Asymmetric synthesis of 2-alkyl-3-phosphonopropanoic acids via P - C bond formation and hydrogenation

Article abstract of DOI:10.1021/ol701500s

Allylic acetates, formed by the acetylation of Baylis Hillman adducts, undergo addition of phosphorus nucleophiles to give stereoselectively the Z-unsaturated esters. TFA cleavage of the fert-butyl ester and asymmetric hydrogenation of the unsaturated aci

Full text of DOI:10.1021/ol701500s

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3619-3622
Asymmetric Synthesis of
2-Alkyl-3-phosphonopropanoic Acids via
P−C Bond Formation and
Hydrogenation
Pallavi A. Badkar, Nigam P. Rath, and Christopher D. Spilling*
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis, One
UniVersity BouleVard, St. Louis, Missouri 63121
cspill@umsl.edu
Received June 24, 2007
ABSTRACT
Allylic acetates, formed by the acetylation of Baylis Hillman adducts, undergo addition of phosphorus nucleophiles to give stereoselectively
the Z-unsaturated esters. TFA cleavage of the tert-butyl ester and asymmetric hydrogenation of the unsaturated acid yields the phosphono
alkyl propanoic acid moiety, commonly found in phosphonate- and phosphinate-based enzyme inhibitors.
The tetracoordinate phosphoryl group is well recognized as
an excellent mimic for the tetrahedral transition state of ester
and amide hydrolysis.1 Thus, phosphonates have become
increasingly common in the development of tools for
biological investigations, and in the generation of lead
compounds for the pharmaceutical industry.2 More recently,
phosphinic acids [RR′P(O)OH] have also become popular
targets as mimics of tetrahedral transition states.3 Both
phosphonate-4 and phosphinate-based3 enzyme inhibitors
commonly contain a 2-alkylpropanoic acid as the carbon
substituent. The additional alkyl residue and resulting ste-
reocenter complicates the synthesis of these molecules and
often results in isomeric mixtures.5
(Figure 1) that show very potent activity.3,4 The phosphorus
carbon bond in the 3-phosphono-2-alkylpropanoic acids is
typically formed by alkylation of a phosphorus nucleophile
with a Michael acceptor,3a,5 but although the chemical yields
are good, there is generally little control of the newly formed
(3) For examples see: (a) Valiaeva, N.; Bartley, D.; Konno, T.; Coward,
J. K. J. Org. Chem. 2001, 66, 5146. (b) Bartley, D.; Coward, J. K. J. Org.
Chem. 2005, 70, 6757. (c) Chen, H.; Noble, F.; Roques, B. P.; Fournie´-
Zaluski, M.-C. J. Med. Chem. 2001, 44, 3523. (d) Jackson, P. F.; Tays, K.
L.; Maclin, K. M.; Ko, Y.-S.; Li, W.; Vitharana, D.; Tsukamoto, T.;
Stoermer, D.; Lu, X.-C. M.; Wozniak, K.; Slusher, B. S. J. Med. Chem.
2001, 44, 4170. (e) Vassiliou, S.; Mucha, A.; Cuniasse, P.; Georgiadis, D.;
Lucet-Levannier, K.; Beau, F.; Kannan, R.; Murphy, G.; Knauper, V.; Rio,
M.-C.; Basset, P.; Yiotakis, A.; Dive, V. J. Med. Chem. 1999, 42, 2610. (f)
Bartlett, P. A.; Kezer, W. B. J. Am. Chem. Soc. 1984, 106, 4282. (g)
Demange, L.; Dugave, C. Tetrahedron Lett. 2001, 42, 6295. (h) McDermott,
A. E.; Creuzet, F.; Griffin, R. G.; Zawadzke, L. E.; Ye, Q.-Z.; Walsh, C.
T. Biochemistry 1990, 29, 5767. (i) Hiratake, J.; Kato, H.; Oda, J. J. Am.
Chem. Soc. 1994, 116, 12059. (j) Demange, L.; Dugave, C. Tetrahedron
Lett. 2001, 42, 6295. (k) Matziari, M.; Beau, F.; Cuniasse, P.; Dive, V.;
Yiptakis, A. J. Med. Chem. 2004, 47, 325.
(4) For examples, see: (a) Majer, P.; Hin, B.; Stoermer, D.; Adams, J.;
Xu, W.; Duvall, B. R.; Delahanty, G.; Liu, Q.; Stathis, M. J.; Wozniak, K.
M.; Slusher, B. S.; Tsukamoto, T. J. Med. Chem. 2006, 49, 2876. (b)
Morphy, J. R.; Beeley, N. R. A.; Boyce, B. A.; Leonard, J.; Mason, B.;
Millican, A.; Millar, K.; O’Connell, J. P.; Porter, J. Biorg. Med. Chem.
Lett. 1994, 4, 2747.
(5) For examples, see: (a) Chen, H.; Noble, F.; Mothe´, A.; Meudal, H.;
Coric, P.; Danascimento, S.; Roques, B. P.; George, P.; Fournie´-Zaluski,
M. C. J. Med. Chem. 2000, 43, 1398. (b) Matziari, M.; Yiotakis, A. Org.
Lett. 2005, 7, 4049.
In spite of the challenging syntheses, there are many
examples of phosphonate and phosphinate enzyme inhibitors
(1) (a) Jacobsen, N. E.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103,
654. (b) Sampson, N. S.; Bartlett, P. A. J. Org. Chem. 1988, 53, 4500. (c)
Bartlett, P. A.; Hanson, J. E.; Giannousis, P. P. J. Org. Chem. 1990, 55,
6268. (d) Bartlett, P. A.; Giangiordano, M. A. J. Org. Chem. 1996, 61,
3433.
(2) For examples, see: (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D.
E. Tetrahedron Lett. 1990, 31, 5587. (b) Patel, D. V.; Rielly-Gauvin, K.;
Ryono, D. E.; Free, C. A.; Rogers, W. L.; Smith, S. A.; DeForrest, J. M.;
Oehl, R. S.; Petrillo, Jr., E. W. J. Med. Chem. 1995, 38, 4557. (c) Wang,
C.-L. J.; Taylor, T. L.; Mical, A. J.; Spitz, S.; Rielly, T. M. Tetrahedron
Lett. 1992, 33, 7667. (d) Dellaria, J. F., Jr.; Maki, R. G. Tetrahedron Lett.
1986, 27, 3337. (e) Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.;
Ruppert, D. Tetrahedron Lett. 1992, 33, 6625.
10.1021/ol701500s CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/11/2007

intermediate alcohol, gave the allylic acetates (1). Dialkyl
phosphites were selected as the model for compounds
containing the P(O)H group. Addition of dialkyl phosphites
to the acetylated Baylis-Hillman adducts (1) in refluxing
N,O-bis(trimethylsilyl)acetamide resulted in the formation
of the phosphono unsaturated esters12 (2) (Scheme 1, Table
Scheme 1. Synthesis of the Unsaturated Esters
Figure 1. Examples of phosphonate and phosphinate enzyme
inhibitors.
Table 1. Addition of Phosphites to Allylic Acetates (1)
no.
R1
R2
R3 yield (%) (2) yield (%) (3) Z/E ratio
stereocenter. This problem has been addressed to some extent
by using a chiral auxiliary on the Michael acceptor.3b,6
However, concern for the environment and a trend toward
“green” chemistry has led to the need for catalytic transfor-
mations.
2a Ph
2b Ph
2c Ph
2d Ph
2e Ph
2f 2-furyl
2g p-MeO-C6H4 t-Bu Me
2h p-Cl-C6H4
2i p-F-C6H4
2j p-Br-C6H4
2k Me
Me Me
t-Bu Me
t-Bu Et
t-Bu Bn
t-Bu i-Pr
t-Bu Me
76
61
73
27
57
70
85
58
77
65
56
Z only
8:1
Z only
Z only
Z only
16:1
Z only
Z only
Z only
Z only
5:1
94
Catalytic asymmetric hydrogenation is a powerful tool for
the introduction of stereocenters.7 Substituted itaconic acids
have been successfully and selectively hydrogenated to give
the corresponding 2-alkylsuccinates,8 which are structurally
similar to the 3-phosphono-2-alkyl propanoic acids of
interest. Therefore, it should be possible to form a phosphono
analogue of itaconic acid as a substrate for asymmetric
hydrogenation. Although we were concerned that the phos-
phoryl group might disrupt the appropriate coordination of
the metal complex to the substrate leading to lower selectivity
and slow reactions, successful examples of the hydrogenation
of phosphonate analogs of commonly used acid substrates
have been reported.9
97
85
96
81
91
89
t-Bu Me
t-Bu Me
t-Bu Me
t-Bu Me
1). With the exception of benzyl phosphite, the yields for
the addition-elimination reactions are generally good. The
corresponding carboxylic acids (3) were obtained by cleaving
the tert-butyl esters with TFA in CH2Cl2.
Phosphono esters (2a) was also prepared as mixture of E
and Z isomers using a published method12a (Scheme 2), as
was the unsubsituted ester (2l). The E isomer showed a signal
in the H NMR spectrum for the alkene hydrogen at 6.95
ppm and the Z isomer showed a signal at 7.75 ppm. This
Herein, we report a method to control the stereochemistry
of the alkylpropanoic acid side chains found in phosphonate
and phosphinate enzyme inhibitors via the asymmetric
hydrogenation of unsaturated precursors. The unsaturated
precursors are formed by the addition of a phosphorus
nucelophile [P(O)H moiety] to acetylated Baylis-Hillman
adducts.
1
(10) (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003,
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Baylis-Hillman reaction of several aldehydes10 with
methyl or tert-butyl acrylate followed by acetylation11 of the
(6) Liu, X.; Hu, E.; Tian, X.; Mazur, A.; Ebetino, F. J. Organomet. Chem.
2002, 646, 212.
(7) For recent reviews of asymmetric hydrogenation, see: (a) Burk, M.
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2003, 103, 3029.
(8) (a) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S. E.
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Tetrahedron Lett. 1996, 37, 7721. (c) Burk, M. J.; Stammers, T. A.; Straub,
J. A. Org. Lett. 1999, 1, 387.
(12) (a) Schoen, W. R.; Parsons, W. H. Tetrahedron Lett. 1988, 29, 5201.
(b) Basavaiah, D.; Pandiaraju, S. Tetrahedron 1996, 52, 2261. (c) Kra¨ıem,
H.; Abdullah, M. I.; Amri, H. Tetrahedron Lett. 2003, 44, 553. (d) Muthiah,
C.; Senthil Kumar, K.; Vittal, J. J.; Kumara Swamy, K. C. Synlett 2002,
11, 1787. (e) Oikawa, H.; Yagi, K.; Ohashi, S.; Watanabe, K.; Mie, T.;
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64, 2368. (f) Fields, S. Tetrahedron Lett. 1998, 39, 6621. (g) Phillion, D.;
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3620
Org. Lett., Vol. 9, No. 18, 2007

able levels of selectivity (Table 2). Neither changes in solvent
or hydrogen pressure showed much effect on the reaction
selectivity.
Scheme 2. Synthesis of E and Z Unsaturated Esters
Since hydrogentation of unstaurated carboxylic acids is
generally more selective than the corresponding esters,8
reaction of the phosphono unsaturated acids were examined.
Unfortnately, hydrogenation of carboxylic acids (3) with
various chiral rhodium catalysts also gave less than satisfac-
tory results (Scheme 3, Table 3). The stereoselectivity of
Scheme 3
clearly identified the product of phosphite addition to the
allylic acetate 2 as the Z isomer. The alkene geometries were
assigned by NOE studies and confirmed in one example (2j)
by single-crystal X-ray diffaction studies on the fully
deprotected acid.13
In a 1995 patent, Talley reported the asymmetric hydro-
genation of some (phosphono) unsaturated esters (2) with a
rhodium dipamp complex. Hydrogenation of the parent
compound (2l, R1 ) H, R2 ) R3 ) Me) gave the saturated
ester with optical rotation ([R]D) of -8.8 (c ) 2.6, MeOH).
The absolute configuration of the chiral center in the product
was assigned as S. No information in the levels of selectivity
or the stereochemistry of the products was reported for the
other examples given in the patent.14
The hydogenation of the parent unsaturated ester 2l with
rhodium dipamp complex was repeated and the reported
value of the optical rotation for the product was confirmed.14
However, in our hands hydrogenation of the substituted Z
phosphono-unsaturated ester (3a) with rhodium dipamp gave
low levels of selectivity (Table 2). Furthermore hydrogena-
Table 3. Asymmetric Hydrogenation of the Unstaurated
Carboxylic Acids Using Rh Catalyst
entry
R1
R3
solvent
ligand
% eea
1
2
3
4
5
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
MeOH
MeOH, Bu3N
MeOH
MeOH, Bu3N
MeOH, Bu3N
Duphos
Duphos
ferrotane
ferrotane
Tangphos
0
30
1
4
52
Table 2. Asymmetric Hydrogenation of the Unsaturated Esters
a Enantiomeric excess determined by HPLC on the methyl ester 4.
no.
R1
R2
R3
solvent
ligand
% eea
hydrogenation improved upon addition of tributylamine to
the reaction mixture, but only to modest levels. After
hydrogenation, the saturated acids (5) were converted to the
corresponding methyl ester (4) by reaction with TMSCHN2
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
t-Bu
t-Bu
Me
Me
Me
Me
Me
Me
Me
MeOH
MeOH
CH2Cl2
PhMe
THF
Dipamp
Duphos
Duphos
Duphos
Duphos
Duphos
Duphos
7
0
34
15
35
36
42
(15) (a) Burk, M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.; Lee,
J. R.; Martinez, J. P. Pure Appl. Chem. 1996, 68, 37. Burk, M. J.; Bienewald,
F.; Challenger, S.; Derrick, A.; Ramsden, J. A. J. Org. Chem. 1999, 64,
3290. (b) Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc. 1998,
120, 4345. (c) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc.
1995, 117, 9375. (d) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002,
41, 1612. (e) Hammadi, A.; Nuzillard, J. M.; Poulin, J. C.; Kagan, H. B.
Tetrahedron: Asymmetry 1992, 3, 1247.
(16) a) Matteoli, U.; Frediani, P.; Bianchi, M.; Botteghi, C.; Gladiali, S.
J. Mol. Catal. 1981, 12, 265. (b) Genet, J. P.; Pinel, C.; Ratovelomanana-
Vidal, V.; Mallart, S.; Pfister, X.; Bischoff, L.; Cano De Andrade, M. C.;
Darses, S.; Galopin, C.; Laffitte, J. A. Tetrahedron: Asymmetry 1994, 5,
675. (c) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi,
T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (d) Ohta, T.; Takaya,
H.; Kitamura, M.; Nagai, K.; Noyori, R. J. Org. Chem. 1987, 52, 3174. (e)
Drienben-Holscher, B.; Kralik, J.; Agel, F.; Steffens, C.; Hu, C. AdV. Synth.
Catal. 2004, 346, 979. (f) Laue, C.; Schroder, G.; Arlt, D. U.S. Patent 5,-
801,261, 1998.
MeOH
THF
a Enantiomeric excess determined by HPLC.
tion of phosphonate (3a) (R1 ) Ph, R2 ) R3 ) Me) in THF
with rhodium complexes8,15 derived from several other
ligands, e.g., Bophoz8a,b, Mbpe,15a Tangphos,8c,15d and Me-
Duphos,15a,b gave saturated product with <3% enantiomeric
excess (HPLC analysis). Only Et-Duphos15a,b gave measur-
(13) See the Supporting Information.
(14) Talley, J. U. S. Patent 5,473,092, 1995.
Org. Lett., Vol. 9, No. 18, 2007
3621

and the methyl esters were analyzed by HPLC to determine
the selectivity.
showed a negative rotation and an 87% enatiomeric excess
of the opposite R isomer (Scheme 4).
Gratifyingly, hydrogenation of carboxylic acids (3) with
the ruthenium catalysts16 (A or B) in methanol and triethy-
lamine at 125 psi H2 gave the saturated acids with good to
high enantiomeric excess (Table 4, Scheme 3). The addition
Scheme 4. Determining the Absolute Configuration
Table 4. Asymmetric Hydrogenation of Unsaturated
Carboxylic Acids Using Ru Catalyst
entry
R1
R3
3, 4, 5
complex
% eea
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Me
a
A
B
A
B
A
B
A
B
A
B
A
B
B
71
91
12
58
65
83
66
85
71
81
62
80
89
2-furyl
Me
Me
Me
Me
Me
Me
f
p-MeO-C6H4
p-Cl-C6H4
p-F-C6H4
p-Br-C6H4
Me
g
h
i
Similarly, methyl (S)-(+)-3-hydroxy-2-methylpropanoate
(8) was converted to the corresponding bromide (9) using
triphenylphosphine and bromine. Arbuzov reaction of the
bromide (9) with trimethyl phosphite gave the saturated
methyl ester (4l). This saturated ester had [R]D ) +8.19 (c
0.26, MeOH) which coresponded to the “R” isomer. The
saturated ester (4l) obtained by the hydrogenation using the
dipamap Rh-catalyst gave a negative rotation, which core-
sponded to the “S” isomer, confirming the early observations
by Talley for this compound.
In conclusion, 2-alkyl-3-phosphonopropanoic acids are
formed with high enantioselectivity by addition of phosphites
to acetylated Baylis-Hillman adducts, cleavage of the tert-
butyl ester and asymmertic hydrogenation with ruthenium
complexes.
j
k
a Enantiomeric excess determined by HPLC on the methyl ester 4.
of a tertiary amine base was critical for high enantiomeric
excess. The (R)-Cl-MeO-BIPHEP-Ru catalyst (complex B)
was more sective than the Binap-Ru catalyst (complex A).
To determine the absolute stereochemistry of the saturated
acids from hydrogenation, the commercially avialable opti-
cally pure (2R)-methyl 2-benzylsuccinic acid (6) was con-
verted into the corresponding phosphonate (4a). Bromode-
carboxylation (Hundsdiecker reaction) of the succinic acid
(6) using bromine and red mercuric oxide in methylene
chloride yielded the desired bromide 7, albeit in very low
yield.17 Arbuzov reaction of the bromide 7 with neat trimethyl
phosphite led to the formation of the saturated ester (4a),
again in low yield. This saturated ester had a postive rotation
([R]D) and an 86% enantiomeric excess of the S isomer
(HPLC). The saturated ester (4a) obtained by hydrogenation
using the (R)-Cl-MeO-BIPHEP-Ru catalyst (complex B)
Acknowledgment. We are grateful to the National
Science Foundation for funding this work (CHE-0313736).
We also thank National Science Foundation for grants to
purchase the NMR spectrometer (CHE-9974801), the mass
spectrometer (CHE-9708640), and the X-ray diffractometer
(CHE-0420497) used in this work. We thank Mr. Joe Kramer
and Prof. R. E. K. Winter, UMsSt. Louis, for mass spectra.
Supporting Information Available: Typical experimen-
tal procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Arney, B. E., Jr.; Wilcox, K.; Campbell, E.; Gutierrez, M. O. J.
Org. Chem. 1993, 58, 6126. (b) Johnson, R.; Ingham, R. Chem. ReV. 1956,
56, 219.
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