Resolved chiral 3,4-diazaphospholanes and their application to catalytic asymmetric allylic alkylation

Article abstract of DOI:10.1021/ja036359f

One-pot condensation of PhPH₂, phthaloyl chloride, and the azine of 2-carboxybenzaldehyde (1) results in the new phosphine, rac-N,N′-phthaloyl-2,3-(2-carboxyphenyl)-phenyl-3,4-diazaphospholane (rac-2), in 88% yield. Resolution via selective cry

Full text of DOI:10.1021/ja036359f

Published on Web 09/03/2003
Resolved Chiral 3,4-Diazaphospholanes and Their Application to Catalytic
Asymmetric Allylic Alkylation
Thomas P. Clark and Clark R. Landis*
Department of Chemistry, UniVersity of Wisconsin, 1101 UniVersity AVenue, Madison, Wisconsin 53706
Received May 27, 2003; E-mail: landis@chem.wisc.edu
Scheme 1. Synthesis and Resolution of Diazaphospholanea
Collections of chiral ligands1 offer the promise of accelerating
the discovery of new catalysts for asymmetric transformations.
Because of the ubiquity of phosphine ligands in catalysis by
organotransition metal complexes, much effort has been directed
toward the synthesis of chiral phosphine libraries. The central
problem is rapidly accessing derivatives of a common scaffold that
translate into significantly different activity and selectivity patterns
(i.e., meaningful diversity). Recently, we reported new methods
for synthesizing racemic 3,4 diazaphospholanes2 that bear structural
similarities with the DuPHOS3 class of phospholanes. Our strategy
is to combine the asymmetry of phospholane-like ring structures
with the diversity of structures and functionalities available in small
peptides. Herein, we report the initial realization of this strategy:
the facile synthesis and resolution of a new functionalized diaza-
phospholane, its elaboration using readily available amino acids,
and the discovery of new monophosphine ligands for highly
enantioselective catalytic allylic alkylations.
a (i) (a) Phthaloyl dichloride, phenyl phosphine, THF; (b) 10% aq. K2CO3;
(c) 3 M HCl. (ii) (a) (S)-R-methylbenzylamine, THF; (b) 10% aq. K2CO3;
(c) 3 M HCl. (iii) (a) (R)-R-methylbenzylamine, THF; (b) 10% aq. K2CO3;
(c) 3 M HCl.
Synthesis of rac-N,N′-phthaloyl-2,3-(2-carboxyphenyl)-phenyl-
3,4-diazaphospholane (rac-2) is performed as a one-pot combination
of phenylphosphine, the azine of 2-carboxybenzaldehyde (1), and
phthaloyl chloride (Scheme 1, see Supporting Information for com-
plete procedures). Reaction scales of tens of grams are convenient
and generate 88% yield of the colorless solid rac-2. Resolution
via selective crystallization of diastereomeric R-methylbenzylam-
monium salts affords both enantiomers of 2 in high yield and >99%
ee on multigram scales. The resolved phospholanes (R,R)-2 and
(S,S)-2 are soluble in polar solvents such as methylene chloride
and methanol and air stable both as solids and in solution.
Py-BOP mediated4 coupling of 2 with various primary and
secondary amines yields the chiral phosphine ligands shown in
Chart 1. The phosphine amide 3l was converted to the oxazoline
3n using established procedures.
Chart 1. Ligand Collection
exhibits (1) selectivity on par with the state-of-the-art catalysts,
(2) strong sensitivity to the nature of the amino acid, and (3) variable
-
By virtue of its synthetic utility and the existence of extensive
literature, palladium-catalyzed enantioselective allylic alkylation5
is attractive for testing new chiral phosphines.6 Whereas the most
common test substrate, 1,3-diphenylallyl acetate (4b), undergoes
highly enantioselective alkylation with dimethyl malonate in the
presence of many different ligands, alkylation of 1,3-dimethylallyl
acetate (4a) is much more challenging. To date, Trost’s diphosphine
ligand is most effective for palladium-catalyzed alkylation of 4a
with few other phosphine ligands demonstrating useful selectivities
and activities. Interestingly, the Trost ligand is rather poor for allyl
acetates bearing bulkier groups such as 4b.5a
response to the presence of PF6 salts.
Both the enantioselectivity (92% ee) and the yield (ca. 92%) for
the asymmetric allylic alkylation of 4a with R,R-3f and R,R-3i rival
the best results to date for this notoriously difficult substrate. To
the best of our knowledge, ligand 3f is unique among previously
reported ligands in being highly effective for both substrates 4a
and 4b under common conditions. Comparisons of matched and
“mismatched” diastereomers (e.g., R,R-3a and S,S-3a) indicate that
the product stereochemistry is determined predominately by the
phospholane ring stereochemistry, rather than that of the amino
acid. Most significant is the exquisite (and unpredictable) sensitivity
of the catalyst to subtle changes in ligand structure as illustrated
by the series: glycine (3e, 46% ee), phenylglycine (3d, 51% ee),
As shown by the data in Table 1, Pd-catalyzed allylic alkylation
of both 4a and 4b with monophosphine ligands derived from 2
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J. AM. CHEM. SOC. 2003, 125, 11792-11793
10.1021/ja036359f CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Pd-Catalyzed Allylic Alkylation Results
In summary, the 3,4-diazaphospholanes comprise readily acces-
sible and versatile ligands for asymmetric catalysis. In this work,
we demonstrate that resolution of 2 combined with simple coupling
chemistry provides access to ligands with meaningful diversity, at
least with respect to catalytic allylic alkylation. We currently are
pursuing clarification of mechanistic issues that have arisen from
this work, application of these ligands to other catalytic transforma-
tions, and further extension of mono- and bis-3,4-diazaphospholanes
through coupling to small peptides and peptoids.
with AgPF
without AgPF
6
6
substrate
ligand
ee (%)
yieldb (%)
ee (%)
yieldb (%)
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
R,R-3a
R,R-3b
R,R-3c
R,R-3d
R,R-3e
R,R-3f
R,R-3g
R,R-3h
R,R-3i
R,R-3j
R,R-3k
R,R-3m
R,R-3n
S,S-3a
S,S-3o
S,S-3p
S,S-3m
S,S-3n
52(16) (S)a
73(2) (S)a
53(10) (S)a
51(4) (S)a
46(6) (S)a
92(1) (S)a
89(1) (S)a
83(1) (S)a
92(1) (S)a
56(9) (R)a
84(1) (S)a
11(4) (S)a
38(4) (S)a
59(4) (R)a
55(6) (S)a
40(1) (R)a
54(3) (S)a
64(1) (R)a
87(9)
20(2)
88(4)
48(11)
66(11)
92(1)
94(4)
84(5)
86(10)
19(8)
77(16)
32(3)
26(5)
87(5)
5(2)
57(4) (S)
47(10) (S)
49(5) (S)
48(4) (S)
29(3) (S)
53(4) (S)
89(1) (S)
46(1) (S)
47(1) (S)
9(2) (R)
78(10)
8(2)
68(16)
26(7)
30(9)
71(7)
84(3)
29(5)
65(3)
4(1)
Acknowledgment. The Department of Energy and Dow Chemi-
cal Co. provided support for this work. We kindly thank Prof. Sam
Gellman for access to HPLC equipment, Prof. Helen Blackwell
for stimulating discussions, and Dr. Ilia Guzei for the crystal-
lographic work.
32(1) (S)
20(1) (S)
23(9)
8(2)
50(3) (R)
44(4) (S)
30(6) (R)
34(2) (S)
60(R)
100(2)
88(4)
38(15)
2(1)
Supporting Information Available: Synthetic and catalytic pro-
cedures, characterization data, and crystallographic coordinates for R,R-2
(PDF and CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
16(5)
14(3)
92(7)
18
4b
4b
4b
4b
4b
4b
R,R-2
71(1) (S)c
92(1) (S)c
56(R)c
32(8)
61(5)
26
50(1) (S)
97(1) (S)
19(2) (R)
75(1) (R)
97(1) (S)
67(1) (R)
13(1)
92(6)
36(4)
88(1)
99(2)
78(10)
R,R-3f
R,R-3m
S,S-3a
S,S-3o
S,S-3p
References
91(6) (R)c
9(1) (R)c
64(2) (R)c
>95
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Our working model ascribes the most active and selective
catalysts to monophosphine Pd-allyl complexes, possibly bidentate8
via coordination of an amidate9 (see below) or amide carbonyl.10
Support for coordination of a single phosphine to palladium in the
active species comes from the observation that allylic alkylations
with 1:1, 2:1, and higher phosphine:palladium ratios give identical
1
ee’s and similar initial rates as measured by H NMR for ligand
3f. The poor activities and selectivities of N,N-disubstituted amides
may reflect poor bidentate binding.
JA036359F
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