Elucidation of the active conformation of cinchona alkaloid catalyst and chemical mechanism of alcoholysis of meso anhydrides

Article abstract of DOI:10.1073/pnas.1004439107

Complementary to enantioselective transformations of planar functionalities, catalytic desymmetrization of meso compounds is another fundamentally important strategy for asymmetric synthesis. However, experimentally established stereochemical models on how a chiral catalyst discriminates between two enantiotopic functional groups in the desymmetrization of a meso substrate are particularly lacking. This article describes our endeavor to elucidate the chemical mechanism and characterization of the active conformation of the cinchona alkaloid-derived catalyst for a desymmetrization of meso cyclic anhydrides via asymmetric alcoholysis. First, our kinetic studies indicate that the cinchona alkaloid-catalyzed alcoholysis proceeds by a general base catalysis mechanism. Furthermore, the active conformer of the cinchona alkaloid-derived catalyst DHQD-PHN was clarified by catalyst conformation studies with a designed, rigid cinchona alkaloid derivative as a probe. These key mechanistic insights enabled us to construct a stereochemical model to rationalize how DHQD-PHN differentiates the two enantiotopic carbonyl groups in the transition state of the asymmetric alcoholysis of meso cyclic anhydrides. This model not only is consistent with the sense of asymmetric induction of the asymmetric alcoholysis but also provides a rationale on how the catalyst tolerates a broad range of cyclic anhydrides. These mechanistic insights further guided us to develop a novel practical catalyst for the enantioselective alcoholysis of meso cyclic anhydrides.

Full text of DOI:10.1073/pnas.1004439107

Elucidation of the active conformation of cinchona
alkaloid catalyst and chemical mechanism
of alcoholysis of meso anhydrides
Hongming Li, Xiaofeng Liu, Fanghui Wu, Liang Tang, and Li Deng1
Department of Chemistry, Brandeis University, Waltham, MA 02454-9110
Edited by Eric N Jacobsen, Harvard University, Cambridge, MA, and approved May 24, 2010 (received for review April 6, 2010)
2
*
Complementary to enantioselective transformations of planar
functionalities, catalytic desymmetrization of meso compounds
is another fundamentally important strategy for asymmetric synth-
esis. However, experimentally established stereochemical models
on how a chiral catalyst discriminates between two enantiotopic
functional groups in the desymmetrization of a meso substrate
are particularly lacking. This article describes our endeavor to
elucidate the chemical mechanism and characterization of the
active conformation of the cinchona alkaloid-derived catalyst for
a desymmetrization of meso cyclic anhydrides via asymmetric
alcoholysis. First, our kinetic studies indicate that the cinchona
alkaloid-catalyzed alcoholysis proceeds by a general base catalysis
mechanism. Furthermore, the active conformer of the cinchona
alkaloid-derived catalyst DHQD-PHN was clarified by catalyst con-
formation studies with a designed, rigid cinchona alkaloid deriva-
tive as a probe. These key mechanistic insights enabled us to
construct a stereochemical model to rationalize how DHQD-PHN
differentiates the two enantiotopic carbonyl groups in the transi-
tion state of the asymmetric alcoholysis of meso cyclic anhydrides.
This model not only is consistent with the sense of asymmetric in-
duction of the asymmetric alcoholysis but also provides a rationale
on how the catalyst tolerates a broad range of cyclic anhydrides.
These mechanistic insights further guided us to develop a novel
practical catalyst for the enantioselective alcoholysis of meso cyclic
anhydrides.
R3N
MeOH
O
O
O
O
Me
O
R
R
+
R
R
R
R
*
*
*
O HNR3
OMe
R3N (10 mol%)
OH
H
8
R3N
O
OMe
MeOH
O
10
O
1
O
1
1a
, R=Me)
(
2
2a
, R=Me)
(
R
R
O
O
9
*
R3N
H O
Me
Scheme 1. General base catalysis mechanism
enantiomeric excess (ee), respectively. This enantioselective alco-
holysis was found to display a first-order dependence on anhy-
dride 1a as well as a first-order dependence on either mono
cinchona alkaloid DHQD-PHN (3) or bis cinchona alkaloid
ðDHQDÞ2AQN (4). The reaction first showed a first-order de-
pendence on methanol, which turned to a zero-order dependence
as an excess amount of methanol was employed. These kinetic
results are consistent with a general base catalysis mechanism
(Scheme 1) in which the cinchona alkaloid first forms an amineal-
cohol hydrogen-bonding complex (8). The alcohol, associated
with and activated by the chiral amine, reacts selectively with
one of the enantiotopic carbonyl groups of 1a. The same first-
order dependence, similar reaction rate, and comparably high en-
antioselectivity displayed by mono cinchona alkaloid 3 and bis
cinchona alkaloid 4, respectively, indicate that one dihydroquini-
dyl group is sufficient to activate methanol as a nucleophile for
the enantioselective alcoholysis as a hydrogen-bonding acceptor.
Next we turned our attention to the characterization of the ac-
tive conformer of DHQD-PHN (3) in the transition state. This
task was particularly challenging because cinchona alkaloids such
as 3 possess considerable conformational flexibility resulting from
rotation around both the C8-C9 and the C40-C9 bonds. Extensive
conformational studies on dihydroquinidine and its derivatives by
Wynberg and coworkers identified four minimum energy confor-
mers: 11 (app-closed), 12 (app-open), 13 (gauche-open), 14
(gauche-closed) (Fig. 2) (11–13). Our NMR studies indicate that
DHQD-PHN (3) in toluene readily adopts all these low energy
conformations (SI Appendix), although Sharpless and coworkers
reported a solid state structure of 3 as determined by X-ray crys-
tallography in which 3 was found to adopt a gauche-open confor-
mation (14).
cinchona alkoloid ∣ desymmetrization ∣ organocatalysis ∣
general base catalysis ∣ hydrogen bonding
omplementary to enantioselective transformations of planar
C
functionalities, catalytic desymmetrization of meso com-
pounds is another fundamentally important strategy for asym-
metric synthesis (1–5). However, our understanding of how a
chiral catalyst discriminates between two enantiotopic functional
groups in a meso substrate at the molecular level is particularly
lacking. Our group reported a desymmetric alcoholysis of a wide
range of meso cyclic anhydrides with modified cinchona alkaloids
to generate highly enantiomerically enriched hemiesters (5–10).
Thus, we have initiated mechanistic studies to investigate how the
modified cinchona alkaloids are able to efficiently differentiate
the two enantiotopic carbonyl groups while tolerating variations
of the substituents of the anhydrides. Herein we describe the ex-
perimental results that have enabled us to construct a transition
state model to answer these mechanistic questions and to develop
a practical catalyst guided by insights gained from our mechan-
istic studies.
Results and Discussion
In order to shed light on the origin of the catalytic activity on the
enantioselective alcoholysis of meso cyclic anhydrides, we carried
out kinetic studies on the methanolysis of cis-2,3-dimethyl succi-
nic anhydride (1a) (SI Appendix). Upon treatment with the mono
cinchona alkaloid DHQD-PHN (3) and the bis cinchona alkaloid
ðDHQDÞ AQN (4) in diethyl ether at room temperature, metha-
nolysis of2anhydride 1a furnished hemiester 2a in 91% and 93%
Author contributions: L.D. designed research; H.L., X.L., F.W., and L.T. performed research;
and L.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
To whom correspondence should be addressed. E-mail: deng@brandeis.edu.
This article contains supporting information online at www.pnas.org/lookup/suppl/
doi:10.1073/pnas.1004439107/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1004439107
PNAS ∣ November 30, 2010 ∣ vol. 107 ∣ no. 48 ∣ 20625–20629

R
N
DHQD
8
OR
H9
O
H8
N
OR
H9
N
H9
H8
N
N
H9
H9
O
N
N
OR
OR
H8
4'
N
H8
MeO
9
MeO
O
OMe
H
H
OMe
H518 H8
Ha
O
N
H1
N
N
R=OMe,DHQD
R=H, DHCN
DHQD-PHN 3
app-closed (11)
app-open (12)
N
MeO
7
OMe
N
N
H9
H8
RO
N
H9
N
N
DHQD
O
DHQD
O
RO
DHCN
N
RO
N
N
H9
H8
RO
N
H8
H9
OMe
H8
N
O
OMe
gauche-closed (14)
(R = H, Ac, or 9-phenanthryl)
gauche-open (13)
H
6
5
DHCN-PHN
(DHQD)2AQN 4
OMe
Fig. 2. Four minimum energy conformations of DHQD and its derivatives.
Fig. 1. Structure of cinchona alkaloids.
intermediate 16 in 77% overall yield. Treatment of 16 with
NaSEt furnished the corresponding 6′-OH derivative, which
was converted to the cinchona alkaloid-diborane complex 17.
The complex 17 was subjected to sequential alkylation of the
6′-OH and allylation of primary alcohol to generate the diene
precursor 19. Ring-closing metathesis of diene 19 with Grubbs
(I) catalyst accomplished the key task of forming the 21-mem-
bered macrocyclic ring. Hydrolysis of the bisborane complex af-
forded the desired rigid catalyst 7. An extensive 1H NMR analysis
of 7 confirmed that it provided a mimicry of a cinchona alkaloid
locked in an app-closed conformation (SI Appendix). To our
delight, under identical reaction conditions, methanolysis of 1a
with 7 proceeded with similarly high enantioselectivity as that
with DHQD-PHN (3) (93% ee for 7 vs. 96% ee for 3). This result
demonstrates unambiguously that a cinchona alkaloid in the
app-closed conformation is able to promote a highly enantiose-
lective alcoholysis, which provides strong experimental evidence
supporting that DHQD-PHN (3) adopts the app-closed confor-
mation as the active conformation when mediating the highly
enantioselective methanolysis of meso anhydride 1a. It is note-
worthy that this conclusion emerging from our studies was impli-
cated neither by X-ray crystallographic nor by NMR studies of
Conformationally rigid cinchona alkaloid derivatives were
shown by Corey et al. to be powerful probes for identifying
the active conformation of cinchona alkaloids as chiral ligands
for the Sharpless asymmetric dihydroxylations of olefins (15–18).
Recently, we have also successfully applied β-isocuperidine as
a probe to elucidate the active conformation of cinchona alka-
loid-derived bifunctional organic catalysts for an asymmetric
conjugate addition of β-ketoesters to nitroalkenes (19). Accord-
ingly, we examined the methanolysis of 1a with a rigid cinchona
alkaloid 6 (Fig. 1) (20), which was designed to mimic a cinchona
alkaloid that is locked in a gauche conformation (open and
closed). The 6-catalyzed methanolysis of 1a, compared to that
catalyzed by DHQD-PHN (3), proceeded with a drastically
reduced enantioselectivity (20% ee vs. 96% ee at −20 °C).
This result prompted us to design and synthesize a previously
undescribed cinchona alkaloid derivative 7 (Fig. 1) and to
investigate its ability to promote the enantioselective alcoholysis.
To our knowledge, 7 represents a unique mimicry for a cinchona
alkaloid derivative locked in an app conformation. As shown in
Scheme 2 our synthesis of 7 began with the preparation of QD-
PHN (15) from quinidine. A three-step sequence of hydrobora-
tion-oxidation-hydrolysis transformed QD-PHN (15) to alcohol
N
2) BH3 (3.5 eq) in THF,then
H2O2, LiOHaq; 65 °C. 55%
N
N
HO
1) NaH, I-PHN, CuI
OH
OPHN
OPHN
66%
3) Acetone/Formaline/1N HCl.
77%
MeO
MeO
MeO
PHN:
N
N
N
QD
15
16
4) NaSEt, DMF, 110 °C;
5) BH3 (4.0 eq.) in THF;
N
H3B
N
H3B
HO
HO
8) AllylCl, NaH, DMF
52%
6) Cs2CO3, 7-bromo-1-heptene;
OPHN
OPHN
HO
7) LiOHaq/THF,65 °C.
45% over 4 steps
O
5
N
BH3
N
18
17
N
BH3
N
H9
O
NOE
O
O
9) Grubbs (I) (30 mol%),
1mM in DCM. 11%
H18
H8
O
H5
O
O
H1
10) Acetone/Formaline/1N
HCl. 34%
Ha
N
N
19
7
Scheme 2. Synthesis of rigid catalyst 7
20626
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www.pnas.org/cgi/doi/10.1073/pnas.1004439107
Li et al.

O
O
O
N
H9
Me
Me
N
H9
Me
Me
3
(10 mol%)
OH
Me
6'
O
Me
O
MeOH (10 eq.)
-20ºC.
OMe
H H8
H H8
O
O
O
O
O
O
1a
Me
Ha
2a
(96% ee)
Ha
Me
N
N
A
B
O
N
H9
N
H9
N
H9
Me
Me
O
Me
Me
Me
Me
6'
Me
O
O
H H8
H H8
H H8
6'
O
6'
O
O
O
O
O
O
O
O
O
O
O
Ha
Me
Ha
Ha
Me
O
Me
Me
Me
N
O
N
N
T2
T3
T1
Scheme 3. Transition state model for 3 catalyzed asymmetric alcoholysis
ground state conformations of 3.
with either the substituent of the alcohol (as shown in T2) or
the C60-OMe group of the cinchona alkaloid 3 (as shown in T3).
This stereochemical model that emerged from our mechanistic
studies is consistent with the sense of asymmetric induction as
determined by analysis of absolute configurations of the hemie-
sters obtained from the cinchona alkaloid-promoted alcoholysis
(6). Moreover, the insensitivity of catalytic enantioselectivity to-
ward variations of the substituents of the meso cyclic anhydrides
can be easily rationalized, as in T1 the substituents of the anhy-
drides are located in an open space where variations of their ster-
ic and electronic properties are well-tolerated by the cinchona
alkaloid catalyst 3.
Nonintuitive predictions can also be made according to this
model: (i) The enantioselectivity of the alcoholysis is expected
to decrease significantly if the C60-OMe is removed from
DHQD-PHN (3) [i.e., using DHCN-PHN (5) as the catalyst].
(ii) Due to steric hindrance, 3-catalyzed alcoholysis with a sec-
ondary alcohol would be dramatically slower than those with pri-
mary alcohols. Importantly, these hypotheses have been verified
by experimental results (Table 1).
This model also suggests that the presence of the sterically
bulky phenanthryl group in DHQD-PHN may enforce an app
conformation for 3; the steric interaction between the bulky
C9-subsituent and the quinuclidinyl group is minimized when
the cinchona alkaloid adopts the app-closed conformation
(11), whereas it is significantly increased when the cinchona
alkaloid adopts the gauche conformations (13 and 14). Following
this line of analysis, we began to explore modified cinchona
alkaloids bearing a bulky substituent at C9 with the goal of devel-
oping a more practical catalyst. Subsequently, we found that
cinchona alkaloid QD-MN (21) that could be easily prepared
in multigram quantity by a two-step route in 60% overall yield
On the basis of this insight into the active conformer of
DHQD-PHN (3) and results from our kinetic studies as described
above, we were able to formulate a transition state model for 3-
catalyzed desymmetric alcoholysis of 1a. As illustrated in
Scheme 3, in the hydrogen-bonding complex between the alcohol
and DHQD-PHN (3) adopting an app-closed conformation, the
substituent of the alcohol is postulated to point away from the
C60-methoxy group of the quinoline ring of 3 in order to avoid
a steric interaction between them (A vs. B). Thus, as shown in
A, the activated alcohol is shielded on three sides by the quinoline
ring, C60-OMe group and the substituent (methyl) of the alcohol.
When anhydride 1a approaches the activated alcohol via the
open corner, the steric repulsion between 1a and the alcohol-
amine complex is minimized when the two methyl groups of
1a are pointing away from the alcohol-amine complex as illu-
strated in T1. In this transition state (T1), the activated alcohol
is able to attack the top carbonyl group (pro-S) in 1a via the
stereoelectronically preferred Dunitz–Burgi angle (21). On the
other hand, such an alignment between the activated alcohol
and the bottom pro-R carbonyl group is not attainable. Thus
the alcoholysis of 1a occurs preferentially with the pro-S carbonyl
group. Alternative transition state assemblies (T2 and T3) could
be conceived in which the anhydride 1a is rotated in various ways
to allow the pro-R carbonyl group to be aligned with the activated
alcohol for the nucleophilic attack via the Dunitz–Burgi angle.
However, compared to T1, they are disfavored because the sub-
stituents of anhydride 1a engage in repulsive steric interactions
Table 1. Asymmetric alcoholysis of succinic anhydride 1a
OMe
N
O
Me
Me
Me
Me
COOH
COOR
Cat. (10 mol%)
OPHN
OPHN
O
N
ROH (10 eq.),
Et2O (0.02 M),
r.t
N
O
H
H
N
2a
1a
5
3
O
OMe
Quinidine, NaH, DMF,
CICH COCI, Pyridine
2
O
O CCH CI
OH
Et O, 0°C to RT
2
0°C to RT
O
2
2
60% over 2 steps
entry
cat.
ROH
t∕h
conv:∕%
ee∕%
N
20
(-)-Menthol
H
N
1
2
3
DHQD-PHN(3)
DHCN-PHN(5)
DHQD-PHN(3)
MeOH
MeOH
Pri OH
2
2
12
77
49
<5
92
70
—
QD-MN (21)
Scheme 4. Preparation of QD-MN (21)
Li et al.
PNAS
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∣
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∣
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20627

Table 2. Asymmetric alcoholysis of cyclic anhydrides 1 with QD-MN and ðDHQDÞ2AQN*
O
O
R
R
R
10 eq. R'OH, Catalyst, Et2O
Anhydride Conc. 0.02 mmol
OH
OR'
O
R
O
O
1
2
†
‡
Entry
Substrate
Catalyst (mol%)
Alcohol (10 eq.)
Temp (°C)
Time
Yield
ee
O
1
2
3
4
QD-MN (10%)
ðDHQDÞ2AQN (5%)
QD-MN (10%)
ðDHQDÞ2 AQN (5%)
CF3CH2OH
CF3CH2OH
MeOH
RT
RT
RT
RT
5 h
9 h
9 h
5 h
91%
90%
90%
89%
94%
90%
90%
94%
O
MeOH
O
1a
1b
1c
O
5
6
7
8
QD-MN (14%)
ðDHQDÞ2AQN (7%)
QD-MN (14%)
ðDHQDÞ2AQN (7%)
CF3CH2OH
CF3CH2OH
MeOH
RT
RT
RT
RT
6 h
5 h
8 h
6 h
93%
96%
91%
92%
95%
91%
90%
94%
O
MeOH
O
O
9
QD-MN (10%)
ðDHQDÞ2AQN (5%)
QD-MN (10%)
ðDHQDÞ2AQN (5%)
CF3CH2OH2
CF3CH2OH
MeOH
RT
RT
RT
RT
7 h
7 h
8 h
4 h
96%
95%
94%
95%
94%
89%
87%
93%
10
11
12
O
MeOH
O
O
13
14
QD-MN (20%)
ðDHQDÞ2AQN (10%)
MeOH
MeOH
RT
RT
36 h
12 h
88%
90%
90%
88%
O
O
1d
O
O
15
16
QD-MN (30%)
MeOH
MeOH
−20
−20
60 h
91%
88%
95%
96%
O
ðDHQDÞ2AQN (15%)
120 h
O
O
1e
O
QD-MN (40%)
ðDHQDÞ2AQN (20%)
17
18
MeOH
MeOH
−20
−20
48 h
96 h
87%
74%
92%
92%
O
O
1f
*The reaction was carried out with 1 (0.02 M in diethyl ether) and R’OH [10 equivalent (eq.)] in the presence of catalyst.
†Conversion was determined by 1H NMR.
‡See the SI Appendix for the determination of the ee value.
from cheap starting materials such as menthol, α-chloroacetyl
development of a new modified cinchona alkaloid, QD-MN 21,
as a more practical catalyst for the enantioselective alcoholysis of
meso anhydrides.
chloride and quinidine (Scheme 4), matches the catalytic effi-
ciency of DHQD-PHN (3) and ðDHQDÞ2AQN (4) for the de-
symmetrization of a wide range of meso anhydrides (Table 2).
In summary, kinetic studies and catalyst conformational stu-
dies employing a designed rigid cinchona alkaloid derivative as
a probe allowed us to determine the origin of catalytic activity
and identify and the active conformer of the cinchona alkaloid
catalyst for the highly enantioselective alcoholysis. These key me-
chanistic insights allowed us to formulate a transition state model
that clarifies the molecular origin of the highly efficient recogni-
tion of enantiotopic carbonyl groups of the meso anhydride by
the modified cinchona alkaloid. This model is consistent with
the observed sense of asymmetric induction and provides a ratio-
nale for the broad scope of the asymmetric alcoholysis established
from previous studies. These mechanistic insights also guided our
Materials and Methods
Dry methanol or 2,2,2-trifluoroethanol (3.0 mmol) was added in one portion
to a stirred solution of anhydride (0.3 mmol) and QD-MN (10–40 mol%) or
ðDHQDÞ2AQN (5–7 mol%) in diethyl ether (15.0 mL) at the temperature
indicated in Table 2. The reaction mixture was stirred at that temperature
and the conversion of the starting material was determined by 1H NMR ana-
lysis. The ee of each product was determined by GC analysis of the products
or by HPLC analysis of a diastereoisomeric mixture of the corresponding
amide-ester prepared from the hemiester.
ACKNOWLEDGMENTS. This work is dedicated to Professor Lixing Dai with
deepest admiration and best wishes. We are grateful for financial support
from the National Institutes of Health (GM-61591).
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