Catalytic Asymmetric Nazarov Reactions Promoted by Chiral Lewis Acid Complexes

Article abstract of DOI:10.1021/ol036133h

(Equation presented) Divinyl ketones bearing α-ester or α-amide groups undergo Nazarov cyclizations to give cylopentenones using copper-bisoxazoline Lewis acid complexes with moderate to good ees.

Full text of DOI:10.1021/ol036133h

ORGANIC
LETTERS
2003
Vol. 5, No. 26
5075-5078
Catalytic Asymmetric Nazarov Reactions
Promoted by Chiral Lewis Acid
Complexes
Varinder K. Aggarwal* and Andrew J. Belfield
School of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol, UK BS8 1TS
V.aggarwal@bristol.ac.uk
Received October 31, 2003
ABSTRACT
Divinyl ketones bearing r-ester or r-amide groups undergo Nazarov cyclizations to give cylopentenones using copper−bisoxazoline Lewis
acid complexes with moderate to good ees.
The Nazarov cyclization is a cationic electrocyclic reaction
that, although initially found to be promoted by strong protic
acids, has since been shown to be promoted by milder, Lewis
acids (the reaction may also be promoted photochemically).1
Since this discovery, the scope of the reaction has been
increased, most notably by Denmark’s silicon-directed reac-
tion2 and West’s “interrupted” Nazarov reaction.3 However,
asymmetric induction has not been widely explored, with
only the related cyclopentannelation reaction reported by
Tius,4 which exploits the axial chirality of allenes, and three
chiral auxiliary-promoted reactions5 described thus far.
During the acid (Lewis or protic)-promoted Nazarov
cyclization, a 4-π conrotatory electrocyclic reaction occurs,
and therefore, asymmetric induction can be achieved if one
is able to control the direction of the conrotation.
On the basis of the seminal contributions from Evans, we
believed that the use of divinyl ketones bearing an R-ester
group together with copper bisoxazoline complexes offered
some potential to control the direction of conrotation. From
X-ray analysis, Evans had found that complexes between
copper bisoxazolines and related alkylidene malonates
adopted a boat conformation 1 in which the copper and
alkenyl groups were positioned at the apex, Figure 1.6
(1) S. E. Denmark, In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 751. (b) Santelli-
Rouvier, C.; and Santelli, M. Synthesis 1983, 429-442. (c) Ramaiah, M.
Synthesis 1984, 529-571.
Figure 1. Boat conformation in Evans’ asymmetric Michael
addition of alkylidene malonates.
(2) Denmark, S. E.; Wallace, M. A.; Walker, C. B. J. Org. Chem. 1990,
55, 5543-5545 and references therein.
(3) Bowder, C. C.; Marmsa¨ter, F. P.; West, F. G. Org. Lett. 2001, 3,
3033-3035 and references therein.
(4) Hu H.; Smith, D.; Cramer, R. E.; Tius, M. A. J. Am. Chem. Soc.
1999, 121, 9895-9896.
(5) (a) Pridgen, L. N.; Huang, K.; Shilcrat, S.; Tickner-Eldridge, A.;
DeBrose, C.; Haltiwanger, R. C. Synlett 1999, 1612-1614. (b) Kerr, D. J.;
Metje, C.; Flynn, B. L. Chem. Commun. 2003, 1380-1381. (c) Harrington,
P. E.; Tius, M. A. Org. Lett. 2000, 2, 2447-2450. (d) Harrington, P. E.;
Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509-8514. (e) Harrington, P.
E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem. Soc. 2002, 124, 10091-
10100.
If the distortion of the copper-complexed alkylidene
malonate also occurs with divinyl ketoesters, one could
expect the alkene moiety to be pushed out of the plane of
(6) (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am.
Chem. Soc. 1999, 121, 1994-1995. (b) Evans, D. A.; Rovis, T.; Kozlowski,
M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134-
9142.
10.1021/ol036133h CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/05/2003

Table 2. Initial Results of Nazarov Cyclizationsa
Figure 2. Nazarov cyclization pathway.
the 1,3-dicarbonyl group (complex 2) and thereby control
the direction of conrotation.
The presence of an R-ester group will, however, neces-
sarily result in a retardation in rate because electron-
withdrawing groups in the R-position destabilize intermediate
5 (Figure 2) which is formed in the RDS.1
entry
ligand
yield (%)
ee (%)
The R-ester-substituted divinyl ketones were prepared in
good yield by nucleophilic addition of the enolate of ethyl
acetate to the acid chloride of the corresponding cinnamic
acid followed by Knovenagel condensation of the resulting
â-keto ester with the appropriate aldehyde, Table 1.7
1
2
3
4
5
6b
10a
10b
10c
10d
10e
10d
85
70
37
35
28
73
5
44
5
71
17
76
a All reactions were carried out with 1 equiv of ligand complex. b This
reaction was carried out using an improved procedure of filtration of the
copper/ligand complex and removal of the precipitated silver salts.
Table 1. Synthesis of Divinyl Ketonesa
which removed any unwanted decomplexed CuBr2 and silver
salts. This method, which gives a homogeneous reaction
mixture, resulted in improved yields and perfectly reproduc-
ible ees, Table 2, entry 6.
These results were obtained using 1 equiv of ligand
complex; lower catalyst loadings resulted in a corresponding
decrease in yield (Table 3, entry 2). Attempts to increase
turnover using molecular sieves,10 hexafluoro-2-propanol,11
NaBPh4,12 LiClO4,12 and TMSCl (to trap the product) were
unsuccessful.
entry
R1
R2
yield of 9 (%)b
1
2
3
4
5
Me
Me
Me
P h
P h
Ph
Me
83
81
67
52
55
p-NO2Ar
Ph
Me
a Reagents and conditions: (i) (a) (COCl)2, DMF, CH2Cl2, 0 °C; (b)
LDA, EtOAc, THF, -78 °C. (ii) (a) TiCl4, CCl4, THF, 0 °C; (b) R2CHO,
THF, 0 °C; (c) pyridine, 0 °C to rt. b Yields quoted are from 8a and 8b,
respectively.
Table 3. Nazarov Cyclizations under Improved Conditions
Initial investigations using substrate 9a with CuBr2,8
ligand, and AgSbF6 in dichloromethane showed us that the
cyclization could be promoted by bisoxazoline-based Lewis
acid complexes, and the results are shown in Table 2.
Phenyl-substituted bisoxazoline 10a gave good yield but
low enantioselectivity. Improved enantioselectivity was
observed with tert-butyl-substituted bisoxazoline 10b (entry
2), but switching to the pyridyl bisoxazoline 10d (entry 4)
resulted in even higher selectivity (71% ee).
The yields and enantioselectivity of the cyclizations were
found to be rather capricious until the precipitated silver salts
were removed by filtration. This was achieved by filtering
the reaction at two stages through 0.45 µm syringe tip filters,9
entry
substrate
equiv
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
9a
9a
9b
9b
9c
9c
9d
9d
9e
9e
1.0
0.5
1.0
0.5
1.0
0.5
1.0
0.5
1.0
0.5
73
42
98
96
35
27
86
86
24
17
76
78
86
86
3
1
42
35
74
79
(7) Andrews, J. F. P.; Regan, A. C. Tetrahedron Lett. 1991, 32, 7731-
7734.
(8) ZnBr2, FeBr2, InBr3, Cu(OTf)2, Sc(OTf)2, and Yb(OTf)3 were all
tested, but CuBr2 proved to be the optimum metal salt.
10
5076
Org. Lett., Vol. 5, No. 26, 2003

The only previous examples of Nazarov cyclizations that
have employed catalytic quantities of Lewis acid3 employed
nucleophiles to trap the intermediate allyl cation 5, the most
effective of which was Et3SiH. However, even this strategy
was unsuccessful,13 furnishing low yields and reduced
enantioselectivity, and so we decided to explore the scope
of the optimized conditions using 1 equiv of the catalyst
(Table 3).
Table 4. Nazarov Cyclization of Amide Bearing Substrates
Entries 3 and 4, Table 3, show that the inclusion of a
phenyl group at R1 results in higher selectivity and greatly
improved catalytic activity. Alkyl groups at R2 result in lower
enantioselectivity (entries 7, 8), and substrates bearing small
alkyl groups at R1 and R2 furnish essentially racemic product
(entries 5, 6). These observations show that a bulky sub-
stituent at R1 promotes turnover and enantioselectivities. High
enantioselectivities are achieved with large groups at R2.
Large groups at R1 also give higher enantioselectivity than
smaller groups, but this site is less sensitive toward steric
hindrance than R2.
entry
substrate
La
equiv
yield (%)
ee (%)
1
2
3
4
5
6
7
8
12a
12a
12a
12a
12b
12b
12b
12b
10a
10a
10b
10b
10b
10b
10a
10c
1.0
0.5
1.0
0.5
1.0
0.5
1.0
1.0
80
56
92
56
72
56
21
29
88
86
86
87
84
85
75
44
a L ) ligand.
Divinyl ketones bearing R-amide groups were also con-
sidered as potential substrates, as they would be expected to
provide similar control in the conformation of the Lewis
acid-substrate complex, but their decreased electron-
withdrawing ability in comparison to esters should result in
faster reactions. Suprisingly, such substrates had never been
tested before in Nazarov cyclizations.
secondary alcohol 14. The relative stereochemistry of 14 was
determined by NOE studies. The alcohol was then derivatized
separately with (R)- and (S)-1-methoxy-1-phenyl-1-trifluo-
romethylacetic acid (MTPA), respectively, to give both
diastereomers of the Mosher’s ester 15 and 16.
1
Analysis of the H NMR spectrum (run in CDCl3) of the
diastereomers 15 and 16 revealed that the signal for the
proton R to the O-MTPA group (circled) appeared upfield
in the (R)-MTPA diastereomer compared with the (S)-MTPA
diastereomer, indicating a shielding interaction with the
phenyl group of the MTPA in the (R)-enantiomer. The ab-
solute stereochemistry of the cyclized product must therefore
have an all-(R)-configuration as drawn in Scheme 1. To
However, rather than improved rates, we observed little
reactivity at all from substrate 12a and the py-box ligand
10d using the previously optimized conditions. We therefore
explored other bisoxazolines (10a-c) and this time found
that ligands 10a and 10b were very effective in terms of
yield and enantioselectivity. Using amide substrates, high
enantioselectivity was observed with both alkyl and aryl
substituents at R1 (Table 4, entries 1, 5). However, as before,
turnover was limited.
Attempts to determine the absolute stereochemistry of the
cyclization products of 11 and 13 by X-ray crystallography
techniques of suitable derivatives were unsuccessful due to
the needle morphology of the crystals. We therefore turned
to the use of Mosher’s ester derivatives,14 which have been
used to assign the absolute stereochemistry of secondary
alcohols by 1H NMR through the analysis of chemical shift
differences between the two ester diastereomers.15 This
required alcohol 14, which was readily prepared from 11b.
Reduction of the ketoester 11b16 followed by selective
MEM protection of the primary alcohol17 gave rise to
Scheme 1. Synthesis of the Moshers’ Esters
(9) (a) Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc.
1996, 118, 5814-5815. (b) Evans, D. A.; Peterson, G. S.; Johnson, J. S.;
Barnes, D. M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63,
4541-4544.
(10) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.;
Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328-5329. (b) Evans, D.
A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635-1649.
(11) See ref 6 and: Kitajima, H.; Katsuki, T. Synlett 1997, 568-570.
(12) Evans, D. A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew.
Chem., Int. Ed. 2001, 40, 1884-1888.
determine the absolute stereochemistry of the keto amide
substrates 13, the keto ester 11b of known absolute config-
uration was converted into the corresponding amide (Scheme
2).18 Comparison of the HPLC trace of this amide with 13a
(13) Gray/brown solid was seen to form on the inside of the flask during
the course on the reaction when Et3SiH was used.
(14) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(15) (a) Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry
2001, 12, 2915-2925. (b) Kuoda, K.; Ooi, T.; Kusumi, T. Tetrahedron
Lett. 1999, 40, 3005-3008.
(16) Brewster, A. G.; Caulkett, P. W. R.; Jessup, R. J. Med. Chem. 1987,
30, 67-70.
(17) Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T. Chem. Pharm. Bull.
1984, 32, 1411-1415.
Org. Lett., Vol. 5, No. 26, 2003
5077

pyramid geometry)19 will result in a distorted complex in
which the alkene substituents are pushed away from the i-Pr
groups of the ligand. This then places the bonding lobes of
the two corresponding orbitals in close proximity, making
them predisposed to cyclization in a clockwise manner
(Figure 4).
Scheme 2. Conversion of 11b to 13a
confirmed that they were identical, showing that both the
ester 11b and amide 13a had the same absolute configuration.
The absolute stereochemistries of the ester- and amide-
substituted divinyl ketones are consistent with a stereochem-
ical model where the chiral bulk of the ligands distort the
plane of the cationic divinyl ketone intermediate (4, Figure
2) to force one mode of conrotation to be favorable. Thus,
in the case of the divinyl keto amide reaction catalyzed by
the copper bis-oxazoline, buttressing of the tert-butyl group
with the alkene moiety will push it away and underneath
the other vinyl group therefore favoring clockwise conrota-
tion (Figure 3).
Figure 4. Stereochemical model for the interaction of py-box
complexes with divinyl keto-esters.
In conclusion, we have developed the first asymmetric
Nazarov cyclization promoted by chiral Lewis acid com-
plexes, achieving good levels of enantioselectivity. Both
divinyl keto esters and keto amides can be employed, with
the latter showng higher levels of enantioselectivity.
Acknowledgment. We thank the EPSRC and Quest
International for a CASE award (A.J.B.).
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 9a-e, 11a-e,
12a,b, 13a,b, 15, and 16. This material is available free of
charge via the Internet at http://pubs.acs.org.
Figure 3. Stereochemical model for the interaction of bisoxazoline
complexes with divinyl keto-amides.
In the same way, reaction of the divinyl keto esters with
the copper py-box catalysts (which adopt a square-based
OL036133H
(18) Hoffman, R. V.; Huizenga, D. J. J. Org. Chem. 1991, 56, 6435-
6439.
(19) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J.
Am. Chem. Soc. 1999, 121, 686-699.
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Org. Lett., Vol. 5, No. 26, 2003