A diastereo- and enantioselective synthesis of α-substituted anti-α,β-diaminophosphonic acid derivatives

Article abstract of DOI:10.1039/b808393b

Highly diastereo- and enantioselective additions of α- nitrophosphonates to imines catalyzed by a chiral Bronsted acid are described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b808393b

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A diastereo- and enantioselective synthesis of a-substituted
anti-a,b-diaminophosphonic acid derivativesw
b
Jeremy C. Wilt,a Maren Pinkz and Jeffrey N. Johnston*a
Received (in College Park, MD, USA) 20th May 2008, Accepted 2nd July 2008
First published as an Advance Article on the web 6th August 2008
DOI: 10.1039/b808393b
Highly diastereo- and enantioselective additions of a-nitrophos-
phonates to imines catalyzed by a chiral Brønsted acid are
described.
tives.1,15,16 However, we immediately faced several obstacles
that prevented the extension of these and other principles
outlined in the literature: (1) the possible activating effect a
phosphonate group might provide was overcome by the steric
demands of the phosphonate group in the addition transition
state, and (2) our initial survey of achiral base and acid
catalysts revealed a complete absence of substrate-controlled
diastereoselection. The latter aspect highlighted the need for a
chiral reagent to impart high levels of diastereoselection.
We describe here how these obstacles can be overcome using
bifunctional catalyst 1, leading in two steps (addition/reduc-
tion) to a-substituted-a,b-diamino phosphonic acids in
diastereo- and enantiomerically enriched form. These trans-
formations constitute the first fully stereocontrolled additions
of a-nitro phosphonates to azomethines.
As structural and functional surrogates for a-amino acids,
a-amino phosphonic acids have been explored widely as tools
for the study and manipulation of disease pathways.1 More
recently, this functionality has surfaced within biologically
active natural products such as K-26.2 a,b-Diamino acids have
attracted interest for similar reasons.3 Accordingly, these
attributes have stimulated the development of methods for
the synthesis of these functional motifs, but few possess the
brevity of carbon–carbon bond-forming reactions to create the
a-substituted amino phosphonic acid or vic-diamine substruc-
tures.4–6 We would like to report the direct synthesis of
a,b-diamino phosphonic acids using a bifunctional catalyst
that activates both reactants. As an additional challenge, we
targeted a-substituted a-amino phosphonic acids, as these
required the development of a strategy to control diastereo-
selection between two hindered reactants. Similar substitu-
tions to create non-proteinogenic tertiary (a-substituted)
a-amino acids have been explored in the development of
enzyme inhibitors, helix-inducing peptide monomers, and
robust analogs of natural amino acids.7,8
Initial experiments clearly indicated that substituted nitro-
phosphonates 3 were considerably less reactive than
nitroethane, requiring 5 days to reach 72% conversion
Table 1 Chiral proton catalyzed additions of a-nitrophosphonates to
azomethines: effect of phosphonate ester sizea
As an approach to a-substituted a,b-diamino acids, the use
of a-substituted nitro acetates9–12 is not complicated by post
addition epimerization, but demands a catalyst effective in
activating this hindered pronucleophile. Additionally, only
high levels of kinetically controlled diastereo- and enantio-
selection can render this approach as practical as it is straight-
forward. Enantioselective additions of nitroalkane derivatives
have proliferated in recent years as a result of a variety of new
catalyst systems.13 We recently disclosed a bifunctional cata-
lyst that could deliver epimerizable a-nitro esters with high
diastereo- and enantioselection.14 In this context, the use of
a-nitro phosphonates appeared to be a straightforward
extension to provide the a-aminophosphonic acid deriva-
Conv.a
(%)
Entry
R
t/d
drb
%eeb
1
2c
3
4
5
6
a
OEt
OEt
3a
3a
3b
3c
3d
3e
5
2
7
8
12
7
72
90
70
68
87
32
4 : 1
1 : 1
2 : 1
4 : 1
3 : 1
12 : 1
65
0
63
80
84
88
OBn
OiPr
OCHEt2
OCHiPr2
All reactions were 0.1 M in substrate. Conversions were approxi-
b
mated by 31P NMR. Diastereomer ratios were measured by
31P NMR and corroborated by HPLC. Enantiomer ratios were
measured using chiral stationary phase HPLC. See ESIw for complete
details. The free base of 1 was used.
c
a Department of Chemistry and Vanderbilt Institute of Chemical
Biology, Vanderbilt University, Nashville, TN 37235-1822, USA.
E-mail: jeffrey.n.johnston@vanderbilt.edu; Fax: (+1) 615 343 1234;
Tel: 615 322 7376
b IU Molecular Structure Center, Indiana University, Bloomington,
IN 47405, USA. E-mail: mpink@indiana.edu
w Electronic supplementary information (ESI) available: Preparation
and analytical data for all new compounds. CCDC 689295. For ESI
and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b808393b
z To whom questions regarding crystallography should be addressed.
ꢀc
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Table 2 Chiral proton catalyzed additions of nitrophosphonates to
azomethinesa
Fig. 1 Effect of phosphonate ester size on putative diastereomeric
transition state arrangements.
Yield
(%)
(Table 1, entry 1). And although the free base of 1 shortened
the reaction time significantly (5 - 2 d), the addition product
was delivered as a 1 : 1 ratio of diastereomers, both as
racemates (Table 1, entry 2). The chiral Brønsted acid did
improve diastereoselection to a modest level (4 : 1) while
providing the major diastereomer in 65% ee and the minor
diastereomer in 11% ee.
Entry
Ar
drb
%eeb
1
2
3
4
5
6
4-ClC6H4
a
b
c
d
e
f
49
68
84
74
78
75
9 : 1
2 : 1
6 : 1
7 : 1
8 : 1
6 : 1
88
67
99
99
99
85
3,4-Me2OC6H3
4-MeOC6H4
4-PhOC6H4
4-AllyloxyC6H4
4-MeO-3-
MeC6H3
The consistently absent (achiral catalysts, e.g. Et3N,
iPr2NEt: 1 : 1 dr) or low diastereoselection in these experi-
ments may be due to a combination of effects. Comparison
was first made to the diastereoselective additions of
nitroethane (with 2a: 17 : 1, 82% ee), using 1. We hypothesized
7
8
9
10
11
12
13
a
4-MeO-3-BrC6H3
4-MeSC6H4
4-PhSC6H4
4-PhC6H4
C6H5
2-Np
4-AcOC6H4
g
h
i
j
k
l
71
86
69
46
54
50
48
5 : 1
15 : 1
12 : 1
10 : 1
5 : 1
83
99
99
88
82
88
97
9 : 1
6 : 1
m
that the addition of
a diethyl phosphonate group to
All reactions were 0.67 M in substrate. Conversions (7 d) were
approximated by 31P NMR: entry 1, 57%; 2, 96%; 3, 93%; 4, 95%;
5, 99%; 6, 92%; 7, 92%; 8, 92%; 9, 94%; 10, 77%; 11, 62%; 12, 67%;
13, 62%. Diastereomer ratios were measured by 31P NMR and
nitroethane to give 3a provides an additional hydrogen bond
acceptor that abrogates the high diastereoselection. We there-
fore considered diastereomeric transition state arrangements
shown in Fig. 1 and tactics to manage this possible competi-
tion. Phosphonate ester size would be used to minimize a
potential catalyst-phosphonate hydrogen bond by increasing
the associated energetic cost. A catalyst–nitro hydrogen bond,
however, would be affected much less by a change in phos-
phonate ester size. The phosphonate ester size could also
improve diastereoselection by providing better differentiation
of the three groups attached to the nucleophilic carbon
(methyl/nitro/phosphonate).
b
corroborated by HPLC. Enantiomer ratios were measured using chiral
stationary phase HPLC. See ESI.w
and absolute configuration by X-ray crystallography (see
ESIw).17 The anti-diastereoselection is consistent across three
nitroalkane addition classes (nitroalkane,18 nitroester,14 and
nitrophosphonate), but opposite that of a-substituted
nitroesters14b using this catalyst class.14c Diastereoselection
was generally high (Table 2, entries 3–13) in the range of
5–15 : 1, with one exception at 2 : 1 dr for disubstituted
aldimine 2b. This substrate also provided the lowest enantio-
selection (67%), whereas the remaining examples ranged from
83%–99% ee (Table 2, entries 3–13).
Small changes in phosphonate ester size (Table 1, entries
1–4) provided only improvement to enantioselection (65–84%
ee) while maintaining some diastereoselection at the 2–4 : 1
level. Fortunately, further branching of the ester led to sig-
nificant improvement in diastereoselection to 12 : 1 (Table 1,
entry 5), but substantial attenuation of rate. With regard to
reactivity, our comparisons were made using 50 mol% catalyst
loadings in an attempt to separate catalyst reactivity from
turnover. Control experiments throughout these studies also
established that there was no detectable product formation at
room temperature or below when using larger phosphonate
esters (3d, 3e) in the absence of catalyst. Low conversion at
long reaction times did mitigate our enthusiasm of substantial
catalyst-induced dual stereoselection. However, we moved
forward due to the unparalleled simplicity with which these
enantioenriched a,a-disubstituted a-amino phosphonic acid
precursors could be produced.
Investigations of less electron rich aldimines led to a notice-
able loss of reactivity (ca. 20% lower yield), but virtually
identical selectivity, when paired with catalyst 1 (Table 2,
entries 1, 10–13). Insofar as bifunctional catalyst 1 is providing
both Lewis acid activation of the Schiff base, and functions as
a general base19 for pronucleophile (3) activation as well, we
have not successfully deconvoluted the catalyst’s roles to
determine the primary reason for this slightly lower reactivity.
We unmasked nitro phosphonates 5 to their underlying
amino phosphonic acid functionality in a representative ex-
ample (Scheme 1). Phosphonate 5d was reduced to the corres-
In order to improve overall rate, we developed a protocol
that employs dichloroethane solvent, slightly higher substrate
concentration (0.67 M), 10 mol% catalyst loading, and a
standard reaction time to produce the desired adducts in good
isolated yield (Table 2). Dichloroethane provided for greater
homogeneity at higher concentration. Electron rich aldimines
can be particularly good substrates, leading to the anti-adducts
5 diastereo- and enantioselectively (Table 2, entries 3–7).
Cocrystallization of 5i and ent-5h led to assignment of relative
Scheme 1 Conversion of a-nitrophosphonates to a-amino phospho-
nates and a-amino phosphonic acids.
ꢀc
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ponding a-amino phosphonate in 84% yield using zinc powder
in HCl/ethanol9 with retention of configuration and without
Boc deprotection. Additionally, warming of this a-amino
phosphonate in 50% aq HCl cleanly forms the fully depro-
tected a,b-diamino phosphonic acid.
Drug Des., 2006, 67, 101 Synthesis: H. Vogt and S. Brase, Org.
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In summary, we have developed the first stereocontrolled
additions of a-nitrophosphonates to imines as a concise route
to a-substituted a,b-diamino phosphonic acids. Key to this
development is the identification of sterically large phospho-
nate ester 3e as a pivotal design element in our use of a chiral
catalyst to achieve simultaneously high diastereo- and enan-
tioselection in the synthesis of the tertiary nitrophosphonate
products.20 The Lewis acidity of these catalysts is clearly
important (the free base is nonselective) for stereocontrol,
but the catalyst efficacy is not compromised by the use of
sterically large nitrophosphonate 3e. These anti-diastereo-
selective additions are—for reasons not yet clear—stereocom-
plementary to similar additions of a-nitro esters which provide
syn-adducts. Studies are underway to further examine our
hypothesis that control of phosphonate hydrogen bonding is
the key to high diastereoselection.
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Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2008, 130, 2170.
15 Enantioselective preparations are limited to a-(mono)substituted a-
aminophosphonates, often by carbon–phosphorus bond formation.
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We are grateful to the NSF (CHE-0415811) for initial
funding, and the Vanderbilt Institute of Chemical Biology
for continued support.
Notes and references
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17 The co-crystal of C29H51N2O7PSꢁC34H53N2O7PS was obtained from
an ethanol solution. C63 H104N4O14P2S2, M = 1267.56, monoclinic,
space group P21,
a
=
14.1975(7),
b
=
13.6185(7),
c = 18.9091(10) A, b = 96.379(1)1, V = 3633.4(3) A3, Z = 2; T
= 130 K. A total of 49 900 reflections were measured of which 14 767
(Rint = 0.0425) were independent and 12 538 observed (I 4 2s(I)).
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full-matrix least squares/difference Fourier cycles.21b All non-
hydrogen atoms were refined with anisotropic displacement para-
meters. All hydrogen atoms were placed in ideal positions and refined
as riding atoms with relative isotropic displacement parameters. The
final residuals were R1 = 0.0521 (I 4 2s(I)) and wR2 = 0.1462 (F2,
all data) with GOF = 1.033, absolute structure parameter ꢂ0.01(7)
established by anomalous dispersion effects in diffraction measure-
ments on the crystal. The largest residual peak (0.77 e Aꢂ3) is located
near disordered isopropyl groups. For a co-crystal of the opposite
enantiomers of RSMe and RSPh; the coordinates of the two
congeners are almost perfectly related by a pseudo inversion center.
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ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 4177–4179 | 4179