Chiral phosphoric acid catalyzed highly enantioselective desymmetrization of 2-substituted and 2,2-disubstituted 1,3-diols via oxidative cleavage of benzylidene acetals

Article abstract of DOI:10.1021/ja507332x

A highly enantioselective catalytic protocol for the desymmetrization of a wide variety of 2-substituted and 2,2-disubstituted 1,3-diols is reported. This reaction proceeds through the formation of an "ortho ester" intermediate via oxidation of 1,3-diol benzylidene acetal by dimethyldioxirane (DMDO) and the subsequent proton transfer catalyzed by chiral phosphoric acid (CPA). The mechanism and origins of enantioselectivity of this reaction are identified using DFT calculations. The oxidation by DMDO is rate-determining, and the phosphoric acid significantly accelerates the proton transfer; the attractive interactions between the benzylidene part of the substrate and the 2,4,6-triisopropyl group of CPA are the key to high enantioselectivity.

Full text of DOI:10.1021/ja507332x

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Communication
Chiral Phosphoric Acid Catalyzed Highly Enantioselective
Desymmetrization of 2-Substituted and 2,2-Disubstituted
1,3-Diols via Oxidative Cleavage of Benzylidene Acetals
Shan-Shui Meng, Yong Liang, Kou-Sen Cao, Lufeng Zou,
Xing-Bang Lin, Hui Yang, K. N. Houk, and Wen-hua Zheng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja507332x • Publication Date (Web): 15 Aug 2014
Downloaded from http://pubs.acs.org on August 17, 2014
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Chiral Phosphoric Acid Catalyzed Highly Enantioselective Desymme-
trization of 2-Substituted and 2,2-Disubstituted 1,3-Diols via Oxida-
tive Cleavage of Benzylidene Acetals
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Shan-Shui Meng, Yong Liang, Kou-Sen Cao, Lufeng Zou, Xing-Bang Lin, Hui Yang,
,2
,1
K. N. Houk,* and Wen-Hua Zheng*
1State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing Univer-
sity, Nanjing, 210093, China
2
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
Supporting Information Placeholder
chiral copper oxazoline complexes for desymmetrization of
2-substituted 1,2,3-triols and 2,2-disubstituted 1,3-diols with
excellent enantioselectivity. Nevertheless, the development
of new strategies to achieve highly enantioselective desym-
metrization of 2-substituted and 2,2-disubstituted 1,3-diols
under mild reaction conditions is still highly demanded.
ABSTRACT: A highly enantioselective catalytic protocol for
the desymmetrization of a wide variety of 2-substituted and
2,2-disubstituted 1,3-diols is reported. This reaction proceeds
through the formation of an “ortho ester” intermediate via
oxidation of 1,3-diol benzylidene acetal by dimethyldioxirane
8
(
DMDO) and the subsequent proton transfer catalyzed by
chiral phosphoric acid (CPA). The mechanism and origins of
enantioselectivity of this reaction are identified using DFT
calculations. The oxidation by DMDO is rate-determining,
and the phosphoric acid significantly accelerates the proton
transfer; the attractive interactions between the benzylidene
part of the substrate and the 2,4,6-triisopropyl group of CPA
are the key to high enantioselectivity.
SCHEME 1. Strategies for Catalytic Enantioselective
Desymmetrization of Diols
Enantioselective desymmetrization of meso or prochiral
compounds is one of the most powerful strategies in asym-
1
metric catalysis. In particular, the desymmetrization of diols
has captured much attention for providing access to im-
portant chiral alcohols, as well as a wide variety of valuable
2
building blocks. Over the past decades, many chiral Lewis
bases and Lewis acids have been demonstrated successfully
2
for desymmetrization of diols (Scheme 1a). However, the
successful substrates are mostly limited to meso-1,2-diols that
2,3
are secondary alcohols. Desymmetrization of 2-substituted
1
,3-diol remains a formidable challenge because of the long
4
distance of pro-stereogenic center with hydroxyl group and
the strong nucleophilicity of primary alcohols.
Benzylidene acetals are widely used in protection of diols
2,5-8
Recently,
10
in organic synthesis and can be selectively oxidized. Recent-
ly, dimethyldioxirane (DMDO) was reported as a good oxi-
intramolecular desymmetrizations of 1,3-diols were realized
using chiral transition-metal catalysts or organocatalysts
dant for selective oxidation of benzylidene acetal 1 to ester 2
9
(
Scheme 1b). Although these approaches have been shown
11
via the proposed intermediate 3 (Scheme 1c). We noted that
to give chiral cyclic compounds efficiently, a pre-installed
a proton transfer process was involved from intermediate 3
to the final product, and we postulated that this key H-
transfer could present new opportunities for asymmetric
catalysis by chiral phosphoric acids, which are demonstrated
9
functional group in the substrate is required.
For the enantioselective desymmetrization of simple 2-
substituted 1,3-diols, only a few direct approaches have been
5-8
12-15
reported. Harada and co-workers described asymmetric
to be excellent chiral proton transfer catalysts.
Herein, we
ring-opening of 1,3-dioxane using chiral boron Lewis acid
with excellent selectivity. Trost and co-workers elegantly
describe the development of this new method for highly en-
antioselective desymmetrization of 2-substituted and 2,2-
disubstituted 1,3-diols. The mechanism and origins of enan-
tioselectivity of this reaction are also revealed by density
functional theory (DFT) calculations.
6
demonstrated highly enantioselective acylation of 2-aryl-1,3-
diols and later 2-alkyl-1,3-diols with chiral dinuclear zinc
7
catalyst. More recently, Kang and co-workers have used
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TABLE 2. Substrate Scopea
We first studied the reaction of 2-phenyl-1,3-propadiol
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benzylidene acetal with DMDO
Brønsted acid (S)-4a (TRIP) (Table 1). We were excited to
find that (S)-TRIP delivered product (S)-2a with 65% ee in
66% yield (entry 1). Further catalyst screening left TRIP re-
maining as the optimal catalyst (entries 2-5). All the yields
are moderate to low, because significant amount of 2-phenyl-
16,17
in the presence of chiral
1
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1
9
1
,3-propadiol supposedly from decomposition of substrate 1a
was observed. At this point, we surmised that the electronic
and steric characters of the acetal may be crucial to the oxi-
dation step and may also affect enantioselectivity. Thus, we
investigated other substrates with different electronic and
steric effects. To our delight, substrate 1b with p-
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methoxyphenyl (PMP) gave the desired product (S)-2b in
9% yield and 95% ee (entry 6).
9
TABLE 1. Reaction Optimizationa
TABLE 3. Substrate Scopea
With the optimal conditions in hand, we next turned our
attentions to the substrate scope. In most cases, the desired
product 2 was obtained with good yield and excellent ee. As
shown in Table 2, a wide range of substrates with electron-
donating and electron-withdrawing groups at ortho-, meta-,
and para-positions of the phenyl ring were found to be suita-
ble in this reaction (2b-2j and 2m). The nature of the aro-
matic ring does not have a significant effect on enantiose-
letivity. The reactions with 1-naphthyl and 2-naphthyl sub-
stituents also led to products (2k and 2l) with high ee. In
addition, alkyl substituents, such as benzyl and tert-butyl
groups, were also tolerated in the reaction, giving the prod-
20
ucts (2n and 2o) with a bit lower ee.
SCHEME 2. Gram-Scale Reactions
Catalytic construction of chiral quaternary stereogenic
center is one of the most challenging areas in modern
21
organic synthesis. Therefore, a broad range of substrates
from 2,2-disubstituted 1,3-diols were examined (Table 3).
Gratifyingly, desired products (2p-2u) with
a
chiral
quaternary stereocenter were obtained with good yield and
19
excellent enantioselectivity. For example, product (S)-2p
containing chiral all-carbon quaternary center was
a
obtained with 91% ee in 95% yield. Particularly, oxindole
based product (2s) was generated in 93% ee, which provides
opportunity for further transformations to indoline
22
To test the practicality of this new method, gram-scale re-
actions were carried out (Scheme 2). Enantioselective
alkaloids. Product 2u with a fluoro-substituted chiral qua-
23
ternary center was obtained in excellent ee as well.
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desymmetrization of 1.0 g of 1b and 1s afforded desired prod-
aryl groups in TS2-a-S. This is the major contribution to the
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ucts 2b and 2s without notable erosion of either yield or en-
antioselectivity, demonstrating that the current method is
suitable to prepare chiral building blocks in organic synthesis.
2.0 kcal/mol preference for the formation of (S)-2b. Since the
attractive interactions between the PMP part of the substrate
and the 2,4,6-triisopropyl group of the catalyst are the key to
high enantioselectivity, we predicted that the replacement of
the PMP group by the methyl group in the substrate would
significantly lower the enantioselectivity (from 40:1 to 3.6:1
To better understand the mechanism and origins of enan-
tioselectivity of this reaction, density functional theory (DFT)
calculations were performed on the reaction of acetal 1b and
DMDO including dimethyl phosphate (Scheme 3) or chiral
o
for the S/R ratio at 0 C by DFT calculations, see the SI). This
24
was later validated by the experimental S/R ratio of 1.3:1 for
the reaction of trans-2-methyl-5-phenyl-1,3-dioxane with
DMDO in the presence of chiral phosphoric acid (S)-4a.
phosphoric acid (Figure 1). As shown in Scheme 3, the diox-
irane oxidation of the tertiary C-H bond of acetal 1b via a
diradical transition state TS1 requires an activation free ener-
gy of 17.1 kcal/mol. The formed radical pair is highly unstable
0
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and rebounds without barrier to form acetone and an “or-
tho ester” intermediate A. This oxidation process is exergonic
by 81.3 kcal/mol. The formation of final product 2b through
an intramolecular [1,3]-proton shift process via TS2 is diffi-
26
cult, requiring an activation free energy of 28.2 kcal/mol.
However, in the presence of dimethyl phosphate as catalyst,
the proton transfer process via TS2-a is very facile with a
barrier of only 4.0 kcal/mol. This is in agreement with previ-
ous discovery that the phosphoric acid is an excellent proton
13,27
shuttle.
Therefore, the oxidation of acetal by DMDO is the
rate-determining step for this reaction, and the overall free
energy barrier is 17.1 kcal/mol, accounting for the low reac-
o
tion temperature of 0 C.
SCHEME 3. DFT-Computed Free Energies for the Reac-
tion between Acetal 1b and DMDO in the Presence of
Dimethyl Phosphate
Figure 1. DFT-optimized chiral phosphoric acid catalyzed
proton transfer transition states TS2-a-R and TS2-a-S
(
carbon, gray; hydrogen, white; oxygen, red; phosphorus,
orange; distances are given in angstroms) and DFT-
computed relative energies (in kcal/mol).
In summary, we have developed a novel protocol for highly
enantioselective desymmetrization of 2-substituted and 2,2-
disubstituted 1,3-diols via oxidative cleavage of benzylidene
acetals in the presence of chiral phosphoric acid. DFT calcu-
lations show that the oxidation of acetal by DMDO is rate-
determining, and the attractive aryl-aryl interactions be-
tween substrate and catalyst are the key to high enantiose-
lectivity. Extensions of the strategy to other systems are cur-
rently underway and will be reported in due course.
To explore the origins of enantioselectivity, we studied bi-
28
phenol-derived chiral phosphoric acid (the model of (S)-4a)
catalyzed proton transfer transition states TS2-a-R and TS2-
a-S, which led to products (R)-2b and (S)-2b, respectively.
The computed free energy of TS2-a-S is 2.0 kcal/mol lower
than that of TS2-a-R (Figure 1). This energy difference corre-
ASSOCIATED CONTENT
Supporting Information
o
sponds to a 40:1 ratio of (S)-2b to (R)-2b at 0 C, in good
agreement with the 95% ee obtained experimentally. There
are no obvious steric clashes in these two diastereomeric
transition states. The main difference is the orientation of p-
methoxyphenyl (PMP) group of the substrate relative to the
2,4,6-triisopropylphenyl group of the catalyst. As shown in
the blue frame in Figure 1, two aryl groups are far way in TS2-
Experimental and computational details. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
29
a-R, while they forms a T-shaped configuration in TS2-a-S,
3
0
wzheng@nju.edu.cn; houk@chem.ucla.edu
indicating attractive aryl-aryl interactions. Further calcula-
tions show a 1.4 kcal/mol advance for the orientation of two
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Notes
(12) Reviews on chiral phosphoric acid (CPA) catalysis: (a) Akiyama,
T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem. Commun. 2008,
097. (c) You, S.–L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190.
d) Kampen, D.; Reisinger, C. M.; List, B. Top. Curr. Chem. 2010, 291,
95. (e) Terada, M. Synthesis 2010, 1929. (f) Rueping, M.; Koenigs, R.
M.; Atodiresei, I. Chem. Eur. J. 2010, 16, 9350. (g) Yu, J.; Shi, F.; Gong,
L. Acc. Chem. Res. 2011, 44, 1156. (h) Rueping, M.; Kuenkel, A.;
Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4939. (i) Čorić, I.; Vellalath, S.;
Müller, S.; Cheng, X.; List, B. Top. Organomet. Chem. 2013, 44, 165.
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The authors declare no competing financial interests.
4
(
3
ACKNOWLEDGMENT
This work is dedicated to Prof. Li-Xin Dai on the occasion of
his 90th birthday. Generous financial support from the Na-
tional Natural Science Foundation of China (21202081), the
Natural Science Foundation of Jiangsu Province (BK2012297),
Research Fund for the Doctoral Program of Higher Education
of China (20120091120026), and the U.S. National Science
Foundation (CHE-1059084) is gratefully acknowledged. Cal-
culations were performed on the Extreme Science and Engi-
neering Discovery Environment (XSEDE), which is supported
by the U.S. NSF (OCI-1053575).
(
13) Selected recent examples of CPA as proton transfer reagent: (a)
Čorić, I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010, 132, 8536. (b)
Xu, B.; Zhu, S.–F.; Xie, X.–L.; Shen, J.–J.; Zhou, Q.–L. Angew. Chem.
Int. Ed. 2011, 50, 11483. (c) Mori, K.; Ehara, K.; Kurihara, K.; Akiyama,
T. J. Am. Chem. Soc. 2011, 133, 6166. (d) Jiang, J.; Xu, H.–D.; Xi, J.–B.;
Ren, B.–Y.; Lv, F.–P.; Guo, X.; Jiang, L.–Q.; Zhang, Z.–Y.; Hu, W.–H. J.
Am. Chem. Soc. 2011, 133, 8428. (e) Maity, P.; Pemberton, R. P.; Tan-
tillo, D. J.; Tambar, U. K. J. Am. Chem. Soc. 2013, 135, 16380.
0
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14) Examples of CPA catalyzed synthesis of chiral acetals: (a) Coric,
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2
1
2
(
25) Zou, L.; Paton, R. S.; Eschenmoser, A.; Newhouse, T. R.; Baran, P.
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(
(
30) Krenske, E. H.; Houk, K. N. Acc. Chem. Res. 2013, 46, 979.
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