Enantioselective molybdenum-catalyzed allylic alkylation using chiral bisoxazoline ligands

Article abstract of DOI:10.1021/ol990602r

(equation presented) 54-86% yield R = Ph, Pr, CH₃, OCH₃, OPh 76 to 99% ee of A A : B = 8 : 1 up to >20 : 1 A series of chiral C₂-symmetric bisoxazolines with trans-1,2-diaminocyclohexane backbones was synthesized. In view

Full text of DOI:10.1021/ol990602r

ORGANIC
LETTERS
1999
Vol. 1, No. 1
141-144
Enantioselective Molybdenum-Catalyzed
Allylic Alkylation Using Chiral
Bisoxazoline Ligands
Frank Glorius and Andreas Pfaltz*
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1,
D-45470 Mu¨lheim an der Ruhr, Germany§
pfaltz@ubaclu.unibas.ch
Received April 17, 1999
ABSTRACT
A series of chiral C -symmetric bisoxazolines with trans-1,2-diaminocyclohexane backbones was synthesized. In view of the promising results
2
obtained by Trost with analogous bispyridine ligands, we tested our new ligands in the enantioselective molybdenum-catalyzed allylic alkylation
of 1- and 3-monosubstituted allylic substrates. Enantiomeric excesses of up to 98% and branched/linear ratios of up to 11:1 were obtained
with (E)-3-(n-alkyl)allyl carbonates. (E)-3-Phenoxyallyl acetate gave a branched/linear ratio of >20:1 and an ee of 98%.
Enantioselective transition metal-catalyzed allylic alkylation
has become an important tool for asymmetric synthesis.1
During the past few years, substantial progress has been
made, and as a result, excellent enantiomeric excesses can
now be obtained with many prochiral or racemic substrates.
Nevertheless, the search for new chiral ligands and catalysts
continues, since there are still classes of substrates which
give unsatisfactory results with the known catalysts.
Unsymmetrically substituted allyl derivatives are particu-
larly demanding substrates, because, in addition to the
requirement of enantiocontrol, the problem of regioselectivity
has to be solved. With most palladium catalysts, monosub-
stituted allyl systems such as 1- or 3-arylallyl derivatives
react with carbon nucleophiles preferentially at the unsub-
stituted terminus, giving rise to an achiral linear product. It
is only recently that catalysts have been discovered that allow
the preparation of chiral, branched regioisomers from 1- or
3-arylallyl esters, with good enantio- and regioselectivity.
Such a reversal of regioselectivity has been achieved using
palladium complexes with certain chiral ligands such as 1,2
tungsten complexes derived from ligand 2,3 related iridium
catalysts,4 and, most recently, with a molybdenum complex5
derived from ligand 3.6 In terms of regio- and enantioselec-
tivity, the chiral molybdenum catalyst developed by Trost5
is clearly the most effective catalyst available today, giving
a branched-to-linear ratio of 49:1 and an ee of 99% in the
reaction of methyl (E)-1-phenylallyl carbonate with dimethyl
malonate.
(2) Pretot, R.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1998, 37, 323.
See, also: Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Chem. Soc., Chem.
Commun. 1997, 561.
(3) Lloyd-Jones, G.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1995, 34,
462.
(4) Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38, 8025.
(5) Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104.
(6) Chapman, R. L.; Vagg, R. S.; Watton, E. C.; Barnes, D. J. J. Chem.
Eng. Data 1978, 23, 349. See, also: Adolfsson, H.; Moberg, C. Tetrahe-
dron: Asymmetry 1995, 6, 2023.
(7) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339. (b) Pfaltz, A. Acta Chem.
Scand. 1996, 50, 189.
§ New address: Department of Chemistry, University of Basel, St.
Johanns-Ring 19, CH-4056 Basel, Switzerland.
(1) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. Hayashi,
T. In Catalytic Asymmetric Synthesis; Ojima, Ed.; VCH Publishers: New
York, 1993; pp 325-365. Frost, C. G.; Howarth, J.; Williams, J. M. J.
Tetrahedron: Asymmetry 1992, 3, 1089. Consiglio, G.; Waymouth, R. M.
Chem. ReV. 1989, 89, 257.
(8) End, N.; Pfaltz, A. J. Chem. Soc., Chem. Commun. 1998, 589.
10.1021/ol990602r CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/24/1999

2. In the synthesis of 5a, the imidate derived from benzamide
was coupled with L-serine methyl ester hydrochloride to give
the oxazoline ester 8a in 73% overall yield. The correspond-
ing carboxylic acid was obtained in 76% yield by hydrolysis
with 2 N aqueous sodium hydroxide solution at room
temperature. Finally, coupling with (S,S)-1,2-diaminocyclo-
hexane, using standard procedures, gave the desired ligand
5a in 95% yield from the carboxylic acid.
Scheme 2
In the course of our work on chiral oxazoline ligands,7
we have prepared a series of bisoxazolines with a trans-1,2-
diaminocyclohexane backbone. Although these ligands were
originally designed for other applications,8 Trost’s promising
results with ligand 3 prompted us to test the bisoxazolines
4-6 in the molybdenum-catalyzed allylic alkylation of
monosubstituted allyl derivatives.
For our initial allylic alkylation experiments, methyl (E)-
3-phenyl-2-propenyl carbonate 9a was used as a test substrate
to compare the performance of our ligands with ligand 3.
The bisoxazolines 4 and 5b were found to induce similar
levels of enantioselectivity as the bispyridine ligand 3;
however, the branched/linear ratios were lower and the
reactions somewhat slower (Table 1, entries 1-3). Further-
Table 1. Enantioselective Allylic Alkylation Using Substrates 9a and
9ba
Ligands 4-6 can be readily synthesized using chiral amino
alcohols and trans-1,2-diaminocyclohexane as commercially
available enantiopure components. For example, ligand 4 was
obtained in just two steps from ethyl oxamate; initial reaction
with (S)-valinol afforded the oxazoline 7 which was coupled
to (S,S)-1,2-diaminocyclohexane as shown in Scheme 1.
entry
R
ligand time, days % yieldb 10:11 % ee of 10c
1d
2
3
4
5
6
7
8
Ph
Ph
Ph
Pr
Pr
Pr
Pr
Pr
3
4
3 h
0.5
1
1.5
2
1.5
2.5
1.5
70
86
83
80
69
84
54
83
49:1
14:1
6:1
8:1
2:1
8:1
2:1
8:1
99 (R)
99 (R)
98 (R)
98 (-)
96 (+)
98 (-)
86 (+)
97 (-)
5b
3
5b
6b
5c
6c
Scheme 1
a All reactions were carried out under argon. b Isolated combined yields.
c Determined by HPLC using Daicel Chiralcel OJ and GC using Chiraldex
γ-CD-TA columns. d Entry taken from ref 5 (reaction at room temperature).
Although the yield of the latter reaction was low, the
procedure is attractive because it is simple and avoids
additional steps for the activation of the carboxyl group of
7.
more, in line with observations by Trost,5 the corresponding
branched substrate reacted with significantly lower ee (with
5b 84% vs 98% ee; Scheme 3).
Similarly, the diastereomeric ligands 5 and 6 were prepared
from the corresponding amides as exemplified in Scheme
Next we turned our attention toward the analogous alkyl-
substituted substrates. Recently, achiral iridium9 and rhod-
142
Org. Lett., Vol. 1, No. 1, 1999

The phenyl-substituted ligands 5a and 6a gave higher
branched/linear ratios, although at the expense of lower ee’s
(entries 4 and 5). The best results with the bisoxazoline
ligands were obtained with the n-propyl-substituted deriva-
tives 5b and 6b, comparing favorably with the bispyridine
ligand 3. Specifically, by employing ligand 5b, a 9:1 mixture
of 13 and 14 was obtained in 81% yield with an ee of 97%
(entry 6), whereas ligand 6b gave an 11:1 mixture of 13
and 14 in 80% yield and an ee of 96% (entry 7). The
isopropyl-substituted ligands 5c and 6c gave slightly lower
selectivities (entries 8 and 9) and the tert-butyl-substituted
ligand 6d afforded only racemic product with a low
branched/linear ratio. These results show that by systematic
variation of the substituents in the oxazoline ring, the regio-
as well as the enantioselectivity can be optimized.
Once again, the corresponding branched substrate reacted
with considerably lower enantioselectivity (80% vs 97% ee
with ligand 5b; Scheme 3).
Finally, the phenoxy- and methoxy-substituted allylic
acetates 15a and 15b were studied as substrates. The Pd-
(PPh3)4-catalyzed reaction of 15b with diethyl methyl-
malonate has been reported by Cazes and co-workers to yield
only the branched product.12
Scheme 3
ium10 catalysts have been described, which give high
branched/linear ratios with such alkylallyl systems. However,
highly enantioselective allylic substitutions with carbon
nucleophiles have not been achieved so far with this class
of substrate.
As expected, (E)-2-hexenyl methyl carbonate 9b was less
reactive than the corresponding 3-phenylallyl derivative and
required reaction times of 1.5-2.5 days at 70 °C. Ligands
3, 6b, and 6c all gave an 8:1 ratio of 10:11 with ee’s of
97-98% (entries 4, 6, and 8). The corresponding diastere-
omers 5b and 5c, which are derived from the opposite
enantiomer of 1,2-diaminocyclohexane, gave lower branched/
linear ratios and, in the case of 5c, a distinctly lower ee
(entries 5 and 7). Ligands 5b,c also induced the opposite
absolute configuration to 6b,c, implying that the enantiose-
lectivity is largely controlled by the trans-diaminocyclohex-
ane unit.
Our results for (E)-2-butenyl methyl carbonate 12 are
summarized in Table 2.11 When ligand 4 was used, a 1.5:1
mixture of 13:14 was obtained in 88% yield with 94% ee
after 1 day at 70 °C (entry 2). Reducing the amount of Mo-
(CO)3(EtCN)3 to 2.5% led to an increase in reaction time
but left the regio- and enantioselectivity virtually unchanged
(entry 3).
Consistent with Cazes’ result, the phenoxy derivative 15a
gave branched/linear ratios of greater than 20:1 in all cases
(Table 3). The best enantioselectivity (98% ee) was achieved
with ligand 5b, whereas the other ligands afforded ee’s of
93-96% ee. However, the methoxy derivative 15b reacted
with distinctly lower regio- and enantioselectivity. In contrast
to the analogous Pd-catalyzed reaction,12 the linear product
Table 3. Enantioselective Allylic AlkylationUsing Substrates 15a and
15ba
Table 2. Enantioselective Allylic Alkylation Using 12a
entry
R
ligand time, days % yieldb 16:17 % ee of 16c
entry
ligand
time, days
% yieldb
13:14
% ee of 13c
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
3
2
79
79
81
78
75
60
52
38
72
54
35
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
6:1
93 (-)
98 (-)
93 (+)
95 (-)
96 (+)
74 (+)
62 (+)
63 (-)
66 (+)
76 (-)
21 (-)
1
2
3
4
5
6
7
8
9
3
4
1
1
5
5
3
1
2
1.5
1
85
88
80
73
76
81
80
81
86
85
5:1
1.5:1
1.5:1
5:1
7:1
9:1
11:1
9:1
7:1
94 (R)
94 (R)
93 (R)
74 (R)
85 (S)
97 (R)
96 (S)
95 (R)
92 (S)
0
5b
6b
5c
6c
3
2
1.5
2
2
1
4d
5a
6a
5b
6b
5c
6c
6d
Ph
Me
Me
Me
Me
Me
Me
5b
6b
5c
6c
6d
1
1
1
1
5:1
5:1
13:1
3:1
10
11
10
2
1.5:1
1
a All reactions were carried out under argon. b Isolated combined yields.
c Determined by GC (Chiraldex γ-CD-TA). d The reaction was performed
with 2.5 mol % Mo(CO)3(EtCN)3 and 3.8 mol % 4.
a All reactions were carried out under argon. b Isolated combined yields.
c Determined by HPLC using Daicel Chiralcel OJ and GC using Chiraldex
γ-CD-TA.
Org. Lett., Vol. 1, No. 1, 1999
143

17b was formed in varying amounts. High branched/linear
ratios of 13:1 to >20:1 could be obtained with ligands 3
and 6c, although the ee’s were only moderate (74-76%;
entries 6 and 10).
In summary, we have shown that high enantio- and
regioselectivities can be obtained in molybdenum-catalyzed
allylic substitutions with monosubstituted 3-alkyl- and 3-phe-
noxyallyl esters, using the bispyridine ligand 3 or analogous
chiral bisoxazolines 5-6. In general, 3, which is structurally
simpler, is the ligand of choice. However, with certain
substrates, the analogous bisoxazolines can give improved
regio- and enantioselectivity. An attractive feature of the
bisoxazoline ligands is the option to fine-tune their structure
by variation of the substituents in the oxazoline rings.
(9) Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647.
(10) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725. (b)
Takeuchi, R.; Kitamura, N. New J. Chem. 1998, 659.
(11) Representative experimental procedure: A solution of ligand 5b
(0.025 mmol) and Mo(CO)3(EtCN)3 (0.017 mmol) in 0.7 mL of freshly
distilled THF was degassed and then stirred at 70 °C in an ampule with a
Teflon-sealed (Young) valve under an argon atmosphere for 1 h. A solution
of dimethyl sodiomalonate (prepared from dimethyl malonate (0.3 mmol)
and NaH (0.22 mmol) in 1.0 mL of THF at room temperature) and (E)-2-
butenyl methyl carbonate (0.17 mmol) were added. The solution was again
degassed, and then stirred at 70 °C for 24 h. After the solution was cooled
to room temperature, water was added. The mixture was extracted with
ether, and the combined extracts were washed with brine and dried over
MgSO4. The solvents were evaporated in vacuo, and the resulting oil was
purified by column chromatography on silica gel (pentane/tert-butyl methyl
ether 10:1) to give 25.7 mg (0.138 mmol; 81% yield) of a 9:1 mixture of
(R)-13 and 14. The enantiomeric excess of 13 and the regioselectivity were
determined by GC. Chiraldex γ-CD-TA, 30 m, 50-100 °C, 1°/min, 90
kPa H2, tR ) 33.4 min ((R)-(+)-13), 34.7 min ((S)-(-)-13), 41.7 min ((E)-
14), 44.2 min ((Z)-14). Restek Rtx-1701, 30 m, 60-120 °C, 2°/min, 60
kPa H2, tR ) 23.2 min (13), 27.4 min ((E)-14), 28.1 min ((Z)-14).
(12) Vicart, N.; Cazes, B.; Gore´, J. Tetrahedron Lett. 1995, 36, 535.
Acknowledgment. F.G. thanks the Max-Planck Society
and the Catalysis Network Nordrhein-Westfalen for a
doctoral fellowship.
Supporting Information Available: General experimen-
tal procedures and analytical data for compounds 4-17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL990602R
144
Org. Lett., Vol. 1, No. 1, 1999