An asymmetric synthesis of trans -fused butyrolactones from endoperoxides

Article abstract of DOI:10.1021/jo400177j

The intermolecular addition of 1,3-dicarbonyl equivalents to endoperoxides in the presence of an organocatalyst yields trans-fused butyrolactones in high yield and enantioselectivities. This methodology expands the synthetic utility of endoperoxides and f

Full text of DOI:10.1021/jo400177j

Note
pubs.acs.org/joc
An Asymmetric Synthesis of trans-Fused Butyrolactones from
Endoperoxides
Joshua Priest, Mark. R. Longland, Mark R. J. Elsegood, and Marc C. Kimber*
Department of Chemistry, Loughborough University, Leicestershire LE11 3TU, U.K.
S
* Supporting Information
ABSTRACT: The intermolecular addition of 1,3-dicarbonyl
equivalents to endoperoxides in the presence of an organo-
catalyst yields trans-fused butyrolactones in high yield and
enantioselectivities. This methodology expands the synthetic
utility of endoperoxides and further underlines their potential
as sources of oxygen functionality for natural and non-natural
product target synthesis.
he oxidation of dienes to yield endoperoxides represents a
selective and green chemical method for introducing
however, the synthetic use of these highly enantio-enriched
hydroxyenone products (5) has been limited.5
T
oxygen functionality within a substrate.1 However, conversion
of these endoperoxide products into useful asymmetric building
blocks1c,2 for natural and non-natural product target synthesis,
without the use of toxic transition metals, has yet to be fully
exploited. For example, Taylor and co-workers in 2002
reported the conversion of endoperoxides (1) into useful
butyrolactones (2) via an intermediary cis-γ-hydroxy-enone (3)
(Scheme 1); however, they were only able to achieve this in an
In a project aimed at investigating the anti-inflammatory
activity of trans-fused xanthanolide natural product analogues,6
we recently required access to enantioenriched trans-fused
butyrolactones (7), which we envisaged could be obtained from
endoperoxides (6) (Scheme 1). While enantioselective routes
toward cis-fused butyrolactones exist6c,i general synthetic routes
toward trans-fused butyrolactones are less common. For
example, in Shishido’s first asymmetric synthesis of the anti-
inflammatory natural product xanthatin,6j they had to convert a
key cis-lactone precursor6k into the trans-lactone using a 3-step
procedure that included a Mitsunobu inversion of the crucial
hydroxyl group.
Scheme 1. Planned Route toward trans-Fused
Butyrolactones
Key to this approach is the trapping of a cyclic
hydroxyenone, a result of the base-catalyzed rearrangement of
endoperoxides, by a 1,3-dicarbonyl equivalent, which we
envisaged would occur via an intermolecular 1,4-conjugate
addition pathway.2g Furthermore, since hydroxy enones such as
5 can be obtained via an organocatalyzed Kornblum−De La
Mare4,7 rearrangement of endoperoxides, this approach would
represent an asymmetric protocol for generating complex trans-
fused butyrolactone scaffolds from endoperoxides, which in
1
turn can be obtained from simple O2 oxidation of dienes.
After initial optimization studies9 we found treatment of
endoperoxide 48 in THF9 in the presence of 10 mol % of
catalyst 8a for a 16 h period followed by addition of
diethylsodiomalonate gave the desired lactone (−)-9a in an
isolated yield of 76% and ee of 92% (Scheme 2 and Table 1;
entry 1),10 while the rearrangement of 4 with catalyst 8b with
subsequent addition of diethylsodiomalonate gave lactone
(+)-9a in a yield of 78% and ee of 94% (entry 2). Lactones
(−)- and (+)-9a contain an acidic proton between the 1,3-
dicarbonyl unit and therefore exist as an inseparable mixture of
diastereomers with the major diastereoisomer, as determined
enantioselective fashion using a Co(II) catalyst, and no
asymmetric examples of bicyclic endoperoxides were included
in their study,2g presumably due to the reactivity of bicyclic
endoperoxides with Co(II) salts, which traditionally delivers the
bis-epoxide products.3 In 2006, Toste and co-workers
successfully desymmetrized bicyclic endoperoxides (4) using
an organocatalytic Kornblum−De La Mare rearrangement;4
Received: January 29, 2013
© XXXX American Chemical Society
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sodiobenzoyl acetate gave the lactone (−)-9d using catalyst
8a in an isolated yield of 82% and an ee of 94% (entry 5). The
endoperoxide 11, obtained in 87% yield from cyclohepta-
diene,11 was also exposed to the optimized reaction conditions
with catalyst 8a delivering (−)-13 in 82% yield and ee of 78%,
while the enantiomer (+)-13 was obtained in an ee of 76% and
a comparable isolated yield using catalyst 8b (entries 6 and 7,
respectively). As with lactones (−)- and (+)-9a, (−)- and
(+)-13 were isolated in a dr of 8:1. When the OTBS-protected
seven-membered endoperoxide 12, derived from commercially
available tropone,12 was treated with catalyst 8a under the
optimized conditions, the lactone (−)-14 was isolated in a good
yield of 74% and an excellent ee of 94%, while catalyst 8b gave
the enantiomer (+)-14 in 70% yield and an ee of 92% (entries 8
and 9, respectively). Once again, due to the acidity of the
proton between the 1,3-dicarbonyl unit, (−)- and (+)-14 were
each isolated as an inseparable mixture of diastereoisomers in a
dr of 8:1.
Scheme 2. Lactone Optimization
ab
,
Table 1. Asymmetric Butyrolactone Formation and Scope
While the absolute stereochemistry of this latter lactone can
be deduced from the work of Toste,4 the relative stereo-
chemistry of ( )-14 was definitively assigned via X-ray
crystallography.13 Importantly, the enantioselective synthesis
of lactones containing a trans-fused 5,7-ring system gives us
access to scaffolds ideal for investigating the biologically active
xanthanolide class of natural products.6a,b Finally, endoperoxide
1 was exposed to the lactonization conditions but gave the
known lactone (+)-2 in a disappointing ee of 10% (entry 10).
Next we explored the installation of a methyl group at the
alpha position of the trans-fused butyrolactone, as many natural
product classes possess this substitution pattern (Scheme 3).
Scheme 3. Direct Installation of the α-Methyl Group
a
b
See the general experimental procedure. 10 mol % of catalyst 8a
c
d
used unless otherwise stated. Isolated yields. Determined by chiral
HPLC. 10 mol % of catalyst 8b. Isolated as an inseparable mixture of
e
f
diastereoisomers.
via NOE, as depicted in Scheme 2. The dr for (−)- and (+)-9a
Desymmetrization of 4 using catalyst 8b followed by addition
of diethylsodiomalonate gave the intermediate sodium salt 15,
which upon treatment with iodomethane followed by acid-
mediated decarboxylation gave the α-methyl-substituted
lactone (+)-19 in a diastereomeric ratio of 4:1 in 66%
yield.14 Alternatively, the rearranged endoperoxide 4 could be
treated with α-methyldiethylsodiomalonate giving lactone 17,
which upon decarboxylation gave (+)-19 in a comparable
chemical yield and a similar diastereomeric ratio of 4:1.
Additionally, as these two processes rely on the decarboxylation
of a common intermediate the stereochemical outcome was the
same in both cases. These two processes were also performed
upon the seven membered endoperoxide 11 using catalyst 8a in
1
was determined to be approximately 9:1 as assigned via H
NMR analysis.
With optimal conditions for lactone formation determined,
we then looked at the scope of this sequence using other 1,3-
dicarbonyls and endoperoxides in the presence of both catalysts
8a and 8b (Scheme 2 and Table 1). Undertaking the reaction
with dimethylsodiomalonate and using catalyst 8a gave lactone
(−)-9b in a comparable isolated yield and ee (entry 3).
Surprisingly, ethyl sodioacetoacetate failed to deliver the
butyrolactone but instead yielded only the alkoxy Michael
addition product 10 as an inseparable mixture of diaster-
eoisomers (entry 4); however, the addition of ethyl
B
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Note
warm to room temperature and stirred for 16 h under N2. The reaction
mixture was then cooled to 0 °C and quenched by the addition of 1 M
HCl, after which it was partitioned between ethyl acetate (50 mL) and
H2O (50 mL), and the aqueous layer was extracted with further
portions of ethyl acetate (2 × 20 mL). The organic layers were then
combined, washed with brine, dried (Na2SO4), and filtered, and the
solvent was removed in vacuo. The crude products were then purified
this case, giving the desired α-methyl-substituted lactone
(−)-20 in good chemical yield and diastereoselectivity.15
The trans stereochemistry of the butyrolactone is installed via
the mechanism shown below in Scheme 4. The hydroxyenone
Scheme 4. trans-Fused Lactone Formation
1
by chromatography. The H NMR, 13C NMR, IR, and MS physical
data for 9a,2g 9b, 9c, 9d, 13, 14, and 22g matched that for the enantio-
enriched examples.
General Experimental Procedure for Enantio-enriched
Lactone Formation. To a solution of the endoperoxide (1.0
mmol) in dry THF (5.0 mL) was added the catalyst (0.1 mmol, 8a
or 8b as indicated below), and the resultant reaction mixture was
stirred at room temperature for 16 h under N2. After this period a
solution of the desired nucleophile (1.0 mmol) [prepared in THF (3.0
mL) by the addition of NaOEt or NaOMe (2.2 mL, 0.5M, 1.1 mmol)
to the required malonate derivative (1.0 mmol)] was added dropwise
to the reaction mixture at 0 °C, and the resultant solution allowed to
warm to room temperature and stirred for a further 16 h under N2.
The reaction mixture was then cooled to 0 °C and quenched by the
addition of 1 M HCl, after which it was partitioned between EtOAc
(50 mL) and H2O (50 mL), and the aqueous layer was extracted with
further portions of ethyl acetate (2 × 20 mL). The organic layers were
then combined, washed with brine, dried (Na2SO4), and filtered, and
the solvent was removed in vacuo. The crude products were then
purified by chromatography. Using this procedure the following
compounds were obtained:
23 undergoes conjugate addition anti to the hydroxyl group, as
depicted in 25, to deliver the addition product 24. This
undergoes lactonization to deliver the trans-fused product 26,
which can then be protonated or trapped by an appropriate
electrophile, therefore giving 27.16
Finally, in reference to accessing xanthanolide analogues, we
investigated the use of the ketone contained within the fused
carbocycle as a synthetic handle (Scheme 5). Accordingly, we
(−)-(3R,3aS,9aR)-Ethyl 2,5-Dioxodecahydrocycloocta[b]-
furan-3-carboxylate ((−)-9a). Prepared using catalyst 8a and
obtained as a colorless viscous oil (193 mg, 76%; Rf 0.50 in 3:2
Scheme 5. Synthesis of Xanthanolide Analogue (−)-29
petroleum ether/ethyl acetate); [α]20 = −41.2 (c 1.00, CHCl3); IR
D
(solution, CHCl3) 3032, 3019, 2942, 1784, 1734, 1708, 1209, 1159
1
cm−1; H NMR (400 MHz; CDCl3) δ 4.30 (dq, J = 2.4, 7.2 Hz, 2H),
4.19 (ddd, J = 3.2, 8.8, 10.0 Hz, 1H), 3.41 (d, J = 12.4 Hz, 1H), 3.19
(ddt, J = 3.6, 10.0, 11.6 Hz, 1H), 2.78−2.68 (m, 2H), 2.43 (dd, J =
11.6, 14.4 Hz, 1H), 2.35 (dt, J = 5.6, 12.8 Hz, 1H), 2.23−2.16 (m,
1H), 1.90−1.70 (m, 4H), 1.48−1.40 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz; CDCl3) δ 211.6, 169.5, 167.0, 84.1, 62.5, 53.9,
45.4, 43.9, 39.0, 31.1, 26.0, 22.1, 14.1; HRMS (ESI-orbitrap) m/z: [M
+ Na]+ calcd for C13H18O5Na for 277.1052, found 277.1039.
(+)-(3S,3aR,9aS)-Ethyl 2,5-Dioxodecahydrocycloocta[b]furan-3-
carboxylate ((+)-9a). Prepared using catalyst 8b and obtained as a
colorless viscous oil (196 mg, 78%); [α]18 = +45.2 (c 1.00, CHCl3);
D
1H and 13C NMR matched that for (−)-9a; HRMS (ESI-orbitrap) m/
were able to selectively install an exomethylene group using the
conditions of Connell and co-workers17 on lactone (−)-20,
giving 28. This compound proved to be unstable and was
directly reduced under Luche conditions18 to yield the allylic
alcohol. Subsequent exposure of this alcohol to trimethyl
orthoacetate gave the Claisen rearrangement product (−)-29 in
a yield of 51% over 3 steps from (−)-20. Therefore using this
approach we have a convenient asymmetric route to trans-fused
xanthanolide analogues in just 5 steps and from readily available
endoperoxides.
In summary, we have developed a convenient and single-pot
method for the synthesis of highly enantioenriched trans-fused
butyrolactones from endoperoxides. Importantly, this process
gives the desired products without the use of transitions metals
and also showcases the use of endoperoxides as environ-
mentally sustainable sources of oxygen functionality.
z: [M + Na]+ calcd for C13H18O5Na for 277.1052, found 277.1041.
(−)-(3R,3aS,9aR)-Methyl 2,5-Dioxodecahydrocycloocta[b]-
furan-3-carboxylate ((−)-9b). Prepared using catalyst 8a and
obtained as a colorless crystalline solid (182 mg, 76%; Rf 0.20 in 1:1
petroleum ether/ethyl acetate; mp 70.0−71.5 °C); [α]20 = −58.0 (c
D
1.00, CHCl3); IR (solution, CHCl3) 3033, 3019, 2946, 1785, 1743,
1
1708, 1216, 1209, 1159 cm−1; H NMR (400 MHz; CDCl3) δ 4.18
(ddd, J = 3.2, 8.8, 11.2 Hz, 1H), 3.86 (s, 3H), 3.42 (d, J = 12.0 Hz,
1H), 3.25−3.18 (m, 1H), 2.80−2.71 (m, 1H), 2.75 (dd, J = 4.0, 14.8
Hz, 1H), 2.43 (dd, J = 11.6, 14.4 Hz, 1H), 2.36 (dt, J = 5.2, 12.8 Hz,
1H), 2.24−2.16 (m, 1H), 1.95−1.72 (m, 4H), 1.50−1.41 (m, 1H); 13C
NMR (100 MHz; CDCl3) δ 211.4, 169.3, 167.0, 84.1, 53.8, 53.3, 45.5,
43.9, 39.0, 31.1, 26.0, 22.1; HRMS (ESI-orbitrap) m/z: [M + Na]+
calcd for C12H16O5Na for 263.0895, found 263.0883.
(−)-(3S,3aS,9aR)-tert-Butyl 2,5-dioxodecahydrocycloocta[b]-
furan-3-carboxylate ((−)-9c). Prepared using catalyst 8a and
obtained as a colorless crystalline solid (191 mg, 68%; Rf 0.65 in 1:1
petroleum ether/ethyl acetate; mp 87−89 °C); [α]26D = −29.6 (c 1.00,
CHCl3); IR (solution, CHCl3) 2938, 1783, 1727, 1709, 1459, 1371,
EXPERIMENTAL SECTION
■
1
1221 cm−1; H NMR (400 MHz; CDCl3) δ 4.11 (ddd, J = 3.2, 8.4,
General Experimental Procedure for Racemic Lactone
Formation. To a solution of the endoperoxide (1.0 mmol) in dry
THF (5 mL) was added a solution of the desired nucleophile (1.0
mmol) [prepared in THF (3.0 mL) by the addition of NaOEt or
NaOMe (2.2 mL, 0.5M, 1.1 mmol) to the required malonate derivative
(1.0 mmol)] dropwise at 0 °C, and the resultant solution allowed to
11.6 Hz, 1H), 3.26 (d, J = 12.4 Hz, 1H), 3.12 (ddt, J = 3.6, 10.0, 14.0
Hz, 1H), 2.77−2.70 (m, 1H), 2.68 (dd, J = 4.0, 14.8 Hz, 1H), 2.41
(dd, J = 12.0, 14.8 Hz, 1H), 2.33 (dt, J = 5.2, 12.8 Hz, 1H), 2.19−2.12
(m, 1H), 1.90−1.69 (m, 5H), 1.49 (s, 9H); 13C NMR (100 MHz;
CDCl3) δ 211.8, 169.8, 165.7, 83.8, 83.4, 54.6, 45.5, 43.7, 39.0, 31.0,
C
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Note
28.0, 26.1, 22.0; HRMS (ESI-orbitrap) m/z: [M + Na]+ calcd for
C15H22O5Na for 305.1365, found 305.1353.
brine (50 mL), dried (Na2SO4), and filtered, and the solvent was
removed in vacuo. The crude material was then dissolved in 50% acetic
acid (10 mL) and refluxed overnight. After this period, the reaction
was cooled and carefully basified with NaHCO3, and the aqueous layer
was extracted with dichloromethane (2 × 40 mL). The combined
organic extracts were then dried (Na2SO4) and filtered, and the solvent
was removed in vacuo. The crude product was then purified by column
chromatography. Method B: To a solution of the endoperoxide 4 or
11 (1.0 mmol) in dry THF (8 mL) was added the catalyst 8a or 8b
(35 mg, 0.1 mmol), and the resultant reaction mixture was stirred at
room temperature for 16 h under N2. After this period a solution of
NaCMe(CO2Et)2 [1.1 mmol; prepared from HCMe(CO2Et)2 (193
mg, 1.1 mmol) and NaOEt (2.2 mL, 0.5 M solution, 1.1 mmol) THF
(5.0 mL)] was added dropwise to the reaction mixture at 0 °C, and the
resultant solution allowed to warm to room temperature and stirred
for a further 16 h under N2. The reaction mixture was then cooled to 0
°C, and a satd solution of NH4Cl (10 mL) was added, partitioned
between CH2Cl2 (50 mL) and H2O (50 mL), and the aqueous layer
was extracted with further portions of CH2Cl2 (2 × 30 mL). The
organic layers were then combined, washed with brine (50 mL), dried
(Na2SO4), and filtered, and the solvent was removed in vacuo. The
crude material was then dissolved in 50% acetic acid (10 mL) and
refluxed overnight. After this period, the reaction was cooled and
carefully basified with NaHCO3, and the aqueous layer was extracted
with CH2Cl2 (2 × 40 mL). The combined organic extracts were then
dried (Na2SO4) and filtered, and the solvent was removed in vacuo.
The crude product was then purified by column chromatography.
Using these methods the following compounds were obtained:.
(−)-(3R,3aS,9aR)-3-Benzoylhexahydrocycloocta[b]furan-2,5-
(3H,6H)-dione ((−)-9d). Prepared using catalyst 8a and obtained as
colorless needles (234 mg, 82%; Rf 0.55 in 1:1 petroleum ether/ethyl
acetate; mp 103−105 °C); [α]26 = −122.8 (c 1.00, CHCl3); IR
D
(solution, CHCl3) 2939, 1773, 1706, 1685, 1449, 1270 cm−1; 1H
NMR (400 MHz; CDCl3) δ 8.05−8.03 (m, 2H), 7.67−7.63 (m, 1H),
7.55−7.51 (m, 2H), 4.38 (d, J = 12.0 Hz, 1H), 4.27 (ddd, J = 3.6, 8.4,
10.0 Hz, 1H), 3.71−3.62 (m, 1H), 2.94−2.88 (m 1H), 2.68 (dd, J =
4.0, 14.8 Hz, 1H), 2.39−2.33 (m, 1H), 2.23−2.19 (m, 1H), 1.96−1.84
(m, 4H), 1.52−1.48 (m, 1H); 13C NMR (100 MHz; CDCl3) δ 211.9,
191.7, 170.0, 135.8, 134.4, 129.6, 128.9, 84.1, 55.5, 45.8, 41.9, 38.6,
31.2, 26.3, 21.7; HRMS (ESI-orbitrap) m/z: [M + Na]+ calcd for
C17H18O4Na for 309.1103, found 309.1091.
(−)-((3R,3aS,8aR)-Ethyl 2,5-Dioxooctahydro-2H-cyclohepta-
[b]furan-3-carboxylate ((−)-13). Prepared using catalyst 8a and
obtained as a colorless crystalline solid (193 mg, 82%; Rf 0.30 in 1:1
petroleum ether/ethyl acetate; mp 64.0−66.0 °C); [α]19 = −25.6 (c
D
1.00, CHCl3); IR (solution, CHCl3) 3029, 2957, 2931, 2859, 1789,
1736, 1709, 1016 cm−1; 1H NMR (400 MHz; CDCl3) δ 4.26 (dq, J =
1.6, 7.2 Hz, 2H), 4.09−4.01 (m, 1H), 3.34 (d, J = 12.4 Hz, 1H), 3.04
(ddt, J = 4.4, 10.4, 12.0 Hz, 1H), 2.78 (dd, J = 4.0, 18.0 Hz, 1H), 2.63
(dt, J = 2.4, 13.2 Hz, 1H), 2.58−2.52 (m, 1H), 2.50−2.43 (m, 1H),
2.37 (dd, J = 12.0, 18.0 Hz, 1H), 2.11−2.02 (m, 1H), 1.80−1.71 (m,
1H), 1.58−1.48 (m, 1H), 1.28 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz; CDCl3) δ 209.4, 169.9, 166.7, 83.6, 62.5, 53.1, 43.3, 43.1, 42.1,
34.0, 20.7, 14.1; HRMS (ESI-orbitrap) m/z: [M + Na]+ calcd for
C12H16O5Na for 263.0895, found 263.0883. (+)-(3S,3aR,8aS)-Ethyl
2,5-Dioxooctahydro-2H-cyclohepta[b]furan-3-carboxylate ((+)-13).
(+)-(3R,3aR,9aS)-3-Methylhexahydrocycloocta[b]furan-2,5-
(3H,6H)-dione ((+)-19). Obtained as a colorless oil (Method A; 130
mg, 66%; Method B; 123 mg, 63%; Rf 0.18 in 3:2 petroleum ether/
Prepared using catalyst 8b (188 mg, 81%); [α]21 = +29.6 (c 1.00,
D
1
CHCl3); H and 13C NMR matched that for (−)-13. HRMS (ESI-
ethyl acetate); [α]19 = +26.4 (c 1.00, CHCl3); IR (solution, CHCl3)
orbitrap) m/z: [M + Na]+ calcd for C12H16O5Na for 263.0895, found
263.0885.
D
1
3025, 2938, 1774, 1705, 991 cm−1; H NMR (400 MHz; CDCl3) δ
4.11 (dt, J = 3.2, 9.2 Hz, 1H), 2.66 (dd, 3.6, 10.4 Hz, 1H), 2.68−2.61
(m, 1H), 2.45 (dd, J = 11.6, 14.0 Hz, 1H), 2.40−2.35 (m, 1H), 2.34
(q, J = 6.8 Hz, 1H), 2.27−2.19 (m, 2H), 1.95−1.85 (m, 1H), 1.85−
1.72 (m, 2H), 1.68−1.59 (m, 1H), 1.54−1.46 (m, 1H), 1.26 (d, J = 6.8
Hz, 3H); 13C NMR (100 MHz; CDCl3) δ 212.8, 177.1, 84.0, 49.0,
45.3, 42.6, 39.9, 31.4, 25.8, 22.9, 12.8; HRMS (ESI-orbitrap) m/z: [M
+ Na]+ calcd for C11H16O3Na for 219.0997, found 219.0992.
(−)-(3R,3aS,7S,8aR)-Ethyl 7-(tert-Butyldimethylsilyloxy)-2,5-
dioxooctahydro-2H-cyclohepta[b]furan-3-carboxylate
((−)-14). Using the general method but on a 0.4 mmol scale, prepared
using catalyst 8a and obtained as colorless needles (107 mg, 74%; Rf
0.45 in 3:1 petroleum ether/ethyl acetate; mp 102.0−103.5 °C);
[α]19 = −35.8 (c 1.00, CHCl3); IR (solution, CHCl3) 2957, 2931,
D
2858, 1789, 1736, 1708, 1260, 1016 cm−1; 1H NMR (400 MHz;
CDCl3) δ 4.28 (dq, J = 2.8, 7.2 Hz, 2H), 4.10 (ddd, J = 3.6, 10.0, 11.6
Hz, 1H), 3.93−3.87 (m, 1H), 3.30 (d, J = 13.2 Hz, 1H), 3.30−3.19
(m, 1H), 3.04 (dd, J = 11.2, 12.0 Hz, 1H), 2.87 (dd, J = 4.8, 17.6 Hz,
1H), 2.68−2.64 (m, 2H), 2.29 (dd, J = 11.6, 17.6 Hz, 1H), 2.03−1.95
(m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 0.87 (s, 9H), 0.08 (s, 6H); 13C
NMR (100 MHz; CDCl3) δ 205.7, 169.4, 166.4, 79.0, 66.1, 62.6, 53.3,
44.8, 43.8, 41.4, 31.0, 25.6, 18.0, 14.1, −4.9; HRMS (ESI-orbitrap) m/
z: [M + Na]+ calcd for C18H30O6SiNa for 393.1709, found 393.1696.
(+)-(3S,3aR,7R,8aS)-Ethyl 7-(tert-Butyldimethylsilyloxy)-2,5-diox-
ooctahydro-2H-cyclohepta[b]furan-3-carboxylate ((+)-14). Using
(−)-(3S,3aS,8aR)-3-Methylhexahydro-2H-cyclohepta[b]-
furan-2,5(3H)-dione ((−)-20). Obtained as a waxy solid (Method A
(performed on a 2.0 mmol scale) 298 mg, 79%; Method B; 124 mg,
68%; Rf 0.35 in 1:1 petroleum ether/ethyl acetate; mp 28−31 °C);
[α]19 = −92 (c 1.00, CHCl3); IR (solution, CHCl3) 3029, 3019,
D
1
2936, 1776, 1703, 1208 cm−1; H NMR (400 MHz; CDCl3) δ 3.97
(ddd, J = 3.2, 9.6, 10.8 Hz, 1H), 2.78 (dd, J = 4.0, 18.0 Hz, 1H), 2.51−
2.47 (m, 2H), 2.36−2.28 (m, 1H), 2.20−2.15 (m, 2H), 2.12−2.08 (m,
1H), 2.07−2.03 (m, 1H), 1.72−1.53 (m, 2H), 1.26 (d, J = 7.6 Hz,
3H); 13C NMR (100 MHz; CDCl3) δ 210.3, 177.4, 83.6, 46.2, 43.5,
43.4, 41.9, 34.3, 20.8, 12.9; HRMS (ESI-orbitrap) m/z: [M + Na]+
calcd for C10H14O3Na for 205.0841, found 205.0836.
the general method and prepared using catalyst 8b (102 mg, 70%);
1
[α]18 = +32.6 (c 1.00, CHCl3). H and 13C NMR matched that for
D
(−)-14. HRMS (ESI-orbitrap) m/z: [M + Na]+ calcd for
C18H30O6SiNa for 393.1709, found 393.1698.
(+)-(3aR,9aS)-Hexahydrocycloocta[b]furan-2,5(3H,6H)-dione
((+)-21). Lactone (+)-9a (0.36g, 1.40 mmol) was dissolved in ethanol
(15 mL) and 2 M KOH (15 mL), and the resultant solution was
stirred at room temperature for 16 h. After this period the reaction
mixture was carefully acidified with 5 M HCl and extracted with
CH2Cl2 (2 × 30 mL), the combined organic layers were dried
(Na2SO4) and filtered, and the solvent was removed in vacuo. The
crude acid was then dissolved in toluene (25 mL) and refluxed for
overnight. The solvent was then removed in vacuo, and the crude solid
was purified by column chromatography (Rf 0.13, 3:2 petroleum
ether/ethyl acetate) to yield the title compound as a colorless solid
General Methylation Conditions. Method A: To a solution of
the endoperoxide 4 or 11 (1.0 mmol) in dry THF (10 mL) was added
the catalyst 8a or 8b (0.1 mmol), and the resultant reaction mixture
was stirred at room temperature for 16 h under N2. After this period a
solution of NaCH(CO2Et)2 [1.1 mmol; prepared from H2C(CO2Et)2
(193 mg, 1.1 mmol) and NaOEt (2.2 mL, 0.50 M solution, 1.1 mmol)
THF (5.0 mL)] was added dropwise to the reaction mixture at 0 °C,
and the resultant solution was allowed to warm to room temperature
and stirred for a further 16 h under N2. The reaction mixture was then
cooled to 0 °C, and iodomethane (94 μL, 1.5 mmol) was added, after
which the reaction mixture was stirred for a further 16 h at room
temperature. A satd solution of NH4Cl (10 mL) was then added, the
solution then partitioned between CH2Cl2 (50 mL) and H2O (50
mL), and the aqueous layer extracted with further portions of CH2Cl2
(2 × 40 mL). The organic layers were then combined, washed with
(194 mg, 76%; mp 74−76 °C); [α]19 = +21.2 (c 1.00, CHCl3); IR
D
(solution, CHCl3) 3011, 3027, 2942, 1780, 1705, 1016 cm−1; 1H
NMR (400 MHz; CDCl3) δ 4.22 (dt, J = 3.2, 9.2 Hz, 1H), 2.77−2.64
(m, 4H), 2.48 (dd, J = 11.2, 13.6 Hz, 1H), 2.42−2.34 (m, 2H), 2.27−
2.21 (m, 1H), 1.93−1.76 (m, 3H), 1.72−1.63 (m, 1H), 1.54−1.46 (m,
1H); 13C NMR (100 MHz; CDCl3) δ 21.4, 174.4, 86.0, 46.4, 41.1,
D
dx.doi.org/10.1021/jo400177j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
39.7, 37.1, 31.6, 25.7, 22.8; HRMS (ESI-orbitrap) m/z: [M + Na]+
calcd for C10H14O3Na for 205.0841, found 205.0836.
(−)-13, (+)-13, (−)-14, (+)-14; crystallographic data or
( )-14. This material is available free of charge via the
Internet at http://pubs.acs.org.
(−)-(3aS,8aR)-Hexahydro-2H-cyclohepta[b]furan-2,5(3H)-
dione ((−)-22). Lactone (−)-13 (241 mg, 1.0 mmol) was dissolved in
50% acetic acid (10 mL) and refluxed overnight. After this period, the
reaction was cooled and basified with NaHCO3, and the aqueous layer
was extracted with dichloromethane (2 × 30 mL). The combined
organic extracts were then dried (Na2SO4) and filtered, and the solvent
was removed in vacuo. The crude product were then purified by
chromatography giving the title compound as a colorless solid (130
AUTHOR INFORMATION
Corresponding Author
*E-mail: M.C.Kimber@lboro.ac.uk.
■
Notes
The authors declare no competing financial interest.
mg, 78%; mp 69.0−70.5 °C); [α]19 = −59.6 (c 1.00, CHCl3); IR
D
(solution, CHCl3) 3019, 2950, 1782, 1704, 1211 cm−1; 1H NMR (400
MHz; CDCl3) δ 4.03 (ddd, J = 3.6, 5.2, 9.6 Hz, 1H), 2.80 (dd, J = 3.6,
18.0 Hz, 1H), 2.74−2.52 (m, 4H), 2.48 (dq, J = 3.6, 12.8 Hz, 1H),
2.40−2.30 (m, 2H), 2.12−2.04 (m, 1H), 1.72 (ddt, J = 4.0, 11.2, 13.2
Hz, 1H), 1.61−1.50 (m, 1H); 13C NMR (100 MHz; CDCl3) δ 210.3,
175.0, 85.6, 44.1, 43.3, 38.6, 35.9, 34.2, 20.8; HRMS (ESI-orbitrap) m/
z: [M + Na]+ calcd for C9H12O3Na for 191.0684, found 191.0679.
(−)-Methyl 3-((3S,3aS,8aR)-3-Methyl-2-oxo-3,3a,4,7,8,8a-
hexahydro-2H-cyclohepta[b]furan-6-yl)propanoate ((−)-29).
To a mixture of (−)-20 (282 mg, 1.55 mmol) and paraformaldehyde
(96 mg, 3.10 mmol) in dry THF (2 mL) were added (iPr)2NH.TFA
(334 mg, 1.55 mmol) and TFA (12 μL, 0.16 mmol). The reaction
mixture was then refluxed for 2 h, after which it was cooled to room
temperature. Another portion of paraformaldehyde (94 mg, 3.10
mmol) added, and the reaction mixture refluxed for a further 6 h. After
this period the reaction mixture was cooled, the solvent was removed
in vacuo, and the residue was dissolved in CH2Cl2 (40 mL) and
washed sequentially with 1 M HCl (30 mL), NaHCO3 (30 mL), and
finally brine (30 mL). The combined organic layers were then dried
(Na2SO4) and filtered, and the solvent was removed in vacuo. The
crude oil was then purified by chromatography (Rf 0.4 in 3:1 ethyl
acetate/petroleum ether) to give the desired methenylated compound
as a colorless oil (182 mg, 61%), which was used without further
purification. The methenylated compound (160 mg, 0.83 mmol) was
dissolved in methanol (6 mL), and to this solution was added
CeCl3·9H2O (308 mg, 0.83 mmol). The reaction mixture was cooled
to 0 °C, and to the stirring solution was added NaBH4 (102 mg, 2.68
mmol) in portions over 20 min. After this addition the reaction
mixture was then monitored by TLC until the disappearance of the
starting material was detected. After approximately 1 h the reaction
was once again cooled to 0 °C and carefully quenched with a satd
solution of NH4Cl. The reaction mixture was then transferred to a
separating funnel, and the aqueous layer was extracted with ethyl
acetate (3 × 20 mL). The resultant combined organic extracts were
dried (Na2SO4) and filtered, and the solvent finally was removed in
vacuo. The crude product was then immediately dissolved in trimethyl
orthoacetate (1.00 mL), and to this mixture was added a propionic
acid (1 drop). This solution was then heated for 16 h at reflux under a
N2 atmosphere. After this period the reaction mixture was cooled, the
residual trimethyl orthoacetate was removed in vacuo, and the crude
product was purified by column chromatography (Rf 0.55 in 5:3 ethyl
acetate/petroleum ether) giving the title compound (−)-29 as a
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the Depart-
ment of Chemistry at Loughborough University.
■
REFERENCES
■
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colorless oil (172 mg, 83% over 2 steps); [α]21 = −50.4 (c 1.00,
D
CHCl3); IR (solution, CHCl3) 2900, 1765, 1733, 1440 cm−1; 1H
NMR (400 MHz; CDCl3) δ 5.77−5.73 (m, 1H), 3.83 (ddd, J = 4.0,
10.0, 11.2 Hz, 1H), 3.67 (s, 3H), 2.91−2.86 (m, 1H), 2.79 (q, J = 6.8
Hz, 1H), 2.52−2.41 (m, 4H), 2.39−2.35 (m, 2H), 2.24−2.16 (m, 1H),
2.11−2.01 (m, 1H), 1.81−1.75 (m, 1H), 1.71−1.60 (m, 1H), 1.31 (d, J
= 6.8 Hz, 3H); 13C NMR (100 MHz; CDCl3) δ 178.5, 173.2, 136.2,
130.0, 79.0, 52.7, 51.8, 38.0, 37.1, 32.8, 27.4, 26.7, 24.0, 15.7; HRMS
(ESI-orbitrap) m/z: [M + Na]+ calcd for C14H20O4Na for 275.1259,
found 275.1256.
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ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental conditions; optimization table for the
formation of (−)-9a; spectral data for all new compounds and
chiral HPLC traces for (−)-9a, (+)-9b, (−)-9b, (−)-9d,
E
dx.doi.org/10.1021/jo400177j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Martin, S. F. Org. Lett. 2005, 7, 4621. (j) Yokoe, H.; Yoshido, M.;
Shishido, K. Tetrahedron Lett. 2008, 49, 3504. (k) Yokoe, H.; Sasaki,
H.; Yoshimura, T.; Shindo, M.; Yoshida, M.; Shishido, K. Org. Lett.
2007, 9, 969.
(7) Kornblum, N.; De La Mare, H. J. Am. Chem. Soc. 1951, 73, 881.
(8) For the preparation of 4, see Smith, C. R; Justice, D. E.; Malpass,
J. R. Tetrahedron 1994, 50, 11039.
(9) Toste reported that CH2Cl2 was the optimum solvent as it
exhibited an enhanced rate for the rearrangement (6 h) as compared
to other solvents.
(10) As indicated in ref 9, the best solvent for the desymmetrization
was found to be CH2Cl2; however, this was found to be incompatible
with the conjugate addition/lactonization reaction. Therefore Table 1
in the Supporting Information summarizes this optimization sequence
using THF.
(11) For the preparation of 11, see Pearson, A. J.; Lai, Y.-S.; Lu, W.;
Pinkerton, A. A. J. Org. Chem. 1989, 54, 3882.
(12) For the preparation of 12, see Johnson, C. R.; Golebioski, A.;
Steensma, D. H. J. Am. Chem. Soc. 1992, 114, 9414.
(13) See the Supporting Information. Crystal data for ( )-14:
C18H30O6Si, M = 370.51, monoclinic, C2, a = 57.606(17), b =
6.594(2), c = 10.648(3) Å, β = 95.468(4)o, V = 4026(2) Å3, Z = 8,
μ(Mo Kα) = 0.145 mm−1, 20441 reflections measured, 9762 unique,
Rint = 0.0520, R1[F2 > 2σ(F2)] = 0.0667, wR2 (all data) = 0.1841. Flack
parameter x = 0.41(13); both enantiomers present in the asymmetric
unit. Space group C2/c was tried but gave a disordered structure.
CCDC 907291 contains 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.
1
(14) This dr was assigned via H NMR of the crude decarboxylated
material, and the stereochemistry of the methyl group within (−)-19
and (+)-20 was assigned using NOE.
(15) An attempt to directly methylate lactones (+)-21 and (−)-22
was also trialed. This involved treatment of the lactone with 2.1 equiv
of LDA, first effecting deprotonation alpha to the ketone and second
alpha to the lactone. However, subsequent addition of 1.0 equiv of
iodomethane failed to deliver (+)-19 or (−)-20, and only generated a
complex mixture in each case.
(16) In context, this sequence should be seen as an intermolecular
conjugate addition route to the trans-fused lactones, complementary to
the intramolecular conjugate addition approach which exclusively give
cis-fused lactones; see (a) Burns, A. R.; McAllister, G. D.; Shanahan, S.
E.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2010, 49, 5574. (b) Kitson,
R. R. A; Taylor, R. J. K.; Wood, J. L. Org. Lett. 2009, 11, 5338.
(c) Edwards, M. G.; Kenworthy, M. N.; Kitson, R. R. A.; Perry, A.;
Scott, M. S.; Whitwood, A. C.; Taylor, R. J. K. Eur. J. Org. Chem. 2008,
4769. (d) Edwards, M. G.; Kenworthy, M. N.; Kitson, R. R. A.; Scott,
M. S.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2008, 47, 1935.
(17) Bugarin, A.; Jones, K. D.; Connell, B. T. Chem. Commum. 2010,
46, 1715.
(18) Butlin, R. J; Linney, I. D.; Mahon, M. F.; Tye, H.; Wills, M. J.
Chem. Soc., Perkins Trans. 1 1996, 95.
F
dx.doi.org/10.1021/jo400177j | J. Org. Chem. XXXX, XXX, XXX−XXX