1995, 60, 2326. (g) Ye, T.; Garcia, F. C.; McKervey, M. A. J. Chem. Soc.,
Perkin Trans. 1 1995, 1373.
compound
R
temp, °C
yield, %
ee, %
a
b
c
c
H
OMe
Br
69
69
69
23
58
40
57
10
91
85
95
98
(8) Clariana, J.; Comelles, J.; Moreno-Manas, M.; Vallribera, A.
Tetrahedron: Asymmetry 2002, 13, 1551.
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47.
(11) For previous enantioselective syntheses of adamantylglycine, see:
(a) Hasegawa, M.; Taniyama, D.; Tomioka, K. Tetrahedron 2000, 56, 10153.
(b) Clariana, J.; Garcia-Granda, S.; Gotor, V.; Gutierrez-Fernandez, A.;
Luna, A.; Moreno-Manas, M.; Vallribera, A. Tetrahedron: Asymmetry 2000,
11, 4549. (c) Galvez, N.; Moreno-Manas, M.; Vallribera, A.; Molins, E.;
Cabrero, A. Tetrahedron Lett. 1996, 37, 6197. (d) Krasutskii, P. A.;
Semenova, I. G.; Novikova, M. I.; Yurchenko, A. G.; Tikhonov, V. P.;
Belikov, V. M.; Belokon, Yu. N. Zh. Org. Khim. 1985, 21, 1458. (e) Augeri,
D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D. R.; Khanna, A.; Robertson,
J. G.; Wang, A.; Simpkins, L. M.; Taunk, P.; Huang, Q.; Han, S.-P.; Abboa-
Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D.
M.; Marcinkeviciene, J.; Chang, S. Y.; Biller, S. A.; Kirby, M. S.; Parker,
R. A.; Hamann, L. G. J. Med. Chem. 2005, 48, 5025. (f) Chen, Y. K.;
Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 12225. For
enantioselective synthesis of adamantyl amino alcohol, see: Takacs, J. M.;
Jaber, M. R.; Vellekoop, A. S. J. Org. Chem. 1998, 63, 2742.
Br
at the tertiary C-H bond occurs because this is electronically
favored and is not sterically encumbered.13 Optimization
studies were conducted with three vinyldiazoacetates 2a-c.
The p-bromo derivative 2b gave the highest enantioselectivity
under refluxing conditions (95% ee), and this could be
(12) (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119,
9075. (b) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1,
233. (c) Davies, H. M. L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999,
1, 383. (d) Davies, H. M. L.; Hansen, T.; Hopper, D.; Panaro, S. A. J. Am.
Chem. Soc. 1999, 121, 6509. (e) Axten, J. M.; Ivy, R.; Krim, L.; Winkler,
J. D. J. Am. Chem. Soc. 1999, 121, 6511. (f) Davies, H. M. L.; Stafford, D.
G.; Hansen, T.; Churchill, M. R.; Keil, K. M. Tetrahedron Lett. 2000, 41,
2035. (g) Mu¨ller, P.; Tohill, S. Tetrahedron 2000, 56, 1725. (h) Davies, H.
M. L.; Antoulinakis, E. G. Org. Lett. 2000, 2, 4153. (i) Davies, H. M. L.;
Ren, P. J. Am. Chem. Soc. 2001, 123, 2070.
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2000, 122, 3063.
3438
Org. Lett., Vol. 8, No. 16, 2006

improved to 98% ee for a room-temperature reaction;
however, the yield was greatly decreased. The most practical
system was the phenylvinyldiazoacetate 2a because the
product was easily purified and enriched by recrystallization.
The selectivity of the C-H activation is sufficiently high
that the reaction can be carried out in hexanes as solvent.
The reaction of 2a has been conducted on a 40-50 g scale,
and a single recrystallization enriches the product (S)-3a to
>99% ee.
Table 2. Enantioselective Intramolecular C-H Insertion
The conversion of 3 to Rh2(S-PTAD)4 is readily achieved
using conventional steps (Scheme 1). LiAlH4-mediated
Scheme 1. Synthesis of Rh2(S-PTAD)4
a ent-7 is the major enantiomer.
synthesis, the Rh2(S-DOSP)4-catalyzed reaction of 8 gener-
ated 9a and 9b with poor diastereoselectivity (2:3 dr) and
enantioselectivity (32% ee).17b Reasonable results were
Table 3. Key Step in the Synthesis of (-)-Ephedradine A
reduction of the ester 3 followed by protection of the alcohol
and oxidative cleavage14 of the alkene generated the acid 4.
A Curtius rearrangement on the acid 4, followed by conver-
sion of the amine to the phthalimide, generated the protected
amino alcohol 5. Oxidation of the alcohol 5 to the acid and
then ligand exchange with dirhodium tetraacetate15 resulted
in the formation of Rh2(S-PTAD)4. A similar sequence
beginning with a Rh2(R-DOSP)4-catalyzed C-H activation
of adamantane generated Rh2(R-PTAD)4.
The first set of experiments compared Rh2(S-PTAD)4 to
the two standard catalysts, Rh2(S-DOSP)4 and Rh2(S-PTTL)4.
Rh2(S-DOSP)4 is the premier chiral catalyst for the reactions
of the donor/acceptor-substituted carbenoids, especially when
the acceptor group is a methyl ester.10,12 In a few cases,
however, the Rh2(S-DOSP)4-catalyzed reaction is not highly
enantioselective and Rh2(S-PTTL)4 results in higher enan-
tioinduction.16 One such system is the intramolecular C-H
insertion of the aryldiazoacetate 6, which generates the
benzodihydrofuran 7 (Table 2).16a,b The Rh2(S-PTTL)4-
catalyzed reaction16b of 6 proceeds with much higher but
opposite enantioinduction than Rh2(S-DOSP)4,16a but Rh2-
(S-PTAD)4 outperforms both of the standard catalysts. The
Rh2(S-PTAD)4-catalyzed reaction formed 7 in 87% ee at
room temperature and 95% ee at -60 °C.
a ent-9a is the major enantiomer. b Poor isolated yield was obtained in
the reaction conducted on a very small scale.
obtained only when a combination of Rh2(S-DOSP)4 and a
chiral auxiliary was used.17 This gave rise to the desired trans
stereoisomer, with an asymmetric induction of 86% de.17 The
Rh2(S-PTTL)4- or Rh2(S-PTAD)4-catalyzed reactions de-
scribed in this current study were much more stereoselective
than the Rh2(S-DOSP)4-catalyzed reaction. Under the opti-
A second example is a key step in the synthesis of a natural
product (-)-ephedradine A (Table 3). In the published
(14) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
(15) Callot, H. J.; Metz, F. Tetrahedron 1985, 41, 4495.
(16) (a) Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Org. Lett. 2001,
3, 1475. (b) Hashimoto, S.; Anada, M.; Saito, H.; Oishi, H.; Kitagaki, S.;
Nakamura, S. Org. Lett. 2002, 4, 3887. (c) Davies, H. M. L.; Hedley, S. J.;
Bohall, B. R. J. Org. Chem. 2005, 70, 10737.
(17) (a) Kurosowa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2003,
125, 8112. (b) Kurosowa, W.; Kan, T.; Fukuyama, T. Synlett 2003, 1028.
Org. Lett., Vol. 8, No. 16, 2006
3439

mized conditions, the Rh2(R-PTAD)4-catalyzed reaction of
8 generated preferentially the cis isomer 9a in a 14:1 dr with
79% ee, without requiring the use of a chiral auxiliary. The
cis isomer 9a can be readily equilibrated to the desired trans
isomer 9b on treatment with sodium methoxide following
Hashimoto’s conditions.16b
Table 5. Enantioselective Intermolecular C-H Insertion
Even though Rh2(S-DOSP)4 gives excellent enantioinduc-
tion with a range of donor substituents in the donor/acceptor-
substituted carbenoids,10 altering the acceptor group can have
a profound effect on the level of enantioinduction.4 This is
clearly seen in the asymmetric cyclopropanation of the
diazophosphonate 10 (Table 4). The Rh2(S-DOSP)4-catalyzed
Table 4. Enantioselective Intramolecular Cyclopropanation
a Opposite enantiomer preferentially formed.
absolute configuration of 12 has not been determined, but if
the sense of asymmetric induction follows the trend of
aryldiazoacetate C-H insertion,19 the predicted configuration
of 12 for the Rh2(S-DOSP)4-catalyzed reaction would be (R)
and for the other catalysts it would be (S).
In summary, these studies demonstrate that the phthalimido
catalysts Rh2(S-PTTL)4 and Rh2(S-PTAD)4 are promising
backup catalysts for Rh2(S-DOSP)4. Even though Rh2(S-
DOSP)4 has been very effective with a wide variety of
substrates, it does have certain substrate limitations, espe-
cially when the acceptor group is not a methyl ester. Both
Rh2(S-PTTL)4 and Rh2(S-PTAD)4 can perform extremely
well in these problem systems with the adamantyl catalyst
Rh2(S-PTAD)4 generally giving slightly higher enantiose-
lectivity than the established tert-butyl catalyst, Rh2(S-
PTTL)4.
a ent-11 is the major enantiomer.
cyclopropanation of styrene results in the formation of 11
in 34% ee.18 The bridged prolinate catalyst Rh2(S-biTISP)2
results in 88% ee.18 In the current study, we demonstrate
that Rh2(S-PTTL)4 or Rh2(S-PTAD)4 is far superior, with Rh2-
(S-PTAD)4 resulting in the highest enantioselectivity (99%
ee).
A similar enhancement in enantioselectivity can be
achieved for intermolecular C-H activation of 1,4-cyclo-
hexadiene by diazophosphonate 10 (Table 5). The Rh2(S-
DOSP)4-catalyzed reaction generated the C-H activation
product 12 in 41% ee, whereas with Rh2(S-PTAD)4 the
opposite enantiomer was preferentially formed (92% ee). The
Acknowledgment. Financial support of this work by the
National Science Foundation (CHE-0350536) is gratefully
acknowledged.
Supporting Information Available: Experimental data
for the reported reactions. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL060893L
(19) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1,
233.
(18) Davies, H. M. L.; Lee, H. G. Org. Lett. 2004, 6, 2117.
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