Catalytic Enantioselective Aza-pinacol Rearrangement

Article abstract of DOI:10.1002/anie.201705539

The first catalytic enantioselective asymmetric aza-pinacol rearrangement is reported. The reactions are catalyzed by a chiral phosphoric acid and proceed via a highly organized transition state involving a cyclic aza-ortho-xylylene intermediate to afford the indoline structures with good to excellent enantioselectivity. The synthetic utility of this method is demonstrated by the asymmetric synthesis of a key intermediate to the natural product minfiensine and the identification of a chiral lead compound to repress antibiotic resistance.

Full text of DOI:10.1002/anie.201705539

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Accepted Article
Title: Catalytic Enantioselective Aza-pinacol Rearrangement
Authors: Yuanyuan Yu, Jingwen Li, Long Jiang, Jing-Ren Zhang, and
Liansuo Zu
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10.1002/anie.201705539
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Catalytic Enantioselective Aza-pinacol Rearrangement
Yuanyuan Yu,+ Jingwen Li,+ Long Jiang, Jing-Ren Zhang* and Liansuo Zu*
Abstract: The first catalytic enantioselective asymmetric aza-pinacol
rearrangement is reported. The reactions are catalyzed by a chiral
phosphoric acid through a highly-organized transition state involving
medicinally important molecules (for example, analogs of the
Wang’s leads,[6] Figure 1).
a
cyclic aza-ortho-xylylene intermediate to afford the indoline
structures with good to excellent enantioselectivities. The synthetic
utility has been demonstrated by the asymmetric synthesis of a key
intermediate to natural product minfiensine and the identification of a
chiral lead compound to repress antibiotic resistance.
The aza-pinacol rearrangement, analogue of the classic pinacol
rearrangement, refers to the 1,2-alkyl, aryl, or hydride migration
from a nitrogen-containing carbon to a vicinal hydroxylated
carbon, generating imine or iminium as the product or transient
intermediate.[1] While pinacol and related semipinacol
rearrangements have been widely utilized in assembling
complex carbonyl-containing molecules,[2] the development of
aza-pinacol rearrangement as synthetic methods has been
rather challenging. The synthetic difficulties mainly arise from
the instability of the rearrangement product (imine or iminium),
the weak driving force of the entire process, and the
unpredictable side reactions associated with the highly reactive
species (imine, iminium, or their tautomer enamine). So despite
the synthetic potential of aza-pinacol rearrangement as powerful
tactics in making nitrogen-containing heterocycles and natural
alkaloids, by far there are only a few reported examples of aza-
pinacol rearrangement.[1] With respect to the enantioselective
asymmetric version of this reaction, only the group of Zhou has
reported the asymmetric hydrogenation of the active
intermediate generated from aza-pinacol rearrangement, in
which the rearrangement itself is a racemic process.[3] Herein we
report the first, to our knowledge, catalytic enantioselective
asymmetric aza-pinacol rearrangement.
Figure 1. Representative indoline natural products and lead compounds.
Chiral phosphoric acid catalysis has emerged as powerful
tactics for asymmetric synthesis.[7] While the phosphoric acid
catalyzed asymmetric semipinacol rearrangement by Tu,[8a]
vinylogous pinacol rearrangement and acyloin rearrangement by
Zhu,[8b,8c] aza-semipinacol rearrangement by Burgi and
Alexakis,[8d] and asymmetric syntheses of indoles and indolines
by List[8e,8f] are truly inspiring, we were particularly inspired by
the seminal work from the group of Antilla, who reported the first
catalytic asymmetric pinacol rearrangement of indole derivatives
(Scheme 1).[9] In their work, the indolyl iminium I[10] was
proposed to interact with the chiral phosphoric acid, providing
the chiral environment for the pinacol rearrangement. We
envisioned that if cyclic aza-ortho-xylylene II,
a putative
intermediate in our aza-pinacol rearrangement, could be
directed by chiral phosphoric acid, asymmetric induction might
be delivered (Scheme 1). While asymmetric transformations
involving aza-ortho-xylylenes, either acyclic or cyclic, have
previously been achieved,[11,12] to our knowledge, such
intermediates have not been utilized to facilitate asymmetric
skeletal rearrangements.
Inspired by the indoline core of a variety of natural
alkaloids,[4] such as minfiensine, aspidophyline A, and
calophyline A (Figure 1), we have recently developed a novel
strategy based on aza-pinacol rearrangement and successfully
demonstrated its synthetic utility in the chemical syntheses of
minfiensine and calophyline A.[5] One remaining chemical
problem in this project is to develop an asymmetric version of
the aza-pinacol rearrangement, which will lay the foundation for
the asymmetric synthesis of indoline natural products and
[*]
Y. Yu, L. Jiang, Prof. Dr. L. Zu
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic
Phosphorus Chemistry & Chemical Biology (Ministry of Education),
Tsinghua University, Beijing 100084 (China)
E-mail: zuliansuo@biomed.tsinghua.edu.cn
J. Li, Prof. Dr. J.-R. Zhang
School of Medicine, Tsinghua University, Beijing 100084 (China)
E-mail: zhanglab@tsinghua.edu.cn
Prof. Dr. J.-R. Zhang, Prof. Dr. L. Zu
Collaborative Innovation Center for Biotherapy, West China Medical
School, Sichuan University, Chengdu, 610041 (China)
Scheme 1. Aza-pinacol rearrangement via aza-ortho-xylylene intermediate.
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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A model reaction of 1a was carried out first to identify the
optimized reaction conditions for the aza-pinacol rearrangement
(Table 1). Both commercial available BINOL- and SPINOL-
derived chiral phosphoric acids were screened for their abilities
in promoting the skeletal rearrangement and controlling the
absolute stereochemistry. In the presence of the (R)-BINOL-
derived chiral phosphoric acids (3a-c), the reaction proceeded
smoothly in toluene to furnish the desired product 2a with varied
yields and enantioselectivities (entry1-3). With this class of
catalysts, the hindered 3c was seen to provide the best results
(95% yield, 77% ee). To our delight, the (R)-SPINOL-derived
analogue (4c) catalyzed the rearrangement with improved
enantioselectivity (80% ee, entry 5). Thus, 4c became the
choice of catalyst for further optimizations. Lowering the
temperature of the reaction further increased the
enantioselectivity, albeit with reduced reaction yields (entry 6-7).
The switch of solvent from toluene to chlorinated solvents (DCM,
DCE) led to the excellent results in terms of both yield and
enantioselectivity (entry 8-9). Attempts to decrease the catalyst
loading to 10 mol% did not affect the reaction yield, but lower
enantioselectivity was observed (entry 10). It should be noted
that using molecular sieves as an additive to remove H2O was
essential for the success of the rearrangement.
Table 1. Catalysts optimization.[a]
Scheme 2. Substrate scope of the aza-pinacol rearrangements. DCE = 1,2-
dichloroethane, M. S. = molecular sieves.
With the optimized reaction conditions identified, the
substrate scope of the aza-pinacol rearrangement was next
examined (Scheme 2). A variety of tertiary alcohols 1 with varied
R1, R2, and pendent nucleophiles (XH) proved to be efficient
substrates. The aza-pinacol rearrangement/cyclization cascade
sequence proceeded smoothly, generating fused indolines 2
with excellent yields and good to excellent enantioselectivities.
The absolute configuration of 2d was determined by single-
crystal X-ray diffraction.[13] The R2 had a marked effect on
enantioselectivity as exemplified by the different ees of 2b (R2 =
Bn) and 2c (R2 = Me). Varying the electronic and steric
properties of the Ar had little effect on both yield and
enantioselectivities (2d-g). Both pyrrolidinoindolines and
furoindolines (2h, 2k) could be synthesized with good to
excellent yields and ees. In addition, substrates bearing a
bromine substituent (R1 = Br) were investigated, generating
indolines with synthetic handles for further elaboration (2i-2l).
Considering the rich chemistry of aryl bromides for coupling
reactions, the divergent syntheses of numerous derivatives
could be possible. Substrates without pendent nucleophiles
were also examined (2m, 2n). While low enantioselectivities
were observed for these two substrates, the reactions served as
Entry
catalyst
3a
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
T (oC)
23
23
23
23
23
-20
0
Yield (%)[b]
ee[c]
0
1
2
3
4
5
6
7
8
9
10
60
62
95
94
94
65
79
94
95
95
3b
-31
-77
74
3c
4a
4c
80
4c
85
4c
84
4c
0
87
4c
DCE
0
88
4c
DCE
0
82[d]
[a] The reaction was catalyzed by 20 mol% catalyst in the specified solvent
(0.05 M). [b] Isolated yields. [c] Determined by chiral HPLC analysis. [d] Using
10 mol% catalyst. DCM = dicholoromethane, DCE = 1,2-dichloroethane, M. S.
= molecular sieves.
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control experiments for the elucidation of the reaction
mechanism, indicating that the formation of iminium (R2 ≠ H)
and the pendent nucleophiles were essential for organizing the
catalytic transition state.
conditions, presumably because the hydrogen bonding
interaction between the chiral phosphate and the pendent
nucleophile became difficult with the placement of the ketal in
the same side (J). This result further supported the proposed
transition state in Scheme 3.
Based on the above results, the reaction pathway for the
aza-pinacol rearrangement was proposed (Scheme 3).
Dehydration of the tertiary alcohol was facilitated by the chiral
phosphoric acid via hydrogen bonding (A), resulting in the
formation of aza-ortho-xylylene intermediate B. The orientation
of the transition state was directed through potential two-site
binding between the bifunctional chiral phosphate and B:
electrostatic interaction via ion pair and hydrogen bonding with
the pendent nucleophile. Subsequently, enantioselective aza-
pinacol rearrangement (C) followed by ring closure delivered the
fused indoline product.
Scheme 3. Proposed catalytic pathway.
To demonstrate the synthetic potential of the phosphoric
acid catalyzed aza-pinacol rearrangement for natural products
synthesis, complex substrates (1o-1q) were prepared and
investigated (Scheme 4). High temperature was required for the
rearrangement of 1o, generating the core structure of natural
product calophyline A (2o) after reduction with NaBH3CN in
modest yield and enantioselectivity. The cascade reaction
sequence included aza-pinacol rearrangement (D), alkene
isomerization (E) and conjugate addition to afford intermediate F,
the instability of which presumably weaken the driving force of
the entire process. To our delight, the aza-pinacol
rearrangement initiated cascade reaction of 1p, involving aza-
pinacol rearrangement and tautomerization (G), elimination of
the ketal (H), isomerization (I) and cyclization, proceeded with
remarkable efficiency (74% yield, 97% ee) under mild conditions
to afford ketone 2p directly. While this type of ketone with varied
protecting groups have been extensively used as the key
intermediate in the total synthesis of natural product
minfiensine,[14] catalytic enantioselective asymmetric synthesis
of the structure has been only previously achieved by Overman
and Jiao using palladium catalysis.[14a,14b,14g] Our approach offer
an organocatalytic alternative to this polycyclic ketone with
minimized functional group elaboration. Surprisingly, substrate
1q (the diastereomer of 1p) was not reactive under identical
Scheme 4. Syntheses of the core structure of calophyline A and advanced
intermediate to minfiensine. DCE = 1,2-dichloroethane.
The diverse biological activities of indoline natural products
have served as the inspirations for the discovery of new lead
compounds. Recently, the group of Wang has identified a potent
lead compound Of1 (Scheme 5), which can be used as a
resistance-modifying agent to resensitize methicillin-resistant
Staphylococcus aureus (MASA) to -lactam antibiotics.[6a,6b]
Antibiotic-resistance threats have become a global problem that
has need urgent attention.[15] While new classes of antibiotics
have proven difficult to develop, the use of antibiotic adjuvants
represents an appealing strategy because they can increase the
life span of the currently used antibiotics and they are less
susceptible to the development of new bacterial resistance.
In addition to the indoline core, the structure of Wang’s lead
compound Of1 contains an exocyclic alkene, which is the
signature of the original synthesis via Gold-catalyzed indole-
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alkyne cyclization.[6] We envisioned that our asymmetric aza-
pinacol rearrangements could allow for the synthesis of a
simplified version of Wang’s lead without the exocyclic alkene
and further examine the stereochemistry-based structure/activity
relationship (SARs).
In summary, we have developed the first phosphoric acid
catalyzed enantioselective aza-pinacol rearrangement and
demonstrated that a cyclic aza-ortho-xylylene intermediate could
be utilized to facilitate asymmetric skeletal rearrangements. This
method provides direct access to the indoline core of a variety of
natural products and medicinally important lead compounds with
good to excellent enantioselectivities. The synthetic utility has
been demonstrated by the organocatalytic asymmetric synthesis
of a key intermediate to natural product minfiensine and
identification of a simplified version of Wang’s lead to fight
antibiotic-resistance.
Acknowledgements
This work is supported by the “1000 Talents Recruitment
Program” (for LZ), Tsinghua-Peiking University Center for Life
Science, National Natural Science Foudation of China (Grant No.
21302107 and 21672123 for LZ; 81671972 and 31530082 for J.-
R.Z), Tsinghua University Research Program (No. 20161080058
for J.-R.Z), and Grand Challenges Exploration of the Bill and
Melinda Gates Foundation (No. OPP1021992 for J.-R.Z).
Scheme 5. Synthesis of the simplified lead compounds 5. PMB
methoxylbenzyl, TFA = trifluoroacetic acid, THF = tetrahydrofuran.
= p-
From 2l, the two step synthetic transformations involving
reductive ring opening and deprotection delivered the simplified
lead compound (R, S)-5. Similarly, (S, R)-5 was prepared from
the enantiomer of 2l, which was obtained by the asymmetric
aza-pinacol rearrangement using (S)-4c as the catalyst.
Gratifyingly, both enantiomers of 5 were seen to potentiate the
activity of several -lactam antibiotics in a multidrug-resistant
MARA strain BAA-1695 with the same level of potency as that of
the Wang’s lead compound (Of1), indicating that the exocyclic
alkene might be not required for the bioactivity (Table 2). The (S,
R)-5 was 2-fold more active in potentiating the activity of
amox/clav, cefazolin and meropenem, albeit no marked
difference in MIC was seen for methicillin and oxacillin. Although
no marked difference in MIC for (R, S)-5 and (S, R)-5 in
potentiating the activity of methicillin toward the multidrug-
resistant MARA strain was observed, further bacteria growth and
killing experiments showed that the (S, R)-5 was more active as
a resistance-modifying agent in killing bacteria (see supporting
information). The structural simplification and stereochemistry-
based structure/activity relationship will further inspire the
development of more potent compounds to repress antibiotic
resistance.
Keywords: indoline • aza-pinacol• phosphoric acid •antibiotics•
rearrangement
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Y. Yu, J. Li, L. Jiang, J.-R. Zhang*, L.
Zu*
Page No. – Page No.
Catalytic Enantioselective Aza-
pinacol Rearrangement
The first catalytic enantioselective asymmetric aza-pinacol rearrangement is
reported, which provides direct access to the indoline core of a variety of natural
products and allows for the identification of a simplified lead compound to repress
antibiotic resistance.
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