A route to the 9,10-secosteroid astrogorgiadiol featuring a key sp 2-sp3 Suzuki type cross-coupling

Article abstract of DOI:10.1016/j.tet.2013.11.102

The described semi-synthetic route differs from the previously published approaches by an original C-7-C-8 disconnection. The kinetic enol triflate of Grundmann ketone was chosen as the CD-ring platform on which to couple an A-ring synthon via a challengi

Full text of DOI:10.1016/j.tet.2013.11.102

Tetrahedron 70 (2014) 186e196
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A route to the 9,10-secosteroid astrogorgiadiol featuring a key
sp2esp3 Suzuki type cross-coupling
*
ꢀ
Guillaume Medard
The Christopher Ingold Laboratories, University College London, 20 Gordon Street, London WC1H 0AJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2013
Received in revised form 24 November 2013
Accepted 28 November 2013
Available online 4 December 2013
The described semi-synthetic route differs from the previously published approaches by an original C-
7eC-8 disconnection. The kinetic enol triflate of Grundmann ketone was chosen as the CD-ring platform
on which to couple an A-ring synthon via a challenging sp2esp3 cross-coupling. A range of A-ring
synthons was synthesized to allow the investigations of various conditions of metal-catalyzed couplings.
Suzuki-type chemistry provided a useful (89% yield) answer. Whereas the last step of the designed
routeda regioselective opening of the epoxide obtained from the alkene, product of the coupling re-
actiondproved more challenging than expected, a hydroboration endgame route completed a formal
synthesis of (ꢀ)-astrogorgiadiol.
Keywords:
Secosteroid
Astrogorgiadiol
Calicoferol
Ó 2013 Elsevier Ltd. All rights reserved.
Astrogorgol
Grundmann ketone
Cross-coupling
1. Introduction
The second retrosynthetic analysis proposes a C-6eC-7 discon-
nection. The route, designed by De Riccardis, is semi-synthetic,
(ꢀ)-Astrogorgiadiol 1, a 9,10-secosteroid, metabolite isolated
from a gorgonian collected in Japan by Fusetani’s team in 19891 has
since been the object of great interest due to its biological potential.
Tested in vitro against 16 human tumor related protein kinases,
(ꢀ)-astrogorgiadiol and related calicoferols and astrogorgols
showed inhibitions in the micromolar range against important ki-
nases involved in cancer development.2 It has also shown unique
property of osteopontin downregulation.3 Since osteopontin plays
a key-role in metastatic diseases, such as cancers,4e6 in de-
myelinating diseases, such as multiple sclerosis,7e10 in the de-
velopment of virulent asthma,11,12 and in osteoporosis,13,14 this
bioactivity makes astrogorgiadiol a synthetic target of choice.
Hitherto two synthetic disconnections have been proposed
(Scheme 1). The group of Taber has been successful in its design of
a total synthesis with a Robinson annulation between an enantio-
merically pure D-ring synthon (3) and an A-ring/C-ring precursor
synthon (2) as a key step.15 Two new routes to this latter synthon
have since been disclosed: one by Taber’s group as an improvement
for large scale synthesis,16 and my own efforts taking advantage of
the opening of 6-methoxy-1-tetralol.17
using Grundmann ketone, which is converted in the hydrindan 5 in
three steps for a key radical coupling with the benzylic iodide 4
obtained in seven steps from 2-methyl-5-nitrobenzoic acid
(Scheme 1).18 Two sets of conditions for the radical coupling were
successful but only with 21% yield for GieseeChatgilialolu’s pro-
cedure and 28% for Hershberger’s procedure. Two more steps
allowed the completion of the synthesis.
The moderate yield of this radical reaction has triggered the
design of a new retrosynthetic analysis: another semi-synthetic
route taking full advantage, like De Riccardis route, of the readily
available Grundmann ketone. But instead of the C-6eC-7 discon-
nection, the proposed analysis features a C-7eC-8 disconnection.
The endeavor to perform a sp2esp3 cross-coupling between a CD-
ring platform 7 derived from Grundmann ketone and an A-ring
synthon 6 obtained from 3-methylanisole was audacious but
proved successful as reported in this article.
2. Results and discussion
2.1. CD-ring platforms
The first synthon 11 was obtained in 53% yield starting from the
commercially available (þ)-vitamin D3 (Scheme 2). Ozonolysis
followed by reduction and reoxidation secured Grundmann ketone
(9) in very good yield (89%). This procedure was introduced by
* Present address: Department of Proteomics and Bioanalytics, Center of Life and
€
€
Food Sciences Weihenstephan, Technische Universitat Munchen, Emil-Erlenmeyer-
Forum 5, 85354 Freising, Germany. Tel.: þ49 (0)8161 712059; fax: þ49 (0)8161
715931; e-mail address: g.medard@tum.de.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.102

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G. Medard / Tetrahedron 70 (2014) 186e196
187
22,23
and used by other groups18,24e27
~
reported by Mourino et al.
proved capricious in my hands.
Boronation of the enol triflate 11 following Takagi et al. pro-
cedure28 was successful in securing 12, an alternative platform for
Suzuki-type couplings (Scheme 3). In the 13C NMR spectrum of the
unsaturated boronate 12, the signal corresponding to C-8 is so
broad that it is indistinguishable from the baseline. This is due to
the quadrupole effect, since the boron resides in an unsymmetrical
environment.
Scheme 3. Synthesis of the alternative CD-ring platform 12: ene boronate derived
from the kinetic enol of Grundmann ketone.
2.2. A-Ring coupling partners
The styrene derivative 17 was obtained via a four-step sequence
in 43% yield (Scheme 4). When treated with N-bromosuccinimide
under the radiation of a 100 W tungsten filament lamp in refluxing
dichloromethane, 3-methylanisole 13 led to the dibromo com-
pound 14 as reported by Hoye et al.29 It has to be noted that two
different pathways are involved: radical (WohleZiegler reaction)
for the benzylic position and polar (electrophilic aromatic sub-
stitution) for the aryl position. The primary bromide 14 could then
selectively be converted into the phosphonium salt 15 by treatment
with triphenylphosphine in refluxing toluene for 20 h. The latter
was then reacted with paraformaldehyde for a Wittig reaction se-
curing the 1-bromo-4-methoxystyrene 16. Coupling with methyl-
magnesium bromide in the presence of NiCl2(PPh3)2 (Kumada
coupling) secured 1-methyl-4-methoxystyrene 17 as a colorless
liquid.
Scheme 1. Retrosynthetic analysis of (ꢀ)-astrogorgiadiol.
19
~
Mourino et al., who preferred this sequence over the mere ozo-
nolysis for the easy separation of the product. The kinetic enolate
was then prepared using KHMDS at ꢀ78 ꢁC and trapped after 2 h
with the triflate donor 10 developed in Comins group20,21 and
which is now commercially available. The reaction however pro-
ceeds in a maximum of 60% yield whereas other attempted pro-
cedures were found to be irreproducible, often leading to the
thermodynamic enolate. Notably, the use of phenyl triflimide as
Scheme 4. Synthesis of the styrene 17, precursor of A-ring synthons.
To get hold of phenethyl boronic esters in order to envision
Suzuki type couplings, hydroboration of the styrene derivative 17
was to be done. Borane, as expected, led to a mixture of
regioisomers. Attempts with pinacol borane or 9-BBN alone failed
to provide the desired compound. I then turned to catalyzed
hydroboration. The selective hydroboronation of styrene de-
rivatives has recently received a lot of interest. The most commonly
used catalyst for catalyzed hydroboration is Wilkinson’s catalyst
RhCl(PPh3)3.30 But this catalyst in the case of styrene favors the
boronation on the benzylic position and not on the desired terminal
position. The mechanism invokes
a h
3-benzylrhodium in-
Scheme 2. Synthesis of the CD-ring platform 11: the kinetic enol triflate of Grund-
mann ketone.
termediate31,32 accounting for the Markovnikov selectivity.

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G. Medard / Tetrahedron 70 (2014) 186e196
188
Depending on the catalyst, one intermediate is favored towards the
other. Yamamoto et al.33 compared different catalysts and found
that the best procedure to get regiospecificity for the terminal
position was the use of [Ir(COD)Cl]2 with 2 equiv of diphenyl-
phosphinoethane as a bidentate ligand. This procedure used with
pinacol borane in THF at rt for 26 h secured the boronic ester 18
with total regioselectivity in 77% yield (Scheme 5). The broad signal
in 13C NMR at 11.6 ppm is the sign that the carbon C-7 is correctly
attached to the boron atom. This peak and the peak at 27.4 ppm
replace the peaks at 115.2 ppm and 134.9 ppm, respectively.
a quantitative formation of the alcohol 19 (both steps could be done
in a single reaction vessel) (Scheme 5). Once obtained, the alcohol
19 could be converted into the halide. The iodide 23 was obtained
in two steps via a Finkelstein-type procedure.36 Alcohol 19 was
treated with mesyl chloride in the presence of triethylamine in
dichloromethane at rt for 30 min, allowing the formation of the
mesylate 22 in 90% yield. The mesylate compound 22 was then
reacted with sodium iodide in refluxing 2-butanone for 2 h yielding
the desired iodide 23 in 91% yield. The bromide 24 was obtained in
87% yield via an Appel reaction37 by treatment of the primary al-
cohol 19 with carbon tetrabromide and triphenylphosphine after
just 5 min in THF at rt.
I also converted the boronic ester 18 into the potassium fluo-
roborate 25 according to Molander’s procedure38 in 66% yield
(Scheme 5) in order to broaden the number of possible A-ring
coupling partners 6 (Scheme 1). The NMR spectra of this ionic
compound had to be recorded in D2O. The 13C NMR signal for C-7 is
so broad that it can only be determined using the HMQC experi-
ment and focusing on the area correlated to the 1H NMR signal of
CH2-7. Compared to the pinacol boronate compound 18, the signals
for pinacol carbons and protons have disappeared. These two ele-
ments confirmed that the pinacol boronate 18 had been converted
into another ionic boron compound successfully.
In an effort to diversify the potential coupling partners 6 and in
case the sp2esp3 cross-coupling would fail, I envisioned that halo-
styrene derivatives might be secured using cross-metathesis, mo-
tivated by the work of Grubbs.39 And, to my delight, the styrene
derivative 17 reacted smoothly (77% yield) with vinyl pinacolboro-
nate under ruthenium catalysis to provide the unsaturated boronate
compound 26 (Scheme 6) and the latter was easily converted (70%
yield) to the iodo compound 27. If I was to consider sp2esp2 cross-
coupling instead of sp2esp3 cross-coupling, these two A-ring cou-
pling partners 26 and 27 are easily and efficiently accessible.
Scheme 6. Cross-metathesis of styrene 17 and vinyl pinacolboronate to secure the
conjugated boronate 26, further converted in the b-iodo styrene 27.
2.3. sp2esp3 cross-coupling
Exploring Furstner’s chemistry,40,41 the coupling of the CD-ring
platform 11 with 4-methoxyphenethylmagnesium chloride 28 was
catalyzed by iron(III) acetylacetonate giving 29 in 70% yield
(Scheme 7). It is noteworthy that the use of DMF as a cosolvent was
necessary and that the use of the suggested THF/NMO mixture as
solvent led to no reaction.
€
Scheme 5. Synthesis of a range of A-ring synthons from styrene precursor 17.
Direct conversion of the pinacolic ester 18 into iodide 23 with
iodine according to Brown’s procedure34 or with iodine mono-
chloride according to Kabalka’s35 was not successful. The primary
alcohol 19 obtained from the styrene derivative was thus identified
as an intermediate to secure the desired phenethyl halides. The
epoxide 21 obtained from reaction of the styrene 17 with m-CPBA
was not stable enough to become a suitable precursor for the al-
cohol 19. The use of disiamylborane or 9-BBN, which should have
secured selectively alcohol 19 from styrene 17, proved unsuccessful
whereas borane was effective but not stereospecific. Flash chro-
matography was able to separate the 9:1 mixture of the 2 isomers
19 and 20 obtained in 79% yield. Treatment of the pinacolic ester 18
with hydrogen peroxide and potassium hydroxide led to
Scheme 7. Iron catalyzed sp2esp3 cross-coupling with model phenethyl Grignard.

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G. Medard / Tetrahedron 70 (2014) 186e196
189
Despite this encouraging result and the similarity of 28 to the A-
ring synthon 6, all attempts to perform the two-step one-pot
sequencedformation of organozinc, organomagnesium or organo-
lithium starting from 23 or 24 and coupling with iron (Fe(acac)3 for
Kumada type reaction40), nickel (NiCl2(dppe) for Kumada type re-
actions42) or palladium (Pd[P(t-Bu)3]2 or Pd(PPh3)4 for Negishi type
reactions and organolithium coupling) catalysts remained un-
successful. Because of the success of the coupling of 28 with 11, I
assume that the conversion of the halide into an organometallic
species is the problematic step. Despite my efforts to activate this
step (Rieke magnesium activation,43,44 halogen-magnesium ex-
change, zinc activation45), the strategy did not prove successful. I did
not pursue further investigations in this field, hypothesizing that the
organometallic I aimed to form could degrade into the benzylic
species resulting from an internal rearrangement with the aryl
methyl group, species which was not isolated. I, instead, focused my
efforts on Stille type and SuzukieMiyaura type cross-coupling.
Fouquet et al.46,47 developed recently a Stille type cross-
coupling of activated alkyltin reagents. This coupling requires
a hypervalent tin species, which is obtained by reaction of the or-
ganic halide with Lappert’s stannylene Sn(N(TMS)2)2. Bromide 24
was thus converted to the hypervalent species using Lappert’s
stannylene and TBAF in THF but it could not be coupled to triflate 11
under Pd2(dba)3 catalysis in refluxing dioxane or with additional
triphenylarsine ligand in DMF.
phenylethyl potassium fluoroborate derivative 25 led again to the
reduction product 31 as the major product.
The breakthrough was the use of slightly modified Marshall’s
conditions50 starting from the bromide 24 and converting it to the
methoxy boronate 32 through an addition of 9-BBNeOMe before
reacting it with the triflate 11 (Scheme 9). These conditions yielded
30 in 89% yield along with an inseparable impurity (w10%), which
could be removed in the next step. This proved to be a reliable,
efficient way to achieve this key step of the synthesis.
With the pinacol boronate 18 in hand, I investigated the possi-
bility of coupling it with the enol triflate 11 via SuzukieMiyaura
type reactions, as the last years have seen lots of progress in this
field with the development of new ligands and new methods. The
Zhou and Fu procedure48 with nickel catalyst and bath-
ophenanthroline was unsuccessful. Zou and Falck’s method-
dreported in 200149dconsists of the in situ generation of the
lithium borate ester derived from an alkyl boronic ester followed by
the palladium-catalyzed coupling with an electrophile. One of the
successful examples of this reaction is the coupling of n-butyl
pinacol boronate with 4-tert-butylcyclohexenol triflate, which ex-
hibits great similarity to my challenge. Unfortunately, when this
procedure was applied to the substrates 11 and 18, only 15% yield of
the desired compound 30 was obtained, the main product 31
arising from a hydride coupling. I therefore tried the same pro-
cedure with an addition of lithium bromide, which inhibited the
reaction. Molander’s conditions38 allowed the formation of 25%
of the desired product 30, the major product being again the
product of reduction 31 (Scheme 8). A coupling attempt with the
Scheme 9. High-yielding sp2esp3 cross-coupling of the CD-ring platform 11 with the
phenethyl bromide A-ring synthon 24.
2.4. Endgame
With all of the carbon atoms installed, the need to formally
hydrate regioselectively and stereoselectively the C-8eC-9 dou-
ble bond arose. That would mean that the hydroxy moiety and
the phenethyl moiety had to be in a cis relationship with the
hydroxy moiety axial and the phenethyl moiety equatorial
(Scheme 10).
Scheme 10. Required formal hydration and demethylation to complete the synthesis.
Epoxidation of the double bond using standard conditions took
place on the less hindered face of the C-ring and installed the ox-
ygen on the desired face (Scheme 11). NOESY experiment of the
obtained epoxide 33 showed that the hydrogen on C-9 is proximate
to the hydrogens on C-18 and to the hydrogens on C-7 and C-6
establishing the expected stereochemistry. The signals in 13C NMR
have shifted from 142.2 to 61.0 ppm for C-8 and from 119.6 to
57.9 ppm for C-9.
An appropriate Lewis acid should complex the oxygen atom of
the epoxide 33. In order to minimize the steric hindrance, the latter
should be as far away as possible from the phenylethyl chain and
Scheme 8. Low-yielding Suzuki coupling with phenethyl boronate 18.

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G. Medard / Tetrahedron 70 (2014) 186e196
190
Scheme 12. Expected stereoselectivity for the polar and radical reduction of epoxide
33.
Hydroboration of the C-8eC-9 double bond was performed
with boraneeTHF, which gave, as expected by the hindrance of
the two faces, 35 as the major product along with traces of 36
after column chromatography (Scheme 13). Oxidation with PCC
and aqueous work-up gave an oil, whose spectra account for one
main compound along with a trace of another structurally very
close compound. Determination of the nature of this compound,
i.e., whether conversion of 37 into 38 through ketoeenolic
Scheme 11. Epoxidation of the coupled product 30 and excerpt of NOESY spectrum
showing spatial proximity of H-9, H-6, H-7, and Me-18 in the product 33.
would therefore elongate and weaken the OeC-8 bond more than
the OeC-9 bond (Scheme 12). The
ated on the C-8 atom, allowing the hydride to add in the
d
þ charge should then be situ-
s* in
a loose SN2 transition state. Furthermore, in such a transition state,
the building of the positive charge on the tertiary carbon is favored
compared to the secondary carbon due to the donating effect of the
sCeC. The occurring Walden inversion would invert the configura-
tion of the phenethyl moiety, establishing the stereochemistry of
the target 34. If we consider a radical pathway, the expected
opening of the epoxide 33 should lead to the most substituted
radical, i.e., C-8 rather than C-9 (Scheme 12). This radical would be
long-lived enough for the phenethyl moiety to switch to a pseudo
equatorial conformation (conformation observed by De Riccardis
for the ketone analogue of this species).18 An axial attack of the
hydrogen atom would then be favored, leading to an equatorial
rather than axial positioning of the phenethyl moiety. Although the
epoxidation was readily achieved, the opening of epoxide 33
proved to be problematic. I investigated polar pathways using
Lewis acids and radical pathways but none of my attempts gave the
expected molecule 34. Were notably attempted Hutchins condi-
tions (cyanoborohydride and boron trifluoride etherate in THF),51
the replacement of boron trifluoride by triphenylborane in the
latter conditions, reduction with triethylsilane together with tri-
methylsilyl triflate or tris(pentafluorophenyl)boron, reaction with
triethylsilyl triflate and L-Selectride, or sodium borohydride and
pinacol borane. Among the investigated radical reactions,
I
attempted the Epling and Wang photochemical approach with
sodium borohydride,52 AIBN or TEMPO promoted reduction with
tributyltin hydride or tris(trimethylsilyl)silane, and reduction with
titanocene dichloride, manganese dust and cyclohexadiene or g-
55e57
terpinene following the work of Rajanbabu53,54 and Gansauer.
€
In a general trend, radical conditions left the epoxide unreacted as
did weak Lewis acids, whereas stronger Lewis acids degraded ep-
oxide 33 into unidentified products.
Scheme 13. Hydroboration of the coupled product 30 followed by oxidation and L-
Selectride reduction of the C-9 hydroxy group.

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G. Medard / Tetrahedron 70 (2014) 186e196
191
tautomerism had occurred during the reaction, was not obvious
since the data for these two compounds are scarce where they
are reported. Taber15 only reported the shift for C-9 in 13C NMR
for these two isomers: 215.5 ppm for 37 and 213.0 ppm for 38.
For calicoferol E (the phenol-deprotected version of 38), full data
can be found:18,58 for C-9 the reported shifts are 213.2 and
213.4 ppm, respectively. The shift
I observed for C-9 was
211.3 ppm and I was therefore unsure of the outcome of the
reaction. I decided to proceed to the reduction with L-Selectride
(Scheme 13). Preparative TLC gave 10 mg of the C-3-hydroxy
methyl-protected (8R,9S) diastereomer of (ꢀ)-astrogorgiadiol 39
as the major product along with traces of the desired product 34,
whose NMR spectra are in good agreement with Taber’s data. The
stereochemistry was established through NOE experiments and
a study of the coupling constants in 1H NMR. It can therefore be
concluded that the expected ketoeenolic tautomerism did not
occur, as this equilibrium would have favored the equatorial
positioning of the phenethyl chain rather than axial and thus
converted 37 into 38.
Comparing the spectra of 35, 39, and 34 (Fig. 1), some in-
teresting facts have to be noted. The signals for H-9 in 35 and 34,
in which the hydrogen is equatorial, sit at approximately 4.0 ppm
whereas it is more shielded (3.8 ppm) for 39, where the hydro-
gen is axial. These signals are broad singlets for 35 and 34 ac-
counting for small equatorial/equatorial and equatorial/axial
coupling constants but it is a multiplet for 39 due to the stronger
axial/axial (H-9/H-11) constant. Looking at the signals for C-18, it
is striking that the presence of the phenylethyl chain in axial
position has shifted the signal downfield (12.7 ppm for 35;
13.5 ppm for 39) compared to 34 where this chain is equatorial
(11.0 ppm).
Scheme 14. Completion of the formal synthesis of (ꢀ)-astrogorgiadiol.
3. Conclusion
In my investigation towards a practical semi-synthesis of
(ꢀ)-astrogorgiadiol, a strategy was conceived, based on the cou-
pling of the kinetic enol triflate of Grundmann ketone as the CD-
ring platform with the phenethyl halide or boronate as the A-ring
coupling partner. The CD-ring platform was obtained starting from
(þ)-vitamin D3. The requisite phenethyl bromide, iodide, pinacol
boronate, and trifluoroborate were obtained starting from 3-
methylanisole. The challenging sp2esp3 coupling of the two frag-
ments was accomplished using a SuzukieMiyaura type reaction, by
way of a 9-BBN methoxy boronate. For the endgame of the syn-
thesis, a hydroboration route and an epoxidation route were in-
vestigated. The hydroboration strategy allowed the completion of
a formal synthesis of (ꢀ)-astrogorgiadiol. This synthesis paves the
way for the generation of other 9-10-secosteroids analogues of
(ꢀ)-astrogorgiadiol, which could outperform the parent natural
molecule for osteopontin downregulation or cancer related kinase
inhibition.
4. Experimental section
4.1. General
All starting materials were obtained commercially from Aldrich,
Avocado, Acros, Lancaster, BDH or Strem and used without further
purification. All solvents were dried prior to use except when in-
dicated otherwise. Flash chromatography was conducted using
Merck silica gel 60 (40e60 mm). TLC was carried out on pre-coated
glass-backed plates (Merck Kiesel-gel 60 F254), visualized at 254 nm
and stained with anisaldehyde or phosphomolybdic acid. Infra-red
(IR) spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR
spectrometer. The wave number is given in cmꢀ1 with peak in-
tensity signified as s, m, and w for strong, medium, and weak, re-
spectively. Mass spectra (FAB, CI or EI) were recorded at the
Departmental Mass Spectrometry Service of the University College
London on a VG Analytical 70S instrument by Dr. Lisa Harris and
John Hill. Proton Nuclear Magnetic Resonance spectra were recor-
ded on Bruker AMX-500, 400 or 300 NMR Spectrometers. The NMR
spectra were recorded with reference to the residual solvent peak
(CHCl3 in CDCl3 at 7.24 ppm for 1H NMR and 77.0 ppm for 13C NMR).
13C DEPT, HMQC, HMBC and COSY were used to determine struc-
tures. In the description of the spectra, the numbering of the carbon
Fig. 1. Comparison of 35, 39, and 34 chemical shifts in NMR spectra.
Taber reports the conversion of 37 to 38 using KOH/MeOH.15
Therefore, the synthesis of 37 along with traces of 38 constitutes
a formal synthesis of (ꢀ)-astrogorgiadiol (Scheme 14). Compound
37 can be converted to 38, which can be reduced to 34 before
proceeding to the deprotection of the phenol following Taber’s
procedure15 to yield (ꢀ)-astrogorgiadiol.

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G. Medard / Tetrahedron 70 (2014) 186e196
192
atoms refers to the numbering that the carbon atoms would have in
(ꢀ)-astrogorgiadiol (steroids numbering).
over, the mixture was stirred for another 30 min then concentrated
under vacuum. Ether (1 L) was added, the mixture was filtered, and
concentrated under vacuum. The procedure was repeated with
ether (1 L) and with petroleum ether (2ꢂ1 L) to remove triphe-
nylphosphine oxide. The resulting oil was purified by elution
through a short pad of silica with neat petroleum ether and allowed
to dry under high vacuum yielding 80% 16 (97 g, 455 mmol) as
a clear oil. Rf 0.51 (2 elutions with neat petroleum ether). 1H NMR
4.1.1. (1R,3aR,7aR)-7a-Methyl-1-((R)-6-methylheptan-2-yl)-
2,3,3a,6,7,7a-hexahydro-1H-inden-4-yl
trifluoromethanesulfonate
(11). A solution of Grundmann ketone 919 (10.6 g, 40 mmol,
1 equiv) in DMF (80 mL) was added by cannula over 1 h to a solu-
tion of KHMDS in toluene (0.5 M, 160 mL, 80 mmol, 2 equiv) diluted
in DMF (80 mL) at ꢀ78 ꢁC. After 90 min, a solution of 10 (17.9 g,
50 mmol, 1.25 equiv) in DMF (100 mL) was added by cannula over
50 min. The mixture was allowed to warm to rt. After 90 min, water
(400 mL) and ether (200 mL) were added and the two phases were
separated. The aqueous phase was extracted with ether
(2ꢂ200 mL), the combined organic phase was dried on MgSO4,
concentrated under vacuum, and purified by column chromatog-
raphy (silica, neat petroleum ether) yielding 60% 11 (9.50 g,
24.0 mmol) as a colorless oil. Rf 0.90 (petroleum ether/ethyl acetate
(500 MHz, CDCl3,
d
): 7.41 (d, J¼8.8 Hz, 1H, H-1), 7.06 (d, J¼3.0 Hz,
1H, H-4), 7.00 (dd, J¼17.4, 10.9 Hz, 1H, H-6), 6.69 (dd, J¼8.8, 3.0 Hz,
1H, H-2), 5.68 (dd, J¼17.4, 0.9 Hz, 1H, H-7 trans to H-6), 5.35 (dd,
J¼10.9, 0.9 Hz, 1H, H-7 cis to H-6), 3.79 (s, 3H, OMe). 13C NMR
(125 MHz, CDCl3, d): 158.9 (C-3),138.1 (C-5),135.8 (C-6),133.4 (C-1),
116.7 (C-7), 115.2 (C-2), 114.3 (C-10), 111.9 (C-4), 55.4 (OMe). HRMS
(EI) calculated for C9H9BrO (Mþ): 211.98313, found 211.98333. Data
consistent with literature values.59
5:1). 1H NMR (500 MHz, CDCl3,
d): 5.55 (m, 1H, H-9), 2.45 (m, 1H),
4.1.5. 4-Methoxy-1-methyl-2-vinylbenzene (17). A solution of
methylmagnesium bromide in ether (3 M, 607 mL, 1.82 mol,
4 equiv) was added to 16 (97 g, 455 mmol,1 equiv) and NiCl2(PPh3)2
(7.4 g, 11.4 mmol, 0.025 equiv) in ether (1 L) at 0 ꢁC and the mixture
was stirred for 40 h at reflux. The reaction was then carefully
quenched at 0 ꢁC with a saturated solution of NH4Cl in water
(300 mL). Ether (300 mL) and brine (600 mL) were then added. The
supernatant was separated and the slurry extracted with ether
(3ꢂ300 mL). The combined organic phase was washed with brine
(300 mL), dried on MgSO4, and concentrated under vacuum. The
obtained oil was purified by elution with neat petroleum ether
through a short pad of silica on a sinter funnel yielding 82% 17
(55.2 g, 373 mmol) as a clear oil. Rf 0.72 (petroleum ether/ethyl
2.28 (m, 2H), 1.98 (m, 2H), 1.74 (m, 1H), 1.52e1.00 (m, 12H), 0.92 (d,
J¼6.5 Hz, 3H, Me-21), 0.85 (d, J¼6.6 Hz, 3H, Me-26 or Me-27), 0.84
(d, J¼6.6 Hz, 3H, Me-27 or Me-26), 0.74 (s, 3H, Me-18). 13C NMR
(125 MHz, CDCl3, d): 150.0 (C-8), 116.0 (C-9), 54.3, 50.1, 45.2, 39.4,
36.0, 34.8, 29.7, 28.3, 28.0, 23.9, 23.8, 22.8, 22.5, 21.5, 18.6, 11.3.
HRMS (EI) calculated for C19H31F3O3S (Mþ): 396.19405, found
396.19300.
4.1.2. 4,4,5,5-Tetramethyl-2-((1R,3aS,7aR)-7a-methyl-1-((R)-6-
methylheptan-2-yl)-2,3,3a,6,7,7a-hexahydro-1H-inden-4-yl)-1,3,2-
dioxaborolane (12). A mixture of 11 (991 mg, 2.5 mmol, 1 equiv),
bis(pinacolato)diboron (698 mg, 2.75 mmol, 1.1 equiv),
PdCl2(PPh3)2 (52.6 mg, 0.075 mmol, 0.03 equiv), PPh3 (39.3 mg,
0.15 mmol, 0.06 equiv), and KOPh [8] (496 mg, 3.75 mmol,
1.5 equiv) in toluene (15 mL) was heated to 50 ꢁC for 1 h. Water
(15 mL) and ether (10 mL) were added and the two phases were
separated. The aqueous phase was extracted with ether (10 mL) and
the combined organic phase was dried on MgSO4, concentrated
under vacuum, and purified by column chromatography (silica, 1%
ethyl acetate in petroleum ether) yielding 76% 12 (716 mg,
1.91 mmol) as a clear oil. Rf 0.47 (petroleum ether/ethyl acetate 9:1).
acetate 5:1). 1H NMR (500 MHz MHz, CDCl3,
d
): 7.05 (d, J¼8.3 Hz,
1H, H-1), 7.03 (d, J¼2.4 Hz, 1H, H-4), 6.91 (dd, J¼17.4, 10.9 Hz, 1H, H-
6), 6.74 (dd, J¼8.3, 2.4 Hz, 1H, H-2), 5.63 (d, J¼17.4 Hz, 1H, H-7 trans
to H-6), 5.29 (d, J¼10.9 Hz, 1H, H-7 cis to H-6), 3.80 (s, 3H, OMe),
2.28 (s, 3H, Me-19). 13C NMR (125 MHz, CDCl3,
d): 157.9 (C-3), 137.6
(C-5), 134.9 (C-6), 132.1 (C-1), 127.7 (C-10), 115.2 (C-7), 113.3 (C-2),
110.6 (C-4), 55.3 (OMe), 18.7 (C-19). IR (neat, cmꢀ1): 2948 (m), 2834
(w), 1605 (m), 1570 (m), 1492 (s), 1463 (m), 1420 (m), 1285 (s), 1243
(s), 1200 (m), 1163 (m), 1113 (m), 1030 (s), 989 (m), 908 (s), 873 (m),
855 (m), 802 (s), 720 (m), 696 (m), 665 (m). HRMS (positive CI)
calculated for C10H13O (MþH): 149.09663, found 149.09693. No
data for this compound were provided in the literature where it is
described.60,61
1H NMR (500 MHz, CDCl3,
d
): 6.40 (br t, J¼3.1 Hz, 1H, H-9), 2.15 (m,
2H), 2.09 (m, 1H), 1.96 (m, 2H), 1.87 (m, 1H), 1.6e0.9 (m, 12H), 1.23
(s, 6H, 2ꢂ Me), 1.21 (s, 6H, 2ꢂ Me), 0.91 (d, J¼6.6 Hz, 3H, Me-21),
0.85 (d, J¼6.6 Hz, 3H, Me-27 or Me-26), 0.84 (d, J¼6.6 Hz, 3H,
Me-26 or Me-27), 0.62 (s, 3H, Me-18). 13C NMR (125 MHz, CDCl3,
d):
142.5 (C-9), 82.7 (2ꢂ C-pin), 54.2, 49.6, 41.5, 39.5, 36.3, 36.2, 36.2,
28.5, 28.0, 25.8, 25.3, 25.1, 24.4, 23.9, 22.8, 22.6, 18.8, 11.0. IR (neat,
cmꢀ1): 2954 (s), 2870 (m),1705 (s),1467 (m),1382 (m),1150 (s), 960
(m), 852 (w), 755 (s), 668 (m).
4.1.6. 2-(5-Methoxy-2-methylphenethyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (18). A solution of pinacol borane in THF (1 M, 90 mL,
90 mmol, 1.2 equiv) was added to a mixture of 17 (11.1 g, 75 mmol,
1 equiv), [Ir(COD)Cl]2 (504 mg, 0.75 mmol, 0.01 equiv), and
diphenylphosphinoethane (598 mg, 1.5 mmol, 0.02 equiv) in THF
(60 mL) at rt. After 26 h, the reaction was quenched by addition of
methanol (70 mL). Water (150 mL) and ether (200 mL) were then
added and the two phases were separated. The aqueous phase was
further extracted with a mixture of ether (200 mL) and methanol
(40 mL). The combined organic phase was then dried on MgSO4,
concentrated under vacuum, and purified by column chromatog-
raphy (silica, petroleum ether/ethyl acetate 9:1) yielding 77% 18
(15.9 g, 57.5 mmol) as a clear oil. Rf 0.59 (petroleum ether/ethyl
4.1.3. (2-Bromo-5-methoxybenzyl)triphenylphosphonium bromide
(15). Compound 14 (169 g, 603 mmol, 1 equiv) and triphenyl-
phosphine (159 g, 603 mmol, 1 equiv) were dissolved in toluene
(1.2 L) and the mixture was refluxed for 22 h. The precipitate was
filtered and dried under high vacuum yielding 94% 15 (308 g,
568 mmol) as a white crystalline solid (mp: 254 ꢁC). 1H NMR
(400 MHz, CDCl3, d): 7.78 (m, 3H, H-para), 7.70 (m, 6H, H-ortho),
7.62 (m, 6H, H-meta), 7.18 (m, 2H, H-1 & H-2), 6.68 (dt, J¼8.9, 2.8 Hz,
1H, H-4), 5.57 (d, J¼14.3 Hz, 2H, H-6), 3.53 (s, 3H, OMe). HRMS
(positive ion FAB) calculated for C26H23BrOP (MꢀBr): 461.06698,
found 461.06608.
acetate 5:1). 1H NMR (500 MHz, CDCl3,
d): 7.01 (d, J¼8.3 Hz, 1H, H-
1), 6.77 (d, J¼2.7 Hz, 1H, H-4), 6.62 (dd, J¼8.3, 2.7 Hz, 1H, H-2), 3.77
(s, 3H, OMe), 2.67 (t, J¼8.2 Hz, 2H, H-6), 2.22 (s, 3H, Me-19), 1.23 (s,
12H, 4ꢂ Me), 1.08 (t, J¼8.2 Hz, 2H, H-7). 13C NMR (125 MHz, CDCl3,
4.1.4. 1-Bromo-4-methoxy-2-vinylbenzene (16).59 Compound 15
(308 g, 568 mmol, 1 equiv) and paraformaldehyde (170 g, 5.68 mol,
10 equiv) were suspended in DME (710 mL). A solution of potas-
sium tert-butoxide (316 g, 2.84 mol, 5 equiv) in ethanol (910 mL)
was then slowly added by cannula over 2 h. Once the addition was
d): 157.8 (C-3), 143.7 (C-5), 130.6 (C-1), 127.7 (C-10), 113.9 (C-4),
110.7 (C-2), 83.1 (2ꢂ C-pin), 55.1 (OMe), 27.4 (C-6), 24.8 (4ꢂ Me),
18.3 (C-19), 11.6 br (C-7). IR (neat, cmꢀ1): 2977 (m), 2935 (m), 1609
(m),1580 (w),1500 (m),1369 (s),1315 (s),1249 (s),1143 (s),1042 (s),
967 (m), 847 (s), 798 (m). MS (positive CI) (m/z, %): 276 (M, 19), 261

ꢀ
G. Medard / Tetrahedron 70 (2014) 186e196
193
(MꢀMe, 11), 205 (35), 177 (MHꢀC(Me2)C(Me2)O, 100), 149
(MꢀBPin, 38), 135 (MꢀCH2BPin, 63). HRMS (positive CI) calculated
for C16H26BO3 (MþH): 277.19749, found 277.19780.
supernatants were collected, combined, and concentrated under
vacuum. The resulting solid was recrystallized from acetone/ether
yielding 66% 25 (169 mg, 0.658 mmol) as a white crystalline solid
(mp: 240 ꢁC). 1H NMR (500 MHz, D2O,
d
): 7.15 (d, J¼8.2 Hz, 1H, H-1),
4.1.7. 2-(5-Methoxy-2-methylphenyl)ethanol (19). A solution of
KOH in water (5%, 4 mL) followed by a solution of H2O2 in water
(27.5%, 4 mL) were added to a solution of 18 (1.10 g, 4 mmol,1 equiv)
in THF (4 mL) at 0 ꢁC. After 30 min the mixture was extracted with
ether (3ꢂ5 mL). The combined organic phase was washed with
brine (5 mL), dried on MgSO4, and purified by column chroma-
tography (silica, petroleum ether/EtOAc 2:1), yielding quantita-
tively 19 (663 mg, 4.0 mmol) as a yellow oil. Rf 0.28 (petroleum
6.91 (d, J¼2.8 Hz, 1H, H-4), 6.75 (dd, J¼8.2, 2.8 Hz, 1H, H-2), 3.82 (s,
3H, OMe), 2.53 (m, 2H, H-6), 2.25 (s, 3H, Me-19), 0.51 (m, 2H, H-7).
13C NMR (125 MHz, D2O,
d): 157.7 (C-3), 147.5 (C-5), 131.7 (C-1),
129.5 (C-10), 114.4 (C-4), 111.8 (C-2), 56.0 (OMe), 29.0 (C-6), 19.1 br
(C-7), 17.9 (C-19). IR (neat, cmꢀ1): 2924 (w), 2836 (w), 1618 (w),
1579 (w), 1494 (m), 1464 (w), 1441 (w), 1348 (w), 1307 (m), 1284
(m), 1251 (m), 1221 (m), 1209 (m), 1160 (w), 1110 (m), 1078 (s), 1052
(s), 1031 (s), 959 (s), 913 (m), 887 (s), 799 (m), 735 (m), 717 (s). MS
(negative ion FAB) (m/z, %): 217 (MꢀK, 14), 199 (MþHꢀKF, 100), 168
(32), 153 (100). HRMS (negative ion FAB) calculated for C10H13BF3
(MꢀK): 217.10115, found 217.10189.
ether/ethyl acetate 2:1). 1H NMR (500 MHz, CDCl3,
d): 7.06 (d,
J¼8.3 Hz, 1H, H-1), 6.73 (d, J¼2.7 Hz, 1H, H-4), 6.67 (dd, J¼8.3,
2.7 Hz,1H, H-2), 3.78 (t, J¼7.0 Hz, 2H, H-7), 3.76 (s, 3H, OMe), 2.83 (t,
J¼7.0 Hz, 2H, H-6), 2.25 (s, 3H, Me-19). 13C NMR (125 MHz, CDCl3,
d): 157.7 (C-3),137.6 (C-5),131.0 (C-1),128.3 (C-10),115.3 (C-4),111.4
4.1.11. 2-(2-Bromoethyl)-4-methoxy-1-methylbenzene
(24).16 Tri
(C-2), 62.3 (C-7), 55.1 (OMe), 36.5 (C-6), 18.3 (C-19). IR (neat, cmꢀ1):
3340 (s br), 2945 (m), 2834 (w), 1609 (m), 1579 (m), 1499 (s), 1465
(m), 1421 (w), 1304 (m), 1286 (m), 1249 (s), 1210 (m), 1159 (m), 1117
(m), 1041 (s), 849 (m), 802 (s), 711 (m). MS (EI) (m/z, %): 166 (M, 8),
148 (MꢀH2O, 7), 131 (100), 121 (MꢀC2H4OH, 14), 109 (81), 91
(MeC2H4OHeMeO, 60). HRMS (EI) calculated for C10H14O2 (Mþ):
166.09883, found 166.09839. Data in partial agreement with the
literature.62
phenylphosphine (1.50 g, 5.7 mmol, 1.9 equiv) and carbon tetra-
bromide (1.89 g, 5.7 mmol, 1.9 equiv) were added to a solution of 19
(499 mg, 3 mmol, 1 equiv) in THF (7.5 mL) at rt. After just 5 min,
ether (10 mL) was added and the mixture was filtered. Brine
(20 mL) was added to the filtrate and the two phases were sepa-
rated. The aqueous phase was further extracted with ether
(3ꢂ10 mL). The combined organic phase was dried on MgSO4,
concentrated under vacuum, and purified by column chromatog-
raphy (silica, 2% ethyl acetate in petroleum ether) yielding 87% 24
(595 mg, 2.6 mmol) as a half solid. Rf 0.86 (petroleum ether/ethyl
4.1.8. 1-(5-Methoxy-2-methylphenyl)ethanol (20). A solution of
BH3$THF in THF (1 M, 14.7 mL, 14.7 mmol, 1.2 equiv) was slowly
added to 17 (1.81 g, 12.2 mmol, 1 equiv) at 0 ꢁC and the mixture was
allowed to warm to rt. After 5 h, the mixture was cooled to 0 ꢁC and
a solution of KOH in water (5%, 12 mL) was carefully added. The
mixture was warmed to rt and a solution of H2O2 in water (27.5%,
12 mL) was added. After 30 min, ether (12 mL) was added and the
two phases were separated. The aqueous phase was extracted with
ether (3ꢂ12 mL) and the combined organic phase was washed with
brine (24 mL), dried on MgSO4, and purified by column chroma-
tography (silica, petroleum ether/EtOAc 2:1) yielding 79% 19 and 20
(1.59 g, 9.57 mmol) as a 9:1 mixture. Further purification by column
chromatography (silica, petroleum ether/EtOAc 2:1) allowed to
isolate 20 as a colorless oil for analysis. Rf 0.43 (petroleum ether/
acetate 2:1). 1H NMR (500 MHz, CDCl3,
d): 7.05 (m, 1H, H-1), 6.70
(m, 2H, H-2 & H-4), 3.76 (s, 3H, OMe), 3.49 (t, J¼8.1 Hz, 2H), 3.12 (t,
J¼8.1 Hz, 2H), 2.24 (s, 3H, Me-19). 13C NMR (75 MHz, CDCl3,
d): 157.9
(C-3), 138.2 (C-5), 131.3 (C-1), 128.0 (C-10), 115.1 (C-2), 112.1 (C-4),
55.3 (OMe), 37.2 (C-6), 31.5 (C-7), 18.4 (C-19). MS (EI) (m/z, %): 230
(Mþ2, 14), 228 (M, 15), 176 (41), 135 (MꢀCH2Br, 79), 91 (100). HRMS
(EI) calculated for C10H13BrO (Mþ): 228.01443, found 228.01417.
Data consistent with literature values.16
4.1.12. 5-Methoxy-2-methylphenethyl methanesulfonate (22). Meth
anesulfonyl chloride (557 mL, 7.2 mmol, 1.2 equiv) was slowly added
to a solution of 19 (997 mg, 6 mmol, 1 equiv) and triethylamine
(4.18 mL, 30 mmol, 5 equiv) in DCM (20 mL) at rt. The exothermic
reaction was stirred for 30 min, then quenched with HCl (0.1 M,
60 mL). DCM (60 mL) was added and the two phases were sepa-
rated. The aqueous phase was further extracted with DCM
(2ꢂ60 mL). The combined organic phase was washed with brine
(60 mL), dried on MgSO4, concentrated under vacuum, and purified
by column chromatography (silica, petroleum ether/ethyl acetate
5:1) yielding 90% 22 (1.32 g, 5.40 mmol) as a clear oil. Rf 0.37 (pe-
ethyl acetate 2:1). 1H NMR (300 MHz, CDCl3,
d): 7.08 (s, 1H, H-4),
7.02 (d, J¼8.1 Hz, 1H, H-1), 6.70 (d, J¼8.2 Hz, 1H, H-2), 5.08 (m, 1H,
H-6), 3.78 (s, 3H, OMe), 2.26 (s, 3H, Me-19), 1.43 (d, J¼6.4 Hz, 3H, H-
7).
4.1.9. 2-(5-Methoxy-2-methylphenyl)oxirane (21). m-CPBA (77%,
247 mg, 1.1 mmol) was added portionwise to a heterogeneous
mixture of 17 (148 mg, 1 mmol) in a solution of NaHCO3 in water
(0.3 M, 6 mL) at 0 ꢁC. After 15 min, the mixture was warmed to rt.
After 24 h, another portion of m-CPBA (247 mg, 1.1 mmol) was
added. After 15 min, the mixture was extracted with ether (10 mL).
The aqueous phase was further extracted with ether (2ꢂ5 mL). The
combined organic phase was washed with a solution of NaHCO3 in
water (0.3 M, 10 mL), dried on MgSO4, and concentrated under
vacuum. Purification by elution through a short pad of silica (pe-
troleum ether/ethyl acetate 5:1) yielded 20% 21 (34 mg, 0.21 mmol)
troleum ether/ethyl acetate 2:1). 1H NMR (500 MHz, CDCl3,
d): 7.06
(d, J¼8.0 Hz, 1H, H-1), 6.71 (s, 1H, H-4), 6.70 (d, J¼8.0 Hz, 1H, H-2),
4.36 (t, J¼7.3 Hz, 2H, H-7), 3.76 (s, 3H, OMe), 3.02 (t, J¼7.3 Hz, 2H, H-
6), 2.86 (s, 3H, O2SMe), 2.25 (s, 3H, Me-19). 13C NMR (125 MHz,
CDCl3, d): 158.0 (C-3), 135.4 (C-5), 131.4 (C-1), 128.4 (C-10), 115.4 (C-
4), 112.3 (C-2), 69.2 (C-7), 55.3 (OMe), 37.4 (O2SMe), 33.2 (C-6), 18.4
(C-19). IR (neat, cmꢀ1): 3026 (w), 2939 (w), 1610 (m), 1580 (m),
1505 (s), 1466 (m), 1351 (s), 1304 (m), 1251 (m), 1170 (s), 1120 (m),
1034 (m), 952 (s), 909 (m), 804 (m), 750 (s), 667 (m).
as a clear oil. 1H NMR (500 MHz, C6D6,
d
): 7.04 (d, J¼2.8 Hz,1H, H-4),
6.86 (d, J¼8.3 Hz, 1H, H-1), 6.72 (dd, J¼8.3, 2.8 Hz, 1H, H-2), 3.62
(dd, J¼4.0, 2.5 Hz,1H, H-6), 3.31 (s, 3H, OMe), 2.58 (dd, J¼6.0, 4.0 Hz,
1H, H-7 trans to H-6), 2.22 (dd, J¼6.0, 2.5 Hz, 1H, H-7 cis to H-6),
2.03 (s, 3H, Me-19).
4.1.13. 2-(2-Iodoethyl)-4-methoxy-1-methylbenzene (23). NaI (4.0
5 g, 27.0 mmol, 5 equiv) was added to a solution of mesylate 22
(1.32 g, 5.40 mmol, 1 equiv) in 2-butanone (54 mL) at rt and the
mixture was heated to reflux for 2 h. Ether (50 mL) and water
(50 mL) were then added and the two phases were separated. The
aqueous phase was further extracted with ether (30 mL) and the
combined organic phase was dried on MgSO4 then concentrated
under vacuum yielding 91% 23 (1.36 g, 4.93 mmol) as a half solid. Rf
0.80 (petroleum ether/ethyl acetate 2:1). 1H NMR (500 MHz, CDCl3,
4.1.10. Potassium
trifluoro(5-methoxy-2-methylphenethyl)borate
(25). KHF2 (469 mg, 6 mmol, 6 equiv) and water (0.8 mL) were
added at rt to a solution of boronate 18 (279 mg, 1 mmol, 1 equiv) in
ether (1.67 mL). After 1.5 h, acetone (3ꢂ15 mL) was added and the

ꢀ
G. Medard / Tetrahedron 70 (2014) 186e196
194
d
): 7.05 (d, J¼8.2 Hz,1H, H-1), 6.71 (d, J¼8.2 Hz, 1H, H-2), 6.69 (s, 1H,
H-4), 3.77 (s, 3H, OMe), 3.27 (t, J¼8.0 Hz, 2H, H-7), 3.14 (t, J¼8.0 Hz,
2H, H-6), 2.23 (s, 3H, Me-19). 13C NMR (125 MHz, CDCl3,
): 157.9 (C-
1611 (m), 1512 (s), 1465 (m), 1366 (m), 1245 (s), 1175 (m), 1035 (m),
821 (m). MS (positive CI) (m/z, %): 383 (MþH, 2), 355
(MꢀCH2CH2Ar, 5), 207 (100).
d
3), 140.1 (C-5), 131.3 (C-1), 127.7 (C-10), 114.7 (C-2), 112.1 (C-4), 55.3
(OMe), 38.3 (C-6), 18.2 (C-19), 3.7 (C-7).
4.1.17. (3R,3aR,7aS)-7-(5-Methoxy-2-methylphenethyl)-3a-methyl-
3-((R)-6-methylheptan-2-yl)-2,3,3a,4,5,7a-hexahydro-1H-indene
(30). Molander’s conditions:38 Compound 11 (119 mg, 0.3 mmol,
1 equiv), 18 (82.8 mg, 0.3 mmol, 1 equiv), Cs2CO3 (293 mg,
0.9 mmol, 3 equiv), and PdCl2(dppf)$CH2Cl2 (22 mg, 0.027 mmol,
0.09 equiv) were heated to reflux in THF (3 mL) and water (0.3 mL)
for 24 h. Ether (10 mL) and brine (5 mL) were then added and the
two phases were separated. The organic phase was dried on MgSO4,
concentrated under vacuum, and purified by column chromatog-
raphy (silica, neat petroleum ether then 1% ethyl acetate in petro-
leum ether) yielding 25% 30 (30 mg, 0.076 mmol) as a clear oil.
Marshall’s conditions:50 A solution of t-BuLi in pentane (1.7 M,
4.9 mL, 8.4 mmol, 4.2 equiv) was added to a solution of 24 (516 mg,
2.2 mmol, 1.1 equiv) in ether (40 mL) at ꢀ78 ꢁC under nitrogen.
After 3 min, a solution of 9-BBNeOMe in THF (1 M, 9.2 mL,
9.2 mmol, 4.6 equiv) was added, followed by THF (40 mL) addition.
After a further 20 min, the cold bath was removed and the mixture
was allowed to warm to rt over 2 h. A solution of K3PO4 in water
(3 M, 3 mL) was then added followed by a solution of 11 (793 mg,
2 mmol, 1 equiv) in DMF (40 mL) and PdCl2(dppf)$CH2Cl2 (146 mg,
0.2 mmol, 0.1 equiv). The mixture was then stirred for a further
19 h. Ether (250 mL) and water (250 mL) were then added and the
two phases were separated. The aqueous phase was extracted with
ether (2ꢂ100 mL), then the combined organic phase was dried on
MgSO4, concentrated under vacuum, and purified two times by
column chromatography (neat petroleum ether then 1% ethyl ac-
etate in petroleum ether) yielding 89% 30 (700 mg, 1.77 mmol)
together with an inseparable impurity (w10%). Rf 0.32 (1% ethyl
4.1.14. (E)-2-(5-Methoxy-2-methylstyryl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (26). A solution of 17 (437 mg, 2.95 mmol,1 equiv) in
DCM (5 mL) followed by vinyl boronate pinacol ester (0.5 mL,
2.95 mmol,1 equiv) was added to a suspension of HoveydaeGrubbs
second generation catalyst (92 mg, 0.148 mmol, 0.05 equiv) in DCM
(10 mL) under nitrogen. The mixture was heated to reflux for 3 h,
concentrated under vacuum, and purified by column chromatog-
raphy (silica, petroleum ether/ethyl acetate 9:1) yielding 77% 26
(619 mg, 2.26 mmol) as a clear oil. Rf 0.51 (petroleum ether/ethyl
acetate 5:1). 1H NMR (400 MHz, CDCl3,
d
): 7.59 (d, J¼18.2 Hz, 1H, H-
6), 7.08 (d, J¼2.7 Hz, 1H, H-4), 7.03 (d, J¼8.3 Hz, 1H, H-1), 6.75 (dd,
J¼8.3, 2.7 Hz, 1H, H-2), 6.06 (d, J¼18.2 Hz, 1H, H-7), 3.76 (s, 3H,
OMe), 2.33 (s, 3H, Me-19), 1.30 (s, 12H, 4ꢂ Me). 13C NMR (100 MHz,
CDCl3, d): 157.8 (C-3), 147.0 (C-6), 137.4 (C-5), 131.3 (C-1), 128.6 (C-
10),128.2 (C-7),114.8 (C-4), 110.3 (C-2), 83.3 (2ꢂ C-pin), 55.2 (OMe),
24.8 (4ꢂ Me), 18.8 (C-19). IR (neat, cmꢀ1): 2977 (m), 1621 (m), 1572
(w), 1495 (m),1456 (m),1348 (s), 1324 (m),1244 (m), 1207 (m),1141
(s), 1039 (m), 995 (m), 969 (m), 849 (m), 811 (m), 718 (w). MS (EI)
(m/z, %): 274 (M, 88), 268 (100), 174 (MꢀC(Me2)C(Me2)O, 76). HRMS
(EI) calculated for C16H23BO3 (Mþ): 274.17348, found 274.17383.
4.1.15. (E)-2-(2-Iodovinyl)-4-methoxy-1-methylbenzene (27). A so-
lution of NaOH in water (3 M, 0.4 mL, 1.2 mmol, 3 equiv) was added
to a solution of 26 (109.7 mg, 0.4 mmol, 1 equiv) in THF (1 mL) at rt
under vigorous stirring. After 10 min, a solution of iodine in THF
(0.2 M, 2.5 mL, 0.5 mmol, 1.25 equiv) was added dropwise over 3 h,
waiting for the disappearance of the orange color between each
drop. Persistence of the color showed the end of the reaction at
which point a saturated solution of Na2S2O3 in water (5 mL) was
added. Extraction with ether (3ꢂ5 mL) followed and the combined
organic phase was dried on MgSO4, concentrated under vacuum,
and purified by column chromatography (silica, 2% ethyl acetate in
petroleum ether) yielding 70% 27 (77 mg, 0.28 mmol) as a clear oil.
Rf 0.65 (petroleum ether/ethyl acetate 5:1). 1H NMR (500 MHz,
acetate in petroleum ether). 1H NMR (500 MHz, CDCl3,
d): 7.02 (d,
J¼8.3 Hz, 1H, H-1), 6.69 (d, J¼2.7 Hz, 1H, H-4), 6.63 (dd, J¼8.3,
2.7 Hz, 1H, H-2), 5.27 (s, 1H, H-9), 3.76 (s, 3H, OMe), 2.68 (m, 1H),
2.55 (m, 1H), 2.22 (s, 3H, Me-19), 2.2e0.9 (m, 20H), 0.94 (d,
J¼6.5 Hz, 3H, Me-21), 0.86 (d, J¼6.6 Hz, 3H, Me-27 or Me-26), 0.85
(d, J¼6.6 Hz, 3H, Me-26 or Me-27), 0.68 (s, 3H, Me-18). 13C NMR
(125 MHz, CDCl3, d): 157.8 (C-3),142.2 (C-8),138.7 (C-5),130.7 (C-1),
127.9 (C-10), 119.6 (C-9), 114.6 (C-4), 110.7 (C-2), 55.2 (OMe), 54.5
(C-17), 51.1 (C-14), 42.3 (C-13), 39.5 (CH2), 36.4 (C-7), 36.2 (C-20),
36.2 (C-11), 35.6 (CH2), 33.0 (C-6), 28.4 (CH2), 28.0 (C-25), 24.6
(CH2), 23.9 (CH2), 23.0 (CH2), 22.8 (C-26 or C-27), 22.6 (C-27 or C-
26), 18.8 (C-21), 18.4 (C-19), 11.2 (C-18).
CDCl3,
d
): 7.59 (d, J¼14.7 Hz, 1H, H-6), 7.03 (d, J¼8.3 Hz, 1H, H-1),
6.84 (s, 1H, H-4), 6.76 (d, J¼8.3 Hz, 1H, H-2), 6.69 (d, J¼14.7 Hz, 1H,
H-7), 3.80 (s, 3H, OMe), 2.25 (s, 3H, Me-19). 13C NMR (125 MHz,
CDCl3, d): 157.9 (C-3), 143.3 (C-6), 137.7 (C-5), 131.2 (C-1), 127.0 (C-
10), 114.0 (C-4), 110.9 (C-2), 77.9 (C-7), 55.3 (OMe), 18.8 (C-19).
4.1.18. (1aR,3aR,4R,6aR,6bS)-6b-(5-Methoxy-2-methylphenethyl)-
3a-methyl-4-((R)-6-methylheptan-2-yl)octahydro-1aH-indeno[4,5-
b]oxirene (33). A solution of 30 (690 mg, 1.74 mmol, 1 equiv) in
DCM (35 mL) was added over 5 min to a mixture of m-CPBA (70%,
858 mg, 3.48 mmol, 2 equiv) and KF (303 mg, 5.22 mmol, 3 equiv)
in DCM (18 mL) at 0 ꢁC. The mixture was stirred for 30 min and then
left static at 4 ꢁC for 16 h before it was poured in a saturated so-
lution of Na2SO3 in water (50 mL). The two phases were separated
and the aqueous phase was further extracted with DCM (50 mL).
The combined organic phase was dried on MgSO4, concentrated
under vacuum, and purified by column chromatography (silica,
neat petroleum ether then 1% ethyl acetate in petroleum ether)
yielding 50% 33 (362 mg, 0.877 mmol) as a colorless oil. 1H NMR
4.1.16. (3R,3aR,7aS)-7-(4-Methoxyphenethyl)-3a-methyl-3-((R)-6-
methylheptan-2-yl)-2,3,3a,4,5,7a-hexahydro-1H-indene (29). A so-
lution of 4-methoxyphenethylmagnesium chloride in THF (0.5 M,
0.6 mL, 0.3 mmol, 1.2 equiv) was added dropwise to a mixture of 11
(99 mg, 0.25 mmol, 1 equiv) and precatalyst Fe(acac)3 (8.82 mg,
0.025 mmol, 0.1 equiv) in DMF (1 mL) at rt. After 2 h, water (30 mL)
was added and the mixture was extracted with ethyl acetate
(2ꢂ25 mL). The combined organic phase was dried on MgSO4,
concentrated under vacuum, and purified by column chromatog-
raphy (silica, neat petroleum ether then 5% ethyl acetate in petro-
leum ether) yielding 70% 29 (67.3 mg, 0.176 mmol) as a colorless oil.
Rf 0.73 (petroleum ether/ethyl acetate 9:1). 1H NMR (300 MHz,
CDCl3,
d
): 7.08 (m, 2H, H-ortho), 6.80 (m, 2H, H-meta), 5.22 (s, 1H,
(500 MHz, CDCl3,
d
): 7.01 (d, J¼8.2 Hz, 1H, H-1), 6.67 (d, J¼2.7 Hz,
H-9), 3.77 (s, 3H, OMe), 2.65 (m, 1H), 2.56 (m, 1H), 2.2e0.94 (m,
20H), 0.94 (d, J¼6.5 Hz, 3H, Me-21), 0.86 (d, J¼6.6 Hz, 3H, Me-27 or
Me-26), 0.85 (d, J¼6.6 Hz, 3H, Me-26 or Me-27), 0.67 (s, 3H, Me-18).
1H, H-4), 6.63 (dd, J¼8.2, 2.7 Hz, 1H, H-2), 3.75 (s, 3H, OMe), 3.08 (d,
J¼2.6 Hz, 1H, H-9), 2.59 (m, 2H, H-6), 2.20 (s, 3H, Me-19), 2.1e0.9
(m, 20H), 0.90 (d, J¼6.6 Hz, 3H, Me-21), 0.86 (d, J¼6.6 Hz, 3H, Me-27
or Me-26), 0.85 (d, J¼6.6 Hz, 3H, Me-26 or Me-27), 0.67 (s, 3H, Me-
DEPT 45 (75 MHz, CDCl3,
d
): 129.2 (2ꢂ C-ortho), 119.5 (C-9), 113.6
(2ꢂ C-meta), 55.3 (OMe), 54.6, 51.1, 39.5, 37.4, 36.4, 36.3, 36.2, 34.2,
28.4, 28.1, 24.6, 23.9, 23.0, 22.9 (C-27 or C-26), 22.6 (C-26 or C-27),
18.8 (C-21), 11.3 (C-18). IR (neat, cmꢀ1): 2931 (s), 2868 (m), 1724 (s),
18). 13C NMR (125 MHz, CDCl3,
d): 157.9 (C-3), 141.6 (C-5), 130.9 (C-
1), 127.8 (C-10), 114.5 (C-4), 110.8 (C-2), 61.0 (C-8), 57.9 (C-9), 55.2
(OMe), 53.4, 53.3, 41.5 (C-13), 39.4 (C-24), 36.1 (C-20), 36.0, 35.0,

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G. Medard / Tetrahedron 70 (2014) 186e196
195
32.9 (C-25), 28.5 (C-6), 28.0 (C-7), 28.0, 23.9, 23.1, 22.8 (C-27 or C-
26), 22.5 (C-26 or C-27), 22.5, 19.0 (C-21), 18.4 (C-19), 11.9 (C-18). IR
(neat, cmꢀ1): 2954 (s), 1610 (w), 1502 (m), 1466 (m), 1381 (w), 1250
(m), 1208 (w), 1161 (w), 1115 (w), 1048 (w), 912 (w), 798 (w), 716
(w).
18). 13C NMR (125 MHz, CDCl3,
d
): 157.7 (C-3), 142.6 (C-5), 130.8 (C-
1), 128.0 (C-10), 115.0 (C-4), 110.5 (C-2), 74.8 (C-9), 56.1, 55.2 (OMe),
51.7, 43.4, 41.9 (C-13), 39.5, 38.3, 36.9, 35.8, 35.3 (C-20), 28.3 (C-6),
28.0 (C-25), 27.9 (C-7), 25.2, 23.8, 23.2, 22.8 (C-26 or C-27), 22.5 (C-
27 or C-26), 18.5 (C-21), 18.4 (C-19), 13.5 (C-18).
4.1.19. (1R,3aS,4R,5R,7aR)-4-(5-Methoxy-2-methylphenethyl)-7a-
methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-inden-5-ol
4.1.22. (1R,3aS,4S,5R,7aR)-4-(5-Methoxy-2-methylphenethyl)-7a-
methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-inden-5-ol
(as-
(35). A solution of borane in THF (1 M, 325
mL, 0.325 mmol,
trogorgiadiol methyl ether) (34). 1H NMR (500 MHz, CDCl3,
d
): 7.02
1.2 equiv) was added to a solution of 30 (107 mg, 0.27 mmol,
1 equiv) in THF (2.7 mL) at 0 ꢁC under nitrogen. After 30 min at 0 ꢁC,
the mixture was slowly warmed to rt and stirred for a further 20 h.
The mixture was then cooled to 0 ꢁC and a solution of KOH in water
(5%, 2 mL) was added, followed by a solution of H2O2 in water (27%,
2 mL), and ether (2 mL). The mixture was then warmed to rt and
stirred for 30 min. The mixture was extracted with ether (3ꢂ6 mL).
The combined organic phase was dried on MgSO4, concentrated
under vacuum, and purified by column chromatography (silica, 5%
ethyl acetate in petroleum ether) yielding 48% 35 (and traces of 36)
(d, J¼8.2 Hz, 1H, H-1), 6.70 (d, J¼2.7 Hz, 1H, H-4), 6.63 (dd, J¼8.2,
2.7 Hz, 1H, H-2), 4.02 (br s, 1H, H-9), 3.75 (s, 3H, OMe), 2.71 (m, 1H),
2.43 (m,1H), 2.22 (s, 3H, Me-19),1.9e0.9 (m, 22H), 0.90 (d, J¼6.6 Hz,
3H, Me-21), 0.85 (d, J¼6.6 Hz, 3H, Me-27 or Me-26), 0.84 (d,
J¼6.6 Hz, 3H, Me-26 or Me-27), 0.67 (s, 3H, Me-18). 13C NMR
(125 MHz, CDCl3, d): 157.8 (C-3), 142.4 (C-5), 130.8 (C-1), 127.9 (C-
10), 114.5 (C-4), 110.7 (C-2), 67.2 (C-9), 56.2, 55.3 (OMe), 47.8, 42.9,
40.9, 39.5, 36.2, 35.8, 34.2, 31.1, 30.4, 30.2, 28.0, 27.8, 24.5, 23.8, 22.8
(C-26 or C-27), 22.6 (C-27 or C-26), 18.7 (C-21), 18.4 (C-19), 11.0 (C-
18). Data consistent with literature values.15,58
(53 mg, 0.129 mmol) as a colorless oil. 1H NMR (500 MHz, CDCl3,
d):
7.02 (d, J¼7.9 Hz, 1H, H-1), 6.67 (d, J¼2.7 Hz, 1H, H-4), 6.64 (dd,
J¼7.9, 2.7 Hz, 1H, H-2), 3.97 (s, 1H, H-9), 3.76 (s, 3H, OMe), 2.66 (m,
1H), 2.40 (m, 1H), 2.20 (s, 3H, Me-19), 1.90e0.86 (m, 22H),
0.86e0.83 (m, 9H, Me-21 & Me-27 & Me-26), 0.65 (s, 3H, Me-18).
Acknowledgements
Novartis Pharma AG and University College London are thanked
for financial support.
13C NMR (125 MHz, CDCl3,
d): 157.8 (C-3), 141.9 (C-5), 130.8 (C-1),
127.8 (C-10), 114.8 (C-4), 110.5 (C-2), 69.6 (C-9), 56.8, 55.3 (OMe),
45.4, 45.1, 42.0, 39.5, 36.0, 35.8, 35.5, 34.4, 28.7, 28.0, 27.3, 25.9, 23.7,
23.2, 22.8 (C-26 or C-27), 22.5 (C-27 or C-26), 18.5 (C-21), 18.4 (C-
19), 12.7 (C-18).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.11.102.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.1.20. (1R,3aS,4R,7aR)-4-(5-Methoxy-2-methylphenethyl)-7a-
methyl-1-((R)-6-methylheptan-2-yl)hexahydro-1H-inden-5(6H)-one
(37). PCC (56 mg, 0.26 mmol, 2 equiv) was added at rt to a solution
of 35 (and traces of 36) (53 mg, 0.129 mmol, 1 equiv) in DCM
References and notes
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