Allylic C-H amination for the preparation of syn-1,3-amino alcohol motifs

Article abstract of DOI:10.1021/ja9054959

A highly selective and general Pd/sulfoxide-catalyzed allylic C-H amination reaction en route to syn-1,3-amino alcohol motifs is reported. Key to achieving this reactivity under mild conditions is the use of electron-deficient N-nosyl carbamate nucleophil

Full text of DOI:10.1021/ja9054959

Published on Web 07/31/2009
Allylic C-H Amination for the Preparation of syn-1,3-Amino
Alcohol Motifs
Grant T. Rice and M. Christina White*
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received July 3, 2009; E-mail: white@scs.uiuc.edu
Abstract: A highly selective and general Pd/sulfoxide-catalyzed allylic C-H amination reaction en route
to syn-1,3-amino alcohol motifs is reported. Key to achieving this reactivity under mild conditions is
the use of electron-deficient N-nosyl carbamate nucleophiles that are thought to promote functional-
ization by furnishing higher concentrations of anionic species in situ. The reaction is shown to be
orthogonal to classical C-C bond-forming/-reduction sequences as well as nitrene-based C-H
amination methods.
Introduction
and demonstrated their strategic use in streamlining complex
molecule synthesis.9 Notably, our group recently reported an
A diverse range of natural products and pharmaceuticals include
syn-1,3-amino alcohols as dominant motifs. Important advances
have been made in asymmetric C-C and C-N bond-forming
reactions to generate ꢀ-amino ketones and ꢀ-hydroxy imines.1,2
Complementary methods that furnish 1,3-amino alcohols with
minimal oxidation-state manipulations would provide strategic
advantages in streamlining their syntheses. Although metal nitrene
systems for aliphatic C-H aminations provide direct routes for
accessing syn-1,3-amino alcohols,3 analogous allylic C-H ami-
nations face challenges in chemoselectivity and/or reactivity,
particularly with terminal olefins.3b,c,4 Such reactions would be
highly valuable in synthetic planning due to the latent functionality
preserved in the unsaturated moiety (Vide infra). We have recently
discovered Pd(II)/sulfoxide catalyst systems that effect predictably
selective allylic C-H esterifications,5 alkylations,6 and aminations,7,8
intramolecular allylic C-H amination reaction of homoallylic
N-tosyl carbamates to generate 5-membered vinyl oxazolidinones
en route to syn-1,2-amino alcohol motifs.7 We now report that the
use of a more electron-deficient N-nosyl carbamate nucleophile
enables a mild Pd(II)/sulfoxide-catalyzed allylic C-H amination
reaction with extraordinary chemoselectivities that furnishes vinyl
syn-1,3-amino alcohol precursors from terminal olefins.
Results and Discussion
(1) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) Wenzel, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. (c) Kochi, T.;
Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003, 125, 11276. (d)
Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki,
M. J. Am. Chem. Soc. 2004, 126, 8777. (e) Josephsohn, N. S.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734. (f) Enders,
D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed. 2005,
44, 4079.
Design Principles. Mechanistic studies indicated that intramo-
lecular allylic C-H amination to form 5-membered vinyl
oxazolidinones proceeds Via Pd(II)/sulfoxide-mediated hetero-
(5) Linear allylic C-H acetoxylation: (a) Chen, M. S.; White, M. C. J. Am.
Chem. Soc. 2004, 126, 1346. Branched allylic C-H esterification: (b)
Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am.
Chem. Soc. 2005, 127, 6970. Oxidative C-H macrolactonization. (c)
Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 9032. For a linear allylic acetoxylation reaction
using DMA solvent see: (d) Mistudome, T.; Umetani, T.; Nosaka,
N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem.,
Int. Ed. 2006, 45, 481.
(2) For some recent examples of asymmetric conjugate addition reactions
with nitrogen nucleophiles to furnish ꢀ-amino ketones see: (a) Myers,
J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959. (b) Guerin,
D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134. (c) Sibi, M. P.;
Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem. Soc.
2003, 125, 11796. (d) Yamigawa, N.; Qin, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13419. (e) Chen, Y. K.;
Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
9328.
(6) Linear allylic C-H alkylation: (a) Young, A. J.; White, M. C. J. Am.
Chem. Soc. 2008, 130, 14090. (b) For a system that also uses Pd(II)/
bis-sulfoxide catalysis see: Lin, S.; Song, C.-X.; Cai, G.-X.; Wang,
W.-H.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 12901.
(3) (a) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935. (b) Fiori, K. W.; Fleming, J. J.; Du Bois, J.
Angew. Chem., Int. Ed. 2004, 43, 4349. A sulfamate product analogous
to 4 was generated Via a chemoselective Rh-nitrene-based reaction in
43% yield: (c) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008,
130, 9220. (d) Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem.,
Int. Ed. 2008, 47, 6825. (e) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.;
Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465.
(4) Interestingly, high chemoselectivities and reactivities have been
reported for intermolecular Rh-nitrene allylic aminations of internal
olefins: Liang, C.; Collet, F.; Robert-Peillard, F.; Mu¨ller, P.; Dodd,
R. H.; Dauban, P. J. Am. Chem. Soc. 2008, 130, 343.
(7) Intramolecular allylic C-H amination to furnish 1,2-amino alcohol
motifs: Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007,
129, 7274.
(8) Intermolecular allylic C-H amination to furnish linear (E)-allylic
amines using N-(methoxycarbonyl)-p-toluenesulfonamide nucleophile: (a)
Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316. (b)
Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem. Soc. 2009.
In press, doi: /10.1021/ja903939k. For a similar system using DMA
solvent see: (c) Liu, G.; Yin, G.; Wu, L. Angew. Chem., Int. Ed. 2008,
47, 4733.
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A R T I C L E S
Rice and White
N-(4-nitrophenylsulfonyl) carbamate group afforded a dra-
matic positive impact on the reaction rate (72 h f 24 h) and
yield (15% f 67%) of 6-membered ring formation (entry
3).15 Interestingly, evaluation of the even more acidic N-(2-
nitrophenylsulfonyl) carbamate group afforded no further
improvement, suggesting that decreasing the electron density
of a nitrogen pro-nucleophile to increase anion concentration
must be balanced with decreasing its nucleophilicity (entry
4). Additional reaction exploration showed that a switch in
the solvent from THF to DCE and the inclusion of additives
16a
known to promote Pd(0) oxidation (e.g., O2
and p-
nitrobenzoic acid16b,c) furnished the syn-oxazinanone in good
yield and diastereoselectivity (entry 5).
Table 1. Allylic C-H Amination Reaction Optimization
Figure 1. Design principles for intramolecular C-H amination.
lytic allylic C-H cleavage to generate a π-allyl Pd(OAc)
intermediate A (Figure 1A).7 Intramolecular functionalization
with the acidic N-tosyl carbamate pro-nucleophile B is ef-
fectively promoted by palladium carboxylate counterion acting
as a base (Figure 1B). This catalytic source of weak base is
regenerated during oxidation of Pd(0) with quinone (Figure 1C).
However, attempts to promote allylic C-H amination to form
a 6-membered oxazinanone with this nucleophile under identical
conditions gave poor yields and conversions even after 72 h
(Table 1, entry 1, 75% recovered starting material).10,11 Given
the higher kinetic barrier for 6- versus 5-membered ring
formation, we reasoned that functionalization was likely the
problematic step. Decreasing the electron density of the nitrogen
is known to assist electrophilic metal catalysis by preventing
nucleophile complexation to the metal.12 We hypothesized that
even in cases like ours where metal/nucleophile interactions are
not likely to be problematic,7,8 switching to a more electron-
poor amine might promote catalysis by increasing the equilib-
rium concentration of the active anionic species C in situ without
prohibitively decreasing its nucleophilicity (Figure 1B).13
Reaction Optimization. Consistent with the hypothesis that
increasing the pro-nucleophile’s acidity will lead to an
improvement in reactivity, examination of a series of
4-substituted N-arylsulfonyl carbamates revealed a positive
correlation between pro-nucleophile acidity and product
yields.14 By simply changing from an N-tosyl carbamate to
an N-(4-chlorophenylsulfonyl) carbamate, a doubling in yield
was achieved in one-third the reaction time [Table 1, entry
2, 15% (72 h) f 38% (24 h)]. Switching to the more acidic
a BisSO ligand ) 1,2-bis(phenylsulfinyl)ethane. b Average of two
runs. c Determined by GC analysis (R ) p-Tol) or 1H NMR (R )
p-ClPh, p-NO2Ph, o-NO2Ph) of crude reaction mixture. d Reaction run
using 10 mol % p-nitrobenzoic acid and oxygenated DCE. e Isolated
yield of major syn product, >20:1 syn:anti.
Interestingly, reactivity and selectivity in this system are
not strongly impacted by steric bulk adjacent to the carbamate
(Table 1, entries 5-7). This is in stark contrast to the allylic
C-H amination system furnishing syn-1,2-amino alcohol
motifs, where one bulky substituent adjacent to the carba-
mate (generally a branching element) was deemed important
for achieving good diastereoselectivity; a bulky quaternary
alkyl substituted carbamate, albeit proceeding with excellent
diastereoselectivity, suffered from poor reactivity (Vide in-
fra).7
(9) (a) Fraunhoffer, K. F.; Bachovchin, D. A.; White, M. C. Org. Lett.
2005, 7, 223. (b) Covell, D. J.; Vermeulen, N. A.; Labenz, N. A.;
White, M. C. Angew. Chem., Int. Ed. 2006, 45, 8217.
(10) Carbamate and N-tosyl carbamate substrates have been observed to
exclusively form 5-membered ring oxazolidinone products in nitrene-
based systems: (a) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed.
2001, 40, 598. (b) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem.
Soc. 2005, 127, 14198.
(11) The inclusion of catalytic amine base, recently discovered to promote
intermolecular allylic C-H aminations with N-tosyl carbamate nu-
cleophiles (ref 8b), gave a minor increase in yield for substrate 2a
(15% f 37%); however, the diastereoselectivity was significantly
diminished (5.1:1 f 1.8:1 syn:anti).
(14) Relative pKa values were based upon benzoic acid analogues: (a) Tao,
L.; Han, J.; Tao, F-.M. J. Phys. Chem. A 2008, 112, 775. (b) Maran,
F.; Celadon, D.; Severin, M. G.; Vianello, E. J. Am. Chem. Soc. 1991,
113, 9320.
(12) This effect has explicitly been demonstrated in the oxidative amination
of olefins Via electrophilic Pd(II) catalysis: (a) Hegedus, L. S.;
McKearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444. (b) Larock, R. C.;
Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996,
61, 3584.
(15) Heating the reaction with N-tosyl carbamate substrates to 65 °C also
promoted reactivity; however, the yields were lower, and inconsistent
results were observed.
(16) (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. Carboxylic
acids have been shown to increase reactivity in oxidative Heck
reactions mediated by Pd(II)/bis-sulfoxide, possibly Via acid-promoted
quinone reoxidation of the metal: (b) Delcamp, J. H.; White, M. C.
J. Am. Chem. Soc. 2006, 128, 15076. (c) Delcamp, J. H.; Brucks, A. P.;
White, M. C. J. Am. Chem. Soc. 2008, 130, 11270.
(13) Pd(0)-mediated allylic substitution of cyclic carbonates to carbamates
proceeds Via anionic nitrogen nucleophiles: Bando, T.; Harayama, H.;
Fukazawa, Y.; Shiro, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org.
Chem. 1994, 59, 1465.
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Allylic C-H Amination toward syn-1,3-Amino Alcohols
Table 2. Allylic C-H Amination Reaction Scope
A R T I C L E S
Scheme 1. Origin of Diastereoselectivity
a 1 (10 mol %), 1,2-bis(phenylsulfinyl)ethane (5 mol %), p-nitrobenzoic acid
(10 mol %), phenyl benzoquinone (2 equiv), oxygenated DCE (0.66 M), 45
°C, 24 h. b dr of crude reaction. c Isolated yield of major syn product.
diastereomeric ratio can be obtained in good yields after standard
column chromatography (see parenthetical yields in Table 2).
Predictable diastereomeric outcomes are crucial for C-H
functionalization methods to find use at late stages of complex
molecule synthesis. Gratifyingly, for substrates containing
multiple stereogenic centers, the diastereomeric outcome of this
reaction is controlled by the stereocenter containing the car-
bamate (Scheme 1). In substrates containing homoallylic (17,
19) or trishomoallylic (13, 14) stereogenic centers the reaction
is consistently syn-selective relative to the N-nosyl carbamate.
Streamlining Synthesis. We have previously demonstrated
the ability of predictably selective C-H amination reactions
to streamline the synthesis of nitrogen containing molecules
by “skipping” oxygenated intermediates that are burdensome
to carry through synthetic sequences.7,8 The ability of this
allylic C-H amination reaction to efficiently access optically
enriched syn-1,3-amino alcohols is highlighted in the syn-
thesis of (+)-allosedridine 25, a member of the sedum
alkaloids that have shown promising memory enhancing
properties (Scheme 2).17 Starting from commercially available
enantioenriched bis-homoallylic alcohol (+)-21, the nitrogen
is introduced at the correct oxidation state Via C-H amination
in only two steps. Major diastereomer (+)-23 was easily
isolated using standard flash column chromatography in 61%
yield with >20:1 diastereomeric purity and with no erosion
in enantiomeric excess (>99% ee). Notably, the N-nosyl group
can be easily deprotected using mild PhSH/K2CO3 conditions
to afford the free oxazinanone in 91% yield.18 Alkylation
furnished (-)-24 whose terminal olefin moieties could be
used to forge the piperdine core Via Grubbs ring-closing
metathesis (RCM).19 Hydrogenation, followed by basic
hydrolysis completed the total synthesis of (+)-allosedridine
25 in six steps and 27% overall yield. By avoiding multiple
functional group manipulations and exploiting the terminal
a Additives: p-nitrobenzoic acid (10 mol %), BisSO ligand (5 mol
%). b Reaction run in oxygenated DCE. c Isolated yield of major syn
product, >20:1 syn:anti.
Reaction Scope. Significantly, use of this more electron-
deficient nitrogen nucleophile proved to be a general solution
for the formation of a wide range of 6-membered oxazi-
nanones (Table 2). Substrates derived from secondary alco-
hols having prochiral allylic C-H bonds show good to
excellent levels of diastereoselectivity favoring the syn-1,3-
isomer (5, 7-12). The observed stereochemical outcome is
consistent with functionalization proceeding Via a chairlike
transition state.13 No conformational biasing element is
required for effecting cyclization as evidenced by efficient
generation of oxazinanone 4 (70%) derived from a primary
alcohol precursor.3c Even a substrate originating from a
sterically hindered tertiary alcohol generated syn-1,3-oxazi-
nanone 6 in good yield.
This method is orthogonal to all other current state-of-the-
art methods for generating this synthetically important motif.
The complementary nature of this method to C-C and C-N
bond-forming/-reduction sequences is highlighted by the syn-
thesis of oxazinanones 7 and 8 having reduction-sensitive
proximal ketone and ester functionalities. In contrast to nitrene-
based systems, perfect chemoselectivity is seen for allylic C-H
amination over benzylic and ethereal C-H amination (9, 10;
(+)-15 and (+)-16, Scheme 1).3 Strikingly, this allylic C-H
amination method shows unprecedented chemoselectivity for
C-H amination of terminal over internal olefins (11 and 12).
In all cases, syn-oxazinanone products of greater than 20:1
(17) Meth-Cohn, O.; Yu, C.-Y.; Lestage, P.; Lebrun, M.-C.; Cagniard, D.-
H.; Renard, P. Eur. Pat. 1050531, 2000.
(18) Fukuyama, T.; Jow, C.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373.
(19) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. For
specific reaction conditions see: (b) Anada, M.; Tanaka, M.; Washio,
T.; Yamawaki, M.; Abe, T.; Hashimoto, S. Org. Lett. 2007, 9, 4559.
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A R T I C L E S
Rice and White
Scheme 2. Total Synthesis of (+)-Allosedridinea
Table 3. 1,2-Amination Rate Increase Using N-Nosyl Carbamates
a Reagents and conditions: (a) NsNCO (1.1 equiv), THF, rt (93%);
(b) standard conditions; (c) isolated yield of major syn product; (d) PhSH
(1.2 equiv), K2CO3 (3 equiv), DMF, 0 °C, 4 h (91%); (e) n-BuLi (1.0
equiv), THF, -78 °C; but-3-enyl trifluoromethanesulfonate (1.2 equiv),
-78 °C to 0 °C, 2 h (89%); (f) Grubbs (II) (8 mol %), toluene, 65 °C,
3 h; H2, Pd-C, MeOH, rt, 2 h (80%); (g) KOH/EtOH (1.7 M), 45 °C,
2 h (73%).
olefin functionality, an allylic C-H amination route affords
the shortest and highest-yielding synthesis of (+)-25 to date.20
syn-1,2-Amino Alcohol Synthesis. Significantly, the discov-
ery that N-nosylcarbamate nucleophiles lead to improved
reactivity for intramolecular allylic C-H aminations could
be used to increase the efficiency of our previously reported
reaction for generating 1,2-amino alcohol motifs. Homoallylic
N-nosyl carbamates 26b and 26d underwent Pd(II)/sulfoxide
1-catalyzed intramolecular allylic C-H amination to furnish
anti-oxazolidinones 27b and 27d in comparable yields and
diastereoselectivities and a 3-fold decrease in reaction times
(72 h f 24 h) to those reported with the analogous N-tosyl
carbamate substrates (Table 3, entries 1, 2). In contrast to
the 1,3-amino alcohol system, however, reactivity with
sterically congested substrates such as tert-butyl 26f and
tertiary alcohol-derived carbamate 26g remained low (entries
3, 4). These results demonstrate a distinct steric limitation
for this chemistry in furnishing 5-membered oxazolidinone
rings that is not observed in generating 6-membered oxazi-
nanone rings. Gratifyingly, the allylic C-H amination
reaction for generating 1,2-amino alcohol motifs also pro-
ceeds with outstanding chemoselectivity. This is illustrated
in the preferential C-H amination of terminal over internal
olefins in the doubly homoallylic N-nosyl carbamate substrate
26h (entry 5). Interestingly, syn-oxazolidinone 27h is ob-
tained in both good yields and diastereoselectivities despite
the lack of an adjacent branching element previously deemed
to be crucial for obtaining synthetically useful diastereomeric
outcomes with this system.
a BisSO ligand ) 1,2-bis(phenylsulfinyl)ethane. b Average of two
runs. c Determined by GC analysis (R′ ) p-Tol) or 1H NMR analysis
(R′ ) p-NO2Ph) of crude reaction mixture.
aminate allylic C-H bonds of terminal olefins preferentially
to internal olefins. This feature, as well as its orthogonality
to nitrene-based C-H aminations and C-C bond-forming/-
reduction sequences, makes it a powerful reaction for 1,3-
amino alcohol synthesis. This allylic C-H amination reaction
is enabled by electronically tuning the pro-nucleophile in
order to increase the equilibrium concentration of active
anionic species under conditions that employ catalytic
amounts of a weak base. The general strategy of decreasing
the pKa of a pro-nucleophile to promote functionalization has
led to a significant rate increase for the previously reported
allylic C-H amination reaction for 1,2-amino alcohol
synthesis and has the potential for application to other
electrophilic metal-catalyzed reactions.
Experimental Procedures
General Experimental Procedures. In a one-dram vial was
added the corresponding carbamate starting material (1 equiv),
phenyl benzoquinone (2 equiv), p-nitrobenzoic acid (0.10 equiv),
1,2-bis(phenylsulfinyl)ethane (0.05 equiv), Pd(OAc)2/ 1,2-
bis(phenylsulfinyl)ethane catalyst 1 (0.10 equiv, Strem Chemicals
or Aldrich Chemical Co.), and a Teflon stir bar. In a separate
flask, O2 gas was simultaneously bubbled through 1,2-dichlo-
roethane for 30 min. The oxygenated 1,2-dichloroethane (0.66
M) was then added to the previous one-dram vial, O2 gas was
blown over the vial for 5 s, and the vial was sealed with a Teflon-
lined cap. The reaction vial was then vortexed until the solution
appeared homogeneous and stirred in a 45 °C oil bath for 24 h.
The solution was allowed to cool to room temperature and then
transferred using a minimum amount of dichloromethane to a
250-mL separatory funnel. The solution was diluted with 15 mL
of diethyl ether and rinsed with 1× 15 mL of aqueous sodium
bisulfite (sat.), 1× 15 mL of water, 1× 15 mL of 5% aqueous
Conclusion
We report herein the discovery that an electron-deficient
N-nosyl carbamate nucleophile furnishes a general Pd(II)-
sulfoxide-catalyzed allylic C-H amination reaction to gener-
ate 6-membered syn-oxazinanones under mild reaction con-
ditions. The extraordinary chemoselectivity of this method
is underscored by its demonstrated ability to selectively
(20) For previous asymmetric syntheses see: (a) Takahata, H.; Kubota, M.;
Ikota, N. J. Org. Chem. 1999, 64, 8594. (b) Passarella, D.; Barilli,
A.; Belinghieri, F.; Fassi, P.; Riva, S.; Sacchetti, A.; Silvani, A.;
Danieli, B. Tetrahedron: Asymmetry 2005, 16, 2225.
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Allylic C-H Amination toward syn-1,3-Amino Alcohols
A R T I C L E S
K2CO3/H2O, and 1× 15 mL of water. The organic layer was
collected and dried over MgSO4, filtered, and concentrated in
Vacuo. The crude reaction mixture was purified using flash
column chromatography. In general, the major syn-diastere-
omer can be isolated by flash chromatography (25-35%
gradient EtOAc/hexanes) directly from the crude reaction
mixture.
Camille Dreyfus Teacher-Scholar Award. We thank Strem Chemi-
cals and the Aldrich Chemical Co. for a gift of commercial catalyst
1, P. Gormisky for confirming 2c, and A. Hamlin for preliminary
studies towards the synthesis of (+)-25.
Supporting Information Available: Experimental procedures,
full characterization, and additional experiments. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support was provided by NIH/
NIGMS (Grant no. GM076153), and kind gifts were received from
Eli Lilly, Bristol-Myers Squibb, Pfizer, Amgen, Abbott, Boehringer
Ingelheim, Roche, the Sloan Foundation, AstraZeneca, and the
JA9054959
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