Asymmetric synthesis of highly substituted β-lactones by nucleophile-catalyzed [2+2] cycloadditions of disubstituted ketenes with aldehydes

Article abstract of DOI:10.1002/anie.200460698

α,α-Disubstituted β-lactones can be obtained by the cycloaddition of the corresponding ketenes with aldehydes (see scheme). For the first time, a chiral PPY derivative, 1, serves as an efficient catalyst for the asymmetric synthesis of β-lactones (PPY = 4-pyrrolidin-1-ylpyridine). To date, this is the only catalyst that is effective for enantioselective cycloadditions of disubstituted ketenes with aldehydes. (Chemical equation presented).

Full text of DOI:10.1002/anie.200460698

Communications
Lactone Synthesis
Asymmetric Synthesis of Highly Substituted
b-Lactones by Nucleophile-Catalyzed [2+2]
Cycloadditions of Disubstituted Ketenes with
Aldehydes**
Jonathan E. Wilson and Gregory C. Fu*
The development of effective methods for the asymmetric
synthesis of b-lactones is an important challenge for a variety
of reasons.[1] Numerous biologically active b-lactone-contain-
ing natural and unnatural products have been described,
including Xenical (tetrahydrolipstatin), an anti-obesity drug
developed by Roche.[2,3] Furthermore, b-lactones serve as
useful intermediates in an array of fields, including materials
science and synthetic organic chemistry.[1,4] The strain of the
four-membered lactone provides an opportunity for a range
of functionalizations; for example, nucleophiles can react
either at the carbonyl group through an addition–elimination
Scheme 1. Proposed pathway for the nucleophile-catalyzed enantiose-
lective synthesis of b-lactones from ketenes and aldehydes.
We have been exploring the utility of planar-chiral DMAP
and PPY derivatives (for example, 1) as catalysts for a range
of transformations,[13] including an asymmetric Staudinger
synthesis of b-lactams that likely proceeds by a pathway
analogous to that depicted in Scheme 1 (DMAP = 4-(dime-
thylamino)pyridine, PPY= 4-pyrrolidin-1-ylpyridine).[14]
ꢀ
sequence or at a C O single bond through an SN2 process.
Thus, a number of recent total syntheses, such as those of
(ꢀ)-laulimalide,[5] (ꢀ)-malyngolide,[6] and trapoxin B,[7] have
exploited enantiopure b-lactones as intermediates.
One attractive route to b-lactones is the overall [2+2]
cycloaddition of a ketene with an aldehyde [Eq. (1)]. Chiral
We were intrigued by the possibility that these nucleo-
philic catalysts might also be useful for b-lactone synthesis.
This sort of an “extension” from reactions of imines to
reactions of aldehydes is not as straightforward as may
appear; for example, in the case of cinchona alkaloid-based
catalysts, an excellent method for enantioselective b-lactam
synthesis from monosubstituted ketenes was reported several
years ago,[15] whereas general conditions for b-lactone syn-
thesis from monosubstituted ketenes, which require a Lewis
acid co-catalyst, have only been developed very recently.[16] In
this Communication, we demonstrate that PPY derivative 1
serves as an effective catalyst for [2+2] cycloadditions of
disubstituted ketenes with aldehydes to furnish the first
catalytic asymmetric route to a,a-disubstituted b-lactones.
In our earlier study, we established that 1 catalyzes a
Staudinger-type cycloaddition of ketenes with imines to
efficiently afford b-lactams with good enantioselectivity
(76–98% yield; 81–98% ee).[14] However, when we apply
these conditions to the corresponding reaction of ketenes with
aldehydes, we obtain essentially none of the desired b-lactone
[Eq. (2)].
nucleophiles and chiral Lewis acids have both been shown to
catalyze this process, sometimes with outstanding enantiose-
lectivity (the postulated mechanism for the nucleophile-
catalyzed cycloaddition is illustrated in Scheme 1).[8–11] To
date, all reports of asymmetric catalysis of this transformation
= =
have described reactions of ketene itself (H2C C O) or of
monosubstituted ketenes. Expanding the scope of such
processes to include disubstituted ketenes would furnish
access to a,a-disubstituted b-lactones, an important class of
synthetic targets.[12]
[*] J. E. Wilson, Prof. Dr. G. C. Fu
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-3611
E-mail: gcf@mit.edu
[**] We thank Ivory D. Hills for X-ray crystallographic studies. Support
has been provided by the National Institutes of Health (National
Institute of General Medical Sciences: R01-GM57034; National
Cancer Institute: training grant CA009112), Merck, and Novartis.
Funding for the MIT Department of Chemistry Instrumentation
Facility has been furnished in part by NSF CHE-9808061 and NSF
DBI-9729592.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460698
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Angewandte
Chemie
Interestingly, by lowering the reaction temperature, we
can generate the targeted [2+2] cycloaddition product in high
yield, and, equally significantly, in high enantiomeric excess
(91% yield, 89% ee; Table 1, entry 1). Furthermore, the two-
tially furnishes the cis diastereomer (ca. 4.5:1 selectivity) with
very good ee (ca. 90%; entries 8 and 9).[18]
We have established that these sterically demanding a,a-
disubstituted b-lactones can be derivatized through reactions
with nucleophiles (Scheme 2). Reagents such as DIBAL-H
Table 1: Catalytic asymmetric cycloaddition of diethylketene with ben-
zaldehyde.
Entry Catalyst
Conditions
Yield [%][a] ee [%][a]
1
5% (ꢀ)-1
THF/toluene (1:1), 91
89
ꢀ788C
2
3
5% (ꢀ)-1
THF, ꢀ788C
92
91
–
5% quinidine
THF/toluene (1:1), <5
ꢀ788C!RT
4[b]
10% O-TMS-quini-
dine, 2 equiv LiClO4
THF/CH2Cl2 (1:1), 21
ꢀ788C!RT
<2
[a] Average of two runs. [b] Because the product b-lactone could not be
separated from a side product, the b-lactone was reduced to a 1,3-diol
with diisobutylaluminum hydride (DIBAL-H). TMS=trimethylsilyl.
Scheme 2. Derivatization of a,a-disubstituted b-lactones.
solvent system that we employed for the synthesis of b-
lactams is unnecessary—the formation of b-lactones proceeds
in very good yield and ee in THF alone (entry 2). It is
important to note that the alkaloid-based methods that have
proved useful for catalytic asymmetric reactions of mono-
substituted ketenes are not effective for the illustrated
cycloaddition of a disubstituted ketene (entries 3[10b] and
4[10d]).
and hydroxide add to the carbonyl group to furnish a 1,3-diol
and a b-hydroxyacid, respectively. Sodium azide, on the other
hand, reacts through an SN2 process to generate a b-
azidoacid.[19,20] These functionalizations proceed in good to
excellent yield with essentially no erosion in enantiomeric
excess.[21]
Our optimized conditions (Table 1, entry 2) are applicable
to a range of [2+2] cycloadditions of disubstituted ketenes
with aldehydes (Table 2). Thus, symmetrical ketenes, both
acyclic and cyclic, couple with aldehydes with good enantio-
selectivity (entries 1–7). Cycloadditions of unsymmetrical
disubstituted ketenes generate b-lactones that bear two
contiguous stereocenters, one quaternary and one tertiary;[17]
we have determined that planar-chiral catalyst 1 preferen-
In conclusion, we have established for the first time that a
chiral PPY derivative (1) can serve as an efficient catalyst for
the asymmetric synthesis of b-lactones; this is the only
catalyst reported to date that is effective for enantioselective
cycloadditions of disubstituted ketenes, which generate a,a-
disubstituted b-lactones. Furthermore, we have shown that
these b-lactones, in addition to being useful structures in their
own right, can be transformed into other important families of
enantioenriched compounds. Additional studies of catalytic
asymmetric reactions of ketenes are underway.
Table 2: Catalytic asymmetric synthesis of b-lactones by cycloadditions
of disubstituted ketenes with aldehydes.
Received: May 18, 2004
Revised: September 10, 2004
Keywords: aldehydes · asymmetric catalysis · cycloaddition ·
.
ketenes · lactones
Entry
R1
R2
R3
ee [%][a]
Yield [%][a]
1
2
3
4
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
Me
Ph
91
89
80
81
89
76
82
91
88
92
77
74
76
67
68
71
48
53
2-naphthyl
4-(CF3)C6H4
4-(MeCO)C6H4
4-MeC6H4
Ph
Ph
Ph
Ph
[1] For a review of the synthesis of optically active b-lactones, see:
H. W. Yang, D. Romo, Tetrahedron 1999, 55, 6403 – 6434.
[2] For reviews of naturally occurring b-lactones, see: a) C. Lowe,
J. C. Vederas, Org. Prep. Proced. Int. 1995, 27, 305 – 346; b) A.
Pommier, J.-M. Pons, Synthesis 1995, 729 – 744.
[3] For studies of analogues of lactacystin b-lactone (and leading
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Chem. Soc. 1998, 120, 2330 – 2336; b) F. Soucy, L. Grenier, M. L.
Behnke, A. T. Destree, T. A. McCormack, J. Adams, L. Pla-
mondon, J. Am. Chem. Soc. 1999, 121, 9967 – 9976.
5
6[b]
7
-(CH2)6-
8[c]
9[c]
iPr
Me
Me
cyclopentyl
[a] Average of two runs. [b] 7% (ꢀ)-1 was used. [c] cis:trans selectivity=
4.2–4.6:1. The ee value is for the cis diastereomer, and the yield is for both
diastereomers.
Angew. Chem. Int. Ed. 2004, 43, 6358 –6360
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Communications
[4] For an example of an application in material science, see: M. E.
Gelbin, J. Kohn, J. Am. Chem. Soc. 1992, 114, 3962 – 3965.
[5] S. G. Nelson, W. S. Cheung, A. J. Kassick, M. A. Hilfiker, J. Am.
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[8] For leading references to methods for the catalytic asymmetric
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114, 771 – 772; Angew. Chem. Int. Ed. 2002, 41, 744 – 746.
[9] For industrial applications of catalytic asymmetric [2+2] cyclo-
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Industry (Eds.: A. N. Collins, G. N. Sheldrake, J. Crosby), Wiley,
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[10] For chiral nucleophilic catalysts, see: a) D. Borrmann, R. Wegler,
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[11] Chiral Lewis acid catalysts: a) for an overview, see: ref. [8];
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[12] Salinosporamide A and omuralide are two examples of natural
products that include an a,a-disubstituted b-lactone. For leading
references, see: L. R. Reddy, P. Saravanan, E. J. Corey, J. Am.
Chem. Soc. 2004, 126, 6230 – 6231.
[13] a) For an early overview, see: G. C. Fu, Acc. Chem. Res. 2000, 33,
412 – 420; b) For more recent reports, see: A. H. Mermerian,
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G. C. Fu, Angew. Chem. 2003, 115, 4051 – 4054; Angew. Chem.
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[14] B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 1578 – 1579.
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[16] See ref. [11b]. Examples of cinchona alkaloid-based intramo-
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[17] For reviews of catalytic asymmetric methods that generate
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[18] Notes: a) Under our standard conditions (Table 2), aryl alkyl
ketenes, monosubstituted ketenes, very electron-rich aldehydes,
and non-aromatic aldehydes are not suitable substrates. b) At
the end of a reaction, we can typically recover about 80% of
catalyst 1.
[19] A. Griesbeck, D. Seebach, Helv. Chim. Acta 1987, 70, 1326 –
1332. For a more recent study, see: S. G. Nelson, K. L. Spencer,
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[20] For a review of the enantioselective synthesis of b-amino acids,
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2002, 58, 7991 – 8035.
[21] In preliminary experiments, we have not observed ring-opening
upon reaction with RSH, R2NH, or R2NLi.
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