Nickel-mediated reductive coupling of neopentyl bromides with activated alkenes at room temperature and its synthetic application

Article abstract of DOI:10.1016/j.tet.2019.06.034

Reductive coupling of sterically hindered neopentyl bromides with activated alkenes mediated by the in situ generated Ni(0) complexes along with some feedstock is achieved in good yield under the mild conditions. This practically useful method of C(sp³)?C(sp³) bond formation provides a complementary approach to the traditional conjugate addition of preformed organometallic reagents to electrophilic olefins, which often requires cryogenic temperature and rigorous exclusion of air and moisture. The robust application of this reductive coupling reaction was demonstrated in a formal synthesis of stereodivergent (?)-copacamphor and (?)-ylangocamphor, which are valuable intermediates for a class of tricyclo[5.3.0.0^3,8]decane sesquiterpenes. Moreover, this convenient protocol resulted in a facile access to the homolog of Corey aldehyde en route to prostaglandins, implying the possible involvement of radical-like species.

Full text of DOI:10.1016/j.tet.2019.06.034

Accepted Manuscript
Nickel-mediated reductive coupling of neopentyl bromides with activated alkenes at
room temperature and its synthetic application
Ouyang Yan, Yu Peng, Wei-Dong Z. Li
PII:
S0040-4020(19)30696-9
https://doi.org/10.1016/j.tet.2019.06.034
TET 30426
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 May 2019
Revised Date: 17 June 2019
Accepted Date: 20 June 2019
Please cite this article as: Yan O, Peng Y, Li W-DZ, Nickel-mediated reductive coupling of neopentyl
bromides with activated alkenes at room temperature and its synthetic application, Tetrahedron (2019),
doi: https://doi.org/10.1016/j.tet.2019.06.034.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Nickel-mediated reductive coupling of
neopentyl bromides with activated alkenes at
room temperature and its synthetic
application
Leave this area blank for abstract info.
Yan Ouyang, Yu Peng,* and Wei-Dong Z. Li*

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Nickel-mediated reductive coupling of neopentyl bromides with activated alkenes at
room temperature and its synthetic application
Yan Ouyang a, Yu Peng b, and Wei-Dong Z. Li b, *
a Key Lab of Natural Product Chemistry and Application, Yili Normal University, Yining 835000, China.
b School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Reductive coupling of sterically hindered neopentyl bromides with activated alkenes mediated
by the in situ generated Ni(0) complexes along with some feedstock is achieved in good yield
under the mild conditions. This practically useful method of C(sp3)−C(sp3) bond formation
provides a complementary approach to the traditional conjugate addition of preformed
organometallic reagents to electrophilic olefins, which often requires cryogenic temperature and
rigorous exclusion of air and moisture. The robust application of this reductive coupling reaction
Available online
was demonstrated in
a formal synthesis of stereodivergent (–)-copacamphor and (–)-
Keywords:
Neopentyl bromide
Nickel
Reductive coupling
Radical
ylangocamphor, which are valuable intermediates for a class of tricyclo[5.3.0.03,8]decane
sesquiterpenes. Moreover, this convenient protocol resulted in a facile access to the homolog of
Corey aldehyde en route to prostaglandins, implying the possible involvement of radical-like
species.
2009 Elsevier Ltd. All rights reserved
.
Synthesis
1. Introduction
yield at 60 °C after 36 h, the inherent danger and inconveniency
of this protocol (e.g., Ni(CO)4 is a volatile, flammable, highly
toxic liquid,11 and its preparation and subsequent reaction is
needed to run in nonpolar and polar solvents respectively) limited
its practical utilization. Even in their hands, the yield of this
transformation was poor and irreproducible, hence they
abandoned this procedure eventually and utilized an umpolung
route involving cyanation, alkylation and decyanation12a in the
total synthesis of (+)-longifolene.12b Consequently, an effective
alkylation approach of neopentyl halides is still in high demand.
The notorious steric hindrance of neopentyl halides is
typically demonstrated in bimolecular nucleophilic substitution
reactions (SN2).1 The extreme difficulty resulting from ‘backside
attack’ of the electrophilic carbon in this kind of halides by the
nucleophile, had been demonstrated by Ingold and co-workers in
a series of seminal papers about kinetic studies,2,3 and further
approved by computational studies later.2f,4 The limited
successful examples mainly focused on the cases with hetero-
2b−d,5
rather than carbon nucleophiles. An alternative nucleophilic
a) Prior study: reductive coupling of alkyl bromides with ArI (ref. 16)
displacement reactions via unimolecular process (SN1) also could
give corresponding products; however, more favourable
carbocation rearrangement2e,6 always accompanied in most of
cases.
I
Ralkyl
Zn
Ralkyl Br
+
FG
FG
Ni(0)•2EC•Py
In a synthetic project, we needed to realize homologation of
(+)-8-bromocamphor ethylene ketal 1. Many attempts such as
enolate alkylation and direct cross–coupling failed,7 which
should be attributed to the remarkable steric encumbrance
embedded this neopentyl structure. We then turned to conjugate
addition reaction promoted by n-Bu3SnH or Zn/Cu couple,8 but
both of them still cannot effectively work on this unique substrate
since competitive reduction of the bromide 1 was predominant.
Although Money and co-workers9 had realized a cross–coupling
between (–)-8-iodocamphor and an π-allyl Ni complex10
b) This work: radical addition of neopentyl bromide
9
8
Br
O
Zn, NiCl2•6H2O
CO2Me
+
Pyridine
CO2Me
O
O
via
O
( )-2a (80%)a
N
( )-1
OMe
MeO
O
gram scale
Ni
Ni(0)•2MA•Py
O
[generated from prenyl bromide and 8 equiv of Ni(CO)4] in 40%
———
Corresponding author. E-mail address: pengyu@swjtu.edu.cn (Y. Peng); wdli@swjtu.edu.cn (W.-D. Z. Li)

ACCEPTED MANUSCRIPT
2
Tetrahedron
Scheme 1. A transferable ligand enables reductive coupling of
neopentyl bromide. [a] A yield of 73% was obtained under 10
mol % Ni condition.
Direct cross-electrophile coupling has already emerged as an
advantageous method for the formation of C−C bonds. It can
avoid some problems associated with preformed organometallic
reagents which are inevitable in conventional cross-coupling of a
nucleophile with an electrophile, therefore leading to generally
excellent functional-group compatibility. A noteworthy advance
is Ni-catalyzed reductive coupling of the challenging unactivated
alkyl halides.13−16 Recently, Weix13a and Gong14a,d,f developed bi-
or tridentate amine ligated Ni complex-catalyzed reactions
toward C(sp3)−C(sp2) and C(sp3)−C(sp3) bond construction, and
these catalytic systems had been further expanded to couplings of
acyl halides13b,14b,c and allyl acetates14d,e with alkyl halides under
reductive conditions. In particular, Ni/(R,R)-diphenyl-Box-
catalyzed asymmetric reductive acyl cross-coupling with
secondary benzyl chlorides had been reported by Reisman;15a
Ni/PCy3-catalyzed reductive carboxylation of benzyl halides with
CO2 had also been realized by Martin.15b More importantly,
Weix13c provided an elegant mechanism insight to this kind of
cross-electrophile couplings, which would enable rational
improvement and reliable application of this strategy.
Independently, we16 have disclosed inter- and unprecedented
intramolecular reductive coupling reactions catalyzed by
Ni(0)•2EC•Py (Scheme 1a: EC = ethyl crotonate; Py = pyridine),
where EC act as π-ligands to Ni and plays an important role on
those transformations with unactivated alkenes. Herein, switch of
this unique ligand (EC) to methyl acrylate (MA) led to a
formation of Ni(0)•2MA•Py complex, which eventually solved
the problem mentioned above and achieved carbon chain
elongation of (+)-1 (Scheme 1b). The resulting (–)-2a could be
easily converted to (–)-11a and (–)-11b, thereby constituting a
formal synthesis of tricyclic sesquiterpenoids (–)-copacamphor
and (–)-ylangocamphor (vide infra). Moreover, several other
electron-deficient olefins were suitable as well, and the generated
analogous Ni complexes promoted reductive coupling of various
neopentyl bromides successfully. The hypotheses involving
radical species were supported by the radical clock experiments
and an efficient synthesis of Corey aldehyde homolog 8.
Scheme 2. Reductive couplings of various neopentyl bromides
and activated olefins.
Other Ni(0) complexes can be prepared in analogy to the
protocol for Ni(0)•2MA•Py, and therefore provided
corresponding addition products in modest to good yields
(Scheme 2). For example, the Ni(0) complex derived from
methyl α-methyl acrylate (MMA) also promoted the reductive
coupling with (+)-1, and 2b as a pair of diastereomers could be
obtained in 78% yield. This convergent and high yielding
synthesis is advantageous compared to the usual methylation of
ester (–)-2a because the latter would suffer from over
methylation. The Ni(0) complex with MMA as ligands also
reductively coupled with (+)-9-bromocamphor ethylene ketal,21
affording ester 3b in 70% yield. Especially, the reaction of this
bromide mediated by the Ni(0) complex generated from more
sterically demanding ethyl α-isopropyl acrylate also proceeded
smoothly, and the corresponding 3c was obtained in 76% yield.
More reactive enones20,22 such as methyl vinyl ketone was
certainly suitable activated alkene for the reductive coupling of
(+)-1, thus delivering the expected ketone (–)-2c in 55% isolated
yield. Besides chiral bromides with a bicyclo[2.2.1] skeleton,
other simple neopentyl bromides also could participate the
reductive couplings with MA, as exemplified in the cases of
4a~4c. Additionally, the successful syntheses of piperidine 4d
and tetrahydropyrroles (4e and 4f) demonstrated mild nature of
the present conditions since none of halides with nitrogen-
containing heterocycles was involved in the related previous
reactions.17−20,22 Some features of the present system are
noteworthy: the described Ni(0) complexes can be generated
from air-stable and moisture-insensitive chemicals including
ligands, hence none of glove box and anhydrous operation is
necessary; the reductive couplings proceed rapidly at room
temperature; the reactions are easily scaled up without significant
loss of the efficiency.
2. Results and discussion
As shown in Scheme 1b and the Experimental Section, once
subjection of (+)-1 to red-brown Ni(0)•2MA•Py complex in situ
generated
from
a
mixture
of
regular
Zn/NiCl2•6H2O/pyridine/methyl acrylate,17 the desired reductive
coupling reaction was smoothly completed within 0.5 hour at
room temperature, and ester (−)-2a was isolated in 80% yield.
Notably, the efficiency of this transformation remains to be
almost identical on a scale of 30 mmol. The reaction catalyzed by
the above complex generated from 10 mol% NiCl2 could also
proceed under otherwise identical conditions, and 73% yield of
(−)-2a can be obtained although the reaction time is very long (4
days) compared with that of the stoichiometric version. To our
surprise, this unique Ni(0) complex did not receive much
attention, and known utilization focused on the side chain
elongation of C-22 steroidal iodide18 and glycosyl bromides.19 To
the best of our knowledge, reductive coupling of neopentyl
bromides with MA has not been reported to date.20 This fact
prompted us to investigate more cases with respect to this kind of
challenging substrates and further expand to diverse conjugate
additions with other activated alkenes. Given the availability of
this Ni(0) complex from benchtop and very cheap materials, the
stoichiometric reaction conditions were employed for the
following studies.
The next radical clock experiments23 indicated that radical
species generated from the bromides by SET process24 with Ni(0)
complexes may be involved in the above reductive couplings. As
shown in Scheme 3, subjection of (3-phenylcyclopropyl)methyl
bromide25 to Ni(0)•2MA•Py furnished product 5 in 40% isolated
yield via regioselective radical rearrangement and subsequent
conjugate addition to MA, accompanying with equal amounts of
homocoupling product from favourable dimerization of the
resulting benzyl radical. The reaction of 6-iodo-1-hexene13c,26

ACCEPTED MANUSCRIPT
3
mediated by this Ni complex also worked well, and radical
cyclization-coupling product 6 and direct addition product 6′ as
an inseparable mixture (1:1.6) were obtained accordingly.
Interestingly, when Zn/NiCl2•6H2O/pyridine were mixed and
heated at 50 °C for 20 min followed by the addition of (+)-1 and
MA, almost no formation of (−)-2a could be observed. This
result highlighted the dual critical roles of MA as not only the
reactive Michael acceptor but also the efficient η2 ligand27 to
Ni(0). This mechanism is different from that of allylnickel(II)
intermediates, where the enone had been proved to be a η3 ligand
assisted by Et3SiCl in the investigation by Weix.22
respective subjection of these two bromohydrins to K2CO3
afforded both epoxyketones (+)-10a and (+)-10b in
diastereomerically pure form, which set the stage for
intramolecular nucleophilic ring-opening promoted by
carbanion33 and can compare the difference of their cyclization
behaviors.34 Stereospecific cyclization of (+)-10a finished rapidly
in the methylsulfinyl sodium solution35 even at room
temperature, providing tricyclic keto-alcohol (–)-11a in 81%
isolated yield, whose stereochemistry was unambiguously
confirmed by single-crystal X-ray diffraction analysis (Figure
1).32 However, the 6-exo-tet cyclization of (+)-10b needed to
raise temperature to 70 °C and prolong reaction time to 5 h, and
the corresponding (–)-11b was isolated in only 50% yield. It is
noteworthy that stereodivergent (–)-11a and (–)-11b could be
easily converted to (–)-copacamphor and (–)-ylangocamphor,
(40%)
Ph
CO2Me
Ph
Br
Ni(0)•2MA•Py
SET
Ph
5
two valuable intermediates en route to
a
class of
tricyclo[5.3.0.03,8]decane sesquiterpenes.9,12b Not only the
stereochemistry but also substituents36 of the epoxide would exert
the influence on cyclization. When H is substituted by Me at
C(12), regioselective cyclization of tetrasubstituted epoxide (+)-
12a could also take place albeit under the rather harsh condition
(see Experimental Section), and the desired product (–)-1332 with
an all-carbon quaternary stereocenter was obtained in 67%
isolated yield.
Ph
I
CO2Me
CO2Me
Ni(0)•2MA•Py
(55%, 1:1.6)
6
+
6'
Scheme 3. Radical clock experiments.
Further support for the plausible radical mechanism came
from the following tin-free synthesis toward Corey aldehyde
analogue for an access to prostaglandins (PGs).28 Inspired by
Stork’s classic radical cyclization–trapping strategy featuring
stereocontrolled formation of two adjacent carbon centers in
PGs,29a,b later the modifications by Keck29c and Scheffold,29d and
the recent extension by Oshima,29e β-halo acetals 7 that is readily
available from cis-2-cyclopentene-1,4-diol monosilyl-ether30 was
subjected to Ni(0)•2MA•Py complex (Scheme 4). Two
inconsequential epimers 8 (dr = 2:1) were produced in fairly
good yields compared to those of previous approaches. It is
noteworthy that methyl esters 8 could be viewed as a new two-
carbon homologation of well-known Corey aldehyde, and served
as another potentially useful precursor to prostaglandins such as
PGF2α (DinoprostTM
(XalatanTM).31
)
and analogs such as Latanoprost
Scheme 5. Stereospecific synthesis of diastereomeric
epoxyketones 10a,b and respective cyclization.
Scheme 4. Stereoselective synthesis of a potential precursor for
PGF2α by tandem cyclization−coupling.
Application of reductive coupling product of neopentyl
bromide (+)-1 was demonstrated in Scheme 5. With sufficient
amounts of methyl ester (–)-2a in hand, its conversion to (+)-
campherenone 9 was straightforward: the addition by MeLi, ketal
hydrolysis and dehydration of the resulting tertiary alcohol; the
whole protocol needed only one column chromatography
purification, and the overall yield of 74% was achieved. Since
direct epoxidation of (+)-9 with m-CPBA didn’t afford either of
the single diastereomer (+)-10a or (+)-10b, we first utilized NBS
to obtain diastereomeric bromohydrins, which can be separated
by careful column chromatography (see Experimental Section),
and absolute stereochemistry of more polar diastereomer (–)-9b
was determined by X-ray crystallographic structure.32 The
Figure 1. X-ray crystal structure of (−)-11a.
3. Conclusion
We have demonstrated in this work a solution on the effective
alkylation of various neopentyl bromides with steric bulk by
means of Ni(0)•2MA•Py complex and analogues-initiated
reductive conjugate addition reactions. As an application of this

ACCEPTED MANUSCRIPT
4
Tetrahedron
alternative C–C coupling protocol, three-carbon homologation
1.80–1.60 (m, 1H), 1.58–1.42 (m, 1H), 1.40–1.38 (m, 2H), 1.37–
1.15 (m, 2H), 1.16 (d, J = 7.2 Hz, 3H), 1.09–0.95 (m, 1H), 0.83
(s, 3H), 0.78 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ =
177.4, 116.9, 64.8, 63.5, 53.3, 51.3, 50.8, 44.2, 41.5, 40.0, 30.4,
30.1, 29.7, 26.6, 17.1, 16.4, 9.8 ppm; (the other isomer) δ =
177.5, 64.9, 44.1, 41.6, 40.2, 29.5 ppm, other signals are
product (–)-2a allowed rapid access to a class of sesquiterpenes
with an unique tricyclo[5.3.0.03,8]decane skeleton. In addition to
the radical clock experiments, the realization of a synthesis of a
potentially useful precursor 8 to PGF2α provided supportive
evidences for the plausible radical-associated mechanism.
Extension studies toward the other type of halides37 and activated
alkenes or ligands38 are currently ongoing, and those results will
be reported in due course.
inseparable; HRMS (ESI): calcd. for C17H29O4 [M+H]+:
+
297.2060, found: 297.2057.
(–)-2c was prepared as a colorless oil (55% yield) according to
the general procedure. Rf = 0.41 (petroleum ether/EtOAc = 6 : 1);
[α]1D6 = –10 (c = 1.5, CHCl3); IR (film): νmax = 2950, 2877, 1715,
1450, 1362, 1112, 1044, 951 cm–1; 1H NMR (300 MHz, CDCl3):
δ = 3.94–3.72 (m, 4H), 2.43 (t, J = 6.9 Hz, 2H), 2.14 (s, 3H),
1.95–1.81 (m, 4H), 1.72–1.59 (m, 2H), 1.52–1.35 (m, 3H), 1.25–
1.15 (m, 1H), 1.08–0.95 (m, 1H), 0.86 (s, 3H), 0.78 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3): δ = 209.7, 117.3, 65.2, 64.8, 53.6,
51.4, 45.0, 44.6, 41.9, 32.7, 30.2, 29.9, 26.9, 20.0, 16.7, 10.1
ppm; EI−MS (70 eV): m/z (% relative intensity) 266 (M+, 14.3),
251 (1.1), 181 (10), 155 (17), 147 (16), 125 (100), 113 (27), 95
4. Experimental section
4.1. General
For product purification by flash column chromatography,
silica gel (200~300 mesh) and petroleum ether (bp 60~90 °C)
were used. All solvents were purified and dried by standard
techniques, and distilled prior to use. Organic extracts were dried
over MgSO4 or Na2SO4, unless otherwise specified. Experiments
were conducted under an argon or nitrogen atmosphere in oven-
dried or flame-dried glassware with magnetic stirring, unless
otherwise noted. NMR spectra were measured on 200, 300 and
400 MHz instruments at room temperature. EI−MS was obtained
on GC/MS QP-2010 SE. High-resolution mass spectral data were
measured with electrospray ionization (ESI), atmosphere
pressure chemical ionization (APCI) and secondary ion mass
spectroscopy (SIMS). Infrared spectra were recorded on an FT-
IR spectrophotometer. The X-ray diffraction studies were carried
out on a Bruker SMART Apex CCD area detector diffractometer
equipped with graphite-monochromated Mo-Kα radiation source.
Melting points were measured on Kofler hot stage and are
uncorrected.
(69); HRMS (ESI): calcd. for C16H27O3 [M+H]+: 267.1955,
found: 267.1963.
+
(+)-3a was prepared as a colorless oil (78% yield) according
to the general procedure. Rf = 0.51 (petroleum ether/EtOAc = 6 :
1); [α] 2D0 = +3 (c = 1.6, CHCl3); IR (film): νmax = 2952, 2877,
1739, 1455, 1438, 1259, 1119, 1047 cm–1; H NMR (300 MHz,
1
CDCl3): δ = 3.94–3.90 (m, 1H), 3.88–3.76 (m, 2H), 3.73–3.69
(m, 1H), 3.67 (s, 3H), 2.30 (t, J = 7.2 Hz, 2H), 2.01–1.82 (m,
2H), 1.78–1.48 (m, 2H), 1.44–1.30 (m, 3H), 1.25–1.16 (m, 3H),
1.06–0.95 (m, 1H), 1.03 (s, 3H), 0.78 (s, 3H) ppm; 13C NMR (75
MHz, CDCl3): δ = 174.2, 117.3, 65.0, 63.6, 53.2, 50.8, 44.4, 42.0,
34.9, 32.6, 29.7, 29.5, 26.5, 20.1, 16.7, 9.8 ppm; HRMS (APCI):
calcd. for C16H27O4+ [M+H]+: 283.1904, found: 283.1903.
4.2. General procedure for the reductive cross-coupling reaction
promoted by the Ni(0) complex
3b was prepared as a colorless oil (70% yield, d.r. = 1:1)
according to the general procedure. Rf
= 0.55 (petroleum
ether/EtOAc = 6 : 1); IR (film): νmax = 2951, 2877, 1737,
To a stirred slurry of Zn (390 mg, 6 mmol) in regular pyridine
(3 mL) was added the electron-deficient alkene (6 mmol) at room
temperature. Under vigorous stirring, NiCl2•6H2O (475 mg, 2
mmol) was added to the above mixture. The temperature then
rose to 50 °C, and stirring was continued for 20 min. The
resulting red-brown Ni(0) complex was cooled to room
temperature, and a solution of the alkyl bromide (2 mmol) in
pyridine (1 mL) was added dropwise. The mixture was stirred for
0.5 h, and then filtered with a short plug (elution with 50 mL of
Et2O) and washed with HCl (1N), water and brine, dried over
MgSO4, filtered and concentrated. The crude product was
purified by flash chromatography on silica gel to afford desired
ester products.
1
1458, 1379, 1319, 1198, 1121, 1048, 967, 845 cm–1; H
NMR (300 MHz, CDCl3):
δ = 3.95–3.90 (m, 1H), 3.88–3.78
(m, 2H), 3.75–3.71 (m, 1H), 3.68 (s, 3H), 2.43–2.34 (m,
1H), 2.02–1.90 (m, 2H), 1.88–1.83 (m, 1H), 1.80–1.67 (m,
1H), 1.65–1.49 (m, 2H), 1.47–1.25 (m, 3H), 1.23–1.15 (m,
1H), 1.15 (d,
J = 7.2 Hz, 3H), 1.04–0.94 (m, 1H), 1.01 (s,
3H), 0.78 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
δ
=
177.2, 117.3, 64.9, 63.6, 53.2, 51.5, 50.7, 44.3, 41.8, 40.1,
30.1, 29.5, 28.7, 26.5, 17.0, 16.6, 9.8 ppm; (the other
isomer) δ = 40.3, 30.4, 28.8, 17.3 ppm, other signals are
+
inseparable; HRMS (ESI): calcd. for C17H29O4 [M+H]+:
297.2060, found: 297.2057.
3c was prepared as a colorless oil (76% yield, d.r. = 1:1)
(–)-2a was prepared as a colorless oil (80% yield) according
to the general procedure. Rf = 0.51 (petroleum ether/EtOAc = 6 :
1); [α]1D5 = –11 (c = 0.7, CHCl3); IR (film): νmax = 2951, 2877,
according to the general procedure. Rf
= 0.67 (petroleum
ether/EtOAc = 6 : 1); IR (film): νmax = 2960, 2876, 1730,
1
1452, 1375, 1318, 1121, 1046, 967 cm–1; H NMR (300
1
1740, 1439, 1264, 1174, 1042, 952 cm–1; H NMR (300 MHz,
MHz, CDCl3):
δ = 4.20–4.10 (m, 2H), 3.94–3.91 (m, 1H),
CDCl3): δ = 3.93–3.67 (m, 4H), 3.64 (s, 3H), 2.28 (t, J = 7.5 Hz,
2H), 1.92–1.83 (m, 3H), 1.76–1.53 (m, 2H), 1.51–1.42 (m, 1H),
1.40–1.30 (m, 2H), 1.22–0.96 (m, 3H), 0.83 (s, 3H), 0.76 (s, 3H)
ppm; 13C NMR (50 MHz, CDCl3): δ = 174.3, 117.0, 64.9, 64.5,
53.3, 51.4, 51.0, 44.2, 41.6, 35.0, 32.5, 29.6, 26.6, 21.0, 16.5, 9.8
ppm; EI−MS (70 eV): m/z (% relative intensity) 282 (M+, 11),
251 (5.4), 194 (8), 181 (17), 149 (10), 125 (100), 95 (85); HRMS
3.88–3.80 (m, 2H), 3.78–3.72 (m, 1H), 2.05–1.92 (m, 2H),
1.88–1.80 (m, 2H), 1.74–1.50 (m, 2H), 1.48–1.33 (m, 4H),
1.29–1.14 (m, 3H), 1.26 (d,
0.94 (d, = 7.8 Hz, 3H), 0.92 (d,
3H) ppm; 13C NMR (75 MHz, CDCl3):
J
= 6.9 Hz, 3H), 1.01 (s, 3H),
= 6.3 Hz, 3H), 0.77 (s,
= 175.7, 117.3,
J
J
δ
64.9, 63.6, 59.8, 53.6, 53.2, 50.8, 44.3, 41.8, 30.9, 30.7,
30.5, 29.5, 26.6, 24.6, 20.5, 16.7, 14.4, 9.8 ppm; (the other
+
(SIMS): calcd. for C16H27O4 [M+H]+: 283.1904, found:
isomer) δ = 175.8, 29.4, 26.3, 20.3, 16.6 ppm, other signals
283.1910.
+
are inseparable; HRMS (SIMS): calcd. for C20H35O4
[M+H]+: 339.2530, found: 339.2540.
2b was prepared as a colorless oil (78% yield, d.r. = 1:1)
according to the general procedure. Rf = 0.47 (petroleum
ether/EtOAc = 6 : 1); IR (film): νmax = 2950, 2877, 1737, 1456,
1380, 1320, 1305, 1268, 1247, 1196, 1171, 1152, 1121, 1046,
1023, 971, 843 cm–1; 1H NMR (300 MHz, CDCl3): δ = 3.97–3.71
(m, 4H), 3.70 (s, 3H), 2.41–2.36 (m, 1H), 2.00–1.82 (m, 4H),
4a39 was prepared as a colorless oil (72% yield) according
to the general procedure. Rf
= 0.55 (petroleum ether/EtOAc
= 8 : 1); IR (film): νmax = 2956, 2870, 1743, 1470, 1437,
1
1364, 1253, 1207, 1173, 1069, 1014 cm–1; H NMR (300

ACCEPTED MANUSCRIPT
5
4.3. Radical clock experiments
MHz, CDCl3):
δ = 3.68 (s, 3H), 2.28 (t, J = 7.5 Hz, 2H),
1.63–1.57 (m, 2H), 1.21–1.16 (m, 2H), 0.89 (s, 9H) ppm; 13C
5
was prepared as a colorless oil (40% yield) according to
the general procedure. Rf 0.50 (petroleum ether/EtOAc = 6
NMR (75 MHz, CDCl3):
29.2 (3C), 20.2 ppm.
4b was prepared as a colorless oil (65% yield) according
to the general procedure. Rf 0.69 (petroleum ether/EtOAc
δ = 174.3, 51.4, 43.6, 34.8, 30.3,
=
: 1); IR (film): νmax = 3027, 2921, 2844, 1737, 1641, 1602,
1493, 1438, 1370, 1204, 1163, 914, 761, 736, 701 cm–1; H
1
=
NMR (300 MHz, CDCl3):
(m, 1H), 7.17–7.13 (m, 2H), 5.73–5.60 (m, 1H), 4.99 (d,
17.1 Hz, 1H), 4.94 (d, = 9.9 Hz, 1H), 3.61 (s, 3H),
2.68 2.58 (m, 1H), 2.38 (t, = 6.9 Hz, 2H), 2.16 (q, = 7.2
Hz, 2H), 2.16–2.02 (m, 1H), 1.91–1.79 (m, 1H) ppm; 13C
NMR (50 MHz, CDCl3): = 174.0, 143.9, 136.5, 128.4
δ = 7.33–7.26 (m, 2H), 7.22–7.19
= 6 : 1); IR (film): νmax = 2928, 2853, 1740, 1603, 1494,
1457, 1364, 1170, 1033, 747, 699 cm–1; 1H NMR (300 MHz,
J
=
J
CDCl3):
3H), 2.58 (t,
1.52 (m, 3H), 1.48–1.10 (m, 5H), 0.88 (s, 3H), 0.84 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3):
= 174.3, 142.8, 128.4
(2C), 128.2 (2C), 125.6, 51.4, 36.5, 36.4, 36.2, 34.4, 32.5,
δ
= 7.30–7.25 (m, 3H), 7.19–7.17 (m, 2H), 3.66 (s,
−
J
J
J
= 6.6 Hz, 2H), 2.28 (t, = 7.2 Hz, 2H), 1.71–
J
δ
δ
(2C), 127.7 (2C), 126.4, 116.2, 51,4, 45.2, 41.2, 32.1, 30.8
ppm; HRMS (ESI): calcd. for C14H18O2Na+ [M+Na]+:
241.1199, found: 241.1200.
29.3, 27.1, 22.5, 19.5 ppm; EI−MS (70 eV): m/z (% relative
intensity) 262 (M+, 1.4), 248 (4), 216 (3), 147 (5), 143 (7),
104 (22), 91 (100), 74 (31).
641 and 6′42 were prepared as colorless oils (1:1.6, 55%
4c40 was prepared as a colorless oil (62% yield) according
yield) according to the general procedure. Rf
= 0.55
(petroleum ether/EtOAc = 8 : 1); IR (film): νmax = 3077,
to the general procedure. Rf
= 0.55 (petroleum ether/EtOAc
2929, 2857, 1742, 1640, 1438, 1362, 1251, 1170, 911 cm–1;
= 6 : 1); IR (film): νmax = 2924, 2851, 1742, 1442, 1257,
1
1199, 1168 cm–1; H NMR (300 MHz, CDCl3):
δ
= 3.66 (s,
1
data for 6′: H NMR (300 MHz, CDCl3):
δ
= 5.85–5.76 (m,
= 17.1, 1.8 Hz, 1H), 4.94 (dd, = 11.7, 1.2
Hz, 1H), 3.67 (s, 3H), 2.31 (t, = 7.5 Hz, 2H), 2.04 (q,
7.2 Hz, 2H), 1.76–1.73 (m, 1H), 1.66–1.42 (m, 3H), 1.41–
1.30 (m, 4H) ppm; 13C/DEPT NMR (75 MHz, CDCl3):
174.2 (s), 138.9 (d), 114.2 (t), 51,4 (q), 34.0 (t), 33.6 (t),
28.9 (t), 28.7 (t), 28.6 (t), 24.9 (t) ppm; data for
: 1H NMR
signals overlap with those of 6′; 13C/DEPT NMR (75 MHz,
CDCl3): = 174.3 (s), 51,4 (q), 39.8 (d), 35.6 (t), 34.3 (t),
1H), 4.99 (dd,
J
J
3H), 2.27 (t, = 7.5 Hz, 2H), 1.70–1.51 (m, 6H), 1.43–1.38
(m, 1H), 1.31–1.16 (m, 7H), 0.84 (s, 3H) ppm; 13C NMR (75
MHz, CDCl3): = 174.6, 51.7, 37.9, 37.6, 37.2, 34.6, 33.5
J
J
J =
δ
δ
=
(2C), 26.8, 26.6 (2C), 22.6 ppm; EI−MS (70 eV): m/z (%
relative intensity) 198 (M+, 0.2), 184 (3), 167 (4), 153 (4),
141 (49), 97 (19), 74 (100), 55 (98), 41 (91).
6
4d was prepared as a colorless oil (66% yield) according
to the general procedure. Rf
δ
= 0.45 (petroleum ether/EtOAc
32.5 (t, 2C), 25.1 (t, 2C), 24.1 (t) ppm.
= 5 : 1); IR (film): νmax = 2923, 2854, 1739, 1597, 1493,
1452, 1258, 1165, 1110, 741, 699 cm–1; 1H NMR (300 MHz,
4.4. Stereoselective synthesis of a precursor for PGF2α
CDCl3):
δ = 7.36–7.19 (m, 5H), 3.64 (s, 3H), 3.58 (s, 2H),
2.62–2.54 (m, 1H), 2.42–2.36 (m, 2H), 2.27–2.10 (m, 2H),
2.08–1.99 (m, 1H), 1.64–1.32 (m, 8H), 0.74 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3):
δ = 174.9, 140.4, 129.0 (2C),
128.0 (2C), 126.7, 66.4, 65.1, 57.9, 51.4, 40.0, 36.7, 31.3,
29.1, 24.7, 21.9 ppm; EI−MS (70 eV): m/z (% relative
To a solution of CeCl3•7H2O (3.73 g, 10 mmol) in MeOH
(20 mL) was added 2-cyclopentene-1,4-dione43 (960 mg, 10
mmol) followed by the addition of NaBH4 (380 mg, 10
mmol) portionwise at 0 °C. Once clear solution turned to a
milky white, and the resulting reaction mixture was further
stirred for 30 min. The mixture was then filtered with a short
plug (elution with 100 mL of CH2Cl2) and concentrated
under reduced pressure. The resulting crude product cis-2-
cyclopentene-1,4-diol (ca. 1 g) could be used directly
without further purification. Colorless solid; mp 59–60 °C
(EtOAc); Rf = 0.12 (petroleum ether/EtOAc = 1 : 1); IR
(film): νmax = 3304, 3114, 2927, 1643, 1437, 1339, 1179,
intensity) 289 (M+, 2.1), 274 (0.4), 258 (1), 216 (8), 174 (3),
160 (21), 134 (21), 91 (100).
4e was prepared as a colorless oil (68% yield) according
to the general procedure. Rf
= 0.35 (petroleum ether/EtOAc
= 5 : 1); IR (film): νmax = 2934, 2795, 1740, 1603, 1493,
1451, 1309, 1166, 1026, 740, 699 cm–1; 1H NMR (300 MHz,
CDCl3):
13.5 Hz, 2H), 2.42–2.23 (m, 2H), 2.21–2.17 (m, 2H), 2.15–
2.05 (m, 1H), 2.01–1.95 (m, 1H), 1.68 (t, = 8.1 Hz, 2H),
1.63–1.58 (m, 2H), 1.35–1.18 (m, 2H), 0.88 (s, 3H) ppm; 13C
NMR (75 MHz, CDCl3): = 174.9, 139.2, 128.7 (2C), 128.1
δ = 7.31–7.20 (m, 5H), 3.66 (s, 3H), 3.41 (q, J =
J
δ
1
1133, 1084, 998, 916, 828, 791, 687 cm–1; H NMR (300
(2C), 126.7, 64.1, 63.2, 54.6, 51.5, 35.6, 34.1, 33.0, 28.7,
+
23.8, 22.1 ppm; HRMS (ESI): calcd. for C17H26NO2
MHz, CDCl3):
δ = 6.01 (s, 2H), 4.63 (brs, 2H), 3.58 (brs,
[M+H]+: 276.1958, found: 276.1958.
1H, –O ), 3.51 (brs, 1H, –O
H
H ), 2.70 (dt, J = 14.7, 6.9 Hz,
1H), 1.56 (dt,
MHz, CDCl3):
J
δ
= 14.7, 3.3 Hz, 1H) ppm; 13C NMR (75
= 136.3, 74.9, 43.4 ppm.
4f was prepared as a colorless oil (47% yield) according
to the general procedure. Rf
= 0.43 (petroleum ether/EtOAc
= 5 : 1); IR (film): νmax = 3067, 3027, 2934, 2795, 1740,
1638, 1603, 1493, 1450, 1439, 1315, 1252, 1171, 996, 914,
1
740, 670 cm–1; H NMR (300 MHz, CDCl3):
δ = 7.31–7.27
(m, 3H), 7.27–7.21 (m, 2H), 5.75–5.66 (m, 1H), 5.01 (d,
15.3 Hz, 1H), 5.00 (d, = 11.1 Hz, 1H), 3.66 (s, 3H), 3.41
(s, 2H), 2.42–2.25 (m, 2H), 2.22–2.15 (m, 2H), 2.10–2.04
(m, 4H), 1.72–1.55 (m, 2H), 1.59 (t, = 6.0 Hz, 2H), 1.32–
1.25 (m, 2H) ppm; 13C/DEPT NMR (50 MHz, CDCl3):
J =
J
NaH (400 mg, 10 mmol, 60% dispersion in mineral oil,
washed three times with -hexane distilled from CaH2) was
n
J
suspended in THF (20 mL), and a solution of the above diol
(1 g) in THF (10 mL) was added dropwise at room
temperature. The resulting mixture was stirred for 1 h, and a
large amount of opaque white precipitates formed. TBSCl
(1.5 g, 10 mmol) was then added portionwise, and vigorous
stirring was continued for 2 h. The mixture was poured into
Et2O (100 mL), washed with 10% aqueous NaHCO3 (20
δ
=
174.6 (s), 139.1 (s), 134.2 (d), 128.7 (d, 2C), 128.0 (d, 2C),
126.7 (d), 117.2 (t), 63.3 (t), 62.2 (t), 54.5 (t), 51.4 (q), 40.0
(t), 35.8 (s), 33.5 (t), 30.9 (t), 28.1 (t), 21.8 (t) ppm; HRMS
+
(ESI): calcd. for C19H28NO2 [M+H]+: 302.2115, found:
302.2115.

ACCEPTED MANUSCRIPT
6
Tetrahedron
mL) and brine (10 mL), dried over MgSO4, filtered and
concentrated. The crude product was purified by flash
1H), 1.23 (t,
J
= 7.2 Hz, 3H) ppm, other signals are
= 137.6
inseparable; 13C/DEPT NMR (75 MHz, CDCl3):
δ
chromatography on silica gel to afford desired cis-4-(
t
-
(d), 133.0 (d), 101.1 (d), 78.9 (d), 74.7 (d), 61.4 (d), 42.4 (t),
15.12 (q), 5.9 (t) ppm, the signals of silyl group are
inseparable.
To a stirred slurry of Zn (195 mg, 3 mmol) in regular
pyridine (2 mL) was added methyl acrylate (0.27 mL, 3
mmol) at room temperature. Under vigorous stirring,
NiCl2•6H2O (238 mg, 1 mmol) was added to the above
mixture. The temperature then rose to 50 °C, and stirring
was continued for 20 min. The resulting red-brown
Ni(0)•2MA•Py complex was cooled to room temperature,
butyldimethylsilanyloxy)-cyclopentene-2-ol44 (1.62 g, 75%).
Colorless oil; Rf = 0.38 (petroleum ether /EtOAc = 5 : 1); IR
(film): νmax = 3368, 3179, 2960, 2928, 2872, 1463, 1379,
1
1239, 1147, 1074, 773, 728 cm–1; H NMR (300 MHz,
CDCl3):
Hz, 1H), 4.64 (t,
= 14.7, 7.2 Hz, 1H), 2.22 (brs, 1H, –O
4.8 Hz, 1H), 0.89 (s, 9H), 0.08 (s, 6H) ppm; 13C/DEPT
NMR (75 MHz, CDCl3): = 136.8 (d), 135.6 (d), 75.1 (d),
δ
= 5.93 (d,
= 6.3 Hz, 1H), 4.57 (brs, 1H), 2.68 (dt,
), 1.50 (dt, = 14.1,
J = 5.7 Hz, 1H), 5.87 (dd, J = 5.4, 1.8
J
J
H
J
δ
75.0 (d), 44.6 (t), 25.9 (q, 3C), 18.2 (s), –4.68 (q), –4.72 (q)
ppm.
and a solution of the β-iodo acetal 7-I (412 mg, 1 mmol) in
pyridine (2 mL) was added dropwise over a 10-min period.
After 0.5 h, the mixture was filtered with a short plug
(elution with 50 mL of Et2O), and washed with water (3 ×
10 mL) and brine (10 mL), dried over MgSO4, filtered and
concentrated. The crude product was purified by flash
chromatography (petroleum ether/EtOAc = 30 : 1→15 : 1)
on silica gel to afford desired
polar) (2:1, 242 mg, 65%) as colorless oils. Data for
polar): Rf 0.58 (petroleum ether/EtOAc = 3 : 1); IR (film):
8
(
less polar) and
8
(
8
more
(less
To an oven-dried round bottom flask were added
N-
=
bromosuccinimide (2.1 mmol) and dry CH2Cl2 (10 mL). The
resulting suspension was cooled to –20 °C, and ethyl vinyl
ether (2.4 mmol) was added dropwise over a 5 min period
νmax = 2953, 2931, 2858, 1742, 1461, 1440, 1370, 1335,
1254, 1172, 1115, 1056, 1006, 938, 882, 837, 776, 667 cm–1;
1H NMR (300 MHz, CDCl3):
δ
= 5.17 (d,
= 7.5, 5.4 Hz, 1H ), 3.71 (q,
3.69–3.61 (m, 1H), 3.64 (s, 3H), 3.37 (dt,
1H), 2.36 (t,
= 12.9, 10.2 Hz, 1H), 1.88 (t,
1H), 1.68–1.59 (m, 1H), 1.56–1.47 (m, 2H), 1.15 (t,
Hz, 3H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H) ppm;
13C/DEPT NMR (75 MHz, CDCl3):
= 174.0 (s), 105.5 (d),
J
J
J
= 4.8 Hz, 1H),
= 8.1 Hz, 1H),
= 14.1, 6.9 Hz,
followed by the addition of the above cis-4-
(t-
4.41 (dt,
J
butyldimethylsilanyloxy)-cyclopentene-2-ol (2.0 mmol) in
CH2Cl2 (5 mL) dropwise over a 10 min period. The reaction
mixture was slowly warmed to room temperature over a
period of 2 h, and was then diluted with Et2O (30 mL) and
poured into a separatory funnel that contained H2O (10 mL).
The aqueous layer was extracted with Et2O (2 × 30 mL), and
the combined organic layers were washed with brine (10
mL), dried over MgSO4, filtered and concentrated under
reduced pressure. The resulting crude residue was purified
by flash column chromatography on silica gel to furnish the
J
= 7.2 Hz, 2H), 2.29–2.20 (m, 2H), 2.07 (dd,
= 6.0 Hz, 1H), 1.86–1.75 (m,
= 7.2
J
J
J
δ
79.8 (d), 78.9 (d), 62.3 (t), 53.0 (d), 51.5 (q), 44.5 (d), 41.0
(t), 39.7 (t), 32.3 (t), 27.9 (t), 25.7 (q, 3C), 17.9 (s), 15.2 (q),
–4.4 (q), –4.9 (q) ppm; HRMS (ESI): calcd. for
C19H36O5SiNa+ [M+Na]+: 395.2224, found: 395.2222. Data
desired
Rf
MHz, CDCl3):
Hz, 1H), 4.63 (t,
β
-bromo acetal 7-Br29d (495 mg, 68%). Colorless oil;
for
8 (more polar): Rf = 0.52 (petroleum ether/EtOAc = 3 :
1
=
0.50 (petroleum ether/EtOAc = 20 : 1); H NMR (300
1); IR (film): νmax = 2933, 2858, 1741, 1468, 1440, 1369,
1
1254, 1171, 1115, 1058, 1024, 952, 884, 836, 776 cm–1; H
δ
= 5.88 (d,
= 6.9 Hz, 1H), 4.58 (q,
= 6.9, 3.0 Hz, 1H), 3.59 (dd, = 9.3, 6.9 Hz, 1H),
= 3.9, 1.2 Hz, 1H), 2.71–2.66 (m, 1H), 1.63 (dt,
= 6.9 Hz, 3H), 0.88 (s, 9H),
0.06 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3): (slightly
major isomer = 137.7, 132.9, 100.7, 79.1, 74.6, 61.4,
41.9, 31.9, 25.8 (3C), 18.1, 15.1, –4.6, –4.7 ppm; (slightly
minor isomer = 137.5, 132.6, 100.5, 79.3, 74.7, 61.7,
J
= 3.0 Hz, 2H), 4.77 (q,
J = 6.0
J
J
= 5.7 Hz, 1H),
NMR (400 MHz, CDCl3):
(q, = 7.6 Hz, 1H ), 3.72 (dt,
3H), 3.53 (td, = 9.6, 6.4 Hz, 1H), 3.36 (dt,
Hz, 1H), 2.41 (ddd, = 18.8, 10.4, 5.6 Hz, 2H), 2.31 (dt,
12.4, 7.2 Hz, 1H), 2.04 (t, = 8.0 Hz, 2H), 2.00–1.93 (m,
1H), 1.91–1.81 (m, 2H), 1.68 (td, = 11.2, 7.2 Hz, 1H),
1.60–1.51 (m, 1H), 1.15 (t, = 7.2 Hz, 3H), 0.84 (s, 9H),
0.01 (s, 3H), –0.001 (s, 3H) ppm; 13C/DEPT NMR (50 MHz,
CDCl3): = 174.3 (s), 105.6 (d), 81.1 (d), 77.6 (d), 62.3 (t),
δ
= 5.12 (d,
= 16.8, 6.8 Hz, 1H), 3.64 (s,
= 16.4, 6.8
J = 4.8 Hz, 1H), 4.43
3.66 (dd,
3.35 (dd,
J
J
J
J
J
J
J
J
= 12.9, 5.1 Hz, 1H), 1.22 (t,
J
J
J =
J
)
δ
J
J
)
δ
42.3, 32.0, 15.2 ppm, the signals of silyl group are
inseparable.
δ
51.5 (q), 51.3 (d), 44.2 (d), 43.2 (t), 38.3 (t), 32.5 (t), 28.2
(t), 25.7 (q, 3C), 17.9 (s), 15.0 (q), –4.2 (q), –4.8 (q) ppm;
HRMS (ESI): calcd. for C19H36O5SiNa+ [M+Na]+: 395.2224,
found: 395.2222.
7-I29b,c was prepared similarly according to the above
procedure for 7-Br. Colorless oil; Rf
= 0.52 (petroleum
ether/EtOAc = 20 : 1); IR (film): νmax = 3065, 2955, 2932,
2889, 2858, 1635, 1611, 1468, 1370, 1254, 1196, 1103,
1077, 1043, 906, 837, 777, 670 cm–1; (slightly major isomer
)
4.5. An effective approach to (+)-campherenone (9)
1H NMR (300 MHz, CDCl3):
(q, = 6.0 Hz, 1H), 4.64 (t,
δ
= 5.92–5.87 (m, 1H), 4.73
J
J
= 6.9 Hz, 1H), 4.57 (q, J = 5.7
Hz, 1H), 3.66 (dd,
Hz, 1H), 3.21 (dd,
7.2 Hz, 1H), 1.65 (dt,
J
J
= 3.6, 2.4 Hz, 1H), 3.59 (dd,
= 5.4, 1.5 Hz, 1H), 2.68 (dt,
= 13.5, 5.7 Hz, 1H), 1.22 (t,
Hz, 3H), 0.87 (s, 9H), 0.06 (s, 6H) ppm; 13C/DEPT NMR
(75 MHz, CDCl3): = 137.5 (d), 132.6 (d), 100.9 (d), 78.9
(d), 74.6 (d), 61.1 (d), 41.8 (t), 25.8 (q, 3C), 18.1 (s), 15.07
(q), 5.8 (t), –4.6 (q), –4.7 (q) ppm; (slightly minor isomer
1H NMR (300 MHz, CDCl3):
= 4.57 (q, = 6.0 Hz, 1H),
= 3.3, 2.4 Hz, 1H), 3.53 (dd, = 7.2, 2.4 Hz, 1H),
= 11.4, 6.9 Hz, 1H), 1.63 (dt, = 12.9, 5.7 Hz,
J
= 6.9, 1.8
= 15.6,
= 7.2
J
J
J
To a stirred solution of methyl ester (–)-2a (2 g, 7.1 mmol) in
Et2O (20 mL) was added MeLi (1.0 M in Et2O, 15.6 mL)
dropwise at –40 °C under Ar. The resulting mixture was stirred
for 30 min, and quenched with water (5 mL) and extracted with
Et2O (3 × 50 ml). The combined organic phases were washed
with water (20 mL), brine (20 mL), and dried over MgSO4. After
the solvent was evaporated in vacuo, the crude residue was
δ
)
δ
J
3.68 (dd,
2.70 (dt,
J
J
J
J

ACCEPTED MANUSCRIPT
7
purified by flash column chromatography (petroleum
ether/AcOEt = 5 : 1) on silica gel to afford 1.9 g (95%) of tertiary
alcohol (–)-2a′ as a colorless oil. Rf = 0.27 (petroleum
ether/AcOEt = 3 : 1); [α]1D6 = –17 (c = 1.0, CHCl3); IR (film):
νmax = 3383, 2960, 2875, 1473, 1378, 1178, 1125, 1049, 947 cm–
1; 1H NMR (300 MHz, CDCl3): δ = 3.90–3.69 (m, 4H), 2.00–1.78
(m, 4H), 1.70–1.55 (m, 1H), 1.50–1.28 (m, 6H), 1.25–1.10 (m,
1H), 1.18 (s, 6H), 1.08–0.95 (m, 1H), 0.82 (s, 3H), 0.76 (s, 3H )
ppm; 13C NMR (75 MHz, CDCl3): δ = 117.1, 71.0, 64.9, 63.5,
53.3, 51.2, 45.1, 44.4, 41.7, 33.3, 29.6, 29.2, 29.1, 26.6, 20.0,
16.6, 9.9 ppm; EI−MS (70 eV): m/z (% relative intensity) 282
(M+, 7.3), 267 (7), 223 (5), 181 (15), 153 (6.2), 125 (100), 95
4.3 mmol) portionwise at room temperature. The resulting
mixture was stirred for 10 min, and quenched with saturated
NaHCO3 (5 mL) and extracted with Et2O (3 × 30 mL). The
combined organic phases were washed with water (10 mL), brine
(10 mL), and dried over MgSO4. After the solvent was
evaporated in vacuo, the crude residue was purified by flash
column chromatography (petroleum ether/AcOEt = 12 : 1 → 9 :
1) on silica gel to afford 510 mg (41%) of bromohydrin (+)-9a
and 630 mg (51%) of bromohydrin (–)-9b as colorless crystals.
Data for (+)-9a: Rf = 0.26 (petroleum ether/AcOEt = 6 : 1); mp
63–64 °C (n-hexane); [α]1D8 = +46 (c = 0.75, CHCl3); IR (film):
νma1x = 3446, 2959, 2880, 1739, 1448, 1378, 1126, 1045, 955 cm–
1; H NMR (300 MHz, CDCl3): δ = 3.87 (dd, J =11.4, 1.8Hz,
1H), 2.35 (dt, J = 15.0, 4.2 Hz, 1H), 2.19 (t, J = 4.2 Hz, 1H),
2.14–2.04 (m, 1H), 2.07 (s, 1H, –OH), 1.92–1.83 (m, 2H), 1.75–
1.55 (m, 2H), 1.49–1.37 (m, 2H), 1.36 (s, 3H), 1.34 (s, 3H),
1.18–1.08 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H), 0.88–0.78 (m, 1H)
ppm; 13C NMR (75 MHz, CDCl3): δ = 219.5, 72.8, 71.8, 58.9,
49.6, 42.8, 39.9, 33.5, 30.3, 30.3, 27.1, 27.1, 26.3, 16.6, 9.5 ppm;
EI–MS (70 eV): m/z (% relative intensity) 318 (M+, 5.3), 316
(M+, 5.2), 303 (3), 301 (3), 219 (25), 179 (53), 137 (32), 109
(98), 81 (100); HRMS (SIMS): calcd. for C15H26O279Br+ [M+H]+:
317.1111, found: 317.1108. Data for (–)-9b: Rf = 0.22 (petroleum
ether/AcOEt = 6 : 1); mp 58–59 °C (n-hexane); [α]1D8 = –32 (c =
0.9, CHCl3); IR (film): νmax = 3450, 2960, 2879, 1738, 1449,
+
(100); HRMS (ESI): calcd. for C17H31O3 [M+H]+: 283.2268,
found: 283.2261.
To a stirred solution of (–)-2a′ (1.9 g, 6.7 mmol) in acetone
(20 mL) was added p-TsOH (100 mg, 0.53 mmol). The resulting
mixture was stirred for 2 h at reflux temperature. Acetone was
evaporated, and the residue was extracted with Et2O (3 × 50 mL).
The combined organic phases were washed with water (20 mL),
brine (20 mL), and dried over MgSO4. After the solvent was
evaporated in vacuo, the crude residue was purified by flash
column chromatography (petroleum ether/AcOEt = 3 : 1) on
silica gel to afford 1.4 g (87%) of keto-alcohol (–)-2a′′ as a
colorless oil. Rf = 0.11 (petroleum ether/AcOEt = 3 : 1); [α]18
=
D
+24 (c = 0.9, CHCl3); IR (film): νmax = 3432, 2961, 1741, 1468,
1378, 1184, 1047 cm–1; H NMR (300 MHz, CDCl3): δ = 2.28–
1379, 1128, 1043, 968 cm–1; H NMR (300 MHz, CDCl3): δ =
1
1
2.18 (m, 2H), 1.95–1.80 (m, 2H), 1.78–1.65 (m, 1H), 1.59–1.20
(m, 7H), 1.22 (s, 6H), 1.20–1.05 (m, 1H), 0.96 (s, 3H), 0.91 (s,
3H) ppm; EI−MS (70 eV): m/z (% relative intensity) 238 (M+,
3.7), 223 (13), 220 (15.8), 205 (5.3), 149 (13), 109 (8), 81 (71),
3.85 (dd, J = 9.6, 3.3 Hz, 1H), 2.21 (dt, J = 15.0, 3.6 Hz, 1H),
2.18 (d, J = 3.6 Hz, 1H), 2.06 (s, 1H, –OH), 1.94–1.81 (m, 4H),
1.75–1.54 (m, 2H), 1.46–1.33 (m, 2H), 1.34 (s, 6H), 1.04–0.82
(m, 1H), 0.96 (s, 3H), 0.93 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3): δ = 219.5, 72.8, 71.2, 59.0, 49.6, 42.9, 40.1, 33.1, 30.11,
30.12, 27.1, 27.0, 26.5, 16.0, 9.5 ppm; EI–MS (70 eV): m/z (%
relative intensity) 318 (M+, 6), 316 (M+, 5.8), 303 (2.8), 301
(3.1), 219 (18.3), 179 (48), 137 (33), 109 (92), 81 (100). This
bromohydrin was dissolved in hexane/EtOAc (5 : 1). After 2
days, colorless single crystals were obtained by slow evaporation
of the solvent at room temperature.
+
41 (100); HRMS (SIMS): calcd. for C15H27O2 [M+H]+:
239.2006, found: 239.2001.
To a stirred solution of keto-alcohol (–)-2a′′ (1.4 g, 5.9
mmol) in benzene (15 mL) was added p-TsOH (50 mg, 0.26
mmol). The resulting mixture was stirred for 4 h at reflux
temperature and the reaction was quenched with saturated
NaHCO3 (5 mL) and extracted with Et2O (2 × 50 mL). The
combined organic phases were washed with water (15 mL), brine
(15 mL), and dried over MgSO4. After the solvent was
evaporated in vacuo, the crude residue was purified by flash
column chromatography (petroleum ether/AcOEt = 100 : 1) on
silica gel to afford 1.16 g (90%) of (+)-camphereneone 9 as a
To a stirred solution of (+)-9a or (–)-9b (100 mg, 0.32
mmol) in MeOH (3 mL) was added K2CO3 (44 mg, 0.32
mmol) one portion at room temperature. The resulting
mixture was stirred for 5 min, and quenched with water (2
mL) and extracted with Et2O (3 × 10 mL). The combined
organic phases were washed with water (5 mL), brine (5
mL), and dried over MgSO4. After the solvent was
evaporated in vacuo, the crude residue was purified by flash
column chromatography (petroleum ether/AcOEt = 16 : 1)
on silica gel to afford 70 mg (95%) of epoxide (+)-10a or
colorless oil, Rf = 0.74 (petroleum ether/AcOEt = 10 : 1); [α]18
=
+32 (c = 1.0, CHCl3), lit.12b [α] 2D5 +30.77 (c = 2.78, CHCl3)D; IR
(film): νmax = 2960, 1744, 1649, 1457, 1364, 1152, 1071 cm–1; 1H
NMR (300 MHz, CDCl3): δ = 5.06 (t, 1H, J = 6.9 Hz), 2.30–2.24
(m, 2H), 2.13–2.03 (m, 1H), 1.94–1.81 (m, 3H), 1.78–1.59 (m,
2H), 1.66 (s, 3H), 1.59 (s, 3H), 1.43–1.25 (m, 2H), 1.20–1.07 (m,
1H), 0.97 (s, 3H), 0.90 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
δ = 219.7, 131.6, 124.3, 58.7, 49.6, 42.8, 39.7, 34.0, 30.0, 27.0,
25.6, 23.9, 17.5, 15.9, 9.2 ppm; EI−MS (70 eV): m/z (% relative
intensity) 220 (M+, 34), 177 (10), 135 (31), 109 (96), 81 (46), 69
(100).
(+)-10b as a colorless oil. Data for (1+8)-10a9
:
Rf
=
0.33
(petroleum ether/AcOEt = 6 : 1); [
α
]
= +20 (c = 1.0,
CHCl3); IR (film): νmax = 2960, 2880,D1743, 1452, 1380,
1
1324, 1123, 1046 cm–1; H NMR (300 MHz, CDCl3):
δ =
2.61 (t,
J = 6.0 Hz, 1H), 2.22–2.14 (m, 2H), 1.92–1.79 (m,
2H), 1.73–1.62 (m, 2H), 1.44–1.26 (m, 3H), 1.26 (s, 3H),
1.22 (s, 3H), 1.04–0.84 (m, 2H), 0.94 (s, 3H), 0.89 (s, 3H)
4.6. Syntheses of diastereomeric epoxyketones 10a and 10b
ppm; 13C NMR (75 MHz, CDCl3):
δ = 219.3, 64.1, 58.6,
58.4, 49.3, 42.6, 39.6, 30.2, 29.9, 26.8, 24.9, 24.8, 18.5,
15.8, 9.1 ppm; EI–MS (70 eV): m/z (% relative intensity)
236 (M+, 4.4), 221 (7.3), 193 (6), 163 (7.2), 135 (38), 109
OH
O
H
H
Br
(87), 95 (97), 41 (100); Data for (+)-10b
:
Rf
=
0.33
O
+
O
NBS
K2CO3
9a
( )-
10a
( )-
18
(petroleum ether/AcOEt = 6 : 1); [
α
]
= +25 (c = 1.0,
CHCl3); IR (film): νmax = 2960, 2879,D1743, 1452, 1380,
Br
H
H
1
1324, 1123, 1047 cm–1; H NMR (300 MHz, CDCl3):
δ =
O
[X-ray]
9
( )-
O
HO
2.60 (t,
J = 6.0 Hz, 1H), 2.28–2.16 (m, 2H), 1.91–1.79 (m,
O
O
2H), 1.72–1.35 (m, 4H), 1.32–1.22 (m, 1H), 1.25 (s, 3H),
1.22 (s, 3H), 1.16–1.10 (m, 2H), 0.92 (s, 3H), 0.88 (s, 3H)
9b
( )-
10b
( )-
(more polar)
To a stirred solution of (+)-camphereneone 9 (860 mg, 3.9
mmol) in THF/H2O (15 mL, v/v = 2:1) was added NBS (765 mg,
ppm; 13C NMR (75 MHz, CDCl3):
δ = 219.1, 64.1, 58.5,

ACCEPTED MANUSCRIPT
8
Tetrahedron
58.2, 49.3, 42.5, 39.6, 30.2, 29.9, 26.8, 24.9, 24.8, 18.5,
(1 mL) was added to the resulting solution dropwise. The
+
15.8, 9.2 ppm; HRMS (SIMS): calcd. for C15H25O2
stirring was continued for 5 h at 150 °C and quenched with
water (1 mL) and extracted with Et2O (3 × 10 mL). The
combined organic phases were washed with water (5 mL),
brine (5 mL), and dried over MgSO4. After the solvent was
evaporated in vacuo, the crude residue was purified by flash
column chromatography (petroleum ether/AcOEt = 14 : 1 →
8 : 1) on silica gel to afford 20 mg (67%) of keto-alcohol (–
[M+H]+: 237.1849, found: 237.1842.
4.7. Comparison of 6-exo-tet cyclization behaviors
NaH (8 mg, 60% dispersion in mineral oil, washed three
times with -hexane distilled from CaH2) was placed in
n
round-bottomed flask, and DMSO (1 mL) was introduced
under Ar. The resulting mixture was heated with stirring to
70–75 °C. Half an hour later, the pale yellow solution was
cooled to room temperature, and a solution of the epoxide
(+)-10a (24 mg, 0.1 mmol) in DMSO (1 mL) was added
dropwise. The stirring was continued for 0.5 h, the mixture
was then quenched with water (1 mL) and extracted with
Et2O (3 × 10 mL). The combined organic phases were
washed with water (5 mL), brine (5 mL), and dried over
MgSO4. After the solvent was evaporated in vacuo, the
crude residue was purified by flash column chromatography
(petroleum ether/AcOEt = 8 : 1) on silica gel to afford 19.5
mg (81%) of keto-alcohol (–)-11a9 as a colorless crystal. Rf
)-13 as a colorless crystal. Rf
= 0.31 (petroleum ether/AcOEt
20
= 5 : 1); mp 95–96 °C (
n
-hexane); [
α
]
= –103 (c = 0.6,
CHCl3); IR (film): νmax = 3524, 3437,D2955, 2876, 1722,
1463, 1375, 1122, 1038, 948 cm–1; H NMR (300 MHz,
1
CDCl3):
δ = 2.77 (d, J = 4.8 Hz, 1H), 1.97 (s, 1H, –OH),
1.89–1.78 (m, 2H), 1.75–1.62 (m, 2H), 1.43–1.28 (m, 2H),
1.26–1.16 (m, 1H), 1.24 (s, 3H), 1.20 (s, 3H), 0.99–0.83 (m,
2H), 0.93 (s, 3H), 0.91 (s, 3H), 0.88 (s, 3H) ppm; 13C/DEPT
NMR (50 MHz, CDCl3):
δ = 224.0 (s), 77.3 (s), 59.6 (d),
58.2 (s), 47.5 (s), 44.7 (d), 43.6 (s), 32.2 (t), 30.2 (t), 28.7
(t), 27.2 (q), 26.0 (q), 24.5 (t), 21.5 (q), 18.6 (q), 9.4 (q)
ppm; HRMS (ESI): calcd. for C16H30O2N+ [M+NH4]+:
268.2272, found: 268.2275. This compound was dissolved
in hexane/EtOAc (4 : 1). After 2 days, colorless single
crystals were obtained by slow evaporation of the solvent at
room temperature.
=
0.15 (petroleum ether/AcOEt = 6 : 1); mp 76–77 °C (n-
16
D
hexane); [
3430, 2961, 2874, 1735, 1472, 1449, 1378, 1194, 1143,
1038, 938 cm–1; 1H NMR (300 MHz, CDCl3):
= 2.31 (d,
= 4.8 Hz, 1H), 2.24 (s, 1H, O ), 2.03–1.84 (m, 1H), 1.74–
α
]
= –20 (c = 2.3, CHCl3); IR (film): νmax =
δ
J
H
4.8. Synthesis of 12-methyl-camphereneone (14)
1.62 (m, 2H), 1.58–1.28 (m, 6H), 1.24 (s, 3H), 1.19 (s, 3H),
1.02–0.82 (m, 1H), 0.944 (s, 3H), 0.936 (s, 3H) ppm;
13C/DEPT NMR (75 MHz, CDCl3):
δ = 224.7 (s), 73.2 (s),
58.4 (s), 53.6 (d), 49.6 (d), 43.4 (s), 42.0 (d), 30.2 (t), 29.9
(t), 28.7 (q), 26.2 (q), 24.3 (t), 21.1 (t), 18.7 (q), 9.6 (q) ppm;
EI–MS (70 eV): m/z (% relative intensity) 236 (M+, 18.6),
221 (18), 175 (20), 149 (23), 95 (34), 59 (37), 40 (100). This
compound was dissolved in hexane/EtOAc (4 : 1). After 2
days, colorless single crystals were obtained by slow
evaporation of the solvent at room temperature.
Methylsulfinyl sodium solution was prepared according to
the above procedure for (–)-11a. Half an hour later, a
solution of epoxide (+)-10b (24 mg, 0.1 mmol) in DMSO (1
mL) was added to the resulting solution dropwise. The
stirring was continued for 5 h at 70 °C, then quenched with
water (1 mL) and extracted with Et2O (3 × 10 mL). The
combined organic phases were washed with water (5 mL),
brine (5 mL), and dried over MgSO4. After the solvent was
evaporated in vacuo, the crude residue was purified by flash
column chromatography (petroleum ether/AcOEt = 15 : 1)
on silica gel to afford 12 mg (50%) of keto-alcohol (–)-11b
To a stirred solution of methyl ester 2b (1.1 g, 3.7 mmol) in
Et2O (10 mL) was added MeLi (1.0 M in Et2O, 9.3 mL) dropwise
at –40 °C under Ar. The resulting mixture was stirred for 30 min,
and quenched with water (5 mL) and extracted with Et2O (3 × 50
ml). The combined organic phases were washed with water (20
mL), brine (20 mL), and dried over MgSO4. After the solvent
was evaporated in vacuo, the crude residue was purified by flash
column chromatography (petroleum ether/AcOEt = 10 : 1) on
silica gel to afford 451 mg (41%) of alcohol (+)-2b′ and 528 mg
(48%) of alcohol (–)-2b′ (epi) as colorless oils. Data for (+)-2b′:
Rf = 0.55 (petroleum ether/AcOEt = 3 : 1); [α] 20 = +13 (c = 3.0,
D
CHCl3); IR (film): νmax = 3404, 2964, 2875, 1473, 1453, 1379,
1
1267, 1124, 1046, 948 cm–1; H NMR (300 MHz, CDCl3): δ =
3.95–3.72 (m, 4H), 2.10–1.99 (m, 1H), 1.95–1.82 (m, 3H), 1.72–
1.64 (m, 2H), 1.43–1.24 (m, 3H), 1.23–1.20 (m, 1H), 1.19 (s,
3H), 1.17 (s, 3H), 1.00–0.75 (m, 2H), 0.91 (d, J = 6.9 Hz, 3H),
0.84 (s, 3H), 0.80 (s, 3H) ppm; 13C/DEPT NMR (75 MHz,
CDCl3): δ = 117.1 (s), 73.6 (s), 64.9 (t), 63.5 (t), 53.3 (s), 51.2
(s), 45.4 (d), 44.4 (t), 41.8 (d), 31.8 (t), 29.8 (t), 27.2 (q and t,
2C), 26.7 (t), 26.1 (q), 16.6 (q), 15.0 (q), 9.9 (q) ppm; HRMS
as a colorless crystal. Rf
= 0.33 (petroleum ether/AcOEt = 6 :
20
1); mp 38–39 °C ( -hexane); [
n
α
]
= –7 (c = 0.5, CHCl3);
D
IR (film): νmax = 3477, 2954, 2878, 1723, 1471, 1445, 1380,
1
1265, 1156, 1109, 1009, 945 cm–1; H NMR (300 MHz,
+
(ESI): calcd. for C18H33O3 [M+H]+: 297.2424, found: 297.2422.
CDCl3):
1H), 1.80 (d,
(m, 4H), 1.40–1.25 (m, 3H), 1.34 (s, 3H), 1.14 (s, 3H), 0.93
(s, 6H) ppm; 13C/DEPT NMR (75 MHz, CDCl3):
= 225.9
δ
= 3.44 (s, 1H, –O
H), 2.52 (s, 1H), 1.94–1.89 (m,
Data for (–)-2b′ (epi): Rf = 0.42 (petroleum ether/AcOEt = 3 : 1);
J
= 3.9 Hz, 1H), 1.81–1.77 (m, 1H), 1.73–1.56
[α] 2D0 = –34 (c = 1.9, CHCl3); H NMR (300 MHz, CDCl3): δ =
1
3.96–3.70 (m, 4H), 1.95–1.86 (m, 3H), 1.82–1.43(m, 3H), 1.42–
1.31 (m, 3H), 1.24–1.19 (m, 2H), 1.17 (s, 3H), 1.15 (s, 3H),
1.05–0.95 (m, 1H), 0.91 (d, J = 6.9 Hz, 3H), 0.83 (s, 3H), 0.80 (s,
3H) ppm; 13C NMR (75 MHz, CDCl3): δ = 117.1, 73.6, 64.9,
63.5, 53.4, 51.3, 45.4, 44.4, 41.7, 31.6, 29.7, 27.3, 27.0, 26.6,
δ
(s), 71.6 (s), 57.6 (s), 54.0 (d), 50.4 (d), 49.0 (s), 48.9 (d),
32.0 (t), 31.6 (t), 30.2 (q), 27.6 (q), 25.2 (t), 21.1 (t), 18.2
(q), 8.5 (q) ppm; HRMS (ESI): calcd. for C15H24O2Na+
[M+Na]+: 259.1669, found: 259.1671.
+
26.0, 16.6, 14.6, 9.9 ppm; HRMS (ESI): calcd. for C18H33O3
[M+H]+: 297.2424, found: 297.2422.
To a stirred solution of alcohol (+)-2b′ and (–)-2b′ (epi) (800
mg, 2.7 mmol) in acetone (10 mL) was added p-TsOH (51 mg,
0.27 mmol). The resulting mixture was stirred for 2 h at reflux
temperature. Acetone was evaporated, and the residue was
extracted with Et2O (3 × 50 mL). The combined organic phases
were washed with water (15 mL), brine (15 mL), and dried over
Methylsulfinyl sodium solution was prepared according to
the above procedure for (–)-11a. Half an hour later, a
solution of epoxide (+)-12a (30 mg, 0.12 mmol) in DMSO

ACCEPTED MANUSCRIPT
9
MgSO4. After the solvent was evaporated in vacuo, the crude
residue was purified by flash column chromatography on silica
gel (petroleum ether/AcOEt = 4 : 1) to afford 544 mg (80%) of
alcohol (+)-2b′′ and (+)-2b′′ (epi) as colorless oils. Data for (+)-
2b′′: Rf = 0.56 (petroleum ether/AcOEt = 2 : 1); [α] 20 = +55 (c =
2.4, CHCl3); IR (film): νmax = 3459, 2962, 2876,D1741, 1466,
1449, 1379, 1175, 1088, 945 cm–1; 1H NMR (300 MHz, CDCl3):
δ = 2.27–2.18 (m, 2H), 1.93–1.79 (m, 3H), 1.75–1.67 (m, 1H),
1.45–1.24 (m, 4H), 1.18 (s, 3H), 1.15 (s, 3H), 1.12–1.01 (m, 1H),
0.97 (s, 3H), 0.96–0.82 (m, 1H), 0.92 (s, 3H), 0.82 (d, J = 6.3 Hz,
3H) ppm; 13C NMR (75 MHz, CDCl3): δ = 219.8, 73.3, 58.7,
49.6, 45.1, 42.6, 39.6, 32.8, 30.0, 27.6, 26.8 (2C), 25.8, 15.9,
14.7, 9.2 ppm; HRMS (ESI): calcd. for C16H32O2N+ [M+NH4]+:
270.2428, found: 270.2431. Data for (+)-2b′′ (epi): Rf = 0.50
(petroleum ether/AcOEt = 2 : 1); [α] 2D0 = +2 (c = 2.2, CHCl3); IR
(film): νmax = 3463, 2962, 2876, 1741, 1466, 1449, 1379, 1173,
and 125 mg (18%) of bromohydrin (+)-14a and 138 mg
(20%) of bromohydrin (+)-14b successively as colorless
crystals. Data for (+)-14a Rf 0.19 (petroleum ether/AcOEt
= 6 : 1); mp 94–96 °C ( -hexane); [
CHCl3); IR (film): νmax = 3464, 2959, 2871, 1739, 1449,
1377, 1049, 950, 862 cm–1; 1H NMR (300 MHz, CDCl3):
2.45 (dt, = 4.5, 17.4 Hz, 1H), 2.28–2.21 (m, 2H), 2.16–
:
=
20
n
α
]
= +20 (c = 0.5,
D
δ
=
J
2.02 (m, 2H), 1.94–1.81 (m, 2H), 1.78–1.68 (m, 1H), 1.66
(s, 3H), 1.49–1.22 (m, 2H), 1.38 (s, 6H), 0.98–0.80 (m, 2H),
0.96 (s, 6H) ppm; 13C/DEPT NMR (75 MHz, CDCl3):
δ =
219.2 (s), 87.5 (s), 75.9 (s), 58.6 (s), 49.4 (s), 42.6 (t), 39.5
(d), 35.3 (t), 30.5 (t), 30.1 (t), 26.8 (t), 25.5 (q), 16.3 (q, 2C),
9.2 (q, 2C) ppm; HRMS (ESI): calcd. for C16H31O2N79Br+
[M+NH4]+: 348.1533, found: 348.1529. Data for (+)-14b
: Rf
=
0.10 (petroleum ether/AcOEt = 6 : 1); mp 108–110 °C (
n
-
20
D
hexane); [
α
]
= +2 (c = 3.0, CHCl3); IR (film): νmax =
1
1053, 949 cm–1; H NMR (300 MHz, CDCl3): δ = 2.27–2.22 (m,
3471, 2961, 2880, 1740, 1449, 1377, 1325, 1051, 952, 862
1
2H), 1.93–1.81 (m, 2H), 1.75–1.58 (m, 2H), 1.45–1.20 (m, 4H),
1.17 (s, 3H), 1.14 (s, 3H), 1.11–1.00 (m, 1H), 0.94 (s, 3H), 0.92
(s, 3H), 0.92–0.79 (m, 1H), 0.87 (d, J = 6.3 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ = 219.8, 73.2, 58.7, 49.7, 45.0, 42.7,
39.6, 32.7, 30.0, 27.6, 26.8 (2C), 25.8, 15.9, 14.6, 9.2 ppm;
HRMS (ESI): calcd. for C16H32O2N+ [M+NH4]+: 270.2428,
found: 270.2431.
cm–1; H NMR (300 MHz, CDCl3):
2.18 (d, = 3.6 Hz, 1H), 1.93–1.84 (m, 2H), 1.77–1.69 (m,
δ = 2.28–2.21 (m, 2H),
J
1H), 1.65 (s, 3H), 1.58–1.52 (m, 1H), 1.47–1.33 (m, 2H),
1.38 (s, 3H), 1.37 (s, 3H), 1.21–1.14 (m, 1H), 0.99 (s, 3H),
0.97 (s, 3H), 0.95–0.84 (m, 1H) ppm; 13C NMR (75 MHz,
CDCl3):
δ = 219.2, 87.1, 75.9, 58.8, 49.3, 42.6, 39.7, 35.3,
30.5, 30.0, 26.9, 26.0, 15.6 (2C), 9.3 (2C) ppm; HRMS
(ESI): calcd. for C16H31O2N79Br+ [M+NH4]+: 348.1533,
found: 348.1529.
To a stirred solution of keto-alcohol (+)-2b′′ and (+)-2b′′ (epi)
(360 mg, 1.43 mmol) in benzene (5 mL) was added p-TsOH (50
mg, 0.26 mmol). The resulting mixture was stirred for 1.5 h at
reflux temperature and the reaction was quenched with saturated
NaHCO3 (3 mL) and extracted with Et2O (2 × 40 mL). The
combined organic phases were washed with water (10 mL), brine
(10 mL), and dried over MgSO4. After the solvent was
evaporated in vacuo, the crude residue was purified by flash
column chromatography on silica gel (petroleum ether/AcOEt =
100 : 1) to afford 284 mg (85%, 1 : 1) of internal alkene 14 and
inseparable terminal alkene as colorless oils. Data for 14: Rf =
0.50 (petroleum ether/AcOEt = 2 : 1); IR (film): νmax = 3059,
To a stirred solution of (+)-14a or (+)-14b (90 mg, 0.27
mmol) in MeOH (2 mL) was added K2CO3 (41 mg, 0.30
mmol) one portion at room temperature. The resulting
mixture was stirred for 5 min. and quenched with water (2
mL) and extracted with Et2O (3 × 10 mL). The organic layer
was washed with water, brine, and dried over MgSO4. After
the solvent was evaporated in vacuo, the crude residue was
purified by flash column chromatography on silica gel
(petroleum ether/AcOEt = 14 : 1) to afford 68 mg (90%) of
epoxide (+)-12a or (+)-12b as a colorless crystal. Data for
1
2958, 2926, 2867, 1744, 1646, 1450, 1377, 1045 cm–1; H NMR
(+)-12a
44 °C (
:
n
Rf
=
0.30 (pe2t0roleum ether/AcOEt = 5 : 1); mp 43–
(300 MHz, CDCl3): δ = 2.32–2.03 (m, 4H), 1.93–1.84 (m, 2H),
1.83–1.65 (m, 2H), 1.61 (s, 6H), 1.59 (s, 3H), 1.45–1.38 (m, 2H),
1.17–1.08 (m, 1H), 0.98 (s, 3H), 0.88 (s, 3H) ppm; 13C NMR (75
MHz, CDCl3): δ = 219.6, 127.3, 124.0, 58.7, 49.6, 42.8, 39.8,
32.3, 31.5, 30.2, 30.0 (2C), 26.9, 21.5, 15.8, 9.3 ppm; HRMS
(ESI): calcd. for C16H27O+ [M+H]+: 235.2057, found: 235.2060.
-hexane); [
α
]
= +18 ( = 1.4, CHCl3); IR (film):
c
D
νmax = 2958, 2929, 1743, 1469, 1449, 1379, 1203, 1078,
1045, 1021, 854 cm–1; 1H NMR (300 MHz, CDCl3):
= 2.20
(dt, = 4.8, 17.4 Hz, 1H), 2.18 (t, = 3.6 Hz, 1H), 1.95–
1.68 (m, 3H), 1.47–1.32 (m, 3H), 1.29 (s, 6H), 1.26 (s, 3H),
1.24–1.17 (m, 1H), 1.08–0.90 (m, 2H), 0.94 (s, 3H), 0.92 (s,
δ
J
J
3H) ppm; 13C/DEPT NMR (75 MHz, CDCl3):
δ = 219.2 (s),
4.9. Syntheses of 12-methyl epoxyketones 12a and 12b
64.3 (s), 62.2 (s), 58.6 (s), 49.4 (s), 42.7 (t), 39.6 (d), 31.1
(t), 30.0 (t), 29.4 (t), 26.9 (t), 21.3 (q), 20.9 (q), 18.6 (q),
15.8 (q), 9.2 (q) ppm; HRMS (ESI): calcd. for C16H30O2N+
[M+NH4]+: 268.2271, found: 268.2268. Data for (+)-12b
: Rf
=
0.27 (petroleum ether/AcOEt = 5 : 1); mp 69–71 °C (
n
-
20
hexane); [
α
]
= +26 (c = 1.7, CHCl3); IR (film): νmax =
D
2960, 2929, 1738, 1470, 1448, 1381, 1201, 1077, 1047,
1020, 858 cm–1; 1H NMR (300 MHz, CDCl3):
δ
= 2.24 (dt,
J
= 4.5, 17.4 Hz, 1H), 2.23–2.19 (m, 1H), 1.92–1.85 (m, 2H),
1.76–1.68 (m, 1H), 1.63–1.60 (m, 1H), 1.47–1.39 (m, 1H),
1.36–1.32 (m, 1H), 1.32 (s, 3H), 1.30 (s, 3H), 1.24 (s, 3H),
1.14–1.07 (m, 2H), 0.94 (s, 3H), 0.93 (s, 3H), 0.88–0.82 (m,
To a stirred solution of the mixture of 14 and terminal
alkene (500 mg, 2.1 mmol) in THF/H2O (6 mL, v/v = 2 : 1)
was added NBS (394 mg, 2.2 mmol) portionwise at room
temperature. The resulting mixture was stirred for 10 min
and quenched with saturated NaHCO3 (3 mL) and extracted
with Et2O (3 × 30 mL). The organic layer was washed with
water (10 mL), brine (10 mL), and dried over MgSO4. After
the solvent was evaporated in vacuo, the crude residue was
purified by flash column chromatography on silica gel
(petroleum ether/AcOEt = 12 : 1 → 8 : 1) to afford 278 mg
(40%) of regioisomeric bromohydrin from terminal alkene
1H) ppm; 13C/DEPT NMR (75 MHz, CDCl3):
δ = 219.1 (s),
64.4 (s), 62.0 (s), 58.6 (s), 49.4 (s), 42.6 (t), 39.6 (d), 31.4
(t), 30.1 (t), 29.6 (t), 26.8 (t), 21.3 (q), 20.8 (q), 18.7 (q),
15.9 (q), 9.2 (q) ppm; HRMS (ESI): calcd. for C16H30O2N+
[M+NH4]+: 268.2271, found: 268.2268.
Acknowledgments

ACCEPTED MANUSCRIPT
10
Tetrahedron
10. (a) Corey, E. J.; Semmelhack, M. F. J. Am. Chem. Soc.1967, 89,
We thank Dr. Shou-Jie Shen and Dr. Yu-Rong Yang for
2755; for a review, see: (b) Semmelhack, M. F. Org. React. 1972,
19, 115.
their assistance. Y. Peng thanks the National Natural Science
Foundation of China (No. 21772078), and the Fundamental
Research Funds for the Central Universities by Ministry of
Education of China (2682019CX70 and 2682019CX71). W.-D.
Z. Li thanks the National Natural Science Foundation of China
(No. 21672030), and the scholars program of Southwest Jiaotong
University for financial support.
11. Shi, Z. Sci. Total Environ. 1994, 148, 293.
12. For Money’s account about this topic, see: (a) Kuo, D. L.; Money,
T. J. Chem. Soc., Chem. Commun. 1986, 1691 (Cf.: footnote**
therein); (b) Kuo, D. L.; Money, T. Can. J. Chem. 1988, 66, 1794.
13. (a) Everson, D.; Jones, B. A.; Weix, D. J. J. Am. Chem. Soc. 2012,
134, 6146; (b) Wotal, A. C.; Weix, D. J. Org. Lett. 2012, 14, 1476;
(c) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192
.
14. (a) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett. 2011,
13, 2138; (b) Wu, F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Org.
Lett. 2012, 14, 3044; (c) Yin, H.; Zhao, C.; You, H.; Lin, Q.;
Gong, H. Chem. Commun. 2012, 48, 7034; (d) Wang, S.; Qian, Q.;
Gong, H. Org. Lett. 2012, 14, 3352; (e) Dai, Y.; Wu, F.; Zang, Z.;
You H.; Gong, H. Chem.−Eur. J. 2012, 18, 808; (f) Xu, H.; Zhao,
C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci. 2013, 4, 4022.
15. (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. J. Am. Chem.
Soc. 2013, 135, 7442; (b) León, T.; Correa, A.; Martin, R. J. Am.
Chem. Soc. 2013, 135, 1221.
16. (a) Yan, C.-S.; Peng, Y.; Xu, X.-B.; Wang, Y.-W. Chem.-Eur. J.
2012, 18, 6039 and 2013, 19, 15438 (Corrigendum); (b) Xu, X.-B.;
Liu, J.; Zhang, J.-J.; Wang, Y.-W.; Peng, Y. Org. Lett. 2013, 15,
550; (c) Peng, Y.; Xu, X.-B.; Xiao, J.; Wang, Y.-W. Chem.
Commun. 2014, 50, 472; (d) Peng, Y.; Xiao, J.; Xu, X.-B.; Duan,
S.-M.; Ren, L.; Shao, Y.-L.; Wang, Y.-W. Org. Lett. 2016, 18,
5170; (e) Xiao, J.; Wang, Y.-W.; Peng, Y. Synthesis 2017, 49,
3576; (f) Xiao, J.; Cong, X.-W.; Yang, G.-Z.; Wang, Y.-W.; Peng,
Y. Chem. Commun. 2018, 54, 2040; (g) Xiao, J.; Cong, X.-W.;
Yang, G.-Z.; Wang, Y.-W.; Peng, Y. Org. Lett. 2018, 20, 1651.
17. (a) Sustmann, R.; Hopp, P.; Boese, R. J. Organomet. Chem.1989,
375, 259, the unusual structure featuring the penta-coordination,
distorted C2-symmetry and head-head conformation of MA can be
seen in the crystal structure; (b) Sustmann, R.; Hopp, P.; Holl, P.
Tetrahedron Lett. 1989, 30, 689.
Supplementary data
Supplementary data related to this article can be found online at
doi:
References and notes
1. (a) Whitmore, F. C.; Wittle; E. L.; Popkin, A. H. J. Am. Chem.
Soc. 1939, 61, 1586; (b) Whitmore, F. C.; Rohrmann, E. J. Am.
Chem. Soc. 1939, 61, 1591; (c) Bartlett, P. D.; Rosen, L. J. J. Am.
Chem. Soc. 1942, 64, 543.
2. (a) Hughes, E. D. Trans. Faraday Soc. 1941, 37, 603; (b)
Dostrovsky, I.; Hughes, E. D. J. Chem. Soc. 1946, 157; (c)
Dostrovsky, I.; Hughes, E. D. J. Chem. Soc. 1946, 161; (d)
Dostrovsky, I.; Hughes, E. D. J. Chem. Soc. 1946, 169; (e)
Dostrovsky, I.; Hughes, E. D.; Ingold, C. K. J. Chem. Soc. 1946,
173; (f) de la Mare, P. B. D.; Fowden, L.; Hughes, E. D.; Ingold,
C. K.; Mackie, J. D. H. J. Chem. Soc. 1955, 3200; for a
monography, see: (g) Ingold, C. K. Structure and Mechanism in
Organic Chemistry, 2nd ed.; Cornell University Press, Ithaca,
1969.
3. For the argument between Evans and Ingold, see: (a) Evans, A. G.
Nature 1946, 157, 438; (b) Hughes, E. D.; Ingold, C. K. Nature
1946, 158, 94; (c) Evans, A. G. Nature 1946, 158, 586; (d)
Hughes, E. D.; Ingold, C. K. Nature 1947, 159, 166.
4. (a) Evans, A. G.; Polanyi, M. Nature 1942, 149, 608; (b) DeTar,
D. F.; McMullen D. F.; Luthra, N. P. J. Am. Chem. Soc. 1978,
100, 2484; (c) Regan, C. K.; Craig, S. L.; Brauman, J. I. Science
2002, 295, 2245; (d) Vayner, G. V.; Houk, K. N.; Jorgensen, W.
L.; Brauman, J. I. J. Am. Chem. Soc. 2004, 126, 9054.
18. (a) Manchand, P. S.; Yiannikouros, G. P.; Belica, P. S.; Madan, P.
J. Org. Chem. 1995, 60, 6574; for a related process studies, see:
(b) Van Arnum, S. D.; Moffet, H.; Carpenter, B. K. Org. Process
Res. Dev. 2004, 8, 769; for a recent application in total synthesis
of kingianins, see: (c) Lim, H. N.; Parker, K. A. J. Org. Chem.
2014, 79, 919.
19. For Ni(COD)/(R,R)-Ph-PyBox-catalyzed reductive coupling, see:
(a) Gong, H.; Andrews, R. S.; Zuccarello, J. L.; Lee, S. J.; Gagné,
M. R. Org. Lett. 2009, 11, 879; for fragmentation and coupling of
tertiary alkyl oxalates, see: (b) Ye, Y.; Chen, H.; Sessler, J. L.;
Gong, H. J. Am. Chem. Soc. 2019, 141, 820; for a related fragment
coupling with tertiary radicals generated by visible-light
photocatalysis, see: (c) Jamison, C. R.; Overman, L. E. Acc.
Chem. Res. 2016, 49, 1578; for other two reports involving radical
additions into activated olefins, see: (d) Qin, T.; Malins, L. R.;
Edwards, J. T.; Merchant, R. R.; Novak, A. J. E.; Zhong, J. Z.;
Mills, R. B.; Yan, M.; Yuan, C.; Eastgate, M. D.; Baran, P. S.
Angew. Chem., Int. Ed. 2017, 56, 260; (e) Lo, J. C.; Kim, D.; Pan,
C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.; Qin, T.; Gutiérrez, S.;
Giacoboni, J.; Smith, M. W.; Holland, P. L.; Baran, P. S. J. Am.
Chem. Soc. 2017, 139, 2484.
20. A sole example about Ni/terpy-catalyzed reductive conjugate
addition/enolate trapping of neopentyl iodide with cyclohexenone
and iPr3SiCl, could be found: Shrestha, R.; Weix, D. J. Org. Lett.
2011, 13, 2766, and see compound 4f there.
21. For its preparation in our laboratory, see: Li, W.-D. Z.; Yang, Y.-
R. Org. Lett. 2005, 7, 3107, and references cited therein.
22. For Mn as the terminal reductant, Ni/neocuproine-catalyzed
conjugate addition of aryl iodides to enones with trapping as the
silyl enol ether: Shrestha, R.; Dorn, S. C. M.; Weix, D. J. J. Am.
5. (a) Wheatley, W. B.; Cheney, L. C. J. Am. Chem. Soc. 1952, 74,
1359; (b) Sugihara, J. M.; Schmidt, D. L.; Calbi, V. D.; Dorrence,
S. M. J. Org. Chem. 1963, 28, 1406; (c) Stephenson, B.; Solladié,
G.; Mosher, H. S. J. Am. Chem. Soc. 1972, 94, 4184.
6. For examples, see: (a) Whitmore, F. C.; Rothrock, H. S. J. Am.
Chem. Soc. 1932, 54, 3431; (b) Nordlander, J. E.; Kelly, W. J. J.
Org. Chem. 1967, 32, 4122.
7. To the best of our knowledge, only scattered reports about cross-
coupling of neopentyl iodides (Not Br) could be found: (a) Park,
K.; Yuan, K.; Scott, W. S. J. Org. Chem. 1993, 58, 4866,
however, diarylzincs (not dialkylzincs) were utilized in most of
their cases; Fu also demonstrated Negishi coupling of the
neopentyl iodide in a case, see: (b) Zhou, J.; Fu, G. C. J. Am.
Chem. Soc. 2003, 125, 14726; for a case invovling Fe/NHC-
catalyzed cross-coupling of neopentyl chloride with 4-
MeOPhMgBr, see: (c) Ghorai, S. K.; Jin, M.; Hatakeyama, T.;
Nakamura, M. Org. Lett. 2012, 14, 1066; for a SRN1 reaction of
neopentyl iodide with acetophenone enolate ion induced by FeBr2
in DMSO, see: (d) Nazareno M. A.; Rossi, R. A. J. Org. Chem.
1996, 61, 1645.
8. (a) Petrier, C.; Dupuy, C.; Luche, J. L. Tetrahedron Lett. 1986, 27,
3149; for later modifications and applications, see: (b) Cornella, I.;
Pérez Sestelo, J.; Mouriño, A.; Sarandeses, L. A. J. Org. Chem.
2002, 67, 4707; (c) Lee, C. K. Y.; Herlt, A. J.; Simpson, G. W.;
Willis, A. C.; Easton, C. J. J. Org. Chem. 2006, 71, 3221; (d)
Fleming, F. F.; Gudipati, S. Org. Lett. 2006, 8, 1557; for non-
traditional organocopper mediated conjugate addition to enones in
water, see: (e) Lipshutz, B. H.; Huang, S.; Leong, W. W. Y.;
Zhong, G.; Isley, N. A. J. Am. Chem. Soc. 2012, 134, 19985; for
the addition of neopentyl cuprate, see: (f) James, P.; Neudörfl, J.;
Eissmann, M.; Jesse, P.; Prokop, A.; Schmalz, H.-G. Org. Lett.
2006, 8, 2763; (g) Tuckmantel, W.; Oshima, K.; Nozaki, H. Chem.
Ber. 1986, 119, 1581.
Chem. Soc. 2013, 135, 751
.
23. Newcomb, M. In Radicals in Organic Synthesis; Renaud, P.; Sibi,
M. Ed.; Wiley–VCH: Weinheim, 2001; Vol. 1, Chapter 3.1., pp
317–336.
24. (a) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351; (b) Kochi, J. K.
Angew. Chem., Int. Ed. 1988, 27, 1227; (c) Rossi, R. A.; Pierini,
A. B.; Peñéñory, A. B. Chem. Rev. 2003, 103, 71, and references
cited therein; see also refs. 25 and 26.
25. For this kind of radical probes in relevant reactions, see: (a)
Guérinot, A.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed.
2007, 46, 6521; (b) Ikeda, Y.; Nakamura, T.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2002, 124, 6514.
9. Eck, C. R.; Hodgson, G. L.; MacSweeney, D. F.; Mills, R. W.;
Money, T. J. Chem. Soc., Perkin Trans I 1974, 1938.

ACCEPTED MANUSCRIPT
11
26. For a related hypothesis concerning radical mechanism in Ni-
catalyzed reductive cyclization of organic halides, see: Kim, H.;
Lee, C. Org. Lett. 2011, 13, 2050.
27. For an elegant review about the effects of olefins on cross-
coupling reactions, see: Johnson, J. B.; Rovis, T. Angew. Chem.,
Int. Ed. 2008, 47, 840.
28. For monographs and reviews, see: (a) Corey, E. J.; Cheng, X.-M.
The Logic of Chemical Synthesis; John Wiley & Sons: New York,
1989; Chapter 11; (b) Nicolaou, K. C.; Montagnon, T. Molecules
That Changed the World; Wiley–VCH: Weinheim, 2008; Chapter
15; (c) Das, S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R. Chem.
Rev. 2007, 107, 3286.
29. (a) Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303; (b)
Stork, G.; Sher, P. M.; Chen, H.-L. J. Am. Chem. Soc. 1986, 108,
6384; (c) Keck, G. E.; Burnett, D. A. J. Org. Chem. 1987, 52,
2958; (d) Busato, S.; Tinembart, O.; Zhang, Z.; Scheffold, R.
Tetrahedron 1990, 46, 3155; (e) Ohmiya, H.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2006, 128, 1886.
30. For non-enzyme enantioselective approach, see: Zhao, Y.;
Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006, 443,
67.
31. Corey, E. J.; Czakó, B.; Kürti, L. In Molecules and Medicine; John
Wiley & Sons: Hoboken, 2007; p102.
32. CCDC 1895951 [(−)-9b], CCDC 1895952 [(−)-11a] and CCDC
1895953 [(−)-13] contain the supplementary crystallographic data
for this paper.
33. For reviews, see: (a) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G.
Tetrahetron 1983, 39, 2323; (b) Smith, J. R. Synthesis 1984, 629;
(c) Taylor, S. K. Tetrahetron 2000, 56, 1149; (d) Fleming, F. F.;
Shook, B. C. Tetrahetron 2002, 58, 1.
36. For selected examples, see: (a) Stork, G.; Cama, L. D.;
Coulson, D. R. J. Am. Chem. Soc. 1974, 96, 5268; (b) Stork, G.;
Cohen, J. F. J. Am. Chem. Soc. 1974, 96, 5270; (c) Nicolaou, K.
C.; Snyder, S. A.; Bigot, A.; Pfefferkorn, J. A. Angew. Chem., Int.
Ed. 2000, 39, 1093.
37. For our demonstration in the skeleton construction of eudesmane
sesquiterpenes employing this methodology, see: Shen, S.-J.; Li,
W.-D. Z. J. Org. Chem. 2013, 78, 7112.
38. (a) Peng, Y.; Luo, L.; Yan, C.-S.; Zhang, J.-J.; Wang, Y.-W. J.
Org. Chem. 2013, 78, 10960; (b) Luo, L.; Zhang, J.-J.; Ling, W.-J.;
Shao, Y.-L.; Wang, Y.-W.; Peng, Y. Synthesis 2014, 46, 1908; (c)
Luo, L.; Zhai, X.-Y.; Wang, Y.-W.; Peng, Y.; Gong, H. Chem.-
Eur. J. 2019, 25, 989.
39. Aiken, K. S.; Eger, W. A.; Williams, C. M.; Spencer, C. M.;
Zercher, C. K. J. Org. Chem. 2012, 77, 5942.
40. Francois, H.; Derion, B.; Lalande, R. Bull. Soc. Chim. Fr. 1970,
617.
41. Vieira, T. O.; Green, M. J.; Alper, H. Org. Lett. 2006, 8, 6143.
42. Zhu, H.; Wickenden, J. G.; Campbell, N. E.; Leung, J. C. T.;
Johnson, K. M.; Sammis, G. M. Org. Lett. 2009, 11, 2019.
43. It is commercially available from Aldrich (CAS no. 930-60-9),
and could also be prepared from cyclopentadiene in large scale:
(a) Blomquist, A. I.; Mayes, W. G. J. Org. Chem. 1945, 10, 134;
(b) Korach, M.; Nielsen, D. R.; Rideout, W. H. Org. Synth. 1962,
42, 36; (c) Rasmusson, G. H.; House, H. O.; Zaweski, E. F.;
DePuy, C. H. Org. Synth. 1962, 42, 50.
44. For a reference about monosilylation of symmetric 1, n-diol, see:
McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.
34. For selected examples about influence of the epoxide
stereochemistry on cyclization, see: (a) Martel, J.; Toromanoff, E.;
Mathieu, J.; Nomine, G. Tetrahedron Lett. 1972, 13, 1491; (b)
Lallemand, J. Y.; Onanga, M. Tetrahetron Lett. 1975, 16, 585; (c)
Warnhoff, E. W.; Srinivasan, V. Can. J. Chem. 1977, 55, 1629;
(d) Levin, S. G.; Pat Bonner, M. Tetrahetron Lett. 1989, 30, 4767;
(e) Morin, M. D.; Rychnovsky, S. D. Org. Lett. 2005, 7, 2051.
35. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345.
Click here to remove instruction text...