Zinc-mediated anionic cyclization of unstabilized ketone enolates with unactivated alkenes

Article abstract of DOI:10.1016/j.tet.2020.131417

We report herein general conditions for a zinc-mediated anionic cyclization of unstabilized ketone enolates. This anionic cyclization allows access to various carbocyclic architectures by utilizing abundant ketones and unactivated alkenes as precursors. The transformation is enabled by the use of Zn(TMP)₂ as base and Zn(OTf)₂ as an additive. The resulting alkylzinc species can be intercepted by electrophiles for tandem C–X and C–O bond formation.

Full text of DOI:10.1016/j.tet.2020.131417

Journal Pre-proof
Zinc-mediated anionic cyclization of unstabilized ketone enolates with unactivated
alkenes
Diego Olivieri, David Huang, Alexandra K. Bodnar, Shijin Yu, Timothy R. Newhouse
PII:
S0040-4020(20)30584-6
https://doi.org/10.1016/j.tet.2020.131417
TET 131417
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 March 2020
Revised Date: 14 July 2020
Accepted Date: 15 July 2020
Please cite this article as: Olivieri D, Huang D, Bodnar AK, Yu S, Newhouse TR, Zinc-mediated anionic
cyclization of unstabilized ketone enolates with unactivated alkenes, Tetrahedron (2020), doi: https://
doi.org/10.1016/j.tet.2020.131417.
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Zinc-Mediated Anionic Cyclization of
Unstabilized Ketone Enolates with
Unactivated Alkenes
Leave this area blank for abstract info.
Diego Olivieri, David Huang, Alexandra K. Bodnar, Shijin Yu, and Timothy R. Newhouse
225 Prospect Street, New Haven, CT 06511
[Zn]
O
O
[Zn]
X
O
anionic
cyclization
electrophilic
trapping
R
R
R
X = H, Cl, Br, I, O

1
Tetrahedron
journal homepage: www.elsevier.com
Zinc-mediated anionic cyclization of unstabilized ketone enolates with unactivated
alkenes
Diego Olivieri,a,† David Huang,a,† Alexandra K. Bodnar,a Shijin Yu,a and Timothy R. Newhousea*
aDepartment of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06511
†These authors contributed equally.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report herein general conditions for a zinc-mediated anionic cyclization of unstabilized
ketone enolates. This anionic cyclization allows access to various carbocyclic architectures by
utilizing abundant ketones and unactivated alkenes as precursors. The transformation is enabled
by the use of Zn(TMP)2 as base and Zn(OTf)2 as an additive. The resulting alkylzinc species can
be intercepted by electrophiles for tandem C–X and C–O bond formation.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
anionic cyclization
zinc enolate
unactivated alkene
ketone
organozinc
A. Carbocyclization of
RO2C
α
- and
β
-Amino Ester Zinc Enolates
Me
RO2C
1. Introduction
1. LDA
2. ZnBr2
n
n
N
R
N
R
The formation of new carbon-carbon bonds via the
carbometalation of unactivated olefins is a powerful synthetic
strategy for converting cheap and abundant feedstock olefins into
higher value products. The carbozincation of alkenes1 is a
particularly useful transformation, as the resulting alkylzinc
intermediates can be readily functionalized via transmetalation to
other transition metal species (Pd, Ni, Cu, Co, Fe) for further
derivatization.2
n = 0 or 1
B. Carbocyclization of Zincated Hydrazones
Me2N
R
1. t-BuLi
2. ZnBr2
3. n-BuLi
Me2N
N
N
Me
R
Seminal studies by Normant and Marek demonstrated that
carbocyclization reactions of organozinc reagents and
unactivated alkenes are valuable synthetic tools for constructing
carbocycles.3 Initial developments in the area of zinc-mediated
intramolecular metallo-ene-allene reactions3a led to the discovery
C. Carbocyclization of Unstabilized Ketone Zinc Enolates (This Work)
O
O
Me
Zn(TMP)2, Zn(OTf)2
R
R
of an anionic cyclization of zinc enolate derivatives,3h,4
a
contrathermodynamic reaction wherein the resulting alkyl metal
species is more basic than the initial enolate.4 α− or β−amino
ester zinc enolates generated by deprotonation with LDA
followed by transmetalation with ZnBr2 were shown to
diastereoselectively cyclize onto unactivated pendant olefins to
give substituted pyrrolidines and piperidines (Figure 1A).5
Related studies revealed that zinc enolates generated by 1,4-
addition of dialkylzinc reagents to unsaturated carbonyls could
also undergo carbozincation with a pendant olefin to provide
substituted proline and pyrrolidine products.6
Figure 1. Carbocyclization of unactivated alkenes with zinc
enolate derivatives.
exploited to prepare proline chimeras of proteinogenic amino
acids in order to study structure activity relationships of
biologically active peptides.7
Another class of intramolecular alkene carbozincation
reactions with enolate derivatives include Nakamura’s work with
zincated hydrazones (Figure 1B).8 Deprotonation of an N,N-
dimethylhydrazone with t-BuLi, followed by formation of the
Concurrent studies by Karoyan and Chassaing also showed
that the aminoester enolate carbozincation reaction can be

2
Tetrahedron
zincate via the successive addition of ZnBr2 and n-BuLi, enables
cyclization with a pendant terminal olefin to give 5- and 6-exo-
trig cyclization products with good cis-diastereoselectivity.
Lactams were also found to be suitable substrates for this
reaction. These important preliminary studies led to the
development of multicomponent alkene functionalization
reactions with azaenolates derivatives, including zincated
hydrazones and zinc enamides.9
(entry 6), toluene (entry 7), and trifluorotoluene (entry 8) gave
lower conversions, even after attempting to promote conversion
Table 1. Optimization of Anionic Cyclization
O
O
Me
H
Zn(TMP)2 (1.2 equiv)
additive (1.5 equiv)
Me
Me
Me
Me
solvent, 80 °C, 4 h
Me
Me
2a
1a
In both transformations, the presence of a coordinating N-
heteroatom on the substrate was crucial for promoting efficient
reactivity and stereoselectivity, but limits the scope and
availability of starting materials. A general method for the
anionic cyclization of unstabilized ketone enolates with
unactivated alkenes has not been reported, despite the prevalence
of ketones in biologically relevant organic molecules. This
transformation would offer significant advantages over the
classical thermal Conia-Ene reaction,10 such as milder reaction
conditions, formation of a reactive intermediate that can undergo
further derivatization, and does not require the use of precious
transition metals such as Pd,11 Au,12 Rh,13 or Ir,14 for which
Entry
Additive
Solvent
Yield (%)a
1
2
3
4
5
none
ZnCl2
ZnBr2
ZnI2
THF
THF
THF
THF
THF
23
20
10
13
75
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
none
6
7
8
8
10
11
1,4-dioxane
toluene
PhCF3
DCE
52
52
32
87
92b
48
DME
DME
a1H-NMR yield was determined using 1,3,5-trimethoxybenzene as an internal
related enolate alkylations with olefins have been developed.15
A
standard. bIsolated yield.
carbozincation with simple ketone enolates would expand the
scope of products that can be accessed, and obviates the need to
prepare an activated species, such as a hydrazone, in a separate
operation.
using higher temperatures with these higher boiling solvents.
Interestingly, the use of 1,2-dichloroethane (DCE) provided a
subtle increase in yield (entry 9). Finally, we found that the
optimal conditions required 1,2-dimethoxyethane (DME) as
We recently reported an anionic cyclization of ketone zinc
1
solvent, which afforded 2a in 92% H-NMR and isolated yield
enolates that may play
a role in the nickel-catalyzed
cycloalkenylation16 and alkene difunctionalization reactions of
ketone enolates.17 However, the conditions used in connection
with nickel catalysis were not directly applicable to cyclization
and electrophile capture. Herein we report general conditions for
the anionic cyclization of ketone zinc enolates and an expansion
of the scope of ketone scaffolds that can undergo this cyclization
reaction. Furthermore, in addition to protonation, we demonstrate
that the resulting alkylzinc species can be intercepted for C−X (X
= Cl, Br, I) and C−O bond formation.
(entry 10). The use of DME with no Lewis acid additive revealed
that the change in solvent from THF alone also provided a
dramatic increase in yield (entry 11). Although speculating on the
reason for this is challenging, a solvent change may perturb the
Schlenk equilibrium, which can result in changes to the
aggregation state of the reactive enolates, as well as the ligands
bound to zinc, to provide a more efficient reaction. Additionally,
solvent-induced conformational changes may also reduce the
kinetic barrier to cyclization.
2.2. Substrate scope of anionic cyclization
2. Results and Discussion
With the optimized conditions in hand, we explored the scope
of the zinc-mediated anionic cyclization (Table 2). 5-exo-trig
cyclizations were similarly efficient, providing 2b−2e in
excellent yields. Remarkably, substrates with two enolizable
positions selectively underwent cyclization to form the cis-fused
bicycle over unproductive pathways or the possible bridged-
bicycle (2e−2f), suggesting that proton transfer between the two
enolizable positions occurs. This advancement overcomes the
need to have kinetic enolate formation for efficient reactivity,
which is a general limitation with our previously reported
enolate-initiated carbocyclizations with unactivated alkenes.16,17
Complex polycyclic products such as 2g–2i were also obtained
under the optimized conditions, and highlights the utility of this
transformation for late stage functionalization of complex
architectures. Acyclic methyl ketones were employed to access
spirocyclic products 2j and 2k as well as cyclohexanone
derivatives 2l and 2m. γ,γ-disubstituted cyclohexanones
selectively cyclized with the longer O-tethered alkene over the
shorter allyl group to form the tetrahydropyran containing
bicyclo[3.3.1]nonane product 2n. Access to 2n is also an
additional example of proton transfer being tolerated under the
reaction conditions. Cyclohexenones bearing an appropriately
long butenyl moiety at the γ-position can cyclize to give the all-
carbon bicyclo[3.3.1]nonane product (2o). Similarly, the
Wieland-Miescher ketone derivative 2p can be accessed, with
cyclization occurring selectively at the more thermodynamically
2.1. Optimization studies
In our previous reports,16,17 we identified that that an anionic
cyclization of zinc enolates and alkenes can be effected by
heating the substrate in the presence of Zn(TMP)2 as base, albeit
in low conversions. Thus, we commenced our optimization using
Zn(TMP)2 and 1a, which was identified as a more challenging
model substrate (Table 1) based on our observations that the 6-
exo-trig cyclization provided lower conversions relative to the
corresponding 5-exo-trig cyclization using the same verbenone
scaffold. In the absence of additives, the zinc cyclization only
provided 23% of 2a (entry 1), with the remainder of the mass
balance being unreacted starting material.
Surprisingly, an examination of zinc halides as additives
(entries 2–4) did not provide an improvement to the conversion,
which is in contrast to our observations for the 5-exo-trig
cyclization wherein ZnBr2 was sufficient for promoting the
cyclization.16 Remarkably, the use of strongly Lewis acidic
Zn(OTf)2 as an additive provided a significant increase in the
yield of 2a (75%, entry 5). Surprisingly, the use of other triflate
salts (Li, Mg, Cu, Fe, Sc, n-Bu4N) were ineffective for promoting
this transformation (see Supplementary Data), highlighting the
essential role of the zinc cation.18
Next, we explored solvents to further optimize the conversion
of the carbozincation. The use of solvents such as 1,4-dioxane

3
stable enolate. Attempts to form bicyclo[3.2.1]octane products
coupling reactions,2 having access to both the alkylzinc and
alkyl halide species broadens the range of reactions that are
accessible. We found that the addition of four equivalents of
commercially available and operationally convenient N-
halosuccinimides was necessary for complete conversion of the
organozinc intermediate to the desired carbohalogenation
product.
from γ,γ-
Table 2. Substrate Scope of Anionic Cyclization
Using N-chlorosuccinimide, carbochlorination products 3a–3b
could be obtained. N-Bromosuccinimide could also be used to
give carbohalogenation products 3c–3e, and generally proceeded
more efficiently than the corresponding chlorination reactions.
Carboiodination with N-iodosuccinimide to give products 3f and
3h was also successful. Carboiodination using I2 as the halogen
source was similarly efficient, providing 3g in excellent yield,
and represents a more atom economical halogenating source.
Importantly, alkene functionality (3b, 3e) which are well known
to undergo halogenation reactions in the presence of N-
halosuccinimides, was tolerated under the reaction conditions.
Alkylzinc halides have also been demonstrated in the
literature to undergo oxidation in the presence of O2.19 Therefore,
we hypothesized that aerobic oxidation of the alkylzinc species
generated by our anionic cyclization conditions should also be
feasible. Indeed, stirring the alkylzinc species under an oxygen
atmosphere provided the corresponding alcohol (3i) and aldehyde
(3j) products with a combined yield of 50%, and demonstrates
the possibility of tandem C–C/C–O bond formation by this
approach.
Table 3. Substrate Scope of Alkene Difunctionalization
disubstituted cyclohexenones bearing an allyl group were
unsuccessful due to poor conversion. Furthermore, poor
conversion was observed if a quaternary center is not present on
the tethered alkene, or when internal alkenes were employed. The
failure of internal olefins to participate in this transformation
suggests that a radical cyclization is unlikely. While the
cyclization reaction exclusively provided cis-fused products for
bicyclic systems,5a,5b the relative stereochemistry of the resulting
methyl group on the newly formed ring depends on the structure
of the ketone scaffold. More structurally rigid motifs provided
better diastereoselectivity for the more thermodynamically
favored product, wherein the methyl group is situated on the less-
hindered, convex face of the resulting bicyclic system.
2.3. Substrate Scope of Alkene Difunctionalization
aI2 was used as the halogen source.
With the scope of the anionic cyclization established, we
hypothesized that the resulting alkylzinc species could be trapped
by the addition of electrophiles to allow for an alkene
difunctionalization reaction (Table 3). We were particularly
interested in exploring the use of electrophilic halogenating
reagents as electrophiles, as the resulting alkyl halide products
are versatile and valuable intermediates that can be used for
subsequent derivatization via substitution or cross-coupling
reactions. While the cyclized alkylzinc species could directly be
used for further substrate elaboration through Negishi-type cross-
2.4. Mechanistic studies
Preliminary mechanistic studies were conducted to further
investigate the nature of the zinc cyclization. Upon complete
consumption of 1a under the reaction conditions, the resulting
intermediate can be quenched with D2O to afford the deuterated
product 2a-d1 in 68% isolated yield with 60% deuterium
incorporation (Figure 2A), confirming the presence of an
alkylzinc intermediate.

4
Tetrahedron
In order to understand why only 60% deuterium
with D2O afforded hydrodehalogenation product 2a-d1 in 22%
yield with 47% deuterium incorporation (Figure 2D),
demonstrating the feasibility of forming similar organozinc
species by conventional approaches. However, ring opened
product 1a-d1 was obtained in 54% yield and determined to have
48% deuterium incorporation at the α-position. The analogous
reaction conducted in DME as solvent resulted in the formation
of dehalogenated species 2a in 11% yield and ring opened
product 1a in 89% yield. Attempts to achieve alkylzinc formation
from 3g via zinc-halide exchange using Et2Zn resulted in 4% ring
opened product 1a and 90% unreacted halide (see Supplementary
Data).20 These results highlight the challenge of zinc enolate
cyclizations with unactivated alkenes due to the
thermodynamically favored reverse reaction. The ring opening
reaction may proceed via anionic opening with transfer of the
zinc ion from C to O, or via a radical-mediated mechanism
involving homolytic fragmentation of the carbon-zinc bond.21 In
contrast, the zinc cyclization under our optimized conditions
provides a straightforward and operationally simple method to
access functionalized alkylzincs in high yields and conversions,
and suggests the structure of the ZnX species (either ZnTMP,
ZnOTf, or some other aggregate) is important for driving the
equilibrium between the zinc enolate and alkylzinc towards the
cyclized product.
incorporation was observed, we wanted to probe whether radical
intermediates6,20 could be involved. If a radical process was
operative, deuterated product 2a-d1 should be observed when a
A. A stable alkylzinc intermediate is formed
D
O
O
60% D
H
Zn(TMP)2, Zn(OTf)2
DME, 80 oC, 4 h
Me
Me
then D2O
Me
Me
Me
1a
Me
2a-d1 (68%)
B. Hydrogen atom abstraction from solvent is not observed
D
O
O
H
Zn(TMP)2, Zn(OTf)2
THF-d8, 80 oC, 4 h
Me
Me
Me
Me
Me
1a
Me
2a-d1 (0%)
C. Proton transfer does not occur
H
O
O
D
D
D
Zn(TMP)2, Zn(OTf)2
DME, 80 oC, 4 h
Me
Me
Me
Me
Me
Me
3. Conclusion
2a-d2 (90%)
1a-d2
D. Preparation of related Negishi reagent is challenging
In conclusion, we have developed an efficient anionic
cyclization of unactivated ketone zinc enolates and unactivated
alkenes using Zn(TMP)2 as base and Zn(OTf)2 as an additive.
The choice of DME as solvent provided a significant increase in
the efficiency of the carbozincation reaction. This specific
combination of additive and solvent was crucial for achieving a
broad substrate scope. The reaction provides access to a variety
48% D
I
D
O
O
O
Zn, LiCl
47% D
H
H
D
THF, 70 oC, 6 h
then D2O
Me
Me
Me
Me
Me
Me
Me
3g
Me
Me
2a-d1 (22%)
1a-d1 (54%)
of carbocyclic skeletons and generates
a reactive and
Figure 2. Mechanistic studies.
conventionally challenging to access alkylzinc species that can
undergo further reaction with electrophiles to give products that
have undergone protonation, halogenation, or hydroxylation. We
anticipate this strategy for C–C bond formation to have broad
utility in multistep synthesis as it provides an approach to
construct cyclic systems using commonly found ketone and
unactivated alkene functional groups, while also forming stable
and reactive functionalized organozinc species for further
derivatization.
deuterated solvent is used for the cyclization reaction, as the
primary alkyl radical formed after cyclization should quickly
abstract a deuteride from the deuterated solvent. While no
deuterated products were obtained using THF-d8 as solvent
(Figure 2B), which argues against an intermediate alkyl radical
undergoing hydrogen atom abstraction, we cannot rule out the
possibility that the radical formed after cyclization is rapidly
reduced by a Zn(II) species20c to prevent deuterium transfer from
the solvent.
4. Experimental Section
Compound 1a-d2 was prepared to investigate whether the
incomplete deuterium incorporation was the result of proton
exchange between the cyclized alkylzinc species and the more
acidic ketone α-protons (Figure 2C). However, after dideuterated
compound 1a-d2 was subjected to the standard conditions and an
aqueous quench, compound 2a-d2 was obtained with no
deuterium incorporation at the methyl group, suggesting that
proton transfer does not occur, despite the primary alkylzinc
species being more basic than the carbonyl α-protons.
Furthermore, these results suggest that the TMP-D formed after
deprotonation also did not undergo proton transfer with the
primary alkylzinc species, as no dideuterated products were
observed after the reaction. The incomplete deuteration
previously observed is likely the result of the alkylzinc species
being quenched by adventitious water. Longer reaction times or
higher reaction temperatures with D2O did not result in higher
levels of deuterium incorporation.
4.1. General Experimental Procedures
All reactions were carried out under an inert nitrogen
atmosphere with dry solvents under anhydrous conditions unless
otherwise stated. All reactions were capped with a rubber septum,
or Teflon-coated silicon microwave cap unless otherwise stated.
Stainless steel cannula or syringe was used to transfer solvent,
and air- and moisture sensitive liquid reagents. Reactions were
monitored by thin-layer chromatography (TLC) carried out on
0.25 mm Merck silica gel plates (60F-254) using UV light as the
visualizing agent and potassium permanganate, an acidic solution
of p-anisaldehyde, phosphomolybdic acid, or I2 on SiO2 as
developing agents. Flash column chromatography employed
SiliaFlash® P60 (40-60 μm, 230-400 mesh) silica gel purchased
from SiliCycle, Inc.
4.2. Materials
All reaction solvents were purified using a Seca solvent
purification system by Glass contour. CuBr·SMe2 was prepared
and purified according to the literature procedure.22 Zn(TMP)2
Attempts to prepare the related Negishi reagent in THF from
alkyl iodide 3g by direct zinc insertion, followed by quenching

5
(0.5 M in toluene) was purchased from Sigma-Aldrich or
prepared according to the literature procedure.17 4-bromo-1-
butene was purchased from Oakwood Products, Inc and purified
via neat filtration through a 2 cm pad of dry silica in a 5.75 inch
pipette prior to use. All other reagents were used as received
without further purification, unless otherwise stated.
(0.8 mmol, 4.0 equiv) in THF (2.0 mL, 0.4 M) was added
dropwise. The reaction vessel was removed from the ice-water
bath and the reaction mixture was stirred at ambient temperature
for 30 minutes.
To the reaction mixture was added sat. aq. NH4Cl (1 mL) and
Et2O (1 mL). The organic phase was separated and the aqueous
phase was extracted with Et2O (2 x 1 mL). For carboiodination
reactions, the combined organic extracts were washed with sat.
aq. Na2S2O3 (2 mL) until the red color of iodine faded. The
organic extracts were filtered over a small pad of dry silica gel
and concentrated under reduced pressure by rotary evaporation.
The crude mixture was purified by flash column chromatography
on silica gel.
4.3. Instrumentation
All new compounds were characterized by means of 1H-
NMR, 13C-NMR, FT-IR (thin film), and GC-MS. Copies of the
1H- and 13C-NMR spectra can be found at the end of each
experimental procedure. NMR spectra were recorded using a
Varian 400 MHz NMR spectrometer, Varian 500 MHz NMR
1
spectrometer, or a Varian 600 MHz NMR spectrometer. All H-
NMR data are reported in δ units, parts per million (ppm), and
were calibrated relative to the signals for residual chloroform
(7.26 ppm) in deuterochloroform (CDCl3). All 13C-NMR data are
reported in ppm relative to CDCl3 (77.16 ppm) and were obtained
with 1H decoupling unless otherwise stated. The following
abbreviations or combinations thereof were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, abq
= ab quartet, br = broad, m = multiplet, and a = apparent. All IR
spectra were taken on an FT-IR/Raman Thermo Nicolet 6700.
Gas chromatography mass spectra (GC-MS) were recorded on an
Agilent Technologies 6890N Network Gas Chromatograph
System with an Agilent Technologies 5973N Mass Selective
Detector. Optical rotation data was obtained using a Perkin-
Elmer 341 polarimeter or a Rudolph Autopol IV polarimeter.
4.5. Substrate Synthesis
Ketones 1a, 1b, 1c, 1d, 1h, 1i, 1j, 1k, 1l, 1m, 1n, 1o, 1p, and
1q were prepared according to our previously reported
procedures.16,17 Ketones 1e23 and 1f24 were prepared according to
the literature procedure. See the Supplementary Data for more
details.
4.5.1. (1S,4S,5R)-4-(2-allylphenyl)-4,6,6-trimethylbicyclo[3.1.1]
heptan-2-one (1g)
To a flame-dried 20 mL microwave vial was added
magnesium turnings (52.8 mg, 2.2 mmol, 1.2 equiv) and a
catalytic amount of I2 (ca 5 mg). The reaction vessel was capped,
evacuated, and backfilled with N2 and THF (4.0 mL, 0.5 M) was
added to the reaction vessel. The reaction vessel was then moved
o
to a 70 C pre-heated oil bath and stirred for 10 minutes. The
4.4. General Procedures
reaction vessel was then removed from the oil bath and to the
reaction mixture was added 1-allyl-2-bromobenzene (0.3 mL, 2.0
mmol, 1.1 equiv) dropwise over 15 minutes as to maintain a
gentle reflux. The reaction vessel was then moved back to a 70
oC oil bath and stirred for 30 minutes. The reaction vessel was
then removed from the oil bath and cooled to ambient
temperature.
4.4.1. General Procedure for Anionic Cyclization
To a flame-dried, 10 mL microwave vial equipped with a
magnetic stir bar was added Zn(OTf)2 (109.1 mg, 0.30 mmol, 1.5
equiv). The vial was capped, evacuated, and flame-dried under
vacuum for 10 seconds (this process was repeated 3 times). The
reaction vessel was backfilled with N2 before 1,2-
dimethoxyethane (2 mL, 0.1 M) was added. To the stirred
mixture was added ketone 1 (0.2 mmol, 1.0 equiv) and Zn(TMP)2
(0.48 mL, 0.5 M in toluene, 0.24 mmol, 1.2 equiv). The reaction
vessel was sealed with parafilm, and placed in an 80 oC preheated
oil bath and stirred until complete conversion was observed by
thin layer chromatography (2−6 hours).
The reaction vessel was removed from the oil bath and cooled
to ambient temperature before sat. aq. NH4Cl (1 mL) and Et2O (1
mL) was added. The organic phase was separated and the
aqueous phase was extracted with Et2O (2 x 1 mL). The
combined organic extracts were filtered over a small pad of dry
silica gel and concentrated under reduced pressure by rotary
evaporation. The crude mixture was purified by flash column
chromatography on silica gel.
In a separate flame-dried 20 mL microwave vial equipped
with a magnetic stir bar was added CuBr•SMe2 (41.3 mg, 0.2
mmol, 10 mol %). The reaction vessel was evacuated and
backfilled with N2 before THF (4 mL, 0.45 M) was added to the
o
reaction vessel. The reaction mixture was then cooled to −40 C
in a dry ice-acetonitrile bath and the previously prepared
Grignard solution was added dropwise over 15 minutes. The
o
reaction mixture was stirred at −40 C for 30 minutes before it
o
was cooled to −78 C in a dry ice-acetone bath and SI-1 (0.28
mL, 1.8 mmol, 1.0 equiv) was added dropwise. The reaction
mixture was stirred for 12 hours and slowly warmed to ambient
temperature.
To the reaction mixture was added sat. aq. NH4Cl (10 mL)
and Et2O (10 mL). The organic phase was separated and the
aqueous phase was extracted with Et2O (2 x 10 mL). The
combined organic extracts were washed with brine (30 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure by rotary evaporation. Purification by flash
column chromatography on silica gel (10% Et2O/hexanes)
afforded 1g (270.3 mg, 56%) as a yellow oil. Rf: 0.36 (10%
Et2O/hexanes) [α]20D: −16.0° (c 1.0, CHCl3) 1H NMR (400 MHz,
CDCl3): δ 7.28 (dd, J = 7.6, 1.6 Hz, 1H), 7.19–7.10 (m, 2H), 7.00
(d, J = 7.2 Hz, 1H), 5.99 (ddt, J = 16.4, 10.0, 6.0 Hz, 1H), 5.14–
5.05 (m, 2H), 3.51 (d, J = 6.0 Hz, 2H), 2.99 (s, 2H), 2.75–2.70
(m, 2H), 2.55 (at, J = 4.8 Hz, 1H), 1.54 (s, 3H), 1.53–1.51 (m,
1H), 1.50 (s, 3H), 1.14 (s, 3H) 13C NMR (101 MHz, CDCl3): δ
213.4, 149.6, 138.1, 137.8, 132.9, 126.0, 125.9, 124.9, 116.5,
55.9, 52.8, 50.6, 40.1, 39.7, 38.5, 30.2, 27.9, 27.0, 25.9 IR (cm–
1): 2925, 1711, 1637, 1483, 1255, 1202, 987, 914, 760, 503, 467
GC-MS (m/z): [M] calc’d for C19H24O: 268.2; found: 268.1.
4.4.2. General Procedure for Carbohalogenation
To a flame-dried, 10 mL microwave vial equipped with a
magnetic stir bar was added Zn(OTf)2 (109.1 mg, 0.30 mmol, 1.5
equiv). The vial was capped, evacuated, and flame-dried under
vacuum for 10 seconds (this process was repeated 3 times). The
reaction vessel was backfilled with N2 before 1,2-
dimethoxyethane (2 mL, 0.1 M) was added. To the stirred
mixture was added ketone 1 (0.2 mmol, 1.0 equiv) and Zn(TMP)2
(0.48 mL, 0.5 M in toluene, 0.24 mmol, 1.2 equiv). The reaction
vessel was sealed with parafilm, and placed in an 80 oC preheated
oil bath and stirred until complete conversion was observed by
thin layer chromatography (2−6 hours).
The reaction vessel was removed from the oil bath and placed
into a 0 oC ice-water bath and stirred for 10 minutes before NXS

6
Tetrahedron
43.5, 40.7, 39.2, 35.1, 33.7, 33.5, 29.8, 27.1, 26.7, 20.5 IR (cm–
4.6. Product Characterization
1): 2952, 2866, 1693, 1458, 1381, 1116, 1072, 555 GC-MS
(m/z): [M] calc’d for C13H22O: 194.2; found: 194.2.
4.6.1.
(1R,3S,5S,8aR)-2,2,5,8a-tetramethyloctahydro-1,3-
methan-onaphthalen-4(1H)-one (2a)
4.6.5. 3,7a-dimethyloctahydro-4H-inden-4-one (2e)
Compound 2a was prepared from 1a (44.1 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (4 hours).
Purification by flash column chromatography on silica gel (3%
Et2O/hexanes) afforded 2a (40.6 mg, 92%) as a colorless oil. Rf:
0.45 (10% Et2O/hexanes): [α]20D: −62.0° (c 1.0, CHCl3) 1H NMR
(400 MHz, CDCl3): δ 2.51 (at, J = 5.2 Hz, 1H), 2.44 (adt, J =
10.8, 6.4 Hz, 1H), 1.89–1.82 (m, 1H), 1.80 (at, J = 6.0 Hz, 1H),
1.75–1.54 (m, 6H), 1.34 (s, 3H), 1.27–1.21 (m, 1H), 1.19 (s, 3H),
1.11 (d, J = 6.4 Hz, 3H), 1.04 (s, 3H), 0.99–0.95 (m, 1H) 13C
NMR (101 MHz, CDCl3): δ 215.7, 59.3, 58.8, 55.0, 40.6, 35.9,
32.2, 31.5, 30.5, 28.0, 27.7, 25.8, 25.2, 22.4, 16.7 IR (cm–1):
2946, 2870, 1463, 1378, 1259, 1203, 1097, 1033, 804, 517 GC-
MS (m/z): [M] calc’d for C15H24O: 220.2; found: 220.2.
Compound 2e was prepared from 1e (33.2 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (2 hours).
Purification by flash column chromatography on silica gel (5%
Et2O/hexanes) afforded 2e (22.6 mg, 68%, dr = 2:1) as a
1
colorless oil. Rf: 0.55 (20% Et2O/hexanes) H NMR (400 MHz,
CDCl3): δ 2.45–2.37 (m, 0.33H), 2.36–2.28 (m, 0.33H), 2.25–
2.17 (m, 1.67H), 2.09–2.02 (m, 1H), 1.95–1.86 (m, 1.67H), 1.85–
1.75 (m, 1.33H), 1.73–1.66 (m, 1.67H), 1.64–1.59 (m, 1H), 1.57–
1.56 (m, 0.67H), 1.53–1.52 (m, 0.33H), 1.43–1.28 (m, 1H), 1.15–
1.08 (m, 1H), 1.07 (s, 0.67H), 1.00–0.96 (m, 5.33H) 13C NMR
(151 MHz, CDCl3): δ 215.6, 215.2, 69.5, 53.8, 50.2, 47.6, 40.5,
40.5, 39.2, 38.1, 37.9, 34.3, 33.9, 33.2, 32.9, 32.3, 30.9, 26.9,
25.3, 22.6, 22.3, 20.2 IR (cm–1): 2952, 2925, 2868, 1710, 1459,
1379, 1233, 1098, 804, 503 GC-MS (m/z): [M] calc’d for
C11H18O: 166.1; found: 166.2.
4.6.2.
(1S,3aR,4R,6S)-1,3a,5,5-tetramethyloctahydro-7H-4,6-
methanoinden-7-one (2b)
Compound 2b was prepared from 1b (41.3 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (2 hours).
Purification by flash column chromatography on silica gel (2%
Et2O/hexanes) afforded 2b (39.7 mg, 96%) as a pale-yellow oil.
4.6.6. 3a,7-dimethyloctahydro-1H-inden-1-one (2f)
Compound 2f was prepared from 1f (33.3 mg, 0.20 mmol, 1.0
equiv) according to the general procedure (4 hours). Purification
by flash column chromatography on silica gel (3% Et2O/hexanes)
afforded 2f (21.4 mg, 64%) as a pale-yellow oil. Rf: 0.41 (10%
1
Rf: 0.43 (10% Et2O/hexanes) [α]20D: −59.0° (c 1.0, CHCl3) H
1
NMR (400 MHz, CDCl3): δ 2.50 (at, J = 5.2 Hz, 1H), 2.42 (adt, J
= 10.8, 6.4 Hz, 1H), 2.00 (at, J = 6.0 Hz, 1H), 1.95–1.89 (m, 1H),
1.84 (d, J = 10.0 Hz, 1H), 1.84–1.78 (m, 1H), 1.71–1.61 (m, 2H),
1.44–1.37 (m, 2H), 1.35 (s, 3H), 1.25 (d, J = 6.4 Hz, 3H), 1.21 (s,
3H), 0.98 (s, 3H) 13C NMR (101 MHz, CDCl3): δ 216.4, 62.9,
58.4, 52.3, 44.6, 44.5, 42.9, 41.1, 34.5, 29.3, 27.4, 25.8, 25.2,
21.4 IR (cm–1): 2947, 2871, 1700, 1462, 1376, 1269, 1201, 1041,
1006, 828, 751, 524 GC-MS (m/z): [M] calc’d for C14H22O:
206.2; found: 206.2.
Et2O/hexanes) H NMR (400 MHz, CDCl3): δ 2.36–2.21 (m,
2H), 2.09–2.01 (m, 1H), 1.63–1.29 (m, 8H), 1.00 (s, 3H), 0.98 (d,
J = 8.0 Hz, 3H), 0.97–0.92 (m, 1H) 13C NMR (101 MHz,
CDCl3): δ 220.5, 63.1, 38.7, 34.9, 34.7, 32.8, 30.5, 29.3, 29.3,
20.7, 19.9 IR (cm–1): 2323, 2870, 1736, 1455, 1379, 1152, 1113,
993, 507 GC-MS (m/z): [M] calc’d for C11H18O: 166.1; found:
166.2.
4.6.7.
(2S,4R,4aR,10S)-3,3,4a,10-tetramethyl-3,4,4a,9,10,10a-
hexahydro-2,4-methanophenanthren-1(2H)-one (2g)
4.6.3.
(3S,5R,7aR)-5-isopropyl-3,7a-dimethyloctahydro-4H-
Compound 2g was prepared from 1g (53.7 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (4 hours).
Purification by flash column chromatography on silica gel (3%
Et2O/hexanes) afforded 2g (28.2 mg, 53%) as a white solid. Rf:
0.42 (10% Et2O/hexanes) [α]20D: −70.0° (c 1.0, CHCl3) 1H NMR
(400 MHz, CDCl3): δ 7.24–7.17 (m, 2H), 7.10 (atd, J = 6.8, 1.2
Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 2.97–2.89 (m, 1H), 2.67–2.60
(m, 2H), 2.51–2.41 (m, 3H), 2.25 (adt, J = 11.2, 6.0 Hz, 1H),
1.59 (s, 3H), 1.39 (s, 3H), 1.20 (s, 3H), 1.09 (d, J = 7.2 Hz, 3H),
0.94 (d, J = 10.8 Hz, 1H) 13C NMR (101 MHz, CDCl3): δ 214.3,
144.5, 135.5, 129.4, 126.8, 126.3, 125.8, 58.2, 58.1, 56.0, 40.4,
39.3, 35.0, 31.0, 28.9, 27.7, 26.0, 25.2, 20.9 IR (cm–1): 2944,
2843, 1702, 1447 1381, 1254, 1181, 973, 760, 729, 520, 487 GC-
MS (m/z): [M] calc’d for C19H24O: 268.2; found: 268.1
inden-4-one (2c)
Compound 2c was prepared from 1c (41.7 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (4 hours).
Purification by flash column chromatography on silica gel (2%
Et2O/hexanes) afforded 2c (27.7 mg, 66%, dr = 2:1) as a
colorless oil. Rf: 0.50 (10% Et2O/hexanes) [α]20D: −13.0° (c 1.0,
1
CHCl3) H NMR (400 MHz, CDCl3): δ 2.45–2.33 (m, 0.33H),
2.26–2.13 (m, 2H), 2.09–2.00 (m, 0.33H), 1.97–1.75 (m, 3.67H),
1.73–1.60 (m, 1.67H), 1.57–1.52 (m, 1H), 1.50–1.43 (m, 1H),
1.41–1.20 (m, 2H), 1.10 (s, 2H), 1.04 (s, 1H), 1.03 (d, J = 6.4 Hz,
2H), 0.96 (d, J = 6.4 Hz, 1H), 0.92 (d, J = 6.8 Hz, 2H), 0.90 (d, J
= 6.4 Hz, 1H), 0.85–0.83 (m, 3H) 13C NMR (101 MHz, CDCl3):
δ 215.7, 215.3, 70.0, 68.0, 55.5, 52.1, 48.3, 45.0, 40.7, 40.4, 38.9,
38.7, 36.0, 34.7, 33.7, 32.7, 30.9, 28.5, 26.5, 26.3, 24.7, 21.6,
21.3, 21.3, 20.4, 20.3, 19.4, 18.6 IR (cm–1): 2952, 2868, 1694,
1458, 1377, 1368, 1169, 986, 659, 563 GC-MS (m/z): [M] calc’d
for C14H24O: 208.2; found: 208.2.
4.6.8. (2S,4aR,4bS,6aS,8S,10aR,10bR,10cR)-2-((tert-butyldi
methylsilyl)oxy)-4a,6a,8,10a-tetramethyl-2,3,4,4a,4b,5,6,6a,7a,
8,9,10,10a,10b,10c,11-hexadecahydropentaleno[1,2-a]phen-
anthren-7(1H)-one (2h)
Compound 2h was prepared from 1h (47.1 mg, 0.10 mmol,
1.0 equiv) according to the general procedure (4 hours).
Purification by flash column chromatography on silica gel (3%
Et2O/hexanes) afforded 2h (43.8 mg, 93%) as a white solid. Rf:
0.45 (10% Et2O/hexanes) [α]20D: −44.0° (c 1.0, CHCl3) 1H NMR
(400 MHz, CDCl3): δ 5.35 (bs, 1H), 3.51–3.45 (m, 1H), 2.59 (d, J
= 7.6 Hz, 0.33 H), 2.30–2.23 (m, 2H), 2.20–2.14 (m, 2.67 H),
1.95–1.86 (m, 1H), 1.84–1.80 (m, 2H), 1.76–1.72 (m, 3H), 1.67–
1.59 (m, 3H), 1.46–1.35 (m, 2H), 1.31–1.13 (m, 6H), 1.11–1.02
(m, 11H), 0.89 (s, 9H), 0.06 (s, 6H) 13C NMR (151 MHz,
4.6.4. 3,5,5,7a-tetramethyloctahydro-4H-inden-4-one (2d)
Compound 2d was prepared from 1d (38.9 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (4 hours).
Purification by flash column chromatography on silica gel (5%
Et2O/hexanes) afforded 2d (28.1 mg, 72%) as a colorless oil. Rf:
1
0.60 (10% Et2O/hexanes) H NMR (500 MHz, CDCl3): δ 2.37–
2.25 (m, 1H), 1.90–1.83 (m, 1H), 1.82 (d, J = 11.5 Hz, 1H),
1.76–1.65 (m, 2H), 1.60–1.56 (m, 1H), 1.53–1.44 (m, 2H), 1.33–
1.21 (m, 2H), 1.11 (s, 3H), 1.09 (s, 3H), 1.08 (s, 3H), 1.03 (d, J =
8.0 Hz, 3H) 13C NMR (151 MHz, CDCl3): δ 219.0, 66.5, 45.3,

7
CDCl3): δ 221.6, 141.7, 120.8, 72.7, 66.7, 57.6, 51.0, 50.9, 47.6,
43.5, 42.8, 37.6, 37.2, 37.1, 35.2, 33.8, 32.8, 32.2, 30.1, 26.1,
25.1, 21.0, 20.0, 19.5, 18.4, 17.9, −4.4 IR (cm–1): 2930, 2857,
1733, 1462, 1383, 1251, 1088, 870, 834, 773, 737, 666, 617 GC-
MS (m/z): [M] calc’d for C30H50O2Si: 470.4; found: 469.4.
3.78 (m, 4H), 2.27–2.18 (m, 4H), 1.91–1.79 (m, 3H), 1.72–1.61
(m, 3H), 1.59–1.38 (m, 4H), 1.12–1.01 (m, 1H), 0.98 (d, J = 6.4
Hz, 3H) 13C NMR (101 MHz, CDCl3): δ 212.6, 110.9, 65.6, 64.3,
56.8, 48.0, 34.8, 33.4, 32.1, 31.0, 29.0, 23.5, 22.3, 21.5 IR (cm–
1): 2929, 2869, 1707, 1450, 1298, 1182, 1102, 1085, 1032, 954,
859, 565 GC-MS (m/z): [M] calc’d for C14H22O3: 238.2; found:
238.2.
4.6.9.
8(1H)-one (2i)
Compound 2i was prepared from 1i (40.0 mg, 0.20 mmol, 1.0
1,3a-dimethyl-2,3,3a,8a-tetrahydrocyclopenta[a]inden-
4.6.12. ethyl-1,4-dimethyl-2-oxocyclohexane-1-carboxylate (2l)
Compound 2l was prepared from 1l (39.7 mg, 0.20 mmol, 1.0
equiv) according to the general procedure (2 hours). Purification
by flash column chromatography on silica gel (10%
Et2O/hexanes) afforded 2l (17.0 mg, 43%) as a colorless oil. Rf:
equiv) according to the general procedure (2 hours). Purification
by flash column chromatography on silica gel (4% Et2O/hexanes)
afforded 2i (30.3 mg, 76%, dr = 1.2:1) as an orange oil. Rf: 0.35
1
(10% Et2O/hexanes) H NMR (500 MHz, CDCl3): δ 7.65 (dd, J
1
0.41 (20% Et2O/hexanes) H NMR (400 MHz, CDCl3): δ 4.19
= 7.5, 3.5 Hz, 1H), 7.63–7.59 (m, 1H), 7.47 (d, J = 7.5 Hz, 1H),
7.36–7.33 (m, 1H), 2.55 (d, J = 10.0 Hz, 0.45H), 2.45–2.35 (m,
0.45H), 2.30–2.27 (m, 0.55 H), 2.06–1.98 (m, 1H), 1.86 (ddd, J =
12.5, 6.5, 5.5 Hz, 0.45H), 1.77 (atd, J = 13.0, 6.0 Hz, 0.55H),
1.69 (adt, J = 12.0, 6.0 Hz, 0.55H), 1.61–1.57 (m, 1H), 1.53 (s,
1.35H), 1.49–1.43 (m, 0.45H), 1.47 (s, 1.65H), 1.22 (d, J = 7.0
Hz, 1.35H), 1.09 (d, J = 7.0 Hz, 1.65H), 0.93 (ddd, J = 24.5,
12.0, 5.5 Hz, 0.55H) 13C NMR (151 MHz, CDCl3): δ 209.1,
208.0, 163.1, 163.0, 137.8, 135.7, 135.5, 135.2, 127.5, 127.5,
124.3, 124.0, 123.5, 122.7, 68.0, 62.9, 51.8, 51.1, 40.7, 39.6,
39.1, 38.7, 34.6, 34.6, 28.5, 27.8, 21.1, 16.1 IR (cm–1): 2954,
2925, 2857, 1709, 1603, 1462, 1285, 764 GC-MS (m/z): [M]
calc’d for C14H16O: 200.1; found: 200.1.
(q, J = 7.0 Hz, 2H), 2.57–2.51 (m, 1H), 2.39 (ddd, J = 13.6, 7.2,
4.0 Hz, 1H), 2.25–2.15 (m, 2H), 1.92–1.84 (m, 1H), 1.73 (ddd, J
= 13.6, 9.2, 4.0 Hz, 1H), 1.52–1.43 (m, 1H), 1.34 (s, 3H), 1.26
(at, J = 7.2 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H) 13C NMR (101
MHz, CDCl3): δ 208.9, 173.3, 61.4, 57.0, 46.8, 33.8, 32.8, 28.9,
20.9, 20.2, 14.2 IR (cm–1): 2935, 2871, 1735, 1712, 1456, 1377,
1258, 1090, 1026, 860 GC-MS (m/z): [M] calc’d for C11H18O3:
198.1; found: 198.2.
4.6.13. ethyl 1-allyl-4-methyl-2-oxocyclohexane-1-carboxylate
(2m)
Compound 2m was prepared from 1m (44.9 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (6 hours).
Purification by flash column chromatography on silica gel (4%
Et2O/hexanes) afforded diastereomers 2ma (6.5 mg, 14%) and
2mb (17.5 mg, 39%) as a colorless oil. 2ma: Rf: 0.51 (20%
4.6.10. 9-methyl-1,4-dioxadispiro[4.0.56.35]tetradecan-7-one (2j)
Compound 2j was prepared from 1j (44.9 mg, 0.20 mmol, 1.0
equiv) according to the general procedure (6 hours). Purification
by flash column chromatography on silica gel (10%
Et2O/hexanes) afforded diastereomers 2ja (12.1 mg, 27%) and
2jb (11.6 mg, 26%) as colorless oils. 2ja: Rf: 0.35 (20%
1
Et2O/hexanes) H NMR (400 MHz, CDCl3): δ 5.79–5.68 (m,
1H), 5.12–4.95 (m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 2.60 (dd, J =
14.0, 7.2 Hz, 1H), 2.49–2.39 (m, 2H), 2.29 (dd, J = 14.0, 8.0 Hz,
1H), 2.18–2.11 (m, 1H), 1.85–1.70 (m, 2H), 1.45–1.34 (m, 2H),
1.24 (t, J = 7.2 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H) 13C NMR (101
MHz, CDCl3): δ 207.1, 171.5, 133.5, 118.4, 61.4, 59.9, 49.5,
39.4, 35.4, 34.9, 31.4, 22.4, 14.3 IR (cm–1): 2956, 2929, 1713,
1439, 1222, 1196, 1143, 1093, 1027, 918, 608 GC-MS (m/z):
[M] calc’d for C13H20O3: 224.1; found: 224.2 2mb: Rf: 0.61 (20%
1
Et2O/hexanes) H NMR (400 MHz, CDCl3): δ 3.99–3.85 (m,
4H), 2.47–2.27 (m, 4H), 1.84–1.63 (m, 4H), 1.62–1.50 (m, 3H),
1.40 (atd, J = 12.8, 5.2 Hz, 1H), 1.27–1.20 (m, 1H), 0.98 (d, J =
6.4 Hz, 3H) 13C NMR (101 MHz, CDCl3): δ 212.4, 118.1, 64.5,
64.3, 58.1, 50.2, 35.0, 34.5, 34.4, 33.7, 31.2, 22.7, 19.2 IR (cm–
1): 2952, 2874, 1698, 1456, 1442, 1309, 1213, 1152, 1126, 1063,
1016, 945, 931, 584, 528, 473 GC-MS (m/z): [M] calc’d for
C13H20O3: 224.1; found: 224.2 2jb: Rf: 0.22 (20% Et2O/hexanes)
1H NMR (400 MHz, CDCl3): δ 3.97–3.88 (m, 4H), 2.51 (ddd, J
= 14.0, 4.8, 0.4 Hz, 1H), 2.22–2.13 (m, 2H), 2.09–1.93 (m, 3H),
1.90–1.72 (m, 3H), 1.66–1.51 (m, 3H), 1.36–1.27 (m, 1H), 0.96
(d, J = 6.8 Hz, 3H) 13C NMR (101 MHz, CDCl3): δ 212.1, 118.3,
65.4, 64.1, 59.9, 47.9, 34.4, 34.1, 32.8, 30.5, 29.9, 21.1, 18.9 IR
(cm–1): 2952, 2874, 1698, 1456, 1442, 1309, 1213, 1152, 1126,
1063, 1016, 945, 931, 584, 528, 473 GC-MS (m/z): [M] calc’d
for C13H20O3: 224.1; found: 224.2.
1
Et2O/hexanes) H NMR (400 MHz, CDCl3): δ 5.78–5.67 (m,
1H), 5.08–5.04 (m, 2H), 4.18 (q, J = 7.2 Hz, 2H), 2.62 (dd, J =
14.0, 6.8 Hz, 1H), 2.55 (dd, J = 13.6, 4.4 Hz, 1H), 2.40 (dd, J =
14.0, 7.6 Hz, 1H), 2.31 (ddd, J = 13.6, 6.4, 4.0 Hz, 1H), 2.26–
2.13 (m, 2H), 1.93–1.85 (m, 1H), 1.77 (ddd, J = 13.6, 10.0, 4.0
Hz, 1H), 1.52–1.44 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H), 0.96 (d, J =
6.4 Hz, 3H) 13C NMR (101 MHz, CDCl3): δ 207.8, 171.7, 133.3,
118.6, 61.3, 60.7, 47.4, 38.5, 32.6, 30.7, 28.5, 19.9, 14.3 IR (cm–
1): 2956, 2929, 1713, 1439, 1222, 1196, 1143, 1093, 1027, 918,
608 GC-MS (m/z): [M] calc’d for C13H20O3: 224.1; found: 224.2.
4.6.14. 1-allyl-4-methyl-2-oxabicyclo[3.3.1]nonan-6-one (2n)
Compound 2n was prepared from 1n (38.9 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (4 hours).
Purification by flash column chromatography on silica gel (8%
Et2O/hexanes) afforded 2n (15.9 mg, 41%) as a colorless oil. Rf:
4.6.11. 9-methyl-1,4-dioxadispiro[4.0.56.45]pentadecan-7-one
(2k)
Compound 2k was prepared from 1k (47.7 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (6 hours).
Purification by flash column chromatography on silica gel (20%
Et2O/hexanes) afforded diastereomers 2ka (13.7 mg, 29%) and
2kb (20.5 mg, 43%) as a colorless oil. 2ka: Rf: 0.32 (20%
1
0.52 (40% Et2O/hexanes) H NMR (500 MHz, CDCl3): δ 5.87
(ddt, J = 17.5, 10.5, 7.5 Hz, 1H), 5.13–5.07 (m, 2H), 3.81 (dd, J =
12.5, 5.5 Hz, 1H), 3.55 (at, J = 12.5 Hz, 1H), 2.57–2.51 (m, 2H),
2.46–2.38 (m, 1H), 2.26 (d, J = 7.5 Hz, 2H), 2.14–2.03 (m, 2H),
2.00–1.93 (m, 1H), 1.91–1.87 (m, 2H), 0.81 (d, J = 6.5 Hz, 3H)
13C NMR (151 MHz, CDCl3): δ 213.3, 133.6, 118.4, 70.9, 68.0,
49.2, 47.1, 39.1, 36.2, 33.5, 32.1, 14.9 IR (cm–1): 2926, 1703,
1440, 1104, 1078, 990, 963, 915, 853, 640, 413 GC-MS (m/z):
[M] calc’d for C12H18O2: 194.1; found: 194.2.
1
Et2O/hexanes) H NMR (400 MHz, CDCl3): δ 3.97–3.86 (m,
4H), 2.43 (dd, J = 13.2, 4.8 Hz, 1H), 2.36–2.29 (m, 2H), 2.18–
2.11 (m, 1H), 2.00–1.88 (m, 1H), 1.76–1.63 (m, 4H), 1.56–1.47
(m, 3H), 1.44–1.31 (m, 3H), 0.98 (d, J = 6.8 Hz, 3H) 13C NMR
(101 MHz, CDCl3): δ 213.8, 111.5, 64.4, 64.3, 55.0, 49.7, 34.0,
33.9, 32.7, 31.5, 29.5, 23.2, 21.7, 20.9 IR (cm–1): 2929, 2869,
1707, 1450, 1298, 1182, 1102, 1085, 1032, 954, 859, 565 GC-
MS (m/z): [M] calc’d for C14H22O3: 238.2; found: 238.2 2kb: Rf:
4.6.15. 5,8-dimethylbicyclo[3.3.1]non-3-en-2-one (2o)
1
0.21 (20% Et2O/hexanes) H NMR (400 MHz, CDCl3): δ 4.03–

8
Tetrahedron
Compound 2o was prepared from 1o (32.9 mg, 0.20 mmol,
hydro-1,3-methanonaphthalen-4(1H)-one (3c)
1.0 equiv) according to the general procedure (4 hours).
Purification by flash column chromatography on silica gel (10%
Et2O/hexanes) afforded 2o (14.3 mg, 43%) as a pale-yellow oil.
Compound 3c was prepared from 1a (44.1 mg, 0.20 mmol,
1.0 equiv) according to the general procedure for
carbohalogenation using NBS (142.4 mg, 0.80 mmol, 4.0 equiv)
as the halogen source. Purification by flash column
chromatography on silica gel (10% Et2O/hexanes) afforded 3c
(47.7 mg, 80%) as a white solid. Rf: 0.45 (10% EtOAc/hexanes)
1
Rf: 0.32 (10% Et2O/hexanes) H NMR (400 MHz, CDCl3): δ
6.53 (dd, J = 10.0, 2.0 Hz, 1H), 6.05 (d, J = 10.0 Hz, 1H), 2.36–
2.32 (m, 1H), 2.08 (dd, J = 12.8, 2.8 Hz, 1H), 1.71–1.53 (m, 3H),
1.45–1.42 (m, 2H), 1.27–1.13 (m, 1H), 1.11 (s, 3H), 0.89 (d, J =
6.4 Hz, 3H) 13C NMR (101 MHz, CDCl3): δ 201.7, 157.0, 131.2,
49.5, 42.6, 34.8, 33.8, 33.6, 28.7, 28.1, 19.7 IR (cm–1): 2956,
2923, 2869, 1670, 1455, 1374, 1218, 1103, 1076, 825, 730, 502
GC-MS (m/z): [M] calc’d for C11H16O: 164.1; found: 164.2.
1
[α]20D: –20.0 (c 1.0, CHCl3) H NMR (500 MHz, CDCl3): δ 3.89
(dd, J = 10.0, 4.0 Hz, 1H), 3.77 (dd, J = 10.0, 6.5 Hz, 1H), 2.56
(at, J = 5.5 Hz, 1H), 2.51 (adt, J =12.5, 6.0 Hz, 1H), 2.18 (d, J =
10.0 Hz, 1H), 2.10–2.04 (m, 1H), 1.84 (at, J = 4.4 Hz, 1H), 1.81–
1.64 (m, 4H), 1.58 (d, J = 11.0 Hz, 1H), 1.52–1.48 (m, 1H), 1.36
(s, 3H), 1.24 (s, 3H), 1.10 (s, 3H), 1.07–1.03 (m, 1H) 13C NMR
(151 MHz, CDCl3): δ 215.0, 58.9, 55.1, 54.0, 41.7, 40.1, 37.7,
36.0, 32.3, 27.9, 27.6, 26.1, 25.9, 25.9, 16.3 IR (cm–1): 2948,
2872, 1699, 1465, 1380, 1274, 1240, 1203, 992, 905, 632, 602
GC-MS (m/z): [M] calc’d for C15H23BrO: 298.1; found: 298.1.
4.6.16. (4aS,7R,8R)-7-methyl-2,3,5,6,7,8-hexahydro-4H-4a,8-
methanobenzo[8]annulene-4,9(1H)-dione (2p)
Compound 2p was prepared from 1p (43.7 mg, 0.20 mmol,
1.0 equiv) according to the general procedure (4 hours).
Purification by flash column chromatography on silica gel (30%
Et2O/hexanes) afforded 2p (32.2 mg, 73%) as a yellow oil. Rf:
0.25 (40% Et2O/hexanes) [α]20D: +64.0° (c 1.0, CHCl3) 1H NMR
(400 MHz, CDCl3): δ 6.08 (s, 1H), 2.66–2.48 (m, 4H), 2.46–2.42
(m, 1H), 2.19–2.05 (m, 3H), 1.90–1.83 (m, 1H), 1.81–1.58 (m,
4H), 1.27–1.22 (m, 1H), 0.91 (d, J = 6.4 Hz, 3H) 13C NMR (151
MHz, CDCl3): δ 211.5, 200.2, 163.2, 129.3, 51.8, 48.4, 38.3,
35.3, 32.6, 32.5, 31.8, 27.3, 22.4, 19.6 IR (cm–1): 2926, 2869,
1708, 1659, 1619, 1454, 1249, 1204, 1116, 1032, 621, 519 GC-
MS (m/z): [M] calc’d for C14H18O2: 218.1; found: 218.2.
4.6.21. 1-(bromomethyl)-3a-methyl-2,3,3a,8a-tetrahydrocyclo-
penta[a]inden-8(1H)-one (3d)
Compound 3d was prepared from 1i (40.1 mg, 0.20 mmol,
1.0 equiv) according to the general procedure for
carbohalogenation using NBS (142.4 mg, 0.80 mmol, 4.0 equiv)
as the halogen source. Purification by flash column
chromatography on silica gel (5% Et2O/hexanes to 10%
Et2O/hexanes) afforded diastereomers 3da (33.6 mg, 60%) and
3db (18.1 mg, 33%) as white solids. 3da: Rf: 0.57 (10%
1
Et2O/hexanes) H NMR (400 MHz, CDCl3): δ 7.74–7.70 (m,
4.6.17. 3-(chloromethyl)-5,5,7a-trimethyloctahydro-4H-inden-4-
one (3a)
2H), 7.49 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 4.14 (dd, J
= 10.4, 3.2 Hz, 1H), 3.33 (at, J = 11.2 Hz, 1H), 2.87–2.78 (m,
1H), 2.17 – 2.09 (m, 2H), 1.97 (atd, J = 12.8, 6.0 Hz, 1H), 1.62
(s, 3H), 0.90 (ddd, J = 26.0, 13.2, 6.4 Hz, 1H) 13C NMR (126
MHz, CDCl3): δ 199.7, 159.5, 137.1, 133.7, 128.5, 124.3, 124.2,
75.5, 57.3, 54.9, 40.0, 32.9, 28.9, 27.9 IR (cm–1): 2965, 2864,
1714, 1604, 1589, 1465, 1214, 764 GC-MS (m/z): [M] calc’d for
C14H15BrO: 278.0; found: 278.0 3db: Rf: 0.23 (10%
Compound 3a was prepared from 1d (38.8 mg, 0.20 mmol,
1.0 equiv) according to the general procedure for
carbohalogenation using NCS (106.8 mg, 0.80 mmol, 4.0 equiv)
as the halogen source. Purification by flash column
chromatography on silica gel (3% Et2O/hexanes) afforded 3a
(27.2 mg, 60%) as a colorless oil. Rf: 0.56 (10% Et2O/hexanes)
1H NMR (600 MHz, CDCl3): δ 3.66 (dd, J = 10.8, 4.8 Hz, 1H),
3.53 (dd, J = 10.8, 6.6 Hz, 1H), 2.86–2.80 (m, 1H), 2.17 (d, J =
7.2 Hz, 1H), 1.89 (addt, J = 12.6, 7.2, 2.4 Hz, 1H), 1.79 (ddd, J =
13.8, 10.8, 3.0 Hz, 1H), 1.68–1.59 (m, 3H), 1.52 (ddd, J = 12.6,
6.6, 2.4 Hz, 1H), 1.48–1.43 (m, 2H), 1.15 (s, 3H), 1.11 (s, 3H),
1.10 (s, 3H) 13C NMR (151 MHz, CDCl3): δ 218.2, 59.3, 49.4,
46.0, 44.0, 43.8, 40.4, 35.4, 33.5, 28.6, 26.8, 26.0 IR (cm–1):
2954, 2869, 1696, 1459, 1384, 1361, 1289, 1105, 1062, 723, 688
GC-MS (m/z): [M] calc’d for C13H21ClO: 228.1; found: 228.1.
1
Et2O/hexanes) H NMR (400 MHz, CDCl3): δ 7.68–7.62 (m,
2H), 7.47 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 3.70 (dd, J
= 10.0, 4.8 Hz, 1H), 3.57 (dd, J = 10.0, 8.0 Hz, 1H), 2.58–2.50
(m, 2H), 1.98 (ddd, J = 14.0, 6.4, 2.0 Hz, 1H), 1.92–1.82 (m,
2H), 1.76–1.67 (m, 1H), 1.54 (s, 3H) 13C NMR (126 MHz,
CDCl3): δ 207.3, 162.5, 135.8, 135.2, 127.9, 124.2, 123.8, 64.7,
51.0, 46.6, 38.9, 37.5, 31.9, 27.8 IR (cm–1): 2955, 2865, 1708,
1603, 1463, 1327, 1288, 1241, 763 GC-MS (m/z): [M] calc’d for
C14H15BrO: 278.0; found: 278.0.
4.6.19. 8-(chloromethyl)-5-methylbicyclo[3.3.1]non-3-en-2-one
(3b)
4.6.22. 5-allyl-3-(bromomethyl)-6,6,7a-trimethyloctahydro-4H-
inden-4-one (3e)
Compound 3b was prepared from 1o (32.6 mg, 0.20 mmol,
1.0 equiv) according to the general procedure for
carbohalogenation using NCS (106.8 mg, 0.80 mmol, 4.0 equiv)
as the halogen source. Purification by flash column
chromatography on silica gel (5% Et2O/hexanes) afforded 3b
(23.9 mg, 60%) as a colorless oil. Rf: 0.15 (10% Et2O/hexanes)
1H NMR (400 MHz, CDCl3): δ 6.61 (dd, J = 10.0, 2.0 Hz, 1H),
6.10 (dd, J = 10.0, 0.8 Hz, 1H), 3.50 (dd, J = 11.2, 6.8 Hz, 1H),
3.23 (dd, J = 10.8, 7.6 Hz, 1H), 2.71–2.66 (m, 1H), 2.14 (ddd, J =
12.8, 3.6, 2.4 Hz, 1H), 1.94–1.84 (m, 2H), 1.59–1.54 (m, 1H),
1.52–1.44 (m, 2H), 1.22–1.11 (m, 1H), 1.16 (s, 3H) 13C NMR
(125 MHz, CDCl3): δ 200.5, 157.4, 131.2, 47.6, 45.9, 41.9, 41.6,
34.2, 34.1, 28.5, 24.0 IR (cm–1): 2926, 2862, 1674, 1456, 828,
731 GC-MS (m/z): [M] calc’d for C11H15ClO: 198.1; found:
198.1.
Compound 3e was prepared from 1q (46.9 mg, 0.20 mmol,
1.0 equiv) according to the general procedure for
carbohalogenation using NBS (142.4 mg, 0.80 mmol, 4.0 equiv)
as the halogen source. Purification by flash column
chromatography on silica gel (5% Et2O/hexanes) afforded 3e
(25.1 mg, 40%) as a light yellow oil. Rf: 0.48 (10% Et2O/hexanes)
1H NMR (500 MHz, CDCl3): δ 5.81–5.73 (m, 1H), 5.01 (d, J =
17.5 Hz, 1H), 4.94 (d, J = 10.5 Hz, 1H), 3.47 (dd, J = 10.0, 5.0
Hz, 1H), 3.34 (dd, J = 10.0, 7.5 Hz, 1H), 2.79–2.72 (m, 1H),
2.47–2.38 (m, 2H), 2.12–2.05 (m, 3H), 1.76–1.43 (m, 7H), 1.17
(s, 3H), 1.05 (s, 3H), 0.87 (s, 3H) 13C NMR (126 MHz, CDCl3):
δ 213.9, 137.7, 115.6, 64.4, 56.6, 49.3, 47.8, 46.5, 43.1, 39.8,
38.4, 31.5, 30.1, 29.9, 28.4, 24.5 IR (cm–1): 2954, 2871, 1699,
1464, 1381, 1369, 1350, 1263, 1230, 1192, 999, 911 GC-MS
(m/z): [M] calc’d for C16H25BrO: 312.1; found: 312.1.
4.6.20. (1R,3S,5S,8aR)-5-(bromomethyl)-2,2,8a-trimethylocta-
4.6.23. (1S,3aR,4R,6S)-1-(iodomethyl)-3a,5,5-trimethyloctahydro

9
-7H-4,6-methanoinden-7-one (3f)
3.83 (dd, J = 10.4, 4.0 Hz, 1H), 3.51 (dd, J = 10.4, 9.6 Hz, 1H),
Compound 3f was prepared from 1b (41.3 mg, 0.20 mmol.
1.0 equiv) according to the general procedure for
carbohalogenation using NIS (180.0 mg, 0.80 mmol, 4.0 equiv)
as the halogen source. Purification by flash column
chromatography on silica gel (10% Et2O/hexanes) afforded 3f
(60.9 mg, 92%) as a yellow oil. Rf: 0.46 (20% Et2O/hexanes)
[α]20D: +1.7° (c 1.0, CHCl3) 1H NMR (400 MHz, CDCl3): δ 3.78
(dd, J = 9.6, 2.8 Hz, 1H), 3.40 (dd, J = 9.6, 7.6 Hz, 1H), 2.54 (at,
J = 5.2 Hz, 1H), 2.51–2.45 (m, 1H), 2.02 (at, J = 6.4 Hz, 1H),
2.00–1.84 (m, 3H), 1.78–1.70 (m, 1H), 1.59 (d, J = 11.2 Hz, 1H),
1.52–1.44 (m, 2H), 1.37 (s, 3H), 1.25 (s, 3H), 1.00 (s, 3H) 13C
NMR (151 MHz, CDCl3): δ 215.5, 60.2, 58.5, 52.3, 50.3, 45.3,
42.5, 39.9, 33.3, 28.6, 27.4, 26.0, 25.3, 15.2 IR (cm–1): 2950,
1701, 1461, 1378, 1250, 1201, 981, 831, 801, 586, 520. GC-MS
(m/z): [M] calc’d for C14H21IO: 332.1; found: 332.1.
2.65 (at, J = 5.2 Hz, 1H), 2.50 (adt, J = 11.2, 6.4 Hz, 1H), 2.21
(d, J = 9.2 Hz, 1H), 2.14–2.03 (m, 2H), 1.83–1.68 (m, 2H), 1.56
(d, J = 11.6 Hz, 1H), 1.48–1.41 (m, 2H), 1.39 (s, 3H), 1.24 (s,
3H), 1.03 (s, 3H) 13C NMR (151 MHz, CDCl3): δ 219.0, 68.2,
61.4, 58.5, 51.8, 50.3, 45.0, 42.3, 40.2, 28.8, 28.4, 27.3, 26.1,
25.1 IR (cm–1): 3425, 2950, 2873, 1686, 1473, 1378, 1273, 1239,
1069, 1027, 521 GC-MS (m/z): [M] calc’d for C14H22O2: 222.2;
found: 222.2 3j: Rf: 0.27 (40% Et2O/hexanes) [α]20D: –6.1° (c
1
0.7, CHCl3) H NMR (400 MHz, CDCl3): δ 11.55 (s, 1H), 4.34
(dd, J = 12.8, 4.8 Hz, 1H), 3.70 (dd, J = 12.8, 9.6 Hz, 1H), 2.69
(at, J = 5.6 Hz, 1H), 2.58–2.48 (m, 2H), 2.46 (d, J = 7.6 Hz, 1H),
2.09 (at, J = 5.6 Hz, 1H), 1.90–1.71 (m, 2H), 1.53 (d, J = 11.6
Hz, 1H), 1.49–1.41 (m, 1H), 1.40 (s, 3H), 1.24 (s, 3H), 1.08 (s,
3H) 13C NMR (151 MHz, CDCl3): δ 220.0, 81.7, 59.3, 59.0,
51.9, 45.7, 45.6, 41.7, 39.7, 28.5, 28.4, 27.3, 26.1, 26.0 IR (cm–
1): 2951, 2877, 2361, 2338, 1701, 1459, 1388, 1272, 1245, 1041,
985, 668 GC-MS (m/z): [M] calc’d for C14H20O2: 220.1; found:
220.2.
4.6.24. (1R,3S,4aR,5S,8aR)-5-(iodomethyl)-2,2,8a-trimethylocta-
hydro-1,3-methanonaphthalen-4(1H)-one (3g)
Compound 3g was prepared from 1a (440 mg, 2.0 mmol. 1.0
equiv) according to the general procedure for carbohalogenation
using I2 (2.0 g, 8.0 mmol, 4.0 equiv) as the halogen source.
Purification by flash column chromatography (15%
Et2O/hexanes) afforded 3g (602 mg, 87%) as a yellow solid. Rf:
4.7. Experimental Procedures and Characterization Data for
Mechanistic Studies
4.7.1. (1R,3S,4aR,5S,8aR)-2,2,8a-trimethyl-5-(methyl-
d)octahydro-1,3-methanonaphthalen-4(1H)-one (2a-d1)
1
0.38 (10% Et2O/hexanes) [α]20D: –8.2° (c 1.0, CHCl3) H NMR
To a flame-dried, 10 mL microwave vial equipped with a
magnetic stir bar was added Zn(OTf)2 (109.1 mg, 0.30 mmol, 1.5
equiv). The vial was capped, evacuated flame-dried under
vacuum for 10 seconds (this process was repeated 3 times). The
reaction vessel was backfilled with N2 before 1,2-
dimethoxyethane (2 mL, 0.1 M) was added. To the stirred
mixture was added ketone 1a (44.0 mg, 0.20 mmol, 1.0 equiv)
and Zn(TMP)2 (0.48 mL, 0.5 M in toluene, 0.24 mmol, 1.2
equiv). The reaction vessel was sealed with parafilm, and placed
in an 80 oC preheated oil bath and stirred for four hours.
(400 MHz, CDCl3): δ 3.74 (dd, J = 9.6, 3.6 Hz, 1H), 3.60 (dd, J =
9.6, 6.4 Hz, 1H), 2.55 (at, J = 5.6 Hz, 1H), 2.50 (adt, J = 10.8, 6.0
Hz, 1H), 2.06 (d, J = 9.6 Hz, 1H), 1.83 (at, J = 5.6 Hz, 1H), 1.77–
1.61 (m, 5H), 1.57 (d, J = 10.8 Hz, 1H), 1.47–1.39 (m, 1H), 1.35
(s, 3H), 1.23 (s, 3H), 1.10 (s, 3H), 1.08–1.03 (m, 1H) 13C NMR
(101 MHz, CDCl3): δ 214.9, 58.9, 55.6, 55.0, 40.1, 37.3, 36.1,
32.3, 28.2, 27.8, 27.6, 25.9, 19.4, 16.3 IR (cm–1): 2947, 2871,
1694, 1464, 1389, 1203, 906, 727, 647, 571, 513, 431 GC-MS
(m/z): [M] calc’d for C15H23IO: 346.1; found: 346.1.
4.6.25. (2S,4R,4aR,10S)-10-(iodomethyl)-3,3,4a-trimethyl-
3,4,4a,9,10,10a-hexahydro-2,4-methanophenanthren-1(2H)-one
(3h)
The reaction vessel was removed from the oil bath and D2O
(2 mL, 110.8 mmol, 554.2 equiv) was added to the reaction
mixture. The mixture was stirred at ambient temperature for 30
miuntes before sat. aq. NH4Cl (1 mL) and Et2O (1 mL) were
added. The organic phase was separated and the aqueous phase
was extracted with Et2O (2 x 1 mL). The combined organic
extracts were filtered over a small pad of dry silica gel and
concentrated under reduced pressure by rotary evaporation.
Purification by flash column chromatography over silica gel (5%
Et2O/hexanes) afforded 2a-d1 (30.0 mg, 68%, 60% D) as a
colorless oil. Rf: 0.46 (10% Et2O/hexanes) [α]20D: −49.0° (c 1.0,
Compound 3h was prepared from 1g (53.7 mg, 0.20 mmol.
1.0 equiv) according to the general procedure for
carbohalogenation using NIS (180.0 mg, 0.80 mmol, 4.0 equiv)
as the halogen source. Purification by flash column
chromatography on silica gel (5% Et2O/hexanes) afforded 3h
(63.9 mg, 81%) as a white solid. Rf: 0.41 (10% Et2O/hexanes)
1
[α]20D: –37.3° (c 1.0, CHCl3) H NMR (400 MHz, CDCl3): δ
7.23–7.19 (m, 2H), 7.14–7.06 (m, 2H), 3.41 (dd, J = 9.6, 7.6 Hz,
1H), 3.32 (dd, J = 9.2, 6.4 Hz, 1H), 2.91–2.81 (m, 3H), 2.72–2.65
(m, 2H), 2.47 (at, J = 5.6 Hz, 1H), 2.32 (adt, J = 11.2, 6.0 Hz,
1H), 1.58 (s, 3H), 1.41 (s, 3H), 1.25 (s, 3H), 0.94 (d, J = 10.8 Hz,
1H) 13C NMR (126 MHz, CDCl3): δ 212.7, 143.9, 134.0, 129.4,
127.3, 126.3, 126.2, 58.2, 55.6, 55.5, 40.7, 39.2, 37.4, 33.3, 30.8,
27.7, 26.4, 25.3, 14.6 IR (cm–1): 2973, 2956, 2924, 1694, 1444,
1236, 1180, 986, 920, 763, 728, 592, 494, 436 GC-MS (m/z):
[M] calc’d for C19H23IO: 394.1; found: 394.1.
1
CHCl3) H NMR (400 MHz, CDCl3): δ 2.51 (t, J = 5.2 Hz, 1H),
2.44 (adt, J = 10.8, 6.4 Hz, 1H), 1.88–1.78 (m, 2H), 1.72–1.55
(m, 6H), 1.34 (s, 3H), 1.29–1.21 (m, 1H), 1.19 (s, 3H), 1.12–1.08
(m, 2.4H), 1.04 (s, 3H), 0.99–0.96 (m, 1H) 13C NMR (151 MHz,
CDCl3): δ 215.7, 59.3, 59.3, 58.8, 55.0, 40.6, 35.9, 32.3, 31.5,
31.4, 30.5, 30.5, 28.0, 27.7, 25.8, 25.3, 22.4, 22.1 (t, J = 19.3
Hz), 16.7 IR (cm–1): 2929, 2871, 1700, 1464, 1379, 1274, 1240,
1202, 787, 516 GC-MS (m/z): [M] calc’d for C19H23DO: 221.2;
found: 221.2.
4.6.26. 1-(hydroxymethyl)-3a,5,5-trimethyloctahydro-7H-4,6-
methanoinden-7-one (3i) and (1S,3aR,4R,6S)-3a,5,5-trimethyl-7-
oxooctahydro-1H-4,6-methanoindene-1-carbaldehyde (3j)
Compound 3i and 3j was prepared from 1b (41.3 mg, 0.20
mmol, 1.0 equiv) according to the general procedure for anionic
cyclization, followed bubbling O2 for 10 minutes and stirring at
room temperature for 24 hours under an oxygen atmosphere
(balloon). Purification by flash column chromatography on silica
gel (40% Et2O/hexanes) afforded 3i (10 mg, 23%) and 3j (12.1
mg, 27%) as colorless oils. 3i: Rf: 0.08 (40% Et2O/hexanes)
4.7.2. (1S,4S,5S)-4,6,6-trimethyl-4-(pent-4-en-1-yl)bicyclo-
[3.1.1]heptan-2-one-3,3-d2 (1a-d2)
To a 10 mL microwave vial was added K2CO3 (332 mg, 2.4
mmol, 3.0 equiv), 1a (176 mg, 0.8 mmol, 1.0 equiv) and D2O
(0.6 mL, 1.33 M). The reaction vessel capped, placed into a
preheated 120 oC oil bath, and stirred for 4 days. To the reaction
mixture was added H2O (2 mL) and Et2O (2 mL) and the organic
phase was separated. The aqueous phase was extracted with Et2O
(2 x 2 mL) and the combined organic extracts were filtered over a
small pad of dry silica gel and concentrated under reduced
1
[α]20D: –29.5° (c 0.3, CHCl3) H NMR (400 MHz, CDCl3): δ

10
Tetrahedron
pressure by rotary evaporation. The crude mixture was
resubjected to the above reaction conditions (4 days) and workup
procedure without further purification to afford 1a-d2 (169 mg,
isolation by preparatory thin layer chromatography (20%
Et2O/hexanes).
95%) as a colorless oil. Rf: 0.45 (10% EtOAc/hexanes) [α]20
:
D
Acknowledgments
1
−16.2° (c 1.0, CHCl3) H NMR (400 MHz, CDCl3): 5.79 (ddt, J
= 17.2, 10.4, 6.8 Hz, 1H), 5.00 (dd, J = 17.2, 1.2 Hz, 1H), 4.95
(d, J = 10.0 Hz, 1H), 2.53 (adt, J = 5.2 Hz, 1H), 2.47 (adt, J =
10.8, 6.0 Hz, 1H), 2.04–1.96 (m, 3H), 1.63 (d, J = 10.8 Hz, 1H),
1.40–1.30 (m, 4H), 1.36 (s, 3H), 1.14 (s, 3H), 1.02 (s, 3H) 13C
NMR (151 MHz, CDCl3): δ 214.9, 138.8, 114.8, 58.3, 51.7, 43.6,
41.1, 34.5, 34.3, 27.6, 26.0, 25.6, 24.9, 23.1 IR (cm–1): 2933,
1708, 1641, 1473, 1388, 1242, 1204, 991, 909, 733, 640, 503
GC-MS (m/z): [M] calc’d for C15H22D2O: 222.2; found: 222.2.
We are grateful for financial support from Yale University,
Amgen, and the Sloan Foundation. Additional support comes
from a Bristol-Myers Squibb Graduate Fellowship (to D.H.), the
Marco Polo Program (scholarship to D.O.), and the Department
of Chemistry, Nankai University (scholarship to S.Y.).
Appendix A. Supplementary data
Supplementary data related to this article could be found at:
4.7.3. (1R,3S,5S,8aR)-2,2,8a-trimethyl-5-(methyl-d)octahydro-
1,3-methanonaphthalen-4(1H)-one-4a-d (2a-d2)
References
Compound 2a-d2 was prepared from 1a-d2 (22.2 mg, 0.1
mmol, 1.0 equiv) according to the general procedure for anionic
cyclization. Compound 2a-d2 (20.0 mg, 90%) was isolated by
preparatory thin layer chromatography (8% EtOAc/hexanes) and
determined to have 0% deuterium incorporation at the methyl
group. Rf: 0.67 (10% EtOAc/hexanes) [α]20D: –38.8° (c 1.0,
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2.44 (adt, J = 10.5, 6.5 Hz, 1H), 1.87–1.82 (m, 1H), 1.80 (at, J =
6.0 Hz, 1H), 1.72–1.54 (m, 5H), 1.34 (s, 3H), 1.25–1.20 (m, 1H),
1.19 (s, 3H), 1.11 (d, J = 6.5 Hz, 3H), 1.04 (s, 3H), 0.98–0.95 (m,
1H) 13C NMR (151 MHz, CDCl3) δ 215.6, 59.3, 58.8, 55.0, 40.7,
35.9, 35.8, 32.3, 31.5, 31.4, 30.5, 30.5, 28.0, 27.9, 27.7, 25.8,
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: