Stereoselective synthesis of donor-acceptor substituted cyclopropafuranones by intramolecular cyclopropanation of vinylogous carbonates: Divergent synthesis of tetrahydrofuran-3-one, tetrahydropyran-3-one, and lactones

Article abstract of DOI:10.1021/ol902301h

"Chemical Equation Presented" A new, highly stereoselective Intramolecular cyclopropanation of vlnylogous carbonate with carbenes using copper catalyst is described. Each of the cyclopropane bonds of these two acceptor substituted cyclopropafuranones can

Full text of DOI:10.1021/ol902301h

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5466-5469
Stereoselective Synthesis of
Donor-Acceptor Substituted
Cyclopropafuranones by Intramolecular
Cyclopropanation of Vinylogous
Carbonates: Divergent Synthesis of
Tetrahydrofuran-3-one,
Tetrahydropyran-3-one, and Lactones
Santosh J. Gharpure,* Manoj K. Shukla, and U. Vijayasree
Department of Chemistry, Indian Institute of Technology Madras,
Chennai 600036, Tamil Nadu, India
sjgharpure@iitm.ac.in
Received October 5, 2009
ABSTRACT
A new, highly stereoselective intramolecular cyclopropanation of vinylogous carbonate with carbenes using copper catalyst is described.
Each of the cyclopropane bonds of these two acceptor substituted cyclopropafuranones can be cleaved with complete regiocontrol by judicious
choice of reaction conditions, leading to a diverse array of frameworks such as tetrahydrofuran-3-one, tetrahydropyran-3-one, and lactones.
Heteroatom-substituted donor-acceptor cyclopropanes (DACs)
are fast emerging as versatile building blocks in organic
synthesis.1 The oxygen-substituted DACs that are fused with
furan/pyran ring have been found to be useful synthons in
the synthesis of cyclic ethers and lactones. As a result of
the push-pull effect of the donor and acceptor substituents,
they show remarkably diverse reactivity with very high
selectivity for cleavage of one of the cyclopropane bonds.
This interesting reactivity of DACs has been exploited in
the synthesis of a variety of natural products.2 It has been
shown that DACs can be used as 1,3-dipoles in cycloaddition
reactions3 and in ring-opening reactions with electrophiles
and nucleophiles.4 However, methods for the regioselective
(2) (a) Fuerst, D. E.; Stoltz, B. M.; Wood, J. L. Org. Lett. 2000, 2,
3521. (b) Chhor, R. B.; Nosse, B.; Sorgel, S.; Bohm, C.; Seitz, M.; Reiser,
O. Chem.sEur. J. 2003, 9, 260. (c) Weisser, R.; Yue, W.; Reiser, O. Org.
Lett. 2005, 7, 5353. (d) Morales, C. L.; Pagenkopf, B. L. Org. Lett. 2008,
10, 157. (e) Haveli, S. D.; Sridhar, P. R.; Suguna, P.; Chandrasekaran, S.
Org. Lett. 2007, 9, 1331. (f) Carson, C. A.; Kerr, M. A. Org. Lett. 2009,
11, 777. (g) Carson, C. A.; Kerr, M. A. Angew. Chem., Int. Ed. 2006, 45,
6560. (h) Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465.
(1) For recent reviews, see: (a) Reissig, H. U.; Zimmer, R. Chem. ReV.
2003, 103, 1151. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321.
10.1021/ol902301h CCC: $40.75
Published on Web 11/05/2009
 2009 American Chemical Society

cleavage of all three bonds of a single DAC by simply
changing the reaction conditions have until date been
missing. One of the common methods for their synthesis is
the intermolecular catalytic cyclopropanation of dihydrofu-
ran/pyran derivatives with diazoesters.5 However, the selec-
tivity of such intermolecular cyclopropanation reaction is
dependent on the pattern of substitution present in dihydro-
furan/pyrans.1 Herein, we describe a highly stereo- and
regioselective synthesis of cyclopropafuranones 1 employing
an intramolecular cyclopropanation of vinylogous carbonates
using copper catalyst. We further demonstrate that these
cyclopropafuranones are good precursors for a diverse array
of structural motifs present in many natural products via
regioselective cleavage of all three bonds of the cyclopropane
moiety.
the diazoketone 2 via a highly stereoselective intramo-
lecular [2 + 1] cycloaddition of the vinylogous carbonate
(Scheme 1).
Scheme 1
Preliminary studies examined the feasibility of the in-
tramolecular cyclopropanation of the vinylogous carbonate
on the diazoketone 2a (R ) Me) (Table 1). The requisite
We envisioned that the cyclopropafuranone 1 with two
different acceptors (CO and CO2Et) could be manipulated
chemoselectively, allowing for the regioselective cleavage
of each of the cyclopropane bonds and thus leading to a
diverse array of structural motifs. Vinylogous carbonates
have been extensively used as excellent radical acceptors
in the synthesis of cyclic ethers.6 In continuation of our
interest in studying the reactivity of vinylogous
carbonates,7a particularly under nonradical conditions7b
that still remain largely underdeveloped,8 we decided to
explore a new synthesis for the cyclopropafuranone 1 from
Table 1. Optimization of the Intramolecular Cyclopropanation
of Vinylogous Carbonate Using Diazoketone 2a (R ) Me)
equiv solvent temp (°C) yield (%)a b
,
entry
catalyst
1
2
3
4
5
6
7
8
9
none
Cu(OTf)2
0
C6H12
reflux
0
30
68
0
72
78
74
0
0.1 CH2Cl2
0.1 CH2Cl2
0.1 CH2Cl2
refluxc
refluxd
refluxc
refluxe
CuI/Cu (powder)
anhyd CuSO4
anhyd CuSO4
Cu(acac)2
Rh2(OAc)4
AgNO3
10
C6H12
0.1 CH2Cl2 refluxc
(3) Some recent examples: (a) Yadav, V. K.; Sriramurthy, V. Angew.
Chem. Int. Ed 2004, 43, 2669. (b) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf,
B. L. J. Am. Chem. Soc. 2007, 129, 9631. (c) Qi, X.; Ready, J. M. Angew.
Chem., Int. Ed. 2008, 47, 7068. (d) Parsons, A. T.; Johnson, J. S. J. Am.
Chem. Soc. 2009, 131, 3122. (e) Young, I. S.; Kerr, M. A. Angew. Chem.,
Int. Ed. 2003, 42, 3023. (f) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am.
Chem. Soc. 2005, 127, 5764. (g) Ivanova, O. A.; Budynina, E. M.; Grishin,
Y. K.; Trushkov, I. V.; Verteletskii, P. V. Angew. Chem., Int. Ed. 2008,
47, 1107.
0.1 CH2Cl2
0.1 CH2Cl2
0.1 CH2Cl2
rt
reflux
reflux
CuCl2
34
a Isolated yield. b In all cases, dr was determined on the crude reaction
mixtures by 1H NMR and was found to be g19:1. c No reaction at rt. d No
reaction with CuI alone. e Using two 100 W tungsten lamps.
(4) (a) Sugita, Y.; Kimura, C.; Hosoya, H.; Yamadoi, S.; Yokoe, I.
Tetrahedron Lett. 2001, 42, 1095. (b) Yu, M.; Pagenkopf, B. L. Org. Lett.
2003, 5, 4639. (c) Sridhar, P. R.; Ashalu, K. C.; Chandrasekaran, S. Org.
Lett. 2004, 6, 1777. (d) Lifchits, O.; Charette, A. Org. Lett. 2008, 10, 2809.
(e) Collum, D. B.; Still, W. C.; Mohamadi, F. J. Am. Chem. Soc. 1986,
108, 2094. (f) Zschiesche, R.; Grimm, E. L.; Reissig, H.-U. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 1086. (g) Khan, F. A.; Czerwonka, R.; Reissig,
H.-U. Eur. J. Org. Chem. 2000, 3607, and references therein.
diazoketone 2a was readily prepared in 79% yield by
treatment of the acid 3a with oxalyl chloride to furnish the
corresponding acid chloride, followed by its reaction with
an ethereal solution of diazomethane.9 The thermal decom-
position of the diazoketone 2a in refluxing CH2Cl2 or
cyclohexane was not successful (Table 1, entry 1). Even
though reaction of diazoketone 2a in the presence of a
catalytic amount of Cu(OTf)2 in CH2Cl2 at room temperature
did not proceed at all, at reflux it gave cyclopropafuranone
1a in 30% yield (Table 1, entry 2).10 Anhydrous CuSO4 was
found to be a useful catalyst in refluxing (using two 100 W
tungsten lamps) cyclohexane, giving rise to cyclopropafura-
none 1a in very good yield and diastereoselectivity. However,
a huge excess of the catalyst was required as a result of the
insolubility of catalyst in cyclohexane. Even though CuI and
AgNO3 did not provide the cyclopropanated product (Table
1, entries 3 and 8), CuI/Cu powder and CuCl2 furnished the
(5) For some selected references, see: (a) Brady, T.; Kim, S. H.; Wen,
K.; Kim, C.; Theodorakis, E. A. Chem.sEur. J. 2005, 11, 7175. (b) Bohm,
C.; Reiser, O. Org. Lett. 2001, 3, 1315. (c) Hoberg, J. O.; Claffey, D. J.
Tetrahedron Lett. 1996, 37, 2533. (d) Kim, C.; Brady, T.; Kim, S. H.;
Theodorakis, E. A. Synth. Commun. 2004, 34, 1951. (e) Monn, J. A.; Valli,
J. M.; Massey, S. M.; Hansen, M. H.; Kress, T. J.; Wepsiec, J. P.; Harkness,
A. R.; Grutsch, J. L.; Wright, R. A.; Johnson, B. G.; Andis, S. L.; Kingston,
A.; Tomlinson, R.; Lewis, R.; Griffey, K. R.; Tizzano, J. P.; Schoepp, D. D.
J. Med. Chem. 1999, 42, 1027. (f) Wheeler, W. J.; O’Bannon, D. D.;
Kennedy, J. H.; Monn, J. A.; Tharp-Taylor, R. W.; Valli, M. J.; Kuo, F.
J. Labelled Compd. Radiopharm. 2005, 48, 605.
(6) (a) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron Lett. 1993,
34, 4831. (b) Lee, E. Pure Appl. Chem. 2005, 77, 2073. (c) Hori, N.;
Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999, 40, 2811.
(d) Evans, P. A.; Raina, S.; Ahsan, K. Chem. Commun. 2001, 2504. (e)
Evans, P. A.; Roseman, J. D. J. Org. Chem. 1996, 61, 2252. (f)
Leeuwenburgh, M. A.; Litjens, R. E. J. N.; Code´e, J. D. C.; Overkleeft,
H. S.; Van der Marel, G. A.; Van Boom, J. H. Org. Lett. 2000, 2, 1275. (g)
Sibi, M. P.; Patil, K.; Rheault, T. R. Eur. J. Org. Chem. 2004, 372. (h)
Chakraborty, T. K.; Samanta, R.; Ravikumar, K. Tetrahedron Lett. 2007,
48, 6389, and references therein.
(9) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley-Interscience:
New York, 1998. (b) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091.
(c) Doyle, M. P. Aldrichimica Acta 1996, 29, 3.
(7) (a) Gharpure, S. J.; Porwal, S. K. Synlett 2008, 242. (b) Gharpure,
S. J.; Reddy, S. R. B. Org. Lett. 2009, 11, 2519.
(8) Selected examples, see: (a) Hart, D. J.; Bennett, C. E. Org. Lett.
2003, 5, 1499. (b) Kwon, M. S.; Woo, S. K.; Na, S. W.; Lee, E. Angew.
Chem., Int. Ed. 2008, 47, 1733. (c) Kerr, M. S.; Rovis, T. J. Am. Chem.
Soc. 2004, 126, 8876. (d) McErlean, C. S. P.; Willis, A. C. Synlett 2009,
233, and references therein.
(10) It is pertinent to mention that although Cu(II) salts are screened as
catalyst precursors, the Cu(I) salts are the catalytically active species in
these type of reactions; see: (a) Moser, W. R. J. Am. Chem. Soc. 1969, 91,
1135. (b) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem.
ReV. 2003, 103, 977.
Org. Lett., Vol. 11, No. 23, 2009
5467

cyclopropanated product in moderate yields (Table 1, entries
3 and 9). Cu(acac)2 (in refluxing CH2Cl2) was found to be
an excellent catalyst for this intramolecular cyclopropanation,
furnishing the cyclopropafuranone 1a in very good yield with
excellent diastereoselectivity (Table 1, entry 6).11 Even
though Rh2(OAc)4 too was found to work well (Table 1, entry
7), given the cost and the regioselectivity problems associated
with it for some of the substrates (see Supporting Informa-
tion), we decided to use Cu(acac)2 as the catalyst of choice.
Table 2 outlines the scope of the intramolecular cyclo-
propanation reaction of vinylogous carbonates with Cu(acac)2
cyclopropafuranone derivative 1f.12 In other cases the
stereochemistry assigned is by analogy to this example and
on the basis of NOE experiments. The stereochemical
outcome of these intramolecular cyclopropanation reactions
are consistent with the transition state structures in which
the cyclopropane ring prefers to be syn to hydrogen on the
C-2 than the bulky alkyl substituent so as to avoid the steric
interaction (see Supporting Information).
A systematic study was undertaken, to test the reactivity
of the DACs synthesized with the emphasis on gaining access
to reaction conditions such that regioselective cleavage of
each bond of the cyclopropane ring can be achieved.
To begin with, the cyclopropafuranone 1a was subjected
to standard radical conditions using n-Bu3SnH and AIBN in
benzene under reflux.13 The cyclopropane ring was cleaved
in a highly regioselective manner, furnishing in quantitative
yield the 3-furanone derivative 4a (cf. scheme 2). The
Table 2. Scope of the Intramolecular Cyclopropanation of
Vinylogous Carbonate (Scheme 1)
yield (%)a
entry
R
step I step II product
drb
1
2
3
4
5
6
7
8
9
CH3
H
CH3CH2
CH3(CH2)3
(CH3)2CHCH2
PhCH2
Ph
BnOCH2
CH3CH2(CH3)CH 2i
CH2dCH-CH2 2j
2a
2b
2c
2d
2e
2f
79
77
70
70
78
78
81
60
69
72
78
76
80
66
70
77
74
70
74
26c
1a
1b
1c
1d
1e
1f
1g
1h
1i
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
Scheme 2
2g
2h
10
2i
reaction was found to work equally well when the side chain
contained a benzyloxymethyl substituent (1h, R ) CH2OBn).
The reactivity of these two acceptor substituted DACs with
Lewis acids was investigated next. The screening of several
Lewis acids revealed that TMSOTf was able to open the
cyclopropane bond of 1a by preferentially complexing with
the ketone leading to the formation of oxonium ion, which
was trapped with hydride from triethylsilane. Initially formed
ketone underwent further reduction, yielding diastereomeric
mixture of the 3-hydroxytetrahydropyran, which was oxi-
dized with PCC to the keto-ester 5a. Repetition of the same
reaction sequence with 1f yielded the keto-ester 5f in
comparable yields (cf. Scheme 3).
a Isolated yield. b Determined on the crude reaction mixtures by 1H NMR.
c Cyclopropanation of olefin was also observed (52%).
as the catalyst. This study demonstrated that vinylogous
carbonates are good substrates for the intramolecular cyclo-
propanation with carbenes. The reaction proceeded smoothly
in the presence of a variety of substitutions such as alkyl,
aryl, or benzyloxy groups. It is interesting to note that
cyclopropafuranones were obtained as the only detectable
products in these cases, and competing side reactions such
as C-H insertion (entries 4-7 and 9), cyclopropanation of
phenyl group (entry 6), or 1,2-shift of the intermediate
oxonium intermediate (entry 8) were not observed. Inciden-
tally, in these cases, it was found that Rh2(OAc)4 gave a
significant amount of these side products (see Supporting
Information). Interestingly, when competitive reaction was
set with a simple olefin present in the side chain, the
cyclopropafuranone 1j was found to be minor product (26%)
and regioisomeric product obtained by intramolecular cy-
clopropanation of olefin was found to be the major product
(52%) (entry 10). In all of the examples, the cyclopropanation
of vinylogous carbonate moiety proceeded with very high
diastereoselectivity. It is pertinent to mention here that the
cyclopropafuranones 1a, 1e, 1f, 1g, and 1i were prepared in
enantiopure forms.
Scheme 3
In another direction, the oxonium ion formed from the
cyclopropafuranone 1a on treatment with TMSOTf could be
trapped by reaction with allyltributyltin furnishing ca. 3:2
(trans/cis) diastereomeric mixture of the trisubstituted tet-
The stereochemistry of the substituents was assigned with
the help of single crystal X-ray diffraction studies on the
(12) CCDC 733601(11a), CCDC 733602 (9a), and CCDC 733603 (1f)
contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(13) (a) Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 9159. (b)
Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 5248.
(11) (a) Hudlicky, T.; Sheth, J. P.; Gee, V.; Barnvos, D. Tetrahedron
Lett. 1979, 20, 4889. (b) Hudlicky, T.; Koszyk, F. J.; Kutchan, T. M.; Sheth,
J. P. J. Org. Chem. 1980, 45, 5020.
5468
Org. Lett., Vol. 11, No. 23, 2009

rahydropyran-3-one 6a. This study demonstrated that cyclo-
propafuranones are versatile intermediates for the synthesis
of THF and THP derivatives.
mediate. Thus, reaction of the alcohol 7a in methanol in the
presence of a catalytic amount of sulfuric acid led to the
formation of an epimeric mixture of the acetal 10a (Scheme
5). Even a carbon nucleophile such as 1,3,5-trimethoxyben-
After demonstrating the regioselective cleavage of the two
of the three cyclopropane bonds, we reasoned that if the
carbonyl of the ester moiety complexes with the Lewis acid,
it would lead to the cleavage of the third bond of the DA
cyclopropane. Thus, chemoselective reduction of the ketones
1a/f using lithium aluminum hydride furnished the corre-
sponding alcohols 7a/f in excellent yield and very good
diastereoselectivity (Scheme 4). The alcohol 7a was then
Scheme 5
Scheme 4
zene could be used to give the arylated furofuranone 11a in
88% yield with excellent diastereoselectivity with aryl
nucleophile trapping the oxonium ion from the less hindered
convex face.12 The oxonium ion intermediate trapping with
sulfur nucleophiles was particularly interesting. Similar to
MeOH, thiophenol (12) as the nucleophile led to the
formation of the lactone 13a. On the other hand, using
ethanedithiol as the nucleophile furnished the δ-valerolactone
derivative 14a in 78% yield by tandem ring-opening-oxonium
ion trapping with ethanedithiol, thioacetalization, and sub-
sequent lactonization. This study unambiguously demon-
strated the diverse and unique reactivity of these DACs.
In conclusion, we have developed a highly regio- and
diastereoselective synthesis of DACs employing intramo-
lecular cyclopropanation of vinylogous carbonates with
carbenes in the presence of Cu(acac)2 as the catalyst. These
two acceptor substituted DACs display hitherto unprec-
edented reactivity allowing for the regioselective cleavage
of each of the cyclopropane bonds by appropriate choice of
reagents leading to divergent synthesis of THF, THP, and
lactone derivatives.
subjected to treatment with TMSOTf and Et3SiH. Interest-
ingly, not only did it lead to the cleavage of the third bond
of the DA cyclopropane but the free hydroxyl group
underwent lactonization in a tandem fashion with the ester
in situ, furnishing the furofuranone 8a. In another direction,
the intermediate oxonium formed from the alcohol 7a in the
presence of TMSOTf could be directly oxidized with
m-CPBA with concomitant lactonization to furnish furo-
furandione 9a in a single step from the alcohol 7a.12 The
aryl group in 7f was found to be unaffected under the reaction
conditions employed and the products 8f and 9f were also
formed in good yields. It is worthwhile mentioning that
furofurandiones are part structures of a series of natural
products such as xylobovide, canadensolide, and sporothri-
olide, and the developed method could be potentially applied
to the synthesis of these natural products and analogues.14,15
This tandem cyclopropane ring-opening-lactonization
sequence was found to be quite general, and a variety of
nucleophiles could be used to trap the oxonium ion inter-
Acknowledgment. We thank DST, New Delhi for finan-
cial support and Mr. V. Ramkumar of the Department of
Chemistry, IIT Madras for the crystallographic data.
(14) (a) Abate, D.; Abraham, W. R.; Meyer, H. Phytochemistry 1997,
44, 1443. (b) McCorkindale, N. J.; Wright, J. L. C.; Brian, P. W.; Clarke,
S. M.; Hutchinson, S. A. Tetrahedron Lett. 1968, 6, 727. (c) Krohn, K.;
Ludewig, K.; Aust, H. J.; Draeger, S.; Schulz, B. J. Antibiot. 1994, 47,
Supporting Information Available: Characterization data
of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
113
.
(15) For some recent examples, see: (a) Adrio, J.; Carretero, J. C. J. Am.
Chem. Soc. 2007, 129, 778. (b) Fernandes, R. A.; Ingle, A. B. Tetrahedron
Lett. 2009, 50, 1122. (c) Mondal, S.; Ghosh, S. Tetrahedron 2008, 64, 2359.
(d) Yu, M.; Lynch, V.; Pagenkopf, B. L. Org. Lett. 2001, 3, 2563
.
OL902301H
Org. Lett., Vol. 11, No. 23, 2009
5469