Efficient asymmetric synthesis of structurally diverse p-stereogenic phosphinamides for catalyst design

Article abstract of DOI:10.1002/anie.201500350

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.

Full text of DOI:10.1002/anie.201500350

Angewandte
Chemie
DOI: 10.1002/anie.201500350
Synthetic Methods
Efficient Asymmetric Synthesis of Structurally Diverse P-Stereogenic
Phosphinamides for Catalyst Design**
Zhengxu S. Han,* Li Zhang, Yibo Xu, Joshua D. Sieber, Maurice A. Marsini, Zhibin Li,
Jonathan T. Reeves, Keith R. Fandrick, Nitinchandra D. Patel, Jean-Nicolas Desrosiers, Bo Qu,
Anji Chen, DiAndra M. Rudzinski, Lalith P. Samankumara, Shengli Ma, Nelu Grinberg,
Frank Roschangar, Nathan K. Yee, Guijun Wang, Jinhua J. Song, and Chris H. Senanayake
Abstract: The use of chiral phosphinamides is relatively
unexplored because of the lack of a general method for the
synthesis. Reported herein is the development of a general,
efficient, and highly enantioselective method for the synthesis
of structurally diverse P-stereogenic phosphinamides. The
method relies on nucleophilic substitution of a chiral phosphi-
nate derived from the versatile chiral phosphinyl transfer agent
1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphina-
mides were utilized for the first synthesis of readily tunable
P-stereogenic Lewis base organocatalysts, which were used
successfully for highly enantioselective catalysis.
O
rganophosphorus compounds have a rich history[1] and
their use as achiral or chiral ligands for transition metal
catalyzed transformations has been rapidly growing in both
laboratory synthesis and industrial production.[2] In spite of
heavy activities in this area and the emergence of a few
methods for the synthesis of alkyl- or aryl-containing P-
stereogenic phosphorus compounds or aminophosphines,[3]
the field of phosphinamide chemistry remains relatively
unexplored, and very few phosphinamides (1; Figure 1), in
particular chiral compounds, have been prepared.
Figure 1. Design concept for P-stereogenic organocatalysts.
L (Figure 1) might serve either as an effective organocatalytic
Brønsted acid (NH site) or a Lewis base (O site) depending
on the nature of the substituent on N, and that the chiral
environment could be induced by the P-stereogenicity. To the
best of our knowledge, the use of P-stereogenic phosphina-
mides as catalysts for asymmetric transformations is here-
tofore unknown, most likely because of the lack of a general
and efficient methodology for preparation of these valuable
compounds in an enantioselective fashion.
A literature survey revealed that only three P-stereogenic
phosphinamides, such as methylphenylphosphinamide
(MPPA) and mesitylphenylphosphinamide (MesPPA; Sche-
me 1a), have been reported in enantiomerically pure/
enriched form, and all were obtained by chiral separations.[6]
In addition, their utility has only been examined for use as
a chiral auxiliary.[6] It is apparent that these approaches have
limited scope because of the use of difficult-to-prepare
nonsymmetrical R1R2P(O)Cl reagents.[6b,c] Therefore, to sys-
tematically explore the P-stereogenic phosphinamides as
a new class of organocatalysts for asymmetric transforma-
tions, it is essential for us to first have an efficient method for
accessing a range of structurally diverse P-stereogenic phos-
phinamides (1). Herein, we describe the development of the
first general asymmetric synthesis of 1 and disclose our initial
findings for their use as asymmetric organocatalysts.
In recent years, phosphoric acid derivatives, in particular
=
the -P( O)-N- motif, have drawn significant attention and
have been incorporated into the design and synthesis of
several Brønsted acid and Lewis base organocatalysts (e.g. A,
B, and C; Figure 1) for asymmetric transformations.[4,5] In all
these cases, non-P-stereogenic phosphoramide motifs were
used, and to achieve high asymmetric induction, a sterically
hindered or rigid carbon backbone is typically needed. We
envisioned that chiral, P-stereogenic phosphinamides such as
[*] Dr. Z. S. Han, L. Zhang, Y. Xu, Dr. J. D. Sieber, Dr. M. A. Marsini,
Dr. Z. Li, Dr. J. T. Reeves, Dr. K. R. Fandrick, Dr. J.-N. Desrosiers,
Dr. B. Qu, D. M. Rudzinski, Dr. L. P. Samankumara, Dr. S. Ma,
Dr. N. Grinberg, Dr. F. Roschangar, Dr. N. K. Yee, Dr. J. J. Song,
Dr. C. H. Senanayake
Department of Chemical Development
Boehringer Ingelheim Pharmaceuticals Inc.
900 Ridgebury Road, Ridgefield, CT 06877 (USA)
E-mail: steve.han@boehringer-ingelheim.com
A. Chen, Dr. G. Wang
Department of Chemistry and Biochemistry
Old Dominion University, Norfolk, VA 23529 (USA)
Recently, we reported an efficient asymmetric method for
the synthesis of P-stereogenic phosphine oxides with diverse
steric and electronic properties using our novel template (5),
[**] We thank Scott Pennino and Keith McKellop for HRMS analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500350.
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BnNHLi with 9a afforded the correspond-
ing 1a-Me and 1a-Bn products in good
yields and high enantiomeric purity.
In light of these encouraging results, we
turned our efforts to the preparation of P-
stereogenic methyl-substituted arylphos-
phinamides analogous to MPPA (1k;
Table 2). Initial attempts to synthesize the
corresponding methylphosphinate by addi-
tion of MeMgCl to 8 afforded low yields
(< 10%). However, this issue was resolved
by utilizing the methyl oxazaphosphinine 2-
oxide derivative 10. The addition of
PhMgCl afforded 11a in 66% yield. The
P-Stereogenic MPPA 1k was then prepared
from 11a in excellent yield and high enan-
tiomeric purity (Table 2).[6a] By using this
methodology, 11b and 11c were prepared
Scheme 1. Strategy for efficient asymmetric synthesis of P-stereogenic phosphinamides
through a double displacement.
from which 6 is prepared with high stereoselectivity and good
from 10 in good yields, and the synthesis of the corresponding
1l and 1m was accomplished as previously described. How-
ever, treatment of 10 with the more sterically hindered o-
tolylMgCl and weakly nucleophilic 4-ClC6H4MgBr resulted in
sluggish reactions and less than 30% yields of the isolated,
desired phosphinate products along with a large amount of
double-addition side-products. We hypothesized that a system
yields using readily available PCl3, R1PCl2, or R1P(O)Cl2
reagents (Scheme 1b).[3h] Cleavage of the P N bond by the
À
first nucleophile provides the chiral intermediate 7. Subse-
À
quent P O bond cleavage of 7 with a second carbon
nucleophile provided P-stereogenic phosphine oxides in
high enantiomeric purity. We envisioned that use of an
“NH2” equivalent as the nucleophile for reaction with 7
should allow a general synthesis of the desired phosphinamide
1.
À
À
containing a more reactive P N bond relative to the P O
Table 1: Synthesis of P-stereogenic diaryl- or alkylarylphosphinamides.
Our initial studies geared toward probing reactivity of the
À
P O bond towards LiNH2 revealed that phosphinates with
a phenol functionality are more reactive than others,[6c,7,8] thus
implying that 5 would have a more general use for the
synthesis of 1 with a potentially wide scope. The stereoselec-
À
tivity for the P O bond cleavage of the chiral phosphinate
9a[3h] was next examined by employing LiNH2 as the
nucleophile (Table 1). To our delight, when a THF solution
of optically pure 9a was added to a LiNH2/NH3 solution,
prepared in situ at À708C, the reaction was completed in less
than 30 minutes to provide the desired P-stereogenic phos-
phinamide 1a in quantitative yield and 99.5:05 e.r. along with
recycled (R)-5a (X = 4-Cl, Ar= p-tolyl).
Encouraged by this finding, the synthesis of diversely
functionalized P-stereogenic diarylphosphinamides was
investigated. A variety of chiral phosphinates (9b–j) were
prepared from 8 in good yield on gram scale.[3h,9a] P-
stereogenic phosphinamides with electron-donating (1b)
and electron-withdrawing (1c) groups were readily prepared
in excellent yields and enantioselectivities, as were the
polyaromatic phosphinamides 1d and 1e. Furthermore,
compounds with sterically hindered aromatic rings (1 f–i)
were also be produced in good yields and with excellent
enantiomeric purity. These results compared favorably with
the previously reported synthesis, for example, for compound
1g, where low yield and low enantiomeric purity (87.5:12.5
e.r.) was obtained.[6b] The compound 1j, containing a tert-
butyl group, was also readily prepared by this method, and the
initial enantiopurity of 95:5 e.r. was upgraded to greater than
99:1 e.r. following recrystallization from dichloromethane and
hexanes. Additionally, reaction of either MeNHLi or
[a] Refer to CCDC 1037717 for crystal structure data.[13] [b] Yield is that of
the isolated product. The e.r. value was determined by HPLC analysis
using a chiral stationary phase. [c] After recrystallization from CH2Cl2/
hexanes. THF=tetrahydrofuran, Ts=4-toluenesulfonyl.
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Table 3: Synthesis of P-stereogenic ferrocenyl arylphosphinamides.
Table 2: Synthesis of methyl-containing P-stereogenic phosphinamides.
Yield is that of the isolated product. The e.r. value was determined by
HPLC analysis using a chiral stationary phase.
Table 4: Enantioselective reduction catalyzed by P-stereogenic phos-
phinamide Lewis bases.
Yield is that of the isolated product. The e.r. value was determined by
HPLC analysis using a chiral stationary phase. [a] Refer to CCDC 1037720
for crystal structure data.[13] [b] Refer to CCDC 1037718 for crystal
structure data.
Entry
R3
R4
19
L
e.r.[b] (yield)[c]
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
19a
19a
19a
19a
19a
19a
19b
19c
19d
L1
L2
L3
L4
L5
L6
L6
L6
L6
66:34 (99%)
69:31 (99%)
bond of 10 would be needed to allow a chemoselective ring-
opening reaction. Therefore, we tested the cyclic template 12
which contains a stronger electron-withdrawing 2,5-dichlor-
obenzenesulfonyl moiety. Reaction of 12 with o-tolylMgBr
and 4-ClC6H4MgBr now provided the desired products 13a
and 13b, respectively, in excellent yields with only trace
amounts of double addition side-products. Thus, methylar-
ylphosphinamides 1n and 1o were prepared in excellent
yields and enantiomeric purities.[9a]
P-stereogenic phosphinamides containing ferrocenyl sub-
stituents could also be prepared using this methodology. The
required phosphinate intermediates 17a–d were synthesized
in moderate to good yields from the corresponding cyclic
compounds 8 and 14–16 (Table 3).[9b] Subsequent aminolysis
with LiNH2/NH3 afforded the ferrocenyl arylphosphinamides
1p–s in excellent yields and enantiopurities. There were also
no difficulties in the preparation of the sterically demanding
phosphinamides 1r and 1s.
3[d]
4[d]
5
65:35 (74%) (S)[e]
82:18 (94%) (S)[e]
92:8 (99%)
6
7
8
9
96:4 (99%)
4-MeOC6H4
4-ClC6H4
4-BrC6H4
96.3:3.7 (99%)
96.2:3.8 (99%)
97.5:2.5 (99%)
[a] Refer to CCDC 1037719 for crystal structure data.[13] [b] Determined
by HPLC analysis using a chiral stationary phase. [c] Yield of isolated
product. [d] Hꢀnig’s base (1 equiv) was added to prevent hydrolysis of
catalyst. Base did not affect the reactivity and selectivity based on control
experiments. [e] Confirmed by comparing with literature.[11] DMF=N,N-
dimethylformamide.
With these P-stereogenic phosphinamides in hand, we
next investigated their utility in asymmetric catalysis. We have
designed and synthesized the first simple and modular family
of P-stereogenic phosphinamide-based bidentate phosphine
=
oxide (P O) Lewis base catalysts (L1–L6) from 1 by simply
changing R1 and R2 only (see footnote of Table 4).[10] And
their reactivities in the asymmetric reduction of chalcone
derivatives were examined.[11] Our preliminary studies using
these P-stereogenic Lewis base catalysts for promoting the
challenging 1,4-reduction of the a,b-unsaturated ketone 19a
with trichlorosilane revealed a high potential for enantiose-
lective catalysis (Table 4). All designed catalysts effected
complete reaction within 24–40 hours at 08C to furnish the
desired product 20a in quantitative yield with significantly
high levels of enantioselectivity. This data verified that the
chiral environment created by the P-stereogenic phosphina-
mide could be used to control asymmetric induction in
catalytic asymmetric processes.[12] It is important to note that
higher selectivity was obtained by the employing sterically
congested catalysts L5 and L6 (entry 5 and 6). Furthermore,
the viability of L6 was demonstrated for the reduction of
electronically differentiated chalcones 19b–d with high selec-
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P-stereogenic phosphinamides as a synthetically accessible
and easily tunable template for constructing useful chiral
ligands and organocatalysts.
In conclusion, we have developed the first general method
for the asymmetric synthesis of P-stereogenic phosphina-
mides with diverse substituents and functionalities in enan-
tiomerically pure form. The methodology relies on the
efficient synthesis of chiral phosphinates from cyclic 1,3,2-
benzoxazaphosphinine 2-oxide intermediates which contain
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À
active P O bonds, thus allowing facile displacement by
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Received: January 14, 2015
Revised: February 10, 2015
Published online: && &&, &&&&
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Keywords: asymmetric catalysis · chirality ·
.
nucleophilic substitution · organocatalyst · phosphinamides
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[12] Refer the Supporting Information for the computational details
and results.
[13] CCDC 1037717,
CCDC 1037718,
CCDC 1037720,
and
CCDC 1037719 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
4
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Chemie
Communications
Synthetic Methods
Z. S. Han,* L. Zhang, Y. Xu, J. D. Sieber,
M. A. Marsini, Z. Li, J. T. Reeves,
K. R. Fandrick, N. D. Patel,
J.-N. Desrosiers, B. Qu, A. Chen,
D. M. Rudzinski, L. P. Samankumara,
S. Ma, N. Grinberg, F. Roschangar,
N. K. Yee, G. Wang, J. J. Song,
Making a ‘Phos’: A general, efficient, and
highly enantioselective method for the
synthesis of the title compounds relies on
nucleophilic substitution of a chiral
phosphinate. These chiral phosphina-
mides were utilized for the synthesis of
readily tunable P-stereogenic Lewis base
organocatalysts.
C. H. Senanayake
&&&& — &&&&
Efficient Asymmetric Synthesis of
Structurally Diverse P-Stereogenic
Phosphinamides for Catalyst Design
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!