Enantioselective Hydrophosphonylation of in Situ Generated N-Acyl Ketimines Catalyzed by BINOL-Derived Phosphoric Acid

Article abstract of DOI:10.1021/acs.orglett.6b03623

An efficient route to pharmacologically interesting isoindolinone-based α-amino phosphonates is described via asymmetric hydrophosphonylation of in situ generated ketimines catalyzed by BINOL-derived phosphoric acid. The reaction proceeds smoothly at ambient temperature affording a variety of α-amino phosphonates with a quaternary stereogenic center embedded in isoindolinone motif in high yields with excellent enantiomeric ratios (up to 98.5:1.5 er). Several interesting transformations of the products into valuable synthetic intermediates are also depicted.

Full text of DOI:10.1021/acs.orglett.6b03623

Letter
pubs.acs.org/OrgLett
Enantioselective Hydrophosphonylation of in Situ Generated N‑Acyl
Ketimines Catalyzed by BINOL-Derived Phosphoric Acid
Arun Suneja,† Rajshekhar A. Unhale,† and Vinod K. Singh*,†,‡
†Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal, MP-462 066, India
‡Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP-208 016, India
S
* Supporting Information
ABSTRACT: An efficient route to pharmacologically inter-
esting isoindolinone-based α-amino phosphonates is described
via asymmetric hydrophosphonylation of in situ generated
ketimines catalyzed by BINOL-derived phosphoric acid. The
reaction proceeds smoothly at ambient temperature affording a
variety of α-amino phosphonates with a quaternary stereogenic
center embedded in isoindolinone motif in high yields with excellent enantiomeric ratios (up to 98.5:1.5 er). Several interesting
transformations of the products into valuable synthetic intermediates are also depicted.
nantiomerically enriched α-amino phosphonates, and
direct and easy strategy is the enantioselective addition of
Ephosphonic acids are considered as important surrogates phosphite to aldimines (commonly known as aza-Pudovik
reaction).12,13 Another attractive approach for the construction
of the C−P bond is the direct catalytic asymmetric Kabachnik−
for α-amino acids with an impressive diversity of biological
activities.1 Their intriguing biological potential is evident from
Fields reaction.14 In contrast, enantioselective synthesis of
quaternary derivatives via functionalized ketimines remains
elusive, due to their lower reactivity than aldimines and
difficulty in enantiofacial discrimination.15 Although few elegant
approaches to these targets have been reported in the
literature,16a,b access to configurationally and conformationally
rigid quaternary α-amino phosphonates is still challenging.
Recently, our research group has developed an expeditious
approach to access enantioenriched isoindolinones via a
Domino Cu(I)-catalyzed one-pot three-component alkynyla-
tion−lactamization strategy.17 Herein, we envision a practical
approach to enantioenriched isoindolinone-based α-amino
phosphonates 5−6 bearing a C-3 quaternary stereogenic center
via phosphoric acid catalyzed hydrophosphonylation of in situ
generated ketimines of 3-hydroxyisoindolinone 3 (Scheme 1).
Initially, a model reaction comprising 3-hydroxy-3-phenyl-
isoindolin-1-one 3a and diphenyl phosphite 4a was carried out
using (S)-BINOL-derived phosphoric acid PA1 (10 mol %) in
dichloromethane (CH2Cl2) at 23 °C. We realized that the
reaction was sluggish and isoindolinone-based α-amino
observed anti-HIV,2 antibacterial,3 antitumor,4 and antifungal5
activities as well as inhibitors of protease,6 and phosphatase
activity.7 Among various nonracemic derivatives, alafosfalin
(1b) is reported as an antibacterial agent,4 and K-26 (1c) as a
natural product,8 having an angiotensin converting enzyme
inhibitory activity (Figure 1; 1a−c).
Figure 1. Representative examples of α-amino phosphonates and
isoindolinones.
Scheme 1. Working Hypothesis (PA*: Chiral Phosphoric
Acid)
On the other hand, isoindolinones are important structural
scaffolds from a synthetic perspective. Substituted isoindoli-
nones are advanced intermediates in the synthesis of various
drug molecules9a−e and complex natural products9f,g (Figure 1;
2a−c). Therefore, stereoselective synthesis of α-amino
phosphonate embedded with isoindolinone motif would be
challenging in the context of drug discovery.9b
Prominent asymmetric approaches toward α-amino phos-
phonates include resolution,10 chiral auxiliary-based pro-
cesses,10 and various enantioselective approaches.11 The most
Received: December 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03623
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
phosphonate 5a was obtained in moderate yield (entry 1, Table
1). To our delight, the reaction could be expedited in better
yield by proceeding in a closed vessel at 40 °C, affording 5a in
69% yield with a 56:44 er after 30 h (entry 2).
corresponding products 5 in synthetically viable yields as shown
in Figure 2. Notably, substrates 3b−f having an electron-rich
a g
,
Table 1. Selected Optimization Studies
bc
,
d
entry PA
solvent
temp (°C) time (h) 5a (%)
er
1
2
3
4
5
6
7
8
9
1
1
2
3
4
5
6
7
5
5
5
5
5
5
5
5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
p-xylene
CH3CN
Et2O
23
40
40
40
40
40
40
40
40
23
23
23
23
23
23
23
23
96
30
28
28
28
28
28
28
16
18
18
14
32
28
14
14
16
52
69
72
67
80
84
74
79
90
88
74
90
32
72
92
95
91
57:43
56:44
58:42
50:50
66:34
79:21
52:48
50:50
85:15
87:13
86:14
88:12
72:28
78:22
89:11
91:9
Figure 2. Scope of reaction with 3-hydroxyisoindolinones.24 a 22 h.
aryl group at the C-3 position reacted smoothly and afforded
5b−f in synthetically viable yields with excellent enantiomeric
ratios (er) of up to 97.5:2.5. Additionally, the substrates 3g−h
having electron-withdrawing functionalities (such as −CF3,
−Br) furnished 5g (24% yield) and 5h (73% yield) with
selectivities of up to 89:11 er, indicating that electronic factors
play a pivotal role in the hydrophosphonylation process.
Gratifyingly, our optimized conditions work fine with a
variety of substrates 3i−l, which afforded products 5i−l with
excellent selectivities of up to 96:4 er. Moreover, substrate 3m
having a furan moiety at C-3 furnished product 5m in 79%
yield and 95:5 er. Under the reaction conditions, 3n having an
alkyl group at the C-3 position failed to react with 4a even at 40
°C. However, this led to the undesired 3-alkylidene
isoindolinones.19
Next, a variety of dialkyl phosphites 4b−d having different
electronic properties were tested for the hydrophosphonylation
reaction with diversely substituted 3-hydroxyisoindolinones 3
(Figure 3). Interestingly, dimethyl and diethyl phosphite 4b−c
furnished isoindolinone-based α-amino phosphonates 6a−b in
moderate yields with excellent selectivities of up to 97:3 er,
when the reaction was conducted at 40 °C. We speculate that
the low reactivity of dialkyl phosphites 4b−c toward ketimines
could be due to higher pKa values11d,20 of the P−H bond,
leading to inefficient phosphonate-phosphite tautomerism.12c
In contrast, bis(2,2,2-trifluoroethyl) phosphite 4d, having
comparatively a lower pKa value than 4c, was found to be a
potent nucleophile and afforded 6c−e in synthetically viable
yields with excellent enantioselectivities (up to 98.5:1.5 er) at
room temperature.
e
e
e
e
e
e
e
f
10
11
12
13
14
15
16
17
PhCH3
PhCH3
PhCH3
g
90:10
a
Reactions were carried out with 0.05 mmol of 3a and 0.065 mmol of
4a in the presence of catalyst PA (10 mol %) at indicated temperature.
Isolated yields after column purification. Decomposition of the rest
of the mass balance. Enantiomeric ratio (er) was determined by chiral
HPLC. 4 Å MS (35 mg). 5 Å MS (35 mg). 3 Å MS (35 mg). MS
denotes molecular sieves.
b
c
d
e
f
g
Encouraged by the preliminary outcome, various chiral
phosphoric acids PA2−PA7 were examined with the model
substrate (entry 3−8). Among them, PA5 was found to be the
best Brønsted acid18 catalyst to afford 5a with very good
chemical yield (84%) and optical yield (79:21 er). However,
further improvement of yield and enantioselectivity was realized
with the use of 4 Å molecular sieves (MS) to afford 5a at room
temperature with CH2Cl2 as a solvent. Afterward, screening of
various solvents, including CHCl3, p-xylene, CH3CN, Et2O, and
toluene, revealed that toluene was the most suitable solvent of
choice for the reaction. It was observed that 5 Å MS was the
best choice as a water scavenger for the reaction. However,
there was no significant change on the enantioselectivity of the
reaction when different pore sizes of the MS were used (see
Supporting Information (SI) for more details). Therefore,
based on our extensive optimization, the substrate scope was
explored using 10 mol % of PA5 in toluene with 5 Å MS (35
mg) at room temperature.
Substrates 3 consisting of a sterically demanding o-
methoxyphenyl and β-naphthyl group at the C-3 position
furnished 6f with a moderate selectivity of 87:13 er and 6g in
28% yield with 93:7 er (Figure 3). It probably indicates that
steric hindrance at the ortho position plays a significant role in
the enantioselectivity of the product formation. It was also
observed that substrate 3 having −F and −CN functionality
afforded 6h−i with excellent selectivities (up to 97:3 er). To
Initially, a series of 3-hydroxy-3-arylisoindolin-1-ones 3 were
subjected to the optimized reaction conditions and afforded the
B
DOI: 10.1021/acs.orglett.6b03623
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Control Experiments
Scheme 3. Synthetic Elaborations to Important
Intermediates
Figure 3. Scope of the reaction with dialkyl phosphites.24 a 20 h at 40
°C. b 22 h at 23 °C.
our delight, heteroaromatic substrate 3m having a furan moiety
afforded product 6j with high yield and excellent 97:3 er.
Rewardingly, a variety of substrates 3 having both electron-
donating and -withdrawing substitution reacted with 4d to
afford products 6k−o in synthetically viable yields with an
excellent level of enantioselectivities (up to 98.5:1.5 er) (Figure
3).
The X-ray structure analysis of the isoindolinone-based α-
amino phosphonate 6b (CCDC 1516982) confirmed the
absolute stereochemistry to be (R) (Figure 3). The absolute
configuration of the other products within this series were
assigned by analogy. In order to show the practical efficacy of
the methodology, a hydrophosphonylation reaction was carried
out on a 1.0 mmol scale using catalyst PA5 (5 mol %),
affording compound 6c with excellent yield and enantiose-
lectivity (91%, 98:2 er) (see SI for details).
To gain some insight into the reaction mechanism, a control
experiment was performed. Under the optimized conditions, N-
methyl protected 3v failed to react with 4a, which indicates the
requirement of a free N−H group is essential for the successful
activation and preorganization of an acyliminium ion
intermediate.19 Furthermore, in the case of trimethyl phosphite
4e as a nucleophile, the reaction led to formation of a trace
amount of 6a (Scheme 2). This probably suggests that the OH
group of the dialkyl phosphite is essential for obtaining the high
yields and enantioselectivity.13b,21
deprotected isoindolinone 8 was obtained, either by
debenzylation or by demethylation reaction in synthetically
viable yields without any loss of enantiopurity. Eventually,
hydrolysis of the phosphonate diester 5b could be achieved
easily by using LiOH·H2O to obtain the α-amino phosphonate
monoester 9 in 76% yield, which could serve as an important
synthon for the phosphono-peptides inhibitors of β-lacta-
mases.23 Furthermore, complete hydrogenolysis of 5b was
carried out in the presence of a PtO2 catalyst to afford
enantiomerically enriched α-amino phosphonic acid 10 in 82%
yield and 97:3 er (see SI for details).
In summary, we have reported the chiral phosphoric acid
catalyzed hydrophosphonylation of in situ generated ketimines
under ambient conditions for the first time, to the best of our
knowledge. A variety of dialkyl and diphenyl phosphites were
utilized to access biologically interesting isoindolinone-based α-
amino phosphonates comprising a quaternary stereogenic
center with remarkably high enantioselectivities (up to
98.5:1.5 er). The usefulness of this protocol has also been
demonstrated by the synthesis of optically active α-amino
phosphonic acid, α-amino phosphonate monoester, and other
valuable synthetic intermediates. Further application of this
strategy is under active investigation in our laboratory.
Finally, to illustrate the synthetic viability of our method-
ology, we converted the isoindolinones 5d and 6c into sulfur
analogues 7a and 7b, respectively, by treatment with Law-
esson’s reagent (Scheme 3). The latter could be used for the
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03623.
■
S
synthesis of thioisomunchnone salts which act as a dipole for
̈
1,3-dipolar cycloaddition reaction.22 In another sequence, O-
C
DOI: 10.1021/acs.orglett.6b03623
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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X-ray data for 6b (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vinodks@iitk.ac.in.
ORCID
Vinod K. Singh: 0000-0003-0928-5543
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support through the J. C. Bose fellowship (DST,
Government of India) and SERB, DST (EMR/2014/001165)
are gratefully acknowledged. We thank Mrs. Anusha Upadhyay,
IISER Bhopal, for the X-ray structure analysis. A.S. and R.A.U.
thank the CSIR, New Delhi for the SRF and SPMF fellowships,
respectively.
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DOI: 10.1021/acs.orglett.6b03623
Org. Lett. XXXX, XXX, XXX−XXX