Cooperative catalysis by carbenes and Lewis acids in a highly stereoselective route to γ-lactams

Article abstract of DOI:10.1038/nchem.727

Enzymes are a continuing source of inspiration for the design of new chemical reactions that proceed with efficiency, high selectivity and minimal waste. In many biochemical processes, different catalytic species, such as Lewis acids and bases, are involved in precisely orchestrated interactions to activate reactants simultaneously or sequentially. This type of 'cooperative catalysis', in which two or more catalytic cycles operate concurrently to achieve one overall transformation, has great potential in enhancing known reactivity and driving the development of new chemical reactions with high value. In this disclosure, a cooperative N-heterocyclic carbene/Lewis acid catalytic system promotes the addition of homoenolate equivalents to hydrazones, generating highly substituted γ-lactams in moderate to good yields and with high levels of diastereo- and enantioselectivity.

Full text of DOI:10.1038/nchem.727

ARTICLES
PUBLISHED ONLINE: 18 JULY 2010 | DOI: 10.1038/NCHEM.727
Cooperative catalysis by carbenes and Lewis acids
in a highly stereoselective route to g-lactams
Dustin E. A. Raup, Benoit Cardinal-David, Dane Holte and Karl A. Scheidt
*
Enzymes are a continuing source of inspiration for the design of new chemical reactions that proceed with efficiency, high
selectivity and minimal waste. In many biochemical processes, different catalytic species, such as Lewis acids and bases,
are involved in precisely orchestrated interactions to activate reactants simultaneously or sequentially. This type of
‘cooperative catalysis’, in which two or more catalytic cycles operate concurrently to achieve one overall transformation,
has great potential in enhancing known reactivity and driving the development of new chemical reactions with high value.
In this disclosure, a cooperative N-heterocyclic carbene/Lewis acid catalytic system promotes the addition of homoenolate
equivalents to hydrazones, generating highly substituted g-lactams in moderate to good yields and with high levels of
diastereo- and enantioselectivity.
iological systems have evolved to activate substrates using acids energy of the highest occupied molecular orbital (HOMO).
and bases simultaneously within an active site. Proteases Simultaneously, an optimal Lewis acid catalyst activates the hydra-
B
achieve astounding efficiency in the hydrolysis of robust zone by lowering the energy of the lowest unoccupied molecular
amide bonds by making use of a serine or cysteine (Lewis base), orbital (LUMO) for an overall productive reaction.
an aspartic acid residue (Brønsted acid) and a histidine residue
We have been investigating new classes of electrophiles with
(Brønsted base) in concert. This catalytic triad is essential for life homoenolate equivalents generated using NHC catalysis to gain
processes, and the precise placement of these catalytic functional direct access to highly useful g-amino acid derivatives35,36 or
groups precludes non-productive interactions. In general, nature natural products37. To achieve this goal, an effective class of imine
takes advantage of enzyme architecture to facilitate a cooperative was required that could deliver highly substituted g-lactams with
reaction manifold, because many catalytic sites contain functional high levels of enantioselectivity and diastereoselectivity23,38. If suc-
groups and/or metals that would be incompatible in simple sol- cessful, this formal [3 þ 2] annulation process could, from two
ution-based chemistry. For example, the reactive thiol of an acyl simple starting materials and a small organic molecule catalyst,
transferase would bind to the active iron centre in a cytochrome if directly produce important five-membered heterocycles with
either one was removed from their protein framework. It has been known biological activity and high occurrence in the structures of
a significant challenge to capitalize on this powerful cooperative natural products. N-acyl hydrazones are well-known substrates for
concept in abiotic systems. In systems using ‘cooperative catalysis’, both Lewis acid-activated cycloadditions and nucleophilic allylation
the combination of Lewis acid and Lewis base activation can reactions39. In these processes, the hydrazone substrates presumably
achieve greater selectivity and more efficient reactivity than either undergo activation by chelation to a Lewis acid with the carbonyl
mode individually, while simultaneously avoiding any substantial oxygen and imine nitrogen atoms to form an activated electrophile
self-inhibition1–6
.
in situ. Our studies exploring the formal cycloadditions using
However, homogeneous catalytic reactions promote random col- N-benzoyl hydrazones and various unsaturated aldehydes were
lisions of all species in solution, facilitating simple acid–base chem- initiated by treating cinnamaldehyde and hydrazone 1a with a
istry or the generation of stable Lewis acid–Lewis base complexes variety of azolium salts and subjecting the mixture to a number of
that will compete with a desired catalytic reaction. Inspired by the reaction conditions. The catalyst generated from benzimidazolium
thiamine pyrophosphate cofactor7,8, N-heterocyclic carbenes 4 displayed promising reactivity during the preliminary screening,
(NHC) have emerged as unique and efficient Lewis base cata- although incomplete conversion of 1a was observed. After surveying
lysts9–11 for a host of new reactions over the last decade, including both amine and inorganic bases, the bicyclic guanidine base 1,5,7-
the generation of acyl anion equivalents12–17, homoenolate equiva- triazabicyclo[4.4.0]dec-5-ene (TBD) was found to efficiently
lents18–23, enolates24,25 and acylvinyl anion equivalents26. However, promote the formal [3 þ 2] cycloaddition. The basicity of TBD in
NHCs have not been applied cooperatively with Lewis acids to gen- tetrahydrofuran (THF) is higher (TBDHþ pKa ¼ 21.0) than diazabi-
erate new carbon–carbon bonds, presumably because these species cycloundec-7-ene (DBU) (DBUHþ pKa ¼ 16.8), which has been
act as exceptional ligands for late transition metals (Fig. 1)27–33
.
heavily used as a base in reported carbene-catalysed reactions40.
This issue has been overcome previously in the literature in a reac- With these initial conditions, we examined the impact of chiral tri-
tion using NHCs and palladium in separate catalytic cycles34.
azolium salts on the efficiency and stereoinduction of the process.
We disclose a cooperative and catalytic NHC/Lewis acid system, Although the reaction progressed with moderate selectivity using
and demonstrate its utility with the highly enantioselective addition chiral triazolium 5 (72% e.e., entry 3, Table 1), higher levels of absol-
of homoenolate equivalents to Lewis acid-activated N-benzoyl ute stereocontrol could not be obtained by lowering the tempera-
hydrazones. In this novel strategy, the NHC combines transiently ture, changing the base or using various protic additives (not
with an aldehyde to generate an unusual nucleophile, raising the shown). Additionally, the yield of the reaction dropped from 70%
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208,
USA. e-mail: scheidt@northwestern.edu
*
766
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.727
ARTICLES
Active
metal
complexes
Late transition
metals
R1
R2
NHC
+
Lewis acid
Early metals
N
N
26
27
28
29
X
12
22
Ti
Fe
Cu
Co Ni
Metathesis
C–H activation
cross-coupling
reduction
44
45
46
47
New
opportunities
Mg
N-Heterocyclic
carbene (NHC)
Ag
Ru Rh Pd
76
77
78
79
Os Ir Pt Au
(δ−)
NHC
R1
N
O
OH
Lewis base
catalysis
Raises
HOMO
H
Ph
Ph
N
X
R2
New cooperative
reactivity!
L
L
Lewis
acid
Mg
N
O
O
Lewis acid
catalysis
Lowers
LUMO
N
CO2Et
CO2Et
p-Tol
N
H
p-Tol
N
H
(δ+)
Figure 1 | Opportunities with NHCs and metals. It has been comprehensively established that NHCs react with enals to afford a new nucleophilic species
and that metal salts can activate chelating electrophiles such as N-acyl hydrazones. Can both of these processes operate in one flask to access reactivity that
is otherwise impossible/inefficient?
the ability to modulate the available electron density of the nucleo-
phile and the electrophile simultaneously in two distinct catalytic
cycles offers unique opportunities for new reaction discovery and
development (Fig. 1). After an extensive survey of early transition
Table 1 | Development of a cooperative carbene catalysis
reaction.
NHC,
Lewis acid,
base
O
O
O
H
and alkali metal salts, the use of 20 mol% magnesium di-tert-butox-
ide41 improved the reaction significantly both in terms of yield and
selectivity (entry 4). Lanthanide trifluoromethanesulfonates (tri-
flates) such as La(OSO2CF3)3 completely inhibited homoenolate
addition, even with an equivalent molar amount of base (for
example, sodium tert-butoxide) to preclude the possibility of poi-
soning by trace acid. Transition-metal triflates, such as
Cu(OSO2CF3)2 and Zn(OSO2CF3)2, were not catalysts alone, but
the addition of base allowed a very modest progression toward the
desired lactam over 24 h (10–30% conversion of hydrazone 1a).
The addition of titanium(IV) alkoxides resulted in very sluggish reac-
tions, with only 40% conversion of hydrazone 1a after 24 h.
Magnesium (II) halides or triflates did not impede the progress of
the reaction, but did not improve the results compared to exper-
iments with only NHCs. Magnesium (II) di-tert-butoxide emerged
as the optimal Lewis acid in terms of enhanced reaction rates, hydra-
zone conversion and isolated yields. In addition to optimizing the
Lewis acid component, a survey of different chiral triazolium salts
identified the 2,6-diethyl substituted azolium 7 as the superior
catalyst in terms of enantioselectivity both with and without the
Lewis acid additive (entries 6–9). The significant and beneficial
impact of this cooperative catalysis protocol becomes evident
when decreased loadings of magnesium(II) and azolium salts are
used. For example, both azolium and Mg(II) sources can be
lowered to 5 mol% without affecting the yield of the reaction or
the high levels of enantioselectivity (entry 9). Decreasing the
NHC loading without the Lewis acid has a deleterious effect on
both yield and conversion (entry 8).
p-Tol
N
p-Tol
NH
N
H
+
N
H
0.25 M THF
60°C
O
Ph
EtO2C
Ph
CO2Et
1.5 equiv. 2a
1a
3aa
Entry NHC/Lewis acid
Base
%
yield*
d.r.†
%
e.e.‡
1
20 mol% 4
20 mol% 4
20 mol% 5
1.2 equiv. DBU 58
20 mol% TBD 70
25 mol% TBD 62
6:1
12:1
—
—
2
3
4
5
6
7
8
9
6:1 72
7:1 86
7:1 80
6:1 90
7:1 97
6:1 90
7:1 97
20 mol% 5/Mg(Ot-Bu)2 25 mol% TBD 78
20 mol% 6/Mg(Ot-Bu)2 25 mol% TBD 84
20 mol% 7
20 mol% 7/Mg(Ot-Bu)2 25 mol% TBD 79
5 mol% 7
25 mol% TBD 63
10 mol% TBD 31
10 mol% TBD 78
5 mol% 7/Mg(Ot-Bu)2
N
N
DBU =
TBD =
N
N
H
N
s
Me
N+
Cl
Mes
N+
R
4
5
6
R =
N+
N
N
I–
BF4–
Ph
BF4
–
Cl
Cl
Et
N
N
N
Me
O
O
7
R =
Et
Ph
Mes = 2,4,6-Me3Ph
*Isolated yields; †Determined by 1H NMR spectroscopy; ‡Determined by high-performance liquid
chromatography (HPLC; chiral stationary phase); d.r., diastereomeric ratio; e.e., enantiomeric excess.
(entry 2) to 62% (entry 3) due to incomplete consumption of the
The proposed cooperative catalytic cycles are outlined in Fig. 2.
hydrazone, a situation that could not be remedied with a single- The azolium precatalyst is deprotonated by the base (TBD) and
catalyst approach. the resultant carbene (NHC) adds to the a,b-unsaturated aldehyde.
We hypothesized that the overall process might benefit from The deprotonation of the aldehyde proton generates the homoeno-
increasing the electrophilicity of the hydrazone substrate and thus late equivalent (enediamine intermediate II), in which the electron
undertook an investigation combining carbene catalysts with density of the heterocyclic ring can then be translated to the
Lewis acidic additives. This strategy to use nucleophilic carbenes b-carbon via the diene portion of the molecule. This nucleophilic
as Lewis base catalysts in the presence of hard, oxophilic Lewis species (II) then undergoes addition to the hydrazone, which is acti-
acids is a challenging goal with significant potential. If successful, vated by chelation to magnesium(II) (intermediate I). However, no
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767

NATURE CHEMISTRY DOI: 10.1038/NCHEM.727
ARTICLES
Ar
HN
a
δ−
R1
OH
O
L
Mg
N
R
N
L
N
R1
H
CO2Et
δ+
Addition
Association
I
II
O
R
R
Ar
O
N
NH
N
X
Catalytic
cycle 1
Catalytic
cycle 2
N
Mg
L
R
L
CO2Et
Dissociation
Acylation
NHC
O
R1
R1
N
Ar
O
N
Mg(Ot-Bu)2
O
N
H
N
N
H
X
Ar
HN
H
R
O
TBD
Azolium salt
CO2Et
EtO2C
R
140
b
120
100
80
60
40
20
0
y =0.7921x–15.208
R2 =0.9822
20
40
60
80
100
[Mg]–1 (M)
120
140
160
180
Figure 2 | Cooperative catalysis between a Lewis acid and an NHC. a, Proposed catalytic cycles 1 (Mg(Ot-Bu)2) and 2 (NHC) meeting at the critical
bond-forming step (box) b, Average kinit values plotted versus the concentration of Mg(Ot-Bu)2 to the negative first power. The experiments were performed
with 1a, cinnamaldehyde, catalyst D, TBD, phenyltrimethylsilane as an internal standard and a range of concentrations of Mg(Ot-Bu)2 in 1 ml THF-d8.
1H NMR spectroscopy (400 MHz) was used to monitor the concentration of the product (2a). The error bars represent 50% of the minimum and maximum
values for kinit calculated. (See Supplementary Information for further details.)
significant change in chemical shift of any of the hydrazone signals been successful. If this reversible magnesium–NHC interaction is
1
was observed by H nuclear magnetic resonance (NMR) upon the taking place, then it is not likely that the two catalytic species are
addition of Mg(Ot-Bu)2.) Once the key carbon–carbon bond is part of a frustrated Lewis acid–base system42. However, TBD is
formed, the NHC-catalytic cycle (cycle 2) is completed by the intra- also Lewis basic and may undergo reversible binding to the mag-
molecular acylation of the magnesium-bonded nitrogen (Mg–N) nesium, thus shifting the equilibrium between the active azolium/
with concomitant ring closure. Finally, the magnesium (II) catalyst protonated TBD and protonated azolium/free-base TBD toward
is regenerated by dissociation from the g-lactam product to restart the inactive precatalyst.
in catalytic cycle 1.
With the optimized catalysis conditions identified, a variety of
Our initial mechanistic investigations of the reactions allow for a hydrazones with modified N-aryl groups were surveyed as potential
cooperative catalysis interpretation. Preliminary kinetic studies were substrates. Mild to moderate electron-withdrawing groups on the
explored to begin elucidating the role of the Mg(Ot-Bu)2. Initial-rate aromatic ring were well tolerated (for example, para-halogen).
kinetic studies were undertaken in triplicate at five concentrations of Without 5 mol% Mg(II), less than 50% conversion was observed
the magnesium salt to determine the kinetic order of the mag- when hydrazone substrates had electron-rich aryl substituents (for
nesium. When the kinit values for each experiment were calculated example, 4-MeO–C6H5). However, in this cooperative catalysis
and plotted against the concentration of the magnesium (II) salt manifold, the yields with these substrates now regularly fall
used, the best-fit model of the kinetic data reaction indicated an between 70 and 80% (3ca, 3ha, Table 2). When varying the imine
inverse first-order relation for Mg(Ot-Bu)2 (Fig. 2b). This result portion of the substrate, glyoxylate-derived hydrazones, including
indicates one of two mechanistic possibilities for the magnesium an oxazolidinone-containing substrate (3ba), reacted efficiently,
salt. The first is that the Lewis basic NHC species is participating but hydrazones from aryl aldehydes (for example, benzaldehyde)
in reversible binding to the Lewis acidic magnesium, and the are still not electrophilic enough to undergo this annulation even
higher concentration of the magnesium salt is simply shifting the with Mg(II) activation (not shown).
equilibrium toward the magnesium-bound azolium species, for
The aldehyde scope was surveyed and a variety of functionalities
which 1H and 13C NMR spectroscopy as well as X-ray crystal struc- proved to be well tolerated. Weakly electron-withdrawing groups
ture experiments to observe and/or isolate this complex have not yet (Br, Cl) also performed well under the reaction conditions
768
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.727
Table 2 | Reaction scope.
ARTICLES
O
O
O
5 mol% 7
5 mol% Mg(Ot-Bu)2
H
Ar
N
Ar
NH
N
H
N
+
TBD
THF, 60°C, 24h
H
O
R
ROC
R
COR
1.5 equiv. 2
1
3
O
O
O
O
O
H
H
N
H
H
N
N
H
p-Tol
p-Tol
N
p-Tol
p-Tol
N
p-Tol
N
N
N
N
N
O
O
O
O
O
EtO C
EtO C
EtO C
2
EtO C
2
EtO C
2
2
2
3ad
Me
Br
Cl
74% yield
93% e.e.
8:1 d.r.
3aa
3ac
3ae
*
3ab
78% yield
97% e.e.†
9:1 d.r.‡
76% yield
96% e.e.
8:1 d.r.
71% yield
95% e.e.
9:1 d.r.
74% yield
90% e.e.
6:1 d.r.
O
O
O
H
O
O
H
N
N
H
N
N
H
N
N
H
N
N
p-Tol
p-Tol
p-Tol
N
p-Tol
p-Tol
N
Cl
O
O
O
O
O
O
EtO C
EtO C
2
EtO C
EtO C
2
EtO C
2
2
2
Me
Cl
OMe
3aj
3ah
3af
3ag
60% yield
94% e.e.
10:1 d.r.
3ai
71% yield
98% e.e.
12:1 d.r.
69% yield
98% e.e.
11:1 d.r.
70% yield
85% e.e.
8:1 d.r.
72% yield
97% e.e.
7:1 d.r.
O
O
O
O
O
O
H
H
N
N
H
N
N
H
H
p-Tol
p-Tol
N
p-Tol
N
N
N
N
N
O
O
p-Tol
O
O
O
O
N
O
EtO C
Ph
Ph
EtO C
EtO C
EtO C
2
2
2
2
O
TBDPSO
CO Me
2
3ca§
3al§
68% yield
3ba
3am
61% yield
95% e.e.
7:1 d.r.
3ak
71% yiel
97% e.e.
20:1 d.r.
97% e.e.
5:1 d.r.
65% yield
95% e.e.
5:1 d.r.
63% yield
90% e.e.
6:1 d.r.
Br
Cl
F
MeO
O
O
O
O
O
H
N
N
H
N
H
N
H
N
H
N
N
N
N
N
O
EtO C
2
O
EtO C
O
EtO C
2
O
EtO C
2
O
EtO C
Ph
Ph
Ph
Ph
Ph
2
2
3da
3ea
3fa
3ga
3ha
78% yield
96% e.e.
6:1 d.r.
81% yield
93% e.e.
5:1 d.r.
76% yield
95% e.e.
5:1 d.r.
70% yield
87% e.e.
5:1 d.r.
85% yield
88% e.e.
10:1 d.r.
*Isolated yields; †% e.e. determined by HPLC; ‡d.r. determined by 1H NMR spectroscopy; §10 mol% NHC/Mg(O-tBu)2, 15 mol% TBD.
(3ad–g). Electron-rich substrates were very well accommodated, and depression35. Various substituted prolines have been used to
including the 2-furyl-substituted enal which was problematic in impart desirable structural attributes and metabolic stability in pep-
earlier studies without the Lewis acid additive (3ah). Finally, an tides and proteins, and the enantioselective synthesis of compounds
alkyl-substituted enal gave moderate yield and excellent selectivity such as 9 should fuel further studies in this area45. Finally, these pyr-
(3aj, 3al, 3am), accommodating g-branching and even silyl rolidines also have the necessary characteristics for secondary ami-
protecting groups.
The cyclic products from this new reaction can be easily generated using this route46,47
converted into high-value pyroglutamic acid derivatives, thereby
In summary, a new formal [3 þ 2] reaction combining a,b-unsa-
ne/iminium catalysis, and new proline-derived catalysts can be
.
leveraging the utility of the overall process. For example, exposure turated aldehydes and hydrazones has been discovered using a novel
of g-lactam 3aa to Raney nickel and H2 in methanol promotes cooperative catalysis concept. The integration of two distinct cataly-
N–N bond scission in high yield (92%, Fig. 3). This 3-phenyl- tic cycles involving both Lewis basic NHCs and Lewis acidic
pyroglutamic ester (8) is a known advanced intermediate for the magnesium(II) salts facilitates the rapid and controlled production
synthesis of clausenamide, a natural product that promotes a protec- of g-lactams in high yields and with exceptional levels of diastereo-
tive effect for the liver against toxins such as carbon tetrachloride and enantioselectivity. Each mode of catalysis, both carbene and
and thioacetamide and also upregulates cytochrome P450 Lewis acid, enhances the reactivity of the nucleophilic and electro-
enzymes37,43. Alternatively, the amide of this unnatural amino philic substrates, respectively. This use of nucleophilic carbene cat-
ester can be selectively reduced to afford 3-phenyl proline deriva- alysis in cooperation with Lewis acid activation highlights an under-
tives44. These compounds are known agonists for the melanocor- explored area of catalysis with significant potential. These initial
tin-4 receptor (MC4R), a G-protein coupled receptor involved in studies demonstrate the broad potential utility and feasibility of
the regulation of appetite, and are potential treatments for anxiety combining Lewis basic carbenes with Lewis acids and should lead
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.727
ARTICLES
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N-heterocyclic carbenes. Aldrichimica Acta 42, 55–66 (2009).
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condensation. J. Org. Chem. 39, 1196–1199 (1974).
13. Stetter, H., Raemsch, R. Y. & Kuhlmann, H. The preparative use of thiazolium
salt-catalyzed acyloin and benzoin formation, i. Preparation of simple acyloins
and benzoins. Synthesis 733–735 (1976).
Me
O
O
H2
H
N
Raney Ni
HN
N
40°C
MeOH
92%
O
EtO2C
Ph
EtO2C
Ph
3aa
8
14. Breslow, R. & Schmuck, C. The mechanism of thiazolium catalysis. Tetrahedron
Lett. 37, 8241–8242 (1996).
13
steps
15. Enders, D. & Kallfass, U. An efficient nucleophilic carbene catalyst for the
asymmetric benzoin condensation. Angew. Chem. Int. Ed. 41, 1743–1745 (2002).
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19. Chan, A. & Scheidt, K. A. Conversion of a,b-unsaturated aldehydes into
saturated esters: an umpolung reaction catalyzed by nucleophilic carbenes.
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20. Sohn, S. S., Rosen, E. L. & Bode, J. W. N-heterocyclic carbene-catalyzed
generation of homoenolates: g-butyrolactones by direct annulations of enals and
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22. Chan, A. & Scheidt, K. A. Highly stereoselective formal [3 þ 3] cycloaddition of
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23. Phillips, E. M., Reynolds, T. E. & Scheidt, K. A. Highly diastereo- and
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BH3
(ref. 46)
O
(ref. 36)
Me
OH
N
HN
H
H
Ph
Ph
EtO2C
Ph
OH
Clausenamide
9
Figure 3 | N–N bond cleavage and further functionalization. The N–N bond
can be cleaved by hydrogenolysis over Raney nickel. Compound 8 can be
converted to the drug clausenamide, which is used in the treatment of viral
hepatitis in 13 steps. Reduction of the amide with borane provides access to
a variety of proline derivatives useful in protein studies as scaffolds
for organocatalysts.
to many more powerful and highly efficient bond-forming reactions
not currently available using either reagent singly. Cooperative
carbene catalysis will continue to grow and facilitate new strategies
to access important target molecules for use in chemical biology,
catalysis and medicine.
Methods
Hydrazone 1 (0.273 mmol), catalyst 7 (5 mol%) and Mg(Ot-Bu)2 (5 mol%) were
combined in a 2 dram oven-dried vial and capped with a Teflon/silicon septum
inside a nitrogen drybox. The vial was removed from the drybox and THF (0.25 M)
added, then the vial was heated with moderate stirring in an aluminium heating
block to 60 8C for 15–20 min. The white suspension turned clear and yellow over the
course of the initial heating. Unsaturated aldehyde 2 (1.5 equiv.) and then TBD
(10 mol%) were immediately added. The reaction was allowed to continue at 60 8C
and was monitored by thin layer chromatography (5% MeOH/CHCl3). Upon
completion (24 h), the reaction was diluted with CH2Cl2 (15 ml) and washed with a
1:1 mixture of saturated aqueous NH4Cl and water (10 ml). The aqueous layer was
back-extracted CH2Cl2 (2 × 15 ml) and the combined organic layers were dried over
anhydrous sodium sulfate and concentrated. The brown oily residue was purified by
flash column chromatography on a Biotage SP-1 chromatography system using a
12–100% ethyl acetate/hexanes gradient to yield the desired product 3.
25. Wadamoto, M., Phillips, E. M., Reynolds, T. E. & Scheidt, K. A. Enantioselective
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Received 24 November 2009; accepted 21 May 2010;
published online 18 July 2010
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Acknowledgements
Support for this work was generously provided by National Institute of General Medical
Sciences (RO1 GM73072), GlaxoSmithKline, AstraZeneca and the Alfred P. Sloan
Foundation. B.C.D. thanks the Fonds Quebecois de la Recherche sur la Nature et les
Technologies for a postdoctoral fellowship. Funding for the Northwestern University
Integrated Molecular Structure Education and Research Center (IMSERC) has been
furnished in part by the National Science Foundation (CHE-9871268). T. Reynolds and
J. Roberts provided X-ray crystallography support.
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to discussions and edited the manuscript.
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Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to K.A.S.
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