Synthesis of Fused Tetrahydrofuran-γ-lactone Motifs via One-Pot Ring Expansion of Cyclopropane Rings

Article abstract of DOI:10.1081/SCC-120037907

An efficient method for constructing fused tetrahydrofuran-γ-lactone scaffolds, such as 8, is presented. Key to this strategy is an acid-catalyzed ring expansion of cyclopropyl precursor 6 that proceeds in the presence of MeSO3H in acetone and produces th

Full text of DOI:10.1081/SCC-120037907

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Synthesis of Fused Tetrahydrofuran‐γ‐lactone Motifs
via One‐Pot Ring Expansion of Cyclopropane Rings
Charles Kim a , Thomas Brady a , Sun Hee Kim a & Emmanuel A. Theodorakis a
a Department of Chemistry , University of California San Diego , 9500 Gilman Drive, La
Jolla, California, 92093‐0358, USA
Published online: 20 Aug 2006.
To cite this article: Charles Kim , Thomas Brady , Sun Hee Kim & Emmanuel A. Theodorakis (2004) Synthesis of Fused
Tetrahydrofuran‐γ‐lactone Motifs via One‐Pot Ring Expansion of Cyclopropane Rings, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:11, 1951-1965, DOI: 10.1081/
SCC-120037907
To link to this article: http://dx.doi.org/10.1081/SCC-120037907
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 11, pp. 1951–1965, 2004
Synthesis of Fused Tetrahydrofuran-g-
lactone Motifs via One-Pot Ring
Expansion of Cyclopropane Rings
Charles Kim, Thomas Brady, Sun Hee Kim, and
*
Emmanuel A. Theodorakis
Department of Chemistry, University of California San Diego,
La Jolla, California, USA
ABSTRACT
An efficient method for constructing fused tetrahydrofuran-g-lactone
scaffolds, such as 8, is presented. Key to this strategy is an acid-catalyzed
ring expansion of cyclopropyl precursor 6 that proceeds in the presence
of MeSO3H in acetone and produces the desired bicyclic system in good
to excellent yields.
Key Words: Cyclopropanation; Ring expansion; Tetrahydrofuran-g-
lactone; Bicyclic system.
*
Correspondence: Emmanuel A. Theodorakis, Department of Chemistry, University of
California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA; E-mail:
etheodor@ucsd.edu or etheodorakis@ucsd.edu.
1951
DOI: 10.1081/SCC-120037907
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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1952
Kim et al.
INTRODUCTION
A wide range of linear, angular, and fused g-butyrolactone ring sys-
tems are encountered in natural product structures. Among them, fusion
of the g-butyrolactone onto a substituted tetrahydrofuran (THF) ring cre-
ates a distinctive motif that features as a substructure in an interesting
but underexplored class of natural diterpenes. Representative members of
this family include the marine diterpenes spongionelin (1),[1] macfarlandin
C (3),[2] norrisolide (4),[3] and the fungal metabolite dermatolactone (2)[4]
(Fig. 1).
The interesting chemical architecture of this bicyclic motif, referred to
also as perhydrofuran [2,3-b] furan moiety, have prompted several approaches
toward its synthesis. These are based on enzymatic Baeyer–Villiger oxidation
of fused cyclobutanones,[5] oxyselenylation of 2,3 dihydrofurans,[6] radical
cyclizations of substituted furans,[7] and acid-catalyzed cyclization of cyclo-
hexanone carboxaldehydes.[8] Nonetheless, all reported strategies suffer from
the multiple steps and the low overall yields.
RESULTS AND DISCUSSION
Attracted by the topological characteristics of such fused bicyclic system
and faced with the limitations of established strategies, we sought to examine
an alternative synthetic entry. Key to this approach was the recognition that
the g-butyrolactone unit can arise from ring expansion of a cyclopropyl
carboxylate ester, such as 6 (Fig. 2). It is well established that the strained
three-membered ring of cyclopropanes can lead, upon activation, to a variety
of ring cleavage and ring expansion reactions (for selected references on ring
expansion of cyclopropanes see Ref.[9]). Based on this, we expected that the
presence of both electron withdrawing and electron donating substituents at
Figure 1. Representative natural products containing a fused tetrahydrofuran-g-lactone
ring system.

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Synthesis of Fused Tetrahydrofuran-g-lactone Motifs
1953
Figure 2. Strategy for the construction of fused tetrahydrofuran-g-lactone motifs.
vicinal positions of the cyclopropyl ring of 6 would allow the cleavage of the
anomeric bond to occur under mild acidic conditions (for selected reviews on
this topic see Ref.[10]). The transiently produced 1,3-dipolar synthon 7 could
then cyclize in situ at the anomeric center to produce the desired bicyclic
ring system of 8. An important advantage of this strategy is that one can
benefit from the existing stereochemistry of the substituted dihydrofuran 5
to install the cyclopropane ring, eventually accessing enantiomerically pure
perhydrofuran [2,3-b] furans (for references on cyclopropyl ring opening
see Ref.[11]). In this manuscript, we present the synthesis and one-step ring
expansion of cyclopropanes of generic structure 6 to form the fused tetra-
hydrofuran g-lactone structures, such as 8.
The synthesis of cyclopropane derivatives 11, 13, 14, 15, and 16 is
shown in Sch. 1 and departed with transformation of D-mannose (9) to the
known glycal 10.[12] We expected that both the acetonide and the benzyl
ether functionalities will shield the top face of vinyl ether 10 and direct
the cyclopropanation from the b-face. Indeed, slow addition of ethyl diazoa-
cetate into a concentrated mixture of 10 and rhodium (II) acetate afforded
cyclopropane 11 in 59% yield (4 : 1 ratio of isomers in favor of the exo
adduct) (for selected references on cyclopropanation chemistry see
Ref.[13]). Exposure of 11 to mildly acidic conditions allowed the deprotec-
tion of the acetonide unit without opening the cyclopropyl ring. The resulting
diol was then oxidatively cleaved (NaIO4) to produce aldehyde 12, which
after methylation (MeMgBr) and subsequent oxidation afforded cyclopro-
pane 13 in 58% combined yield. Alternatively, reduction of aldehyde 12
(NaBH4), followed by silylation of the resulting alcohol (TBDPSCl, imida-
zole) gave rise to cyclopropyl derivative 14. Reductive debenzylation of
14 (H2, Pd/C), followed by oxidation of the resulting alcohol produced
ketone 15 (59% yield), which was further subjected to modified Wittig ole-
fination conditions to form alkene 16. Cyclopropanes 20,[14a] 22,[14b] and
24[14c] were obtained in good yields via a rhodium catalyzed cyclopropana-
tion of ethyl diazoacetate with the corresponding dihydrofurans, following
literature procedures.
The results from the cyclopropane to g-lactone rearrangement are
summarized in Table 1. During our initial studies we examined the conversion

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1954
Kim et al.
Scheme 1. Reagents and conditions: (a) 0.01 equiv. Rh2(OAc)4, 1.1 equiv.
N2CHCO2Et (0.1 M in CH2Cl2, syringe pump addition), CH2Cl2, 258C, 14 hr, 59%;
(b) HCl (10% aq), MeOH/THF: 1/10, 258C, 6 hr, 87%; (c) 3.0 equiv. NaIO4, THF/
H2O: 3/1, 2 hr, 258C, 85%; (d) 1.3 equiv. MeMgBr (1 M in THF), THF, 2788C,
1 hr, 72%; (e) 2.5 equiv. Dess–Martin periodinane, CH2Cl2, 2 hr, 93%; (f) 1.0 equiv.
NaBH4, THF/MeOH: 5/1, 258C, 0.5 hr, 73%; (g) 1.5 equiv. TBDPSCl, 2.0 equiv.
imid, THF, 258C, 4 hr, 95%; (h) 0.1 equiv. Pd/C (10%), H2 (1 atm), 258C, 24 hr,
.
84%; (i) 3.0 equiv. SO3 pyr, 3.0 equiv. Et3N, CH2Cl2/DMSO: 1/1, 08C, 5 hr, 71%;
(j) 1.5 equiv. Ph3PCH3Br, 1.5 equiv. tBuOK (1 M in THF), THF, 608C, 12 hr, 34%.
of cyclopropane 11 to lactone 17 using a variety of acids, such as 10%
H2SO4 or 1 N HCl in refluxing dioxane, or ethanol. In all these cases, we
observed the formation of multiple products, presumably arising from conco-
mitant deprotection of the acetonide group. In order to suppress acetonide
deprotection we subjected 11 to 10% methanesulfonic acid in acetone and
found that, after only 6 hr at 258C, the starting cyclopropyl ester was comple-
tely converted to the desired product 17, which was isolated in 77% yield.
The structure and relative stereochemistry of 17 was unambiguously estab-
lished by a single crystal x-ray analysis, and confirmed that the cyclopropa-
nation in precursor 11 occurred from the more accessible a-face of the
cyclopropyl ring.a Under identical acidic treatment the TBDPS group of
cyclopropane adduct 14 was not cleaved (Table 1, entry 3), allowing iso-
lation of the desired lactone 19 in 83% yield. Similar yields were obtained
during the acid-catalyzed ring expansion of cyclopropanes 13, 20, 22, and
24, indicating that this one-pot reaction is general and synthetically useful.
aThe crystallographic data for structure 17 have been deposited at the Cambridge Crys-
tallographic Data Centre as supplementary publication No: CCDC 212319. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html.

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Synthesis of Fused Tetrahydrofuran-g-lactone Motifs
1955
Table 1. The results from the cyclopropane to g-lactone rearrangement.
Entry
1
Cyclopropane
g-Lactone
Yield (%)
77
2
3
62
83
4
5
6
Decomposition
N/A
79
7
8
48
72
However, cyclopropanes 15 and 16 having an sp2 hybridized center at the
a-carbon of the cyclopropyl ring led to decomposition under the above
conditions.
CONCLUSION
In summary, we describe herein an efficient and general procedure for the
preparation of fused tetrahydrofuran-g-lactone motifs, based on a MeSO3H
catalyzed one-pot ring expansion of the corresponding cyclopropanes.

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1956
Kim et al.
SELECTED EXPERIMENTAL PROCEDURES/DATA
General Techniques
All reagents were commercially obtained (Aldrich, Acros) at highest
commercial quality and used without further purification except where noted.
Air- and moisture-sensitive liquids and solutions were transferred via syringe
or stainless steel cannula. Organic solutions were concentrated by rotary
evaporation below 458C at approximately 20mmHg. All non-aqueous reac-
tions were carried out under anhydrous conditions using flame-dried
glassware within an argon atmosphere in dry, freshly distilled solvents, unless
otherwise noted. THF, diethyl ether (ether, Et2O), dichloromethane (CH2Cl2),
toluene (PhCH3), and benzene (PhH) were purified by passage through a bed
of activated alumina. Yields refer to chromatographically and spectroscopically
(1H NMR, 13C NMR) homogeneous materials, unless otherwise stated.
Reactions were monitored by thin-layer chromatography (TLC) carried out on
0.25mm E. Merck silica gel plates (60F-254) using UV light as the visualizing
agent and 10% ethanolic phosphomolybdic acid (PMA) or p-anisaldehyde
solution and heat as developing agents. E. Merck silica gel (60, particle size
0.040–0.063 mm) was used for flash chromatography. Preparative TLC
separations were carried out on 0.25 or 0.50mm E. Merck silica gel plates
(60F-254). NMR spectra were recorded on Varian Mercury 300, 400 and/or
Unity 500 MHz instruments and calibrated using the residual undeuterated
solvent as an internal reference. The following abbreviations were used to
explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
b, broad. IR spectra were recorded on a Nicolet 320 Avatar FT-IR spectrometer
and values are reported in cm21 units. High resolution mass spectra (HRMS)
were recorded on a VG 7070 HS mass spectrometer under chemical ionization
(CI) conditions or on a VG ZAB-ZSE mass spectrometer under fast atom
bombardment (FAB) conditions. X-ray data were recorded on a Bruker
SMART APEX 3 kW Sealed Tube x-ray diffraction system.
Cyclopropane 11. Compound 10[12] (1.1 g, 3.97 mmol) was dissolved in
10 mL of dichloromethane and 5 mg of Rh2(OAc)4 was added. Ethyl diazo-
acetate (0.5 g, 4.3 mmol) was dissolved in 10 mL of dichloromethane and
added to the stirring 2,3-dihydrofuran/rhodium mixture over a 12-hr period
via the syringe pump. The residue was then concentrated and subjected to
silica gel chromatography to provide 0.9 g of the title compound 11 (59%).
[a]2D5: 25.0 (c ¼ 0.9, CH2Cl2); IR (film) nmax 2984, 2935, 1715, 1268,
1
1187, 1097; Rf ¼ 0.5 (50% ether in hexanes); H NMR (400 MHz, CDCl3)
d 7.35 (m, 5H), 4.71 (d, J ¼ 11.6 Hz, 1H), 4.59 (d, J ¼ 12 Hz, 1H), 4.35
(m, 2H), 4.18 (d, J ¼ 4.8 Hz, 1H), 4.07 (m, 3H), 3.95 (dd, J ¼ 6.0, 8.4 Hz,
1H), 3.68 (m, 1H), 2.34 (t, J ¼ 4.4, 4.8 Hz, 1H), 1.89 (d, J ¼ 2.8 Hz, 1H),

ORDER
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Synthesis of Fused Tetrahydrofuran-g-lactone Motifs
1957
1.40 (s, 3H), 1.36 (s, 3H), 1.24 (t, J ¼ 6.8, 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 170.6, 137.5, 128.2, 127.6, 127.5, 108.6, 81.9, 78.8, 72.7, 72.1, 66.5,
64.9, 60.7, 28.5, 26.7, 25.4, 21.4, 14.3; HRMS, calcd for C20H26O6
(M þ Naþ): 385.1627, found: 385.1623.
Cyclopropane 13. Compound 11 (1 g, 2.7 mmol) was dissolved in 50 mL
of a (1/1) THF/methanol solution and cooled to 08C. A 20 mL of aqueous HCl
(1 M) was added to the cooled, stirring solution and stirring was continued for
6 hr. The solution was diluted with ethyl acetate and carefully neutralized with
saturated sodium bicarbonate solution. The diol was extracted three times with
50 mL ethyl acetate, dried over magnesium sulfate and concentrated on the
rotary evaporator. The crude residue was purified by silica gel chromatography
(60% ether in hexanes) to yield 0.75 g of analytically pure diol (87%).
[a]2D5 ¼ 215.1 (c ¼ 1.1, CH2Cl2); IR (film) nmax 3393, 2924, 1718, 1449,
1406, 1274; Rf ¼ 0.2 (50% ether in hexanes); 1H NMR (400 MHz, CDCl3) d
7.38–7.33 (m, 5H), 4.80 (d, J ¼ 11.6 Hz, 1H), 4.56 (d, J ¼ 11.6 Hz, 1H),
4.37 (d, J ¼ 4.8 Hz, 1H), 4.30 (d, J ¼ 5.2 Hz, 1H), 4.12 (q, J ¼ 7.2 Hz, 2H),
4.01–3.97 (m, 1H), 3.76 (dd, J ¼ 11.6 Hz, 3.4 Hz, 1H), 3.66–3.61 (m, 2H),
2.40 (t, J ¼ 4.2 Hz, 1H), 2.10 (br.s, 2H), 1.88 (d, J ¼ 4.0 Hz, 1H), 1.25
(t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 171.8, 138.8, 129.9,
129.0, 82.1, 80.7, 73.2, 70.7, 66.5, 65.3, 62.1, 28.9, 23.0, 15.6; HRMS calcd
for C17H22O6 (M þ Naþ): 345.1314, found: 345.1299.
The diol (0.75 g, 2.3 mmol) was added to a round-bottom flask and
dissolved in 50 mL of a 1/1 mixture of THF/H2O. Sodium periodate (0.5 g,
6.9 mmol) was added and the reaction mixture was stirred for 2 hr. The
reaction was cooled to 08C and quenched with saturated sodium thiosulfate
and sodium bicarbonate (50 mL each). The reaction mixture was diluted with
ethyl acetate and extracted three times with 75 mL of ethyl acetate. The
combined organics were dried over magnesium sulfate and concentrated en
vacuo to give ꢀ0.7 g of the crude unstable aldehyde 12, which was immedi-
ately treated with ꢀ1.1 equiv. (0.84 mL, 2.5 mmol) of methylmagnesium
bromide (3 M in ether) in 25 mL of THF at 08C. The reaction was stirred
for 30 min at 08C, then diluted with 50 mL of ether. The organic layer was
washed with 100 mL of saturated ammonium chloride. The aqueous
layer was extracted twice with 50 mL of ether. The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated on the rotary
evaporator. The resulting alcohol, mixture of diastereomers, was dissolved
in 50 mL of dichloromethane and treated with Dess–Martin periodinane
(2.1 g, 5 mmol) and stirred for 2 hr. The reaction was quenched with sodium
thiosulfate and sodium bicarbonate (50 mL each). The aqueous phase was
extracted twice with 50 mL of dichloromethane, filtered, dried over mag-
nesium sulfate, and concentrated on the rotary evaporator. The crude ketone
was subjected to silica gel chromatography (30% ether in hexanes) to afford

ORDER
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1958
Kim et al.
ketone 13 in 49% yield (four steps). [a]2D5: 27.7 (c ¼ 1.0, CH2Cl2); IR (film)
1
nmax 1717, 1454, 1183, 1118, 1094; Rf ¼ 0.6 (50% ether in hexanes); H
NMR (400 MHz, CDCl3) d 7.34–7.26 (m, 5H), 4.63–4.39 (m, 4H), 4.12
(q, J ¼ 7.2 Hz, 2H), 4.04 (d, J ¼ 5.2 Hz, 1H), 2.37 (t, J ¼ 4.8 Hz, 1H), 2.21
(s, 3H), 1.79 (d, J ¼ 3.6 Hz, 1H), 1.26 (t, J ¼ 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 205.4, 170.3, 137.9, 128.5, 126.0, 127.7, 86.1, 80.3,
78.8, 72.3, 65.7, 60.9, 28.3, 27.4, 21.8, 14.2; HRMS, calcd for C17H20O5
(M þ Naþ): 327.1208, found: 327.1198.
Cyclopropane 14. The crude aldehyde 12 (0.7g, ꢀ2.3 mmol, prepared as
previously described for 13) was dissolved in a 1/1 mixture of isopropanol/
THF and cooled to 08C. Sodium borohydride (0.12 g, 4 mmol) was added to
the solution and stirring was continued for 30min at 08C. The reaction was then
diluted with water and extracted three times with 75mL of ethyl acetate. The
combined organic layers were dried over magnesium sulfate and concentrated
on the rotary evaporator. The crude residue was purified on silica gel (50%
ether in hexanes) to yield 0.47g of the primary alcohol (70%, two steps). [a]2D5:
212.7 (c ¼ 1.0, CH2Cl2); IR (film) nmax 3444, 2926, 1715, 1412; Rf ¼ 0.2
1
(50% ether in hexanes); H NMR (400 MHz, CDCl3) d 7.39–7.32 (m, 5H),
4.76 (d, J ¼ 11.6Hz, 1H), 4.48 (d, J ¼ 11.6Hz, 1H), 4.43 (dd, J ¼ 5.2, 0.8 Hz,
1H), 4.24 (d, J ¼ 5.2 Hz, 1H), 4.11 (q, J ¼ 7.2 Hz, 2H), 4.00 (dd, J ¼ 10.4,
6.4 Hz, 1H), 3.85–3.77 (m, 2H), 2.39 (dd, J ¼ 4.8, 4.0 Hz, 1H), 1.84 (dd,
J ¼ 4.0, 1.2 Hz, 1H), 1.25 (t, 7.2 Hz, 3H); 13C NMR (100MHz, CDCl3) d
170.7, 137.1, 128.7, 128.2, 127.7, 81.5, 80.3, 72.0, 65.2, 60.8, 60.7(2), 22.2,
14.2; HRMS, calcd for C16H20O5 (M þ Naþ): 315.1209, found: 315.1201.
The alcohol (0.47 g, 1.5 mmol) and imidazole (0.11 g, 1.6 mmol) were
dissolved in 10mL THF and TBDPS-Cl (0.44 g, 1.6 mmol) was added to the
stirring solution. The reaction was stirred at room temperature for 3 hr and
quenched with water. The solution was diluted with ether and extracted three
times with 50mL of ether. The combined organic layers were dried over
magnesium sulfate and concentrated on the rotary evaporator. The product
was isolated by silica gel chromatography (25% ether in hexanes) to yield
0.77g of the protected alcohol 14 (93%). [a]2D5 ¼ 25.3 (c ¼ 1.0, CH2Cl2); IR
(film); nmax 3065, 2930, 2855, 1697, 1423, 1109; Rf ¼ 0.6 (30% ether in
hexanes); 1H NMR (400MHz, CDCl3) d 7.72–7.65 (m, 4H) 7.44–7.25
(m, 11H), 4.68 (d, J ¼ 11.6Hz, 1H), 4.54 (d, J ¼ 12Hz, 1H), 4.34 (dd,
J ¼ 4.8 Hz, 0.6 Hz, 1H), 4.18 (d, J ¼ 4.8 Hz, 1H), 4.11 (q, J ¼ 7.2 Hz, 2H),
4.0 (dd, J ¼ 10.4Hz, 6.2 Hz, 1H), 3.85–3.75 (m, 2H), 2.34 (t, J ¼ 4.4 Hz,
1H), 1.91 (dd, J ¼ 3.6 Hz, 1.0 Hz, 1H), 1.25 (t, J ¼ 7.0 Hz, 3H), 1.06 (s, 9H);
13C NMR (100MHz, CDCl3) d 170.8. 137.6, 135.4, 135.3, 134.5, 133.3,
133.1, 129.6 129.5, 129.4, 128.3, 127.6, 127.5, 127.4, 82.1, 78.7, 72.0, 64.8,
64.7, 61.2, 60.7, 28.4, 26.9, 26.7, 21.6, 21.5, 19.3, 14.4; HRMS calcd for
C32H38O5Si (M þ Naþ): 553.2387, found: 553.2367.

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Synthesis of Fused Tetrahydrofuran-g-lactone Motifs
1959
Cyclopropane 15. Compound 14 (5 g, 9.4 mmol) was dissolved in 150 mL
ofTHF, palladiumhydroxide, (10%oncarbon, 0.5 g)wasaddedandtheflaskwas
capped with a septum, evacuated and filled with hydrogen gas from a balloon.
The reaction flask was periodically evacuated and replenished with hydrogen
gas (four times over a 12hr period). The reaction was stirred under an argon
atmosphere for an additional 12hr. The solution was filtered through a plug of
celite and concentrated on the rotary evaporator. The crude residue was purified
on silica gel (50% ether in hexanes) to yield 3 g of the secondary alcohol (75%).
[a]2D5 ¼ þ10.8 (c ¼ 2.0, CH2Cl2); IR (film) nmax 3435, 3074 2930, 1714, 1105;
Rf ¼ 0.4 (50% ether in hexanes); 1H NMR (400MHz, CDCl3) d 7.69 (m, 4H),
7.45–7.38 (m, 6H), 4.51 (d, J ¼ 4.8 Hz, 1H), 4.40 (dd, J ¼ 5.2 Hz, 1.2 Hz,
1H), 4.11 (q, J ¼ 7.2 Hz, 2H), 3.97–3.95 (m, 2H), 3.68 (q, J ¼ 9.6 Hz, 5.0 Hz,
1H), 2.31 (t, J ¼ 4.6 Hz, 1H), 1.85 (dd, J ¼ 3.6 Hz, 1.2 Hz, 1H), 1.25
(t, J ¼ 7.2 Hz, 3H), 1.07 (s, 9H); 13C NMR (100MHz, CDCl3) d 170.4, 135.4,
135.3, 135.2, 135.5, 132.2, 129.8, 127.7, 127.6, 81.0, 80.9, 73.7, 73.6, 64.9,
64.8, 62.0, 60.6, 31.3, 31.2, 26.9, 26.8, 22.2, 22.1, 19.2, 14.3; HRMS calcd for
C25H32O5Si (M þ Naþ): 463.1917, found: 463.1921.
The alcohol (1.2g, 2.7 mmol) was dissolved in 60mL of a 1/1 mixture of
DMSO/dichloromethane. The reaction was cooled by an ice bath and triethyl-
amine (3.75 mL, 27mmol) was added followed by addition of sulfur trioxide–
pyridine complex (4.34 g, 27mmol) in four portions over a 2-hr period. The
reaction was stirred for an additional 4 hr at 08C and quenched with brine.
The mixture was extracted three times with 125 mL of ethyl acetate. The com-
bined organic layers were dried over magnesium sulfate and concentrated on the
rotary evaporator. The ketone 15 was purified on silica gel (25% ether in
hexanes) to yield 0.91g of analytically pure compound (77%). [a]2D5 ¼ þ23.7
(c ¼ 1.0, CH2Cl2); IR (film) nmax 3071, 2931, 2851, 1755, 1725, 1426;
1
Rf ¼ 0.7 (30% ether in hexanes); H NMR (400MHz, CDCl3) d 7.73–7.67
(m, 4H), 7.44–7.38 (m, 6H), 4.88 (td, J ¼ 4.4 Hz, 1.2 Hz, 1H), 4.18
(q, J ¼ 6.8 Hz, 2H), 3.93 (dd, J ¼ 10.8Hz, 2.8 Hz, 1H), 3.89 (t, J ¼ 2.8 Hz,
1H), 3.85 (dd, J ¼ 10.8Hz, 2.4 Hz, 1H), 2.67 (t, J ¼ 4.4 Hz, 1H), 2.35 (dd,
J ¼ 3.2 Hz, 1.6 Hz, 1H), 1.29 (t, J ¼ 7.2 Hz, 3H), 1.05 (s, 9H); 13C NMR
(100MHz, CDCl3) d 206.9, 168.6, 135.9, 133.2, 133.1, 130.1, 130.0,
128.0(2), 127.9, 81.3, 67.1, 64.1, 61.7, 33.0, 28.0, 26.9, 26.8, 19.5, 14.4;
HRMS calcd for C25H30O5Si (M þ Naþ): 461.1760, found: 461.1767.
Cyclopropane 16. Methyltriphenylphosphonium
bromide
(10 g,
28 mmol) was dissolved in 10 mL of anhydrous THF in a flame dried flask
under an argon atomosphere. NaHMDS (27 mL, 1 M) was added via syringe
at room temperature to the Wittig reagent and the mixture was stirred for
30 min. The ketone 15 (3.0 g, 7.1 mmol) was dissolved in anhydrous THF
(10 mL) and added dropwise to the bright yellow solution. The reaction was
judged complete (by TLC) after 30 min of stirring at room temperature. The

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Kim et al.
reaction was diluted with 100 mL of ether followed by 300 mL of brine. The
aqueous phase was extracted with 3–150 mL portions of ether. The combined
organic layers were dried over magnesium sulfate and concentrated on the
rotary evaporator. The residue was purified by silica gel (10% ether in hex-
anes) to yield 2.1 g of olefin 16 (68%). [a]2D5 ¼ þ15.0 (c ¼ 1.0, CH2Cl2);
IR (film) nmax 3478, 2924, 2848, 1697; Rf ¼ 0.6 (30% ether in hexanes);
1H NMR (400 MHz, CDCl3) d 7.71 (m, 4H), 7.41–7.36 (m, 6H), 5.22
(d, J ¼ 2.4 Hz, 1H), 4.90 (s, 1H), 4.38 (dd, J ¼ 4.4 Hz, 0.4 Hz, 1H), 4.33–
4.28 (m, 1H), 4.12 (dq, J ¼ 6.8 Hz, 1.2 Hz, 2H), 3.69 (dd, J ¼ 4.4 Hz,
3.2 Hz, 2H), 2.67 (t, J ¼ 4.2 Hz, 1H), 1.95 (dd, J ¼ 2.4 Hz, 0.8 Hz, 1H),
1.25 (t, J ¼ 7.2 Hz, 3H), 1.08 (s, 9H); 13C NMR (100 MHz, CDCl3) d
170.1, 146.6, 135.5, 135.4, 135.1, 134.6, 129.5, 129.4 127.5, 106.7, 82.5(2),
66.3, 66.0, 65.9, 60.7, 32.6, 27.0, 26.9, 26.6, 24.9, 19.3, 19.2, 19.1, 14.3;
HRMS calcd for C26H32O4Si (M þ Naþ): 459.1967, found: 459.1973.
Cyclopropane 20. The cyclopropane, prepared by literature proce-
dure,[14a] (2.5g, 5.2 mmol) and imidazole (0.36 g, 5.3 mmol) were dissolved
in 20mL THF and TBDPS-Cl (1.4g, 5.3 mmol) was added to the stirring solu-
tion. The reaction was stirred at room temperature for 3 hr and quenched with
water. The solution was diluted with ether and extracted three times with
100 mL of ether. The combined organics were dried over magnesium sulfate
and concentrated on the rotary evaporator. The product was isolated by silica
gel chromatography (25% ether in hexanes) to yield 2.0 g of the protected alco-
hol 20 (95%). Rf ¼ 0.4 (30% ether in hexanes); 1H NMR (400MHz, CDCl3) d
7.77–7.68 (m, 4H), 7.48–7.37 (m, 6H), 4.49 (d, J ¼ 4.4 Hz, 1H), 4.41
(d, J ¼ 4.4 Hz, 1H), 4.08 (q, J ¼ 7.2 Hz, 2H), 3.89 (d, J ¼ 10.0Hz,
1H), 3.35 (dd, J ¼ 10.8Hz, 4.4 Hz, 1H), 2.26 (t, J ¼ 3.6 Hz, 1H), 1.64 (dd,
J ¼ 3.6 Hz, 1.2 Hz, 1H), 1.22 (t, J ¼ 7.2 Hz, 3H), 1.11 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 170.8, 135.6, 134.8, 129.8 129.5, 127.8, 127.6, 75.1,
74.1, 72.0, 65.2, 60.6, 31.3, 26.8, 26.5, 21.4, 19.0, 14.1; HRMS calcd for
C24H30O4Si (M þ Naþ): 433.1811, found: 433.1979.
Cyclopropane 22. This compound was prepared by the rhodium catalyzed
cyclopropanation of n-butyl vinyl ether and ethyl diazoacetate following a
literature procedure.[14b] Z-22: 1H NMR (300MHz, CDCl3) d 4.16 (q,
J ¼ 7.2 Hz, 2H), 3.57–3.47 (m, 2H), 3.41–3.34 (m, 1H), 1.72–0.82 (m, 13H);
1
E-22: H NMR (300 MHz, CDCl3) d 4.11 (q, J ¼ 6.9 Hz, 2H), 3.59–3.49
(m, 3H), 1.76–0.82 (m, 13H); HRMS calcd for C10H18O3 (M þ Naþ):
209.1154, found: 209.1159.
Cyclopropane 24. 2-Butoxy-2,3-dihydrofuran[14c] (1.0 g, 7.0 mmol) was
dissolved in 50 mL of dichloromethane and Rh2(OAc)4 (ꢀ15 mg, 0.03 mmol)
was added. Ethyl diazoacetate (0.85 g, 7.4 mmol) dissolved in 8 mL of
dichloromethane was added via syringe pump over 8 hr. The dichloromethane
was removed on the rotary evaporator and the residue was purified by silica

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Synthesis of Fused Tetrahydrofuran-g-lactone Motifs
1961
gel chromatography (25% ether in hexanes) to yield 1.2 g of cyclopropane 24.
1
Major isomer: H NMR (400 MHz, CDCl3) d 5.21 (dd, J ¼ 6.8, 1.2 Hz, 1H),
4.27–4.21 (m, 1H), 4.15–4.06 (m, 2H), 3.71–3.63 (m, 1H), 3.40–3.25
(m, 1H), 2.23–2.19 (m, 1H), 2.15–2.07 (m, 2H), 2.01 (dd, J ¼ 13.6, 1.2 Hz,
1H), 1.58–1.21 (m, 7H), 0.91 (t, J ¼ 7.2 Hz, 3H); HRMS calcd for
C12H20O4 (M þ Naþ): 251.1259, found: 251.1262.
General Procedure for the Conversion of Cyclopropane
Derivatives to g-Lactones
To a solution of the cyclopropyl adduct (0.44 mmol) in acetone (1 mL)
was added 1.0 mL of 10% methanesulfonic acid solution in acetone at
258C. The reaction mixture was stirred overnight, quenched by triethylamine
(0.26 mL) in an ice bath and then stirred for 30 min. The solution was concen-
trated in vacuo and purified by column chromatography (ether/petroleum
ether) to give the corresponding g-lactone.
Lactone 17. [a]2D5: 221.7 (c ¼ 1.68, CH2Cl2); IR (film) nmax 1785, 1067,
1
982; H NMR (400 MHz, CDCl3) d 7.37–7.31 (m, 5H), 6.16 (d, J ¼ 5.6 Hz,
1H), 4.63 (d, J ¼ 1.6 Hz, 2H), 4.43 (q, J ¼ 7.6 Hz, 1H), 4.14 (dd, J ¼ 8.8,
6.0 Hz, 1H), 4.02–3.99 (m, 2H), 3.91 (d, J ¼ 2.8 Hz, 1H), 3.22–3.19
(m, 1H), 2.84 (dd, J ¼ 18.8, 11.6 Hz, 1H), 2.35 (dd, J ¼ 18.8, 5.2 Hz, 1H),
1.42 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) d 174.4, 137.3,
128.5, 128.0, 127.6, 109.3, 107.2, 83.4, 81.9, 72.1, 67.2, 45.0, 31.4, 26.8,
25.4; HRMS, calcd for C18H22O6 (M þ Naþ): 357.1314, found: 357.1330.
Lactone 18. [a]2D5: 253.5 (c ¼ 0.85, CH2Cl2); IR (film) nmax 3634, 3528,
1
2918, 2861, 1780, 1731; H NMR (400 MHz, CDCl3) d 7.34 (m, 3H), 7.23
(m, 2H), 6.33 (d, J ¼ 5.6 Hz, 1H), 4.54 (m, 2H), 4.46 (d, J ¼ 11.6 Hz, 1H),
4.15 (d, J ¼ 4 Hz, 1H), 3.23 (m, 1H), 2.84 (dd, J ¼ 19.2, 11.6 Hz, 1H), 2.33
(dd, J ¼ 5.2, 18.8 Hz, 1H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) d
204.8, 173.5, 136.2, 128.5, 128.2, 127.6, 107.4, 85.4, 85.1, 72.2, 44.3, 31.1,
28.4; HRMS, calcd for C15H16O5 (M þ Csþ): 409.0052, found: 409.0055.
Lactone 19. [a]2D5: 218.0 (c ¼ 1.3, CH2Cl2); IR (film) nmax 2931, 2857,
1
1784, 1427, 1109; H NMR (400MHz, CDCl3) d 7.71–7.65 (m, 4H), 7.43–
7.10 (m, 11H), 6.16 (d, J ¼ 5.6 Hz, 1H), 4.60 (d, J ¼ 12Hz, 1H), 4.53
(d, J ¼ 12Hz, 1H), 4.42 (m, 1H), 4.03–4.09 (m, 3H), 3.19 (m, 1H), 2.83 (dd,
J ¼ 18.8, 11.6Hz, 1H), 2.35 (dd, J ¼ 18.4, 5.2 Hz, 1H), 1.06 (s, 9H); 13C
NMR (100MHz, CDCl3) d 174.6, 137.2, 135.5, 134.8, 133.0, 132.8, 129.8,
129.7, 129.6, 129.5, 128.5, 128.0, 127.8, 127.7, 127.6, 107.2, 83.2, 81.3, 72.1,
60.7, 44.6, 31.8, 26.7, 26.5, 19.1; HRMS, calcd for C30H34O5Si (M þ Naþ):
525.2073, found: 525.2069.

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Kim et al.
1
Lactone 21. H NMR (400MHz, CDCl3) d 7.66–7.61 (m, 4H), 7.47–7.39
(m, 6H), 6.21 (d, J ¼ 5.6 Hz, 1H), 4.15 (d, J ¼ 3.2 Hz, 1H), 4.00
(d, J ¼ 10.4Hz, 1H), 3.83 (dd, J ¼ 10.4, 3.6 Hz, 1H), 2.98–2.94 (m, 1H),
2.50 (dd, J ¼ 19.2, 11.6Hz, 1H), 2.00 (dd, J ¼ 19.2, 4.80Hz, 1H), 1.08
(s, 9H); 13C NMR (100MHz, CDCl3) d 174.5, 135.6, 135.5, 133.0, 132.7,
130.2, 130.1, 128.0, 127.9, 108.0, 78.7, 74.0, 48.4, 31.4, 26.7, 19.0; HRMS,
calcd for C22H26O4Si (M þ Naþ): 405.1498, found: 405.1502.
1
Lactone 23. H NMR (300MHz, CDCl3) d 5.51 (dd, J ¼ 5.4, 2.1 Hz, 1H),
3.83–3.76 (m, 1H), 3.55–3.48 (m, 1H), 2.72–2.61 (m, 1H), 2.46–2.39 (m, 2H),
2.27–2.07 (m, 1H), 1.59–1.20 (m, 4H), 0.91 (t, J ¼ 7.5 Hz, 3H);13C NMR
(100 MHz, CDCl3) d 176.7, 104.2, 69.4, 31.5, 28.8, 26.9, 19.1, 13.8; HRMS,
calcd for C8H14O3 (M þ Naþ): 181.0841, found: 181.0844.
Lactone 25. 1H NMR (400 MHz, CDCl3) d 6.12 (d, J ¼ 7.4 Hz, 1H),
5.27 (d, J ¼ 6.0 Hz, 1H), 3.79 (dd, J ¼ 7.2, 4.8 Hz, 1H), 3.37 (dd, J ¼ 7.2,
4.8 Hz, 1H), 3.19–3.14 (m, 1H), 2.80 (dd, J ¼ 14.4, 6.8 Hz, 1H), 2.64 (dd,
J ¼ 14.0, 2.4 Hz, 1H), 2.19–2.12 (m, 1H), 2.01 (d, J ¼ 12.8 Hz, 1H), 1.55–
1.20 (m, 4H), 0.90 (t, J ¼ 4.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
175.1, 134.2, 108.4, 105.7, 67.9, 39.3, 36.9, 36.0, 19.4, 14.0; HRMS, calcd
for C10H16O4 (M þ Naþ): 223.0946, found: 223.0949.
ACKNOWLEDGMENT
Financial support from the NIH (CA086079) is gratefully acknowledged.
We also thank Dr. P. Gantzel (UCSD, x-ray Facility) for the reported crystal-
lographic structure.
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Received in the USA January 3, 2004

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