Bifunctional Iminophosphorane Catalyzed Enantioselective Ketimine Phospha-Mannich Reaction

Article abstract of DOI:10.1055/s-0035-1560530

The enantioselective phospha-Mannich reaction of diethyl phosphite to unactivated N-DPP-protected ketimines catalyzed by a bifunctional iminophosphorane (BIMP) superbase organocatalyst is described. The reaction is applicable to ketimines bearing electron

Full text of DOI:10.1055/s-0035-1560530

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 21–24
letter
21
G. P. Robertson et al.
Letter
Synlett
Bifunctional Iminophosphorane Catalyzed Enantioselective
Ketimine Phospha-Mannich Reaction
Gerard P. Robertson
P(PMP)3
Alistair J. M. Farley
N
P(O)Ph2
H-bond
donor
P(O)Ph2
R2
BIMP cat.
(10 mol%)
HN
O
P
Brønsted
superbase
S
N
H
Darren J. Dixon*
N
H
OEt
OEt
+
R2
R1
EtO
P
H
R1
Et2O
F3C
N
EtO
BIMP cat.
The Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
darren.dixon@chem.ox.ac.uk
O
10 examples
up to >99% yield
and up to 71% ee
CF3
Dedicated to Professor Steven V. Ley on the occasion of his 70th
birthday
Received: 06.10.2015
Accepted after revision: 24.10.2015
Published online: 11.11.2015
lyst-enabled substrate activation and enantioface discrimi-
nation;7 a problem that necessitates the use of metal ion
catalysts, stoichiometric additives or the use of activated
ketimine electrophiles. For example, Shibasaki and co-
workers reported the highly enantioselective N-thiophos-
phinoyl ketimine phospha-Mannich reaction under cop-
per(I) catalysis,8a whereas Nakamura et al. used catalytic
quantities of commercially available cinchona alkaloids in
the presence of super stoichiometric quantities of Na2CO3,
for the enantioselective addition of diethyl phosphite to N-
mesitylene sulfonyl protected ketimines.8b Very recently,
Chimni and co-workers and Reddy and co-workers de-
scribed the catalytic enantioselective phospha-Mannich re-
action of reactive isatin-derived ketimines catalyzed by bi-
functional cinchona-derived thiourea and squaramide cata-
lysts, respectively.8c,d
In an attempt to overcome the reactivity problem of cer-
tain classes of electrophiles and pro-nucleophiles, we re-
cently developed a new class of bifunctional superbase or-
ganocatalysts incorporating for the first time the triarylimi-
nophosphorane moiety as the Brønsted base and with it
achieved the first general enantioselective organocatalytic
ketimine nitro-Mannich reaction.9 The juxtaposition of
both the organosuperbase10 and an appropriate hydrogen
bond donor group over a chiral scaffold was critical for suc-
cessful enantioselective catalysis (high reactivity and enan-
tiocontrol). As a part of this program into the development
of novel asymmetric methodologies for challenging electro-
philes, we wish to report the first organocatalytic enantio-
selective phospha-Mannich reaction of unactivated N-DPP
ketimines.
DOI: 10.1055/s-0035-1560530; Art ID: st-2015-d0800-l
Abstract The enantioselective phospha-Mannich reaction of diethyl
phosphite to unactivated N-DPP-protected ketimines catalyzed by a bi-
functional iminophosphorane (BIMP) superbase organocatalyst is de-
scribed. The reaction is applicable to ketimines bearing electron-rich
and electron-poor aryl substituents and occurs with excellent yields and
moderate enantioselectivities under mild reaction conditions.
Key words asymmetric catalysis, bifunctional organocatalysis, phos-
pha-Mannich, ketimine, superbase
α-Aminophosphonic acid derivatives are α-amino acid
analogues that have found widespread use as biologically
relevant peptide mimics1 and have shown a range of biolog-
ical activities such as antibacterial,2a,b anti-HIV2c,d and pro-
tease inhibition.2e,f As important biological building blocks,
their absolute configuration is significant and accordingly
new improved methods for their enantioselective synthesis
is desirable.3
A direct approach to access such compounds is through
the 1,2-addition of phosphite pro-nucleophiles to imine
electrophiles.4 These reactions can be catalyzed by Brønsted
bases and chiral Brønsted bases can be used to impart
enantioselectivity.5 To date, much attention has focussed on
asymmetric phospha-Mannich reactions to imine electro-
philes derived from aldehydes (aldimines) and highly enan-
tioselective examples using both metal-rich and metal-free
catalyst systems have been reported.6 In the latter case the
emphasis has been largely placed on the development of
methodologies using bifunctional single enantiomer tertia-
ry amine Brønsted base/H-bond donor organocatalysts.5 In
contrast, the corresponding reaction of ketimines has been
much less studied due to their substantially reduced elec-
trophilicity and the difficulties associated with poor cata-
We chose the 1,2-addition of diethyl phosphite 3 to the
unactivated N-DPP-protected ketimine derived from ace-
tophenone 2a as our model system for testing the perfor-
mance of our bifunctional iminophosphorane (BIMP) cata-
lysts (Table 1 and Figure 1). Promising reactivity was initial-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 21–24

22
G. P. Robertson et al.
Letter
Synlett
ly established using 10 mol% of our previously reported
first-generation tert-leucine derived BIMP catalyst 1a with
triphenylphosphine (Table 1, entry 1). After just 24 hours at
room temperature, 74% yield of product 4a was afforded
with an encouraging ee of 56%. However, switching to the
analogous but more basic catalyst 1b derived from tris(p-
methoxyphenyl)phosphine gave rise to a significant boost
in reactivity and a slight boost in enantiocontrol; adduct 4a
was afforded in quantitative yield and with 58% ee (Table 1,
entry 2). The analogous L-phenylalanine or L-valine-derived
catalysts, 1c and 1d respectively, resulted in a drop in enan-
tioselectivity in both cases (Table 1, entries 3 and 4). Em-
ploying catalyst 1e, possessing the diphenylmethyl group as
part of its chiral scaffold, resulted in a drop in the enantio-
selectivity to 23% ee (Table 1, entry 5). Simple modification
of the thiourea hydrogen bond donor group of the first-gen-
eration BIMP organocatalysts led to no improvement in the
level of enantiocontrol (Table 1, entries 6 and 7), and ac-
cordingly alternative second-generation BIMP organocata-
lyst designs were considered. Introducing an additional
amino acid residue11 between the iminophosphorane moi-
ety and Schreiner-type thiourea12 allowed diastereomers
1h and 1j to be synthesized and compared in the reaction.
Interestingly neither catalyst outperformed 1b, but taken
together showed that the valine residue in both catalysts
was dominating enantioselectivity (Table 1, entries 8 and
10). Building on these observations catalyst 1i was tested in
the reaction in the hope that an additional boost in selectiv-
ity would be witnessed, but disappointingly enantioselec-
tivity was reduced to 42% ee (Table 1, entry 9). Having iden-
tified the best catalyst as 1b, a brief re-optimization of the
reaction conditions, with respect to solvent, concentration
and temperature, was carried out but no augmentation of
the enantioselectivity was observed and the optimal condi-
tions remained the same as for Table 1, entry 2.13
P(R2)3
R1
Ph
N
P(PMP)3
Ph
S
N
S
NH
NH
F3C
NH
F3C
NH
CF3
1a: R1 = t-Bu, R2 = Ph
CF3
1e
1b: R1 = t-Bu, R2 = PMP
1c: R1 = Bn, R2 = PMP
1d: R1 = i-Pr, R2 = PMP
P(PMP)3
N
1f: EWG = C(O)NH(m,m-(CF3)C6H3)
1g: EWG = C(O)(m,m-(CF3)2C6H3)
NH
EWG
PMP = para-methoxyphenyl
O
H
N
H
F3C
N
N
H
S
R3
N
Table 1 Proof of Concept and Optimization Studies in the Ketimine
P(PMP)3
Phospha-Mannich Reactiona
CF3
1h: R3 = i-Pr
1i: R3 = t-Bu
P(O)Ph2
HN
P(O)Ph2
+
O
P
1 (10 mol%)
N
EtO
EtO
0.05 M, Et2O, 24 h
P(OEt)2
Ph
O
H
Ph
H
N
H
N
O
F3C
N
2a
3
4a
H
S
N
P(PMP)3
Entry
Catalyst
Yield (%)b
ee (%)c
CF3
1j
1
2
1a
1b
1c
1d
1e
1f
74
99
56
58
45
47
23d
51
8
Figure 1 First- and second-generation BIMP catalysts
3
60
With optimized conditions in hand, we next investigat-
ed the substrate scope and found good tolerance over a
range of electron-rich and electron-deficient aromatic ket-
imines: yields were typically >99% and enantioselectivities
ranged from 41 to 62% ee (Scheme 1). Furthermore, a 3-pyr-
idyl substrate performed well (>99% yield, 53% ee) and
pleasingly the reaction was also applicable to the ethyl ho-
mologue of 2a which afforded product 4j in 71% ee and in
quantitative yield. Absolute configuration of 4a was estab-
lished as S by comparison of the specific rotation of a deriv-
ative with that of a literature compound (see Supporting In-
formation).
4
85
5
>99
>99
84
6
7
1g
1h
1i
8
>99
70
55
42
17d
9
10
1j
41
a Reactions were performed using 3 (0.20 mmol), 2a (2.0 equiv) and cata-
lyst (10 mol%).
b Isolated yield.
c Determined by HPLC analysis on a chiral stationary phase.
d Enantiomer (R)-4a was obtained.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 21–24

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G. P. Robertson et al.
Letter
Synlett
References and Notes
P(O)Ph2
P(OEt)2
HN
R2
R1
P(O)Ph2
O
P
1b (10 mol%)
N
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+
EtO
EtO
0.05 M, Et2O, 24 h
H
R1
R2
O
4a–j
2a–j
3
O
P
O
P
O
Ph
Ph
Ph
Ph
Ph
Ph
P
HN
O
HN
HN
P(OEt)2
O
P(OEt)2
P(OEt)2
O
O
O
4b
4c
4d
O
90% yield
62% ee
>99% yield
58% ee
78% yield
41% ee
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O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
P
P
P
HN
HN
HN
P(OEt)2
P(OEt)2
P(OEt)2
O
O
O
F
4g
Cl
4e
Br
4f
>99% yield
54% ee
86% yield
46% ee
98% yield
56% ee
O
O
P
O
Ph
Ph
Ph
Ph
Ph
Ph
P
P
HN
HN
HN
F3C
P(OEt)2
P(OEt)2
P(OEt)2
O
O
O
N
4h
4i
CF
4j
>99% yield
53% ee
3 >99% yield
52% ee
>99% yield
71% ee
Scheme 1 Scope of the BIMP-catalyzed phospha-Mannich reactiona
In summary we have developed an organocatalytic ket-
imine phospha-Mannich reaction of diethyl phosphite to
unactivated N-DPP ketimines with excellent yields and
moderate enantioselectivities. Further work focussing on
the development of novel asymmetric methodologies for
challenging electrophiles is ongoing in our group and the
results will be disclosed in due course.
Acknowledgment
This work was supported by the EPSRC (Studentship to G.P.R. and
A.J.M.F. and Doctoral Prize [EP/M50659X/1] to A.J.M.F.), AstraZeneca
(Studentship to A.J.M.F.) and the SCI (Postgraduate Scholarship to
A.J.M.F.)
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560530.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 21–24

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G. P. Robertson et al.
Letter
Synlett
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(13) Representative Procedure for the Enantioselective Ketimine
Phospha-Mannich Reaction: To a solution of ketimine 2a (128
mg, 0.40 mmol, 2.0 equiv) and catalyst 1b (15 mg, 0.020 mmol,
0.10 equiv in 4.0 mL of diethyl ether) was added diethyl phos-
phite 3 (26 μL, 0.20 mmol, 1.0 equiv) at rt. Stirring was main-
tained for 24 h whereupon the crude reaction mixture was
purified directly by flash column chromatography [petroleum
ether to petroleum ether–EtOAc (1:2), EtOAc then EtOAc–MeOH
(9:1)] to afford the phospha-Mannich addition product 4a.
Diethyl {(1S)-1-[(Diphenylphosphoryl)amino]-1-phenylethyl}-
phosphonate (4a): The title compound 4a was isolated in 99%
yield (91 mg) and 58% ee as a colorless solid. 1H NMR (500 MHz,
CDCl3): δ = 1.03 (t, J = 7.0 Hz, 3 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.82
(d, JPH = 17.0 Hz, 3 H), 3.53 (ddq, J = 10.0, 7.0, 7.0 Hz, 1 H), 3.81
(ddq, J = 10.0, 7.0, 7.0 Hz, 1 H), 4.03–4.20 (m, 3 H), 7.18–7.30 (m,
5 H), 7.31–7.47 (m, 4 H), 7.51 (dd, J = 7.5, 1.5 Hz, 2 H), 7.55–7.64
(m, 2 H), 7.82–7.91 (m, 2 H). 31P NMR (162 MHz, CDCl3): δ =
20.1 (JPP = 29.3 Hz), 24.8 (JPP = 29.3 Hz). HRMS: (ESI+): m/z calcd
for C24H29NNaO4P2: 480.1464; found: 480.1454. See Supporting
Information for full characterization data.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 21–24