Carbonylation of epoxides to substituted 3-hydroxy-α-lactones

Article abstract of DOI:10.1021/ol702475e

Substituted 3-hydroxy-δ-lactones (3HLs) are valuable intermediates in the synthesis of pharmaceuticals and other biologically active natural products. Herein we report the first example of the catalytic carbonylation of substituted homoglycidols to 3HLs using HCo(CO)₄. Upon optimization of the catalyst and reaction conditions, a functionally diverse set of 3HLs was prepared. Mechanistic insight was gained by observation of the carbonyiation reaction using in situ IR spectroscopy, and we propose a mechanism that is consistent with previously studied epoxide carbonyiation systems.

Full text of DOI:10.1021/ol702475e

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5581-5583
Carbonylation of Epoxides to
Substituted 3-Hydroxy- -Lactones
δ
John W. Kramer, Daniel Y. Joh, and Geoffrey W. Coates*
Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell UniVersity, Ithaca, New York 14853-1301
gc39@cornell.edu
Received October 22, 2007
ABSTRACT
Substituted 3-hydroxy-δ-lactones (3HLs) are valuable intermediates in the synthesis of pharmaceuticals and other biologically active natural
products. Herein we report the first example of the catalytic carbonylation of substituted homoglycidols to 3HLs using HCo(CO)4. Upon optimization
of the catalyst and reaction conditions, a functionally diverse set of 3HLs was prepared. Mechanistic insight was gained by observation of the
carbonylation reaction using in situ IR spectroscopy, and we propose a mechanism that is consistent with previously studied epoxide
carbonylation systems.
Substituted 3-hydroxy-δ-lactones (3HLs) are common struc-
tural motifs in natural products1 and are valuable as
intermediates in the synthesis of a variety of pharmaceutical
compounds.2-5 3HLs are most prominent in the class of
HMG-CoA reductase inhibitors known as statins, which are
among the most potent cholesterol-lowering drugs available
and constitute five of the top 100 selling drugs.5 All approved
statins have side chains comprising either a 3HL or the
hydrolyzed 3,5-dihydroxycarboxylic acid analogue (Figure
1), which are essential for the bioactivity of statin drugs.6
Figure 1. Structures of two common statin drugs with 3HL portions
3HLs have also been used in the synthesis of important drugs
such as tetrahydrolipstatin,2 a lipase inhibitor prescribed for
the treatment of obesity, and the antiretroviral agent tipranavir.3
Furthermore, dehydration of 3HLs produces a class of
biologically active R,â-unsaturated lactone natural products.4
highlighted.
As a result of their synthetic value, the synthesis of 3HLs
has received a great deal of attention in recent years.7-10
Biocatalytic routes have proven successful in the synthesis
(1) Aggarwal, V. K.; Bae, I.; Lee, H.-Y. Tetrahedron 2004, 60, 9725-
9733.
(2) Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1999, 64, 8059-8062.
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R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 3139-3140.
(4) Stevenson, R.; Weber, J. V. J. Nat. Prod. 1988, 51, 1215-1219.
(5) (a) Tolbert, J. A. Nat. ReV. Drug DiscoVery 2003, 2, 517-526. (b)
de Lorenzo, F.; Feher, M.; Martin, J.; Collot-Teixeira, S.; Dotsenko, O.;
McGregor, J. L. Curr. Med. Chem. 2006, 13, 3385-3393.
(6) (a) Ranganathan, A.; Timoney, M.; Bycroft, M.; Corte´s, J.; Thomas,
I. P.; Wilkinson, B.; Kellenberger, L.; Hanefeld, U.; Galloway, I. S.;
Staunton, J.; Leadlay, P. F. Chem. Biol. 1999, 6, 731-738. (b) Greenberg,
W. A.; Varvak, A.; Hanson, S. R.; Wong, K.; Huang, H.; Chen, P.; Burk,
M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5788-5793.
(7) (a) Gijsen, H. J.; Wong, C.-H. J. Am. Chem. Soc. 1995, 117, 7585-
7591. (b) Heine, A.; Luz, J. G.; Wong, C.-H.; Wilson, I. A. J. Mol. Biol.
2004, 343, 1019-1034.
(8) (a) Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C.; Winkler, T.
Tetrahedron 1995, 51, 3549-3558. (b) Kim, S.-J.; Kang, H.-Y.; Sherman,
D. H. Synthesis 2001, 1790-1793. (c) Le Sann, C.; Mun˜oz, D. M.; Saunders,
N.; Simpson, T. J.; Smith, D. I.; Soulas, F.; Watts, P.; Willis, C. L. Org.
Biomol. Chem. 2005, 3, 1719-1728.
(9) Reddy, M. V. R.; Brown, H. C.; Ramachandran, P. V. J. Organomet.
Chem. 2001, 624, 239-243.
(10) Fournier, L.; Gaudel-Siri, A.; Kocienski, P. J.; Pons, J.-M. Synlett
2003, 107-111.
10.1021/ol702475e CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/21/2007

of statin side chains, although substrate scope is limited.7
Synthetic routes to substituted 3HLs have employed a variety
of methods, including aldol reactions using chiral auxiliaries,8
reduction of diketoesters followed by cyclization,1 allyl
boration and ring-closing metathesis,9 and rearrangement of
â-lactones.10 These methods, however, involve multiple steps
and can suffer from low stereoselectivity.
Table 1. Catalyst Screening for 3HL Formation
Our laboratory has recently reported a number of catalysts
that are active for the carbonylation of a functionally diverse
array of epoxides to â-lactones.11 However, the expected
â-lactone was not formed in the carbonylation of glycidol;
instead, 3-hydroxy-γ-valerolactone was the sole product
(Scheme 1).12 While this method could be utilized in the
conversiona (%)
entry
catalyst
δ-lactone (7)
â-lactone (8)
1
2
3
4
5
6
7
1
2
3
4
5
16
73
33
58
83
84
27
67
42
17
Scheme 1. Carbonylation of Glycidol to
3-Hydroxy-γ-valerolactone
Co2(CO)8
HCo(CO)4
67
>99
33
NDc
b
a Conversions determined by 1H NMR spectroscopy; diastereomeric ratios
of 6, 7, and 8 ca. 1:1. b Prepared in situ; see Supporting Information for
details. c ND ) Not Detected.
synthesis of γ-lactone natural products such as (-)-grandin-
olide,13 this result led us to consider the carbonylation of
substituted homoglycidols as a potential route to 3HLs. Such
a process would provide simple access to δ-lactones with a
variety of substitution starting from commercially available
epoxides and aldehydes (Scheme 2).14
(2 and 5) produced more 3HL (7); thus, we reasoned that a
catalyst that is active for epoxide ring opening but slow for
â-lactone ring closing would give better selectivity for 3HL.
When we used HCo(CO)4 (entry 7) which is not known to
produce â-lactones but is effective for the alkoxy carbonyl-
ation of epoxides to â-hydroxy esters,16 3HL was formed as
the exclusive product.
Scheme 2. Convergent Synthesis of Homoglycidols
Our proposed mechanism for the carbonylation of homo-
gylcidols by HCo(CO)4 (Scheme 3) is analogous to that of
Scheme 3. Proposed Mechanism for Competing δ-Lactone
and â-Lactone Formation
Our initial efforts to carbonylate 4-hydroxy-1,2-epoxy-
nonane (6)15 to δ-lactone 7 using known epoxide carbonyl-
ation catalysts resulted in mixtures of â- and δ-lactones
(Table 1, entries 1-6). In general, catalysts that are highly
active for epoxide carbonylation to â-lactone (1 and 3) were
more selective for â-lactone (8). This selectivity could be
exploited in the synthesis of tetrahydrolipstatin and other
â-lactone-containing lipase inhibitors.2 Less active catalysts
(11) (a) Getzler, Y. D. Y. L.; Mahadevan, V.; Lobkovsky, E. B.; Coates,
G. W. J. Am. Chem. Soc. 2002, 124, 1174-1175. (b) Mahadevan, V.;
Getzler, Y. D. Y. L.; Coates, G. W. Angew. Chem., Int. Ed. 2002, 41, 2781-
2784. (c) Schmidt, J. A. R.; Mahadevan, V.; Getzler, Y. D. Y. L.; Coates,
G. W. Org. Lett. 2004, 6, 373-376. (d) Kramer, J. W.; Lobkovsky, E. B.;
Coates, G. W. Org. Lett. 2006, 8, 3709-3712. (e) Rowley, J. M.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2007, 129, 4948-
4960.
(12) (a) Brima, T. U.S. Patent Appl. 4,968,817; Chem. Abstr., 1990, 114,
185246. (b) Church, T. L.; Getzler, Y. D. Y. L.; Byrne, C. M.; Coates, G.
W. Chem. Commun. 2007, 657-674.
(13) Zemribo, R.; Champ, M. S.; Romo, D. Synlett 1996, 278-280.
(14) See Supporting Information.
other epoxide carbonylations by Lewis acid based catalysts.17
The first step involves protonation and ring opening of the
epoxide by HCo(CO)4 to form a cobalt alkyl complex. After
insertion of CO, the resulting cobalt acyl intermediate can
cyclize to form either 3HL (Pathway A) or the more strained
â-lactone (BL; Pathway B). Another potential mechanism
for 3HL formation could involve a BL intermediate and its
(15) Epoxides 6, 6a-6d, and 6g-6j and their corresponding 3HLs were
prepared as a ca. 1:1 mixture of diastereomers. Similar rates of carbonylation
were observed for both epoxide diastereomers.13
(16) Heck, R. F. J. Am. Chem. Soc. 1963, 85, 1460-1463.
(17) Church, T. L.; Getzler, Y. D. Y. L.; Coates, G. W. J. Am. Chem.
Soc. 2006, 128, 10125-10133.
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Org. Lett., Vol. 9, No. 26, 2007

subsequent rearrangement to 3HL. However, using in situ
IR spectroscopy, BL was not observed during the carbonyl-
ation of 6.14 Furthermore, rearrangement of BL 8 to 3HL 7
was negligible under the reaction conditions, eliminating this
mechanistic possibility.
After the reaction conditions were optimized for efficient
δ-lactone formation,14 a variety of substituted homoglycidols
were carbonylated (Table 2).15 Both alkyl- (entries 1 and 2)
B) competitive with 3HL formation. The alkene- and
fluoroether-substituted epoxides (entries 7 and 8) required a
higher catalyst loading to reach full conversion. Finally, the
important synthetic intermediates 7i and 7j were synthesized
under standard conditions. Both 7i and 7j have been used in
the synthesis of more complex statin drugs.18,6b
The (3R,5R) absolute stereochemistry is essential to the
efficacy of statin drugs,6b and the ability to control the
stereochemical outcome of the carbonylation is of great
importance for any synthetic application. Our proposed
mechanism (Scheme 3) predicts retention of stereochemistry
of these homoglycidols. To test this mechanistic hypothesis
we carbonylated (R,R)-6b under standard conditions (Figure
2). Analysis by 1H and 13C NMR spectroscopy indicated the
Table 2. Synthesis of 3HLs Using HCo(CO)4
Figure 2. Carbonylation of enantiopure homoglycidol (R,R)-6b
with retention of stereochemistry.
trans diastereomer was formed exclusively, and optical
rotation established the product as the (3R,5R) isomer.14 Thus,
the carbonylation occurs with retention of both stereocenters.
The synthesis of 3HLs by carbonylation of homoglycidols
is an efficient method to access functionally diverse and
optically pure lactones. We anticipate the substrate range and
simple catalyst preparation will make this procedure useful
in a variety of synthetic applications. We are currently
applying this methodology to incorporate new functional
groups for the synthesis of natural products.
Acknowledgment. We thank Dr. Christopher Byrne
(Cornell University) for discussions and materials relating
to catalyst preparation. This work was supported by the
National Science Foundation (CHE-0243605) and the De-
partment of Energy (DE-FG02-05ER15687) and by the
National Institutes of Health through a Chemical/Biology
Interface (CBI) Training Grant (to J.W.K.).
a Yield of isolated product. b 6% â-lactone formed. c 4% â-lactone
formed. d 5 mol % catalyst used.
Supporting Information Available: Experimental pro-
cedures, in situ IR data, full characterization of all new
compounds, and 1H and 13C NMR spectra for all δ-lactones.
This material is available free of charge via the Internet at
http://pubs.acs.org.
and aryl-substituted (entry 3) homoglycidols were carbonyl-
ated cleanly to 3HLs. Disubstituted homoglycidols (entries
4-6) produced 7d and the spiro 3HLs 7e and 7f; however,
a small amount of â-lactone was also formed in these
carbonylations. We believe the more sterically hindered
tertiary alcohols undergo slower ring closing, making â-lac-
tone formation from a secondary alcohol (Scheme 3, Pathway
OL702475E
(18) MacKeith, R. A.; McCague, R.; Olivo, H. F.; Roberts, S. M.; Taylor,
S. J. C.; Xiong, H. Bioorg. Med. Chem. 1994, 2, 387-394.
Org. Lett., Vol. 9, No. 26, 2007
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