New synthetic technology for efficient construction of α-hydroxy-β-amino amides via the passerini reaction

Article abstract of DOI:10.1021/ol0061485

The Passerini reaction of N-protected amino aldehydes, isonitriles, and TFA using pyridine-type bases proceeds under mild conditions and directly affords α-hydroxy-β-amino amide derivatives in moderate to high yields. These adducts are readily hydrolyzed to αhydroxy-β-amino carboxylic acids. Application of these key intermediates to concise syntheses of P₁-α-ketoamide protease inhibitors is illustrated.

Full text of DOI:10.1021/ol0061485

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2769-2772
New Synthetic Technology for Efficient
Construction of r-Hydroxy-â-amino
Amides via the Passerini Reaction1
J. Edward Semple,* Timothy D. Owens, Khanh Nguyen, and Odile E. Levy
Department of Medicinal Chemistry, CorVas International, Inc.,
3030 Science Park Road, San Diego, California 92121
ed•semple@corVas.com
Received June 1, 2000
ABSTRACT
The Passerini reaction of N-protected amino aldehydes, isonitriles, and TFA using pyridine-type bases proceeds under mild conditions and
directly affords r-hydroxy-â-amino amide derivatives in moderate to high yields. These adducts are readily hydrolyzed to r-hydroxy-â-amino
carboxylic acids. Application of these key intermediates to concise syntheses of P -r-ketoamide protease inhibitors is illustrated.
1
R-Hydroxy-â-amino carboxylic acid and amide subunits are
found in numerous pharmaceuticals and natural products that
express potent biological activity.2 Prominent examples of
R-hydroxy-â-amino carboxylates (“norstatines”) have re-
cently emerged, underscoring their importance in medicinal
chemistry. The clinically proven anticancer drug paclitaxel
(Taxol) features N-benzoyl-3-phenylisoserine 1 esterified to
the C-13 hydroxyl function of baccatin III3 (Figure 1).
Bestatin 2 is a prototypical member of a growing family of
peptidyl R-hydroxy-â-amino amide natural products isolated
from bacterial cultures that demonstrate potent inhibition of
aminopeptidases and prolyl endopeptidases.4
These subunits also serve as convenient, chemically stable
precursors for the synthesis of R-ketoamide transition-state
analogue inhibitors of serine5 and cysteine6 proteases. R-Ke-
toamide scaffolds, including the potent thrombin inhibitor
37 and the calpain inhibitor 4,8 serve as useful leads in drug
discovery platforms, while the biologically active natural
(1) Dedicated to the memory of Joseph E. Semple.
(2) Semple, J. E. Abstracts of Papers, 219th National Meeting of the
American Chemical Society, San Francisco, CA, March 26-30, 2000;
American Chemical Society: Washington, DC, 2000; ORGN.667.
(3) Taxol: (a) Ha, H. J.; Park, G. S.; Ahn, Y. G.; Lee, G. S. Bioorg.
Med. Chem. Lett. 1998, 8, 1619. (b) Review: Nicolaou, K. C.; Dai, W.
M.; Guy, R. K. Angew. Chem., Intl. Ed. Engl. 1994, 106, 38.
(4) Bestatin: (a) Suda, H.; Takita, T.; Aoyagi, T.; Umezawa, H. J.
Antibiot. 1976, 29, 600. (b) Pearson, W. H.; Hines, J. V. J. Org. Chem.
Figure 1. Representative examples of biologically active R-hy-
droxy-â-amino acid, R-hydroxy-â-amino amide, and R-ketoamide
derivatives.
1989, 54, 4235 and references therein.
(5) Semple, J. E.; Rowley, D. C.; Brunck, T. K. Ripka, W. C. Bioorg.
Med. Chem. Lett. 1997, 7, 315.
products cyclotheonamide9 and eurystatin 510 incorporate the
(6) Otto, H. H.; Schirmeister, T. Chem. ReV. 1997, 97, 133.
reactive R-ketoamide moiety in a macrocyclic array.
10.1021/ol0061485 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/15/2000

As a result of their diverse structural variety, profound
biological activity, and synthetic utility, approaches to
R-hydroxy-â-amino carboxylate classes have received in-
creased attention over the past decade. Although these
methods often proceed with satisfactory to high levels of
stereocontrol,11 final target preparation usually requires many
steps. Classical approaches, such as homologation of R-amino
aldehydes 6 via cyanohydrin,12 2-(TMS)-thiazole,13 or
orthothioformate14 procedures, continue to receive consider-
able attention due to their utility and practicality, even though
products obtained by these protocols are diastereomeric at
the newly created R-hydroxy center. Although each of the
above methods has merits, limitations in scope are also
evident.
Our exploratory programs on small molecule covalent
inhibitors of the blood coagulation proteases thrombin (fIIa)15
and factor Xa (fXa),16 the plasminogen activator urokinase
(uPA),17 and the NS3A hepatitis C virus (HCV) protease18
necessitated the development of new synthetic technology
for the rapid construction of diverse R-hydroxy-â-amino
carboxylic amide and acid derivatives such as 7 and 8 (Figure
2). In our laboratories, elaboration of these intermediates is
followed by a late-stage oxidation step, which minimizes
racemization issues with the P1-R-ketoamide targets 9.5,11,14
Figure 2. Strategy for the construction of R-hydroxy-â-amino
amides 7 and corresponding acids 8 from aldehyde 1 and their
potential elaboration into R-ketoamide subunit 9. PG denotes
N-protecting group.
We envisioned that application of the classic Passerini
reaction employing N-R-protected amino aldehydes 6 as
substrates would provide a novel, concise approach to these
key synthons while complimenting current and more tradi-
tional protocols. In this Letter, we report the successful
implementation of this strategy, which has demonstrated
broad scope and general utility.
The Passerini reaction is a powerful, atom-economical,
multiple-component reaction (MCR) between isonitrile,
aldehyde (or ketone), and carboxylic acid components19 that
generates a significantly more complex R-acyloxy-carbox-
amide adduct. Related protic or Lewis acid-catalyzed pro-
cesses20 between isonitrile, aldehyde (or ketone), and water
components afford R-hydroxyamide derivatives. The scope
of the latter reactions may be limited since they occur under
vigorous, highly acidic conditions that may not be tolerated
by delicate or sensitive functionalities.
(7) Webb, T. R. Miller, T. A.; Vlasuk, G. P. U.S. Pat. 5371072, 1994.
(8) Harbeson, S. L.; Abelleira, S. M.; Akiyama, A.; Barrett, R.; Carroll,
R. M.; Straub, J. A.; Tkacz, J. N.; Wu, C.; Musso, G. J. Med. Chem. 1994,
37, 2918.
(9) (a) Fusetani, N.; Matsunaga, S.; Matsumoto, H.; Takebayashi, Y. J.
Am. Chem. Soc. 1990, 112, 7053. (b) Maryanoff, B. E.; Greco, M. N.; Zhang,
H. C.; Andrade-Gordon, P.; Kauffman, J. A.; Nicolaou, K. C.; Liu, A.;
Brungs, P. H. J. Am. Chem. Soc. 1995, 117, 1225.
In accordance with the proposed Passerini mechanism,19c
reaction of protected R-amino aldehydes 6, isonitriles 10,
and trifluoroacetic acid in the presence of a pyridine-type
base leads directly to R-hydroxy-â-amino amide derivatives
7 in moderate to excellent yield (Scheme 1). Presumably,
the reaction proceeds through trifluoroacetoxy intermediate
11, which undergoes facile hydrolysis upon extractive
workup with saturated aqueous sodium bicarbonate solution
and/or silica gel flash chromatographic purification, and
delivers product 7.21 Thus, application of this technology
allows for the concise construction of R-hydroxy-â-amino
amide-containing molecules that traditionally require many
steps to prepare.
The reactions proceed under mild, nearly neutral condi-
tions, typically from 0 °C to ambient temperature. Dichloro-
methane is the solvent of choice. In our hands, this chemistry
is readily scalable from 0.1 mmol to 0.5 mol. In cases with
less reactive aldehyde or isonitrile components, higher
reactant concentrations (ca. 0.5-5 M) or slow removal of
solvent affords the best yield of adduct 7.
(10) (a) Schmidt, U. Weinbrenner, S. J. Chem. Soc., Chem. Commun.
1994, 1003. (b) Wasserman, H. H.; Peterson, A. K. J. Org. Chem. 1997,
62, 8972.
(11) For an excellent compilation of the leading stereospecific and
asymmetric approaches to R-hydroxy-â-amino acids and amides, see:
Wasserman, H. H.; Xia, M.; Jorgensen, M. R.; Curtis, E. A. Tetrahedron
Lett. 1999, 40, 6163 and references therein.
(12) See refs 4a, 5a, 7, 8, 9b,c and Iizuka, K.; Kamijo, T.; Harada, H.;
Akahane, K.; Kuboto, T.; Umeyama, H.; Kiso, Y. J. Med. Chem. 1990, 33,
2707.
(13) (a) Review: Dondoni, A.; Perrone, D. Aldrichimica Acta 1997, 30,
35. (b) Dondoni, A.; Perrone, D. Synthesis 1993, 1162. (c) Piron, J.; Tourwe,
D. Lett. Pept. Sci. 1995, 2, 229.
(14) (a) Brady, S. F.; Sisko, J. T.; Stauffer, K. J.; Colton, C. D.; Qui,
H.; Lewis, S. D.; Ng, A. S.; Shafer, J. A.; Bogusky, M. J.; Veber, D. F.;
Nutt, R. F. Bioorg. Med. Chem. 1995, 3, 1063. (b) Iwanowicz, E. J.; Lin,
J.; Roberts, D. G. M.; Michel, I, M.; Seiler, S. M. Bioorg. Med. Chem.
Lett. 1992, 2, 1607.
(15) (a) Minami, N. K.; Reiner, J. E.; Semple, J. E. Bioorg. Med. Chem.
Lett. 1999, 9, 2625. (b) Reiner, J. E.; Lim-Wilby, M. S.; Brunck, T. K.;
Uong, T. H.; Goldman, E. A.; Abelman, M. A.; Nutt, R. F.; Semple. J. E.;
Tamura S. Y. Bioorg. Med. Chem. Lett. 1999, 9, 895. (c) Semple, J. E.
Tetrahedron Lett. 1998, 39, 6645.
(16) (a) Tamura, S. Y.; Levy, O. E.; Reiner, J. E.; Uong, T. H.; Goldman,
E. A.; Brunck, T. K.; Semple, J. E. Bioorg. Med. Chem. Lett. 2000, 10,
745. (b) Ho, J. Z.; Levy, O. E.; Gibson, T. S.; Nguyen, K.; Semple, J. E.
Bioorg. Med. Chem. Lett. 1999, 9, 3459.
(17) Tamura, S. Y.; Weinhouse, M. I.; Roberts, C. A.; Goldman, E. A.;
Masukawa, K.; Anderson, S. M.; Cohen, C. R.; Bradbury, A. E.; Bernadino,
V. T.; Dixon, S. A.; Ma, M. G.; Nolan, T. G.; Brunck, T. K. Bioorg. Med.
Chem. Lett. 2000, 10, 983.
To illustrate the scope and generality of the method, 20
(18) Han, W.; Hu, Z.; Jiang, X.; Decicco, C. P. Bioorg. Med. Chem.
Lett. 2000, 10, 711 and references therein.
(20) (a) Aqueous mineral acid-catalyzed versions: Hagedorn, I.; Eholzer,
U. Chem. Ber. 1965, 98, 936. (b) Lewis-acid catalysis with BF3‚Et2O or
AlCl3 to directly produce R-hydroxyamides: Muller, E.; Zeeh, B. Liebigs
Ann. Chem. 1966, 696, 72. (c) BF3‚Et2O catalysis: Muller, E.; Zeeh, B.
Liebigs Ann. Chem. 1968, 715, 47. (d) TiCl4 activation: Carofiglio, T.;
Cozzi, P. G.; Floriani, C.; Chiesa-Villa, A.; Rizzoli, C. Organometallics
1993, 12, 2726. (f) Seebach, D.; Adam, G.; Gees, T.; Schiess, M.; Weigand,
W. Chem. Ber. 1988, 121, 507. (g) Seebach, D.; Schiess, M. HelV. Chim.
Acta 1983, 66, 1618.
(19) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Passerini, M.;
Ragni, G.; Gazz. Chim. Ital. 1931, 61, 964. (c) Ugi, I. in Isonitrile Chemistry;
Ugi, I., Ed.; Academic Press: New York, 1971, Chapter 7. (d) Bienayme,
H. Tetrahedron Lett. 1998, 39, 4255. (e) Armstrong, R. W.; Combs, A. P.;
Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29,
123. (f) Ziegler, T.; Kaisers, H. J.; Schlomer, R.; Koch, C. Tetrahedron
1999, 55, 8397.
2770
Org. Lett., Vol. 2, No. 18, 2000

Scheme 1a
Table 1. R-Hydroxy-â-amino Amides 7a-y Produced via
TFA-Catalyzed Passerini Reaction of Scheme 1
compd
7
%
yield
PG
R1
R2
a
Boc
Boc
Boc
Boc
(CH2)3NHC(dNH)NHNO2 t-Bu
92
78a
46
62
68
69
37
75
67
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
CH2Ph
CH2Chx
CH2SMe
t-Bu
t-Bu
CH2CO2Me
CH2CO2t-Bu
CH2CO2Et
Fmoc CH(CH3)2
Fmoc CH2Ph-4-(t-BuO)
Boc
Fmoc (CH2)3NHC(dNH)NHPmc CH2CH2Ph
Boc
Cbz
Fmoc
Fmoc CH3
Fmoc CH2CH3
Fmoc CH(CH3)2
Fmoc (CH2)2CH3
Fmoc CH2CH(CH3)2
Fmoc (CH2)3CH3
Fmoc CH2Ph
Fmoc CH2Ph-4-(t-BuO)
Fmoc CH2Ot-Bu
Fmoc CH2CO2t-Bu
Fmoc (CH2)3NHC(dNH)NHPmc CH2CO2Allyl
Fmoc (CH2)4NHBoc
Fmoc CH3(CH)Ot-Bu
Fmoc allo-CH3(CH)Ot-Bu
a Reagents and conditions: (a) 2 equiv of TFA, 4 equiv of
pyridine, CH2Cl2, 0 °C to rt; (b) extractive workup or silica gel
flash chromatography.
(CH2)3NHC(dNH)NHNO2 CH2CO2Et
CH2Ph
d-CH2Ph
H
CH2CO2Allyl
(S)-CH(i-Bu)CO2Bn 65
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
77
83
73
68
87
85
69
67
66
68
60
76
79
62
74
protected R-amino aldehyde derivatives 622 and 7 representa-
tive isonitriles 1019 were subjected to the reaction conditions.
The resulting products 7a-y are collected in Table 1, where
25 examples embracing a variety of R-N-protecting groups
and assorted side-chain functionalities are shown.23 Allyl
ester derivatives 7k-y, featuring orthogonal protecting
groups, served as versatile intermediates for the construction
of focused R-ketoamide protease inhibitor libraries. Full
details of this chemistry will be disclosed in a separate
communication.24
s
t
u
v
w
x
y
CH2CO2Allyl
CH2CO2Allyl
CH2CO2Allyl
a Yield of 7b using 2,4,6-collidine as base.
In agreement with literature precedent, formation of the
new hydroxy methine center proceeds without appreciable
stereoselectivity.19f,20f We typically observed ca. 1:1 to 3:1
diastereomeric ratios by NMR and HPLC analysis. However,
we note retention of configuration at the original aldehyde
and isonitrile (cf. 7j) chiral centers. For applications to our
ultimate R-ketoamide targets (cf. 17 below), the stereochem-
istry at the R-hydroxy center is inconsequential since it is
removed during a late-stage oxidation step. Nonetheless, we
are intrigued by the prospect of effecting a stereocontrolled
Passerini reaction since this would further enhance the utility
of the technology.
While TFA serves as an essential component of this MCR,
it is also a relatively strong acid (pKa ) 0.3) whose presence
may lead to undesired side reactions. Indeed, in the absence
of pyridine, complex mixtures resulted when reactants
containing N-Boc or tert-butyl ester protecting groups were
employed. Using the formation of intermediate 7o from allyl
isocyanoacetate and N-R-Fmoc-nVal-H as a model reaction,
we surveyed a variety of organic bases whose pKa values
ranged from 5 to 11. In general, tertiary trialkylamines gave
inferior results. Pyridine, 2,6-lutidine, 2,4,6-collidine, and 2,6-
di-tert-butylpyridine, with pKa’s of 5.2-7.4, were optimal
and provided adduct 7o in 68-87% yield. Furthermore,
utilization of these mild pyridine bases minimizes the
potential for R-amino aldehyde racemization that may occur
in the presence of stronger trialkylamine bases.22 Although
other more subtle mechanistic factors cannot be excluded,20d,21
our results suggest that the pyridine-type additives simply
serve as mild and efficient bases in these Passerini reactions.
We quickly adapted this technology to a concise synthesis
of bestatin 24 (Scheme 2). Thus, reaction of N-R-Cbz-d-
Phe-H 12 and the isonitrile derivative 13 (each freshly
prepared in two steps as outlined and utilized immediately)
with TFA in pyridine produced adduct 7j in 65% yield. NMR
and HPLC analysis of 7j indicated a ca. 1.5:1 mixture of
diastereomers at the new hydroxy center with retained
configuration at the original aldehyde and isonitrile chiral
centers. Separation of the R-hydroxy diastereomers, hydro-
genolysis, and HPLC separation afforded bestatin 2 in
satisfactory overall yield.25
(21) Passerini reaction of simple aldehydes and ketones with TFA and
pyridine: Lumma, W. J. Org. Chem. 1981, 46, 3668.
(22) (a) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.;
Lanman, B. A.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359. (b) Jurczak,
J.; Golebiowski, A. Chem. ReV. 1989, 89, 149. (c) Ho, P. T.; Ngu, K. J.
Org. Chem. 1993, 58, 2313. (d) Hyun, S. I.; Kim, Y. G. Tetrahedron Lett.
1998, 39, 4299. (e) Fehrentz, J. A.; Pothion, C.; Califano, J. C.; Loffet, A.;
Martinez, J. Tetrahedron Lett. 1994, 35, 9031.
(23) All new compounds were characterized by full spectroscopic (NMR,
low/high resolution MS) data. Yields refer to spectroscopically and
chromatographically homogeneous (g95% by HPLC, TLC) materials.
General procedure for the synthesis of 7a-y: Trifluoroacetic acid (2.0
equiv) was added dropwise to a cooled solution (-10 to 0 °C) of freshly
prepared R-N-protected-amino aldehyde (1.0 equiv), isonitrile (1.2-1.5
equiv), and pyridine (4.0 equiv) in dichloromethane [0.25-2.0 M] under a
nitrogen atmosphere while maintaining the temperature at e0 °C. After
0.5-2 h at 0 °C, the bath was removed and the reaction was stirred at
ambient temperature for 12 to 72 h. In cases with sluggish reactants, the
solution was slowly concentrated to afford a heavy oil, which was further
stirred until TLC or HPLC analysis revealed complete consumption of the
R-amino aldehyde component. The resultant slurry was dissolved in ethyl
acetate and extracted successively with three portions each of 1 N HCl, a
saturated NaHCO3 solution, and brine. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated. The crude product was either
recrystallized or purified by flash column chromatography on silica gel using
ethyl acetate/hexane or dichloromethane/methanol gradient systems. Pure
products were obtained as either nearly colorless solids or as colorless to
pale yellow viscous oils.
(25) 1H NMR and 13C NMR data for bestatin 2 was in full agreement
with literature values4b and matched an authentic commercial sample
(Sigma). Chiral HPLC: tR ) 14.0 min (Chiracel AD column; 2-propanol,
hexane 10-30% gradient; 0.5 mL/min flow rate).
(24) Levy, O. E.; Nguyen, K.; Owens, T. D.; Semple, J. E. 16th American
Peptide Symposium, Minneapolis, MN, June 26-July 1, 1999; P.6653.
Org. Lett., Vol. 2, No. 18, 2000
2771

Scheme 2a
Scheme 4a
a Reagents and conditions: (a) BH3‚THF, 0 °C to rt, 84%; (b)
Pyr‚SO3, Et3N, DMSO, CH2Cl2, ∼5 °C to rt, ∼quant.; (c)
CH3CO2CHO, Et3N, 0 °C to rt, 98%; (d) Cl3CO2CCl, NMM,
CH2Cl2, -40 to -15 °C, 86%; (e) 12, TFA, pyridine, CH2Cl2, 0
°C to rt, 65%; (f) H2, Pd/C; (g) HPLC separation, 29% for two
steps.
a Reagents and conditions: (a) CNCH2CO2Et, TFA, pyridine,
CH2Cl2, 0 °C to rt, 38%, (see Table 1); (b) HCl, EtOH, 0 °C, 10
min, ∼quant.; (c) (S)-2-oxo-3-(BnSO2-amino)piperidine-1-acetic
acid 15, EDC, HOBt, DIEA, CH3CN, rt, 68%; (d) H2, Pd/C, HOAc,
EtOH, H2O, 40 psi, ∼quant.; (e) DMSO, EDC, Cl2CHCO2H,
toluene, 0 °C to rt; (f) RP-HPLC, 61%.
Selected tert-butyl amide intermediates serve as precursors
for the preparation of norstatine derivatives (Scheme 3). The
technology as the key step. In this concise approach, N-R-
Boc-argininal 1426 was reacted with ethyl isocyanoacetate
and TFA, employing pyridine as base, and produced the
adduct 7g as a ca. 1:1 mixture of R-hydroxy diastereomers.
Our previous route to this intermediate proceeded in seven
steps from 14 via a classical cyanohydrin homologation-
peptide coupling protocol.5,7 Cleavage of the Boc group to
generate the corresponding amino alcohol was followed by
coupling with lactam acetic acid derivative 1526 and delivered
the advanced intermediate 16. Hydrogenolysis, followed by
Moffatt oxidation and RP-HPLC purification, provided the
R-ketoamide target 17 in good overall yield and with the
indicated chirality.
Scheme 3a
a Reagents and conditions: (a) 6 N HCl, 70 °C to reflux; (b)
Boc2O, Na2CO3, H2O; NaHSO4, H2O.
In conclusion, the Passerini reaction of R-amino aldehydes
6, isonitriles 10, and TFA in the presence of pyridine-type
bases proceeds under mild conditions and provides a concise
route to R-hydroxy-â-amino amide derivatives 7a-y. Hy-
drolysis of representative adducts afforded the corresponding
R-hydroxy-â-amino acids 8a-c. Both classes serve as useful
advanced intermediates for the synthesis of biologically
active molecules. We envision broad applications of this new
technology to R-hydroxy-â-amino amides, R-hydroxy-â-
amino acid derivatives, peptidyl and peptidomimetic R-ke-
toamide protease inhibitors, and natural products featuring
R-ketoamide moieties.27
appropriate tert-butylamide precursors 7a-c were obtained
in 46-92% yields as described above (Table 1). Interestingly,
Passerini adduct 7b was obtained in 71% or 24% yield with
added 2,4,6-collidine or pyridine, respectively, underscoring
the importance of judicious base selection. Hydrolysis
followed by N-â-reprotection with Boc2O to facilitate product
isolation and purification afforded the R-hydroxy-N-â-Boc-
amino acid derivatives 8a-c in the listed quantities and in
satisfactory overall yields.
Scheme 4 outlines the synthesis of the novel, potent
R-ketoargininamide thrombin inhibitor 17 using our new
(26) Semple, J. E.; Rowley, D. C.; Brunck, T. K.; Ha-Uong, T.; Minami,
N. K.; Owens, T. D.; Tamura, S. Y.; Goldman, E. A.; Siev, D. V.; Ardecky,
R. J.; Carpenter, S. H.; Ge, Y.; Richard, B. M.; Nolan, T. G.; Håkanson,
K.; Tulinsky, A.; Nutt, R. F.; Ripka, W. C. J. Med. Chem. 1996, 39, 4531.
(27) After this paper was submitted, we became aware of a recent related
publication: Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985.
Acknowledgment. The authors thank Ruth F. Nutt,
Terence K. Brunck, and Susan Y. Tamura for stimulating
discussions in this area.
OL0061485
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Org. Lett., Vol. 2, No. 18, 2000