Enantioselective Trapping of Oxonium Ylides by 3-Hydroxyisoindolinones via a Formal SN1 Pathway for Construction of Contiguous Quaternary Stereocenters

Article abstract of DOI:10.1021/acs.orglett.7b03916

An enantioselective Rh(II)/chiral phosphoric acid co-catalyzed three-component reaction via trapping of oxonium ylides with 3-hydroxyisoindolinones by a formal S_N1 pathway is described. This reaction allows for the efficient synthesis of isoindolinone derivatives with two contiguous quaternary stereogenic centers in high yields (up to 93%) with excellent enantioselectivities and moderate diastereoselectivities under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.7b03916

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Trapping of Oxonium Ylides by
3‑Hydroxyisoindolinones via a Formal SN1 Pathway for Construction
of Contiguous Quaternary Stereocenters
Zhenghui Kang,† Dan Zhang,‡ Jiayi Shou,† and Wenhao Hu*,†,‡
†Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular
Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
‡School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
S
* Supporting Information
ABSTRACT: An enantioselective Rh(II)/chiral phosphoric
acid co-catalyzed three-component reaction via trapping of
oxonium ylides with 3-hydroxyisoindolinones by a formal SN1
pathway is described. This reaction allows for the efficient
synthesis of isoindolinone derivatives with two contiguous
quaternary stereogenic centers in high yields (up to 93%) with
excellent enantioselectivities and moderate diastereoselectiv-
ities under mild reaction conditions.
onstruction of chiral quaternary carbon stereocenters in
an asymmetric catalytic manner remains one of the most
the heteroatom (Scheme 1b).5,6 For example, introduction of a
N/O atom can convert the carbonium ions into stabilized N-
acyliminium/oxocarbenium ions.5,6 Various nucleophiles, such
as silyl ketene acetals,5a alcohols5b indoles,5c and so forth have
been demonstrated via the formal SN1 reaction. However, only
one chiral quaternary stereocenter has been constructed. The
enantioselective construction of contiguous quaternary stereo-
centers by the formal SN1 pathway has not yet been reported.
Multicomponent reactions involving trapping of onium-
ylides generated in situ from metal carbenoids have gained
significant attention for the construction of complex molecules
with high diversity and selectivity accompanied by high atom
and step economy in recent years. Trapping of onium ylides
with a wide scope of reactive electrophiles via nucleophilic
addition to the prochiral sp2-hybridized carbon atom of double
bonds (e.g., C=O, C=N, and C=C) has been reported by us
and other research groups (Scheme 2a).7,8 In light of the
unique nucleophilicity of the onium ylide intermediates,9 we
envisioned that the onium ylides could be employed in the
enantioselective nucleophilic substitution at the sp3-hybridized
carbon atom of racemic 3-aryl-3-hydroxyisoindolinones by
means of the formal SN1 pathway via the in situ generated N-
acyl ketiminium6 in the presence of Brønsted acid (Scheme
2b). The reaction could give rise to two contiguous chiral
quaternary stereocenters containing an isoindolin-1-one moi-
ety.
C
challenging and demanding topics in modern organic
chemistry.1 Particularly, the intermolecular formation of C−C
bonds between two contiguous quaternary stereogenic centers
is extremely difficult due to the stronger steric hindrance and
weaker C−C bond strength.2 Thus, stereoselective control of
contiguous quaternary centers is a problematic task owing to
harsh conditions for the bond formation. Efforts have been
devoted to addressing these challenges over the past few
decades, mainly focusing on nucleophilic addition and radical
reactions.2,3 On the other hand, enantioselective SN1-type
nucleophilic substitution at the sp3-hybridized carbon atom of
racemic electrophiles is one of the most classical and powerful
methods for the formation of covalent bonds (Scheme 1a).4
Scheme 1. Asymmetric Nucleophilic Substitution of Racemic
Tertiary Electrophiles
However, enantioselective SN1 reactions are far less developed
than the nucleophilic addition reactions because of the difficult
enantiocontrol of the active planar cationic intermediate
generated as an electrophile in SN1 reactions.4a,b Recent
enhancements for the control of enantioselectivity in
nucleophilic substitution between a racemic electrophile and
a nucleophile in the formal SN1 pathway involve introducing a
heteroatom adjacent to the procarbocationic center so that the
resultant cabocation can be stabilized by lone pair electrons on
The reaction of 3-phenyl 3-hydroxyisoindolinone (3a) with
methyl phenyldiazoacetate (1a) and benzyl alcohol (2a) in the
10,7b,8c
presence of both [PdCl(η3-C3H5)]2
and rac-phosphoric
acid in dichloromethane at 25 °C was initially tested. Desired
Received: December 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03916
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
anti-isomers) and moderate dr (entry 8). Further investigation
of chiral PPA revealed that 5e was the best Brønsted acid
catalyst for the reaction.11 When changing [PdCl(η3-C3H5)]2 to
Rh2(OAc)4, a significant increase in yield was observed, but the
ee and dr remained unaffected (entry 9). Further optimizations
under Rh2(OAc)4 catalysis indicated that the enantioselectivity
could be improved by lowering the temperature to −20 °C but
at the expense of reaction yield (entry 10). After screening
various benzyl alcohols and temperatures, significant improve-
ment of yields and enantioselectivities were observed by
replacing benzyl alcohol with 2-methoxybenzyl alcohol to afford
4ab in the presence of Rh2(OAc)4 and 5e at −20 °C (entries 11
and 12).11
Scheme 2. Trapping Onium Ylides with 3-
Hydroxyisoindolinone via the Formal SN1 Pathway
Having established optimal conditions, we turned our
attention to evaluating the substrate scope for this Rh(II)/
chiral PPA-cocatalyzed three-component reaction. A series of 3-
aryl-3-hydroxyisoindolinones 3 were subjected to the desired
transformation with 1a and 2b, and the reaction afforded the
corresponding products 4 in good yields with high
enantioselectivities and moderate diastereoselectivities (Table
2). Isoindolinones 3 bearing p-alkoxy substituents on Ar2
product 4aa was observed in moderate yield along with 6a
derived from the reaction of 3a and 2a as the main side product
(Table 1, entry 1). The yield of 4aa was enhanced to 90%, but
a
Table 1. Selected Optimization Studies
a
Table 2. Substrate Scope of 3-Hydroxyisoindolinones
b
c
d
entry
3
PPA
t
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
rac-5a
rac-5a
5b
25
40
4aa: 50
4aa: 90
4aa: 80
4aa: 85
4aa: 76
4aa: 90
trace
71:29
69:31
76:24
56:44
56:44
58:42
40
0/0
0/0
5c
40
5d
40
0/0
5e
40
26/21
5e
0
5e
0
4ab′: 40
4ab′: 62
4ab′: 30
4ab: 70
4ab: 65
55:45
53:47
51:49
57:43
60:40
70/76
74/64
84/80
89/90
91/95
e
9
5e
0
e
10
5e
−20
−10
−20
ef
,
11
12
5e
ef
,
5e
a
Unless otherwise noted, all reactions were conducted on a 0.2 mmol
b
scale of 3, 1:2:3 = 1.5:1.2:1. Combined yield of anti- and syn-isomers
c
d
after isolation. Ratio of syn/anti determined by crude 1H NMR. The
ee for syn-4/ee for anti-4 determined by HPLC analysis using a chiral
e
stationary phase. Rh2(OAc)4 (1 mol %) instead of [PdCl(η3-C3H5)]2.
f
2-Methoxybenzyl alcohol 2b instead of benzyl alcohol 2a.
a
Unless otherwise noted, all reactions were conducted on a 0.2 mmol
the temperature has to be elevated to 40 °C (entry 2).11
Different chiral BINOL-derived phosphoric acids (PPA) were
then evaluated to fulfill catalytic enantioselective control
(entries 3−6)11 among which only 5e was found to afford
4aa in an enantioselective manner (entry 6) under such
conditions. For improving the enantioselectivity, the temper-
ature was reduced to 0 °C, but no desired product was obtained
(entry 7) due to the low reactivity of 3a at 0 °C. For increasing
the reactivity of the substrate, the introduction of a p-
methoxyphenyl substituent on the 3-aryl-3-hydroxyisoindoli-
none backbone (3b) resulted in product 4ab′ in 40% yield with
substantially enhanced ee (70% ee for syn-isomers, 76% ee for
b
scale of 3, 1:2:3 = 1.5:1.2:1. Combined yield of anti- and syn-isomers
c
d
after isolation. Ratio of syn/anti determined by crude 1H NMR. The
ee for syn-4/ee for anti-4 determined by HPLC analysis using a chiral
e
stationary phase. Performed at 25 °C.
proceeded efficiently to provide the corresponding products
(4ac−4ad) in good yields and enantioselectivities with
moderate diastereoselectivities. When more electron-rich 4-
N,N-dialkylamino groups were placed on Ar2, a significant
increase in yields and enantioselectivities was observed, and
products 4ae and 4af were furnished in excellent yields and
enantioselectivities. Notably, the substrate with a 4-N-
B
DOI: 10.1021/acs.orglett.7b03916
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Letter
morpholino group on Ar2 could afford product 4af in 92% yield
with excellent enantioselectivities (95% ee for syn-4af and 93%
ee for the anti-4af) at 25 °C. These observations indicate the
electron-donating property of the aryl groups at the C-3
position (Ar2) plays a pivotal role in the trapping process.
Similar results (4ag: 76% yield, syn/anti 59:41, 95%/94% ee)
were obtained using the substrate with a 4-methoxy-3-methyl
substituent on Ar2. Isoindolinone motifs bearing different
substituents were then surveyed. A 5,6-dimethyl or dichloro
substituent on the phthalimide aromatic ring did not change
the efficiency of the reaction and gave the products 4ai−4am in
good yields with high enantioselectivities. Moreover, the
substrates with a naphthalene ring were also effective for
providing 4an or 4ao in good yields and high ee values.
To further elaborate the substrate scope, we then
investigated a variety of diazo compounds with 2b and 3. As
shown in Table 3, in the case of Ar3 = 4-MeOC6H4, methyl
Scheme 3. Control Experiments
product was observed when the model reaction was performed
without chiral PPA, or N-methylated 3-hydroxyisoindolinone
was employed as substrate under the otherwise identical
reaction conditions.12 These experiments indicate the require-
ment of a free N−H functionality and the essential role of chiral
PPA for the successful formation and activation of a ketiminium
intermediate.13 Additional control experiments (Scheme 3, eq
3) demonstrated that 6b, with or without 2b, could convert to
product 4ab under the reaction conditions. These observations
strongly support that there is chemical equilibrium between 6b
and the ketiminium intermediate (V).14
a
Table 3. Substrate Scope of Diazo Compounds
b
c
d
entry
3
1:R
4: yield (%)
dr
ee (%)
1
2
3
4
5
6
7
3b
3b
3b
3b
3b
3b
3b
3f
1b: 4-Cl
4bb: 70
4bc: 78
4bd: 75
4be: 82
4bf: 72
4bg: 81
4bh: 83
4fi: 90
54:46
45:55
46:54
47:53
57:43
51:49
39:61
66:34
64:36
62:38
65:35
60:40
89/93
87/91
90/94
85/91
85/93
94/95
90/94
95/92
91/90
94/92
93/91
95/93
1c: 4-Br
On the basis of the mechanistic investigations described
above, we posit a possible mechanism as shown in Scheme 4.
1d: 4-Me
1e: 4-OMe
1f: 3-Br
1g: 3-OMe
1h: 3,4-diMe
1i: 4-F
Scheme 4. Proposed Mechanism
e
8
e
9
3f
1c: 4-Br
4fc: 90
4fe: 93
4fg: 92
4fh: 93
e
10
3f
1e: 4-OMe
1g: 3-OMe
1h: 3,4-diMe
e
11
3f
e
12
3f
a
Unless otherwise noted, all reactions were conducted on a 0.2 mmol
b
scale of 3, 1:2:3 = 1.5:1.2:1. Combined yield of anti- and syn-isomers
c
d
after isolation. Ratio of syn/anti determined by crude 1H NMR. The
ee for syn-4/ee for anti-4 determined by HPLC analysis using a chiral
e
stationary phase. Performed at 25 °C.
aryldiazo acetates bearing either electron-withdrawing or
-donating substituents at the ortho, meta, or para positions of
the phenyl ring were found to react successfully with 2b and 3b,
leading to the desired products 4bb−4bh in good yields (70−
83%) with high ee (up to 95%). The highest ee value (94% ee
for syn-4bg, 95% ee for anti-4bg) was obtained in the case of
Ar1 = 3-MeOC6H4. Importantly, when Ar3 = 4-N-morpholino
phenyl, the reaction maintained its high efficiency at 25 °C,
affording 4fi−4fh in significantly increased yields (90−93%)
with excellent enantioselectivities (90−95% ee) regardless of
the position and electronic nature of the substituents on the
phenyl ring of the diazo compounds (entries 8−12).
Control experiments starting from the O−H insertion
product 7a and 3b were conducted under the standard
conditions in which no three-component product was observed.
The result excludes the possibility that desired product 4 was
formed through a stepwise O−H insertion/Mannich addition
pathway (Scheme 3, eqs 1 and 2). Furthermore, no desired
product was obtained, and the corresponding O−H insertion
N-Acyl ketiminium ions (V) formed from the dehydration of 3
establish chemical equilibrium with 6 and 2 rapidly in the
presence of chiral PPA.14 Meanwhile, Rh2(OAc)4 decomposes
diazo compounds 1 to form electrophilic rhodium carbene
intermediate I, which reacts with alcohol 2 to give rhodium-
associated oxonium ylide intermediate II and its enolate
counterpart III. In addition, intramolecular proton transfer may
give corresponding enol form IV.15 The resulting intermediates
II, III, or IV react with the N-acyl ketiminium (V) immediately
to provide products 4.
In conclusion, we have developed a Rh2(OAc)4 and chiral
PPA-cocatalyzed enantioselective formal SN1 reaction between
a racemic 3-hydroxyisoindolinone and a transient oxonium
ylide by means of the Mannich-type pathway. This approach is
an unprecedentedly catalytic enantioselective SN1-type process
C
DOI: 10.1021/acs.orglett.7b03916
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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for the onium ylide trapping via ketiminium generated in situ.
This method provides facile access to the construction of two
contiguous quaternary carbon centers, and a range of optically
active multisubstituted isoindolinone derivatives can be
obtained from simple starting materials with good yields and
high enantioselectivities. Efforts are ongoing to improve the
diastereoselectivities and understand the mechanism better.
ASSOCIATED CONTENT
* Supporting Information
■
S
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ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03916.
Bhandary, S.; Singh, V. K. Tetrahedron Lett. 2017, 58, 145. (c) Glavac,
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Accession Codes
CCDC 1583165 and 1587746 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Supporting Information.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: huwh9@mail.sysu.edu.cn.
ORCID
Dan Zhang: 0000-0003-0200-8527
Wenhao Hu: 0000-0002-1461-3671
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from NSFC (21332003).
■
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DOI: 10.1021/acs.orglett.7b03916
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