A Relay Strategy Actuates Pre-Existing Trisubstituted Olefins in Monoterpenoids for Cross-Metathesis with Trisubstituted Alkenes

Article abstract of DOI:10.1021/acs.joc.0c00067

A retrosynthetic disconnection-reconnection analysis of epoxypolyenes - substrates that can undergo cyclization to podocarpane-type tricycles - reveals relay-actuated Δ^6,7-functionalized monoterpenoid alcohols for ruthenium benzylidene catalyzed olefin cross-metathesis with homoprenyl benzenes. Successful implementation of this approach provided several epoxypolyenes as expected (E/Z, ca. 2-3:1). The method is further generalized for the cross-metathesis of pre-existing trisubstituted olefins in other relay-actuated Δ^6,7-functionalized monoterpenoid alcohols with various other trisubstituted alkenes to form new trisubstituted olefins. Epoxypolyene cyclization of an enantiomerically pure, but geometrically impure, epoxypolyene substrate provides an enantiomerically pure, trans-fused, podocarpane-type tricycle (from the E-geometrical isomer).

Full text of DOI:10.1021/acs.joc.0c00067

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Article
A Relay Strategy Actuates Pre-Existing Trisubstituted Olefins in
Monoterpenoids for Cross-Metathesis with Trisubstituted Alkenes
Karim A. Bahou, D. Christopher Braddock,* Adam G. Meyer, G. Paul Savage, Zhensheng Shi,
and Tianyou He
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ABSTRACT: A retrosynthetic disconnection−reconnection analysis of
epoxypolyenessubstrates that can undergo cyclization to podocarpane-
type tricyclesreveals relay-actuated Δ6,7-functionalized monoterpenoid
alcohols for ruthenium benzylidene catalyzed olefin cross-metathesis with
homoprenyl benzenes. Successful implementation of this approach provided
several epoxypolyenes as expected (E/Z, ca. 2−3:1). The method is further
generalized for the cross-metathesis of pre-existing trisubstituted olefins in
other relay-actuated Δ6,7-functionalized monoterpenoid alcohols with various
other trisubstituted alkenes to form new trisubstituted olefins. Epoxypolyene
cyclization of an enantiomerically pure, but geometrically impure,
epoxypolyene substrate provides an enantiomerically pure, trans-fused, podocarpane-type tricycle (from the E-geometrical isomer).
denes as developed by Grubbs.7 Such catalysts are widely used
to accomplish the ring-closing metathesis of disubstituted,
INTRODUCTION
■
Biomimetically inspired polyene cyclizations have emerged as a
trisubstituted, and even tetrasubstituted olefins.8 In contrast,
powerful synthetic strategy for the stereocontrolled con-
and quite surprisingly, there are only limited reports on the
struction of complex polycarbocyclic scaffolds of biological
formation of unfunctionalized trisubstituted olefins (as
significance,1 where epoxypolyene cyclizations of terminally
required here) by cross-metathesis using ruthenium benzyli-
functionalized geranyl units with nucleophilic aromatic head-
dene pre-catalysts.9 Grubbs and co-workers initially showed
groups have provided synthetic access to podocarpane-type
that ruthenium pre-catalyst 1 was competent for the cross-
tricyclic diterpene skeleta (Figure 1a).2 Such cyclization
metathesis of geminally disubstituted olefins with terminal
substrates are typically constructed in two steps via metal-
olefins (Figure 1c).10,11 Subsequently, Robinson and co-
catalyzed cross-coupling methodology of an electrophilic
workers showed that the cross-metathesis of sterically
geranyl species in conjunction with a benzylic organometallic,
challenging allyl branched 1,1-disubstituted olefins performed
andeither before or after C−C bond construction
considerably better using a (terpenoid) prenyl rather than an
regioselective functionalization of the geranyl alkene at the
allyl partner using precatalyst 2 (Figure 1d).12 With this latter
terminus of the chain (Figure 1a).3 Each of these steps is
literature precedent in mind, we therefore selected trisub-
subject to a potential disadvantage: the former is subject to
stituted olefins as the cross-metathesis partners (Figure 1b,
competing allylic SN2′ substitution, and the latter to nonperfect
regioselective oxidation, regardless of the order of implemen-
tation.4 During the course of our studies, we had reason to
consider an alternative disconnection of such functionalized
linear monoterpenoid derivatives by olefin cross-metathesis,
but of the two terminal olefin species that are revealed, the
epoxide-containing component is synthetically nonsimplified
(Figure 1b). Nonetheless, a “reconnection” operation5 reveals
a geraniol derivative with a pre-existing trisubstituted olefin
that we expected could be actuated for cross-metathesis by the
application of Hoye’s relay strategy.6 For reasons outlined
below, we also elected to “reconnect” the terminal alkene
component from the initial disconnection as a trisubstituted
alkene.
reconnection).13 As envisioned, this overall stratagem not only
opens up the possibility of an alternative, modular, synthetic
route to such cyclization precursors, but perhaps more
significantly could provide a general approach to the
functionalization of pre-existing trisubstituted olefins in acyclic
monoterpenoid alcohols by cross-metathesis (Figure 1e).14
Herein, we report the success of this unprecedented olefin−
olefin combination to form new unfunctionalized trisubstituted
Received: January 10, 2020
The catalyst(s) of choice for the above proposition would be
the commercially available well-defined ruthenium benzyli-
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Figure 1. (a) Representative epoxypolyene cyclization and previous generic synthetic approach; (b) proposed alternative disconnection,
reconnections, and relay incorporation; (c,d) previous ruthenium benzylidene-catalyzed cross-metathesis reactions to produce unfunctionalized
trisubstituted olefins; (e) this work.
Scheme 1. Synthesis of Relay-Modified Δ6,7-Functionalized
olefins by cross-metathesis (Figure 1e), where the overall
transformation can be classified as a relay cross-metathesis.
This relay cross-metathesis reaction (“ReXM”) distinguishes
itself from the very limited literature precedent for such
reactions by being the first such example to form isolated,
unconjugated, trisubstituted alkenes where all previous reports
have formed conjugated alkenes.15,16
Monoterpenes (E)-5a and (Z)-5a
RESULTS AND DISCUSSION
■
We commenced our investigations with two main objectives in
mind: (i) demonstration of proof-of-principle ReXM of
monoterpenoid alcohol derivatives with homoprenylbenzenes
to prepare representative epoxypolyene cyclization substrates;
(ii) exemplification of the method as a general approach for the
functionalization of pre-existing trisubstituted olefins in acyclic
monoterpenoid alcohols. Accordingly, we assembled relay-
modified Δ6,7-functionalized monoterpenes (E)-5a and (Z)-5a
from geraniol [(E)-3] and nerol [(Z)-3] via allylation17 and
epoxidation with mCPBA (Scheme 1). We also prepared diols
(S)- and (R)-5b via Sharpless dihydroxylation18 of triene (E)-4
in excellent enantiomeric purityconfirmed by conversion to
their respective benzoates 5c and chiral stationary phase high-
performance liquid chromatography (HPLC) analysis (see
Supporting Information)and thence acetonides (S)- and
(R)-5d (Scheme 2) by ketalization. Relay-free acetonide (S)-
5e was prepared from geranyl acetate as a control substrate by
the use of Scafato’s methods.19 Control substrate (S)-5f was
prepared by the action of Grubbs catalyst 1 on (S)-5d, thereby
inherently confirming the ability of the allyl group to function
as a relay in this situation. Boronates (S)- and (R)-5g were also
prepared from diols (S)- and (R)-5b by direct condensation
with phenyl boronic acid in ethyl acetate. These latter
substrates, now incorporating UV-active chromophores,
could be analyzed directly by HPLC for enantiomeric purity
and were found to have identical enantiomeric excesses to
benzoates (S)- and (R)-5c (see the Supporting Information).
Attention now turned to the assembling of a collection of
suitable trisubstituted alkenes for this study. Trisubstituted
alkenes 7a and 7d−7k were prepared by the Wittig reaction of
isopropyl phosphonium iodide (6) with aldehydes (Scheme
3).20 Alternatively, trisubstituted alkene 7c could be prepared
by the reaction of the corresponding benzylic Grignard reagent
with prenyl bromide under Pd(0) catalysis.3b The former
method is preferred, as nonperfect regioselectivity from
competing SN2′ attack is possible in the latter. Prenyl acetone
7l was commercially available, as was terminal alkene 7b,
which was used for control experiments (vide infra).
With these substrates in hand, we selected relay (E)-5a and
trisubstituted alkene 7a as the partner olefin to test in the
proposed ReXM reaction. It is well established that
trisubstituted olefinsclassified as type III olefins21do not
homodimerize, and this prompted us to use trisubstituted
alkene 7a in excess with the expectation that this would
thereby help facilitate the desired cross-metathesis. Although
various attempts to mediate the proposed ReXM in toluene or
B
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Scheme 2. Synthesis of Various Δ6,7-Functionalized
Monoterpenes 5b−g
Table 1. ReXM of Relay-Actuated Δ6,7-Functionalized
Monoterpenoids with Homoprenyl Benzenes Using 10 mol
% GII Catalyst (1)
Scheme 3. Synthesis of Various Trisubstituted Alkenes
dichloromethane solution failed, neat epoxide (E)-5a under-
went smooth ReXM using 10 mol % 1 with trisubstituted
alkene 7a (5 equiv) at 50 °C to provide functionalized
epoxypolyene 8a in excellent isolated yield (Table 1, entry 1).
Surprisingly, the use of Hoveyda−Grubbs precatalyst 2 under
identical conditions gave only a trace of the product 8a in a
complex product mixture (entry 2), and all further metatheses
were conducted with catalyst 1. In further stark contrast, the
use of terminal olefin 7b under the same conditions (entry 3)
with epoxide (E)-5a gave instead direct cross-metathesis
product 9a and isomerized vinyl ether 10a as the major
epoxide-containing products, demonstrating that the use of a
trisubstituted alkene is critical for these reactions. Control
experiments with acetonides (S)-5d−f (entries 5−7)22 verify
also the vital role of the relay in this ReXM process, and a
comparison with the reaction with Z-epoxide (Z)-5a (entry 4)
a
0.25 mmol scale, conditions: olefin (5 equiv), GII (1) (10 mol %),
b
neat, 50 °C, 1 h. Percentage isolated yields shown after
C
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Table 1. continued
Table 2. ReXM of Relay-Actuated Δ6,7-Functionalized
Monoterpenes with Various Trisubstituted Olefins Using 10
mol % GII Catalyst
c
chromatography. Figures in parentheses are the E/Z ratio
1
determined by H NMR and assigned on the basis of characteristic
13C NMR shielded methyl resonances for E-isomers (see the
d
Experimental Section for details) Hoveyda−Grubbs II catalyst 2
e
(10 mol %) employed E/Z ratio determined by 1H NMR and
3
assigned on the basis of characteristic JH−H coupling constants.
establishes the olefin geometry in the relay substrate as
unimportant. Further examples of epoxides (E)- and (Z)-5a
with various homoprenyl benzenes 7c-g establish the generality
of the method (entries 8−13).23 In all successful cases, the
ReXM products 8a-g were obtained with moderate E-olefin
selectivity (ca. 2−3:1), as inseparable isomers, which is a
limitation of the method.24 However, these selectivities are
directly comparable to those previously reported for the
formation of trisubstituted olefins by cross-metathesis with
ruthenium benzylidene precatalysts (cf Figure 1c,d).10−12
A possible catalytic cycle for this ReXM process using
representative epoxide (E)-5a with homoprenyl benzene 7a
invokes Diver15 for the conversion of A to B with loss of
dihydrofuran (Figure 2). The regioselective reactions of
Figure 2. Possible catalytic cycle for the ReXM reaction.
ruthenium species of type B with trisubstituted olefins have
been proposed by Robinson,12 which would produce the
ReXM product 8a and ruthenium isopropylidene C. In this
scenario, the catalytic cycle would be closed by re-initiation of
ruthenium isopropylidene C11a on the terminal olefin of relay
epoxide (E)-5a with concomitant loss of isobutylene.25 This
mechanism is consistent also with the results obtained using
nerol versus geraniol-derived substrates (cf, Table 1, entries 1
vs 4 & entries 8 vs 9) as the same ruthenium alkylidene of the
type B should be formed after initial relay metathesis.
With the ReXM method established for the reaction with
homoprenyl benzenes, we explored further reactions with a
variety of relay substrates and different trisubstituted alkenes as
a general method for the functionalization of pre-existing
trisubstituted olefins in acyclic monoterpenoid alcohols (Table
2). Thus, epoxide (E)-5a underwent smooth ReXM with
aliphatic trisubstituted alkene 7h to give ReXM product 8h in
excellent yield (Table 2, entry 1). α-Branching of the alkyl
chain as in olefin 7i (entry 2) proved to be detrimental to the
process, where β,β-dimethylstyrene (7j) and prenylbenzene
(7k) (entries 3−4) as partner olefins also failedproducing
only truncated alkene 5hpresumably on the basis of
increased steric demand in each of these partner olefins.
Readily available prenyl acetone 7l gave the ReXM product 8i
(entry 5), but diol (S)-5b unexpectedly failed to undergo
ReXM (entry 6), resulting in truncated compound 5i and
a
0.25 mmol scale, conditions: olefin (5 equiv), GII (1) (10 mol %),
b
neat, 50 °C, 1 h. Percentage isolated yields shown after
D
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various other trisubstituted alkenes to form new trisubstituted
olefins, thereby facilitating the ability to valorize terpene
biomass. The limitation inherent in the method regarding E/Z
selectivity requires further advances in catalyst development to
provide E- and Z-selective ruthenium benzylidene catalysts for
trisubstituted olefins. However, in this situation, this can be
overcome by cyclization of a E/Z-epoxypolyene substrate to
give a separable, enantiomerically pure, podocarpane-type
tricycle (from the E-geometrical isomer) in comparable yield
to such cyclizations already reported in the literature.2
Table 2. continued
c
chromatography. Figures in parentheses are the E/Z ratio
1
determined by H NMR and assigned on the basis of characteristic
13C NMR shielded methyl resonances for E-isomers (see the
d
Experimental Section for details). “Truncated” compound 5h was
not isolated because of its volatility but assigned on the basis of a
e
characteristic 1H resonance at δ 4.72 (m, 2H) ppm. E/Z ratio
1
determined by H NMR and assigned on the basis of characteristic
3JH−H coupling constants.
isomerized product 10b (implicating catalyst decomposition to
a ruthenium hydride species).26 Acetonides (S)- & (R)-5d and
boronates (S)- & (R)-5g, however, participated cleanly in
ReXM reactions (entries 7−13) to provide the desired
products (S)- & (R)-8b, 8j−l without complication. In these
latter instances, these substrates are all derived from highly
enantioselective Sharpless dihydroxylations of geranyl allyl
ether [(E)-4, vide infra], thereby providing the ReXM adducts
in uniformly high enantiomeric excess, which we flag as an
advantage of this methodology.
In order to overcome the inherent E/Z mixture limitation of
this cross-metathesis method, we elected to demonstrate an
epoxypolyene cyclization with the expectation that any
resulting products would have more marked polarity differ-
ences. Accordingly, we prepared ReXM product (R)-8c from
enantiomerically pure epoxide (R,E)-5a and homoprenyl
methoxybenzene (7c) in good yield (81%) as an inseparable
2:1 E/Z mixture (Scheme 4). Boron trifluoride-promoted
EXPERIMENTAL SECTION
■
Experimental Techniques. All reactions were carried out in
oven-dried glassware. Air-sensitive reactions were performed under a
positive pressure of nitrogen unless stated otherwise. Reaction
temperatures other than room temperature were achieved using an
oil bath, ice/water bath, or dry ice/acetone. “Concentrated” refers to
concentrating of the solution in vacuo. “Chromatographed” refers to
flash column chromatography on silica gel, particle size 33−70 or 40−
63 μm, unless otherwise stated. “DCVC” refers to dry column vacuum
chromatography on silica gel, particle size 33−70 μm.30 Analytical
thin-layer chromatography was performed on silica gel 60 F254 pre-
coated aluminum-backed plates and visualized with either irradiation
with UV light (254 nm) or potassium permanganate, vanillin, or
phosphomolybdic acid staining. Brine refers to a saturated aqueous
NaCl solution.
Characterization. Fourier transform infrared (IR) spectra were
recorded neat using an attenuated total reflection (ATR)-IR
spectrometer and absorptions are reported to the nearest wave-
number. The (expected) very weak CC and sp2 C−H bond
stretches for trisubstituted alkenes 7 and 8 failed to be automatically
pick peaked because they fell under the peak picking threshold,
although they can be observed (in most cases) by careful inspection of
the spectra.29 1H and 13C NMR spectra were recorded on either a
Bruker DRX-400 or Bruker AV-400. Chemical shifts (δ) are expressed
Scheme 4. ReXM-Epoxypolyene Cyclization Sequence
1
in parts per million (ppm) relative to the residual solvent peak. H
NMR spectra were recorded at 400 MHz. 13C NMR spectra were
recorded at 101 MHz. NMR acquisitions were performed at 298 K
unless stated otherwise. Abbreviations are: s, singlet; d, doublet; t,
triplet; q, quartet; qu., quintet; m, multiplet. High-resolution mass
spectrometry (HRMS) was conducted by the Imperial College
Department of Chemistry Mass Spectrometry Service.
Reagents. Allyl bromide was distilled freshly before use; otherwise
all reagents were obtained from commercial suppliers and used as
received.
Solvents. All reactions were carried out in anhydrous solvents.
HPLC grade CH2Cl2, THF, and EtOAc were dried by passing
through a column of alumina beads. Extraction solvents, chromatog-
raphy eluents (n-hexane, petrol, pentanes, CH2Cl2, Et2O, and EtOAc),
and BuOH were used as received. “Petrol” refers to petroleum ether
(40−60 °C). Petroleum ether (40−60 °C), EtOAc, CH2Cl2, and
Et2O were of GPR grade and pentanes were of HPLC grade.
epoxypolyene cyclization of this E/Z mixture provided single
enantiomer podocarpane-type tricycle 11 (56% yield based on
E-8c) as a single diastereoisomer, which was readily separated
away from the other components in the reaction mixture.27 To
the best of our knowledge, tricycle 11 has not previously been
prepared in a single enantiomer form,28 thereby validating the
utility of this two-step metathesis-cyclization sequence.29
t
(E)-1-(Allyloxy)-3,7-dimethylocta-2,6-diene [(E)-4].17 Using a
modified procedure of Rao and Senthilkumar, to a mixture of neat
geraniol [(E)-3] (5.30 mL, 30 mmol, 1.0 equiv), allyl bromide (7.8
mL, 90 mmol, 3.0 equiv), and TBAI (554 mg, 1.50 mmol, 5 mol %)
was added crushed KOH pellets (3.37 g, 60.0 mmol, 2.0 equiv) at
room temperature and the mixture was stirred for 18 h. The crude
reaction mixture was purified by loading directly onto a pad of silica
gel and eluting with n-hexane, to give allyl ether (E)-4 (5.78 g, 29.7
mmol, 99%) as a colorless oil. 10.14469/hpc/5738. Rf 0.60 (n-
CONCLUSIONS
■
In conclusion, we have designed and demonstrated a novel
ruthenium benzylidene-catalyzed relay cross-metathesis
(“ReXM”) reaction for the preparation of podocarpane-type
epoxypolyene cyclization substrates from relay-actuated Δ6,7-
functionalized monoterpenoid alcohols with homoprenyl
benzenes. It constitutes also a general method for the cross-
metathesis of pre-existing trisubstituted olefins in other relay-
actuated Δ6,7-functionalized monoterpenoid alcohols with
1
hexane); IR (ATR, neat) 1670, 1647 cm−1; H NMR (400 MHz,
CDCl3): δ 5.93 (ddt, J = 17.2, 10.3, 5.7 Hz, 1H), 5.39−5.33 (m, 1H),
5.27 (dq, J = 17.3, 1.7 Hz, 1H), 5.18 (dq, J = 10.4, 1.4 Hz, 1H), 5.13−
5.06 (m, 1H), 4.00 (d, J = 6.8 Hz, 2H), 3.97 (dt, J = 5.7, 1.4 Hz, 2H),
2.16−1.96 (m, 4H), 1.68 (d, J = 1.3 Hz, 3H), 1.66 (s, 3H), 1.60 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 140.2, 135.1, 131.7,
E
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124.0, 120.8, 117.0, 70.9, 66.6, 39.6, 26.4, 25.7, 17.7, 16.5; HRMS
(EI+) m/z: [M]•+ calcd for C13H22O, 194.1671; found, 194.1682.
(E)-3-(5-(Allyloxy)-3-methylpent-3-en-1-yl)-2,2-dimethyloxirane
[(E)-5a).31 To a stirred solution of ether (E)-4 (1.41 g, 7.28 mmol, 1.0
equiv) in CH2Cl2 (30 mL) was added dropwise a solution of mCPBA
(1.63 g, 77%, 7.28 mmol, 1.0 equiv) in CH2Cl2 (30 mL) over ca. 0.5 h
at 0 °C. The mixture was allowed to warm to room temperature
gradually. After a total reaction time of 18 h, the reaction mixture was
concentrated, dissolved in EtOAc (100 mL), and washed with a
saturated aqueous NaHCO3 solution (3 × 50 mL), brine (100 mL),
dried over Na2SO4, concentrated, and chromatographed (20−50%
Et2O in pentanes), to give epoxide (E)-5a (1.71 g, 8.1 mmol, 81%) as
a colorless oil. 10.14469/hpc/5820. Rf 0.57 (30% EtOAc in
1H), 5.47−5.37 (m, 1H), 5.28 (dq, J = 17.2, 1.6 Hz, 1H), 5.19 (dq, J
= 10.3, 1.4 Hz, 1H), 4.03−3.93 (m, 4H), 3.36 (dd, J = 10.5, 2.0 Hz,
1H), 2.31 (ddd, J = 14.7, 9.7, 5.2 Hz, 1H), 2.16−2.06 (m, 1H), 1.99−
1.81 (br s, 2H), 1.68 (s, 3H), 1.66−1.56 (m, 1H), 1.51−1.39 (m,
1H), 1.20 (s, 3H), 1.16 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3):
δ 140.1, 134.9, 121.2, 117.1, 78.1, 73.1, 71.2, 66.5, 36.6, 29.5, 26.5,
23.2, 16.5; HRMS (ES+) m/z: [M + Na]+ calcd for C13H24O3Na,
251.1623; found, 251.1631. (R,E)-8-(Allyloxy)-2,6-dimethyloct-6-
ene-2,3-diol [(R)-5b] was prepared under identical conditions but
using AD-mix-β. [α]2D0 +26.1 (c 1.0, CHCl3).
(R,E)-3-(5-(Allyloxy)-3-methylpent-3-en-1-yl)-2,2-dimethyloxir-
ane [(R,E)-5a].31 To a solution of diol (S)-5b (208 mg, 0.91 mmol,
1.0 equiv) in CH2Cl2 (1.8 mL) at 0 °C was added MsCl (0.11 mL, 1.4
mmol, 1.5 equiv) followed by pyridine (0.59 mL, 7.3 mmol, 8.0
equiv) dropwise. The reaction mixture was allowed to gradually warm
to room temperature and was stirred for 20 h, after which the mixture
was poured into a suspension of K2CO3 (1.9 g, 14 mmol, 15 equiv) in
MeOH (9 mL). This suspension was stirred for a further 18 h. The
reaction mixture was then concentrated, diluted with H2O (80 mL),
and extracted with EtOAc (3 × 40 mL). The combined organics were
washed with a saturated aqueous CuSO4 solution (3 × 50 mL), then
brine (50 mL), dried over Na2SO4, concentrated, and chromato-
graphed (5−10% EtOAc in petrol), to give epoxide (R,E)-5a (171
mg, 0.81 mmol, 89%) as a colorless oil. Rf 0.57 (30% EtOAc in
pentanes); [α]2D2 +4.1 (c 1.0, CHCl3). Data are otherwise identical to
the racemic material (E)-5a.
1
pentanes); IR (ATR, neat) 3075, 1670 cm−1; H NMR (400 MHz,
CDCl3): δ 5.92 (ddt, J = 17.5, 10.5, 5.7 Hz, 1H), 5.43−5.36 (m, 1H),
5.26 (dq, J = 17.2, 1.7 Hz, 1H), 5.17 (dq, J = 10.5, 1.5 Hz, 1H), 3.99
(d, J = 6.8 Hz, 2H), 3.97−3.94 (m, 2H), 2.70 (t, J = 6.2 Hz, 1H),
2.26−2.07 (m, 2H), 1.68 (s, 3H), 1.67−1.62 (m, 2H), 1.29 (s, 3H),
1.25 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 139.2, 135.0,
121.4, 117.0, 71.1, 66.5, 64.0, 58.4, 36.2, 27.2, 24.9, 18.7, 16.5; HRMS
(CI+) m/z: [M − H]+ calcd for C13H21O2, 209.1536; found,
209.1535.
(Z)-1-(Allyloxy)-3,7-dimethylocta-2,6-diene [(Z)-4].17 Using a
modified procedure of Rao and Senthilkumar, to a neat mixture of
nerol [(Z)-3] (5.30 mL, 30 mmol, 1.0 equiv), allyl bromide (7.8 mL,
90 mmol, 3.0 equiv), and TBAI (554 mg, 1.50 mmol, 5 mol %) was
added crushed KOH pellets (3.37 g, 60.0 mmol, 2.0 equiv) at room
temperature and the mixture was stirred for 18 h. The crude reaction
mixture was purified by loading directly onto a pad of silica gel and
eluting with n-hexane, to give allyl ether (Z)-4 (5.81 g, 29.9 mmol,
quant.) as a colorless oil. 10.14469/hpc/5741. Rf 0.65 (n-hexane); IR
(ATR, neat) 3091, 1670 cm−1; 1H NMR (400 MHz, CDCl3): δ 5.92
(ddt, J = 17.3, 10.3, 5.6 Hz, 1H), 5.41−5.32 (m, 1H), 5.30−5.24 (m,
1H), 5.21−5.13 (m, 1H), 5.14−5.04 (m, 1H), 4.00−3.92 (m, 4H),
2.12−2.02 (m, 4H), 1.75 (d, J = 1.2 Hz, 3H), 1.68 (s, 3H), 1.60 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 140.4, 135.1, 131.9,
123.9, 121.8, 116.8, 71.0, 66.3, 32.3, 26.7, 25.7, 23.5, 17.6; HRMS
(EI+) m/z: [M]•+ calcd for C13H22O, 194.1671; found, 194.1670.
(Z)-3-(5-(Allyloxy)-3-methylpent-3-en-1-yl)-2,2-dimethyloxirane
[(Z)-5a]. To a stirred solution of ether (Z)-4 (1.41 g, 7.28 mmol, 1.0
equiv) in CH2Cl2 (30 mL) was added dropwise a solution of mCPBA
(1.63 g, 77%, 7.28 mmol, 1.0 equiv) in CH2Cl2 (30 mL) over ca. 0.5 h
at 0 °C. The mixture was allowed to warm to room temperature
gradually. After a total reaction time of 18 h, the reaction mixture was
concentrated, dissolved in EtOAc (100 mL), and washed with a
saturated aqueous NaHCO3 solution (3 × 50 mL), brine (100 mL),
dried over Na2SO4, concentrated, and chromatographed (20−50%
Et2O in pentanes), to give epoxide (Z)-5a (1.60 g, 7.6 mmol, 76%) as
a colorless oil. 10.14469/hpc/5742. Rf 0.25 (10% EtOAc in n-
hexane); IR (ATR, neat) 3075 cm−1; 1H NMR (400 MHz, CDCl3): δ
5.92 (ddt, J = 17.3, 10.4, 5.7 Hz, 1H), 5.46−5.38 (m, 1H), 5.27 (dq, J
= 17.2, 1.6 Hz, 1H), 5.17 (dq, J = 10.4, 1.4 Hz, 1H), 4.03−3.93 (m,
4H), 2.70 (t, J = 6.3 Hz, 1H), 2.29−2.15 (m, 2H), 1.76 (d, J = 1.2 Hz,
3H), 1.71−1.54 (m, 2H), 1.30 (s, 3H), 1.26 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3): δ 139.5, 134.9, 122.4, 117.0, 71.2, 66.2, 63.9,
58.4, 28.9, 27.5, 24.9, 23.4, 18.7; HRMS (ES+) m/z: [M − H]+ calcd
for C13H21O2, 209.1542; found, 209.1547.
(S,E)-8-(Allyloxy)-2-hydroxy-2,6-dimethyloct-6-en-3-yl Benzoate
[(S)-5c]. To a solution of diol (S)-5b (25.0 mg, 0.11 mmol, 1.0 equiv)
in pyridine (1 mL) was added benzoyl chloride (16 μL, 0.14 mmol,
1.3 equiv) and the reaction mixture was stirred at room temperature
for 18 h. Then was added additional benzoyl chloride (33 μL, 0.28
mmol, 2.6 equiv) and the mixture was stirred for an additional 5 h.
The reaction mixture was diluted with EtOAc (25 mL) and washed
with a 1 M aqueous HCl solution (3 × 20 mL) and a saturated
aqueous NaHCO3 solution (3 × 20 mL). The organics were dried
over Na2SO4, concentrated, and chromatographed on silica gel (20%
EtOAc in n-hexane), to give benzoate (S)-5c (33.0 mg, 0.11 mmol,
99%) as a colorless oil. 10.14469/hpc/5744. Rf 0.41 (40% EtOAc in
n-hexane); [α]2D0 −16.7 (c 1.0, CHCl3); IR (ATR, neat) 3600−3250,
1
3064, 1715 cm−1; H NMR (400 MHz, CDCl3): δ 8.11−8.02 (m,
2H), 7.63−7.54 (m, 1H), 7.50−7.42 (m, 2H), 5.91 (ddt, J = 17.3,
10.4, 5.7 Hz, 1H), 5.38−5.30 (m, 1H), 5.30−5.22 (m, 1H), 5.20−
5.14 (m, 1H), 5.07 (dd, J = 9.6, 3.3 Hz, 1H), 4.01−3.86 (m, 4H),
2.13−2.03 (m, 2H), 1.98−1.74 (m, 3H), 1.65 (s, 3H), 1.27 (s, 6H);
13C{1H} NMR (101 MHz, CDCl3): δ 166.8, 139.4, 135.1, 133.3,
130.2, 129.8, 128.6, 121.4, 117.1, 80.4, 72.8, 71.2, 66.6, 36.1, 27.9,
26.7, 25.3, 16.7; HRMS (ES+) m/z: [M + Na]+ calcd for
C20H28O4Na, 355.1885; found, 355.1894. HPLC (CHIRALCEL
OD; 10% IPA in n-hexane; 0.5 mL/min) tR = 10.1 min (major),
10.9 min (minor) (96:4). (R,E)-8-(Allyloxy)-2-hydroxy-2,6-dimethy-
loct-6-en-3-yl benzoate [(R)-5c] was prepared under identical
conditions from diol (R)-5b. [α]3D1 +12.4 (c 0.8, CHCl3). HPLC
(CHIRALCEL OD; 10% IPA in n-hexane; 0.5 mL/min) tR = 9.9 min
(minor), 10.6 min (major) (4:96).
(S,E)-5-(5-(Allyloxy)-3-methylpent-3-en-1-yl)-2,2,4,4-tetramethyl-
1,3-dioxolane [(S)-5d]. To a solution of diol (S)-5b (1.05 g, 4.59
mmol, 1.0 equiv) in CH2Cl2 (9 mL) were added dimethoxypropane
(5.60 mL, 45.9 mmol, 10.0 equiv) and pyridinium p-toluenesulfonate
(577 mg, 2.30 mmol, 0.5 equiv) at room temperature and the mixture
was stirred for 18 h. The reaction mixture was concentrated and
loaded directly onto a column of silica gel and chromatographed (5−
10% EtOAc in petrol) to give acetonide (S)-5d (1.11 g, 4.13 mmol,
90%) as a colorless oil. 10.14469/hpc/5745. Rf 0.23 (5% EtOAc in
petrol); [α]2D4 2.1 (c 1.0, CHCl3); IR (ATR, neat) 3075, 1670 cm−1;
1H NMR (400 MHz, CDCl3): δ 5.99−5.86 (m, 1H), 5.44−5.35 (m,
(S,E)-8-(Allyloxy)-2,6-dimethyloct-6-ene-2,3-diol [(S)-5b].31 Using
a modified procedure of Sharpless,18 to a vigorously stirred solution of
AD-mix-α (7.0 g, 1.4 g mol−1) in tBuOH (75 mL) and H2O (75 mL)
was added MeSO2NH2 (476 mg, 5.0 mmol, 1.0 equiv) followed by
ether (E)-4 (972 mg, 5.0 mmol, 1.0 equiv). The reaction mixture was
allowed to stir for 16 h. The mixture was quenched by the addition of
a 20% Na2SO3 aqueous solution (150 mL) and extracted with EtOAc
(3 × 50 mL). The combined organics were washed with brine, dried
over MgSO4, concentrated, and chromatographed (40% EtOAc in n-
hexane), to give diol (S)-5b (632 mg, 2.8 mmol, 55%) as a colorless
oil. 10.14469/hpc/5743. Rf 0.36 (40% EtOAc in n-hexane); [α]D20
−26.1 (c 1.0, CHCl3); IR (ATR, neat) 3600−3100, 3075, 1666 cm−1;
1H NMR (400 MHz, CDCl3): δ 5.93 (ddt, J = 17.2, 10.3, 5.7 Hz,
1H), 5.27 (br d, J = 17.2 Hz, 1H), 5.17 (br d, J = 10.4 Hz, 1H), 3.99
(d, J = 6.8 Hz, 2H), 3.96 (d, J = 5.7 Hz, 2H), 3.65 (dd, J = 9.5, 3.3 Hz,
1H), 2.34−2.20 (m, 1H), 2.13−2.00 (m, 1H), 1.68 (s, 3H), 1.69−
1.58 (m, 1H), 1.56−1.43 (m, 1H), 1.41 (s, 3H), 1.32 (s, 3H), 1.23 (s,
3H), 1.08 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 139.6,
F
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135.0, 121.1, 117.0, 106.5, 82.9, 80.1, 71.1, 66.5, 36.7, 28.6, 27.5, 26.9,
26.1, 22.9, 16.6; HRMS (EI+) m/z: [M]•+ calcd for C16H28O3,
268.2038; found, 268.2050. (R,E)-5-(5-(Allyloxy)-3-methylpent-3-en-
1-yl)-2,2,4,4-tetramethyl-1,3-dioxolane [(R)-5d] was prepared under
identical conditions from diol (R)-5b. [α]2D4 −1.5 (c 1.0, CHCl3).
(S)-2,2,4,4-Tetramethyl-5-(3-methylbut-3-en-1-yl)-1,3-dioxolane
[(S)-5f]. To a solution of (S,E)-acetonide (S)-5d (100 mg, 0.37 mmol,
1.0 equiv) in CH2Cl2 (37 mL) was added ruthenium benzylidene 1
(3.2 mg, 0.0037 mmol, 1 mol %). The mixture was heated to reflux
with stirring for 2 h. The reaction mixture was concentrated and
loaded directly onto a column of silica gel and chromatographed (5%
EtOAc in petrol) to give alkene (S)-5f (57 mg, 0.28 mmol, 77%) as a
colorless oil. 10.14469/hpc/5755. Rf 0.53 (5% EtOAc in petrol);
equiv) in THF (10 mL) was added dropwise over 20 min to
magnesium turnings (0.478 g, 20.0 mmol, 1.2 equiv) in THF (10 mL)
and at 0 °C. The reaction was warmed to room temperature and the
mixture was stirred for 3 h. To the mixture was added dropwise a
solution of tetrakis(triphenylphosphine)palladium(0) (0.226 g, 0.196
mmol, 1.5 mol %) and 1-bromo-3-methylbut-2-ene (2.4 mL, 20.1
mmol, 1.0 equiv) in THF (10 mL) at −78 °C. The reaction mixture
turned to green immediately and was stirred for an additional 3 h
before warming to room temperature. The reaction mixture was
stirred for 16 h and quenched with ice water (20 mL), then extracted
with Et2O (2 × 20 mL). The organics were washed with water (20
mL), brine (20 mL), dried over Na2SO4, concentrated, and
chromatographed (20% EtOAc in n-hexane) to give alkene 7c (2.29
g, 12.3 mmol, 70%, containing 5% of inseparable p-methoxytoluene).
[α]2D4 −1.4 (c 1.0, CHCl3); IR (ATR, neat) 3071, 1648 cm−1; H
1
1
NMR (400 MHz, CDCl): δ 4.74 (s, 1H), 4.71 (s, 1H), 3.68 (dd, J =
9.4, 3.5 Hz, 1H), 2.31−2.17 (m, 1H), 2.12−2.00 (m, 1H), 1.74 (s,
3H), 1.71−1.60 (m, 1H), 1.57−1.46 (m, 1H), 1.42 (s, 3H), 1.32 (s,
3H), 1.24 (s, 3H), 1.10 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3):
δ 145.2, 110.1, 106.5, 82.8, 80.1, 34.9, 28.6, 27.4, 26.9, 26.0, 22.9,
22.6; HRMS (EI+) m/z: [M]•+ calcd for C12H22O2, 198.1620; found,
198.1612.
10.14469/hpc/5761. Rf 0.20 (10% EtOAc in n-hexane); H NMR
(400 MHz, CDCl3): δ 7.12 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz,
2H), 5.18 (t, J = 7.1, 1H), 3.80 (s, 3H), 2.58 (t, J = 7.8 Hz, 2H), 2.27
(app. q, J = 7.8 Hz, 2H), 1.70 (s, 3H), 1.58 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3): δ 157.7, 134.6, 132.1, 129.3, 123.8, 113.6, 55.3,
35.2, 30.3, 25.7, 17.7; HRMS (CI+) m/z: [M − H]+ calcd for
C13H17O, 189.1274; found, 189.1272.
(S,E)-5-(5-(Allyloxy)-3-methylpent-3-en-1-yl)-4,4-dimethyl-2-
phenyl-1,3,2-dioxaborolane [(S)-5g]. Phenylboronic acid (315 mg,
2.63 mmol, 1.05 equiv) was added to a solution of diol (S)-5b (570
mg, 2.5 mmol, 1 equiv) in EtOAc (10 mL). After 90 min, the reaction
mixture was concentrated, passed through a silica plug (15% EtOAc in
petrol; 150 mL), and evaporated to give boronate (S)-5g (775 mg,
2.50 mmol, 99%) as a pale beige viscous oil. 10.14469/hpc/6317.
1-Methoxy-3-(4-methylpent-3-en-1-yl)benzene (7d). Following
the general procedure for the formation of trisubstituted alkenes
using (CH3)2CHPPh3I 6 (3.8 g, 8.8 mmol, 1.8 equiv), THF (10 mL),
nBuLi (3.5 mL, 2.5 M in hexanes, 8.8 mmol, 1.8 equiv), and 3-(3-
methoxyphenyl)propanal33 (0.8 g, 4.9 mmol, 1.0 equiv) gave alkene
7d (0.55 g, 59%) as a colorless oil. 10.14469/hpc/6318. Rf 0.85 (10%
1
EtOAc in petrol); H NMR (400 MHz, CDCl3): δ 7.22−7.15 (m,
[α]2D5 −17.1 (c 1.0, CHCl3); IR (ATR, neat) 3075 cm−1; H NMR
1
1H), 6.82−6.77 (m, 1H), 6.76−6.72 (m, 2H), 5.23−5.12 (m, 1H),
3.80 (s, 3H), 2.71−2.57 (m, 2H), 2.29 (app. q, J = 7.6 Hz, 2H), 1.69
(d, J = 1.3 Hz, 3H), 1.58 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3):
δ 159.7, 144.2, 132.2, 129.3, 123.8, 121.0, 114.3, 111.1, 55.2, 36.3,
30.0, 25.8, 17.8; HRMS (CI+) m/z: [M + H]+ calcd for C13H19O,
191.1430; found, 191.1430.
(400 MHz, CDCl3): δ 7.82 (d, J = 7.1 Hz, 2H), 7.51−7.42 (m, 1H),
7.41−7.33 (m, 2H), 6.00−5.89 (m, 1H), 5.46 (t, J = 6.6 Hz, 1H),
5.28 (d, J = 17.2 Hz, 1H), 5.19 (d, J = 10.3 Hz, 1H), 4.06 (dd, J =
10.3, 3.4 Hz, 1H), 4.02 (d, J = 6.7 Hz, 2H), 3.99 (d, J = 5.7 Hz, 2H),
2.48−2.38 (m, 1H), 2.23−2.12 (m, 1H), 1.81−1.69 (m, 1H), 1.73 (s,
3H), 1.68−1.59 (m, 1H), 1.44 (s, 3H), 1.29 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3): δ 139.6, 135.0, 134.8, 131.3, 127.8, 121.2, 117.1,
85.3, 82.1, 71.2, 66.6, 36.4, 29.9, 28.8, 23.5, 16.7; MS (EI+) m/z:
[M]•+ calcd for C19H2711BO3, 314.2053; found, 314.2062. HPLC
(CHIRALCEL OD-H, 1% IPA in n-hexane; 1.0 mL/min) tR = 8.5
min (major), 10.8 min (minor) (95:5). (R,E)-5-(5-(Allyloxy)-3-
methylpent-3-en-1-yl)-4,4-dimethyl-2-phenyl-1,3,2-dioxaborolane
[(R)-5g] was prepared under identical conditions from diol (R)-5b.
[α]2D5 +15.8 (c 1.0, CHCl3). HPLC (CHIRALCEL OD-H, 1% IPA in
n-hexane; 1.0 mL/min) tR = 8.5 min (minor), 10.8 min (major)
(3:97).
1-Methoxy-2-(4-methylpent-3-en-1-yl)benzene (7e).34 Following
the general procedure for the formation of trisubstituted alkenes using
(CH3)2CHPPh3I 6 (3.9 g, 9.0 mmol, 1.8 equiv), THF (10 mL), nBuLi
(3.6 mL, 2.5 M in hexanes, 9.0 mmol, 1.8 equiv), and 3-(2-
methoxyphenyl)propanal35 (0.82 g, 5.0 mmol, 1.0 equiv) gave alkene
7e (0.73 g, 3.8 mmol, 76%) as a colorless oil. 10.14469/hpc/6319. Rf
1
0.20 (5% EtOAc in petrol); H NMR (400 MHz, CDCl3): δ 7.22−
7.10 (m, 2H), 6.92−6.81 (m, 2H), 5.21 (m, 1H), 3.83 (s, 3H), 2.68−
2.57 (m, 2H), 2.31−2.20 (m, 2H), 1.69 (d, J = 1.4 Hz, 3H), 1.58 (d, J
= 1.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 157.5, 131.8,
130.8, 129.8, 126.9, 124.3, 120.3, 110.2, 55.3, 30.6, 28.3, 25.7, 17.6;
MS (CI+) m/z: [M + H]+ calcd for C13H19O, 191.1430; found,
191.1431.
General Procedure for Preparation of Trisubstituted
Alkenes 7 via Wittig Olefination of Aldehydes. Using a modified
procedure of Pfaltz,20 to a suspension of (CH3)2nCHPPh3I 6 (7.8 g, 18
mmol, 1.8 equiv) in THF (20 mL) was added BuLi (11.25 mL, 1.6
M in hexanes, 18 mmol, 1.8 equiv) dropwise at 0 °C. After 30 min,
the required aldehyde (1.0 equiv) was added dropwise and the
mixture was stirred for 18 h. The mixture was quenched by addition
of H2O (15 mL) and the THF was removed by concentration. The
mixture was diluted with Et2O (100 mL) and filtered through a pad of
Celite. The organics were washed with H2O (3 × 20 mL), dried over
Na2SO4, and concentrated. The crude material was purified by
DCVC, eluting with pentanes, to give the desired trisubstituted
alkene.
1-Methyl-4-(4-methylpent-3-en-1-yl)benzene (7f).36 Following
the general procedure for the formation of trisubstituted alkenes
using (CH3)2CHPPh3I 6 (2.5 g, 5.8 mmol, 1.2 equiv), THF (10 mL),
nBuLi (2.3 mL, 2.5 M in hexanes, 5.8 mmol, 1.2 equiv), and 3-(4-
methylphenyl)propanal37 (0.72 g, 4.9 mmol, 1.0 equiv) gave alkene 7f
(0.51 g, 2.9 mmol, 60%) as a colorless oil. 10.14469/hpc/6320. Rf
1
0.93 (10% EtOAc in petrol); IR (ATR, neat) 3042 cm−1; H NMR
(400 MHz, CDCl3): δ 7.10 (s, 4H), 5.26−5.12 (m, 1H), 2.66−2.56
(m, 2H), 2.33 (s, 3H), 2.29 (app. q, J = 7.7 Hz, 2H), 1.70 (s, 3H),
1.59 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 139.5, 135.2,
132.2, 129.1, 128.4, 124.0, 35.8, 30.3, 25.8, 21.2, 17.8; HRMS (EI+)
m/z: [M]•+ calcd for C13H18, 174.1409; found, 174.1411.
(4-Methylpent-3-en-1-yl)benzene (7a).32 Following the general
procedure for the formation of trisubstituted alkenes using hydro-
cinnamaldehyde (1.32 mL, 10.0 mmol, 1.0 equiv) gave alkene 7a
(0.99 g, 6.1 mmol, 61%) as a colorless oil. 10.14469/hpc/5759. Rf
1-Chloro-4-(4-methylpent-3-en-1-yl)benzene (7g).38 Following
the general procedure for the formation of trisubstituted alkenes
using (CH3)2CHPPh3I 6 (3.9 g, 9.0 mmol, 1.8 equiv), THF (10 mL),
nBuLi (3.6 mL, 2.5 M in hexanes, 9.0 mmol, 1.8 equiv), and 3-(4-
chlorophenyl)propanal39 (843 mg, 5.0 mmol, 1.0 equiv) gave alkene
7g (828 mg, 4.3 mmol, 85%) as a colorless oil. 10.14469/hpc/6321.
Rf 0.30 (5% EtOAc in petrol); 1H NMR (400 MHz, CDCl3): δ 7.26−
7.21 (m, 2H), 7.13−7.08 (m, 2H), 5.13 (m, 1H), 2.63−2.56 (m, 2H),
2.31−2.22 (m, 2H), 1.68 (d, J = 1.4 Hz, 3H), 1.54 (d, J = 1.4 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 140.8, 132.5, 131.4,
1
0.44 (pentanes); IR (ATR, neat) 3027 cm−1; H NMR (400 MHz,
CDCl3): δ 7.31−7.22 (m, 2H), 7.22−7.12 (m, 3H), 5.24−5.09 (m,
1H), 2.68−2.58 (m, 2H), 2.29 (q, J = 7.7 Hz, 2H), 1.68 (s, 3H), 1.56
(s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 142.5, 132.3, 128.6,
128.3, 125.8, 123.9, 36.3, 30.2, 25.8, 17.8; HRMS (CI+) m/z: [M +
H]+ calcd for C12H17, 161.1330; found, 161.1325.
1-Methoxy-4-(4-methylpent-3-en-1-yl)benzene (7c).3b To a
solution of p-methoxybenzyl chloride (2.26 mL, 16.6 mmol, 1.0
G
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129.8, 128.3, 123.3, 35.4, 29.9, 25.7, 17.7; MS (CI+) m/z: [M − H]+
calcd for C12H1435Cl, 193.0779; found, 193.0777.
yloxy)pent-3-en-1-yl)oxirane (10a). Following the general procedure
for relay cross-metathesis using epoxy allyl ether (E)-5a (53 mg) and
alkene 7b (165 mg), with regular addition of 7b at 10 min intervals to
keep the reaction volume constant throughout the whole reaction
process, gave first 10a (14.3 mg, 0.07 mmol, 27%) as a colorless oil
and a mixture of E/Z geometrical isomers [E/Z = 49:51], and second
9a (29.0 mg, 0.09 mmol, 37%) as a colorless oil. 9a: 10.14469/hpc/
6466. Rf 0.30 (10% EtOAc in pentanes); IR (ATR, neat) 3023, 1670
2-Methylnon-2-ene (7h).40 Following the general procedure for
the formation of trisubstituted alkenes using heptanal (1.40 mL, 10.0
mmol, 1.0 equiv) gave alkene 7h (0.59 g, 4.2 mmol, 42%) as a
colorless oil. 10.14469/hpc/5756. Rf 0.94 (pentanes); 1H NMR (400
MHz, CDCl3): δ 5.24−5.01 (m, 1H), 2.03−1.88 (m, 2H), 1.69 (d, J =
1.4 Hz, 3H), 1.60 (s, 3H), 1.36−1.23 (m, 8H), 0.89 (t, J = 6.7 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 131.2, 125.1, 32.0, 30.0,
29.2, 28.2, 25.9, 22.8, 17.8, 14.3; HRMS (EI+) m/z: [M]•+ calcd for
C10H20, 140.1560; found, 140.1554.
1
cm−1; H NMR (400 MHz, CDCl3): δ 7.31−7.26 (m, 2H), 7.21−
7.15 (m, 3H), 5.80−5.70 (m, 1H), 5.66−5.56 (m, 1H), 5.42−5.35
(m, 1H), 3.95 (d, J = 6.8, 2H), 3.91 (dd, J = 6.0, 0.9 Hz, 2H), 2.71
(m, 3H), 2.38 (m, 2H), 2.27−2.07 (m, 2H), 1.71−1.62 (m, 5H), 1.30
(s, 3H), 1.26 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 141.9,
139.1, 133.7, 128.4, 128.3, 127.1, 125.8, 121.5, 70.8, 66.3, 64.0, 58.4,
36.2, 35.5, 34.1, 27.2, 24.9, 18.7, 16.5. HRMS (CI+) m/z: [M + H]+
calcd for C21H31O2, 315.2319; found, 315.2323. 10a: 10.14469/hpc/
6469. Rf 0.60 (10% EtOAc in pentanes); IR (ATR, neat) 1662 cm−1;
1H NMR (400 MHz, CDCl3): δ 6.22 (dq, J = 12.5, 1.6 Hz, 0.51H,
(E)-9a), 5.96 (dq, J = 6.3, 1.7 Hz, 0.49H, (Z)-9a), 5.41 (m, 1H), 4.79
(dq, J = 13.3, 6.7 Hz, 0.51H, (E)-9a), 4.38 (appr. qu., J = 6.8 Hz,
0.49H, (Z)-9a), 4.26 (d, J = 6.7 Hz, 1.02H, (E)-9a), 4.18 (d, J = 6.7
Hz, 0.98H, (Z)-9a), 2.70 (t, J = 6.3 Hz, 1H), 2.28−2.07 (m, 2H),
1.73−1.60 (m, 5H), 1.57 (dd, J = 6.8, 1.7 Hz, 1.53H, (E)-9a), 1.55
(dd, J = 6.7, 1.6 Hz, 1.47H, (Z)-9a), 1.30 (s, 3H), 1.26 (d, J = 1.7 Hz,
3H). The E/Z ratio was determined by integration of the resonances
at δ 4.26 (major) and 4.18 (minor) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 146.2, 145.1, 139.8, 139.7, 128.5, 121.0, 120.4, 101.2, 98.8,
68.2, 65.7, 64.0, 58.4, 36.2, 36.2, 27.1, 24.9, 18.8, 16.6, 12.7, 9.3.
HRMS (CI+) m/z: [M + H]+ calcd for C13H23O2, 211.1693; found,
211.1694.
4-Ethyl-2-methyloct-2-ene (7i). Following the general procedure
for the formation of trisubstituted alkenes using 2-ethylhexanal (1.56
mL, 10.0 mmol, 1.0 equiv) gave alkene 7i (0.87 g, 5.7 mmol, 57%) as
a colorless oil. 10.14469/hpc/5760. Rf 0.92 (pentanes); 1H NMR
(400 MHz, CDCl3): δ 4.79 (br d, J = 9.8 Hz, 1H), 2.13−2.01 (m,
1H), 1.71 (d, J = 1.4 Hz, 3H), 1.60 (d, J = 1.3 Hz, 3H), 1.45−1.06
(m, 8H), 0.87 (t, J = 7.1 Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3): δ 130.8, 130.4, 39.8, 35.8, 29.8, 29.0, 26.0,
23.1, 18.4, 14.3, 11.9; HRMS (EI+) m/z: [M]•+ calcd for C11H22,
154.1721; found, 154.1716.
(2-Methylprop-1-en-1-yl)benzene (7j).20 Following the general
procedure for the formation of trisubstituted alkenes using
benzaldehyde (1.02 mL, 10.0 mmol, 1.0 equiv) gave alkene 7j (1.30
g, 9.8 mmol, 98%) as a colorless oil. 10.14469/hpc/5757. Rf 0.58
1
(pentanes); IR (ATR, neat) 3021, 1657 cm−1; H NMR (400 MHz,
CDCl3): δ 7.37−7.28 (m, 2H), 7.28−7.15 (m, 3H), 6.29 (s, 1H), 1.93
(s, 3H), 1.88 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 138.9,
135.6, 128.9, 128.2, 125.9, 125.3, 27.0, 19.6; HRMS (EI+) m/z: [M]•+
calcd for C10H12, 132.0934; found, 132.0933.
(3-Methylbut-2-en-1-yl)benzene (7k).41 Following the general
procedure for the formation of trisubstituted alkenes using phenyl-
acetaldehyde (1.17 mL, 10.0 mmol, 1.0 equiv) gave alkene 7k (0.40 g,
2.8 mmol, 28%) as a colorless oil. 10.14469/hpc/5758. Rf 0.63
(pentanes); IR (ATR, neat) 3027 cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.33−7.23 (m, 2H), 7.22−7.13 (m, 3H), 5.40−5.27 (m,
1H), 3.35 (d, J = 7.4 Hz, 2H), 1.75 (d, J = 1.4 Hz, 3H), 1.72 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ 141.9, 132.6, 128.5, 128.4,
(S)-2,2,4,4-Tetramethyl-5-(3-methyl-6-phenylhex-3-en-1-yl)-1,3-
dioxolane [(S)-8b]. Following the general procedure for relay cross-
metathesis using acetonide (S)-(5d) (67 mg) and alkene 7a (200 mg)
gave trisubstituted alkene (S)-8b (51 mg, 0.17 mmol, 68%) as a light
brown oil and a mixture of E/Z geometrical isomers (E/Z = 70:30).
10.14469/hpc/6326. Rf 0.58 (5% EtOAc in petrol); IR (ATR, neat)
1
3023 cm−1; H NMR (400 MHz CDCl3): δ 7.32−7.24 (m, 2H),
7.23−7.15 (m, 3H), 5.29−5.20 (m, 1H), 3.66 (dd, J = 9.3, 3.5 Hz, E-
8b, 0.70H), 3.62 (dd, J = 9.6, 3.3 Hz, Z-8b, 0.30H), 2.70−2.61 (m,
2H), 2.38−2.27 (m, 2H), 2.27−2.10 (m, 1H), 2.09−1.96 (m, 1H),
1.74−1.68 (m, Z-8b, 0.90H), 1.67−1.59 (m, 1H), 1.58 (s, E-8b,
2.10H), 1.53−1.42 (m, 1H), 1.43 (s, E-8b, 2.10H), 1.43 (s, Z-8b,
0.90H), 1.33 (s, E-8b, 2.10H), 1.32 (s, Z-8b, 0.90H), 1.24 (s, E-8b,
2.10H), 1.23 (s, Z-8b, 0.90H), 1.11 (s, E-8b, 2.10H), 1.08 (s, Z-8b,
0.90H). The E/Z ratio was determined by integration of the
resonances at δ 1.11 (major) and 1.08 (minor) ppm; 13C{1H}
NMR (101 MHz, CDCl3): δ 142.3, 135.1, 128.5, 128.2, 125.7, 125.2,
124.1, 106.5, 82.8, 82.7, 80.1, 80.1, 36.7, 36.3, 36.1, 29.9, 29.8, 28.9,
28.6, 28.6, 27.8, 27.6, 26.9, 26.1, 23.3, 22.9, 16.0. The E-isomer was
identified as the major isomer on the basis of a characteristic shielded
methyl resonance23 at 16.0 versus 23.3 ppm for the minor Z-isomer;
HRMS (EI+) m/z: [M − CH3]+ calcd for C19H27O2, 287.2011; found,
287.2022. Data for (R)-8b was identical.
125.8, 123.3, 34.5, 25.9, 17.9; HRMS (EI+) m/z: [M]•+ calcd for
C11H14, 146.1090; found, 146.1084.
General Procedure for Preparation of Trisubstituted
Alkenes 8 via Relay Cross-Metathesis. To a neat mixture of
relay alkene 5 (0.25 mmol, 1.0 equiv) and alkene 7 (1.25 mmol, 5.0
equiv) was added ruthenium benzylidene 1 (21 mg, 0.025 mmol, 10
mol %). The mixture was heated to 50 °C using an oil bath for 1 h
under a strong positive pressure of N2 (g) via a needle in/out to aid
the removal of volatiles. The resulting mixture was loaded directly
onto a column of silica gel and chromatographed.
2,2-Dimethyl-3-(3-methyl-6-phenylhex-3-en-1-yl)oxirane (8a).2a
Following the general procedure for relay cross-metathesis using
epoxy allyl ether (E)-5a (53 mg) and alkene 7a (200 mg) gave
trisubstituted alkene 8a (51 mg, 0.21 mmol, 84% from (E)-5a; 42 mg,
0.17 mmol, 69% from (Z)-5a) as a colorless oil and a mixture of E/Z
geometrical isomers [E/Z = 73:27 (from (E)-5a) or 79:21 (from (Z)-
5a)]. 10.14469/hpc/5763. Rf 0.50 (10% EtOAc in pentanes); IR
3-(6-(4-Methoxyphenyl)-3-methylhex-3-en-1-yl)-2,2-dimethylox-
irane (8c).2a Following the general procedure for relay cross-
metathesis using epoxy allyl ether (E)- or (Z)-5a (53 mg) and
alkene 7c (250 mg, containing 5% p-methoxytoluene) gave
trisubstituted alkene 8c (45 mg, 0.17 mmol, 66% from (E)-5a; 41
mg, 0.16 mmol, 60% from (Z)-5a) as a brown oil and a mixture of E/
Z geometrical isomers [E/Z = 66:34 (from (E)-5a) or 67:33 (from
(Z)-5a)]. 10.14469/hpc/5817. Rf 0.35 (5% EtOAc in petrol); 1H
NMR (400 MHz, CDCl3): δ 7.10 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6,
2H), 5.25 (br t, J = 7.2 Hz, 1H), 3.79 (s, 3H), 2.72−2.66 (m, 1H),
2.63−2.54 (m, 2H), 2.34−2.23 (m, 2H), 2.21−2.04 (m, 2H), 1.70 (d,
J = 1.3 Hz, Z-8c, 1H), 1.60 (s, E-8c, 2H), 1.66−1.46 (m, 2H), 1.30 (s,
3H), 1.26 (s, E-8c, 2H), 1.25 (s, Z-8c, 1H); The E/Z ratio was
determined by integration of the resonances at δ 1.60 (major) and
1.70 (minor) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 157.8,
134.9, 134.9, 134.5, 129.4, 125.3, 124.4, 113.8, 113.8, 64.3, 64.2, 58.4,
55.4, 36.4, 35.5, 35.2, 30.3, 30.2, 28.6, 27.6, 27.5, 25.0, 25.0, 23.5,
1
(ATR, neat) 3026 cm−1; H NMR (400 MHz, CDCl3): δ 7.30−7.22
(m, 2H), 7.20−7.12 (m, 3H), 5.25−5.18 (m, 1H), 2.72−2.59 (m,
3H), 2.37−2.26 (m, 2H), 2.20−2.01 (m, 2H), 1.71−1.52 (m, 5H),
1.28 (s, 3H), 1.24 (s, E-8a, 2.19H), 1.24 (s, Z-8a, 0.81H). The E/Z
ratio was determined by integration of the resonances at δ 1.24(4)
(major) and 1.23(9) (minor) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 142.4, 142.3, 135.0, 135.0, 128.6, 128.4, 128.4, 125.9,
125.9, 125.2, 124.4, 64.3, 64.2, 58.5, 58.5, 36.5, 36.4, 36.2, 30.1, 30.0,
28.7, 27.6, 27.5, 25.1, 25.1, 23.5, 18.9, 18.9, 16.1. The E-isomer was
identified as the major isomer on the basis of a characteristic shielded
methyl resonance23 at 16.1 versus 23.5 ppm for the minor Z-isomer;
HRMS (CI+) m/z: [M + H]+ calcd for C17H25O, 245.1905; found,
245.1900.
((E)-6-(((E)-3,7-Dimethylocta-2,6-dien-1-yl)oxy)hex-4-en-1-yl)-
benzene (9a) and 2,2-Dimethyl-3-((3E)-3-methyl-5-(prop-1-en-1-
H
https://dx.doi.org/10.1021/acs.joc.0c00067
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
18.9, 18.8, 16.1. The E-isomer was identified as the major isomer on
the basis of a characteristic shielded methyl resonance23 at 16.1 versus
23.5 ppm for the minor Z-isomer; HRMS (CI+) m/z: [M + H]+ calcd
for C18H27O2, 275.2011; found, 275.2008. Data for (R)-8c was
identical.
CDCl3): δ 7.25−7.20 (m, 2H), 7.12−7.08 (m, 2H), 5.22−5.15 (m,
1H), 2.71−2.64 (m, 1H), 2.64−2.56 (m, 2H), 2.34−2.23 (m, 2H),
2.21−2.01 (m, 2H), 1.69 (q, J = 1.3 Hz, Z-8g, 0.66H), 1.64−1.57 (m,
2H), 1.55 (s, E-8g, 2.34H), 1.29 (s, 3H), 1.26 (s, E-8g, 2.34H), 1.25
(s, Z-8g, 0.66H). The E/Z ratio was determined by integration of the
resonances at δ 1.26 (major) and 1.25 (minor) ppm; 13C{1H} NMR
(101 MHz, CDCl3): δ 140.6, 135.3, 131.4, 129.8, 128.3, 128.3, 124.6,
123.8, 64.1, 58.3, 36.3, 35.6, 35.3, 29.7, 29.7, 28.5, 27.4, 27.3, 24.9,
23.3, 18.7, 16.0. The E-isomer was identified as the major isomer on
the basis of a characteristic shielded methyl resonance23 at 16.0 versus
23.3 ppm for the minor Z-isomer; HRMS (CI+) m/z: [M + H]+ calcd
for C17H24O35Cl, 279.1510; found, 279.1510.
3-(6-(3-Methoxyphenyl)-3-methylhex-3-en-1-yl)-2,2-dimethylox-
irane (8d).3d Following the general procedure for relay cross-
metathesis using epoxy allyl ether (E)-5a (9.5 mg, 0.04 mmol, 1.0
equiv) alkene 7d (44 mg, 0.23 mmol, 5.0 equiv), and ruthenium
benzylidene 1 (3.4 mg, 0.004 mmol, 10 mol %) gave trisubstituted
alkene 8d (7.5 mg, 0.024 mmol, 61%) as a colorless oil and a mixture
of E/Z geometrical isomers (E/Z = 72:28). 10.14469/hpc/6322. Rf
1
0.45 (10% EtOAc in pentanes); H NMR (400 MHz, CDCl3): δ
2,2-Dimethyl-3-(3-methyldec-3-en-1-yl)oxirane (8h). Following
the general procedure for relay cross-metathesis using epoxy allyl
ether (E)-5a (53 mg) and alkene 7h (175 mg) gave trisubstituted
alkene 8h (51 mg, 0.23 mmol, 92%) as a colorless oil and a mixture of
E/Z geometrical isomers (E/Z = 70:30). 10.14469/hpc/5762. Rf 0.57
(10% Et2O in pentanes); 1H NMR (400 MHz, Acetone-d6): δ 5.24−
5.14 (m, 1H), 2.64 (t, J = 6.3 Hz, Z-8h, 0.3H), 2.61 (t, J = 6.2 Hz, E-
8h, 0.7H), 2.24−1.95 (m, 4H), 1.72−1.52 (m, 5H), 1.38−1.25 (m,
8H), 1.23 (s, Z-8h, 0.9H), 1.23−1.22 (m, 3H), 1.21 (s, E-8h, 2.1H),
0.92−0.85 (m, 3H). The E/Z ratio was determined by integration of
the resonances at δ 1.21 (major) and 1.23 (minor) ppm; 13C{1H}
NMR (101 MHz, DMSO-d6): δ 133.8, 125.6, 124.7, 62.8, 62.7, 57.6,
57.5, 35.9, 31.2, 29.5, 29.3, 28.4, 28.3, 28.0, 27.3, 27.2, 26.9, 24.6,
24.6, 23.1, 22.1, 18.5, 18.5, 15.7, 13.9. The E-isomer was identified as
the major isomer on the basis of a characteristic shielded methyl
resonance23 at 15.7 versus 23.1 ppm for the minor Z-isomer; HRMS
(CI+) m/z: [M + H]+ calcd for C15H29O, 225.2213; found, 225.2212.
8-(3,3-Dimethyloxiran-2-yl)-6-methyloct-5-en-2-one (8i).42 Fol-
lowing the general procedure for relay cross-metathesis using epoxy
allyl ether (E)-5a (53 mg) and alkene 7l (0.18 mL) gave trisubstituted
alkene 8i (34 mg, 0.16 mmol, 64%) as a light brown oil and a mixture
of E/Z geometrical isomers (E/Z = 73:27). 10.14469/hpc/5764. Rf
7.23−7.14 (m, 1H), 6.80−6.76 (m, 1H), 6.74 (d, J = 1.4 Hz, 1H),
6.75−6.70 (m, 1H), 5.31−5.12 (m, 1H), 3.80 (s, 3H), 2.72−2.66 (m,
1H), 2.65−2.59 (m, 2H), 2.37−2.27 (m, 2H), 2.22−2.03 (m, 2H),
1.70 (d, J = 1.3 Hz, 0.84H, Z-8d), 1.66−1.54 (m, 2H), 1.58 (d, J = 1.2
Hz, 2.16H, E-8d), 1.30 (s, 3H), 1.26 (s, 2.16H, E-8d), 1.25 (s, 0.84H,
Z-8d). The E/Z ratio was determined by integration of the resonances
at δ 1.58 (major) and 1.70 (minor) ppm. 13C{1H} NMR (101 MHz,
CDCl3): δ 159.7, 144.1, 135.0, 129.3, 125.2, 124.3, 121.0, 114.4,
111.1, 64.3, 64.2, 58.5, 55.3, 36.5, 36.2, 29.9, 28.7, 27.6, 25.0, 23.5,
18.9, 16.1. The E-isomer was identified as the major isomer on the
basis of a characteristic shielded methyl resonance23 at 16.1 versus
23.5 ppm for the minor Z-isomer; HRMS (ES+) m/z: [M + H]+ calcd
for C18H27O2, 275.2011; found, 275.2008.
3-(6-(2-Methoxyphenyl)-3-methylhex-3-en-1-yl)-2,2-dimethylox-
irane (8e). Following the general procedure for relay cross-metathesis
using epoxy allyl ether (E)-5a (53 mg) and alkene 7e (238 mg) gave
trisubstituted alkene 8e (54 mg, 0.20 mmol, 78%) as a light brown oil
and a mixture of E/Z geometrical isomers (E/Z = 68:32). 10.14469/
hpc/6323. Rf 0.15 (4% EtOAc in petrol); 1H NMR (400 MHz
CDCl3): δ 7.20−6.81 (m, 4H), 5.30−5.22 (m, 1H), 3.83 (s, E-8e,
2.10H), 3.82 (s, Z-8e, 0.90H), 2.74−2.66 (m, 1H), 2.67−2.59 (m,
2H), 2.33−2.23 (m, 2H), 2.20−2.02 (m, 2H), 1.70 (d, J = 1.3 Hz, Z-
8e, 0.90H), 1.69−1.44 (m, 2H), 1.58 (d, J = 1.3 Hz, E-8e, 2.10H),
1.30 (s, 3H), 1.26 (s, E-8e, 2.10H), 1.26 (s, Z-8e, 0.90H). The E/Z
ratio was determined by integration of the resonances at δ 1.26
(major) and 1.26 (minor) ppm; 13C{1H} NMR (101 MHz, CDCl3):
δ 157.5, 134.5, 130.6, 129.8, 127.0, 127.0, 125.7, 124.8, 120.3, 120.3,
110.2, 64.2, 64.2, 58.4, 55.2, 36.3, 30.8, 30.5, 28.5, 28.2, 27.5, 24.9,
23.4, 18.8, 18.7, 15.9. The E-isomer was identified as the major isomer
on the basis of a characteristic shielded methyl resonance23 at 15.9
versus 23.4 ppm for the minor Z-isomer; HRMS (ES+) m/z: [M +
H]+ calcd for C18H27O2, 275.2011; found, 275.2007.
1
0.21 (20% Et2O in pentanes); IR (ATR, neat) 1715 cm−1; H NMR
(400 MHz, CDCl3): δ 5.15−5.07 (m, 1H), 2.69 (t, J = 6.3 Hz, Z-8i,
0.27H), 2.65 (t, J = 6.3 Hz, E-8i, 0.73H), 2.47−2.41 (m, 2H), 2.29−
2.21 (m, 2H), 2.12 (s, 3H), 2.19−2.00 (m, 2H), 1.68−1.56 (m, 5H),
1.29 (s, Z-8i, 0.81H), 1.28 (s, E-8i, 2.19H), 1.25 (s, Z-8i, 0.81H), 1.24
(s, E-8i, 2.19H). The E/Z ratio was determined by integration of the
resonances at δ 1.24 (major) and 1.25 (minor) ppm; 13C{1H} NMR
(101 MHz, CDCl3): δ 208.8, 135.6, 135.6, 124.2, 123.3, 64.2, 64.1,
58.5, 58.4, 43.9, 43.8, 36.4, 30.1, 30.1, 28.6, 27.5, 27.5, 25.0, 25.0,
23.4, 22.5, 22.3, 18.9, 18.9, 16.1. The E-isomer was identified as the
major isomer on the basis of a characteristic shielded methyl
resonance23 at 16.1 versus 23.4 ppm for the minor Z-isomer; HRMS
(ES+) m/z: [M + H]+ calcd for C13H23O2, 211.1693; found, 211.1693.
(S)-2,6-Dimethylhept-6-ene-2,3-diol (5i).43 Following the general
procedure for relay cross-metathesis using diol (S)-5b (57 mg) and
alkene 7a (200 mg) gave truncated alkene 5i (10 mg, 0.06 mmol,
24%) as an inseparable 85:15 mixture containing (S,6E)-2,6-dimethyl-
8-(prop-1-en-1-yloxy)oct-6-ene-2,3-diol (10b) (E/Z = 2:1). Vinyl
ether 10b was identified by comparison of spectroscopic data with
epoxide analogue 10a, and the E/Z ratio was determined by 1H NMR
2,2-Dimethyl-3-(3-methyl-6-(p-tolyl)hex-3-en-1-yl)oxirane (8f).2a
Following the general procedure for relay cross-metathesis using
epoxy allyl ether (E)-5a (53 mg) and alkene 7f (218 mg) gave
trisubstituted alkene 8f (43 mg, 0.16 mmol, 65%) as a colorless oil
and a mixture of E/Z geometrical isomers (E/Z = 72:28). 10.14469/
1
hpc/6414. Rf 0.31 (10% EtOAc in pentanes); H NMR (400 MHz,
CDCl3): δ 7.09 (s, 4H), 5.29−5.21 (m, 1H), 2.74−2.67 (m, 1H),
2.65−2.58 (m, 2H), 2.36−2.27 (m, 2H), 2.33 (s, 3H), 2.23−2.04 (m,
2H), 1.72 (d, J = 1.4 Hz, 0.84H, Z-8f), 1.72−1.51 (m, 2H), 1.62 (s,
2.16H, E-8f), 1.34 (s, 3H), 1.30 (s, 2.16H, E-8f), 1.29 (s, 0.84H, Z-
8f). The E/Z ratio was determined by integration of the resonances at
δ 1.62 (major) and 1.72 (minor) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 139.3, 139.2, 135.2, 135.2, 134.8, 129.1, 129.0, 128.4,
125.3, 124.5, 64.2, 64.2, 58.4, 36.4, 35.9, 35.7, 30.2, 30.1, 28.6, 27.5,
27.5, 25.0, 25.0, 23.4, 21.1, 18.9, 18.8, 16.1. The E-isomer was
identified as the major isomer on the basis of a characteristic shielded
methyl resonance23 at 16.1 versus 23.4 ppm for the minor Z-isomer;
HRMS (ES+) m/z: [M + H]+ calcd for C18H27O, 259.2062; found,
259.2056.
3-(6-(4-Chlorophenyl)-3-methylhex-3-en-1-yl)-2,2-dimethyloxir-
ane (8g). Following the general procedure for relay cross-metathesis
using epoxy allyl ether (E)-5a (53 mg) and alkene 7g (244 mg) gave
trisubstituted alkene 8g (47 mg, 0.17 mmol, 68%) as a light brown oil
and a mixture of E/Z geometrical isomers (E/Z = 78:22). 10.14469/
hpc/6325. Rf 0.25 (4% EtOAc in petrol); 1H NMR (400 MHz
3
and assigned on the basis of characteristic JH−H coupling constants.
10.14469/hpc/5765. Rf 0.40 (40% EtOAc in petrol); IR (ATR, neat)
1
3600−3100, 3075, 1648 cm−1; H NMR (400 MHz, CDCl3): δ 6.22
(dq, J = 12.6, 1.6 Hz, 0.1H, E-10b), 5.96 (dq, J = 6.2, 1.6 Hz, 0.05H,
Z-10b), 5.42 (tq, J = 6.7, 1.3 Hz, 0.15H, 10b), 4.84−4.76 (m, 0.1H,
10b), 4.74 (s, 0.85H), 4.73 (s 0.85H), 4.44−4.35 (m, 0.05H, Z-10b),
4.26 (d, J = 6.7 Hz, 0.1H, Z-10b), 4.18 (d, J = 6.7 Hz, 0.2H, E-10b),
3.36 (d, J = 10.6 Hz, 0.85H), 3.34 (d, J = 11.9 Hz, 0.15H, 10b), 2.38−
2.20 (m, 2H), 2.16−2.01 (m, 2H), 1.74 (d, J = 1.2 Hz, 2.6H), 1.69 (d,
J = 1.4 Hz, 0.5H, 10b), 1.67−1.53 (m, 1.5H), 1.50−1.39 (m, 1H),
1.21 (s, 2.5H), 1.20 (s, 0.5H, 10b), 1.16 (s, 2.5H), 1.15 (s, 0.5H,
10b). For 5i only: 13C{1H} NMR (101 MHz, CDCl3): δ 145.9, 110.5,
79.4, 72.7, 35.0, 29.6, 26.6, 23.4, 22.6; HRMS (ES+) m/z: [M − OH]+
calcd for C9H17O, 141.1279; found, 141.1283.
(S)- and (R)-4,4-Dimethyl-5-(3-methyl-6-phenylhex-3-en-1-yl)-2-
phenyl-1,3,2-dioxaborolane [(S)-8j and (R)-8j]. Following the
I
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general procedure for relay cross-metathesis using boronates (S)- or
(R)-5g (59 mg, 0.19 mmol, 1.0 equiv), alkene 7a (150 mg, 0.94
mmol, 5.0 equiv), and ruthenium benzylidene 1 (16 mg, 0.019 mmol,
10 mol %) gave trisubstituted alkenes (S)-8j (38 mg, 0.11 mmol,
58%) or (R)-8j (44 mg, 0.13 mmol, 68%) as brown oils and a mixture
of E/Z geometrical isomers [(S)-8j: E/Z = 60:40; (R)-8j: E/Z =
62:38]. 10.14469/hpc/6328. Rf 0.40 (5% EtOAc in petroleum ether,
streaking); 1H NMR (400 MHz, CDCl3): δ 7.85−7.78 (m, 2H),
7.50−7.32 (m, 3H), 7.30−7.14 (m, 5H), 5.32−5.23 (m, 1H), 4.03
(dd, J = 10.0, 3.5 Hz, E-8j, 0.60H), 3.98 (dd, J = 10.4, 3.2 Hz, Z-8j,
0.40H), 2.69−2.62 (m, 2H), 2.44−2.06 (m, 4H), 1.72 (d, J = 1.3 Hz,
Z-8j, 1.20H), 1.74−1.63 (m, 1H), 1.59 (s, E-8j, 1.80H), 1.62−1.47
(m, 1H), 1.42 (s, E-8j, 1.80H), 1.41 (s, Z-8j, 1.20H), 1.28 (s, E-8j,
1.80H), 1.25 (s, Z-8j, 1.20H). The E/Z ratio was determined by
integration of the resonances at δ 1.28 (major) and 1.25 (minor)
ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 142.3, 135.1, 135.0,
134.8, 131.3, 128.5, 128.5, 128.2, 127.7, 125.7, 125.4, 124.2, 85.2,
85.1, 82.1, 82.0, 36.4, 36.1, 30.1, 30.0, 29.8, 28.8, 28.7, 28.6, 23.5,
23.4, 23.3, 16.1. The E-isomer was identified as the major isomer on
the basis of a characteristic shielded methyl resonance23 at 16.1 versus
23.3 ppm for the minor Z-isomer; HRMS (CI+) m/z: [M + H]+ calcd
for C23H3011BO2, 349.2333; found, 349.2332.
was added dropwise boron trifluoride diethyl etherate (44 μL, 0.36
mmol, 2.0 equiv) and the reaction mixture was stirred at −78 °C for 1
h before allowing to warm to room temperature. The reaction mixture
was quenched by the addition of saturated aqueous NaHCO3 (30
mL), extracted with CH2Cl2 (3 × 10 mL), dried (Na2SO4),
evaporated, and chromatographed (10−15% EtOAc in petrol) to
give tricycle 11 (18.2 mg, 0.066 mmol, 56% from (R,E)-8c) as a
colorless viscous oil. 10.14469/hpc/6333. Rf 0.33 (20% EtOAc in
petrol); [a]2D6 +34.2 (c 1.0, CHCl3); IR (ATR, neat) 3600−3200
cm−1; 1H NMR (400 MHz, CDCl3): δ 6.97 (d, J = 8.4 Hz, 1H), 6.79
(d, J = 2.7 Hz, 1H), 6.67 (dd, J = 8.4, 2.7 Hz, 1H), 3.77 (s, 3H),
3.38−3.25 (m, 1H), 2.91 (ddd, J = 16.8, 6.6, 1.5 Hz, 1H), 2.79 (ddd, J
= 16.8, 11.8, 7.1 Hz, 1H), 2.27 (dt, J = 13.0, 3.5 Hz, 1H), 1.93−1.68
(m, 4H), 1.57 (dd, J = 13.0, 4.7 Hz, 1H), 1.38 (d, J = 5.8 Hz, 1H),
1.32 (dd, J = 12.2, 2.4 Hz, 1H), 1.20 (s, 3H), 1.07 (s, 3H), 0.90 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 157.7, 150.6, 129.8,
127.3, 111.0, 110.2, 78.7, 55.3, 49.8, 39.0, 37.8, 36.9, 29.8, 28.2, 28.0,
24.8, 18.9, 15.4; HRMS (ES+) m/z: [M + H]+ calcd for C18H27O2,
275.2011; found, 275.2018.
ASSOCIATED CONTENT
■
sı
* Supporting Information
(S)- and (R)-6-Methyl-8-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-
oct-5-en-2-one [(S)-8k and (R)-8k].39 Following the general
procedure for relay cross-metathesis using acetonide (S)- or (R)-5d
(67 mg) and alkene 7l (158 mg) gave trisubstituted alkenes (S)-8k
(46 mg, 0.17 mmol, 69%) or (R)-8k (42 mg, 0.16 mmol, 62%) as
colorless oils and a mixture of E/Z geometrical isomers [(S)-8k: E/Z
= 73:27; (R)-8k: E/Z = 70:30]. 10.14469/hpc/5767. Rf 0.24 (10%
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c00067.
1
Copies of H and 13C NMR spectra for all compounds
and HPLC chromatograms for enantiomeric excess
determinations of (S)- and (R)-5c and (S)- and (R)-
5g (PDF)
1
EtOAc in petrol); IR (ATR, neat) 1715 cm−1; H NMR (400 MHz,
CDCl3): δ 5.14−5.07 (m, 1H), 3.61 (dd, J = 9.4, 3.4 Hz, 1H), 2.48−
2.38 (m, 2H), 2.30−2.10 (m, 3H), 2.11 (s, 3H), 2.04−1.93 (m, 1H),
1.69−1.64 (m, Z-8k, 0.81H), 1.61 (s, E-8k, 2.19H), 1.60−1.51 (m,
1H), 1.48−1.40 (m, 1H), 1.39 (d, J = 0.8 Hz, 3H), 1.31−1.28 (m,
3H), 1.23−1.20 (m, 3H), 1.06 (s, 3H). The E/Z ratio was determined
by integration of the resonances at δ 1.61 (major) and 1.69−1.64
(minor) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 208.6, 135.7,
124.1, 123.0, 121.3, 106.5, 106.4, 82.8, 82.6, 80.1, 43.9, 43.7, 36.6,
29.9, 28.9, 28.6, 28.6, 27.6, 27.5, 26.8, 26.0, 26.0, 23.2, 22.9, 22.4,
22.2, 16.0. The E-isomer was identified as the major isomer on the
basis of a characteristic shielded methyl resonance23 at 16.0 versus
23.2 ppm for the minor Z-isomer; HRMS (EI+) m/z: [M]•+ calcd for
C16H28O3, 268.2038; found, 268.2045.
(S)- and (R)-8-(5,5-Dimethyl-2-phenyl-1,3,2-dioxaborolan-4-yl)-
6-methyloct-5-en-2-one [(S)-8l and (R)-8l]. Following the general
procedure for relay cross-metathesis using boronates (S)- or (R)-5g
(59 mg, 0.19 mmol, 1.0 equiv), alkene 7l (118 mg, 0.94 mmol, 5.0
equiv), and ruthenium benzylidene 1 (16 mg, 10 mol %) gave
trisubstituted alkenes (S)-8l (32 mg, 0.10 mmol, 55%) or (R)-8l (35
mg, 0.11 mmol, 60%) as brown oils and a mixture of E/Z geometrical
isomers ((S)-8l: E/Z = 74:26; (R)-8l: E/Z = 76:24). 10.14469/hpc/
6329. Rf 0.10 (10% EtOAc in petrol); IR (ATR, neat) 1715 cm−1; 1H
NMR (400 MHz, CDCl3): δ 7.84−7.79 (m, 2H), 7.49−7.43 (m, 1H),
7.40−7.34 (m, 2H), 5.17 (m, 1H), 4.04 (dd, J = 10.0, 3.4 Hz, E-8l,
0.76H), 4.03 (dd, J = 10.0, 3.4 Hz, Z-8l, 0.24H), 2.48 (t, J = 7.4 Hz,
2H), 2.38−2.26 (m, 3H), 2.16−2.05 (m, 1H), 2.14 (s, E-8l, 2.28H),
2.11 (s, Z-8l, 0.72H), 1.80−1.52 (m, 2H), 1.71 (d, J = 1.3 Hz, Z-8l,
0.72H), 1.67 (d, J = 1.3 Hz, E-8l, 2.28H), 1.44 (s, Z-8l, 0.72H), 1.43
(s, E-8l, 2.28H), 1.28 (s, 3H). The E/Z ratio was determined by
integration of the resonances at δ 1.67 (major) and 1.71 (minor)
ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 208.8, 208.7, 135.7,
135.6, 134.8, 131.3, 131.3, 127.8, 127.7, 124.3, 123.1, 85.3, 85.1, 82.1,
82.1, 43.9, 43.7, 36.4, 30.1, 30.0, 29.9, 29.8, 28.8, 28.5, 23.4, 23.4,
23.3, 22.4, 22.3, 16.1. The E-isomer was identified as the major isomer
on the basis of a characteristic shielded methyl resonance23 at 16.1
versus 23.3 ppm for the minor Z-isomer; HRMS (CI+) m/z: [M +
H]+ calcd for C19H2811BO3, 315.2126; found, 315.2117.
AUTHOR INFORMATION
■
Corresponding Author
D. Christopher Braddock − Department of Chemistry,
Molecular Sciences Research Hub, Imperial College London,
London W12 0BZ, U.K.; orcid.org/0000-0002-4161-7256;
Email: c.braddock@imperial.ac.uk
Authors
Karim A. Bahou − Department of Chemistry, Molecular Sciences
Research Hub, Imperial College London, London W12 0BZ,
U.K.; orcid.org/0000-0002-8302-5283
Adam G. Meyer − CSIRO Manufacturing, Jerry Price
Laboratory, Clayton 3168, Victoria, Australia
G. Paul Savage − CSIRO Manufacturing, Jerry Price
Laboratory, Clayton 3168, Victoria, Australia; orcid.org/
0000-0001-7805-8630
Zhensheng Shi − Department of Chemistry, Molecular Sciences
Research Hub, Imperial College London, London W12 0BZ,
U.K.; orcid.org/0000-0001-6320-4201
Tianyou He − Department of Chemistry, Molecular Sciences
Research Hub, Imperial College London, London W12 0BZ,
U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00067
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank CSIRO and Imperial College London for a
studentship (to K.A.B.), the China Scholarship Council for a
scholarship (to Z.S.) and the EPSRC (grant no. EP/P030742/
1 to D.C.B.) for financial support.
(2R,4aR,10aS)-6-Methoxy-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthren-2-ol (11).2a To a solution of epoxy alkene
(R)-8c (50 mg, 0.18 mmol, 1.0 equiv) in CH2Cl2 (1.8 mL) at −78 °C
J
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1
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chromatography.
́
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the crude reaction mixtures in CDCl3 (δH 5.87 (s, 2H), 4.62 (s, 4H)).
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(d, J = 5.4 Hz, 1H) ppm, 2 diastereoisomers] and endocyclic [ca. 8%,
δH 5.23 (br s, 1H) and 5.19 (br s, 1H) ppm, 2 diastereoisomers] and
exocyclic [ca. 10%, δH 4.95, 4.71, 4.87, and 4.66 ppm, 2
diastereoisomers] alkenes were observed in the 1H NMR of the
crude reaction mixture, based on previous reports of the
corresponding des-methoxy compounds in the literature (see e.g.,
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(28) Tricycle 11 has previously only been reported as a racemate
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(29) (a) 1H NMR, 13C NMR, IR and MS data are available via a
data repository as: Bahou, K. A.; Braddock, D. C.; Shi, Z.; He, T. A
Relay Strategy Actuates Pre-Existing Trisubstituted Olefins in
Monoterpenoids for Cross Metathesis with Trisubstituted Alkenes.
Imperial College HPC Data Repository 2019, DOI: 10.14469/hpc/
5737. (b) An earlier version of this article was deposited to the
ChemRxiv preprint server on the 16th December 2019.
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https://dx.doi.org/10.1021/acs.joc.0c00067
J. Org. Chem. XXXX, XXX, XXX−XXX