Palladium-Catalyzed Enantioselective Desymmetrizing Aza-Wacker Reaction: Development and Application to the Total Synthesis of (?)-Mesembrane and (+)-Crinane

Article abstract of DOI:10.1002/anie.201712521

Reported is an unprecedented catalytic enantioselective desymmetrizing aza-Wacker reaction. In the presence of a catalytic amount of a newly developed Pd(CPA)₂(MeCN)₂ catalyst (CPA=chiral phosphoric acid), a pyrox ligand, and molecul

Full text of DOI:10.1002/anie.201712521

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Palladium-Catalyzed Enantioselective Desymmetrizing Aza-
Wacker Reaction: Development and Application to the Total
Synthesis of (-)-Mesembrane and (+)-Crinane
Authors: Xu Bao, Qian Wang, and Jieping Zhu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712521
Angew. Chem. 10.1002/ange.201712521
Link to VoR: http://dx.doi.org/10.1002/anie.201712521
http://dx.doi.org/10.1002/ange.201712521

10.1002/anie.201712521
Angewandte Chemie International Edition
COMMUNICATION
Palladium-Catalyzed Enantioselective Desymmetrizing Aza-
Wacker Reaction: Development and Application to the Total
Synthesis of (–)-Mesembrane and (+)-Crinane
Xu Bao, Qian Wang, Jieping Zhu*
Abstract: We report in this paper an unprecedented catalytic
enantioselective desymmetrizing aza-Wacker reaction. In the
reaction of 3,3-disubstituted cyclohexa-1,4-dienes.[11] However,
the catalytic enantioselective version has remained unknown.
presence of
a
catalytic amount of newly developed
We report herein
a
Pd(CPA)2(MeCN)2/pyrox-catalyzed
Pd(CPA)2(MeCN)2 catalyst (CPA stands for chiral phosphoric acid),
a pyrox ligand and molecular oxygen, cyclization of properly
functionalized prochiral 3,3-disubstituted cyclohexa-1,4-dienes
afforded enantioenriched cis-3a-substituted-tetrahydroindoles in
good yields with excellent enantioselectivities. A cooperative effect
between the phosphoric acid and the pyrox ligand ensured the
efficient transformation. This reaction was tailor-made for
Amaryllidaceae and Sceletium alkaloids as illustrated by its
application in the development of the concise and divergent total
synthesis of (–)-mesembrane and (+)-crinane.
enantioselective desymmetrizing aza-Wacker reaction of
cyclohexa-1,4-dienes 1 for the synthesis of enantioenriched
cis-3a-substituted tetrahydroindoles.[12] A cooperative effect
between chiral phosphoric acid (CPA) and chiral pyrox ligand
is key to the development of this enantioselective
transformation.[6g] Divergent total synthesis of (–)-mesembrane
and (+)-crinane, representative structures of Amaryllidaceae
and Sceletium alkaloids,[13] featuring this reaction as a key
step will also be documented.
a) Yang's work: Pd(II)-catalyzed enantioselective oxidative domino cyclization
R
R
O
O
Pd(II), (–)-sparteine, O2
NH
The Pd(II)-catalyzed Wacker reaction has found
widespread application in the synthesis of natural products
and designed bioactive compounds.[1] The asymmetric
N
Ar
Ar
H
b) This work: Pd(II)-catalyzed desymmetrizing aza-Wacker reaction and its
synthetic application
Wacker-type cyclization involving
a
key stereocenter-
NMe
generating oxypalladation step has also been successfully
developed for the synthesis of chiral non-racemic
oxaheterocycles.[2,3] On the other hand, the development of
oxidative enantioselective intramolecular aza-Wacker type
reaction remained inherently more challenging and only few
examples have been reported in the literature.[4-6] Yang and
co-workers reported in 2006 the first examples of Pd(II)/(–)-
sparteine catalyzed oxidative domino cyclization of 2-allyl-
acrylanilides (Scheme 1a).[5] Other groups have subsequently
reported different catalytic conditions for the oxidative
MeO
NHP
MeO
Ts
Pd(CPA 2
) , L*
N
R = Ar
3 (–)-mesembrane
R
N
O2
R
O
1
2
O
4 (+)-crinane
Scheme 1. Enantioselective aza-Wacker reaction.
enantioselective
aminoalkenes.[6]
cyclization
of
N-acyl
or
N-tosyl
3-Phenyl-3-[2-(4-tolylsulfonyl)]aminoethyl-cyclohexa-1,4-
diene (1a) was chosen as a test substrate.[14] Heating a
toluene solution of 1a in the presence of Pd(OAc)2, pyridine,
Na2CO3 under O2 atmosphere afforded indeed 2a in 65% yield
(entry 1, Table 1).[11] However, the same reaction using (–)-
sparteine as ligand provided 2a in only 8% yield (entry 2). We
therefore turned our attention to the chiral quinox and pyrox
type ligands[15] using a more electrophilic Pd(TFA)2 as a Pd(II)
source (Figure 1). The results are summarized in Table 1. In
quinox series, L4 derived from (1R,2S)-1-amino-2-indanol was
a superior ligand than those (L1-L3) derived from the acyclic
amino alcohols in terms of product ee (entries 7 vs 3-6). The
same trend was observed in the pyrox series with L7 being a
better ligand than L5 and L6 (entries 10 vs 8, 9). Tuning the
electronic and steric properties of L7 led to the decrease of
both the yield and the ee of the product (L8-L10, entries 11-
13). Unfortunately, varying the solvents and the bases failed to
increase the synthetic efficiency of this transformation. Adding
molecular sieves (MS) to the reaction mixture decreased the
yield of 2a (entries 14-16).[16] However, the enantioselectivity
was significantly increased when 5 Å MS were added into the
reaction mixture (entry 16).
The difficulties associated with the development of
oxidative aza-Wacker reaction are due to a) the reversibility of
the aminopalladation step;[7] b) the competing syn- and anti-
aminopalladation processes;[8] and c) the limited choice of
chiral ligands. Most of the phosphine-based ligands are in fact
incompatible with the oxidative conditions. In connection with
our research program dealing with the Pd(0)-catalyzed
enantioselective difunctionalization of alkenes,[9] we became
interested in addressing this challenging topic. In designing
such a transformation, we paid particular attention on its
potential application in natural product synthesis.[10] Landais
and co-workers have reported a Pd(II)-catalyzed aza-Wacker
[*]
Dr. X. Bao, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/anie.201712521
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of the reaction conditions.[a]
between the CPA and the pyrox ligand. The pyrox ligand
determined the sense of the enantioselectivity, whereas the
presence of CPA-7 increased not only the enantioselectivity of
the reaction but also the yield of the product. While Pd[(R)-
CPA 7]2(MeCN)2 was isolable and was spectroscopically
characterized (Supporting information), all attempts to isolate
and characterize the Pd-CPA-pyrox ternary complex failed.
Ts
TsHN
N
Pd source, ligand, O2
Na2CO3, Toluene, 50 o
C
1a
2a
entry
1[d]
2
3
4
5
6
7
8
Pd salt
ligand
pyridine
(–)-sparteine
additive
---
---
---
---
---
---
---
yield (%)[b]
ee (%)[c]
---
---
9
-20
3
16
51
40
59
70
62
56
52
70
75
81
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
65
8
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L7
L7
L7
27
trace
9
Table 2. Effects of the chiral acids on the reaction outcome.[a]
Ts
TsHN
N
Pd source, ligand, O2
Na2CO3, Toluene, 50 o
9
16
13
25
41
27
23
18
23
24
22
C
1a
2a
---
---
---
---
---
---
9
entry
1
2
3
4
5
6
7
8
acids[b]
yield (%)[c]
trace
trace
7
trace
9
33
ee (%)[d]
---
---
56
---
16
84
88
80
84
94
93
10
11
12
13
14
15
16
(R)-mandelic acid
(S)-N-Boc-Phe
(R)-CPA 1
(R)-CPSA 4
(R)-CPA 5
(R)-CPA 2
(R)-CPA 3
(S)-CPA 3
PA 6
3 Å MS[e]
4 Å MS
5 Å MS
31
23
48
32
63
10
[a] 1a (0.1 mmol), PdX2 (0.01 mmol), ligand (0.02 mmol), Na2CO3 (0.2
mmol), O2, toluene (2.0 mL), 50 oC. [b] Yields refer to the isolated products.
[c] Determined by SFC analysis on a chiral stationary phase. [d] Performed
at 80 °C. [e] MS = molecular sieves (70.0 mg).
9
[e]
[e]
10
11
12
Pd[(R)-CPA 3]2(MeCN)2
Pd[(R)-CPA 7]2(MeCN)2 [f]
Pd[(R)-CPA 7]2(MeCN)2
3
O
O
N
L1 R = tBu
L2 R = iPr
L3 R = Ph
R1
[a] 1a (0.1 mmol), Pd(TFA)2 (0.01 mmol), L7 (0.02 mmol), Na2CO3 (0.2
mmol), O2, 5 Å MS (70.0 mg), toluene (2.0 mL), 50 oC. [b] Acid (0.02 mmol).
[c] Yields refer to the isolated products. [d] Determined by SFC analysis on
a chiral stationary phase. [e] Catalyst loading (0.01 mmol). [f] Without ligand
L7. Abbrev. CPA = Chiral Phosphoric Acid.
N
N
N
R
L4
R1
O
N
L7 R1 = R2 = R3 = H
O
R2
R3
L8 R1 = OMe, R2 = R3 = H
L9 R1 = R3 = H, R2 = CF3
L10 R1 = R2 = H, R3 = Me
N
R2
N
N
L5 R1 = H, R2 = tBu
L6 R1 = R2 = Ph
R
Ar
OH
COOH
O
O
O
O
Ph
P
P
Figure 1. Structures of quinox and pyrox surveyed.
Tf
OH
(R)-mandelic acid
O
O
N
H
NHBoc
R
Ar
Ar = 2,4,6-TrisiPr-C6H2
(R)-CPA 1 R = 2,4,6-TrisiPr-C6H2
(R)-CPSA 4
Ph
COOH
The aforementioned results were far from satisfactory, we
set out to examine the cooperative effects between the chiral
pyrox ligand L7 and acid additives.[17] Adding (R)-mandelic
acid or (S)-N-Boc phenylalanine to the above optimized
conditions [Pd(TFA)2, L7, Na2CO3, O2, 5 Å MS, toluene, 50 °C]
shut down the reaction (entries 1 and 2, Table 2).[18,19] Chiral
phosphoric acids having a bulky substituent at the C3, C3’
positions [(R)-CPA 1, 4 and 5, Figure 2] exerted also a
deleterious effect on the reaction outcome (entries 3-5).[20,21]
However, addition of the less hindered CPAs [(R)-CPA 2, 3]
increased slightly the yield and ee of the product 2a (entries 6-
7). Interestingly, adding (S)-CPA 3 to the reaction mixture led
to the product with diminished yield and ee, while adding
achiral biphenol-derived phosphoric acid (PA 6) increased
slightly the yield of 2a (entry 9, Table 2, vs entry 16, Table 1).
The pronounced counterion effect led us to assume that
trifluoroacetic acid (TFA) present in the reaction mixture might
also impact the reaction outcome. We therefore synthesized
Pd[(R)-CPA 3]2(MeCN)2 and Pd[(R)-CPA 7]2(MeCN)2
complexes following literature procedures.[21a,22] Gratefully,
both pre-catalysts displayed superior reactivity than the in situ
combination of Pd(TFA)2 and CPA (entries 10, 11). Using
Pd[(R)-CPA 7]2MeCN2 as catalyst, compound 2a was isolated
in 63% yield with 93% ee. It is important to stress that the
cyclization of 1a catalyzed by Pd[(R)-CPA 7]2MeCN2 alone
afforded the product 2a in a low yield and ee (entry 12).
Furthermore, cyclization of 1a catalyzed by Pd[(R)-CPA
7]2(MeCN)2 and ent-L7 furnished ent-2a in only 16% yield with
72% ee. These results indicated a strong cooperative effect
(R)-CPA 2 R = Ph
(R)-CPA 3 R = H
(S)-N-Boc-Phe
H
Ar
O
O
R
R
(R)-CPA 5
Ar = 2,4,6-TrisiPr-C6H2
O
O
O
PA 6 R = H,
(R)-CPA 7 R = Me
P
P
OH
O
OH
Ar
H
Figure 2. Structures of the carboxylic acids and phosphoric acids surveyed.
With the optimum conditions in hand, the scope of this
catalytic enantioselective aza-Wacker reaction was next
explored (Scheme 2). The products with different C3a-
aromatic substituents were obtained in good yields with
excellent ees (2a-2j). As expected, the aryl bromide was
stable under these mild Pd(II)-catalyzed reaction conditions
(2e), so were the standard hydroxyl and amino protective
groups (OTBS, OBn, OAc and phthalimide). The
tetrahydroindoles substituted by a functionalized alkyl group at
C3a position were also accessible (2k-2o), albeit with slightly
reduced enantiomeric excesses. Importantly, the C3a-
unsubstituted tetrahydroindole 2p can also be synthesized
with excellent ee. Although the yield of 2p was moderate, we
noted that the corresponding indoline, the oxidized derivative,
was not detected. Finally, the substrate bearing an easily
removable N-(4-nitro)phenylsulfonamide function cyclized to
afford 2q in 61% yield with 93% ee. The absolute configuration
of 2a (3aS, 7aR) was determined by X-ray crystallographic
analysis and that of the others were assigned accordingly.
This article is protected by copyright. All rights reserved.

10.1002/anie.201712521
Angewandte Chemie International Edition
COMMUNICATION
Ts
demethylation of 5 (BBr3, CH2Cl2) followed by methylenation of
the resulting catechol furnished 6 in 92% yield with 92% ee.
Pd[(R)-CPA 7@ꢀꢁMeCN)2, L7
Na2CO3, O2, Toluene, 5 Å MS, 50 °C
Ts
N
TsHN
R
R
The ee of
6 was upgraded to > 99% by a simple
1a-1r
2a-2r
recrystallization and its absolute configuration was
unambiguously determined by X-ray crystallographic analysis.
Removal of the N-Ts group followed by the Pictet-Spengler
reaction converted 6 to (+)-crinane (4) in 76% yield over 2
steps {[α]25 + 8.2 (c 1.0, CHCl3); lit.[25c] [α]20 + 7.01 (c 1.0,
Ts
N
N
OMe
R
R
2e R = Br, 51%, 82% ee
2f R = OTBS, 61%, 90% ee
2g R = OMe, 57%, 89% ee
2a R = H, 63% , 93% ee
2b R = Me, 65% , 92% ee
2c R = OMe, 65%, 93% ee
2d R = OBn, 56%, 95% ee
D
D
CHCl3). The spectroscopic data of the synthetic (–)-
mesembrane (3) and (+)-crinane (4) are identical with those
reported for the natural products.
Ts
N
2a
Ts
Ts
N
H
N
R
OMe
2p 44%, 92% ee
In summary, we reported a catalytic enantioselective
desymmetrizing aza-Wacker reaction. In the presence of a
catalytic amount of newly developed chiral Pd(CPA)2(MeCN)2
complex, a pyrox ligand and molecular oxygen, cyclization of
functionalized prochiral 3,3-disubstituted cyclohexa-1,4-dienes
afforded enantioenriched cis-3a-substituted tetrahydroindoles
in good yields with excellent enantioselectivities. A cooperative
effect between the chiral pyrox ligand and the phosphoric acid
increased both the yield and the ee of the product. Specifically,
the pyrox ligand determined the sense of enantioselectivity,
while the matched chiral phosphoric acid increased
synergistically both the ee and the yield of the product.
Application of this reaction allowed us to develop the concise
and divergent total synthesis of (–)-mesembrane and (+)-
crinane.
ArO2S
N
2k R = OMe, 49%, 82% ee
2l R = OBn, 63%, 81% ee
2m R = OTBS, 55%, 84% ee
2n R = 4-BrC6H4COO,
55% yied, 90% ee
2o R = NPhth, 62% ,91% ee
OR
2h R = OTBS, 61%, 90% ee
2i R = OMe, 60%, 92% ee
2j R = OAc, 71%, 90% ee
2q Ar = 4-NO2-Ph,
61%, 93% ee
Scheme 2. Scope of desymmetrizing aza-Wacker reaction.
Ts
Pd>ꢀS)-CPA 7]2(MeCN)2
ent-L7, Na2CO3, O2
TsHN
N
Pd(OH)2, H2
MeOH, RT, 98%
5 Å MS, Toluene, 50 °C
OMe
OMe
1g
MeO
56%, 90% ee
ent-2g
OMe
Ts
NMe
N
a) Na, naphthalene, THF, -78 °C, to RT
b) aq HCHO, ZnCl2, NaBH3CN, MeOH
86% over 2 steps
MeO
MeO
MeO
Acknowledgements
5
MeO
3 (–)-mesembrane
a) BBr3, CH2Cl2
b) Cs2CO3, CH2Br2, DMF, 90 °C
92% over 2 steps
We thank EPFL (Switzerland), Swiss National Science
Foundation (SNSF) for financial supports. We thank Dr. F.-T
Farzaneh and Dr. R. Scopelliti for X-ray crystallographic
analysis of 2a and 6.
Ts
N
a) Na, naphthalene
THF, -78 °C, to RT
N
b) HCHO, 6 N HCl
MeOH, 60 °C
76% over 2 steps
O
O
O
O
6
4 (+)-crinane
>99% ee after one recrystalization
Keywords: Aza-Wacker • asymmetric synthesis • palladium •
chiral Brønsted acid • cooperative effect • alkaloids
Scheme 3. Divergent synthesis of (–)-mesembrane and (+)-crinane.
[1]
[2]
B. W. Michel, L. D. Steffens, M. S. Sigman, Org. React. 2014, 84, 2.
a) T. Hosokawa, T. Uno, S. Inui, S.-I. Murahashi, J. Am. Chem. Soc.
1981, 103, 2318; b) T. Hosokawa, C. Okuda, S.-I. Murahashi, J. Org.
Chem. 1985, 50, 1282; c) Y. Uozumi, K. Kato, T. Hayashi, J. Am.
Chem. Soc. 1997, 119, 5063; d) A. Thorarensen, A. Palmgren, K.
Itami, J.-E. Bäckvall, Tetrahedron Lett. 1997, 38, 8541; e) K. Itami, A.
Palmgren, A. Thorarensen, J.-E. Bäckvall, J. Org. Chem. 1998, 63,
6466; f) Y. Uozumi, K. Kato, T. Hayashi, J. Org. Chem. 1998, 63,
5071; g) Y. Uozumi, H. Kyota, K. Kato, M. Ogasawara, T. Hayashi, J.
Org. Chem. 1999, 64, 1620; h) M. A. Arai, M. Kuraishi, T. Arai, H.
Sasai, J. Am. Chem. Soc. 2001, 123, 2907; i) R. M. Trend, Y. K.
Ramtohul, E. M. Ferreira, B. M. Stoltz, Angew. Chem. Int. Ed. 2003,
42, 2892; Angew. Chem. 2003, 115, 2998; j) R. M. Trend, Y. K.
Ramtohul, B. M. Stoltz, J. Am. Chem. Soc. 2005, 127, 17778; k) L. F.
Tietze, K. M. Sommer, J. Zinngrebe, F. Stecker, Angew. Chem. Int.
Ed. 2005, 44, 257; Angew. Chem. 2005, 117, 262; l) Y. J. Zhang, F.
Wang, W. Zhang, J. Org. Chem. 2007, 72, 9208; m) K. Takenaka, S.
C. Mohanta, M. L. Patil, C. V. L. Rao, S. Takizawa, T. Suzuki, H.
Sasai, Org. Lett. 2010, 12, 3480; n) Q. Liu, K. Wen, Z. Zhang, Z. Wu,
Y. J. Zhang, W. Zhang, Tetrahedron 2012, 68, 5209.
The cis-3a-aryloctahydroindole possessing an all carbon
quaternary stereocenter is a key structural motif found in
Amaryllidaceae and Sceletium alkaloids.[13] These natural
products attracted considerable attention over the years due to
their diverse structures and potent bioactivities. Although
elegant synthetic routes have been developed, catalytic
enantioselective synthesis remained rare.[23] Since both
enantiomers of some members of these families of natural
products exist in nature, the development of catalytic
enantioselective approach is particularly appealing. The
asymmetric aza-Wacker reaction developed in this study is
indeed tailor-made for these alkaloids as illustrated by the
realization of divergent synthesis of (–)-mesembrane (3)[24] and
(+)-crinane (4),[25] the latter being a basic framework for
Amaryllidaceae (Scheme 3). Treatment of 1g with Pd[(S)-CPA
7]2(MeCN)2 and ligand ent-L7 under otherwise standard
conditions furnished ent-2g (56%, 90% ee). Hydrogenation of
ent-2g in the presence of Pearlman’s catalyst provided 5 in
98% yield. Removal of N-Ts followed by reductive N-
methylation with aqueous formaldehyde furnished (–)-
[3]
[4]
For reviews, see: a) R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev.
2011, 111, 2981; b) P. Kocovsky, J.-E. Bäckvall, Chem. Eur. J. 2015,
21, 36.
Pd(II)-catalyzed non-oxidative enantioselective aminopalladation,
see: L. E. Overman, T. P. Remarchuk, J. Am. Chem. Soc. 2002, 124,
12.
mesembrane (3) in 86% overall yield {[α]25
-
13.8 (c 1.2,
D
MeOH); lit.[24a] [α]20
-
14.6 (c 1.0, MeOH)}. On the other hand,
D
This article is protected by copyright. All rights reserved.

10.1002/anie.201712521
Angewandte Chemie International Edition
COMMUNICATION
[5]
a) K.-T. Yip, M. Yang, K.-L. Law, N.-Y. Zhu, D. Yang, J. Am. Chem.
Soc. 2006, 128, 3130; b) W. He, K.-T. Yip, N.-Y. Zhu, D. Yang, Org.
Lett. 2009, 11, 5626; c) W. Du, Q. Gu, Y. Li, Z. Lin, D. Yang, Org.
Lett. 2017, 19, 316; d) Q.-S. Gu, D. Yang, Angew. Chem. Int. Ed.
2017, 56, 5886; Angew. Chem. 2017, 129, 5980.
P. Smalley, J. D. Cuthbertson, M. J. Gaunt, J. Am. Chem. Soc. 2017,
139, 1412; Non-oxidative Pd(II)-CPA catalyzed enantioselective
transformations, see: f) D. Zhang, H. Qiu, L. Jiang, F. Lv, C. Ma, W.
Hu, Angew. Chem. Int. Ed. 2013, 52, 13356; Angew. Chem. 2013,
125, 13598; g) S.-Y. Yu, H. Zhang, Y. Gao, L. Mo, S. Wang, Z.-J.
Yao, J. Am. Chem. Soc. 2013, 135, 11402; Pd(0)-CPA-catalyzed
enantioselective C-H functionalization, see: h) P.-S. Wang, H.-C. Lin,
Y.-J. Zhai, Z.-Y. Han, L.-Z. Gong, Angew. Chem. Int. Ed. 2014, 53,
12218; Angew. Chem. 2014, 126, 12414; i) S.-B. Yan, S. Zhang, W.-
L. Duan, Org. Lett. 2015, 17, 2458; j) H. Wang, H.-R. Tong, G. He, G.
Chen, Angew. Chem. Int. Ed. 2016, 55, 15387; Angew. Chem. 2016,
128, 15613; k) L. Yang, R. Melot, M. Neuburger, O. Baudoin, Chem.
Sci. 2017, 8, 1344.
[6]
a) T. Tsujihara, T. Shinohara, K. Takenaka, S. Takizawa, K. Onitsuka,
M. Hatanaka, H. Sasai, J. Org. Chem. 2009, 74, 9274; b) F. Jiang, Z.
Wu, W. Zhang, Tetrahedron Lett. 2010, 51, 5124; c) C. Ramalingan,
K. Takenaka, H. Sasai, Tetrahedron 2011, 67, 2889; d) R. I.
McDonald, P. B. White, A. B. Weinstein, C. P. Tam, S. S. Stahl, Org.
Lett. 2011, 13, 2830; e) R. Jana, T. P. Pathak, K. H. Jensen, M. S.
Sigman, Org. Lett. 2012, 14, 4074; f) G. Yang, C. Shen, W. Zhang,
Angew. Chem. Int. Ed. 2012, 51, 9141; Angew. Chem. 2012, 124,
9275; g) Y.-P. He, H. Wu, L. Xu, Y.-L. Su, L.-Z. Gong, Org. Chem.
Front. 2014, 1, 473; h) F. Yu, P. Chen, G. Liu, Org. Chem. Front.
2015, 2, 819; i) W. Zhang, P. Chen, G. Liu, Angew. Chem. Int. Ed.
2017, 56, 5336; Angew. Chem. 2017, 129, 5420.
[21] Cooperative effect between chiral P and N ligand with CPA in Pd(0)-
catalyzed asymmetric transformations, see: a) G. Jiang, R. Halder, Y.
Fang, B. List, Angew. Chem. Int. Ed. 2011, 50, 9752; Angew. Chem.
2011, 123, 9926; b) H.-C. Lin, P.-S. Wang, Z.-L. Tao, Y.-G. Chen, Z.-
Y. Han, L.-Z. Gong, J. Am. Chem. Soc. 2016, 138, 14354; c) For
Pd(II)-catalyzed, see ref 6g.
[7]
[8]
J.-E. Bäckvall, E. E. Björkman, Acta. Chem. Scand. B 1984, 38, 91.
a) J. P. Wolfe, Synlett 2008, 2913; b) A. B.; Weinstein, S. S. Stahl,
Angew. Chem. Int. Ed. 2012, 51, 11505; Angew. Chem. 2012, 124,
11673.
[22] (R)- and (S)-CPA 7 were synthesized according to a) S. Kanoh, N.
Tamura, M. Motoi, H. Suda, Bull. Chem. Soc. Jpn. 1987, 60, 2307; b)
E. Alberico, S. Karandikar, S. Gladiali, ChemCatChem. 2010, 2, 1395.
[23] Recent examples, see: a) Q. Gu, S.-L. You, Chem. Sci. 2011, 2,
1519; b) M.-X. Wei, C.-T. Wang, J.-Y. Du, H. Qu, P.-R. Yin, X. Bao,
X.-Y. Ma, X.-H. Zhao, G.-B. Zhang, C.-A. Fan, Chem. Asian J. 2013,
8, 1966; c) X.-D. Zuo, S.-M. Guo, R. Yang, J.-H. Xie, Q.-L. Zhou,
Chem. Sci. 2017, 8, 6202; d) K. Du, H. Yang, P. Guo, L. Feng, G. Xu,
Q. Zhou, L. W. Chung, W. Tang, Chem. Sci. 2017, 8, 6247.
[9]
a) A. Pinto, Y. Jia, L. Neuville, J. Zhu, Chem. Eur. J. 2007, 13, 961;
b) W. Kong, Q. Wang, J. Zhu, J. Am. Chem. Soc. 2015, 137, 16028;
c) W. Kong, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2016, 55, 9714;
Angew. Chem. 2016, 128, 9866; d) W. Kong, Q. Wang, J. Zhu,
Angew. Chem. Int. Ed. 2017, 56, 3987; Angew. Chem. 2017, 129,
4045; (e) X. Bao, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2017, 56,
9577; Angew. Chem. 2017, 129, 9705.
[10] Target-driving development of synthetic methodologies, examples
from our group, see: a) Z. Xu, Q. Wang, J. Zhu, Angew. Chem. Int.
Ed. 2013, 52, 3272; Angew. Chem. 2013, 125, 3354; b) T. Buyck, Q.
Wang, J. Zhu, Angew. Chem. Int. Ed. 2013, 52, 12714; Angew.
Chem. 2013, 125, 12946; c) J.-B. Gualtierotti, D. Pasche, Q. Wang, J.
Zhu, Angew. Chem. Int. Ed. 2014, 53, 9926; Angew. Chem. 2014,
126, 10084; d) Z. Xu, Q. Wang, J. Zhu, J. Am. Chem. Soc. 2015, 137,
6712; e) D. Dagoneau, Z. Xu, Q. Wang, J. Zhu, Angew. Chem. Int.
Ed. 2016, 55, 760; Angew. Chem. 2016, 128, 770; f) C. Piemontesi,
Q. Wang, J. Zhu, J. Am. Chem. Soc. 2016, 138, 11148.
[24] a) N. H. Martin, D. Rosenthal, P. W. Jeffs, Org. Mass Spectrom. 1976,
11, 1; b) T. M. Capps, K. D. Hargrave, P. W. Jeffs, A. T. McPhail, J.
Chem. Soc., Perkin Trans. 2 1977, 1098. Enantioselective synthesis
of (-)-mesembrane, see: c) M. Mori, S. Kuroda, C.-S. Zhang, Y. Sato,
J. Org. Chem. 1997, 62, 3263.
[25] a) W. C. Wildman, J. Am. Chem. Soc. 1956, 78, 4180 For selected
enantioselective synthesis of (+)-crinane, see: b) T. Kano, Y. Hayashi,
K. Maruoka, J. Am. Chem. Soc. 2013, 135, 7134; (-)-crinane, see: c)
Y.-R. Gao, D.-Y. Wang, Y.-Q. Wang, Org. Lett. 2017, 19, 3516.
[11] a) R. Beniazza, J. Dunet, F. Robert, K. Schenk, Y. Landais, Org. Lett.
2007, 9, 3913; Base promoted cyclization, see: b) R. Lebeuf, F.
Robert, K. Schenk, Y. Landais, Org. Lett. 2006, 8, 4755.
[12] For a recent review on enantioselective desymmetrization, see: X.-P.
Zeng, Z.-Y. Cao, Y.-H. Wang, F. Zhou, J. Zhou, Chem. Rev. 2016,
116, 7330.
[13] a) N. Gericke, A. M. Ciljoen, J. Ethnopharma. 2008, 119, 653; b) Z.
Jin, Nat. Prod. Rep. 2016, 33, 1318.
[14] R. Lebeuf, J. Dunet, R. Beniazza, D. Ibrahim, G. Bose, M. Berland, F.
Robert, Y. Landais, J. Org. Chem. 2009, 74, 6469.
[15] G. C. Hargaden, P. J. Guiry, Chem. Rev. 2009, 109, 2505.
[16] B. A. Steinhoff, A. E. King, S. S. Stahl, J. Org. Chem. 2006, 71, 1861.
[17] M. Rueping, R. M. Koenigs, I. Atodiresei, Chem. Eur. J. 2010, 16,
9350.
[18] Pd(II)-chiral N-monoprotected amino acid in Pd(II)-catalyzed
asymmetric C-H functionalization, see: a) B.-F. Shi, N. Maugel, Y.-H.
Zhang, J.-Q. Yu, Angew. Chem. Int. Ed. 2008, 47, 4882; Angew.
Chem. 2008, 120, 4960; b) M. Wasa, K. M. Engle, D. W. Lin, E. J.
Yoo, J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 19598; c) L. Chu, X.-C.
Wang, C. E. Moore, A. L. Rheingold, J.-Q. Yu, J. Am. Chem. Soc.
2013, 135, 16344; d) P. Jain, P. Verma, G. Xia, J.-Q. Yu, Nat. Chem.
2017, 9, 140 and references cited therein.
[19] Cooperative effect of phosphine ligand and carboxylic acid in Pd(0)-
catalyzed C-H functionalization, see: T. Saget, S. J. Lemouzy, N.
Cramer, Angew. Chem. Int. Ed. 2012, 51, 2238; Angew. Chem. 2012,
124, 2281.
[20] Oxidative Pd(II)-CPA catalyzed enantioselective transformations,
see: a) H. Alper, N. Hamel, J. Am. Chem. Soc. 1990, 112, 2803; b) Z.
Cai, T. J. Rainey, J. Am. Chem. Soc. 2012, 134, 3615; c) G. Jindal, R.
B. Sunoj, J. Am. Chem. Soc. 2014, 136, 15998; d) T. Jiang, T.
Bartholomeyzik, J. Mazuela, J. Willersinn, J.-E. Bäckvall, Angew.
Chem. Int. Ed. 2015, 54, 6024; Angew. Chem. 2015, 127, 6122; e) A.
This article is protected by copyright. All rights reserved.

10.1002/anie.201712521
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
MeO
MeO
NMe
Asymmetric Synthesis
NHP
*
*
Pd(CPA)2(MeCN)2
NP
R = Ar
Xu Bao, Qian Wang, and Jieping
Zhu*__________ Page – Page
3 (–)-mesembrane
R
*
*
L*, O2, Na2CO3
H
R
N
1
2
Palladium-Catalyzed Enantioselective
Desymmetrizing Aza-Wacker Reaction:
Development and Application to the
Total Synthesis of (–)-Mesembrane and
(+)-Crinane
O
*
*
CPA =
L* =
O
O
O
Me
Me
O
4 (+)-crinane
P
OH
O
N
N
H
Be cooperative: In the catalytic enantioselective cyclization of 1 to 2, the pyrox ligand determined the
sense of enantioselectivity, while the matched chiral phosphoric acid increased synergistically both the
ee and the yield of the product. A concise and divergent total synthesis of (–)-mesembrane and (+)-
crinane was subsequently developed.
This article is protected by copyright. All rights reserved.