Versatile approaches for the synthesis of fused-ring γ-lactones utilizing cyclopropane intermediates

Article abstract of DOI:10.1021/ol400362t

A highly effective acid-catalyzed cyclopropyl ester to γ-lactone skeletal rearrangement has been demonstrated and applied to the synthesis of a variety of bi- and tricyclic functionalized lactones, rigid and highly compact structures for use as biological

Full text of DOI:10.1021/ol400362t

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Versatile Approaches for the Synthesis
of Fused-Ring γ‑Lactones Utilizing
Cyclopropane Intermediates
Timothy R. Newhouse, Philip S. J. Kaib, Andrew W. Gross, and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
corey@chemistry.harvard.edu
Received February 7, 2013
ABSTRACT
A highly effective acid-catalyzed cyclopropyl ester to γ-lactone skeletal rearrangement has been demonstrated and applied to the synthesis of a
variety of bi- and tricyclic functionalized lactones, rigid and highly compact structures for use as biological probes.
γ-Lactones have served as versatile intermediates in
countless syntheses of complex molecules, and as a con-
sequence, many studies have been directed at increasing
synthetic access to this structural subunit. As a result,
there is now a large repetoire of methods for γ-lactone
synthesis.1,2 The most generally useful processes are those
which allow stereocontrol by internal delivery or catalytic
entantioselective access to complex chiral structures.
Such processes include the following: (1) intramolecular
DielsꢀAlder reactions of acrylate esters,3 (2) intramolecu-
lar addition of diazo esters to carbonꢀcarbon double
bonds,4 (3) addition of acrylate esters to ketonic carbonyls
induced by SmI2,5 (4) intramolecular or intermolecular
cycloaddition of ketenes to carbonꢀcarbon double bonds
followed by BaeyerꢀVilliger oxidation,6 (5) intramolecular
or intermolecular cycloaddition of β-keto acids to carbonꢀ
carbon double bonds induced by Mn3O(OAc)7,7 (6) in-
tramolecular halo- and hydroxylactonization,8 and (7)
intramolecular addition of radicals to carbonꢀcarbon
double bonds.9
This paper reports new and short routes to a variety of
chiral γ-lactones using tactical combinations of a cyclo-
propyl ester to γ-lactone skeletal rearrangement10 and a
range of enantioselective processes.
We provide as the first illustration of our approach the
enantioselective synthesis of the tricyclic keto-lactone (1)
shown in Scheme 1. The starting point was the R-ester 3,
which was prepared enantioselectively as previously de-
scribed, using the chiral oxazaborolidinium ion 2 as cata-
lyst.11 The β-ketoester 4 was accessed from 3 by Claisen
condensation and then transformed into the correspond-
ing R-diazoketone using tosyl azide and triethylamine.
(1) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John
Wiley: New York, 1988.
(2) (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry:
Mechanisms, Reactions, and Structure, 5th ed.; John Wiley: New York,
2001. (b) Ogliaruso, M. A.; Waefe, J. F. Synthesis of Lactones and Lactams:
John Wiley: New York, 2010; online.
(3) For an early example with a δ-lactone, see: Corey, E. J.; Danheiser,
R. L.; Chandrasekaran, S.; Siret, P.; Gras, J.-L. J. Am. Chem. Soc. 1978,
100, 8031–8034.
(7) (a) Heiba, E. I.; Dessau, R. M.; Koehl, W. J. J. Am. Chem. Soc.
1968, 90, 5905–5906. (b) Corey, E. J.; Kang, M. C. J. Am. Chem. Soc.
1984, 106, 5384–5385.
(8) (a) Ma, S.; Chen, G. Angew. Chem. Int. Ed. 2010, 49, 8306–8308.
(b) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.;
Sinha-Bagchi, A.; Keinan, E. Tetrahedron Lett. 1992, 33, 6407–6410.
(9) Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc. 1987,
109, 6187–6189.
(10) This work was initiated by A.W.G. at Harvard in 1982 and
completed recently by T.R.N. and P.S.J.K. For a related example, see:
Kolsaker, P.; Jensen, A. K. Acta Chem. Scand. 1988, B 42, 345–353.
(11) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388–
6390.
(4) Doyle, M. P.; Pieters, R. J.; Martin, S. F.; Austin, R. E.; Oalmann,
€
C. J.; Muller, P. J. Am. Chem. Soc. 1991, 113, 1423–1424.
(5) (a) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett.
1986, 27, 5763–5764. (b) See also: Corey, E. J.; Zheng, G. Z. Tetrahedron
Lett. 1997, 38, 2045–2048.
(6) (a) Corey, E. J.; Kang, M.-c.; Desai, M. C.; Ghosh, A. K.; Houpis,
I. N. J. Am. Chem. Soc. 1988, 110, 649–651. (b) Corey, E. J.; Weinschenker,
N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675–5677.
r
10.1021/ol400362t
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the keto lactone 1 in 83% yield (X-ray structure as shown
in Scheme 1).
Scheme 1. Synthesis of Ketolactone 1a
A direct and efficient route to the chiral tricyclic keto
lactone 6 is summarized in Scheme 2. The acetoacetate
ester of (()-2-cyclohexenol was converted into (R)-3-ace-
tonylcyclohexene by the method of Burger and Tunge12 via
the π-allyl Pd complex with the C2-symmetric TrostꢀVan
Vranken bisphosphine (TVVP).13 The desired chiral tri-
cyclic keto lactone 6 was readily obtained from 8 via the
sequence R-methoxycarbonylation, Regitz diazo transfer,
Cu(TBS)-catalyzed internal [2 þ 1] cycloaddition, and
acid-catalyzed cyclopropane to lactone rearrangement
via the intermediates 9 and 10.
The prochiral tricyclic bis-lactone corresponding to 6
(11) could also be accessed rapidly using the cyclopropyl
ester to γ-lactone rearrangement (see Scheme 3). Methyl
2-cyclohexenylmalonate (12) was transformed via the
corresponding diazoester 13 to the cyclopropyl ester lac-
tone 14, rearrangement of which proceeded at 45 °C to
afford bis-lactone 11.
Scheme 3. Synthesis of Bislactone 11a
a Reagents and conditions: (a) isoprene (5.0 equiv), cat. 2 (0.20 equiv),
PhMe (1.0 M), ꢀ5 °C, 15 h, 96%, 99% ee; (b) EtOAc (2.5 equiv), LDA
(2.5 equiv), THF, ꢀ78 to ꢀ45 °C, 3.5 h, 94%; (c) TsN3 (1.1 equiv),
Et3N (0.5 M), 23 °C, 39 h, 99%; (d) Cu(TBS) (0.06 equiv), PhMe (0.02 M),
111 °C, 6 h, 87%; (e) TMSOTf (3.0 equiv), H2O (1.5 equiv), i-PrNO2
(20 mM), 23 °C, 17 h, 83%.
Scheme 2. Synthesis of Ketolactone 6a
a Reagents and conditions: (a) ClCOCH2CO2Me, Et3N, CH2Cl2,
0ꢀ23 °C, 93%; (b) TsN3 (1.2 equiv), Et3N (1.0 M), 23 °C, 0.5 h, 96%;
(c) Cu(TBS) (0.06 equiv), PhMe (0.02 M), 111 °C, 15 h, 89%; (d)
TMSOTf (3.0 equiv), H2O (1.5 equiv), i-PrNO2 (20 mM), 45 °C, 5 h, 61%.
In a similar fashion, the bicyclic bis-lactone 15 (Scheme 4)
was synthesized from methyl cinnamyl malonate (16) and
diazoester 17.14 Cyclopropyl to γ-lactone rearrangement
converted 17 to 15 and a minor diastereomer (ratio 5:1) in
83% yield. The structure of 15 was demonstrated by single-
crystal X-ray diffraction analysis.
A final example of the application of our methodol-
ogy to a short synthesis of a bicyclic keto lactone (19) is
outlined in Scheme 5. 6-Methyl-5-hepten-2-one (20) was
transformed first into the R-diazo-β-keto ester 21, which
a Reagents and conditions: (a) and (b) ref 12; (c) NaH (6.0 equiv),
CO(OMe)2 (2.1 equiv), 1,4-dioxane (0.5 M), 101 °C, 3 h, 87%; (d) TsN3
(1.1 equiv), Et3N (1.0 M), 23 °C, 2 h, 95%; (e) Cu(TBS) (0.06 equiv),
PhMe (0.05 M), 111 °C, 15 h, 84%; (f) TMSOTf (3.0 equiv), H2O
(1.5 equiv), i-PrNO2 (20 mM), 110 °C, 3 h, 67%.
(12) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113–4115.
(13) (a) Van Vranken, D. L.; Trost, B. M. Chem. Rev. 1996, 96, 395–
422. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2944.
(14) The corresponding ethyl ester of 18 has been prepared by the
method of: Xu, X.; Lu, H.; Ruppel, J. V.; Cui, X.; de Mesa, S. L.; Wojtas,
L.; Zhang, X. P. J. Am. Chem. Soc. 2011, 133, 15292–15295. The
conversion of the methyl ester 17 to 18 proceeds in 95% yield and
92% ee (personal communication with Xue Xu and X. Peter Zhang).
Internal [2 þ 1]-cycloaddition to the CꢀC double bond of
the diazo substrate was promoted by bis-(N-t-butyl-
salicylaldiminato)copper(II) (Cu(TBS)) as catalysttoform
the tricyclic β-keto ester 5. Finally, treatment of 5 with
trimethylsilyl triflate and a small amount of water (to
generate some triflic acid) in i-PrNO2 at 23 °C produced
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 4. Synthesis of Bislactone 15a
Scheme 5. Synthesis of Ketolactone 19a
a Reagentsandconditions:(a) CO(OMe)2 (2.1equiv), NaH(6.0equiv),
1,4-dioxane(0.5 M), 101°C, 3 h;(b)TsN3 (1.2 equiv), Et3N (1.0 M), 23°C,
0.5 h; (c) Cu(TBS) (0.06 equiv), PhMe (0.02 M), 111 °C, 13 h, 85%; (d)
TMSOTf (3.0 equiv), H2O (1.5 equiv), i-PrNO2 (20 mM), 23 °C, 3 h, 86%.
a Reagents and conditions: (a) (i) cinnamyl alcohol (1.0 equiv),
Meldrum’s acid (1.0 equiv), PhMe (3 M), 90 °C, 12 h, (ii) TMSCHN2
(1.5 equiv), C6H6/MeOH (4:1), 23 °C, 10 min, 82%; (b) TsN3 (1.1 equiv),
Et3N (1.0 M), 23 °C, 2 h, 87%; (c) Cu(TBS) (0.06 equiv), PhMe (0.05 M),
111 °C, 15 h, 86%; (d) TMSOTf (3.0 equiv), H2O (1.5 equiv), i-PrNO2
(20 mM), 40 °C, 24 h, 83% (5:1 dr).
In conclusion, the five sequences reported above and
summarized in Schemes 1ꢀ5 demonstrate a useful meth-
odology for the construction of a range of bi- to polycyclic
lactones withcontrol of stereochemistry and a minimum of
synthetic steps.16 These rigid and compact structues could
be of value as small, ligand-efficient probes for screening
purposes in medicinal research.
by internal [2 þ 1]-cycloaddition provided the bicyclic keto
ester 22. Acid catalyzed rearrangement of 22 produced
(þ)-19 in good overall yield from 20. Although our experi-
ments employed racemic 22 to generate (()-19, a catalytic
enantioselective preparation of chiral 22 from 21 has been
reported,15 the use of which would lead to chiral ketolac-
tone 19.
Acknowledgment. Dr. Shao-Zhen Liang is gratefully
acknowledged for acquisition of all X-ray crystal struc-
tures. This work was supported by Bristol-Myers Squibb
through a Postdoctoral Fellowship to T.R.N. The Fritz und
Maria Hofmann-Stiftung and the Richard-Winter-Stiftung
is acknowledged for financial support to P.S.J.K.
(15) Cho, D.-J.; Jeon, S.-J.; Kim, H.-S.; Cho, C.-S.; Shim, S.-C.; Kim,
T.-J. Tetrahedron: Asymmetry 1999, 10, 3833–3848.
(16) General procedure for the cyclopropyl ester to γ-lactone rear-
rangement: To a solution of TMSOTf (54 μL, 0.30 mmol, 3.0 equiv) in
i-PrNO2 (4 mL) was added H2O (2.7 μL, 0.15 mmol, 1.5 equiv) by
dropwise addition. After stirring at ambient temperature for 10 min, the
cyclopropane (0.1 mmol, 1.0 equiv) as a solution in i-PrNO2 (1 mL) was
added. After being stirred for the appropriate time and temperature, the
reaction mixture was treated with aq phosphate buffer (pH = 7, 25 mL)
and the organic phase was separated. The aqueous phase was extracted
with EtOAc (5 ꢁ 25 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography provided the product.
Supporting Information Available. Procedures, full
characterization, spectra, and X-ray data (CIF files). This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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