Enantioselective β-lactone formation from ketene and aldehydes catalyzed by a chiral oxazaborolidine

Article abstract of DOI:10.1021/ol061979h

(Chemical Equation Presented) A novel catalytic system has been developed for the enantioselective synthesis of β-lactones from ketene and aldehydes.

Full text of DOI:10.1021/ol061979h

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4943-4945
Enantioselective
from Ketene and Aldehydes Catalyzed
by a Chiral Oxazaborolidine
â-Lactone Formation
Vijay Gnanadesikan and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford
Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received August 9, 2006
ABSTRACT
A novel catalytic system has been developed for the enantioselective synthesis of
â-lactones from ketene and aldehydes.
The enantioselective synthesis of â-lactones from ketenes
and aldehydes has progressed slowly since the pioneering
discovery by Wynberg of the effectiveness of cinchona
alkaloids as nucleophilic catalysts for the reaction of chloral
with ketene.1,2 The Wynberg reaction has been considerably
extended by the studies of Romo, Nelson, and co-workers.3
of the type RCH2CHO with ketene generated in situ from
acetyl bromide and i-Pr2NEt.4 Nelson’s method with 1 as
catalyst has been used with a range of ketenes and aldehydes
having an R-methylene group. The mechanistic basis for
enantioselectivity is unclear. Finally, the very specific case
of â-lactone formation from trimethylsilylketene and R-keto
esters using Cu(II)-BOX complexes has been described by
Evans and Janey.5 The work presented herein started from
the hypothesis that a useful and mechanistically clear
enantioselective route to chiral â-lactones might be possible
using the same chiral oxazaborolidines (2) that have been
applied so successfully for the borane-mediated enantiose-
lective reduction (CBS reduction) of ketones.6 The pathway
that was envisaged for catalytic enantioselective â-lactone
Nelson and co-workers have also developed the novel
catalyst 1 for effecting â-lactone formation from aldehydes
(4) (a) Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc. 1999,
121, 9742-9743. (b) Nelson, S. G.; Wan, Z. Org. Lett. 2000, 2, 1883-
1886. (c) Nelson, S. G.; Spencer, K. L. Angew. Chem., Int. Ed. 2000, 39,
1323-1325. (d) Nelson, S. G.; Kim, B.-K.; Peelen, T. J. J. Am. Chem.
Soc. 2000, 122, 9318-9319. (e) Nelson, S. G.; Peelen, T. J.; Wan, Z.
Tetrahedron Lett. 1999, 40, 6541-6543. (f) Nelson, S. G.; Zhu, C.; Shen,
X. J. Am. Chem. Soc. 2004, 126, 14-15.
(1) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166-
168.
(2) For reviews, see: (a) Schneider, C. Angew. Chem., Int. Ed. 2002,
41, 744-746. (b) Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403-
6434.
(3) (a) Wang, Y.; Zhao, C.; Romo, D. Org. Lett. 1999, 1, 1197-1199.
(b) Tennyson, R. L.; Romo, D. J. Org. Chem. 2000, 65, 7248-7252. (c)
Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123,
7945-7946. (d) Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004,
126, 5352-5353.
(5) Evans, D. A.; Janey, J. M. Org. Lett. 2001, 3, 2125-2128.
(6) (a) Corey, E. J.; Bakshi, R.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551-5553. (b) Corey, E. J.; Bakshi, R.; Shibata, S.; Chen, C.-P.;
Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926. (c) Corey, E. J.;
Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-2012.
10.1021/ol061979h CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/16/2006

formation from catalyst 2, an aldehyde, and ketene is outlined
in Scheme 1.
N-acetyl derivative of (S)-R,R-diphenyl-2-pyrrolidinometha-
nol. This result led us to suppose that the reaction of ketone
with 2 produces the bidentate coordination product C rather
than B of Scheme 1. The formation of this more stabilized
Scheme 1
intermediate serves to explain both the low level of catalytic
activity of catalyst 2 and the low enantioselection. Clearly,
the reaction of aldehyde with C via an open (i.e., noncyclic)
transition state might not be very face selective. It was hoped
that the addition of lithium triflate to the reaction mixture
might result in the conversion of C into a more reactive
intermediate D and lead to more useful results. Unfortunately,
although lithium triflate produced some rate enhancement
(52% yield after 7 h at -40 °C in CH2Cl2), the 7:3
enantioselectivity was not significantly improved.
We then explored the use of two new catalysts, 5 and 6.
These oxazaborolidines were readily made from (S)-(-)-R,R-
diphenyl-2-pyrrolidinomethanol by heating with the corre-
sponding borate esters. When these catalysts (10 mol %) were
used in the test reaction of 3-phenylpropionaldehyde and
ketene in CH2Cl2 at -40 °C, the (R)-â-lactone predominated,
but the yield and enantioselectivity of the reaction was if
anything slightly lower than with 2, R′ ) Ph, as catalyst.
In the case of the catalyzed reduction of ketones by borane
and 2, borane coordinates with the nitrogen of 2 to form a
cis-fused oxazaborolidine-BH3 complex (at N) which then
binds the ketone because of the enhanced Lewis acidity of
the ring boron.6 As a result, the coordinated BH3 and
carbonyl groups are both activated and brought into proxim-
ity for face-selective hydride transfer from BH3 to CdO.
We hypothesized that ketene might coordinate to the nitrogen
of 2 in a similar way to form intermediate A in Scheme 1.
Attachment of an aldehyde at the ring boron of A might then
lead to the ternary complex B, which could then undergo
C-C coupling and elimination of a â-lactone 3 with
regeneration of catalyst 2. We were encouraged to find that
treatment of 3-phenylpropionaldehyde and 10 mol % of 2,
R′ ) C6H5, in CH2Cl2 solution at -40 °C with a solution of
ketene7 in CH2Cl2 (at -40 °C) for 7 h did produce
dextrorotatory (R)-â-lactone 4.8 However, both the yield
(20%) and enantioselectivity (7:3) were unsatisfactory. The
absolute configuration of the major enantiomer was deter-
mined to be R as expected for the pathway outlined in
Scheme 1. A possible reason for the slowness of the reaction
(poor conversion to â-lactone after 7 h reaction time) was
determined from quenching of the reaction mixture with
water and identification of one of the species present as the
A different type of oxazaborolidine, the zwitterion 7, could
be prepared cleanly by reaction of (S)-(-)-R,R-diphenyl-2-
pyrrolidinomethanol with catechol isopropyl borate in CH2-
Cl2 at 23 °C for 3 h followed by removal of volatile
components in vacuo.9 Although this compound was not an
active catalyst, it could be transformed into one by reaction
with tri-n-butyltin triflate (1 equiv) in CH2Cl2 at -78 °C for
30 min.10 When a solution of this activated form of
precatalyst 7 in CH2Cl2 at -78 °C was treated with various
aldehydes and ketene (10 equiv) in CH2Cl2 at -78 °C for
24 h, chiral dextrorotatory â-lactones were obtained in fair
(7) The preparation of ketene was carried out by thermolysis (1 atm N2)
of commercially available diketene. The ketene was trapped at -78 °C
under nitrogen in dichloromethane (ca. 5 M). Diketene was placed in a
round-bottom flask attached to one end of a Pyrex glass tube in a thermolysis
oven. The other end was attached to a receiving flask containing dry
dichloromethane at -78 °C. After the oven had stabilized at 550 °C, diketene
was heated to gentle boiling allowing the vapor to pass through the Pyrex
glass tube. Ketene condensed as a white fog which was collected in stirred
dichloromethane at -78 °C. The ketene solution was stored under N2 at
-78 °C and is stable at that temperature for at least two weeks. Background
references for synthesis of ketene: (a) Moore, H. W.; Wilbur, D. S. J. Org.
Chem. 1980, 45, 4483-4491. (b) Andreades, S.; Carlson, H. D. Org. Synth.
1965, 45, 50-54.
(9) A 100-mL, two-necked, round-bottomed flask equipped with a stir
bar was charged with (S)-(-)-R,R-diphenyl-2-pyrrolidinemethanol (2.53 g,
10 mmol, from Aldrich or Lancaster) and 40 mL of dichloromethane. The
resulting solution was stirred at room temperature for about 10 min. A
solution of catechol isopropylborate (1.78 g, 10 mmol) in 10 mL of
dichloromethane was added slowly at room temperature over about 10 min.
The resulting solution was stirred at room temperature for 3 h. Concentration
in vacuo (ca. 0.1 mmHg, 1 h) afforded 7 as clear oil. The solution of 7 can
be stored under N2 at -20 °C as a 0.25 M dichloromethane solution for a
long period of time without noticeable decomposition.
(8) For absolute configuration, see: Nelson, S. G.; Spencer, K. L. J.
Org. Chem. 2000, 65, 1227-1230.
4944
Org. Lett., Vol. 8, No. 21, 2006

Scheme 2. Possible Pathway for the Catalyzed
Enantioselective Formation of Chiral â-Lactones
yields (60-78% range) and moderately good enantioselec-
tivity (12:1 to 5:1 range). The results with six different
aldehydes are summarized in Table 1. In each case, the
predominating enantiomer was 3.8
Table 1. Oxazaborolidine-Catalyzed Enantioselective Addition
of Ketene to Aldehydes
entry
RCHO
% yield (isolated)
% ee, configa
1
2
3
4
5
6
PhCH2CH2CHO
n-C5H11CHO
BnOCH2CH2CHO
cyclo-C6H11CHO
Me2CHCHO
73
78
58
78
62
72
81, R
84, R
65, R
70, S
68, S
67, R
coordinated aldehyde, C-C bond formation and extrusion
of â-lactone should be a favorable reaction pathway. In
accordance with the intermediacy of G and the geometry of
the coordinated aldehyde that is precedented by many
previously observed reactions,6 the absolute configuration
expected for this pathway is that which is actually observed
(3) for the various entries in Table 1. The sequence shown
in Scheme 2 provides a logical, coherent, and satisfying
explanation for all our results. It also provides a basis for
further development of this enantioselective methodology
toward improved yields and enantioselectivities.
The scope of this approach to the catalytic enantioselective
synthesis of chiral â-lactones has yet to be fully explored
with a broader range of substrates. However, it can be noted
that entries 4 and 5 of Table 1 provide the first demonstration
of â-lactone formation from R-branched aldehydes and
ketene. With regard to the scope of our â-lactone-forming
process, another obvious direction for further work is the
development of a methodology for the preparation of pure
(cold) solutions of higher homologues of ketene in the
aldoketene series (i.e., monosubstituted ketenes). We hope
to report on this aspect of the methodology in due course.
Me2CHCH2CHO
a For analytical methods, see ref 8.
The mechanistic hypothesis leading to the use of tri-n-
butyltin triflate to activate 7 for catalysis of the reaction
between an aldehyde and ketene is outlined in Scheme 2.
Activation of the precatalyst 7 by tri-n-butyltin triflate could
reasonably be expected to produce the ion pair E, which by
reaction with ketene should form the intermediate F.
Intermediate F should be a sufficiently strong boron Lewis
acid to coordinate with the aldehyde and generate the reactive
complex G as a transient species. Because G contains two
mutually reactive units, the nucleophilic CH2 of the ketene
acetal subunit and the electrophilic carbonyl carbon of the
(10) To a solution of 7 (200 µL, 0.05 mmol, 0.25 M in dichloromethane)
in dichloromethane (1.0 mL) at -78 °C was added Bu3SnOTf (200 µL,
0.05 mmol, 0.25 M in dichloromethane). After 30 min, a precooled 5 M
solution of ketene in dichloromethane (1 mL, 5 mmol) was added at -78
°C followed by hydrocinnamaldehyde (66 µL, 0.5 mmol). The resulting
homogeneous mixture was kept at -78 °C for 24 h and then quenched by
addition of saturated aqueous Na2HCO3 (0.5 mL) at the same temperature.
After being warmed to room temperature, the reaction mixture was diluted
with H2O (5 mL) and extracted with CH2Cl2 (3 × 5 mL). The combined
extracts were washed with brine (5 mL), dried (Na2SO4), and concentrated
in vacuo. The residue was purified by flash column chromatography (ether/
hexane, 3:7) to afford the â-lactone 4 (64 mg, 73%) as a colorless oil.
Enantioselectivity (91:9) was determined by HPLC analysis using a Daicel
Chiralcel OD-H column, flow rate 1 mL/min, hexane-i-PrOH (9:1); retention
Acknowledgment. We are grateful to Professor Masakat-
su Shibasaki for his encouragement of this research.
Supporting Information Available: Experimental pro-
cedures, physical data, and analysis of enantioselectivity for
the â-lactones listed in Table 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
times 15.9 min (S) and 18.1 min (R); [R]23 +5.62 (c 0.3, CHCl3).
OL061979H
D
Org. Lett., Vol. 8, No. 21, 2006
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