Asymmetric hydrogenation of α- And β-enamido phosphonates: Rhodium(I)/monodentate phosphoramidite catalyst

Article abstract of DOI:10.1002/anie.201104912

High efficiency and enantioselectivity have been achieved in the Rh ^I-catalyzed asymmetric hydrogenation of α- and β-enamido phosphonates using a monophosphoramidite as the chiral ligand (see scheme; cod=1,5-cyclooctadiene), thus affording the optically active amino phosphonates with a turnover frequency of up to 1800 h^-1 and high ee values. Copyright

Full text of DOI:10.1002/anie.201104912

DOI: 10.1002/anie.201104912
Synthetic Methods
Asymmetric Hydrogenation of a- and b-Enamido Phosphonates:
Rhodium(I)/Monodentate Phosphoramidite Catalyst**
Jinzhu Zhang, Yang Li, Zheng Wang, and Kuiling Ding*
Optically active a- and b-amino phosphonic acid derivatives
are bio-isosteric analogues of the corresponding amino acids,
and have found widespread use in biochemistry and pharma-
ceuticals as active substances in anticancer drugs, enzyme
inhibitors, catalytic antibodies, herbicides, bactericides, and
antibiotics.[1] Consequently, considerable research efforts
have been devoted to the asymmetric synthesis of these
compounds over the past decades.[2] Several catalytic asym-
metric methods involving different types of bond-forming
processes have been developed in recent years for the
synthesis of the a-amino phosphonic acid derivatives.[3]
Among these protocols, catalytic asymmetric hydrogenation
(AH) is particularly attractive and potentially practical when
considering both atom efficiency and environmental con-
cerns.[4] In spite of the great potential, however, so far the AH
of a-enamino phosphonic acid derivatives has only received
limited attention. Since the first report by Schçllkopf and co-
workers in 1985,[5] a couple of catalytic systems based on RhI-
or RuII/bisphospines have been developed for the AH of a-
enamido phosphonates, thus affording the a-amino phos-
phonic acid derivatives in good efficiency and varying levels
of enantioselectivity.[3b,6] In contrast, catalytic asymmetric
protocols that can provide direct access to b-amino phos-
phonic acid derivatives are remarkably scarce.[3a,7] Specifi-
cally, catalytic AH of b-enamido phosphonates remains less
explored despite some notable achievements made very
recently for the AH of b-aryl-substituted b-enamido phos-
phonates by using rhodium- or iridium/diphosphine cata-
lysts.[8–10] It seems somewhat surprising that to date no
successful use of readily available monodentate chiral phos-
phine ligands in the RhI-catalyzed AH of a- or b-enamido
phosphonates has been achieved, despite the great successes
in the AH of their dehydroamino acid analogues.[11] Apart
from easy preparation and good stability, an important
advantage of using monodentate phosphine ligands is that
they may allow the use of ligand mixtures for rapid generation
of a chiral catalyst library and hence high-throughput screen-
ing for a targeted reaction.[12] Herein, we present our results
on the use of a monodentate phosphoramidite ligand,
DpenPhos,[13a–b] for the efficient RhI-catalyzed AH of a wide
variety of a- and b-enamido phosphonates to give the
corresponding a- and b-amino phosphonates in excellent
optical purities.
The study was initiated by screening the RhI complexes of
some well-established phosphoramidite ligands[11b,13–14]
(Scheme 1) using (E)-dimethyl 1-benzamido-2-phenylvinyl-
phosphonate (1a), a benchmark substrate for AH of a-
enamido phosphonates (see Table 1 for reaction equation).
The reactions were performed in dichloromethane at an
ambient pressure of hydrogen with 1 mol% of the catalyst,
which was made in situ by reacting [Rh(cod)2]BF4 (cod =
cycloocta-1,5-diene) with the corresponding phosphoramidite
ligand in a 1:2 molar ratio. Under such reaction conditions,
this class of complexes demonstrated a distinct behavior in
catalytic activity, that is, either active or inactive depending on
[*] Dr. J. Zhang, Y. Li, Dr. Z. Wang, Prof. Dr. K. Ding
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P.R. China)
E-mail: kding@mail.sioc.ac.cn
[**] Financial support from the National Natural Science Foundation of
China (Nos. 21172237, 20821002, 21032007), the Major Basic
Research Development Program of China (Grant No.
2010CB833300), and the Chinese Academy of Sciences is gratefully
acknowledged. We also thank Prof. Jiabi Chen of SIOC for his kind
help in growing the single crystals of the [Rh(cod){(S,S)-L6}2]BF4
complex.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104912.
Scheme 1. Chiral monodentate phosphoramidites used in this study.
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Communications
Table 1: RhI/(S,S)-L6 catalyst used for the AH of b-substituted a-
whether or not the relevant phosphoramidite ligand carried a
enamido phosphonates.[a]
À À
P N H moiety within its structure. Whereas full conversions
could be achieved within 1 hour when using (S)-L2 and (S,S)-
L6–L8, no product was detected under analogous reaction
conditions when using (R,R)-L1, MonoPhos, SIPHOS, (S,S)-
L3, or (R,R)-L4–L5 (see the Supporting Information). All
these experimental facts clearly indicate the importance of
Product S/C[b]
ee [%][c]
À À
the P N H moiety of the ligand for catalytic activity, and may
Entry
R
provide a suitable platform for either multicomponent
catalyst assemblies or substrate organizations through hydro-
gen-bonding interactions in the catalysis.[13b–c] Catalysts of the
DpenPhos series [(S,S)-L6–L8] gave the best results, thus
yielding 2a in 97–98% ee irrespective of the variation in
either R1 or R3. The solvent effect is also dramatic in terms of
reactivity and enantioselectivity (see the Supporting Infor-
mation). For the AH of 1a using the Rh/(S,S)-L6 catalyst,
CH2Cl2, ClCH2CH2Cl, toluene, or iPrOH yielded full con-
versions with ee values above 96%, whereas the protic solvent
methanol only resulted in poor conversion (29%) and a
significantly reduced ee value (40%) under otherwise identi-
cal reaction conditions. Under optimized reaction conditions,
hydrogenation of a number of b-aryl-substituted (E)-dimethyl
a-benzamido phosphonates catalyzed by Rh/(S,S)-L6
afforded the corresponding a-amino phosphonate esters
with high ee values (Table 1, entries 1–5). Considering that
Cbz is an amine protecting group that is easier to remove than
Bz, we next turned to the N-Cbz-protected a-enamido
phosphonate esters 3a–q to investigate the substrate scope.
Gratifyingly, the hydrogenation turned out to be quite general
and the Rh/(S,S)-L6 catalyst worked very well with a variety
of substrates (Table 1, entries 6–22). All the reactions were
accomplished within 1 hour at room temperature with an
ambient pressure of hydrogen, thus providing the correspond-
ing chiral phosphonates 4 in quantitative conversion with high
ee values (97– > 99%) in most cases. Neither the electronic
nature nor the steric hindrance of the b substituent (R) had
any obvious influence upon the enantioselectivity and re-
activity (Table 1, entries 6–21), and consistently high ee values
were obtained for substrates with aromatic (Table 1,
entries 6–17), heteroaromatic (entry 18), and alkyl
(entries 19–21) substituents at the b positions. An exception
was found in the case of the b-styryl-substituted substrate 3q,
wherein the double bond in proximity to the N-Cbz group was
selectively hydrogenated with full conversion, albeit with a
slightly lower ee value (Table 1, entry 22). It is noteworthy
that the productivity of the Rh/(S,S)-L6 catalyst can be very
high under elevated hydrogen pressures, as shown in the case
of the hydrogenation product 4o, whose R isomer is the
synthetic precursor of the potent aminopeptidase inhibitor
(R)-phospholeucine.[15] After a prolonged reaction at 40 atm
of H2 with a catalyst loading of 0.01 mol% (S/C = 10000), (S)-
4o was isolated in high yield (95%) on gram scale with
excellent enantioselectivity (Table 1, entry 23). Finally, the
Rh/(S,S)-L6 system was also efficient in the catalytic AH of
the terminal N-Cbz enamido phosphonate 5, to give (S)-6
(whose R isomer is the synthetic precursor to the potent
antibacterial agent Alafosfalin)[16] in high optical purity
(Table 1, entry 24). To verify the tolerance of the catalyst
system for the E- or Z-isomeric substrate, both E and
1
2
3
4
5
6
7
8
Ph (1a)
2a
2b
2c
2d
2e
4a
4b
4c
4d
4e
4 f
4g
4h
4i
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
>99 (S)
>99 (S)
>99 (S)
>99 (S)
>99 (S)
98 (S)
97(S)
98 (S)
98 (S)
98 (S)
98 (S)
>99 (S)
97 (S)
98 (S)
98 (S)
4-FC6H4 (1b)
4-ClC6H4 (1c)
4-BrC6H4 (1d)
3-ClC6H4 (1e)
Ph (3a)
2-MeC6H4 (3b)
3-ClC6H4 (3c)
3-BrC6H4 (3d)
3-MeOC6H4 (3e)
4-FC6H4 (3 f)
4-ClC6H4 (3g)
4-BrC6H4 (3h)
4-NO2C6H4 (3i)
4-MeOC6H4 (3j)
9
10
11
12
13
14
15
4j
16
(3k)
4k
100
>99 (S)
17
18
19
20
2-naphthyl (3l)
2-thienyl (3m)
c-hexyl (3n)
iPr (3o)
tBu (3p)
styryl (3q)
iPr (3o)
H (5)
Ph [(E)-7]
Ph [(Z)-7]
4l
4m
4n
4o
4p
4q
4o
6
100
100
100
100
100
100
10000
100
100
100
100
98 (S)
97 (S)
>99 (S)
98 (S)
98 (S)
86 (S)
21
22
23[d]
24
98 (S)
>99 (S)
99 (+)
88 (+)
95 (+)
25[e]
26[e]
27[e]
8
8
8
Ph [(E)/(Z)-7] (E/Z=2.88:1)
[a] Reaction conditions: [1a-e]=0.1m; [3a-q]=0.2m, [5]=0.2m; [Rh-
(cod)2]BF4 =1 mol%, RhI/(S,S)-L6=1:2. Conversion always >99%
(31P NMR). [b] Substrate/catalyst (S/C) molar ratio. [c] Determined by
chiral HPLC analysis using a chiral stationary phase. Absolute config-
urations of 2a–c were assigned by comparison of [a]D with the literature
values, 4c and 4o by X-ray analysis (see the Supporting Information),
and 4a by derivatizing to a known compound; absolute configurations of
2d–e, 4b, 4d–n, 4p–q determined by CD analysis (see the Supporting
Information). [d] PH =40 atm, 16 h. The yield of the isolated 4o is 95%.
2
[e] With catalyst RhI/(R,R)-L6, PH =5 atm, 3 h. Bz=benzoyl,
2
Cbz=benzyloxycarbonyl.
Z isomers of ethyl b-phenyl-a-enamido phosphonates [(E)-7
and (Z)-7] were prepared and submitted to the hydrogena-
tion. It was found that the reactions proceeded with complete
conversion of the substrates and afforded the corresponding
a-amino phosphonate ester 8 in 99 and 88% ee, respectively,
with the same sense of asymmetric induction (Table 1,
entries 25 and 26). For the AH of an E/Z-isomeric mixture
of 7 (E/Z = 2.88:1), a satisfactory ee value (95%) of the
product 8 was obtained upon full conversion of the substrate
(Table 1, entry 27), thus attesting to the robustness of the
protocol.
To further demonstrate the efficiency of the present
catalysis, we carried out a series of reaction profile studies on
the hydrogenation of 3o using the catalyst [Rh-
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Angew. Chem. Int. Ed. 2011, 50, 11743 –11747

Table 2: RhI/(S,S)-L6 or RhI/(S,S)-L8 catalyst used for the AH of Z or E isomers of b-
(cod)2]BF4/(S,S)-L6. The effects of the substrate
concentration, catalyst concentration, and hydrogen
pressure on the reaction rates were examined. The
consumption of 3o was evaluated by 1H NMR
analysis of aliquots taken from the active hydro-
genation mixture, and the reaction profiles, which
were measured under standard conditions (molar
ratio Rh/(S,S)-L6 = 1:2, T= 268C, CH2Cl2 solvent),
are shown in Figure S5 in the Supporting Informa-
tion. There is no apparent incubation period shown
in the profiles in Figure S5(a), thus suggesting a fast
activation of the precatalyst by hydrogenation of the
cod ligand. In most cases the initial rates are almost
maintained until approximately 50–70% conversion.
The reactions proceed at nearly the same rates for all
the tested substrate concentrations (see Figure S6 in
the Supporting Information), thus indicating a zero-
order dependence of the hydrogenation rate on
substrate concentration. There is a consistent en-
hancement in the initial reaction rates with the
catalyst concentrations from 0.25 to 1.0 mm,
although the profile at [Rh] = 0.25 mm demonstrates
a complex behavior at the early stage of the reaction
[Figure S5(b)]. As shown in Figure S5(c), the cata-
lytic activity increases significantly with ascending
hydrogen pressures, with a TOF value of 1800 hÀ1
being achieved at 4 atm hydrogen (60% conversion
within 2 min). Altogether, the RhI/(S,S)-L6 system
demonstrates high efficiency and excellent enantio-
selectivity in the AH of a broad range of a-enamido
phosphonates, thus suggesting its potential utility in
the synthesis of optically active a-amino phospho-
nates.
enamido phosphonates[a]
Entry Substrate
R
PG Ligand
PH
t
ee [%][b]
2
[atm] [h]
1
2
3
4
5
6
7
8
(Z)-9a
(Z)-9b
(Z)-9c
(Z)-9d
(Z)-9e
(Z)-9 f
(Z)-9g
(Z)-9h
(Z)-9i
(Z)-9j
(Z)-9k
(Z)-9l
(E)-9g
C6H5
4-MeC6H4
4-MeOC6H4 Bz
4-FC6H4
4-ClC6H4
4-BrC6H4
2-ClC6H4
2-naphthyl
3-thienyl
cyclohexyl
2-pyridyl
2-CF3C6H4
2-ClC6H4
Bz
Bz
(S,S)-L6 10
16
>99 (R)
98 (R)
96 (R)
98 (R)
98 (R)
>99 (R)
>99 (R)
95 (R)
>99 (R)
>99 (R)
46 (R)
n.r.
81 (R)
93 (R)
88 (À)
96 (À)
>99 (R)
(S,S)-L6
(S,S)-L6
5
5
12
12
16
16
16
16
16
16
16
24
16
16
16
16
16
24
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Ac
Ac
Bz
(S,S)-L6 10
(S,S)-L6 10
(S,S)-L6 10
(S,S)-L6 10
(S,S)-L6 10
(S,S)-L6 10
(S,S)-L6 10
(S,S)-L6 45
(S,S)-L6 10
(S,S)-L6 10
(S,S)-L6 10
(S,S)-L8 10
(S,S)-L8 10
(S,S)-L6 40
9
10
11[c]
12
13
14
15
16
17[d]
9g (E/Z=1:4) 2-ClC6H4
(E)-9m
(Z)-9m
(Z)-9 f
4-MeC6H4
4-MeC6H4
4-BrC6H4
[a] Unless otherwise specified, the conversions were >99% as determined by
31P NMR analysis. Reaction conditions: [9a–m]=125 mm, [Rh-
(cod)2]BF4 =1.25 mm, Rh/(S,S)-L6 (or (S,S)-L8)=1:2. [b] Determined by chiral
HPLC analysis using a chiral stationary phase. Absolute configuration of 10e was
determined by X-ray crystal structure analysis, while those of 10a–d and 10 f–k were
assigned by comparison of their CD spectra to that of (R)-10e (see the Supporting
Information), [c] 15% conversion. [d] 0.1 mol% catalyst loading, 95% conversion.
n.r.= no reaction, PG=protecting group.
higher hydrogen pressure (45 atm; Table 2, entry 11). The
Encouraged by these results, we moved to examine the
catalytic efficiency of RhI/(S,S)-L6-type complexes in the AH
of the more demanding b-enamido phosphonate esters.
Compound (Z)-9b was used as the model substrate for
optimization of the reaction conditions and ligand screening.
RhI/(S,S)-L6 was again found to be optimal in terms of both
reactivity and enantioselectivity, and effected complete con-
version into 10b (98% ee) after 12 hours in CH2Cl2 under
5 atm H2 (see the Supporting Information). Extension of the
protocol to the AH of a series of b-enamido phosphonate
esters was also generally successful, and the results are
summarized in Table 2. For the (Z)-b-enamido phosphonates
having an aromatic substituent, the reactions proceeded
smoothly to full conversions and the enantioselectivities
were generally excellent, ranging from 95 to greater than
99% ee (Table 2, entries 1–8). An exception is the reaction
involving the substrate with a strongly electron-withdrawing
2-CF3-substituted phenyl group [(Z)-9l]; in this case no
product was detected under similar reaction conditions
(Table 2, entry 12). It is also noteworthy that by using this
protocol, for the first time, (Z)-b-enamido phosphonates
bearing a b-heteroaryl or an b-alkyl substitutent can be
hydrogenated with excellent enantioselectivity (Table 2,
entries 9 and 10, respectively). However, the system is
substantially less efficient for the substrate with a b-2-pyridyl
substituent as the reaction proceeds sluggishly even under a
RhI/Dpenphos catalytic system RhI/(S,S)-L6 or RhI/(S,S)-L8
also gave satisfactory results in the AH of (E)-b-enamido
phosphonates, albeit with a somewhat lower enantioselectiv-
ity compared to their Z isomers (Table 2, entries 13 versus 7,
and 15 versus 16). The catalyst can therefore tolerate the use
of an E/Z = 1:4 isomeric mixture of substrate 9g to afford the
corresponding product with a compromised enantioselectivity
(Table 2, entry 14). It is noteworthy that so far not a single
catalyst has been reported to be efficient for the hydro-
genation of Z/E mixtures of b-enamido phosphonates. Finally,
under a reduced catalyst loading of 0.1 mol%, the AH of (Z)-
9 f under 40 atm of H2 afforded 95% conversion into 10 f with
a greater than 99% ee after 24 hours (Table 2, entry 17).
To understand the structural details of the catalyst
precursor, a single crystal of the complex [Rh(cod){(S,S)-
L6)}2]BF4 was grown from the CH2Cl2/acetone/n-hexane
(1:1:1) solvent mixture and characterized by X-ray crystallog-
raphy. As shown in Figure 1, the complex contains two
phosphoramidite ligands, (S,S)-L6, coordinated to rhodium
through the P atom, with a square-planar coordination
arrangement around the metal center. Such a pattern is
typical for closely related Rh/phosphoramidite complexes
reported previously by the groups of Reetz[17] and Zhou[18] as
well as ourselves.[13a] The Rh P bond lengths of [Rh(cod)-
À
{(S,S)-L6)}2]BF4 (2.2679(12) and 2.2727(13) ꢀ) are essentially
in keeping with the literature values of these complexes,
Angew. Chem. Int. Ed. 2011, 50, 11743 –11747
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
in high enantioselectivity (> 99% ee) by using this procedure.
Moreover, the catalyst was also successful in the AH of a
variety of b-substituted (Z)- or (E)-b-enamido phosphonate
esters, with ee values ranging from 95% to greater than 99%
in most cases. The X-ray crystallographic analysis reveals that
the catalyst precursor contains two ligand moieties in its
structure, and an NLE study demonstrates that the rhodium
species involved in the catalysis contains more than one
monodentate phosphoramidite ligand within or at the periph-
ery of the catalytic cycle. These salient features suggest that
the present approach is likely to find use in the synthesis of
optically active a- or b-amino phosphonic acid derivatives.
Figure 1. Crystal structure of [Rh(cod){(S,S)-L6)}2]BF4·(CH3COCH3)4-
(CH2Cl2). The hydrogen atoms, solvent molecules, and the BF4
counteranion have been omitted for clarity. The thermal ellipsoids are
shown at 50% probability.
Received: July 14, 2011
Revised: August 25, 2011
Published online: October 11, 2011
À
Keywords: asymmetric hydrogenation · enantioselectivity ·
.
phosphane ligands · rhodium · synthetic methods
whereas the P-Rh-P bite angle [93.78(4)8] is distinctly smaller.
There is a hydrogen bond formed between one of the (S,S)-L6
ligands and a lattice enclathrated acetone molecule in the
complex (see the Supporting Information). The hydrogena-
tion of the substrate 3o using this isolated Rh/(S,S)-L6
complex afforded 4o in 99% ee, which is essentially the same
as that attained using the corresponding in situ prepared
complex, thus suggesting that [Rh(cod){(S,S)-L6}2]BF4 should
indeed be the catalyst precursor in the reaction. Furthermore,
31P NMR spectroscopy of the in situ prepared Rh/(S,S)-L6
(1:2 molar ratio) complex indicated the clean formation of a
single species in the solution (see the Supporting Informa-
tion). Moreover, the nonlinear effect (NLE)[19] of the [Rh-
(cod)2]BF4/(S,S)-L6 catalyzed hydrogenation of 3a was exam-
ined using (S,S)-L6 with varying ee values under the reaction
conditions shown in Table 1. A positive NLE was observed for
this catalytic system (see Figure S6 in the Supporting Infor-
mation), thus indicating that the Rh species involved in the
catalysis should contain more than one monodentate phos-
phoramidite ligand within or at the periphery of the catalytic
cycle. Finally, investigation of the effect of the Rh/L ratio on
rate and ee value, in combination with the some preliminary
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1
31P and H NMR studies on the [Rh(cod)2BF4]/L6 systems
generated in situ with Rh/L molar ratios of 1:1, 1:2, 1:3, and
1:4, shows that a [Rh(L6)2] species should be responsible for
the catalysis (see the Supporting Information).
In conclusion, chiral monodentate phosphoramidite
DpenPhos ligands bearing a primary amine moiety [(S,S)-
L6–L8] have been found to be highly efficient in the RhI-
catalyzed AH of a- and b-enamido phosphonates, including a
wide variety of b-aryl-, b-heteroaryl-, and b-alkyl-substituted
substrates. For the RhI/(S,S)-L6-catalyzed AH of a-enamido
phosphonates, ee values ranging from 96% to greater than
99% were obtained in most cases under an ambient pressure
of H2 at room temperature. The resulting catalyst is very
reactive (turnover frequency of up to 1800 hÀ1 at 4 atm
hydrogen), and the S enantiomer of the potent aminopepti-
dase inhibitor (R)-phospholeucine could be obtained on gram
scale with 98% ee under a very low catalyst loading (S/C =
10000). The S enantiomer of a synthetic precursor to the
potent antibacterial agent Alafosfalin could also be obtained
11746 www.angewandte.org
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www.angewandte.org 11747