SN2 ring opening of β-lactones: An alternative to catalytic asymmetric conjugate additions

Article abstract of DOI:10.1021/jo025519n

Merging catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions with ensuing Grignard-mediated ring opening of the derived enantiomerically enriched β-lactones is presented as a generally useful asymmetric synthesis of β-disubstituted

Full text of DOI:10.1021/jo025519n

SN2 Rin g Op en in g of â-La cton es: An Alter n a tive to Ca ta lytic
Asym m etr ic Con ju ga te Ad d ition s
Scott G. Nelson,* Zhonghui Wan, and Magdalena A. Stan
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
sgnelson@pitt.edu
Received J anuary 12, 2002
Merging catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions with ensuing
Grignard-mediated ring opening of the derived enantiomerically enriched â-lactones is presented
as a generally useful asymmetric synthesis of â-disubstituted carboxylic acids. Enantiomerically
enriched â-lactones are subject to efficient SN2 ring opening with a variety of copper-modified alkyl
Grignard reagents, including highly branched nucleophiles. Considerable structural variation in
the lactone electrophile is also tolerated. Phenyl- and vinyl-derived organometallics are not efficient
nucleophiles for the ring-opening reactions.
In tr od u ction
constructions. A mechanistically distinct approach to
effecting identical bond constructions emerges from an
analysis of SN2 ring opening of â-lactone electrophiles
with carbon-based nucleophiles (Figure 1). In comparison
to prototypical conjugate additions, this reaction design
reconstitutes the enone electrophile as an optically active
â-lactone with SN2 ring opening providing a surrogate
for the conjugate nucleophilic addition. This report
describes the successful implementation of this reaction
design as a versatile asymmetric synthesis of â-disbusti-
tuted carboxylates relying on catalytic asymmetric acyl
halide-aldehyde cyclocondensations as the source of the
requisite â-lactone electrophiles (eq 1). This reaction
strategy allows a variety of differentially substituted
organocuprates to be employed in the ring opening of
structurally diverse 4-substituted 2-oxetanones resulting
in a highly general synthesis of enantiomerically enriched
â-disubstituted carboxylic acids.
Conjugate nucleophilic additions to enone electrophiles
constitute fundamentally important transformations in
organic synthesis.1 The strategic nature of these bond
constructions has resulted in the development of a
number of highly successful strategies for effecting
catalytic asymmetric conjugate hydride, heteroatom, and
carbon nucleophile addition reactions.2,3 Each of these
transformations successfully achieves catalyst-based ste-
reocontrol during the conjugate addition of various nu-
cleophiles to achiral enone electrophiles. The ready
availability of the requisite achiral enone electrophiles
from the olefination of simple carbonyl starting materials
renders these transformations especially attractive bond
(1) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771.
(2) Reviews of asymmetric conjugate additions: (a) Sibi, Mukund.
P.; Manyem, S. Tetrahedron 2000, 56, 8033. (b) Krause, N.; Hoffman-
Ro¨der, A. Synthesis 2001, 171.
(3) Selected recent examples of asymmetric conjugate additions.
Amide anions: (a) Sibi, M. P.; Asano, Y. J . Am. Chem. Soc. 2001, 123,
9708. Organoboron reagents: (b) Chong, J . M.; Shen, L. X.; Taylor, N.
J . J . Am. Chem. Soc. 2000, 122, 1822. (c) Sakuma, S.; Sakai, M.; Itooka,
R.; Miyaura, N. J . Org. Chem. 2000, 65, 5951. (d) Hayashi, T. Synlett
2001, 879 and references therein. (e) Senda, T.; Ogasawara, M.;
Hayashi, T. J . Org. Chem. 2001, 66, 6852. Enolate additions: (f)
Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975. (g) Kim, Y. S.;
Matsunagag, S.; Das, J .; Sekine, A.; Ohshima, T.; Shibasaki, M. J . Am.
Chem. Soc. 2000, 122, 6506. (h) List, B.; Pojarliev, P.; Martin, H. J .
Org. Lett. 2001, 3, 2423. (i) Betancourt, J . M.; Barbas, C. F. Org. Lett.
2001, 3, 3737. Hydride additions: (j) Yun, J .; Buchwald, S. L. Org.
Lett. 2001, 3, 1129 and references therein. (k) Sibi, M. P.; Asano, Y.;
Sausker, J . B. Angew. Chem., Int. Ed. 2001, 40, 1293. Organozinc
reagents: (l) Bennett, S. M. W.; Brown, S. M.; Cunningham, A.; Dennis,
M. R.; Muxworthy, J . P.; Oakley, M. A.; Woodward, S. Tetrahedron
2000, 56, 2847. (m) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A.
H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865 and
references therein. (n) Arena, C. G.; Calabro, G.; Francio, G.; Faraone,
F. Tetrahedron: Asymmetry 2000, 11, 2387. (o) Delapierre, G.; Con-
stantieux, T.; Brunel, J . M.; Buono, G. R. Eur. J . Org. Chem. 2000, 3,
2507. (p) Degrado, S. J .; Mizutani, H.; Hoveyda, A. H. J . Am. Chem.
Soc. 2001, 123, 755-756. (q) Hupe, E.; Knochel, P. Angew. Chem., Int.
Ed. 2001, 40, 3022. (r) Chataigner, I.; Gennari, C.; Ongeri, S.; Piarulli,
U.; Ceccarelli, S. Chem. Eur. J . 2001, 7, 2628 and references therein.
(s) Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J . Am. Chem. Soc.
2001, 123, 4358 and references therein. (t) Kobayashi, S.; Ogawa, C.;
Kawamura, M.; Sugiura, M. Synlett 2001, 983.
Resu lts a n d Discu ssion
â-Lactones offer considerable versatility as intermedi-
ates for synthesis enterprises.4 Ring opening via nucleo-
philic addition at the carbonyl residue affords access to
a variety of ester and amide aldol-type adducts depending
on the choice of nucleophile (eq 2).5 However, ring strain
within the â-lactone nucleus can elicit electrophilic
(4) Pommier, A.; Pons, J .-M. Synthesis 1993, 441.
(5) Nelson, S. G.; Wan, Z. Org. Lett. 2000, 2, 1883.
10.1021/jo025519n CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/29/2002
4680
J . Org. Chem. 2002, 67, 4680-4683

SN2 Ring Opening of â-Lactones
nation processes used to prepare achiral enone electro-
philes required for prototypical conjugate additions.10
The reactivity of simple â-lactones toward carbon-based
nucleophiles was first recognized by Fujisawa.7 Optically
active â-butyrolactone was found to undergo regioselec-
tive SN2 ring opening with alkyl Grignard reagents in
the presence of a Cu(I) catalyst (eq 3). Despite Fujisawa’s
findings in this area, the development of this reaction
design as a generally useful alternative to conjugate
addition reactions had previously been hampered by the
limited availability of optically active â-lactone electro-
philes. Optically active â-lactones had previously been
available only by resolution of racemic â-butyrolactone,
asymmetric diketene dihydrogenation, multistep synthe-
sis, or modestly enantioselective ketene-aldehyde cy-
cloadditions.11
F IGURE 1. Strategies for asymmetric catalytic conjugate
additions
character reminiscent of that expressed by epoxides.
Appropriate tuning of the nucleophile reactivity can lead
to scission of the Calkyl-O bond in an SN2 reaction
pathway.6,7,8
The convenient availability of highly enantiomerically
enriched 4-substituted 2-oxetanones provided by the AAC
reactions prompted us to explore â-lactone ring opening
as a realistic and general alternative to prototypical
conjugate additions. To evaluate the generality of the
organocuprate-mediated SN2 â-lactone ring opening, we
selected the copper-mediated addition of isopropyl Grig-
nard, a branched nucleophile, and 4-cyclohexyl-2-oxet-
anone, an R-branched electrophile, as a stringent test
reaction (eq 4). Reacting lactone 2 with the Gilman
reagent derived from isopropylmagnesium bromide and
CuBr‚DMS afforded exclusive SN2 ring opening in yield-
ing the â-disubstituted acid 3 (90%). The success of this
test reaction suggested that the cuprate-mediated ring
openings would be relatively insensitive to steric pertur-
bations within the reaction components and foreshad-
owed our ultimate success in establishing their general
utility.
On the basis of the bifunctional electrophilic character
expressed by â-lactones, we have been interested in
developing optically active 4-substituted 2-oxetanones as
generally useful platforms for asymmetric organic syn-
thesis. Catalytic asymmetric acyl halide-aldehyde cyclo-
condensation (AAC) reactions have been developed as an
operationally simple approach to highly enantiomerically
enriched â-lactones.9 This reaction technology provides
convenient and economical access to the optically active
electrophiles required as substrates for implementing the
alternative “conjugate addition” reaction design. Indeed,
from an operational perspective, the AAC â-lactone
synthesis closely resembles the one-step aldehyde olefi-
(6) The SN2 ring-opening pathway provides entry to a variety of
versatile synthesis building blocks, including â-amino acids, â-dialkyl
carboxylates, and â-thiocarboxylic acids: (a) Arnold, L. D.; Kalantar,
T. H.; Vederas, J . C. J . Am. Chem. Soc. 1985, 107, 7105. (b) Griesbeck,
A.; Seebach, D. Helv. Chim. Acta 1987, 70, 1326. (c) Arnold, L. D.;
May, R. G.; Vederas, J . C. J . Am. Chem. Soc. 1988, 110, 2237. (d)
Castagnani, R.; De Angelis, F.; De Fusco, E.; Giannessi, F.; Misiti, D.;
Meloni, D.; Tinti, M. O. J . Org. Chem. 1995, 60, 8318. (e) Bernabei, I.;
Castagnani, R.; De Angelis, F.; De Fusco, E.; Giannessi, F.; Misiti, D.;
Muck, S.; Scafetta, N.; Tinti, M. O. Chem. Eur. J . 1996, 2, 826. (f)
Nelson, S. G.; Spencer, K. L. Angew. Chem. 2000, 39, 1323.
(7) (a) Sato, T.; Kawara, T.; Kawashima, M.; Fujisawa, T. Chem.
Lett. 1980, 571. (b) Sato, T.; Kawara, T.; Nishizawa, A.; Fujisawa, T.
Tetrahedron Lett. 1980, 21, 3377. (c) Fujisawa, T.; Sato, T.; Kawara,
T.; Ohashi, K. Tetrahedron Lett. 1981, 22, 4823. (d) Sato, T.; Naruse,
K.; Fujisawa, T. Tetrahedron Lett. 1982, 23, 3587. (e) Sato, T.; Itoh,
T.; Hattori, C.; Fujisawa, T. Chem. Lett. 1983, 1391. (f) Kawashima,
M.; Sato, T.; Fujisawa, T. Tetrahedron 1989, 45, 403.
Examining the scope of cuprate-mediated SN2 lactone
ring openings was initiated by preparing the requisite
enantiomerically enriched â-lactone electrophiles. Asym-
metric AAC reactions of acetyl bromide and various
aldehydes catalyzed by Al(III) complex 1 delivered the
enantioenriched â-lactones 4a -f (eq 1).9a In accord with
the preliminary test reaction, reacting the optically active
â-lactones 4a -f with various alkyl Grignard reagents and
a stoichiometric quantity of CuBr‚DMS and chlorotrim-
ethylsilane (TMSCl) elicited efficient SN2 lactone ring-
(8) (a) Griesbeck, A.; Seebach, D. Helv. Chim. Acta 1987, 70, 1326.
(b) Tempkin, O.; Blacklock, T. J .; Burke, J . A.; Anastasia, M.
Tetrahedron: Asymmetry 1996, 7, 2721.
(9) (a) Nelson, S. G.; Peelen, T. J .; Wan, Z. J . Am. Chem. Soc. 1999,
121, 9742. (b) Nelson, S. G.; Spencer, K. L. J . Org. Chem. 2000, 65,
1227. (c) Reference 5.
(10) Heathcock, C. H. The Aldol Reaction: Group I and II Enolates.
In Comprehensive Organic Synthesis: Additions to C-C π-Bond Part
2; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon Press:
New York, 1991; Vol. 2, Chapter 1.6, p 181.
(11) Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403.
J . Org. Chem, Vol. 67, No. 14, 2002 4681

Nelson et al.
TABLE 1. Cu p r a te-Med ia ted Rin g-Op en in g Rea ction s of
stoichiometric CuBr additive was typically utilized in the
standard alkyl Grignard-mediated â-lactone ring-opening
procedures.
â-La cton es 4
% yield
config-
entry
lactone 4
R1 (%ee)a
Grignardb (5-17)c urationd
Regardless of the copper stoichiometry used in these
â-lactone ring openings, conducting the reactions in the
presence of trimethylsilyl chloride was imperative for
achieving consistently high reaction yields. For example,
reacting lactone 4a with the methyl Gilman reagent
derived from MeMgBr and CuBr provided up to 25% of
the tertiary alcohol 18 derived from carbanion addition
to the carbonyl function (eq 6). However, the same
reaction incorporating a stoichiometric amount of TMSCl
afforded the desired SN2 addition adduct 5 (88% yield)
as the exclusive reaction products. This effect becomes
even more dramatic for more sterically hindered orga-
nometallics that, in the absence of the TMSCl additive,
afford predominately carbonyl addition. While the ben-
eficial effects of added TMSCl on a variety of organocop-
per-mediated addition reactions is well-documented,14 the
precise role the TMSCl additive is playing in these
reactions, and, indeed, the present lactone ring openings
remains unclear.
R2-MgBr
a
b
c
d
e
f
g
h
i
CH2CH2Ph 4a (S, 97)
4a
4a
4a
CH3
CHMe2
CMe3
CH2Ph
CH2Ph
CH2Ph
88 (5)
88 (6)
80 (7)
94 (8)
R
R
R
S
S
R
S
R
S
S
CH2CHMe2 4b (S, 95)
91 (9)
CC6H11 4c (S, 98)
87 (10)
84 (11)
78 (12)
88 (13)
82 (14)
CH2OCH2Ph 4d (R, 92) CH3
4d
4d
CHMe2
CH2Ph
CH3
j
CH2CH2OCH2Ph 4e
(R, 93)
k
l
m
4e
4e
CHMe2
CMe3
CH3
84 (15)
74 (16)
84 (17)
S
S
R
CH2CH2OTBDPS 4f
(S, 92)
a
Lactones 4a ,b,d -f were prepared as described in ref 9a;
b
lactone 4c was prepared as described in ref 9b. Commercially
available organomagnesium bromide reagents were used as cu-
prate precursors. c Values are for chromatographically purified
d
materials. Absolute configurations of acids 11 and 13 were
unambiguously established; see ref 16. Configurations of the
remaining â-disubstituted acids were assigned by analogy to these
determinations.
opening to afford the enantiomerically enriched â-disub-
stituted acids 5-17 in 74-94% yield (eq 5).
Alkyl Grignard-mediated â-lactone ring opening is
virtually insensitive to the steric environment of both the
lactone electrophile and the nucleophilic carbon atom
under the optimized reaction conditions. Copper-medi-
ated Grignard additions involving â-lactones bearing
branched alkyl substituents or highly branched nucleo-
philes, including tert-butylmagnesium bromide, were
subject to equally efficient lactone ring opening (Table
1, entries b, c, f, and l). Considerable structural variation
is also tolerated in the electrophilic reaction component,
including â-lactones possessing oxygen functionality
incorporating several common ether protecting groups
(entries g-m). Cis-3,4-disubstituted 2-oxetanones 198
also participated in efficient Grignard-mediated ring
opening, providing a strategy for stereoselectively intro-
ducing vicinal tertiary carbon stereocenters (eq 7). Pre-
cedent indicated that each of these SN2 ring-opening
reactions would proceed with rigorous inversion of the
2-oxetanone stereocenter;15 the veracity of this prediction
was unambiguously confirmed for the â-chiral carboxylic
The efficiency of these Grignard-mediated ring-opening
reactions exhibited considerable sensitivity to the stoi-
chiometry of the copper-modified Grignard reagents.
High yields of the methyl-addition adducts 5 (Table 1,
entries a, g, j, and m) were achieved only using the
putative methyl Gilman reagent derived from a stoichio-
metric quantity of CuBr‚DMS and 2 equiv of methyl-
magnesium bromide. Ring-opening reactions employing
substoichiometric Cu(I) additives were not generally
effective in providing clean SN2 addition for the range of
alkyl Grignard and 4-substituted â-lactones evaluated in
this study.12 Nucleophilc addition of larger alkyl Grignard
reagents (isopropyl- or tert-butylmagnesium bromide)
could be accomplished using 5 mol % CuBr‚DMS with
no apparent deleterious effects on the reaction yield.
These results are consistent with the observation that
alkyl Grignard reagents react with â-lactone electrophiles
only slowly at low temperatures (<-30 °C); at higher
reaction temperatures, unmodified alkyl Grignard re-
agents add exclusively to the lactone carbonyl.13 Despite
these observations, reactions employing stoichiometric
amounts of the CuBr additive provided the greatest
substrate generality and reproducibility. As a result,
(14) (a) Corey, E. J .; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019.
For reviews: (b) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41,
135. (c) Lipshutz, B. H. In Organometallics in Synthesis; A Manual;
Schlosser, M., Ed.; J ohn Wiley & Sons: New York, 1994; Chapter 4, p
283.
(15) For SN2 â-lactone ring opening with inversion of configuration,
see refs 6b,f and 7b-f. The ring opening of lactone 19 to afford
exclusively the anti diastereomer of 2,3-dimethyl-4-benzyloxybutanoic
acid (eq 7) provides additional evidence for configurational inversion
upon SN2 â-lactone ring opening.
(12) The addition of geranyl Grignard to â-butyrolactone has been
achieved using 5 mol % Li2CuCl4. See ref 7.
(13) Alkyl Grignard reagents participate in nucleophilic addition to
â-lactone electrophiles only slowly at temperatures below -30 °C.
4682 J . Org. Chem., Vol. 67, No. 14, 2002

SN2 Ring Opening of â-Lactones
acids 11 and 13 by comparing their optical rotations with
derived â-disubstituted carboxylates in either enantio-
meric series via the readily available catalyst 1. This
methodology also allows the introduction of a consider-
able variety of structurally diverse alkyl groups at the
incipient â-stereocenter. As a result, this reaction tech-
nology represents a useful complement to traditional
asymmetric conjugate addition reactions.
reported values.16
Exp er im en ta l Section
In contrast to the successful ring-opening reactions
employing sp3-hybridized carbanions, sp2-hybridized nu-
cleophiles, including vinyl- and phenyl-derived organo-
metallics, do not provide efficient SN2 lactone ring
opening. Vinyl Grignard, with either substoichiometric
or stoichiometric Cu(I) additives, adds predominately to
the lactone carbonyl providing, ultimately, the product
of conjugate addition to the intervening vinyl ketone (eq
8).7e Aryl Grignard reagents afford poor yields of the
â-disubstituted carboxylates (<50%) contaminated with
significant amounts of the aryl ketone adduct resulting
from nucleophilic attack at the carbonyl residue. In this
regard, these lactone ring-opening reactions that function
most efficiently with alkyl nucleophiles complement
existing asymmetric conjugate additions of aryl and
alkenyl boronic acids.3b-e Moreover, the utility of com-
mercially available Grignard reagents in these conjugate
addition surrogates extends the range of functional
nucleophiles relative to those conjugate additions requir-
ing organozinc nucleophiles.
Gen er a l. The catalyst complex 1 was prepared according
to the published procedure.9a Lactones 4a ,b,d -f,9a 4c,9b and
195 were prepared according to published procedures.
Gen er a l P r oced u r e for SN2 Cu p r a teAd d ition to â-La c-
ton es 4. In a flame-dried 25 mL flask was weighed 215 mg of
CuBr‚DMS (1.5 mmol). Dimethyl sulfide (0.5 mL) and THF
(15 mL) were added, and the resulting mixture was cooled to
-50 °C. A solution of the alkyl Grignard reagent (3.0 mmol)
was added, and the reaction mixture was stirred for 30 min
at -50 °C. The reaction mixture was then warmed to -30 °C,
and stirring was continued for another 30 min to allow
complete formation of the cuprate. The reaction mixture was
cooled to -50 °C, and a solution of the â-lactone 4 (1.0 mmol)
in 2 mL of THF was added. After stirring for 30 min at -50
°C, TMSCl (1.5 mmol) was added and the reaction was then
allowed to warm to ambient temperature over approximately
3 h; stirring was continued until all the lactone was consumed
(as monitored by TLC). The reaction mixture was poured into
a mixture of saturated NH4Cl (30 mL) and 1 M HCl (10 mL),
and the mixture was extracted with diethyl ether (3 × 30 mL).
The combined organic portions were washed with saturated
NH4Cl and brine and dried over MgSO4. After evaporation of
the solvent, the product mixture was purified by flash chro-
matography.
Ack n ow led gm en t. The National Science Founda-
tion (CHE-9875735), the Merck Research Laboratories,
and the Bristol-Myers Squibb Foundation are gratefully
acknowledged for their generous support.
Emerging from this two-step AAC-cuprate addition
sequence is a general and highly versatile alternative to
asymmetric conjugate addition reactions for generating
optically active â-disubstituted carboxylic acids. Utilizing
the catalyzed asymmetric AAC methodology as the
stereochemically defining event provides access to the
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and proton and carbon NMR spectra are provided for
compounds 5-17. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Schmid, R.; Hansen, H. J . Helv. Chim. Acta 1990, 73, 1258.
J O025519N
J . Org. Chem, Vol. 67, No. 14, 2002 4683