Proline-based P,N ligands in palladium-catalyzed asymmetric π-allyl additions

Article abstract of DOI:10.1002/(SICI)1521-3773(19990917)38:18<2750::AID-ANIE2750>3.0.CO;2-5

Excellent yields and at least 95 % ee can be achieved for the addition of dimethyl malonate to cycloalkenyl acetates by using a palladium complex of the new phosphanyldihydrooxazole ligand L as a catalyst (see scheme). The ligand L can be synthesized from

Full text of DOI:10.1002/(SICI)1521-3773(19990917)38:18<2750::AID-ANIE2750>3.0.CO;2-5

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[7] p-Nitrophenyl sulfate is available from Sigma Co. (US$ 18.90 per g).
[8] S. G. Ramaswamy, W. B. Jakoby, Methods Enzymol. 1987, 143, 201 ± 7.
[9] [35S]PAPS is available from NEN Life Science Products (US$ 1013 per
100 mCi). The half-life of 35S is 87.1 d. End-point methods of 35S
detection on TLC normally involve indirect qualitative determination
of radioactivity.
[10] a) A. D. Marshall, J. F. Darbyshire, W. B. Jakoby, J. Biol. Chem. 1997,
272, 9153; A. D. Marshall, J. F. Darbyshire, W. B. Jakoby, Chem. Biol.
Interact. 1998, 109, 107; b) Y. S. Yang, S. W. Tsai, E. S. Lin, Chem. Biol.
Interact. 1998, 109, 129; c) W.-X. A. Guo, Y.-S. Yang, X. Chen, P.
McPhie, W. B. Jakoby, Chem. Biol. Interact. 1994, 92, 25 ± 31; d) Y.-S.
Yang, J.-J. Pan, J.-K. Hwang, Protein Eng. 1997, 10, 70.
AcO
CO2Me
CO2Me
CH2(CO2CH3)2
MeO2C
MeO2C
cation/base
[{π-C3H5PdCl}2]
ligand
n
n
n
1 n = 0
2 n = 1
3 n = 2
4 n = 0
5 n = 1
6 n = 2
Scheme 1. Asymmetric addition of dimethylmalonate to cyclic allyl
acetates 1 ± 3.
knowledge there are currently only two systems that give
greater than 95% ee with these types of substrates.[16±22]
Herein we report the synthesis of new phosphanyldihydroox-
azole ligands that can be used to catalyze this substitution in
high enantiomeric excess. The results obtained with these
ligands are comparable to the most selective catalysts for the
reaction of this substrate. Additionally, these ligands are
readily accessible from common amino acids and are proving
useful in the catalysis of a number of asymmetric trans-
formations.
The design of this system was founded on the observation
that ligands based on proline often result in reasonably high
stereodifferenation. There have been a number of examples
of proline-based bisphosphane systems that have resulted in
selective catalysis.[23±27] For this reason a series of proline-
based phosphanyldihydrooxazole ligands was synthesized.
The synthesis of this class of ligand begins with commer-
cially available tert-butoxycarbonyl (BOC)-protected trans
4-hydroxy-l-proline (7) which could be coupled to either an
amino acid ester or an amino alcohol (Scheme 2). The
dihydrooxazole was formed through reduction of the ester
[11] Y.-S. Yang, A. D. Marshall, P. McPhie, W.-X. A. Guo, X. Xie, X. Chen,
W. B. Jakoby, Protein Expression Purif. 1996, 8, 423 ± 429.
[12] E.-S. Lin, Y.-S. Yang, Anal. Biochem. 1998, 264, 111 ± 117.
[13] X. Chen, Y. S. Yang, Y. Zheng, B. M. Martin, M. W. Duffel, W. B.
Jakoby, Protein Expression Purif. 1992, 3, 421 ± 6.
[14] S. Ozawa, K. Nagata, D. Gong, Y. Yamazoe, R. Kato, Nucleic Acids
Res. 1990, 18, 4001.
[15] LineWeaver, a graphical enzyme kinetics program for the Macintosh,
was provided by Dr. Ian Ollmann, California Institute of Technology.
[16] The N-acetyllactosamine dimer generously provided by Kathryn M.
Koeller (Research group of Prof. Wong, Scripps Research Institute).
[17] M. Schultze, C. Staehelin, H. Rohrig, M. John, J. Schmidt, E.
Kondorosi, J. Schell, A. Kondorosi, Proc. Natl. Acad. Sci. USA 1995,
92, 2706 ± 2709.
Â
[18] P. Lerouge, P. Roche, C. Faucher, F. Maillet, G. Truchet, J. C. Prome, J.
Â
Â
Denarie, Nature 1990, 344, 781.
Proline-Based P,N Ligands in Palladium-
HO
HO
X
Catalyzed Asymmetric p-Allyl Additions**
a, b
O
c
R
OY
+
CO2H
OH
N
N
BOC
Scott R. Gilbertson* and Dejian Xie
NH2
NH
BOC
7
R
8
9
10
R = iPr
R = Ph
R = tBu
X= O Y= Me
X= O Y= Me
X= H2 Y=H
11
12
13
R = iPr 78%
R = Ph 86%
R = tBu 87%
The development of new ligands for use in asymmetric
catalysis has undergone incredible growth in the last ten years.
One of the reactions that has been investigated extensively is
the palladium-catalyzed addition of nucleophiles to allyl
acetates.[1, 2] One of the first substrates to yield to catalysis
with high selectivity was 1,3-diphenylprop-2-enyl acetate.[3±11]
There are now a number of catalysts that have been
developed that will catalyze the asymmetric addition of
malonate to this substrate in greater than 90% enantiomeric
excess. A type of substrate that has been significantly more
difficult to achieve high selectivity with has been the cyclic
allyl acetates 1 ± 3 (Scheme 1).[12±15] To the best of our
S
Ph2P
MsO
d, e
N
R
N
R
N
O
N
BOC
17
18
19
BOC
O
14
15
16
R = iPr 61%
R = Ph 56%
R = tBu 90%
R = iPr 60%
R = Ph 36%
R = tBu 22%
Scheme 2. Synthesis of the dihydrooxazole ligands 17 ± 19. EDC/HOBt,
RT, CH2Cl2; b) when X ˆ O, LiBH4, THF, 08C to RT; c) MeSO2Cl, Et3N,
‡
CH2Cl2, RT; d) Ph2P Na , THF, 788C to RT; e) S8 or Na2S2O2, CH3OH/
H2O, 458C. EDC ˆ 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
HOBt ˆ 1-hydroxy-1H-benzotriazole. Ms ˆ mesyl.
[*] Prof. S. R. Gilbertson, Dr. D. Xie
Department of Chemistry, Washington University
Saint Louis, MO 63130 (USA)
to an alcohol and formation of a bis-mesylate by reaction with
methanesulfonyl chloride. The primary mesylate then under-
went cyclization to form the dihydrooxazole ring (14 ± 16).
After this reaction, the secondary mesylate was subjected to
substitution by sodium diphenylphosphide. Following substi-
tution the phosphane is protected as the phosphane sulfide.
The ligands are purified as the phosphane sulfides and then
converted to phosphanes (20 ± 25) by reduction with Raney
Fax: (‡1)314-935-4481
E-mail: srg@wuchem.wustl.edu
[**] This work was partially supported by the National Institutes of Health
(NIH) (grant no. R01 GM56490-01) and Washington University. We
also gratefully acknowledge the Washington University High-Reso-
lution NMR Facility, partially supported by the NIH (1S10R02004),
and the Washington University Mass Spectrometry Resource Center,
partially supported by the NIH (RR00954), for their assistance.
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Angew. Chem. Int. Ed. 1999, 38, No. 18

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(20) was replaced with d-valine (23) resulted in a significant
decrease in the rate of the reaction as well as a decrease in the
reactionꢁs selectivity (entry 6); however, the major product is
the same enantiomer in both cases. Catalysis by a variety of
complexes with different R groups next to nitrogen resulted in
variable results. Substitution of l-phenylalanine (21) for l-
valine gives lower selectivity (76% ee, entry 7). Use of ligand
22 in the same stoichiometry as ligand 20 resulted in a
decrease in selectivity (entry 10). Ligand 25, which does not
possess a chiral center next to the dihydrooxazole nitrogen,
gives the product in 90% yield and 80% ee (entry 9). The
effect of solvent on the reaction was also probed. It was found
that acetonitrile gives the highest selectivity with DMF and
methylene chloride giving selectivities above 80% ee (entries
13 and 11, respectively). When the reaction conditions found
for cyclopent-2-enyl acetate (1) were used with cyclohex-2-
enyl acetate (2) the reaction proceeded in high yield and with
good selectivity. Catalysis of the addition to the cyclohept-2-
enyl allyl acetate (3) proceeded in good selectivity and at a
faster rate than for 2 (Scheme 3).
Ph2P
Ph2P
Ph2P
N
N
N
R
R
N
BOC
N
BOC
N
BOC
O
O
O
20 R = iPr
21 R = Ph
22 R = tBu
23 R = iPr
24 R = Ph
25
nickel before coordination to palladium. This route is
appealing because it allows the synthesis of a wide variety
of analogues. The R group on the dihydrooxazole ring is easily
changed by simply coupling a different amino acid ester to
trans-hydroxyproline. Another point of differentiation in this
ligand system is at the nitrogen of the proline ring. Our inital
studies have been with the nitrogen protected with a BOC
group but there is clearly the possibility to make systematic
changes to this portion of the molecule.
The reaction with cyclopent-2-enyl acetate (1) and dimethyl
malonate, at 08C, using ligand 20 provided the desired
substitution product in 94% yield and 90% ee (Table 1,
entry 1). Reduction of the temperature to 208C resulted in
an increase in selectivity to 94% ee. At 358C the selectivity
improves to 96% ee. It was felt that modification of the R
CO2CH3
20 / [{π-C3H5PdCl}2]
OAc
CO2CH3
CH2(CO2Me)2,
TBAF/BSA
CH3CN, RT
5
93%
2
Table 1. Reactions of cyclic allyl acetate 1 with dimethylmalonate cata-
lyzed by palladium complexes of ligands 20 ± 25.
89:11 (S):(R)
CO2CH3
CO2CH3
6
OAc
20 / [{π-C3H5PdCl}2]
CH2(CO2Me)2,
TBAF/BSA
CH3CN, –20 ˚C
3
96%
90:10 (S):(R)
Entry[a,b]
Ligand
T [8C]
solvent
Yield [%] Ratio S:R[c]
Scheme 3. Asymmetric addition of dimethylmalonate to cyclohex-2-enyl
acetate 2 and cyclohept-2-enyl acetate 3 by using palladium complexes of
the new phosphanyldihydrooxazole ligand 20.
1
2
3
4[d]
5
6
7
8
9
10[e]
11
12
13
14
20
20
20
20
20
23
21
24
25
22
20
20
20
20
0
20
35
0
20
0
0
0
0
0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
C6H6
94
99
79
96
95
93
99
91
90
92
99
30
90
86
95:5
97:3
98:2
93:7
93:7
Figure 1 shows a model of the metal complex with an allyl
group attached. It has been shown in other phosphanyldihy-
drooxazole systems that addition of the nucleophile to the
allyl group takes place at the carbon that is trans to the
phosphane on the metal center.[4±7, 9, 28±30] To obtain the
products observed with our catalyst the two methylenes of
the five-membered ring must point down toward the BOC
group. It is not obvious from this model what structural
features are responsible for this preference in orientation, but
given the high selectivity it is clearly favored. It is interesting
that the configuration of the carbon center next to dihy-
drooxazole nitrogen does not have a stronger effect on the
selectivity of the catalysis; the same enantiomer is obtained as
the major product regardless of its stereochemistry.
84:16
88:12
88:12
90:10
84:16
91:9
86:14
93:7
90:10
0
25
0
DMF
THF
0
[a] The phosphane ligand is generated by reduction of the phosphane
sulfide with Raney nickel. [b] Reactions were run with 2 mol% Pd to
3 mol% ligand. [c] Enantiomeric ratios were determined by NMR
spectroscopy using the [Eu(hfbc)] shift reagent (hfbc ˆ 3-(heptafluorobu-
tyryl)-d-camphorate). The absolute stereochemistry was determined by
comparison of optical rotations with the literature. [d] The ratio of Pd/
ligand of 1/1 was used. [e] 2 mol% Pd was used.
Ligand 20 has proven to be very effective in the control of
the addition of dimethyl malonate to allyl acetates 1 ± 3. This
system differs from other phosphanyldihydrooxazole ligands
in that the dominating chirality is not the chiral center next to
the dihydrooxazole nitrogen but rather the chirality of the two
hydroxyproline-derived chiral centers. We are currently
looking at catalysis of the addition of other nucleophiles with
this system. Derivatives of this ligand are also being devel-
oped for use in other transition metal catalyzed reactions.
group next to the dihydrooxazole nitrogen atom would result
in an increase in the selectivity. In the phosphanyldihydroox-
azole systems reported previously it has been shown that
changing the stereochemistry of the group next to the
nitrogen alters the selectivity of the catalysts in favor of the
other enantiomer. In the proline-based system reported here
this is not the case. Catalysis with the ligand where l-valine
Angew. Chem. Int. Ed. 1999, 38, No. 18
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Figure 1. Model of the metal complex with an allyl group attached.
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Experimental Section
Procedure for p-allyl alkylation: The phosphanyldihydrooxazole ligand
was mixed with [{Pd(h3-C3H5)Cl}2] in degassed solvent, followed by
addition of the cyclic allylic acetate. To this mixture a solution containing
dimethyl malonate (3 equiv), tetrabutylammonium fluoride (TBAF)
(3 equiv) and N,O-bis(trimethylsilyl)acetamide (BSA) (3 equiv) was added
slowly through a addition funnel (30 min). After the reaction was complete,
water was added to quench the reaction and the organic solvent was
removed by evaporation. The water layer was then extracted with diethyl
ether twice and the ether solution was washed with saturated NaHCO3,
brine, and dried over Na2SO4. Evaporation of solvent gave a residue that
was chromatographed by using EtOAc/n-hexanes (10/90, v/v) as an eluant
to afford a colorless oil.
The enantiomeric purity was determined by integration of the NMR signals
of the methyl residues on the dimethyl malonate, upon titration with
europium chiral shift reagent [Eu(hfbc)3].
DNA Responds to Ionizing Radiation as an
Insulator, Not as a ªMolecular Wireº**
Michael G. Debije, Michael T. Milano, and
William A. Bernhard*
The ligand with the opposite configuration can be synthesized from d-
hydroxyproline, which is accessible from l-hydroxyproline.[30]
Received: March 4, 1999 [Z13109IE]
German version: Angew. Chem. 1999, 111, 2915 ± 2918
The understanding of electron and hole transfer in DNA is
critical to predicting the biological consequences of exposure
to ionizing radiation. These processes are biologically relevant
since about 50% of the consequential damage is produced by
direct-type events,[1] that is, from one-electron loss (holes) and
one-electron gain directly by the DNA[2] or by fast transfer of
holes and electrons to the DNA from adjacent solvent.[3]
Transfer processes are chemically relevant since the distribu-
Keywords: alkylations ´ asymmetric catalysis ´ palladium ´
P,N ligands
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Walter, L. Zsolnai, Tetrahedron Lett. 1994, 35, 1523 ± 1526.
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Am. Chem. Soc. 1996, 118, 1031 ± 1037.
[8] M. Bovens, A. Togni, L. M. Venanzi, J. Organomet. Chem. 1993, 451,
C28 ± C31.
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Williams, J. Chem. Soc. Perkin Trans. 1 1994, 2065 ± 2071.
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[*] Prof. W. A. Bernhard, M. G. Debije, M. T. Milano
Department of Biochemistry and Biophysics
University of Rochester
Rochester, NY 14642 (USA)
Fax: (‡1)716-275-6007
E-mail: william_bernhard@urmc.rochester.edu
[**] We thank Loren Williams and Gary Hu for providing crystals of
d(CGATCG):anthracycline, Tom Colby and Michael Strickler for
assistance in verifying crystal structures, and Yurii Razskazovskii for
his helpful discussions. The technical assistance of Kermit R. Mercer
was invaluable. The investigation was supported by PHS Grant 2-R01-
CA32546, awarded by the National Cancer Institute, DHHS. The
contents of this paper are solely the responsibility of the authors and
do not necessarily represent the official views of the National Cancer
Institute.
[11] S. R. Gilbertson, C.-W. Chang, J. Org. Chem. 1998, 63, 8424 ± 8431.
2752
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Angew. Chem. Int. Ed. 1999, 38, No. 18