Gold(I)-catalyzed formation of bicyclo[4.2.0]oct-1-enes

Article abstract of DOI:10.1021/jo400139g

Gold(I) catalysts effectively promote the Cope rearrangement of acyclic 1,5-dienes bearing a terminal cyclopropylidene. When this methodology is applied to cyclic substrates an unexpected transformation occurs, resulting in the formation of a tricyclic compound incorporating a bicyclo[4.2.0]oct-1-ene core, a portion of which is found in a number of natural products. Density functional theory calculations (M06 and M06-2X) reveal insight into the mechanism and thermodynamics of this unique transformation.

Full text of DOI:10.1021/jo400139g

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Note
Gold(I)-Catalyzed Formation of Bicyclo[4.2.0]oct-1-enes
Ryan J. Felix, Osvaldo Gutierrez, Dean J Tantillo, and Michel R Gagné
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400139g • Publication Date (Web): 17 Apr 2013
Downloaded from http://pubs.acs.org on April 18, 2013
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Gold(I)-Catalyzed Formation of
Bicyclo[4.2.0]oct-1-enes
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Ryan J. Felix†, Osvaldo Gutierrez‡, Dean J. Tantillo‡* and Michel R. Gagné†*
†Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
‡Department of Chemistry, University of California – Davis, Davis, California 95616
mgagne@unc.edu; djtantillo@ucdavis.edu
Abstract: Gold(I) catalysts effectively promote the Cope rearrangement of acyclic 1,5ꢀdienes bearing a terminal
cyclopropylidene. When this methodology is applied to cyclic substrates an unexpected transformation occurs,
resulting in the formation of a tricyclic compound incorporating a bicyclo[4.2.0]octꢀ1ꢀene core, a portion of which is
found in a number of natural products. Density functional theory calculations (M06 and M06ꢀ2X) reveal insight
into the mechanism and thermodynamics of this unique transformation.
Transition metal catalysts play a prominent role in promoting the kinetic viability of a variety of synthetic
reactions. When used in combination with thermodynamically favorable transformations, like the consumption of
CꢀC unsaturation1ꢀ2 and the release of ring strain,3ꢀ11 numerous useful methodologies have emerged. The
construction of complex polycyclic structures from relatively simple starting materials has been the subject of a
number of research efforts aimed at accessing biomimetic carbocycles.12ꢀ16
In our own effort to utilize ring strain and unsaturation for biomimetic polycyclization reactions, we discovered
that 1,5ꢀdienes with a terminal alkylidene cyclopropane preferentially undergo Cope rearrangements instead of the
expected cascade cyclizations under Au(I) catalysis (Scheme 1).17 This reaction is driven thermodynamically by the
relief of ring strain in the cyclopropylidene moiety.18ꢀ19 In this contribution we extend the scope of this
rearrangement to cyclic substrates like 1 (R = Me, Ph) with the goal of using alkylidene cyclopropane strain release
to access medium sized carbocycles,20ꢀ22 which suffer from their own strain (Scheme 1). To our surprise the Cope
rearrangement was seemingly not followed and tricyclic compounds 2, which feature a bicyclo[4.2.0]octꢀ1ꢀene core,
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are formed instead (eq 1). This bicyclic skeleton is present in a number of natural products including
welwitindolinone A, and the protoilludane class of sesquiterpenes.23ꢀ26
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Scheme 1. Gold Catalyzed Cope Rearrangements
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Employing 10 mol% of the Gagosz catalyst,27 Ph3PAuNTf2 (Tf = trifluoromethanesulfonyl), allows the reaction to
proceed cleanly over 12 hours at room temperature to a single product (2). The rearranged 2a and 2b are isolable
via flash chromatography in good yield (76% and 88% yield, respectively), and were identified by an analysis of the
NOESY NMR spectra of 2b. The assignment of 2a was made based on similarities in the NMR spectra to 2b. Key
correlations are shown in Figure 1.
The phenyl ring was assigned to the concave face of the molecule through a correlation between HA (7.35 ppm)
and HB (1.85 ppm), but not between HA and HC (1.50 ppm) (Figure 1a), as well as the signal between HD (3.40 ppm)
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and HE (1.75 ppm) (Figure 1b). The cisꢀring configuration was assigned by the key interactions between the
diaxially oriented HE (1.75 ppm) and HF (1.85 ppm), HG (1.90 ppm) with HI (3.0 ppm) (Figure 1c), and the
supporting resonance between HA and HB. A more inꢀdepth discussion of the NOESY data is provided in the
Supporting Information.
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b)
a)
HD
HA
CH3
HE
CH3
HB
HC
HF
c)
CH3
HE
HI
HG
HF
Figure 1. Selected NOESY correlations in NMR spectrum of bicyclo[4.2.0]octꢀ1ꢀene 2b. 3D representations made in PyMOL.28ꢀ
32
To explore the scope of the reaction a series of additional substrates were synthesized, varying in ring size and
substitution on the pendant alkene (Scheme 2). These were obtained in two steps from the cyclic enone via a Cuꢀ
mediated Michael addition at low temperature, followed by a Wittig reaction. The former reactions were generally
high yielding for commercially available Grignard reagents (68ꢀ94%), but low yields were obtained from the
Grignard reagent prepared from αꢀbromostyrene (18ꢀ58%). The resulting ketone could be transformed, in poor to
moderate yield, into the desired substrate with cyclopropyltriphenylphosphonium bromide and NaH, facilitated by
the phase transfer catalyst tris[2ꢀ(2ꢀmethoxyethoxy)ethyl]amine (TDAꢀ1).33 It was hoped that the cyclopentylidene
and cycloheptylidene substrates would provide access to tricyclic compounds that varied in ring structure (eqs 2 and
3, respectively).
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Scheme 2. Synthesis of Cyclic Substrates.
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O
R4
O
n
R2
CuI
MgBr
R4
+
THF,-41°C
18-94%
R3
n
R1
9
R2
R1
R2, R3 = H, Me
R4 = H, Me, Ph
n = 1-3
R1 = H, Me
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R3
O
NaH, TDA-1
R4
+ Ph3P
R2
R4
Br
THF, 62°C
17-47%
n
R1
n
R1
R2
R3
R3
1c
3a
1d
1e
4a
Ph
Ph
3b
[Au]
(2)
?
Ph
[Au]
?
(3)
Ph
Unfortunately, the additional substrates gave neither the tricyclic products nor the analogous originally
hypothesized medium ring products. Despite considerable experimentation compounds 1cꢀ1e, and 4a gave
complex, intractable mixtures of compounds. Attempts to optimize via choice of solvent (nitromethane, 1,2ꢀ
dichloroethane) and catalyst (e.g. (R)ꢀBINAP(AuCl)2, (S)ꢀxylylꢀPHANEPHOS(AuCl)2), or activating agent (AgBF4,
AgSbF6, AgPF6), failed to simplify the reaction mixtures. It was observed that in the case of 4a the identity of the
counterꢀion affected the ratio of products observed in the GCꢀMS but not the number of species formed. For
compounds 3a and 3b two major products were formed along with a number of minor products. Control reactions
with HClꢁEt2O gave the same products in the same ratios, as did a separate control reaction between 3a and AgPF6
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in DCM, suggesting unproductive, Brønsted Acid catalyzed alkene isomerization pathways. These isomerization
reactions removed the ring strain of the methylenecyclopropane by transformation of the exocyclic alkene into an
endocyclic olefin (within the cyclopentyl ring, see Supporting Information). Identical control reactions with the 6ꢀ
and 7ꢀ membered ring substrate analogs were sluggish and did not produce the same reaction mixtures observed as
when Au(I) complexes were reacted. No tricyclic product was formed when the control reactions were run with 1a
and 1b, supporting a gold catalyzed transformation for the production of 2.
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Insight into the reaction’s mechanism and limitations was achieved through density functional theory (DFT)
calculations using the M06/6ꢀ31G(d) method with the SDD basis set for Au and a DCE solvent continuum (CPCM),
as implemented in GAUSSIAN09.34ꢀ37 Two potential pathways for the rearrangement were examined, the first
proceeding through the originally envisioned Cope rearrangement/ring expansion, which initiates by Au(I)
activation of the alkylidene cyclopropane (A, Figure 2). Cyclization initiated by complexation at this point of
unsaturation is predicted to proceed with a barrier of 22 kcal/mol (relative to B), passing through tertiary carbocation
A1 to give the cyclooctenes A2/A3, in a stepwise formal [3s,3s] sigmatropic rearrangement that is exergonic by ~3ꢀ
5 kcal/mol (see the Supporting Information for additional details). From this point a second electrophilic cyclization
is initated at the endocyclic alkene to give A4 (via A3-TS)38. Unexpectedly, no transition state structure could be
found to enable the direct ring expansion of the cyclopropane in A4. Instead a conformational change is needed (via
A4-TS) to orient the bonds and associated orbitals for facile ring expansion (see A5). Expansion of the
cyclopropane to the tetracyclic 6ꢀ5ꢀ4ꢀ3 intermediate C proceeds through A5-TS, the highest energy transition state
structure in the predicted pathway. Deprotonation followed by protodemetallation provides the complexed product
2a, with the overall process being exergonic by more than 25 kcal/mol.
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Figure 2. Computed relative free energies (kcal/mol) for species involved in potential rearrangements of 1a.
An alternative pathway, which avoids formation of a cyclooctene intermediate but converges with pathway A at
structure A4, involves initiation of the Cope rearrangement at the pendant alkene instead of the cyclopropylidene
moiety. In this pathway, cyclization of B to A4 proceeds directly through a transition state structure (B-TS, 22.9
kcal/mol) that is only slightly higher energy than A-TS.
The failure of substrates 1cꢀ1e were also probed computationally and the results are summarized in Table 1. First,
each of these reactions was found to be at least slightly endergonic, with each pathway suffering some additional
defficiency. Substitution at R2 creates steric interactions with the cyclohexyl ring and increases the relative energy
of A-TS. In these cases ((Z)ꢀ1c and 1e), a transition state structure leading from the starting material to the ring
expanded product could not be located. In addition, compound (E)ꢀ1c, rearranges through a secondary carbocation
rather than a tertiary carbocation (c.f. Figure 2). While substrate 1d demonstrated an achievable ring expansion
barrier the analogous A5-TS was too high in energy (31 kcal/mol) for conversion to C. The source of this high
barrier appears to result from a steric clash between methyl groups. .
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Table 1. Energetics of Ring Expansion for Cyclohexyl Substrates
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R2
R3
R1
R2
R3
R1
Catalyzed
A-TS
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Uncatalyzed
Ha
R
R2
H
R3
H
Substrate
G
G
1
1a
Me
H
-1.8
4.7
-2.6
6.1
0.1
1.1
5.9
21.9
(Z)-1c
(E)-1c
1d
Me
H
H
N/A
27.7
22.4
N/A
H
Me
Me
Me
-1.2
-0.3
4.4
Me
H
H
1e
Me
a Calculated enthalpies and Gibbs free energies for formation of A2, along with computed relative energies for A-TS, in kcal/mol. b M06ꢀ
2X/6ꢀ31G(d) (gas phase) calculations employed for uncatalyzed reaction and M06/SDDꢀ6ꢀ31G(d) (DCE) for catalyzed.
In summary, we have described a Au(I)ꢀcatalyzed Cope rearrangement of cyclic cyclopropylidenes into unique
tricyclic compounds with a bicyclo[4.2.0]octꢀ1ꢀene core, a structural motif present in several classes of natural
products. The reaction proceeds efficiently at room temperature to provide the products in good yields. Quantum
chemical calculations provide insight into the mechanism and thermodynamics of the reaction.
Experimental Section
All reagents were purchased from commercial sources and used as received unless otherwise noted. All glassware
was flameꢀdried under vacuum unless otherwise indicated. Anhydrous CH2Cl2, diethyl ether, and pentanes were
passed through a column of alumina. Column chromatography was performed using SilaFlash P60 40ꢀ63 ꢂm (230ꢀ
400 mesh). All NMR spectra were recorded on either a 600 MHz or 400 MHz spectrometer at STP. H, and 13
C
1
chemical shifts are reported in parts per million (ppm) relative to residual solvent resonances (CDCl3 or CD2Cl2).
High resolution mass spectra (EI/HRMS) were obtained on a doubleꢀfocusing magnetic sector spectrometer .
General Procedure A for Michael Addition Reactions. (For the preparation of 3-methyl-3-(prop-1-en-2-
yl)cyclohexanone) To a flameꢀdried 100 mL roundꢀbottom flask under N2 was added CuI (3.45 g, 18.2 mmol, 2.00
eq.) then THF (18 mL). The reaction vessel was cooled to ꢀ41°C before the addition of the Grignard reagent,
isopropenylmagnesium bromide (0.5 M THF, 36.3 mL, 18.2 mmol, 2.00 eq.) over 30 min. The reaction was stirred
at ꢀ41°C for 30 min before transferring in 3ꢀmethylꢀ2ꢀcyclohexenꢀ1ꢀone (1.03 mL, 9.08 mmol, 1.00 eq.) dissolved in
THF (9 mL) via cannula. The reaction was then stirred 1.5 h at ꢀ41°C before quenching with saturated aqueous
NH4Cl (50 mL). The aqueous layer was separated and the organic layer was washed 2 additional times with
saturated aqueous NH4Cl. The combined aqueous washes were then extracted with Et2O (2x). The combined
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organic layers were washed with brine until the aqueous layer was no longer blueꢀtinted. The organic layers were
then dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (15%
EtOAc/Petroleum Ether) provided the product compound as a yellow oil (1.30 g, 94% yield).
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General Procedure B for Wittig cyclopropylidination. (For preparation of 3-cyclopropylidene-1-methyl-1-
(prop-1-en-2-yl)cyclohexane (1a)) To a Schlenk flask loaded with a suspension of dry NaH (0.102 g, 4.26 mmol,
1.30 eq.) in THF (25 mL) under N2 atmosphere was added cyclopropyltriphenylphosphonium bromide (1.63 g, 4.26
mmol, 1.30 eq.) at rt. The reaction flask was then equipped with a condenser and heated to 62°C for 18 h. To the
resulting orange suspension was then added the ketone (3ꢀmethylꢀ3ꢀ(propꢀ1ꢀenꢀ2ꢀyl)cyclohexanone, 0.500 g, 3.28
mmol, 1.00 eq.) and tris[2ꢀ(2ꢀmethoxyethoxy)ethyl]amine (TDAꢀ1) (0.105 mL, 0.328 mmol, 0.10 eq.) in THF (6
mL). The reaction was stirred for 5 h at 62°C before cooling to rt and quenching with saturated aqueous NaHCO3.
The reaction was diluted with deionized H2O and Et2O before separating the layers. The aqueous layer was
extracted with Et2O (2x) and the combined organic layers were then washed with brine (2x). The organic layer was
then dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (Hexanes)
provided the product compound as a colorless oil (0.269 g, 47%). A small amount of CH2Cl2 was used to load the
material onto the column.
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General procedure C for preparation and use of (1-phenylvinyl)magnesium bromide: (For preparation of 3-
methyl-3-(1-phenylvinyl)cyclohexanone) To a flameꢀdried 100ꢀmL 3ꢀneck RBF equipped with a condenser under N2
atmosphere was added Mg (0.467 g, 19.2 mmol, 2.12 eq) and THF (32.3 mL) and a few small crystals of I2. Alphaꢀ
bromoꢀstyrene (2.35 mL, 18.1 mmol, 2.00 eq) was dissolved in THF (4 mL) then added to the reaction mixture. The
solution was heated to 70°C for 5ꢀ15 minutes until the consumption of Mg appeared to have stopped. After cooling
to room temperature the Grignard solution (~0.5 M) was transferred via cannula to a suspension of CuI (3.45 g, 18.1
mmol, 1.00 eq) in THF (36 mL) at ꢀ41°C. The reaction was stirred at ꢀ41°C for 30 min before transferring in a
solution of 3ꢀmethylꢀ2ꢀcyclohexenꢀ1ꢀone (1.03 mL, 9.07 mmol, 1.00 eq.) dissolved in THF (9 mL) via cannula. The
reaction was then stirred 1.5 h at ꢀ41°C before quenching with saturated aqueous NH4Cl (50 mL). The aqueous
layer was separated and the organic layer was washed 2 additional times with saturated aqueous NH4Cl. The
combined aqueous washes were then extracted with EtOAc (2x). The combined organic layers were washed with
brine until the aqueous layer was no longer blueꢀtinted, and finally dried over MgSO4, filtered, and concentrated in
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vacuo. Purification by silica gel chromatography (15% EtOAc/Petroleum Ether) provided the product compound as
a yellow oil as a mixture with styrene (1.32 g total, 0.971 g product, 50% yield).
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General Procedure D for Au(I) Catalyzed Rearrangement: (For preparation of 6,7-
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dimethyltricyclo[5.3.1.0]undec-4-ene (2a)) To a 1ꢀdram vial equipped with a stirbar was added Ph3PAuNTf2 (0.011
g, 0.0142 mmol, 0.10 eq) followed by DCM (0.5 mL). The reaction was stirred briefly before addition of 1a
(0.025g, 0.142 mmol, 1.00 eq). The reaction was then stirred for 12 h before concentrating in vacuo. A pipette
column was then used for purification by silica gel chromatography (Hexanes) to provide the product compound as a
colorless oil (0.019 g, 76%). A small amount of DCM was used to add the material to the column.
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1
3-methyl-3-(prop-1-en-2-yl)cyclohexanone: Yellow oil (1.30 g, 94% yield). H NMR: (600 MHz, CDCl3) δ 4.80
(s, 1H), 4.71 (s, 1H), 2.58 (d, J = 14.4 Hz, 1H), 2.28 (dt, J = 15.0, 5.7 Hz, 1H), 2.22ꢀ2.18 (m, 1H), 2.17 (d, J = 14.4
Hz, 1H), 1.91ꢀ1.87 (m, 1H), 1.84ꢀ1.77 (m, 1H), 1.71ꢀ1.67 (m, 1H), 1.69 (s, 3H), 1.56 (ddd, J = 13.2, 9.6, 3.6 Hz,
1H), 1.06 (s, 3H); 13CꢀNMR: (150 MHz, CDCl3) δ 211.9, 150.0, 112.0, 52.7, 43.9, 41.0, 35.0, 27.0, 22.0, 19.3.
HRMS (EI+) calculated for C10H16O 152.12012, found 152.12093.
3-cyclopropylidene-1-methyl-1-(prop-1-en-2-yl)cyclohexane (1a): Colorless oil (0.269 g, 47% yield). 1H NMR:
(600 MHz, CDCl3) δ 4.74 (s, 1H), 4.73 (s, 1H), 2.41 (d, J = 13.2 Hz, 1H), 2.26ꢀ2.22 (m, 1H), 2.17ꢀ2.14 (m, 1H),
2.13 (d, J = 13.2 Hz, 1H), 1.71 (s, 3H), 1.71ꢀ1.68 (m, 1H), 1.55ꢀ1.50 (m, 2H), 1.47ꢀ1.44 (m, 1H), 0.99ꢀ0.96 (m, 4H),
0.94 (s, 3H); 13CꢀNMR: (150 MHz, CDCl3) δ 152.9, 126.1, 113.9, 109.4, 43.8, 41.0, 36.5, 33.2, 25.9, 23.4, 19.8,
2.13, 2.10. HRMS (EI+) calculated for C13H20 176.15650, found 176.15722.
3-methyl-3-(1-phenylvinyl)cyclohexanone: Characterization data matched that previously reported.39
(1-(3-cyclopropylidene-1-methylcyclohexyl)vinyl)benzene (1b): Synthesized following general procedure B using
3ꢀmethylꢀ3ꢀ(1ꢀphenyvinyl)cyclohexanone. Stirred 5 h at 62°C after addition of ketone in THF. Purified by silica
1
gel chromatography (Hexanes) to give a colorless oil (0.281g, 36% yield). H NMR: (400 MHz, CD2Cl2) δ 7.30ꢀ
7.22 (m, 3H), 7.16ꢀ7.13 (m, 2H), 5.23 (d, J = 1.6 Hz, 1H), 4.82 (d, J = 1.6 Hz, 1H), 2.46 (d, J = 13.2 Hz, 1H), 2.31
(dt, J = 13.2, 5.2 Hz, 1H), 2.23 (d, J = 12.8 Hz, 1H), 2.15ꢀ2.09 (m, 1H), 1.75ꢀ1.69 (m, 1H), 1.68ꢀ1.60 (m, 1H), 1.59ꢀ
1.46 (m, 2H), 1.06 (s, 3H), 1.02ꢀ0.89 (m, 4H); 13CꢀNMR: (100 MHz, CD2Cl2) δ 159.6, 144.0, 129.7, 127.8, 126.8,
126.1, 114.5, 113.5, 44.5, 41.5, 37.2, 33.4, 25.9, 23.7, 2.21. HRMS (EI+) calculated for C18H22 238.17215, found
238.17139.
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3-methyl-3-(prop-1-enyl)cyclohexanone: Synthesized following general procedure A using 1ꢀpropenylmagnesium
bromide solution (0.5 M THF). Purified by silica gel chromatography (15% EtOAc/Petroleum Ether) to give a
yellow oil as a 1:1 inseperable mixture of E/Z isomers (0.981 g, 71% yield). Spectroscopic data reported is of the
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mixture of isomers. H NMR: (600 MHz, CD2Cl2) δ 5.39 (ddt J = 12.0, 7.8, 7.2 Hz, 1H), 5.36ꢀ5.29 (m, 2H), 5.20
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(dq, J = 11.7, 1.8 Hz, 1H), 2.45 (d, J = 13.2 Hz, 1H), 2.34 (dt, J = 13.8, 1.8 Hz, 1H), 2.22ꢀ2.16 (m, 5H), 2.10 (d, J =
13.8 Hz, 1H), 1.95ꢀ1.91 (m, 1H), 1.88ꢀ1.76 (m, 4H), 1.69 (dd, J = 7.2, 1.8 Hz, 3H), 1.64ꢀ1.55 (m, 3H), 1.62 (d, J =
4.8 Hz, 3H), 1.16 (s, 3H), 1.00 (s, 3H); 13CꢀNMR: (150 MHz, CD2Cl2) δ 211.6, 211.5, 139.4, 137.0, 125.6, 123.4,
55.1, 52.8, 41.7, 41.4, 41.3, 38.1, 37.5, 28.2, 27.6, 23.1, 22.7, 18.4, 14.8. HRMS (EI+) calculated for C10H16O
152.12012, found 152.12048.
3-cyclopropylidene-1-methyl-1-(prop-1-enyl)cyclohexane (1c): Synthesized following general procedure B using
3ꢀmethylꢀ3ꢀ(propꢀ1ꢀenyl)cyclohexanone. Stirred 2.5 h at 62°C after addition of ketone in THF. Purified by silica
gel chromatography (Hexanes) to give a colorless oil as a 1:1 inseparable mixture of E/Z isomers (0.185 g, 32%
yield). Spectroscopic data reported is of the mixture of isomers. 1H NMR: (600 MHz, CD2Cl2) δ 5.43ꢀ5.36 (m,
1H), 5.35ꢀ5.29 (m, 2H), 5.23 (dq, J = 12.0, 1.8 Hz, 1H), 2.39 (d, J = 12.6 Hz, 1H), 2.29ꢀ2.23 (m, 1H), 2.21 (d, J =
13.2 Hz, 1H), 2.17ꢀ2.10 (m, 2H), 2.06 (d, J = 19.5 Hz, 1H), 2.04 (d, J = 19.8, 1H), 1.86ꢀ1.82 (m, 1H), 1.71 (dd, J =
7.2, 1.8 Hz, 3H), 1.63 (dd, J = 4.8, 1.2 Hz, 3H), 1.61ꢀ1.46 (m, 6H), 1.44ꢀ1.38 (m, 2H), 1.11 (s, 3H), 1.03ꢀ0.95 (m,
8H), 0.91 (s, 3H); 13CꢀNMR: (150 MHz, CD2Cl2) δ 141.9, 139.3, 126.4, 126.2, 123.9, 121.1, 114.2, 114.0, 47.7,
45.4, 39.3, 39.0, 38.9, 38.3, 33.5, 33.4, 27.2, 26.5, 24.2, 23.7, 18.6, 15.0, 2.21, 2.17, 2.11. HRMS (EI+) calculated
for C13H20 176.15650, found 176.15742.
(E)-3-(but-2-en-2-yl)-3-methylcyclohexanone: Synthesized following general procedure A using 1ꢀmethylꢀ1ꢀ
propenylmagnesium bromide solution (0.5 M THF). Stirred 2 h at ꢀ41°C after addition of eneꢀone. Purified by
silica gel chromatography (15% EtOAc/Petroleum Ether) to give a yellow oil; 3:1 ratio of inseperable diastereomers
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(1.13 g, 75% yield). Spectroscopic data reported is of the mixture of isomers. H NMR: (600 MHz, CD2Cl2) δ 5.31
(q, J = 7.8 Hz, 1H), 5.24 (q, J = 6.6 Hz, (1/3) = 1H, minor isomer), 2.69 (d, J = 13.8 Hz, 1H), 2.54 (d, J = 14.4 Hz,
(1/3) = 1H, minor isomer), 2.29ꢀ2.20 (m, 2H), 2.18ꢀ2.12 (m, 2H), 1.93ꢀ1.74 (m, 2H), 1.70ꢀ1.67 (m, 6H), 1.56ꢀ1.55
(m, 1H), 1.14 (s, 3H), 1.03 (s, (1) = 3H, minor isomer); 13CꢀNMR: (150 MHz, CD2Cl2) δ 211.9, 211.8, 140.9, 140.8,
121.7, 119.4, 54.1, 53.0, 44.7, 44.3, 41.4, 41.3, 36.3, 35.3, 27.2, 26.2, 24.2, 22.8, 22.4, 15.9, 14.0, 12.4. HRMS
(EI+) calculated for C11H18O 166.13577, found 166.13636.
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(E)-1-(but-2-en-2-yl)-3-cyclopropylidene-1-methylcyclohexane (1d): Synthesized following general procedure B
using (E)ꢀ3ꢀ(butꢀ2ꢀenꢀ2ꢀyl)ꢀ3ꢀmethylcyclohexanone. Stirred 4.5 h at 62°C after addition of ketone in THF. Purified
by silica gel chromatography (Hexanes) to give a colorless oil as an inseperable 3:1 ratio of diastereomers (0.106 g,
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17% yield). Spectroscopic data reported is of the mixture of isomers. H NMR: (600 MHz, CD2Cl2) δ 5.33ꢀ5.30 (m,
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(1/3) = 1H, minor isomer), 5.26ꢀ5.23 (m, 1H), 2.54 (d, J = 13.2 Hz, 1H), 2.37 (d, J = 12.6 Hz, (1/3) = 1H, minor
isomer), 2.28ꢀ2.24 (m, 1H), 2.20ꢀ2.16 (m, 1H), 2.13 (d, J = 13.2 Hz, 1H), 2.01ꢀ1.97 (m, 1H), 1.69 (bs, 6H), 1.60ꢀ
1.50 (m, 3H), 1.06 (s, 3H), 0.99 (bs, 4H), 0.91 (s, (1) = 3H, minor isomer); 13CꢀNMR: (150 MHz, CD2Cl2) δ 143.23,
143.16, 126.9, 126.7, 120.3, 116.7, 114.1, 113.8, 45.4, 44.1, 41.64, 41.58, 37.6, 36.8, 33.6, 33.5, 25.5, 25.3, 24.03,
23.99, 23.7, 16.1, 14.0, 12.6, 2.4, 2.21, 2.19, 2.1. HRMS (EI+) calculated for C14H22 190.17215, found 190.17239.
3-methyl-3-(2-methylprop-1-enyl)cyclohexanone: Synthesized following general procedure A using 2ꢀmethylꢀ1ꢀ
propenylmagnesium bromide solution (0.5 M THF). Stirred 1.5 h at ꢀ41°C after addition of eneꢀone. Purified by
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silica gel chromatography (15% EtOAc/Petroleum Ether) to give a yellow oil (1.02 g, 68% yield). H NMR: (600
MHz, CD2Cl2) δ 5.03 (s, 1H), 2.41 (d, J = 12.6 Hz, 1H), 2.21 (d, J = 4.8 Hz, 2H), 2.17 (d, J = 13.2 Hz, 1H), 1.93 (bs,
1H), 1.83 (bs, 2H), 1.71 (s, 3H), 1.67 (s, 3H), 1.60 (bs, 1H), 1.15 (s, 3H); 13CꢀNMR: (150 MHz, CD2Cl2) δ 211.7,
133.6, 131.0, 55.6, 41.4, 40.9, 38.3, 28.3, 27.6, 23.1, 19.5. HRMS (EI+) calculated for C11H18O 166.13577, found
166.13609.
3-cyclopropylidene-1-methyl-1-(2-methylprop-1-enyl)cyclohexane (1e): Synthesized following general procedure
B using 3ꢀmethylꢀ3ꢀ(2ꢀmethylpropꢀ1ꢀenyl)cyclohexanone. Stirred 3 h at 62°C after addition of ketone in THF.
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Purified by silica gel chromatography (Hexanes) to give a colorless oil (0.206 g, 33% yield). H NMR: (600 MHz,
CD2Cl2) δ 5.04 (s, 1H), 2.35 (d, J = 13.2 Hz, 1H), 2.26ꢀ2.24 (m, 1H), 2.12 (bs, 1H), 2.02 (d, J = 12.6 Hz, 1H) 1.82ꢀ
1.79 (m, 1H), 1.70 (s, 3H), 1.64 (s, 3H) 1.57ꢀ1.54 (m, 1H), 1.51ꢀ1.45 (m, 1H), 1.42ꢀ1.38 (m, 1H), 1.08 (s, 3H), 1.03ꢀ
0.98 (m, 4H); 13CꢀNMR: (150 MHz, CD2Cl2) δ 133.5, 131.4, 126.6, 114.1, 48.0, 39.5, 38.0, 33.5, 28.3, 27.1, 24.2,
19.5, 2.2, 2.1. HRMS (EI+) calculated for C14H22 190.17215, found 190.17146.
3-methyl-3-(prop-1-en-2-yl)cyclopentanone: Synthesized following general procedure A using
isopropenylmagnesium bromide (0.5 M THF) and 3ꢀmethylcyclopentꢀ2ꢀenone. Stirred 1.5 h at ꢀ41°C after addition
of eneꢀone. This material was sufficiently pure to be taken on without further purification as a yellow oil (0.991 g,
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79% yield). H NMR: (600 MHz, CD2Cl2) δ 4.78 (t, J = 1.8 Hz, 1H), 4.71 (s, 1H), 2.38 (d, J = 17.4 Hz, 1H), 2.28ꢀ
2.24 (m, 2H), 2.09 (d, J = 17.4 Hz, 1H), 2.07ꢀ2.02 (m, 1H), 1.88ꢀ1.84 (m, 1H), 1.79 (s, 3H), 1.17 (s, 3H); 13CꢀNMR:
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(150 MHz, CD2Cl2) δ 218.9, 151.6, 109.5, 51.6, 45.3, 37.1, 34.3, 25.9, 19.8. HRMS (EI+) calculated for C9H14O
138.10447, found 138.10502.
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3-cyclopropylidene-1-methyl-1-(prop-1-en-2-yl)cyclopentane (3a): Synthesized following general procedure B
using 3ꢀmethylꢀ3ꢀ(propꢀ1ꢀenꢀ2ꢀyl)cyclopentanone. Stirred 5 h at 62°C after addition of ketone in THF. Purified by
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silica gel chromatography (Hexanes) to give a colorless oil (0.096g, 18% yield). H NMR: (600 MHz, CDCl3) δ
4.70 (s, 1H), 4.68 (s, 1H), 2.47ꢀ2.41 (m, 3H), 2.23 (d, J = 15.0 Hz, 1H), 1.82ꢀ1.77 (m, 1H), 1.76 (s, 3H), 1.63ꢀ1.58
(m, 1H), 1.04 (s, 3H), 0.97ꢀ0.95 (m, 4H); 13CꢀNMR: (150 MHz, CDCl3) δ 153.1, 130.6, 111.4, 108.2, 47.7, 44.7,
37.2, 30.0, 25.4, 20.3, 2.5, 2.4. HRMS (EI+) calculated for C12H19 (M+1) 163.14868, found 163.14901.
3-methyl-3-(1-phenylvinyl)cyclopentanone: Synthesized following general procedure C using 3ꢀmethylcyclopentꢀ
2ꢀenone. Stirred 4 h at ꢀ41°C after addition of eneꢀone. Purification by gradient silica gel chromatography
(Petroleum Ether to 95:5 Pet. Ether:Et2O to 90:5:5 Pet. Ether:Et2O:EtOAc) provided the product compound as a
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yellow oil (0.327g, 18% yield) H NMR: (600 MHz, CDCl3) δ 7.31ꢀ7.26 (m, 3H), 7.15ꢀ7.14 (m, 2H), 5.17 (s, 1H),
4.96 (s, 1H), 2.50 (d, J = 17.4 Hz, 1H), 2.31ꢀ2.28 (m, 2H), 2.20ꢀ2.14 (m, 1H), 2.15 (dd, J = 17.4, 1.8 Hz, 1H), 1.86
(ddt, J = 9.6, 6.6, 1.8 Hz, 1H), 1.25 (s, 3H); 13CꢀNMR: (150 MHz, CDCl3) δ 218.8, 156.4, 142.3, 128.8, 128.0,
127.2, 113.8, 51.9, 45.2, 36.7, 34.5, 26.6. HRMS (EI+) calculated for C14H16O 200.12012, found 200.11936.
(1-(3-cyclopropylidene-1-methylcyclopentyl)vinyl)benzene (3b): Synthesized following general procedure B
using 3ꢀmethylꢀ3ꢀ(1ꢀphenylvinyl)cyclopentanone. Stirred 8.5 h at 62°C after addition of ketone in THF. Purified by
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silica gel chromatography (Hexanes) to give a colorless oil (0.221 g, 30% yield). H NMR: (600 MHz, CDCl3) δ
7.29ꢀ7.24 (m, 3H), 7.20ꢀ7.18 (m, 2H), 5.17 (d, J = 1.2 Hz, 1H), 4.87 (d, J = 1.2 Hz, 1H), 2.57 (d, J = 15.6 Hz, 1H),
2.44 (bs, 2H), 2.26 (d, J = 15.6 Hz, 1H), 1.97ꢀ1.92 (m, 1H), 1.66ꢀ1.62 (m, 1H), 1.13 (s, 3H), 0.96ꢀ0.94 (m, 4H); 13Cꢀ
NMR: (150 MHz, CDCl3) δ 158.4, 143.7, 130.3, 128.8, 127.7, 126.7, 112.6, 111.7, 47.8, 45.4, 37.8, 29.8, 26.2, 2.5,
2.4. HRMS (EI+) calculated for C17H20 224.15650, found 224.15584.
3-(1-phenylvinyl)cycloheptanone: Synthesized following general procedure C using 2ꢀcycloheptenꢀ1ꢀone. Stirred
1.5 h at ꢀ41°C after addition of eneꢀone. Purification by gradient silica gel chromatography (Petroleum Ether to 95:5
Pet. Ether:Et2O to 90:5:5 Pet. Ether:Et2O:EtOAc) provided the product compound as a pale yellow oil (1.13 g, 58%
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yield). H NMR: (400 MHz, CDCl3) δ 7.32ꢀ7.31 (m, 4H), 7.29ꢀ7.26 (m, 1H), 5.19 (s, 1H), 5.02 (s, 1H), 2.82 (t, J =
10.4 Hz, 1H), 2.70ꢀ2.61 (m, 1H), 2.69 (t, J = 14.4 Hz, 1H), 2.55ꢀ2.51 (m, 2H), 2.07ꢀ2.03 (m, 1H), 1.99ꢀ1.90 (m,
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2H), 1.69ꢀ1.59 (m, 1H), 1.52ꢀ1.35 (m, 2H); 13CꢀNMR: (100 MHz, CDCl3) δ 214.1, 154.0, 142.0, 128.6, 127.7,
126.8, 111.7, 49.7, 44.2, 41.0, 37.3, 29.3, 24.4. HRMS (EI+) calculated for C15H18O 214.13577, found 214.13519.
1-cyclopropylidene-3-(1-phenylvinyl)cycloheptane (4a): Synthesized following general procedure B using 3ꢀ(1ꢀ
phenylvinyl)cycloheptanone. Stirred 3.5 h at 62°C after addition of ketone in THF. Purified by silica gel
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chromatography (Hexanes) to give a colorless oil (0.367 g, 47% yield). H NMR: (400 MHz, CDCl3) δ 7.39ꢀ7.37
(m, 2H), 7.33ꢀ7.29 (m, 2H), 7.27ꢀ 7.25 (m, 1H), 5.19 (s, 1H), 5.06 (s, 1H), 2.71 (d, J = 14.0 Hz, 1H), 2.64 (t, J =
10.4 Hz, 1H), 2.52 (d, J = 14.8 Hz, 1H), 2.42ꢀ2.36 (m, 1H), 2.28 (t, J = 12.4 Hz, 1H), 1.94ꢀ1.91 (m, 1H), 1.85ꢀ1.79
(m, 2H), 1.56ꢀ1.49 (m, 1H), 1.44ꢀ1.30 (m, 2H), 0.99ꢀ0.93 (m, 4H); 13CꢀNMR: (100 MHz, CDCl3) δ 155.7, 143.0,
128.9, 128.4, 127.3, 126.8, 116.8, 110.6, 44.9, 41.0, 36.7, 34.6, 28.5, 27.8, 2.35. HRMS (EI+) calculated for C18H22
238.17215, found 238.17115.
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6,7-dimethyltricyclo[5.3.1.0]undec-4-ene (2a): Colorless oil (0.019 g, 76%). H NMR: (600 MHz, CDCl3) δ.5.17
(s, 1H), 2.82ꢀ2.75 (m, 1H), 2.50ꢀ2.46 (m, 1H), 2.01 (bs, 1H), 1.74ꢀ1.70 (m, 3H), 1.63 (dd, J = 13.8, 2.4 Hz, 1H),
1.50ꢀ1.40 (m, 3H), 1.32 (dt, J = 12.3, 4.2 Hz, 1H), 1.26 (d, J = 11.4 Hz, 1H), 0.94 (d, J = 7.2 Hz, 3H), 0.87 (dt, J =
13.8, 5.4 Hz, 1H), 0.84 (s, 3H); 13CꢀNMR: (150 MHz, CDCl3) δ 143.1, 121.7, 48.9, 46.5, 42.2, 35.8, 34.9, 33.4,
32.5, 30.8, 28.9, 22.2, 14.7. HRMS (EI+) calculated for C13H20 176.15650, found 176.15578.
7-methyl-6-phenyltricyclo[5.3.1.0]undec-4-ene (2b): Synthesized following general procedure D using compound
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1b. Purified by silica gel chromatography (Hexanes) to give a colorless oil (0.022 g, 88% yield). H NMR: (600
MHz, CDCl3) δ 7.31ꢀ7.26 (m, 4H), 7.22ꢀ7.20 (m, 1H), 5.37 (s, 1H), 3.35 (s, 1H), 2.95ꢀ2.88 (m, 1H), 2.59 (dt, J =
13.8, 5.4 Hz, 1H), 1.91ꢀ1.88 (m, 1H), 1.84ꢀ1.76 (m, 3H), 1.70 (d, J = 10.8 Hz, 1H), 1.45ꢀ1.41 (m, 3H), 1.07ꢀ1.04 (m,
1H), 0.97 (s, 3H), 0.79 (dt, J = 13.8 5.4 Hz, 1H); 13CꢀNMR: (150 MHz, CDCl3) δ 145.2, 142.7, 130.0, 127.8, 126.2,
119.4, 55.4, 49.7, 46.4, 36.3, 35.4, 33.7, 32.6, 31.4, 29.3, 22.5. HRMS (EI+) calculated for C18H22 238.17215, found
238.17229.
Corresponding Authors: Email: mgagne@unc.edu; djtantillo@ucdavis.edu
Notes: The authors declare no competing financial interest.
Acknowledgments: The UNC group acknowledges the National Institute of General Medicine (GMꢀ60578). The
UCD group acknowledges the National Science Foundation, the University of California Institute for Mexico and
the United States, UCD & Humanities Graduate Research Award, and an R. B. Miller Gradaute Fellowship to O.G.
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Supporting Information: H and 13C NMR spectroscopic data for all new compounds and discussion of 2D
NMR spectroscopic data for compound 2b, as well as coordinates and energies for all computed structures and
complete ref. 34 is provided. This information is available free of charge via the Internet at http://pubs.acs.org.
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