Asymmetric Lewis Acid-Catalyzed Diels-Alder Reactions of α,β-Unsaturated Ketones and α,β-Unsaturated Acid Chlorides

Article abstract of DOI:10.1021/ol035524t

(Equation presented) Conformational analysis, van der Waals attractions, and transition structure calculations are combined to design an asymmetric Lewis acid-catalyzed Diels-Alder reaction for simple acyclic α,β-unsaturated ketones and α,β-unsaturated acid chlorides, giving up to 83 and 92% ee, respectively. The two-point-binding chiral recognition mechanism, Lewis acid-Lewis base coordination with boron and a van der Waals attraction with the naphthyl group, uses the inherent enone unit of simple α,β-unsaturated carbonyl compounds, ending the need for auxiliary oxygen binding sites on the dienophile.

Full text of DOI:10.1021/ol035524t

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4293-4295
Asymmetric Lewis Acid-Catalyzed
Diels−Alder Reactions of
r,â-Unsaturated Ketones and
r,â-Unsaturated Acid Chlorides
Joel M. Hawkins,* Mitch Nambu, and Stefan Loren
Pfizer Global Research and DeVelopment, Groton, Connecticut 06340, and
Department of Chemistry, UniVersity of California, Berkeley, Berkeley, California
94720
joel_m_hawkins@groton.pfizer.com
Received August 12, 2003
ABSTRACT
Conformational analysis, van der Waals attractions, and transition structure calculations are combined to design an asymmetric Lewis acid-
catalyzed Diels−Alder reaction for simple acyclic r,â-unsaturated ketones and r,â-unsaturated acid chlorides, giving up to 83 and 92% ee,
respectively. The two-point-binding chiral recognition mechanism, Lewis acid−Lewis base coordination with boron and a van der Waals attraction
with the naphthyl group, uses the inherent enone unit of simple r,â-unsaturated carbonyl compounds, ending the need for auxiliary oxygen
binding sites on the dienophile.
Asymmetric Lewis acid-catalyzed reactions of R,â-unsatur-
ated ketones are challenging due to nonselective metal
coordination of the carbonyl oxygen lone pairs. This
indiscriminate binding of the typically sterically and elec-
tronically similar lone pairs allows reaction from multiple
isomeric transition states, resulting in poor enantiocon-
trol.1,2 Here we describe the combined use of conformational
analysis, van der Waals attractions, and transition structure
calculations to design an asymmetric Lewis acid-catalyzed
Diels-Alder reaction for simple acyclic R,â-unsaturated
ketones.3,4 Generalizing this analysis, we further present
the first enantioselective asymmetric Lewis acid-catalyzed
Diels-Alder reactions of R,â-unsaturated acid chlorides.
We previously described enantioselective Diels-Alder
reactions of R,â-unsaturated esters catalyzed by asymmetric
Lewis acid 1 with up to 99.5% ee.5,6 Aromatic alkyldichlo-
roborane 1 was designed to bind and activate R,â-unsaturated
esters via conformation 2, with approach of the dienophile
from the top face opposite the naphthalene moiety. Active
conformation 2 was predicted by conformational analysis and
supported by measurements reflecting the solid state (a series
of five dienophile-catalyst crystal structures),6 solution state
(3) MacMillan recently described the use of organocatalysts to replace
the selective lone pair binding problem by iminium geometry control, thus
providing the first reported enantioselective catalytic Diels-Alder reactions
with simple ketone dienophiles.1
(4) Corey recently described an enantioselective Lewis acid-catalyzed
Diels-Alder reaction with ethyl vinyl ketone: Ryu, D. H.; Lee, T. L.; Corey,
E. J. J. Am. Chem. Soc. 2002, 124, 9992. Ryu, D. H.; Corey, E. J. J. Am.
Chem. Soc. 2003, 125, 6388.
(1) For a detailed discussion, see: Northrup, A. B.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2002, 11, 2458.
(2) For the preferential coordination of electronically differentiated
substituted benzophenone lone pairs allowing maximum π-electron donation
in an asymmetric reduction system, see: Corey, E. J.; Helal, C. J.
Tetrahedron Lett. 1995, 36, 9153.
(5) Hawkins, J. M.; Loren, S. J. Am. Chem. Soc. 1991, 113, 7794.
(6) Hawkins, J. M.; Loren, S.; Nambu, M. J. Am. Chem. Soc. 1994, 116,
1657.
10.1021/ol035524t CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/15/2003

(selective shielding of dienophile protons by the arene),5 and
transition state (degree and sense of asymmetric induction
under Curtin-Hammett conditions).5,6
conformation, transition structure calculations by Houk
predict an inherent electronic preference for an s-cis con-
formation in the transition state. Calculated Diels-Alder
transition structures for the reaction between acrolein com-
plexed with BH3 and butadiene show a preference for s-cis
geometries over s-trans geometries by 1.9 (endo) and 2.7
(exo) kcal/mol due to a smaller separation of induced charge.8
Thus, theory predicts a preference for transition states
resulting from s-cis conformation 11 over s-trans conforma-
tion 10.
The binding of a planar, polarized, and electron-deficient
ligand L to 1 via preferred general conformation 3 can be
understood in terms of the chair cyclohexane and peri
interactions present in the carbon framework, a staggered
C-B bond connecting the chiral carbon framework to the
coordinated metaloid, and an electrostatic and dipole-
induced dipole attraction between the boron-activated ligand
L and the electron-rich and polarizable arene of the catalyst.
For ligand L corresponding to an R,â-unsaturated carbonyl
compound, four conformations are possible, 4-7. The boron
may bind anti or syn to the nonolefinic group X, and the
enone unit may be s-trans or s-cis. For R,â-unsaturated esters,
the ester alkyl fragment R preferentially resides syn peri
planar to the carbonyl oxygen, blocking binding of the B
syn to X ) OR (conformations 6 and 7). The binding of B
anti to OR further blocks s-cis conformation 5 on steric
grounds, thus favoring anti s-trans conformation 4. A
staggered O-B bond should also be favored in 4, and
combining ester fragment 4 with catalyst fragment 3 leads
to preferred reactive conformation 2, as observed.5,6
For R,â-unsaturated ketones, superimposing carbonyl
fragments 4-7 on catalyst fragment 3 with a staggered B-O
bond and positioning of the polar complexed carbonyl over
the polarizable arene gives conformations 8-11. Conforma-
tion 11 is sterically preferred over conformation 9 for small
R groups, and conformation 87 gives the same product
enantiomer as conformation 11, with diene approach opposite
the naphthalene in each case. Thus, the main competition
for enantiocontrol for R,â-unsaturated ketones is between
conformations 11 and 10.
The dipole-induced dipole attraction between the polar-
ized and electron-deficient boron-activated R,â-unsaturated
ketone and the polarizable and electron-rich naphthalene built
into catalyst 1 should further enhance reaction through s-cis
conformation 11 over s-trans conformation 10 since the entire
enone unit lies over the naphthalene in 11. Thus, both Houk’s
calculations for a general electronic preference for s-cis
transition states and the secondary van der Waals attraction
designed into catalyst 1 predict 1 to enantioselectively
catalyze Diels-Alder reactions of R,â-unsaturated ketones
by approach of the diene from the top face of conformation
11 with optimum asymmetric induction for small R groups.
To test this hypothesis, Diels-Alder reactions between
four different R,â-unsaturated ketones and cyclopentadiene
were performed under catalysis by chiral Lewis acid 1 (Table
1, entries 1-4).9,10 Enantioselectivities up to 83% were
obtained with very high endo selectivities. In each case, the
(7) Crystal structure of the benzylidene acetone‚BF3 complex shows BF3
coordination to the lone pair on the carbonyl oxygen syn to the R,â-double
bond in an s-trans conformation.4 This is analogous to conformation 8 except
that the B-O bond is eclipsed in the BF3 complex. An attractive H-F
interaction in this eclipsed conformation is proposed for these BF3
complexes.4
(8) Birney, D. M.; Houk, K. N. J. Am. Chem. Soc. 1990, 112, 4127.
(9) Representative Procedure. Catalyst 1 (29 mg, 0.10 mmol, 10 mol
%) was dissolved in 0.90 mL of dry CH2Cl2 under argon and cooled to
-74 °C. Methyl vinyl ketone (70 mg, 1.0 mmol) was added with stirring,
followed by 0.45 mL (5.7 mmol, 5.7 equiv) of cyclopentadiene. After 1 h,
the reaction was quenched by the addition of 1 mL of saturated NaHCO3
(aq) and warmed to room temperature. The reaction mixture was diluted
with ether, washed with NaHCO3 (aq) and water, dried (Na2SO4), and
concentrated to a clear oil, 81% ee according to GC (J&W Cyclodex-B
column). Silica chromatography yielded 82 mg (63%) of clear oil, [R]D
+65.6° (c 4.36, ethanol). Products were characterized by 1H NMR, 13C
NMR, and high-resolution mass spectra. Acid chloride reactions were
quenched with an excess of 25% TEA/methanol to give the corresponding
methyl esters.
For R,â-unsaturated carbonyl compounds such as ketones
lacking a pronounced steric preference for an s-cis or s-trans
(10) Cyclohexadiene reacts considerably slower than cyclopentadiene
with methyl vinyl ketone under the conditions of Table 1.
4294
Org. Lett., Vol. 5, No. 23, 2003

reaction from conformation 11; thus, catalyst 1 is predicted
to enantioselectively catalyze Diels-Alder reactions of R,â-
unsaturated acid chlorides with approach of the diene from
the top face of conformation 11, R ) Cl.
Table 1. Asymmetric Diels-Alder Reactions of
R,â-Unsaturated Ketones and R,â-Unsaturated Acid Chlorides
Catalyzed by 1
To test this hypothesis, three different of R,â-unsaturated
acid chlorides were treated with cyclopentadiene and catalyst
1 (Table 1, entries 5-7). Crotonyl chloride gives 92% ee
with an absolute configuration consistent with approach of
the diene from the predicted open face of conformation 11
(entry 5). γ-Substituted species give 76-80% ee, again
consistent with model 11 (entries 6-7). Thus, R,â-unsatur-
ated acid chlorides behave according to the model proposed
above, providing the first asymmetric Lewis acid-catalyzed
Diels-Alder reactions of R,â-unsaturated acid chlorides.
We have described asymmetric Lewis acid-catalyzed
Diels-Alder reactions of simple acyclic R,â-unsaturated
ketones and R,â-unsaturated acid chlorides giving up to 83
and 92% ee, respectively. Like the reactions of R,â-
unsaturated esters reported previously,5,6 these reactions are
catalyzed by alkyldichloroborane 1 with readily understand-
able chiral recognition mechanisms involving two-point-
binding asymmetric catalysis: Lewis acid-Lewis base
coordination with boron and a van der Waals attraction with
the naphthalene. This form of two-point-binding uses the
inherent enone unit of simple R,â-unsaturated carbonyl
compounds, ending the need for auxiliary oxygen binding
sites on the dienophile.12 Alkyldichloroborane 1 was designed
not only to provide the enantioselectivities described here
for three different carbonyl systems but more importantly
to serve as a well-defined framework for the exploration of
chiral recognition mechanisms for asymmetric catalysis. Our
work has shown that judicious conformational constraints,
van der Waals attractions, and charge effects in the transition
state can be applied to both design and promote novel
enantioselectivities. Extension of these concepts to the more
reactive dibromo congener of 1, including R,â-unsaturated
anhydride dienophiles, will be described shortly.
entry R1
R2
temp, time
yield (%) endo:exo % ee
1
2
3
4
5
6
7
Me
Et
H
H
H
-74 °C, 1 h
-78 °C, 24 h
-30 °C, 20 h
-30 °C, 20 h
-20 °C, 52 h
-18 °C, 48 h
63
92
81
73
>100:1
>100:1
32:1
81a,b
83a,c
16b,d
71a,c
iPr
Me Me
32:1
Cl
Cl
Cl
Me
Et
88e
64e
60e
>10:1e 92f
>10:1e 76a,g
>10:1e 80h
CH2Br -18°C, 72 h
a Enantiomeric excess determined by chiral stationary phase GC.
b Absolute configuration correlated by comparison to the literature optical
rotation: Nakazaki, M; Naemura, K.; Kondo, Y. J. Org. Chem. 1976, 41,
1229. c Absolute configuration correlated with the corresponding methyl
ester (ref 5) by addition of EtMgBr (entry 2) or MeLi (entry 4) to the ketone
and ester and comparing optical rotations of the resulting tertiary alcohols.
d Enantiomeric excess determined by comparison to the literature optical
rotation (see footnote b). e Isolated as the corresponding methyl esters.
f Enantiomeric excess determined by chiral stationary phase GC of the
corresponding aldehyde. Correlated vs the corresponding methyl ester (ref
5). g Same enantiomer favored as for reaction of the corresponding methyl
ester (95% ee). h Enantiomeric excess and correlation determined as for
entry 5 after reduction of the bromide and ester followed by oxidation to
the aldehyde.
absolute configuration of the product corresponds to the
approach of cyclopentadiene from the predicted top open
face of conformation 11. Small ketone groups R1 ) Me and
i
Et are well tolerated (entries 1, 2, and 4), but R1 ) Pr
significantly lowers the enantioselectivity (entry 3), consistent
with the congested positioning of R in conformation 11.
Vinyl substituent R2 ) H or Me is well tolerated (entries 1,
2, and 4), consistent with the open space around the trans
vinyl position in conformation 11. Thus, R,â-unsaturated
ketones behave according to the model proposed above.
This model can be extended to R,â-unsaturated acid
chlorides by considering potential reactive conformations
8-11, R ) Cl. As discussed above for R ) small alkyl,
conformation 11 should be favored over conformation 9 on
the basis of steric effects and favored over conformation 10
on the basis of electronic effects (s-cis transition state and
maximized van der Waals attraction between the enone unit
and the arene). Crystal structures generally show the binding
of acid chlorides to metals at the carbonyl oxygen syn to
chlorine, further supporting conformation 11.11 Any reaction
through conformation 8 gives the same enantiomer as
Acknowledgment. We thank Professor MacMillan for a
preprint of his work1,3 and helpful discussions. Chemistry at
Berkeley was supported by the NSF (Presidential Young
Investigator Award, CHE-8857453), the Camille and Henry
Dreyfus Foundation (Teacher-Scholar Award), and the
Smith Kline & French Laboratories (Fellowship for S.L.).
OL035524T
(11) For crystal structures of acid chloride complexes with AlCl3, see:
Rasmussen, S. E.; Broch, N. C. Acta Chem. Scand. 1966, 20, 1351 (benzoyl
chloride). Chevrier, P. B.; Le Carpentier, J.-M.; Weiss, R. Acta Crystallogr.
B 1972, 28, 2659 (toluoyl chlorides). Le Carpentier, J.-M.; Weiss, R. Acta
Crystallogr. B 1972, 28, 1437 (propionyl chloride).
(12) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92, 1007.
Org. Lett., Vol. 5, No. 23, 2003
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