Diametric stereocontrol in dynamic catalytic reduction of racemic acyl phosphonates: Divergence from α-Keto ester congeners

Article abstract of DOI:10.1021/ja310980q

An unexpected dichotomy was observed in the Ru-catalyzed asymmetric transfer hydrogenation of acyl phosphonates: reduction proceeded from the opposite face relative to that observed in the analogous reduction of α-keto esters. The first highly selective catalytic hydrogenation of acyl phosphonates was utilized in the dynamic kinetic resolution of α-aryl acyl phosphonates, providing β-stereogenic α-hydroxy phosphonic acid derivatives.

Full text of DOI:10.1021/ja310980q

Communication
pubs.acs.org/JACS
Diametric Stereocontrol in Dynamic Catalytic Reduction of Racemic
Acyl Phosphonates: Divergence from α‑Keto Ester Congeners
Michael T. Corbett and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
crucial in providing high levels of facial selectivity. We were
ABSTRACT: An unexpected dichotomy was observed in
the Ru-catalyzed asymmetric transfer hydrogenation of
acyl phosphonates: reduction proceeded from the opposite
face relative to that observed in the analogous reduction of
α-keto esters. The first highly selective catalytic hydro-
genation of acyl phosphonates was utilized in the dynamic
kinetic resolution of α-aryl acyl phosphonates, providing β-
stereogenic α-hydroxy phosphonic acid derivatives.
interested in testing the notion that the α-keto ester/acyl
phosphonate relationship could be exploited in the context of
our laboratory’s ongoing work involving dynamic kinetic
resolution5 by asymmetric transfer hydrogenation (DKR−
ATH). We recently documented a new Ru(II)-catalyzed DKR−
ATH of β-aryl α-keto esters B, providing hydride delivery from
the Si face to afford α-hydroxy esters E with high levels of
diastereo- and enantioselectivity (path c).6 Extrapolating from
precedent, we proposed that the dynamic reduction of racemic
α-aryl acyl phosphonate B would proceed with an analogous
facial preference; however, in the event, the reduction occurred
from the opposite diastereotopic face, providing the quasidias-
tereomeric product F with excellent levels of selectivity (path
d).7
Context. The leading methodology in the literature for the
enantioselective preparation of α-hydroxy phosphonates is the
addition of dialkyl phosphites to aldehydes (Pudovik reaction).8
Despite its synthetic utility as a C−P bond-forming reaction,
the absence of a diastereoselective variant hinders its
incorporation in complex-molecule synthesis. In principle, a
complementary approach to the enantioselective Pudovik
reaction is the asymmetric reduction of acyl phosphonates.
Recently, Goulioukina and Beletskaya reported the first
catalytic asymmetric hydrogenation of acyl phosphonates, albeit
with modest selectivity (up to 77.5:22.5 er).9 Despite the
wealth of methodologies developed to access this important
structural motif, methodologies designed to access β-stereo-
genic α-hydroxy phosphonates efficiently are scarce.10 The
development of the title reaction would provide a flexible entry
point into new α-hydroxy phosphonic acid derivatives; this
subunit appears in compounds exhibiting antibacterial, antiviral,
antibiotic, pesticidal, and anticancer properties.11
he asymmetric synthesis of small molecules has profited
T
from the development of well-defined homogeneous
catalysts.1 Asymmetric catalysis relies on the fundamental
paradigm that privileged catalysts generate well-defined chiral
spaces that provide an environment capable of effectively
directing similarly structured small molecules for enantiofacial
discrimination.2 This characteristic is practically useful insofar
as a seminal advance can pave the way for useful extensions
based on structurally related congeners. Deviations from this
principle are rare and important in understanding substrate/
catalyst interactions.3 Herein we disclose an unusual diametric
reversal in diastereofacial selection in the asymmetric transfer
hydrogenation of acyl phosphonates compared to the related α-
keto esters. The reactions described provide access to new β-
stereogenic α-hydroxy phosphonic acid derivatives that have
previously been inaccessible in stereoisomerically pure form.
Background/Rationale. α-Keto esters and acyl phosphonates
A behave analogously in the bis(oxazoline)Cu(II)-catalyzed
asymmetric hetero-Diels−Alder reaction with vinyl ethers to
provide dihydropyrans C and D, respectively (Figure 1, paths a
and b).4 Activation of the dicarbonyl moiety via chelation is
Results. When α-aryl acyl phosphonate 1b was employed as a
test substrate, Noyori’s RuCl[(S,S)-TsDPEN](p-cymene)
complex12 was found to provide hydroxy phosphonate 2b
with modest anti/syn selectivity but excellent levels of
enantiocontrol for both diastereomers (Table 1, entry 1). On
the basis of our group’s recent success in tuning the
diastereoselectivity of the DKR−ATH of β-chloro-α-keto esters
through the application of a bulky m-terphenylsulfonamide
ligand,6b aminosulfonamide L2 was employed in the reduction
of 1b in N,N-dimethylformamide (DMF) and delivered a
marked increase in diastereoselectivity (entry 2). Changing the
solvent to dimethyl sulfoxide (DMSO) resulted in a boost in
Received: November 7, 2012
Published: January 8, 2013
Figure 1. Reversal in enantiofacial selectivity.
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 1. Ligand/Substrate Optimization
b
b
c
entry
1
L
solvent
conv. (%)
anti:syn
er
d
1
2
3
4
5
6
7
1b
1b
1b
1b
1b
1a
1c
L1
L2
L2
L3
L3
L3
L3
DMSO
DMF
>95
>95
>95
>95
3:1
14:1
20:1
22:1
29:1
>30:1
−
>99.5:0.5 (98.5:1.5)
99:1
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
−
DMSO
DMF
e
e
DMSO
DMSO
DMSO
>95 (93)
>95 (91)
19
a
b
c
Reactions were performed on 0.155 mmol scale. Determined by 31P NMR analysis of the crude reaction mixture. Determined by chiral HPLC
d
e
analysis. Syn isomer. The value in parentheses is the isolated yield.
diastereoselection up to 20:1 (entry 3). α-Naphthyl ethyl-
enediamine-derived L3 was tested and found to engender even
higher levels of diastereocontrol (entries 4 and 5). Both
dimethyl and diethyl phosphonates were found to provide
comparable levels of reactivity and selectivity (entries 5 and 6);
however, the bulkier diisopropyl phosphonate 1c suffered from
reduced reactivity, presumably because of its increased steric
requirements (entry 7).
selectivity. Heteroaromatic substituents were also amenable to
the reaction, providing the N-Ts-indoyl product 2k in 94%
yield with excellent levels of diastereo- and enantiocontrol.
Ortho substitutents resulted in reduced reactivity, necessitating
elevated temperatures (45 °C) and longer reaction times to
provide 2j with 6:1 dr and 98.5:1.5 er.13
The identity of the α-aliphatic substituent was also
investigated to probe the steric sensitivity of the system
(Table 3). Linear aliphatic substituents were tolerated,
The reaction scope was next examined (Table 2). A variety of
electron-releasing and electron-withdrawing aryl groups were
tolerated, providing products in uniformly high yield and
a
Table 3. Alkyl Substrate Scope
a
Table 2. Aromatic Substrate Scope
a
b
As in Table 2. 36 h.
providing products in equally high yield and selectivity and
allowing for the incorporation of alkene and alkyne functional
handles. The sterically demanding cyclopropyl acyl phospho-
nate reacted slower under the reaction conditions, requiring 36
h to provide 2p with 5:1 dr and excellent enantiocontrol.
To probe the utility of this reaction further, bicyclic substrate
1q was subjected to the reduction conditions and afforded 2q
in high yield with comparable levels of selectivity as for the
acyclic examples (Scheme 1). In contrast to ortho-substituted
2j, hydroxy phosphonate 2q was obtained with excellent levels
of diastereoselectivity, suggesting that the ortho substituent
occupies a sterically encumbering conformation when uncon-
a
Reactions were performed on a 0.155 mmol scale employing 5 equiv
of 5:2 HCO2H:NEt3. Isolated yields of analytically pure material are
reported. Diastereomeric ratios were determined by 31P NMR analysis
of the crude reaction mixtures; enantiomeric ratios were determined
by chiral HPLC analysis. The reaction was performed at 45 °C for 20
h.
b
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Journal of the American Chemical Society
Communication
Scheme 1. DKR−ATH of Cyclic Substrate 1q
strained, causing nonideal substrate−catalyst interactions. The
absolute stereochemistry of the products was established as
(1R,2R) via X-ray crystallographic analysis of 2e and 2q,
confirming the anti orientation of the alcohol and aryl groups.14
The presence of a β-substituent was found to be unnecessary
for high levels of enantioselectivity (Scheme 2). Despite the
Figure 2. Variables that potentially account for the stereoselectivity
inversion.
by the fact that the carbonyl activation mode in the
(amido)Ru(II) complex is dramatically different (outer-
sphere/bifunctional) than in the bis(oxazoline)Cu(II) systems
(inner-sphere chelation control), where acyl phosphonates and
α-keto esters experience identical influence from the chiral
catalyst.
Scheme 2. ATH of Acyl Phosphonates
In summary, an unexpected reversal in facial selectivity was
observed in the Ru-mediated asymmetric transfer hydro-
genation of acyl phosphonates in comparison with their
structural mimics, α-keto esters. This dichotomy in reactivity
was exploited in the development of an extremely selective
dynamic kinetic resolution of α-aryl acyl phosphonates to
provide β-stereogenic α-hydroxy phosphonic acid derivatives.
The first highly selective catalytic reduction of acyl
phosphonates also provides complementary access to challeng-
ing Pudovik adducts. The precise identification of key catalyst/
substrate interactions, reactant orientations, and activation
modes will be important for understanding the divergence
between α-keto esters and acyl phosphonates and exploiting
this finding in future applications.
ASSOCIATED CONTENT
■
development of excellent catalysts for highly asymmetric
Pudovik reactions involving aromatic aldehydes, simple
aliphatic aldehydes typically provide lower levels of selectivity.8
Although the reduction of aryl acyl phosphonate 3a under the
optimized reaction conditions provided (R)-4a15 with only 92:8
er, the reduction of aliphatic acyl phosphonates proceeded to
provide enantiopure products 4b−d in high yield.16 The
excellent levels of enantiocontrol observed for 4b−d are a
marked improvement over those obtained using Pudovik-based
methodologies, highlighting the potential utility and comple-
mentarity of this transfer hydrogenation in the preparation of
enantiopure α-hydroxy phosphonic acids bearing one stereo-
center.
S
* Supporting Information
Experimental procedures and spectral and HPLC data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
jsj@unc.edu
Notes
The authors declare no competing financial interest.
Obtaining a full understanding of the turnover in stereo-
selectivity will require further investigation, but some initial
observations that are relevant to the unusual effects we have
uncovered can be offered (Figure 2). Despite being electronic
congeners of α-keto esters, acyl phosphonates are tetrahedral
rather than trigonal at the α-carbon, a circumstance that alters
the steric environment at the ketone undergoing reduction.
The impact of this geometric change is probably compounded
ACKNOWLEDGMENTS
■
The project described was supported by Award R01
GM084927 from the National Institute of General Medical
Sciences. M.T.C. acknowledges the University of North
Carolina at Chapel Hill Department of Chemistry for an
Ernest L. Eliel Graduate Fellowship. X-ray crystallography
performed by Dr. Peter S. White.
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Journal of the American Chemical Society
Communication
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