Aliphatic C-H to C-C conversion: Synthesis of (-)-cameroonan-7α-ol

Article abstract of DOI:10.1021/jo200075v

In the course of a synthesis of the tricyclic sesquiterpene (-)- cameroonan-7α-ol from the acyclic (〈)-citronellal, seven aliphatic C-H bonds were converted to C-C bonds, and three rings and four new stereogenic centers were established. 2011 American Chemical Society.

Full text of DOI:10.1021/jo200075v

ARTICLE
pubs.acs.org/joc
Aliphatic C-H to C-C Conversion: Synthesis of (-)-Cameroonan-7r-ol
Douglass F. Taber* and Christopher G. Nelson
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S Supporting Information
b
ABSTRACT: In the course of a synthesis of the tricyclic sesquiterpene (-)-
cameroonan-7R-ol from the acyclic (þ)-citronellal, seven aliphatic C-H
bonds were converted to C-C bonds, and three rings and four new
stereogenic centers were established.
’ INTRODUCTION
via enantioretentive C-H functionalization7 of the C-4 methine
of (þ)-citronellal 3. To that end, the R-diazo-β-ketoester 5 was
constructed (Scheme 1). The synthesis commenced with a three-
step sequence of LiAlH4 reduction, tosylation, and nucleophilic
displacement of (þ)-3 to provide the known nitrile 4.8 Homo-
logation to the β-ketoester 1 was accomplished via Blaise
reaction9 of the nitrile 4 with BrCH2CO2Et. We found that
reproducibly high yields in this reaction could be achieved using
activated Zn0 metal10 and in situ activation with a catalytic amou-
Cameroonan-7R-ol (2), a sesquiterpene from the essential oil
of the rhizome Echinops giganteus var. lelyi, was originally
described by Weyerstahl in 1997.1 While the essential oil is a
complex mixture of several sesquiterpenes, (-)-2 is believed to
be the major contributor to its strong woody, patchouli-like
fragrance. The tricyclic skeleton of (-)-cameroonanol (2) is
biogenetically derived from farnesyl pyrophosphate, through
polyene cyclization and carbocationic rearrangements.2 Com-
posed of three cis-fused five-membered rings and five contiguous
stereogenic centers in a dense configuration, (-)-2 offers
significant synthetic challenges.
12
nt of TFA.11 Diazo transfer using MsN3 then provided the
requisite R-diazo-β-ketoester 5 for C-H functionalization.
Using catalytic Rh2(Oct)4, 5 readily cyclized to 6.
Scheme 1
Previous syntheses of (()-2 focused on dipolar cycloaddition
to a racemic bicyclooctenone.3 We sought an alternative ap-
proach, based on ring construction by C-H to C-C bond
functionalization (eq 1). There has been a great deal of attention
paid recently to the selective oxidation of aliphatic C-H bonds
to C-O bonds.4 The direct conversion of aliphatic C-H bonds
to C-C bonds is strategically at least as important.5,6 Herein, we
report the first synthesis of enantiopure (-)-cameroonan-7R-ol
(2), starting (Scheme 1) from the acyclic (þ)-citronellal (3). We
envisioned that, by the judicious conversion of seven aliphatic
C-H bonds to C-C bonds, it could be possible to incorporate
the complete carbon skeleton of 1 into (-)-cameroonan-7R-ol
(2). Of particular note is a sequence of RhII-catalyzed C-H
functionalization followed by MnIII-mediated oxidative radical
cyclization for the stereocontrolled construction of [3.3.0]-fused
bicyclooctanes in enantiomerically pure form.
MnIII Oxidative Radical Cyclization. We planned next to
cyclize the β-ketoester 6 with Mn(OAc)3. As described by
Snider,13 oxidative radical generation, followed by subsequent
cyclization, further oxidation and deprotonation, would provide
the second ring of 2 (Scheme 2). Its application to the synthesis
’ RESULTS AND DISCUSSION
Cyclization by Rh-Carbenoid C-H Functionalization.
We planned to establish the absolute configuration of (-)-2
Received: January 12, 2011
Published: February 23, 2011
r
2011 American Chemical Society
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Scheme 2
of (-)-cameroonanol (2) immediately raised a question of
selectivity, as one ring and at least one additional stereogenic
center are formed in the cyclization. We expected preference for
the formation of the cis-5/5-fused versus the corresponding
trans-5/5 or 6/5 bicyclic products. The relative stereochemical
orientation of the pendant alkyl side chain (i.e., endo vs exo
selectivity) in the product had yet to be investigated using this
method, although radical cyclizations in general proceed with
endo selectivity.14
derivatives were more directly accessible from 9, we turned our
attention to that intermediate.
In the event (Scheme 2), we observed that the cyclization did
proceed with high preference for the cis-5/5-fused products, as
expected. Initially, the use of anhydrous acetonitrile solvent led to
the endo-alkene 7 as the dominant product. The use of acetic acid
as a solvent shortened the reaction time considerably but also
delivered a more complex mixture of products.15 Conveniently,
after treatment of that crude reaction material with water, the
hemiketal 8 and the endo-alkene 7 emerged as the major
products. Furthermore, products 7, 9, or 10 could each be
selectively obtained from the crude reaction mixture in high
overall yield depending upon the dehydration conditions. This
iterative protocol of cyclization followed by dehydration allowed
endo or exo cyclization products to be selectively obtained.
Stereoselective Reduction. Each of the three bicycles (7, 9,
and 10) from MnIII-mediated cyclization could potentially be
useful for the synthesis of (-)-cameroonanol (2). Each was
independently investigated, beginning with the endo-alkene 7.
Installation of the gem-dimethyl moiety was accomplished using
methyl iodide and potassium hydride in paraffin [KH(P)].16a
Chemoselective ketone reduction of 7 with NaBH4 provided the
secondary alcohol 11 as a single diastereomer (eq 2). However,
alcohol 11 was prone to undesired cyclization to the cyclic ether
12 under mildly acidic conditions. Conversely, when the cis-fused
lactone 10 was subjected to identical NaBH4 reduction, the
opposite stereoselectivity was observed (eq 3). Attempts to
fragment the protected lactone 13 ultimately resulted in the
formation of tetrasubstituted alkenes of type 14. As these
We were pleased to observe that reduction of the ketone 9
delivered the desired alcohol 15 with high diastereocontrol
(Scheme 3). Before manipulation of the alkyl side chain, we
sought to protect the potentially sensitive β-hydroxy ester 15.
Benzyl ether formation under Williamson etherification condi-
tions16b provided 16 with complete inversion of the secondary
carbinol center, presumably by a retro-aldol/aldol process. After
screening a variety of benzylation procedures, we found that the
protocol developed by Dudley17 delivered the benzyl ether 17
cleanly and with retention of relative configuration.
Alkyl Side Chain Functionalization. Attempts to cyclize 17
(Scheme 4) by direct allylic deprotonation were unsuccessful.
We therefore functionalized the allylic C-H of 17 to set the stage
for the construction of final ring of (-)-2. Exposure of the alkene
17 to singlet oxygen regioselectively formed the alcohol 18.
Optimized dehydration conditions suppressed formation of the
undesired 20, giving clean conversion to the diene 19. Initial
attempts to functionalize the diene 19 as the thioether under
standard radical conditions were low yielding and proceeded
with poor regiocontrol. However, the use of Lewis acidic silica
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Scheme 3
Scheme 5a
Scheme 4
a Reagents and conditions: (a) mCPBA, CH2Cl2, -78 °C, 61% 23a,b,
37% 24; (b) PhMe, microwave, 120 °C, 23a,b/24 = 3:1; (c) H2WO4
(0.1 equiv), H2O2, RT, 24 h, 76%; (d) LDA, -40 °C, 90%.
Scheme 6
nanoparticles (SNPs)18 allowed the selective functionalization of
the terminal alkene. Concomitant (and desired) alkene isomer-
ization provided an inseparable mixture of E/Z-allylic thioethers
21 in good yield.
Completion of the Synthesis. Formation of the final ring
of (-)-2 was accomplished by cyclization of the Z-allylic sulfone
24 derived from the thioether 21 (Scheme 5). While direct oxida-
tion of the thioether 21 to the sulfone 24 was possible, an
iterative oxidation sequence by way of the sulfoxides 22 and 23
proved useful for two reasons. First, the intermediate Z- and
E-allylic sulfoxide isomers could be chromatographically resolved.
Further, we found that the E-allylic sulfoxides 22a,b could be
equilibrated to a 3:1 mixture of E:Z-allylic sulfoxides under
microwave conditions.19 This allowed for increased throughput
to the Z-allylic sulfoxides 23a,b that were oxidized to the sulfone
24. On exposure to LDA,20 24 smoothly cyclized to the enone
25. The corresponding E-allylic sulfone did not cyclize.
Having successfully installed the all-cis-5/5 ring fusions, we
next turned our attention to the final stereocenter of 2. Specifi-
cally, we required a method for introducing hydrogen to the more
congested face of enone 25 to establish the C9 stereocenter
(Scheme 6). Among the various known protocols for enone
reduction, methods based on hydrogenation or nucleophilic
hydride delivery were anticipated to deliver the wrong diaster-
eomer (i.e., product 27) via approach from the more sterically
accessible face of the enone 25. However, dissolving metal
reduction had been shown to deliver the thermodynamically
more stable products from β-substituted cyclic enones.21
SmI2/HMPA/NH4Cl22 proved to be an efficient system for
the reduction of the enone 25, providing a 1:1 mixture of
desulfonylated C-9 methyl diastereomers (that is, 28 and epi-
28, Scheme 6). However, the two ketone diastereomers were
not separable. Mg/MeOH effected the chemoselective re-
duction of the enone 25 to a separable mixture of 26 and 27.
The relative configuration of the secondary methyl group was
confirmed by the conversion of 26 to C-9-epi-cameroonanol
(epi-2).23 It seemed that the combined steric effect of the C-4
methyl group and developing C-2 to C-9 syn-pentane inter-
action slow protonation from the desired face during the
reduction, even when using a small proton source such as
NH4Cl.
The ketone 27 was subject to SmI2-mediated desulfonylation
to deliver the ketone 28. Wolff-Kishner reduction was followed
by deprotection to complete the synthesis of the volatile (-)-
cameroonan-7R-ol (2). The spectroscopic data (IR, MS, 1H, and
13C NMR) for synthetic (-)-2 fully agreed with those previously
reported [RD ref 1 = (-) 34°; obs = (-) 37°].
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’ CONCLUSION
yield from citronellal). The analytical data for nitrile 4 match those
previously reported:8 TLC Rf (PE/MTBE = 20:1) = 0.39; [R]20D = (þ)
3.7 (c 2.15 CHCl3); 1H NMR δ 5.10 (1H, m), 2.01 (2H, m), 1.76-1.68
(1H, m), 1.70 (3H, s), 1.62 (3H, s), 1.61-1.56 (1H, m), 1.50 (1H, m),
The first total synthesis of enantiomerically pure (-)-camer-
oonan-7R-ol (2) has been accomplished. Central to the synthesis
is the specific conversion of aliphatic C-H bonds to C-C
bonds. The procedure presented for the stereoselective two-
stage construction of the first two rings of (-)-cameroonanol (2)
from the acyclic ester 1 exemplifies the strategic efficiency of
C-H bond functionalization in natural product synthesis. We
anticipate that the sequence of RhII-mediated C-H functiona-
lization followed directly by MnIII oxidative radical cyclization
developed here will become a general method for the construc-
tion of bicyclic intermediates with the control of both relative
and absolute configuration. In the application described here,
this two-step strategy enabled the controlled installation of the
two contiguous cyclic quaternary centers of (-)-cameroonan-
7R-ol (2).
1.36 (1H, m), 1.21 (1H, m), 0.94 (3H, d, J = 6.5 Hz); 13C NMR24
δ
131.7, 120.0, 36.3, 32.2, 25.2, 14.9; d 124.1, 31.6, 25.68, 18.7, 17.6; IR
(film, cm-1) 1672, 2247, 2359, 2921; HRMS calcd for C11H20N (M þ
H) 166.1596, obsd 166.1598.
Ethyl (6R)-6,10-Dimethyl-3-oxoundec-9-enoate (1). Zn metal (Zn dust,
17.8 g, 271.9 mmol, 3.1 equiv) was washed successively with 3 N
aqueous HCl, H2O, EtOH, and anhydrous Et2O. After removal of all
solvent under high vacuum, the activated Zn metal was added to 50 mL
of THF and the slurry was brought to reflux. Trifluoroacetic acid (65 μL,
0.88 mmol, 0.01 equiv) was added, followed by a minor amount of
BrCH2CO2Et (ca. 0.5 mL) until the reaction mixture became green.
Nitrile 4 (14.47 g, 87.7 mmol) was then added in one portion. After
stirring for 20 min, a solution of BrCH2CO2Et (21.4 mL, 193 mmol,
2.2 equiv) in 21 mL of THF was added dropwise via addition funnel over
1 h. Upon complete addition, the reaction was stirred at reflux for 0.5 h.
After cooling to room temperature, 100 mL of 3 N aqueous HCl was
added and the reaction stirred for 2 h at room temperature. The reaction
material was partitioned between EtOAc and, sequentially, saturated
aqueous NaHCO3 and brine. The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. The residue was chromato-
graphed to afford β-ketoester 1 as a colorless oil (18.34 g, 72.2 mmol,
82% yield): TLC Rf (PE/MTBE = 20:1) = 0.15; [R]20D = (-) 3 (c 2.7
CHCl3); 1H NMR δ 5.08 (1H, m), 4.20 (2H, q, J = 7.1 Hz), 3.44 (2H, s),
2.54 (2H, m), 1.97 (2H, m), 1.68 (3H, s), 1.60 (3H, s), 1.65-1.58 (1H,
m), 1.42 (2H, m), 1.28 (1H, m), 1.28 (3H, t, J = 7.1 Hz), 1.17 (1H, m),
0.89 (3H, d, J = 6.3 Hz); 13C NMR δ u 203.1, 167.3, 131.3, 61.3, 49.3,
’ EXPERIMENTAL SECTION
General Procedures. 1H NMR and 13C NMR spectra were
recorded, as solutions in deuteriochloroform (CDCl3) unless otherwise
indicated, at 400 and 100 MHz, respectively. 13C multiplicities were deter-
mined with the aid of a JVERT pulse sequence, differentiating the
signals for methyl and methine carbons as “d” from methylene and
quaternary carbons as “u”. The infrared (IR) spectra were determined as
neat oils. Rf values indicated refer to thin-layer chromatography (TLC)
on 2.5 ꢀ 10 cm, 250 mm analytical plates coated with silica gel GF,
unless otherwise noted, and developed in the solvent system indicated.
Microwave reactions were performed using a CEM Discover Labmate
microwave reactor with vertically focused IR temperature sensor. All
glassware was oven-dried and rinsed with dry solvent before use. THF
and diethyl ether were distilled from sodium metal/benzophenone ketyl
under dry nitrogen. Toluene, dichloromethane, and acetonitrile were
distilled from calcium hydride under dry nitrogen. CH2Cl2 is dichloro-
methane, MTBE is methyl-tert-butyl ether, and PE is petroleum ether.
All reactions were conducted under N2 and stirred magnetically.
(4R)-4,8-Dimethylnon-7-enenitrile (4). To a slurry of LiAlH4 (11.81
g, 311 mmol, 1.2 equiv) in 450 mL of THF, in a 2 L multineck round-
bottom flask (equipped with a reflux condenser, addition funnel and
N2 inlet adapter) submerged in a 0 °C ice bath, was added a solution of
(R)-citronellal3(39.95 g, 259 mmol) in 70 mL of THF dropwise via addition
funnel over 30 min. Upon complete addition, the ice bath was removed
and the reaction was stirred at room temperature for 1 h. The reaction
was quenched according to the method of Micovic.23 After stirring at
room temperature overnight, 20 g of Na2SO4 was added and the mixture
was filtered through Celite to remove the white precipitate. The filter
cake was thoroughly washed with Et2O and concentrated in vacuo.
The residue was diluted with 108 mL of anhydrous pyridine and
cooled to 0 °C under an N2 atmosphere. p-Toluenesulfonyl chloride
(76.52 g, 401.5 mmol, 1.55 equiv) was added in three equal portions
over 15 min intervals. The reaction was gradually stirred to room
temperature with the ice bath. After 4 h at room temperature, the
reaction material was partitioned between Et2O and, sequentially, 1 N
aqueous HCl and saturated aqueous NaHCO3. The combined organic
extracts were dried with Na2SO4 and concentrated in vacuo.
40.8, 36.8, 30.3, 25.4; d 124.6, 31.9, 25.7, 19.2, 17.6, 14.1; IR (film, cm-1
)
1643, 1743, 2921; HRMS calcd for C15H26O3 (M þ Na) 277.1780, obsd
277.1771.
Ethyl (6R)-2-Diazo-6,10-dimethyl-3-oxoundec-9-enoate (5). To a
solution of β-ketoester 1 (10.0 g, 39.37 mmol) and MeSO2N3 (7.15 g,
59.06 mmol, 1.5 equiv) in 79 mL of acetonitrile at room temperature was
added NEt3 (11.05 mL, 78.74 mmol, 2.0 equiv) dropwise via syringe.
Stirring was continued for 3.5 h at room temperature. The reaction
material was diluted with 10% aqueous NaOH and extracted with Et2O.
Combined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The residue was chromatographed to afford R-diazo-β-ketoester
5 as a colorless oil (10.21 g, 36.5 mmol, 93% yield): TLC Rf (PE/MTBE
= 20:1) = 0.46; [R]20D = (-) 6.1 (c 3.0 CHCl3); 1H NMR δ 5.09 (1H,
m), 4.30 (2H, q, J = 7.1 Hz), 2.86 (2H, m), 1.98 (2H, m), 1.68 (1H, m),
1.68 (3H, s), 1.60 (3H, s), 1.46 (2H, m), 1.33 (1H, m), 1.33 (3H, t, J =
7.1 Hz), 1.18 (1H, m), 0.90 (3H, d, J = 6.4 Hz); 13C NMR δ u 193.4,
161.4, 131.2, 75.8, 61.3, 38.0, 36.8, 31.3, 25.5; d 124.7, 32.2, 25.7, 19.3,
17.6, 14.3; IR (film, cm-1) 1658, 1720, 2135, 2921; HRMS calcd for
C15H24N2O3 (M þ Na) 303.1685, obsd 303.1689.
Ethyl (2R)-2-Methyl-2-(4-methylpent-3-en-1-yl)-5-oxocyclopenta-
necarboxylate (6). Rh2(Oct)4 (142 mg, 0.182 mmol, 0.005 equiv)
was added to 530 mL of CH2Cl2, and the mixture was sonicated to
homogeneity over 10 min. To the resultant pale green homogeneous
solution was added a solution of diazo compound 5 (10.2 g, 36.4 mmol)
in 200 mL of CH2Cl2 dropwise via addition funnel over 1 h. The reaction
was stirred for 1 h at room temperature and then concentrated in vacuo.
The residue was chromatographed to afford a mixture β-ketoesters 6
(both R-epimers and enol) as a colorless oil (7.85 g, 31.14 mmol, 85%
yield): TLC Rf (PE/MTBE = 20:1) = 0.40; 1H NMR δ 10.98 (0.15H, br
s, OH), 5.07 (1H, m), 4.24-4.11 (2H, m), 2.98 (0.52H, s), 2.89 (0.30H,
s), 2.51-2.29 (2H, m), 2.20-1.74 (4H, m), 1.67 (3H, m), 1.60-1.40
(5H, m), 1.31-1.23 (3H, m), 1.12 (0.46H, s), 1.10 (0.90H, s), 1.09
(1.54H, s); 13C NMR δ u 213.5, 212.8, 168.8, 168.6, 132.0, 131.7, 60.9,
60.8, 59.6, 45.0, 44.0, 43.8, 41.7, 40.3, 37.5, 36.2, 36.1, 33.9, 33.4, 33.2,
The residue was diluted with 860 mL of 2:1 EtOH/H2O, and KCN
(50.5 g, 777 mmol, 3.0 equiv) was added. The temperature was increased
to 70 °C, and the mixture was stirred overnight (16 h). After cooling to
room temperature, the reaction mixture was concentrated in vacuo (to
remove the bulk of the EtOH) and extracted with CH2Cl2. Combined
organic phases were dried (Na2SO4) and concentrated in vacuo. The
residue was distilled bulb-to-bulb (bath = 100-105 °C, 0.05 Torr) to
afford the known nitrile 4 as a pale yellow oil (36.32 g, 220 mmol, 85%
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30.9, 23.8, 23.1, 22.9; d 124.9, 124.0, 123.8, 65.8, 64.8, 27.4, 25.7, 25.6,
25.4, 21.2, 17.6, 17.5, 14.2, 14.2, 14.1; IR (film, cm-1) 1649, 1726, 2968;
HRMS calcd for C15H25O3 (M þ H) 253.1804, obsd 253.1807.
MnIII Oxidative Radical Cyclization Method A. (1R,5S,8R)-1-
Ethoxycarbonyl-5-methyl-8-(prop-1-en-2-yl)bicyclo[3.3.0]octan-2-
J = 1.6, 6.0 Hz), 2.76 (1H, ddd, J = 4.5, 7.5, 12.0), 2.25 (1H, dt, J = 9.0,
14.3 Hz), 1.97 (3H, s), 1.89-1.67 (6H, m), 1.47 (1H, m), 1.33 (3H, t,
J = 7.1 Hz), 1.30 (6H, br s), 1.12 (3H, s); 13C NMR (100 MHz, CDCl3)
δ u 171.6, 168.9, 119.3, 87.5, 80.1, 60.5, 54.7, 40.6, 37.0, 36.9, 26.9; d
55.3, 29.7, 24.4, 24.3, 22.1, 14.3; HRMS calcd for C17H26O5 (M þ Na)
333.1678, obsd 333.1674.
one (7). A dry mixture of Mn(OAc)3 2H2O (12.92 g, 48.20 mmol, 2.0
3
equiv) and Cu(OAc)2 H2O (4.82 g, 24.10 mmol, 1.0 equiv) was purged
(1R,4S,7S,10R)-1-Ethoxy-10-ethoxycarbonyl-3,3,7-trimethyl-2-
oxatricyclo[2.2.2.1]decane (8b). 42 mg, TLC Rf (PE/MTBE = 6.5:1) =
0.61; 1H NMR (400 MHz, CDCl3) δ 4.17 (2H, m), 3.62 (1H, dq, J = 7.1,
8.9 Hz), 3.38 (1H, dq, J = 7.1, 8.9 Hz), 3.10 (1H, dd, J = 5.8, 7.7 Hz),
2.11-1.97 (2H, m), 1.83-1.64 (5H, m), 1.40 (1H, m), 1.33 (3H, s),
1.28 (3H, t, J = 7.1 Hz), 1.24 (3H, s), 1.11 (3H, s), 1.08 (3H, t, J = 7.1
Hz); 13C NMR (100 MHz, CDCl3) δ u 172.4, 119.2, 85.4, 79.1, 60.1,
58.0, 54.9, 41.0, 36.8, 34.5, 26.9; d 55.7, 29.6, 24.7, 15.3, 14.2; HRMS
calcd for C17H28O4 (M þ Na) 319.1885, obsd 319.1880.
3
with argon for 10 min and diluted with 240 mL of acetonitrile.
β-Ketoester 6 (6.08 g, 24.10 mmol) was added, and the reaction was stirred
at room temperature overnight (16 h) under an atmosphere of argon.
The reaction mixture was filtered through Celite, diluted with saturated
aqueous NaHCO3, and extracted with Et2O. The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo. The residue
was chromatographed to afford endo-alkene 7 as a colorless oil (3.57 g,
14.30 mmol, 59% yield) accompanied by a complex mixture of other
isomers (1.81 g, ca. 7 mmol). For 7: TLC Rf (PE/MTBE = 10:1) = 0.31;
(1R,5R,8S)-4,4,8-Trimethyl-3-oxatricyclo[6.3.0.01,5]undecan-2,11-
1
[R]20 = (þ) 61.4 (c 1.52, CHCl3); H NMR (400 MHz, CDCl3)
dione (10). 6.5 mg; TLC Rf (PE/MTBE = 4:1) = 0.22; mp = 102 °C;
D
1
δ 4.78 (2H, d, J = 48 Hz), 4.20 (2H, m), 3.43 (1H, dd, 11.8, J = 12.0 Hz),
2.50 (1H, ddd, J = 6.1, 8.7, 18.1 Hz), 2.28 (1H, m), 1.79 (3H, s), 1.64-
1.91 (6H, m), 1.27 (3H, t, J = 7.1 Hz), 1.17 (3H, s); 13C NMR (100
MHz, CDCl3) δ u 214.1, 171.7, 144.8, 111.4, 71.2, 61.1, 53.6, 40.5, 39.7,
35.1, 29.1; d 52.6, 26.1, 23.7, 14.2; IR (film, cm-1), 1643, 1732, 2958,
3086; HRMS calcd for C15H22O3 (M þ Na) 273.1467, obsd 273.1459.
MnIII Oxidative Radical Cyclization Method B. To a mixture
[R]20 = (þ) 119.1 (c 1.33 CHCl3); H NMR (400 MHz, CDCl3)
D
δ 2.76 (1H, t, J = 8.1 Hz), 2.57 (2H, m), 1.91 (4H, m), 1.75 (2H, m),
1.53 (3H, s), 1.39 (3H, s), 1.32 (3H, s); 13C NMR (100 MHz, CDCl3)
δ u 214.8, 173.0, 84.4, 73.8, 53.8, 41.2, 37.9, 32.6, 28.0; d 56.9, 31.2, 24.3,
23.1; IR (film, cm-1) 1313, 1462, 1729 (br), 2939; HRMS calcd for
C13H19O3 (M þ H) 223.1334, obsd 223.1332.
Selective Product Formation. The following is the optimized
procedure for the selective formation of the endo alkene product 7 from
the β-ketoester 6.
of Mn(OAc)3 2H2O (14.63 g, 54.6 mmol, 2.0 equiv) and Cu-
3
(OAc)2 H2O (5.46 g, 27.3 mmol, 1.0 equiv) in 136 mL glacial acetic
3
acid was added β-ketoester 6 (6.88 g, 27.3 mmol), and the reaction
mixture was purged with argon while stirring rapidly. The heterogeneous
solution was stirred at 80 °C under an argon atmosphere. Upon
complete consumption of β-ketoester 6, 20 mL of H2O was added
and the reaction gradually cooled to room temperature. The reaction
mixture was filtered through Celite and concentrated in vacuo to remove
the bulk of the acetic acid. The residue was diluted with saturated
aqueous NaHCO3 and extracted with Et2O. The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo to afford 6.9 g
of crude product consisting mainly of hemiketal 8 and endo product 7.
This crude mixture was used in smaller portions as needed (and purified
when required) to develop and optimize the procedures described below.
Analysis of Product Mixture. A small portion of the crude
reaction material (235 mg), prior to treatment with H2O, was chromato-
graphed to afford the following pure materials along an additional
amount of unresolved material (45 mg).
(1R,5S,8R)-1-Ethoxycarbonyl-5-methyl-8-(prop-1-en-2-yl)bicyclo-
[3.3.0]octan-2-one (7). A mixture of Mn(OAc)3 2H2O (268 mg, 1.0
3
mmol, 2.0 equiv), Cu(OAc)2 H2O (100 mg, 0.5 mmol, 1.0 equiv), and
3
β-ketoester 6 (126 mg, 0.5 mmol) was subject to the conditions
described in Method B above. The residue was chromatographed to
afford endo-alkene product 7 (47 mg, 0.19 mmol, 38% yield) along with a
mixture of isomers (61 mg). This mixture of isomers was diluted with
dry toluene (2.5 mL), and p-toluenesulfonic acid monohydrate (9 mg,
0.05 mmol, 0.05 equiv) was added. The reaction mixture was stirred at
reflux for 1 h. After cooling to room temperature, the reaction material
was diluted with 5% aqueous NaOH and extracted with Et2O. The
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. The residue was chromatographed to afford endo-alkene 7
(47 mg, 0.19 mmol, 37% yield, 75% overall yield from β-ketoester 6) as a
viscous yellow oil and lactone 10 (12 mg, 0.05 mmol, 11% yield). The
data for 7 prepared by Method B was identical to the data for 7 prepared
by Method A.
(1R,5S,8R)-1-Ethoxycarbonyl-5-methyl-8-(prop-1-en-2-yl)bicyclo-
[3.3.0]octan-2-one (7). 34.5 mg.
The following are the optimized procedures for the selective forma-
tion of the lactone 10 or the tetrasubstituted alkene 9 directly from the
β-ketoester 6.
(1R,5S,8S)-1-Ethoxycarbonyl-5-methyl-8-(prop-1-en-2-yl)bicyclo-
[3.3.0]octan-2-one(7b). 7 mg, TLC Rf (PE/MTBE = 6.5:1) = 0.39;
1H NMR (400 MHz, CDCl3) δ 4.88 (2H, m), 4.14 (2H, m), 2.78 (1H, m),
2.52 (2H, m), 2.17 (1H, m), 1.79 (3H, s), 1.98-1.67 (5H, m), 1.25 (3H,
t, J = 7.2 Hz), 1.17 (3H, s); 13C NMR (100 MHz, CDCl3) δ u 214.9,
169.4, 144.4, 111.6, 71.0, 60.4, 54.8, 38.4, 36.6, 31.2, 30.0; d 53.0, 24.3,
23.4, 14.1; HRMS calcd for C15H22O3 (M þ Na) 273.1467, obsd
273.1459.
(1R,4S,7S,10R)-10-Ethoxycarbonyl-1-hydroxy-3,3,7-trimethyl-2-
oxatricyclo[2.2.2.1]decane (8). 54 mg; TLC Rf (PE/MTBE = 4:1) =
0.32; [R]20D = (-) 18.5 (c 0.61 CHCl3); 1H NMR (400 MHz, CDCl3)
δ 5.08 (OH, s), 4.25 (2H, m), 3.04 (1H, t, J = 9.3 Hz), 2.15 (1H, dd, J =
6.0, 12.8), 1.90-1.54 (7H, m), 1.34 (3H, t, J = 7.1 Hz), 1.33 (3H, s), 1.27
(3H, s), 1.07 (3H, s); 13C NMR (100 MHz, CDCl3) δ u 176.0, 114.5,
83.9, 74.9, 61.1, 56.9, 40.6, 40.3, 34.6, 26.4; d 59.3, 30.1, 23.9, 23.4, 14.3;
IR (film, cm-1) 1724, 2967, 3456; HRMS calcd for C15H24O4 (M -
OH) 251.1647, obsd 251.1644.
(1R,5R,8S)-4,4,8-Trimethyl-3-oxatricyclo[6.3.0.01,5]undecan-2,11-
dione (10). A mixture of Mn(OAc)3 2H2O (268 mg, 1.0 mmol, 2.0 equiv),
3
Cu(OAc)2•H2O (100 mg, 0.5 mmol, 1.0 equiv), and β-ketoester 6 (126 mg,
0.5 mmol) was subject to the conditions described in Method B above.
The resultant crude mixture was then diluted with dry toluene
(2.5 mL), and p-toluenesulfonic acid monohydrate (100 mg, 1.05 mmol,
1.05 equiv) was added. The reaction was stirred at reflux for 4 h. After
cooling to room temperature, the reaction material was diluted with 5%
aqueous NaOH and extracted with Et2O. The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo. The residue was
chromatographed to afford lactone 10 (97 mg, 0.44 mmol, 87% yield) as
a viscous clear oil which crystallized upon standing.
(1S,5S)-1-Ethoxycarbonyl-5-methyl-8-(propan-2-ylidene)bicyclo-
[3.3.0]octan-2-one (9). A mixture of Mn(OAc)3 2H2O (268 mg,
3
1.0 mmol, 2.0 equiv), Cu(OAc)2 H2O (100 mg, 0.5 mmol, 1.0 equiv),
3
(1S,4S,7S,10R)-10-Ethoxycarbonyl-1-acetoxy-3,3,7-trimethyl-2-
oxatricyclo[2.2.2.1]decane (8a). 11 mg; TLC Rf (PE/MTBE = 6.5:1)
and β-ketoester 6 (126 mg, 0.5 mmol) was subject to the conditions
described in Method B above. The resultant crude mixture was
then diluted with dry toluene (2.5 mL), and p-toluenesulfonic acid
1
= 0.26; H NMR (400 MHz, CDCl3) δ 4.25 (2H, m), 3.15 (1H, dd,
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ARTICLE
monohydrate (9 mg, 0.05 mmol, 0.05 equiv) was added. The reaction
was stirred at reflux for 4 h. After cooling to room temperature, the
reaction material was diluted with 5% aqueous NaOH and extracted with
Et2O. The combined organic extracts were dried (Na2SO4) and con-
centrated in vacuo. The residue was chromatographed to afford tetra-
substituted alkene 9 (103 mg, 0.44 mmol, 82% yield) as a viscous
yellow oil along with lactone 10 (20 mg, 0.09 mmol, 18%). For 9: TLC Rf
(PE/MTBE = 6.5:1) = 0.42; [R]20D = (-) 147 (c 1.9 CHCl3); 1H NMR
(400 MHz, CDCl3) δ 4.24-4.10 (2H, m), 2.60-2.50 (1H, m), 2.49-
2.30 (3H, m), 1.89-1.79 (2H, m), 1.71 (3H, s), 1.68 (3H, s), 1.65-1.55
(2H, m), 1.25 (3H, 7, J = 7.1 Hz), 1.18 (3H, s), 1.01 (3H, s); 13C NMR
(100 MHz, CDCl3) δ u 213.9, 170.6, 131.8, 131.3, 72.4, 60.8, 55.4, 37.1,
37.0, 31.2, 30.3; d 23.2, 22.9, 22.5, 14.3; IR (film, cm-1) 1033, 1257,
1378, 1453, 2939; HRMS calcd for C15H22O3 (M þ Na) 273.1467, obsd
273.1461.
(1S,2R,5S)-1-Ethoxycarbonyl-3,3,5-trimethyl-8-(propan-2-ylide-
ne)bicyclo[3.3.0]octan-2-ol (15). To a slurry of KH(P) [2.63 g KH(P),
50 wt % KH, 32.88 mmol KH, 3.0 equiv] in 27 mL toluene was added
tetrasubstituted alkene 9 (2.74 g, 10.96 mmol) dropwise over
10 min. After stirring for 5 min, CH3I (6.83 mL, 110 mmol, 10 equiv)
was added followed by a small amount of non-anhydrous Et2O to initiate
the reaction. The reactor was equipped with a condenser and stirred at
room temperature for 3 h. The reaction material was cooled to 0 °C,
diluted with Et2O, and then quenched by slow addition of saturated
aqueous NH4Cl. After extraction with Et2O, the combined organic
extracts were dried (Na2SO4) and concentrated in vacuo. The residue
was chromatographed to afford the gem-dimethyl ketone as a colorless
oil (2.54 g, 10.16 mmol, 83% yield): TLC Rf (PE/MTBE = 10:1) = 0.46;
[R]20D = (-) 140 (c 1.0 CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.18
(2H, m), 2.50 (1H, m), 2.37 (1H, m), 1.82 (1H, d, J = 13.5 Hz), 1.75
(1H, d, J = 13.5 Hz), 1.74-1.62 (2H, m), 1.71 (3H, s), 1.69 (3H, s), 1.26
(3H, t, J = 7.0 Hz), 1.22 (3H, s), 1.15 (3H, s), 1.11 (3H, s); 13C NMR
(100 MHz, CDCl3) δ u 217.5, 171.1, 132.9, 131.4, 73.3, 60.7, 52.6, 47.9,
46.5, 38.7, 30.1; d 28.8, 27.9, 24.8, 22.7, 22.4, 14.3; IR (film, cm-1) 1031,
1731, 2936; HRMS calcd for C17H26O3 (M þ H) 279.1960, obsd
279.1967.
benzyl ether 17 (2.02 g, 5.47 mmol, 76% yield) as an inseparable
mixture with Bn2O (607 mg, 3.06 mmol) and residual alcohol 12
(470 mg, 1.68 mmol, 23% recovered). For 17: TLC Rf (PE/MTBE =
20:1) = 0.63; [R]20D = (-) 12.2 (c 2.3 CHCl3; material is 84 wt % benzyl
ether 17 and 16 wt % Bn2O); 1H NMR (400 MHz, CDCl3) δ 7.38-7.23
(10H, m), 4.88 (1H, d, J = 11.8 Hz), 4.68 (1H, d, J = 11.8 Hz), 4.56
(1.76H, s, Bn2O), 4.40 (1H, s), 4.15 (2H, dq, J = 1.1, 7.3 Hz), 2.49
(1H, dd, J = 7.5, 15.5 Hz), 2.38 (1H, m), 1.56-1.63 (5H, m), 1.50-1.44
(5H, m), 1.25 (3H, t, J = 7.1 Hz), 1.03 (3H, s), 1.00 (3H, s), 0.95 (3H, s);
13C NMR (100 MHz, CDCl3) δ u 176.3, 139.8, 138.3, 135.0, 127.9, 74.6,
72.1 (Bn2O), 68.1, 60.2, 52.9, 52.2, 39.8, 39.1, 31.2; d 128.4, 128.0, 127.8,
127.7, 127.6, 127.0, 91.8, 32.3, 26.5, 24.9, 23.3, 22.8, 14.4; IR (film, cm-1
)
1114, 1207, 1364, 1453, 2361, 2936; HRMS calcd for C24H34O3 (M þ H)
371.2586, obsd 371.2600.
(1S,5S,8R)-8-Benzyloxy-1-ethoxycarbonyl-5,7,7-trimethyl-2-(2-
hydroxyprop-2-yl)bicyclo[3.3.0]oct-2-ene (18). A solution of benzyl
ether 17 (1.07 g, 2.88 mmol) and methylene blue (photosensitizer,
11 mg, 0.03 mmol, 0.01 equiv) in 7.2 mL of MeOH was prepared in a
100 mL Pyrex glass test tube. A smaller diameter test tube was then
submerged into the solution to create a thin film annular reactor. The
reactor was capped and irradiated with a flood lamp (120 W, 12 in. from
reactor) as O2 was bubbled through the solution. A water bath was used
to thermostat the reaction at 20-25 °C as it was irradiated. After 9 h, the
reaction was diluted with 10 mL of Et2O, PPh3 (755 mg, 2.88 mmol,
1.0 equiv) was added, and the reaction was stirred overnight (12 h).
Aqueous H2O2 (30 wt %, 1.5 mL, 5.0 equiv) was added and the reaction
stirred 1.5 h at room temperature. The reaction mixture was partitioned
between Et2O and, sequentially, saturated aqueous Na2S2O3 and brine.
The combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. The residue was chromatographed to afford alcohol
18 (780 mg, 2.02 mmol, 70% yield) as a colorless oil and residual alkene
starting material (298 mg, 0.81 mmol, 28% recovered). For 18: TLC Rf
(PE/MTBE = 20:1) = 0.22; [R]20D = (-) 4.78 (c 1.0 CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.39-7.28 (5H, m), 5.55 (1H, t, J = 2.4 Hz), 4.68
(1H, d, J = 10.8 Hz), 4.63 (1H, d, J = 10.8 Hz), 4.59 (1H, s), 4.50 (OH, s),
4.18 (2H, m), 2.41 (2H, d, J = 2.4 Hz), 1.71 (1H, d, J = 13.6 Hz), 1.54
(1H, d, J = 13.6 Hz), 1.30 (3H, s), 1.29 (3H, s), 1.27 (3H, t, J = 7.2 Hz),
1.15 (3H, s), 1.09 (3H, s), 1.04 (3H, s); 13C NMR (100 MHz, CDCl3)
δ u 174.6, 153.3, 137.3, 75.4, 73.8, 70.3, 60.7, 55.5, 50.2, 49.2, 40.4;
d 128.5, 128.5, 128.4, 128.0, 90.9, 32.0, 31.9, 31.5, 27.2, 22.7, 14.2; IR
(film, cm-1) 1227, 1366, 1366, 1455, 1718, 2930, 3456; HRMS calcd for
C24H34O4 (M þ Na) 409.2355, obsd 409.2351.
To a solution of ketone (2.29 g, 8.24 mmol) in 36 mL 1:1 v/v MeOH/
EtOH at 0 °C was added NaBH4 (2.73 g, 71.9 mmol, 8.7 equiv) in small
portions over 1 h. The reaction was stirred to room temperature over 2 h,
diluted with 15 mL of 15% aqueous NaOH, and stirred for 3 h at room
temperature. The reaction mixture was diluted with H2O and extracted
with Et2O. The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. The residue was chromatographed to afford
alcohol 15 (2.04 g, 7.29 mmol, 74% yield from 9) as a colorless oil which
solidified upon standing (mp = 38-39 °C): TLC Rf (PE/MTBE = 10:1)
= 0.38, [R]20D = (-) 28.2 (c 1.0 CHCl3); 1H NMR (400 MHz, CDCl3)
δ 4.47 (1H, d, J = 7.3 Hz), 4.15 (2H, m), 2.52 (1H, dd, J = 6.6, 14.7 Hz),
2.37 (1H, m), 1.80 (OH, d, J = 7.3 Hz), 1.71 (3H, s), 1.66-1.51 (7H,
m), 1.24 (3H, t, J = 7.1 Hz), 1.13 (3H, s), 1.02 (3H, s), 0.93 (3H, s); 13C
NMR (100 MHz, CDCl3) δ u 175.4, 135.7, 128.5, 69.5, 60.4, 53.3, 52.9,
(1S,5S,8R)-8-Benzyloxy-1-ethoxycarbonyl-5,7,7-trimethyl-2-(propan-2-
ylidene)bicyclo[3.3.0]oct-2-ene (19). To a solution of alcohol 18
(386 mg; 1.0 mmol) and anhydrous DMF (233 μL, 3.0 mmol, 3.0 equiv)
in 10 mL of CH2Cl2 at -78 °C was added SOCl2 (183 μL, 2.5 mmol,
2.5 equiv) dropwise. After 10 min at -78 °C, 2,6-lutidine (582 μL,
5.0 mmol, 5.0 equiv) was added dropwise over 10 min. The reaction was
gradually stirred to -40 °C over 20 min, and additional SOCl2 (183 μL, 2.5
mmol, 2.5 equiv) was added. The reaction was warmed to -20 °C and
quenched with 1 N aqueous HCl. The reaction material was partitioned
between CH2Cl2 and, sequentially, H2O and saturated aqueous NaHCO3.
The combined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The residue was chromatographed to afford diene 19 (276 mg, 0.75
mmol, 79% yield) as a yellow oil and residual alcohol starting material (47
mg, 0.12 mmol, 12% recovered). For 19: TLC Rf (PE/MTBE = 10:1) =
0.66, [R]20D = (þ) 81.6 (c 1.84 CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.34-7.20 (5H, m), 5.84 (1H, t, J = 2.4 Hz), 4.78 (2H, d, J = 12.5 Hz), 4.70
(1H, d, J = 11.6 Hz), 4.60 (1H, d, J = 11.6 Hz), 4.41 (1H, s), 4.17 (2H, m),
2.46 (1H, d, J = 17.6 Hz), 2.40 (1H, d, J = 17.6 Hz), 1.83 (3H, s), 1.72 (1H,
d, J = 13.4 Hz), 1.52 (1H, d, J = 13.4 Hz), 1.25 (3H, t, J = 7.0 Hz), 1.08 (3H,
s), 1.00 (3H, s), 0.99 (3H, s); 13C NMR (100 MHz, CDCl3) δ u 175.3,
146.0, 140.6, 139.5, 112.1, 74.3, 73.3, 60.6, 55.4, 51.5, 49.7, 41.6; d 130.8,
128.0, 127.5, 127.0, 90.2, 30.7, 27.3, 23.2, 22.5, 14.2; IR (film, cm-1) 1718,
40.3, 39.5, 31.3; d 83.5, 31.3, 26.4, 24.2, 22.8, 22.7, 14.38; IR (film, cm-1
)
1206, 1453, 1712, 2942, 3519; HRMS calcd for C17H28O3 (M þ H)
281.2117, obsd 281.2121.
(1S,2R,5S)-2-Benzyloxy-1-ethoxycarbonyl-3,3,5-trimethyl-8-(propan-2-
ylidene)bicyclo[3.3.0]octane (17). A mixture of alcohol 15 (2.02 g,
7.20 mmol), benzyloxypyridinium triflate (BnOPT, 3.65 g, 10.44 mmol,
1.45 equiv), and MgO (421 mg, 10.44 mmol, 1.45 equiv) in 14.5 mL
anhydrous dichloroethane (freshly distilled from CaH2) was stirred at
80 °C for 8 h. Additional BnOPT (1.26 g, 3.6 mmol, 0.5 equiv) and MgO
(145 mg, 3.6 mmol, 0.5 equiv) were added, and the mixture was stirred at
80 °C for an additional 8 h. After cooling to room temperature, the
reaction mixture was filtered through Celite to remove precipitates, and
the filter cake was washed thoroughly with Et2O. The filtrate was
concentrated in vacuo and the residue chromatographed to afford
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The Journal of Organic Chemistry
ARTICLE
2928, 3418; HRMS calcd for C24H32O3 (M þ H) 368.2351, obsd
368.2341.
3.08 (0.6H, d, J = 13.8 Hz), 2.97 (0.4H, d, J = 13.5 Hz), 2.64 (1H, m),
2.50 (1H, m), 1.94 (1.8H, s), 1.88-1.78 (2.2H, m), 1.62-1.47 (3H, m),
1.32 (3H, m), 1.07 (6H, m), 0.87 (2H, s), 0.85 (1H, s); 13C NMR (100
MHz, CDCl3) δ u 176.0, 176.0, 145.1, 144.9, 144.4, 142.9, 138.8, 138.3,
125.0, 122.4, 74.9, 74.7, 67.8, 67.8, 67.2, 66.0, 61.4, 60.9, 52.9, 52.6, 52.0,
51.9, 39.2, 39.1, 38.6, 38.5, 32.1, 32.1; d 130.7, 130.4, 129.1, 129.0, 128.0,
127.9, 127.7, 127.5, 127.1, 127.0, 124.2, 123.6, 91.6, 91.4, 32.4, 32.3, 26.2,
26.2, 24.9, 24.7, 22.4, 20.2, 14.2, 14.1; IR (film, cm-1) 1242, 1381, 1451,
1713, 2932; HRMS calcd for C30H38O4S (M þ H) 495.2569, obsd
495.2566.
Isomerization of E-Allylic Sulfoxides (22a,b). A solution of allylic
sulfoxides 22a,b (37 mg, 0.075 mmol) in 1.5 mL of toluene was
irradiated in a microwave reactor (P = 150 W, Tramp = 23-120 °C over
10 min, Thold = 120 °C, 15 min). The reaction material was concentrated
in vacuo and the residue chromatographed to afford Z-allylic sulfoxides
23a,b (7.7 mg, 0.016 mmol, 21% yield) and E-allylic sulfoxides 22a,b
(25.8 mg, 0.052 mmol, 70% recovered yield).
(1S,2R,5S)-E and Z-2-Benzyloxy-1-ethoxycarbonyl-3,3,5-trimethyl-
8-[1-(phenylthio)propan-2-ylidene]bicyclo[3.3.0]octane (21). A mix-
ture of diene 19 (380 mg, 1.03 mmol), thiophenol (115 μL, 1.13 mmol,
1.1 equiv), and silica nanoparticles (SNPs, 19 mg, 5 wt %) in a small vial
was stirred vigorously at room temperature for 18 h. The reaction
mixture was filtered through Celite and concentrated in vacuo. The
residue was chromatographed to afford a 1:1.5 Z:E mixure of allylic
thioethers 21 (412 mg, 0.86 mmol, 84% yield) as a colorless oil: TLC Rf
(PE/MTBE = 100:1) = 0.22; 1H NMR (400 MHz, CDCl3) δ 7.38-6.90
(10H, m), 4.95 (0.4H, d, J = 11.5 Hz, Z-isomer), 4.88 (0.6H, d, J = 11.7
Hz, E-isomer), 4.77 (0.4H, d, J = 11.7 Hz, E-isomer), 4.69 (0.7H, d, J =
11.7 Hz, Z-isomer), 4.43 (1H, m), 4.24-4.09 (2H, m), 3.98 (0.4H, d, J =
11.5 Hz, Z-isomer), 3.66 (0.6H, d, J = 11.1 Hz, E-isomer), 3.44 (0.6H, d,
J = 11.1 Hz, E-isomer), 3.18 (0.4H, d, J = 11.5 Hz, Z-isomer), 2.59-2.37
(2H, m), 1.78 (1.1H, s), 1.64 (1.8H, s), 1.61-1.45 (4H, m), 1.23-1.30
(3H, m), 1.09 (1H, s), 1.04 (3H, s), 1.00 (2H, s), 0.96 (1H, s), 0.94 (2H,
s); 13C NMR (100 MHz, CDCl3) δ u 175.7, 175.5, 140.7, 139.7, 139.6,
140.0, 139.0, 137.9, 127.3, 126.6, 74.6, 74.6, 68.6, 68.0, 60.8, 60.5, 53.0,
52.9, 52.1, 51.8, 49.7, 49.5, 41.0, 40.9, 40.4, 40.3, 39.9, 39.4, 39.0, 38.8,
31.8, 31.0; d 129.4, 128.6, 128.5, 128.1, 128.0, 127.6, 127.8, 127.5, 127.1,
127.0, 125.7, 124.7, 91.8, 91.3, 32.5, 32.2, 26.5, 26.4, 25.0, 24.7, 20.8,
20.4, 14.4, 14.2; IR (film, cm-1) 1218, 1452, 1582, 1714, 2945; HRMS
calcd for C30H38O3S (M þ H) 479.2620, obsd 479.2612.
(1S,2R,5S)-Z-2-Benzyloxy-1-ethoxycarbonyl-3,3,5-trimethyl-8-[1-
(phenylsulfonyl)propan-2-ylidene]bicyclo[3.3.0]octane (24). A mix-
ture of Z-allylic sulfoxides 23a,b (70 mg, 0.142 mmol), aqueous H2O2
(30 wt %, 73 μL, 5.0 equiv), and H2WO4 (3.5 mg, 0.014 mmol, 0.1
equiv) in 700 μL of 1:1 of MeOH/THF was stirred vigorously at room
temperature for 20 h. The reaction mixture was then diluted with
saturated aqueous NaHCO3 and extracted with Et2O. The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo. The
residue was chromatographed to afford Z-allylic sulfone 24 (55 mg,
(1S,2R,5S)-E-2-Benzyloxy-1-ethoxycarbonyl-3,3,5-trimethyl-8-[1-
(phenylsulfinyl)propan-2-ylidene]bicyclo[3.3.0]octane (22a,b) and
(1S,2R,5S)-Z-2-Benzyloxy-1- ethoxycarbonyl-3,3,5-trimethyl-8-[1-(phen-
ylsulfinyl)propan-2-ylidene]bicyclo[3.3.0]octane (23a,b). To a solu-
tion of allylic thioethers 22 (410 mg, 0.86 mmol) in 4.0 mL of CH2Cl2
at -78 °C was added a solution of m-CPBA (148 mg, 0.86 mmol,
1.0 equiv) in 4.6 mL of CH2Cl2 dropwise via syringe over 10 min. The
reaction material was stirred at -78 °C for 30 min and diluted with 5 mL
of saturated aqueous Na2S2O3. The reaction material was diluted with
H2O and extracted with CH2Cl2. The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo. The residue was chromato-
graphed to afford a mixture of E-allylic sulfoxides 22a,b (260 mg, 0.526
mmol, 61% yield) and Z-allylic sulfoxides 23a,b (155 mg, 0.314 mmol,
37% yield, dr = 1.5:1).
0.108 mmol, 76% yield): TLC Rf (PE/EtOAc = 6.5:1) = 0.46; [R]20
=
D
(-) 80.6 (c 1.35 CHCl3);1H NMR (400 MHz, CDCl3) δ 7.77 (2H, d, J
= 7.6 Hz), 7.57 (1H, t, J = 7.4 Hz), 7.48 (2H, t, J = 7.6 Hz), 7.12 (1H, t, J
= 7.3 Hz), 7.05 (2H, t, J = 7.3 Hz), 6.85 (2H, d, J = 7.5 Hz), 4.69 (1H, d, J
= 10.8 Hz), 4.55-4.40 (3H, m), 4.25 (2H, m), 3.33 (1H, d, J = 14.5 Hz),
2.65 (1H, dd, J = 7.9, 16.7 Hz), 2.50 (1H, m), 1.92 (3H, s), 1.90 (1H, m),
1.59-1.48 (3H, m), 1.33 (3H, t, J = 7.0 Hz), 1.09 (3H, s), 1.08 (3H, s),
0.83 (3H, s); 13C NMR (100 MHz, CDCl3) δ u 175.7, 145.8, 141.6,
138.4, 120.1, 74.8, 67.8, 63.5, 61.1, 52.6, 52.0, 39.0, 38.3, 32.2; d 133.0,
129.0, 128.0, 127.5, 127.5, 127.1, 91.4, 32.4, 26.0, 24.9, 20.9, 14.2; IR
(film, cm-1) 1366, 1452, 1730, 2360, 2949; HRMS calcd for C30H38O5S
(M þ Na) 533.2338, obsd 533.2332.
(1R,5R,8S,11R)-11-Benzyloxy-4,8,10,10-tetramethyl-3-phenylsulfon-
yltricyclo[6.3.0.01,5]undec-3-en-2-one (25). To a solution of Et2NH
(220 μL, 1.56 mmol, 14 equiv) in 200 μL of THF at -78 °C was added
n-BuLi (2.09 M, 641 μL, 12.0 equiv). The solution was gradually stirred
to -40 °C, and a solution of Z-allylic sulfone 25 (57 mg, 0.112 mmol) in
300 μL of THF was added dropwise. The reaction was stirred to -20 °C
and quenched with saturated aqueous NH4Cl. The reaction mixture was
diluted with H2O and extracted with Et2O. The combined organic
extracts were combined, dried (Na2SO4), and concentrated in vacuo.
The residue was chromatographed to afford R-sulfonylenone 25 (47 mg,
0.101 mmol, 90% yield) as a viscous oil: TLC Rf (PE/EtOAc = 5:1) =
0.54; [R]20D = (-) 21.8 (c 0.55 CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.05 (2H, d, J = 7.5 Hz), 7.56 (1H, t, J = 7.4 Hz), 7.47 (2H, t, J = 7.4
Hz), 7.27 (3H, m), 6.93 (2H, m), 4.00 (1H, s), 3.98 (1H, d, J = 11.9 Hz),
3.83 (1H, d, J = 11.9 Hz), 3.49 (1H, d, J = 9.8 Hz), 2.62 (3H, s), 2.18
(1H, m), 1.81 (1H, dd, J = 6.7, 13.5 Hz), 1.64-1.54 (2H, m), 1.50 (1H,
d, J = 14.0 Hz), 1.28 (1H, m), 1.05 (3H, s), 0.99 (3H, s), 0.92 (3H, s);
13C NMR (100 MHz, CDCl3) δ u 202.3, 186.6, 140.5, 138.3, 138.3, 73.0,
71.5, 53.9, 50.2, 40.4, 40.1, 27.0; d 133.6, 128.8, 128.2, 128.1, 127.4,
127.1, 91.4, 53.8, 31.9, 26.4, 24.9, 17.6.; IR (film, cm-1) 2957, 2361,
1707, 1604, 1453, 1320, 1154; HRMS calcd for C28H32O4S (M þ H)
465.2100, obsd 465.2090.
E-Allylic Sulfoxide 22a (major). TLC Rf (PE/EtOAc = 5:1) = 0.13;
[R]20D = (-) 24.6 (c 1.79 CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.68
(2H, d, J = 7.6 Hz), 7.40-7.24 (8H, m), 4.80 (1H, d, J = 11.2 Hz), 4.67
(1H, d, J = 11.2 Hz), 4.47 (1H, s), 4.20 (2H, dq, J = 1.7, 7.0 Hz), 3.81
(1H, d, J = 12.2 Hz), 3.43 (1H, d, J = 12.2 Hz), 2.52 (1H, m), 2.25 (1H,
dd, J = 6.8, 16.0), 1.63-1.45 (7H, m), 1.30 (3H, t, J = 7.0 Hz), 1.09 (3H,
s), 1.04 (3H, s), 1.00 (3H, s); 13C NMR (100 MHz, CDCl3) δ u 175.2,
145.3, 144.4, 139.2, 121.5, 75.1, 69.1, 66.8, 60.7, 53.0, 52.2, 40.1, 39.0,
31.6; d 130.8, 128.9, 128.2, 128.0, 127.3, 92.3, 32.3, 26.4, 25.4, 22.5,
14.4; IR (film, cm-1) 1040, 1724, 2936; HRMS calcd for C30H38O4S
(M þ H) 495.2569, obsd 495.2564.
E-Allylic Sulfoxide 22b (minor). TLC Rf (PE/EtOAc = 5:1) = 0.16;
[R]20D = (-) 42.9 (c 0.96 CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.63
(2H, m), 7.45 (3H, m), 7.35-7.29 (4H, m), 7.25 (1H, m), 4.81 (1H, d, J
= 11.5 Hz), 4.67 (1H, d, J = 11.5 Hz), 4.43 (1H, s), 4.19 (2H, m), 3.75
(1H, d, J = 12.8 Hz), 3.44 (1H, d, J = 12.8 Hz), 2.73 (1H, dd, J = 7.4, 15.7
Hz), 2.37 (1H, m), 1.65 (1H, td, J = 7.4, 11.7 Hz), 1.58-1.47 (6H, m),
1.31 (3H, t, J = 7.1 Hz), 1.06 (3H, s), 1.01 (3H, s), 0.90 (3H, s); 13C
NMR (100 MHz, CDCl3) δ u 175.2, 145.2, 144.5, 139.3, 121.9, 74.8,
69.1, 66.5, 60.7, 53.0, 52.4, 40.1, 38.9, 31.5; d 131.0, 129.0, 128.1, 127.7,
127.2, 124.4, 92.0, 32.3, 26.4, 25.2, 22.3, 14.4; IR (film, cm-1) 1036,
1208, 1452, 1714, 2934; HRMS calcd for C30H38O4S (M þ H)
495.2569, obsd 495.2567.
(1R,3S,4R,5R,8S,11R)-11-Benzyloxy-4,8,10,10-tetramethyl-3-phenylsu-
lfonyltricyclo[6.3.0.01,5]undecan-2-one (26) and (1R,3R,4S,5R,8S,11R)-
11-Benzyloxy-4,8,10,10-tetramethyl-3-phenylsulfonyltricyclo[6.3.0.01,5]-
undecan-2-one (27). A mixture of enone 26 (138 mg, 0.30 mmol,
1
Z-Allylic Sulfoxides 23a,b. TLC Rf (PE/EtOAc = 5:1) = 0.25; H
NMR (400 MHz, CDCl3) δ 7.60-6.82 (10H, m), 4.70-4.06 (6H, m),
1880
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The Journal of Organic Chemistry
ARTICLE
1.0 equiv) and Mg turnings (154 mg, 6.34 mmol, 20 equiv) in 5 mL of a
1:1 v/v mixture of MeOH/THF was sonicated at room temperature
until bubbling from the surface of the Mg turnings was visible and
the mixture turned cloudy gray. Small portions of NH4Cl (45 mg,
0.85 mmol, 2.8 equiv/portion) were introduced at 15 min intervals with
continuous sonication until the reaction mixture became cloudy white
(ca. 10 portions, 8.5 mmol NH4Cl). The reaction was quenched with
3 N aqueous HCl (slow addition!) until clear and diluted with H2O. The
biphasic mixture was extracted with Et2O, dried (Na2SO4), and con-
centrated in vacuo. The residue was chromatographed to afford ketones
26 (45.8 mg, 0.098 mmol, 33% yield), 27 (28.7 mg, 0.062 mmol, 21%
yield), and residual enone 25 (60.7 mg, 0.131 mmol, 44% recovered).
Ketone 26 (major diastereomer): TLC Rf (PE/EtOAc = 6.6:1) = 0.52;
[R]20D = (þ) 30 (c 0.4 CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.00
(dd, J = 8.4, 1.3 Hz, 2H), 7.57 (d, J = 7.4 Hz, 1H), 7.50 (dd, J = 8.1, 6.7
Hz, 2H), 7.36-7.28 (m, 5H), 4.21 (d, J = 11.6 Hz, 1H), 4.08 (d, J = 11.6
Hz, 1H), 3.82 (s, 1H), 3.72 (d, J = 13.0 Hz, 1H), 3.30-3.22 (m, 1H),
2.84-2.69 (m, 1H), 1.99-1.88 (m, 2H), 1.59-1.48 (m, 2H), 1.42 (dd,
J = 11.6, 7.3 Hz, 1H), 1.37 (d, J = 6.7 Hz, 3H), 1.30 (d, J = 13.5 Hz, 1H),
1.06 (s, 3H), 0.90 (s, 3H), 0.77 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ u 211.8, 138.9, 138.5, 73.8, 73.4, 54.4, 52.1, 42.8, 42.6, 27.6; d 133.8,
129.5, 128.8, 128.2, 127.8, 127.5, 92.7, 73.7, 49.0, 33.1, 30.6, 26.3, 22.9,
16.8; IR (film, cm-1) 2931, 1729, 1455, 1312, 1149, 1084; HRMS calcd
for C28H34O4S (M þ Na) 489.2076, obsd 489.2054.
The crude filtrate was taken up in triethylene glycol (400 μL) and
hydrazine monohydrate (100 μL, 0.1 mmol, 12 equiv). The reaction
material was stirred at 130 °C for 2 h. KOH (2 mg, 0.04 mmol, 4 equiv)
was added, and the reaction mixture was stirred at 140 °C for 6 h. After
cooling to room temperature, the mixture was diluted with H2O and
extracted with Et2O. The combined organic fractions were dried
(Na2SO4) and concentrated in vacuo.
The crude concentrate was then diluted with 0.5 mL of EtOH, and
10% Pd/C (ca. 5 mg) was added. The reaction mixture was stirred
vigorously under H2 (balloon) for 2.5 h at room temperature. The
reaction material was filtered through Celite and concentrated in vacuo
to afford epi-2 (0.5 mg, 26% yield from 26): TLC Rf (PE/MTBE = 20:1)
= 0.28; 1H NMR (400 MHz, CDCl3) δ 3.46 (br s, 1H), 2.51 (dd, J =
15.1, 7.4 Hz, 1H), 1.94-1.82 (m, 2H), 1.61 (m, 2H), 1.52-1.36
(m, 5H), 1.32 (m, 2H), 1.02 (s, 3H), 1.01 (s, 3H), 0.97 (s, 3H), 0.94
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ u 66.7, 53.2, 49.1,
42.9, 39.6, 34.2, 32.6, 24.3; d 89.2, 49.7, 39.3, 31.6, 26.4, 23.3, 15.8. These
data were congruent with those previously reported.3b
(1S,2R,5S,8S,9R)-3,3,5,9-Tetramethyltricyclo[6.3.0.01,5]undecan-2-
ol: (-)-cameroonan-7R-ol (2). A mixture of ketone 28 (12 mg, 0.037
mmol), anhydrous N2H4 (38 μL, 1.22 mmol, 33 equiv), and KOH
(34 mg, 0.61 mmol, 16 equiv) was stirred at 170-180 °C for 18 h in a
sealed vial. The reaction material was diluted with 5% aqueous NaOH
and extracted with Et2O. The combined organic extracts were dried
(Na2SO4), concentrated in vacuo, and filtered through a short plug of
silica gel.
The crude material was diluted with 200 μL of dry THF and cooled to
-78 °C. Liquid NH3 (ca. 1 mL) was condensed into the reactor, and a
single piece of Na (ca. 50 mg, 2.17 mmol) was added. The blue reaction
solution with blue foam was stirred at -78 °C for 10 min, and MeOH
was slowly added to dissipate the blue color. Excess NH3 was removed
by warming the reaction to room temperature. The reaction material
was then concentrated in vacuo and chromatographed to afford
(-)-cameroonan-7R-ol 2 (2.0 mg, 24% yield): TLC Rf (PE/MTBE =
20:1) = 0.35; [R]20D = (-) 37 (c 0.10 CHCl3); 1H NMR (400 MHz,
CDCl3) δ 3.69 (s, 1H), 1.90 (t, J = 8.0 Hz, 1H), 1.84-1.72 (m, 1H),
1.69-1.58 (m, 2H), 1.55 (d, J = 14.3 Hz, 1H), 1.52-1.47 (m, 1H),
1.44-1.38 (m, 3H), 1.41 (d, J = 14.2 Hz, 1H), 1.36-1.29 (m, 1H), 1.25
(t, J = 5.3 Hz, 1H), 1.04 (s, 3H), 1.00 (d, J = 6.6 Hz, 3H), 0.97 (s, 3H),
0.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ u 67.1, 52.6, 47.5, 39.9,
38.6, 36.1, 35.3, 29.0; d 89.7, 51.3, 43.8, 32.5, 25.7, 23.9, 19.4; IR (film,
cm-1) 3485, 2932, 2866, 1459; GC-MS (EI, 70 eV) m/z (rel. intensity
%) 222 (2), 204 (18), 189 (14), 166 (25), 148 (32), 135 (100), 124 (33),
109 (24); HRMS calcd for C15H25 (M - OH) 205.1956, obsd 205.1955.
Ketone 27 (minor diastereomer): TLC Rf (PE/EtOAc = 6.6:1) =
0.56; [R]20D = (-) 45.5 (c 0.22 CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.91-7.87 (m, 2H), 7.71-7.64 (m, 1H), 7.62-7.56 (m, 2H), 7.24
(dd, J = 5.0, 1.9 Hz, 3H), 7.15 (dd, J = 6.8, 2.8 Hz, 2H), 4.48 (d, J = 11.8
Hz, 1H), 4.14 (d, J = 11.8 Hz, 1H), 3.88 (s, 1H), 3.13 (d, J = 11.1 Hz,
1H), 2.60-2.54 (m, 1H), 2.45-2.33 (m, 1H), 2.14-2.01 (m, 1H),
1.74-1.66 (m, 1H), 1.62 (d, J = 14.1 Hz, 1H), 1.59-1.54 (m, 2H), 1.52
(d, J = 14.1 Hz, 1H), 1.29 (d, J = 6.6 Hz, 3H), 1.10 (s, 3H), 0.99 (s, 3H),
0.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ u 212.2, 138.8, 138.4, 75.9,
74.2, 55.8, 54.7, 41.8, 41.5, 30.8; d 133.9, 129.4, 128.8, 128.3, 127.6,
127.5, 95.5, 77.2, 49.8, 36.7, 32.1, 27.2, 24.0, 20.9; IR (film, cm-1) 2957,
1730, 1455, 1313, 1149, 1086; HRMS calcd for C28H34O4S (M þ Na)
489.2076, obsd 489.2061.
(1R,4S,5R,8S,11R)-11-Benzyloxy-4,8,10,10-tetramethyltricyclo-
[6.3.0.01,5]undecan-2-one (28). To a solution of R-sulfonyl ketone 27
(22 mg; 0.047 mmol) in 400 μL of dry THF at -78 °C (thoroughly
purged with N2) was added SmI2 (2.35 mL of 0.1 M stock solution in
THF, 0.235 mmol, 5.0 equiv) rapidly via syringe. The reaction material
was stirred for 10 min at -78 °C and brought to room temperature in
the presence of O2. The reaction material was then concentrated in
vacuo and chromatographed to afford ketone 28 (14.1 mg, 0.043 mmol,
92% yield): TLC Rf (PE/MTBE = 10:1) = 0.67; [R]20 = (þ) 6.2
’ ASSOCIATED CONTENT
D
(c 0.65 CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35-7.23 (m, 5H),
4.46 (q, J = 11.7 Hz, 2H), 4.06 (s, 1H), 2.68 (ddd, J = 7.4, 5.2, 2.1 Hz,
1H), 2.42 (dd, J = 19.5, 10.5 Hz, 1H), 2.19-2.08 (m, 1H), 1.87 (dd, J =
19.1, 6.8 Hz, 1H), 1.88-1.83 (m, 1H), 1.61 (d, J = 13.9 Hz, 1H), 1.70-
1.52 (m, 3H), 1.47 (d, J = 13.8 Hz, 1H), 1.10 (s, 3H), 1.03 (s, 3H), 0.99
(m, 6H); 13C NMR (100 MHz, CDCl3) δ u 222.7, 138.9, 73.8, 73.7,
54.9, 53.3, 47.6, 42.3, 41.2, 31.6; d 128.2, 127.5, 127.3, 92.3, 51.7, 34.3,
31.9, 27.1, 24.0, 21.2; IR (film, cm-1) 2953, 1727, 1458, 1109; HRMS
calcd for C22H30O2 (M þ Na) 349.2144, obsd 349.2149.
S
Supporting Information. General experimental proce-
b
dures and 1H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: taberdf@udel.edu.
(1S,2R,5S,8S,9S)-3,3,5,9-Tetramethyltricyclo[6.3.0.01,5]undecan-2-ol;
C-9-epi-cameroonan-7R-ol (epi-2). To a solution of R-sulfonyl
ketone 26 (4 mg, 8.6 μmol) in 200 μL of dry THF at -78 °C was
added SmI2 (0.1 M stock solution in THF, 1.0 mL, 0.1 mmol) rapidly via
syringe. The reaction solution was stirred at -78 °C for 10 min and
brought to room temperature in the presence of O2. The reaction
material was concentrated in vacuo and filtered through a short plug of
silica gel.
’ ACKNOWLEDGMENT
We thank Mr. John Dykins for mass spectrometric measure-
ments, supported by the NSF (0541775), Dr. GlennYap for the
X-ray analysis, Dr. Shi Bai for NMR assistance (NSF CRIF:MU,
CHE 0840401), and the NIH (GM42056) for financial support.
1881
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The Journal of Organic Chemistry
ARTICLE
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