Cascade radical-mediated cyclisations with conjugated ynone electrophores. An approach to the synthesis of steroids and other novel ring-fused polycyclic carbocycles

Article abstract of DOI:10.1039/b703373g

A cascade radical-mediated Diels-Alder reaction with the iododienynone 16b produced the tricyclic ketone 17 (22%). By contrast, treatment of the substituted furans 36 and 47 with Bu₃SnH-AIBN, instead led to the tetracycles 44 and 58 respectivel

Full text of DOI:10.1039/b703373g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Cascade radical-mediated cyclisations with conjugated ynone electrophores.
An approach to the synthesis of steroids and other novel ring-fused polycyclic
carbocycles†
Gerald Pattenden,* Davey A. Stoker and Nicholas M. Thomson
Received 6th March 2007, Accepted 17th April 2007
First published as an Advance Article on the web 4th May 2007
DOI: 10.1039/b703373g
A cascade radical-mediated Diels–Alder reaction with the iododienynone 16b produced the tricyclic
ketone 17 (22%). By contrast, treatment of the substituted furans 36 and 47 with Bu3SnH–AIBN,
instead led to the tetracycles 44 and 58 respectively, rather than the anticipated oestranes, i.e. 38 and 48.
In a separate study, attempted cascade radical-mediated cyclisations from the ortho-aryl substituted
iododienynones 72 and 73, leading to the ring-D aromatic steroid 7, instead gave the macrocyclic
ketone 76 or the novel bridged tricycles 77/82, respectively, depending on whether benzene or heptane
was used as solvent in the reactions.
cycloaddition (Scheme 1). In a second study, we have explored
an approach to ring-D aromatic steroids, such as nicandrenone 8,
based on the cascade of 14-endo-dig, 6-exo-trig and 6-exo/endo-
trig radical cyclisations between 6 and 7, shown in Scheme 1.
Introduction
Applications of cascade radical-mediated cyclisation reactions
towards the construction of a wide array of ring-fused polycyclic
carbo- and heterocycles abound in the literature.1 Over more than
a decade, our research group has explored a number of comple-
mentary radical-mediated macrocyclisation–transannulation and
Results and discussion
sequential cascade ring forming reactions to elaborate a plethora
of linear, angular, and other ring-fused systems found amongst
natural products,2 including terpenoids, taxoids3 and steroids.4
Within these studies we have used alkyl, allyl, vinyl, acyl and
oxy-centred radical intermediates, and implicated a number of
substituted alkene and alkyne electrophores, i.e. radical acceptors.
In several investigations we have demonstrated that a terminal con-
jugated ynone electrophore has particular advantages in cascade
reactions involving substrates which incorporate additional alkene
unsaturation, e.g. the cascade 12-endo-dig, 6-exo-trig cyclisation
of the precursor 1 to the tricyclic 6,8,6-ring fused ‘taxane’ system
2.3,5 In a continuation of our studies of the use of the ynone
electrophore in the elaboration of interesting ring-fused systems,
we have now examined their scope in two new approaches to
steroid synthesis. Thus, in one study we have examined an oestrane
ring synthesis of 5 based on a macrocyclisation from a substrate,
viz 3, which includes an ynone electrophore and a 1,3-diene unit,
leading to 4, followed by radical-like transannular Diels–Alder
A radical-mediated Diels–Alder approach to the synthesis of
oestranes
A wealth of ingenious methods have been developed to synthesise
oestranes and other steroids. Methods based on biogenetic-
type electrophilic cyclisations of polyene precursors,6 Diels–
Alder reactions,7 and transition metal-catalysed cyclisations of
enynes and triynes,8 are particularly prominent. Cascade radical-
mediated processes to synthesise steroids have also been ex-
amined by several authors,9 including ourselves.10 In addition,
Deslongchamps et al.11 have described some useful examples of
transannular Diels–Alder reactions in steroid ring constructions,
and Malacria and Journet12 have used radical-based intramolecu-
lar Diels–Alder reactions in oestrane synthesis.
To demonstrate credence for the proposed radical-mediated
Diels–Alder approach to oestranes, presented in Scheme 1, we first
examined the less elaborate x-iodo-1,3-diene ynone system 16b.13
The ynone 16b was elaborated via a Suzuki coupling reaction
between the known E-vinyl iodide 1114 and the E-vinylboronic
acid 10 derived from the known acetylene 9,15 in the presence of
Pd(PPh3)4 and aqueous LiOH (Scheme 2). This coupling reaction
led to the conjugated E,E-diene 12a which, using a sequence of
functional group transformations, i.e. 12a → 12b → 13a → 13b
→ 14, was next converted into the aldehyde 14. Treatment of
School of Chemistry, The University of Nottingham, University Park,
Nottingham, England, UK NG7 2RD. E-mail: gp@nottingham.ac.uk;
Fax: +44 0115 9513535; Tel: +44 0115 9513530
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b703373g
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Scheme 1
the aldehyde 14 with acetylenemagnesium bromide led to the
corresponding sec-alcohol 15, which was then oxidised to the
ynone 16a using Dess–Martin periodinane. Finally, exchange of
bromide for iodide under Finkelstein conditions gave the x-iodo-
1,3-dieneynone system 16b.
When a solution of 16b in benzene was treated with Bu3SnH–
AIBN at 80 ◦C for 8 h, work-up and chromatography gave a
single diastereoisomer of the expected tricyclic enone 17, but in a
modest yield of 22%; the only other product characterised was the
dienynone 16c resulting from reduction of the carbon-to-iodide
bond in the starting material 16a. The structure of the tricyclic
enone 17 followed from comparison of its spectroscopic data with
those of similar compounds prepared earlier by Roush et al.,16 who
used a sequence based on an intramolecular Wadsworth–Emmons
olefination from an appropriate ketophosphonate precursor, viz 18
→ 19, followed by an in situ intramolecular Diels–Alder reaction.
The cis, syn, cis stereochemistry assigned to 17 was based on
detailed NOE studies together with molecular modelling and
Scheme 2 Reagents and conditions: (i) catecholborane, THF, 67 ◦C, 14 h, 77%; (ii) H2O, 4 h, 87%; (iii) Pd(OAc)2, PPh3, 11, THF, aq. LiOH, 40 ◦C, 16 h,
82%; (iv) Ac2O, NEt3, DMAP, DCM, 0 ◦C, 4 h, 91%; (v) TBAF, THF, 2 h, 79%; (vi) CBr4, PPh3, DCM, 0 ◦C, 30 min, 89%; (vii) K2CO3, MeOH, 2 h,
97%; (viii) Dess–Martin periodinane, DCM, 30 min, 89%; (ix) ≡–MgBr, THF, 0 ◦C → rt, 30 min, 98%; (x) Dess–Martin periodinane, DCM, 30 min,
82%; (xi) NaI, acetone, 16 h, quant.; (xii) Bu3SnH, AIBN, benzene, 80 ◦C, 8 h, 16c = 6%, 17 = 22%.
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group interconversions was then converted into the aldehyde 34b.
Treatment of this aldehyde 34b with acetylenemagnesium bromide
led to the propargylic alcohol 34c which, after oxidation to the
corresponding ketone 35a and exchange of bromide for iodide,
gave the furyliodoynone 24.
Much to our disappointment, the furyliodoynone 24 was
unstable in hot benzene, and treatment of solutions in benzene
with Bu3SnH–AIBN under a range of temperatures led largely to
polymeric material. Only in one case, using Bu3SnH in the presence
of Et3B at 0 ◦C,22 were we able to generate a radical centre from the
substrate 24, but this was immediately quenched by H• producing
35b in 37% yield. Unperturbed, we reasoned that the correspond-
ing ortho benzene-substituted furyliodoynone analogue 36 of 24
would be more robust to heat, and allow us to realise a cascade
radical-mediated macrocyclisation–transannulation Diels–Alder
sequence, via 37, producing the oestrane 38.
The arylfuran iodoynone 36 was rapidly accessed via the adduct
39a resultingfrom a Stille coupling reaction between the previously
synthesised furylstannane 30b and 2-iodobenzeneacetonitrile
(Scheme 5). The arylfuran 39a was next elaborated to the aldehyde
40b in three straightforward synthetic steps, which was then
converted into the iodoynone 36 using chemistry developed earlier
in the synthesis of the analogue 24.
When a dilute solution of the arylfuran iodoynone 36 in reflux-
ing benzene was treated with Bu3SnH–AIBN, a single tetracyclic
product was isolated in 45% yield (69% based on recovered
starting material). The NMR spectroscopic data recorded for the
tetracycle were not consistent with the expected oestrane ring
system 38. Instead, the data, i.e. the presence of three olefinic
protons, one of which, absorbing at dH 5.89 correlated with a
carbon resonance at dC 89.8 ppm next to oxygen, were consistent
with the alternative tetracyclic [6,8,6,5] ring-fused dihydrofuran
structure 44. The tetracyclic ether 44 is produced from 36 via initial
13-endo-dig macrocyclisation of the alkyl radical intermediate 43
leading to the vinyl radical species 37 which equilibrates with the
geometrical isomer 46 (Scheme 6). A 6-exo-trig cyclisation at C-2
of the furan ring in 46, accompanied by allylic migration then
produces the benzylic radical intermediate 45 which is quenched
by H-abstraction leading to 44.
1
comparison of vicinal coupling data in its H NMR spectrum,
with those of similar compounds described by Roush et al.16 The
formation of exclusively the cis, syn, cis-diastereoisomer 17 from
16b is interesting and most likely implicates a pathway involving
a 13-endo-dig radical macrocyclisation, leading to 20, followed
by in situ H• quench to the E,E,Z-trienone intermediate 22 and
Diels–Alder transannulation through an “endo-like” transition
state (Scheme 3). It is conceivable that a tandem 6-exo-trig, 5-
exo-trig radical cyclisation from the E,E,E-trienone intermediate
21, via 23,17 would also produce 17, but this pathway would also be
expected to lead to a mixture of diastereoisomers of the tricyclic
enone.
We next decided to examine a cascade radical cyclisation from
the corresponding x-iodoynone 24 where the 1,3-diene unit is
accommodated within a furan ring. Furans are well known
to act as excellent dienes in Diels–Alder cycloadditions,18 and
the proposed sequence 24 → 25 → 26, would simultaneously
introduce an ether bridge in the adduct 26 permitting further
elaboration, as required.
The furyliodoynone 24 was prepared in a straightforward
manner, starting from the known substituted propanols 27a19 and
28a20 (Scheme 4). Thus, protection of 27a as its TBDPS ether
27b, followed by conversion into the corresponding 5-furyllithium
species 30a using BuLi, and quenching with Bu3SnCl first gave
the relatively unstable furylstannane 30b.21 Without isolation
and purification, the stannane 30b was reacted immediately with
the E-vinyl iodide 29, in the presence of Pd(PPh3)2Cl2, leading
to the substituted vinylfuran 31a which was characterised as
the alcohol 31b. The E-vinyl iodide 29 was prepared from
the alcohol 28a after oxidation to 28b followed by a Wittig
olefination reaction with ICH2 PPh3I− in the presence of KOt−Bu.
Hydrogenation of 31b next gave 32 which by successive functional
+
Scheme 3
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Scheme 4 Reagents and conditions: (i) PCC, silica, DCM, 4 h, 60%; (ii) ICH2+PPh3I−, KOt−Bu, THF, −60 → −40 ◦C, 2 h, 97%; (iii) TBDPSCl, NEt3,
DMAP, DCM, 16 h, 97%; (iv) (a) t−BuLi, THF, −78 → −20 ◦C, 3 h, then Bu3SnCl, −20 ◦C → rt, 3 h, then 29, Pd(PPh3)2Cl2, THF, 67 ◦C, 16 h, (b) PPTS,
MeOH, 24 h, 40%; (v) Pd(OH)2, H2, MeOH, 6 h, 96%; (vi) Ac2O, NEt3, DMAP, DCM, 0 ◦C, 6 h, 74%; (vii) TBAF, THF, 2h, 96%; (viii) CBr4, PPh3,
DCM, 0 ◦C, 20 min, 95%; (ix) K2CO3, MeOH, 4 h, 98%; (x) Dess–Martin periodinane, DCM, 20 min, 70%; (xi) ≡–MgBr, THF, 0 ◦C → rt, 30 min, 84%;
(xii) Dess–Martin periodinane, DCM, 30 min, 88%; (xiii) NaI, K2CO3, acetone, 14 h, quant.; (xiv) Et3B, Bu3SnH, Tol, 0 ◦C, 48 h, 37%.
We surmised that the driving force for the formation of 44 from
36 not only had its origins in the relative stabilisation and reactivity
of the equilibrating vinyl radical intermediates 37 and 46,17 but
also in the stabilisation of the product radical centre in 45, by
the neighbouring benzene ring and adjacent oxygen centre. To
overcome the latter stabilisation, we therefore finally decided to
examine a radical cascade from the cyclohexene analogue of 36,
i.e. 47, in anticipation of synthesising the modified steroidal ring
system 48.
The substituted cyclohexene 47 was synthesised via a Stille
coupling reaction between the furylstannane 30b and the vinyl-
triflate 51 derived in two straightforward steps from the known
hemiaminal 49,23 which gave the furanylcyclohexene 52a in 85%
yield (Scheme 7). A series of functional group manipulations
allowed the conversion of 52a into the substituted aldehyde 53c
which was then converted into the x-iodoynone 47 using synthetic
methods and procedures already developed in the synthesis of the
related compounds 16b, 24 and 36.
When a solution of the x-iodoynone 47 in benzene was treated
with Bu3SnH–AIBN, work-up and chromatography gave a single
diketone product, as colourless crystals, in 40% yield. Detailed
1
analysis of the H and 13C NMR spectroscopic data failed to
resolve the structure of the product, and suitable crystals for
X-ray analysis could not be grown. We therefore treated the
diketonic product with DIBAL-H which led to a crystalline diol,
viz 59 suitable for X-ray analysis. The X-ray crystal structure
of the diol (Fig. 1)24 demonstrated that the diketone product
resulting from treatment of the x-iodoynone 47 has the novel and
unusual tetracyclic diene dione structure 58. The formation of 58
presumably results from an initial 13-endo-dig macrocyclisation
from the radical intermediate 54 leading to 55, which then
undergoes 6-exo-trig transannular cyclisation leading to the new
radical intermediate 56 (Scheme 8). Instead of being quenched by
H-abstraction, leading to a structure similar to 44, the radical 56
then undergoes a precedented fragmentation25 to the enedione
species 57. A final 5-exo-trig radical cyclisation, involving the
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Scheme 5 Reagents and conditions: (i) 2-iodobenzeneacetonitrile, Pd(PPh3)2Cl2, THF, 67 ◦C, 16 h, 89%; (ii) TBAF, pTSA, THF, 12 h, 75%; (iii) CBr4,
PPh3, DCM, 0 ◦C, 30 min, 85%; (iv) (a) DIBAL-H, Tol, −78 → 0 ◦C, 4.5 h, (b) ≡–MgBr, THF, −78 ◦C → rt, 2h, 60%; (v) Dess–Martin periodinane,
DCM, 2 h, 50%; (vi) NaI, K2CO3, acetone, 14 h, 77%.
Scheme 6
Bu3SnH–AIBN led to the polycyclic enone 63 in 40% yield,
via a cascade of 13-endo-dig (to 61), 5-exo-trig and 6-exo–endo-
trig radical cyclisations (Scheme 9).29 As an approach to ring-D
aromatic steroids we reasoned that, by analogy, the iododienynone
64, which contains a trisubstituted, rather than a disubstituted,
double bond, and one more methylene carbon in its side-chain
compared to 60, should undergo a similar cascade of radical
cyclisations leading to the polycycle 7, as a possible progenitor
cyclohexene double bond in 57 then leads to the tetracyclic diene
to nicandrenones, e.g. 8.30
dione 58.
In order to establish proof of principle, we first prepared both
the E- and Z-isomers of the trisubstituted double bonds in 64
A radical-mediated cyclisation approach to ring-D aromatic
steroids
where R = H and OMe, i.e. 72a, 73a, 72b and 73b (Scheme 10).
These syntheses were carried out in a fairly straightforward
manner starting from readily available starting materials. Thus,
separate Julia olefination reactions between the benzothiazole
sulfone 66, derived in two steps from the secondary alcohol
65b,31 and the previously synthesised aldehydes 67a and 67b,29
using NaHMDS as base, first led to 3 : 2 mixtures of E- and
Z-isomers of the corresponding trisubstituted alkene products
68a and 68c respectively. The E- and Z-isomers were easily
separated following deprotection to the corresponding alcohols
68b/d and chromatography. The pure E- and Z-isomers of 68b
The family of insect antifeedant compounds known as nican-
drenones, e.g. 8, isolated from the Peruvian “shoofly” plant Nican-
dra physaloides is probably the best-known group of naturally
occurring ring-D aromatic steroids.26 Although some detailed
studies have been made of the possible origin of the aromatic rings
in these compounds,27 relatively little attention has been given to
their total synthesis.28
In an earlier study, which resulted in a synthesis of epi-oestrone
62, we showed that treatment of the iododienynone 60 with
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Scheme 7 Reagents and conditions: (i) (a) HCl, reflux, 5h, (b) TBSCl, NEt3, DMAP, 16 h, 65%; (ii) (a) LDA, THF, −78 ◦C → rt, 2 h, (b) PhNTf2, THF,
−78 → 0 ◦C, 3 h, 99%; (iii) (a) 30b, Pd(PPh3)2Cl2, THF, 67 ◦C, 5 h, (b) PPTS, MeOH, 48 h, 85%; (iv) Ac2O, NEt3, DMAP, DCM, 0 ◦C, 6 h, 96%; (v)
TBAF, THF, 1.5 h, 98%; (vi) NCS, PPh3, K2CO3, DCM, 0 ◦C, 30 min, 94%; (vii) K2CO3, MeOH, 16 h, 94%; (viii) Dess–Martin periodinane, DCM, 0 ◦C,
30 min, 76%; (ix) ≡–MgBr, THF, 0 ◦C → rt, 30 min, 94%; (x) Dess–Martin periodinane, DCM, 30 min, 87%; (xi) NaI, K2CO3, 2-butanone, 80 ◦C, 10 h,
66%.
Scheme 8
procedures to those used earlier in the elaborations of 24, 36 and
47.
Addition of Bu3SnH–AIBN, over 8 hours, to a refluxing solution
of the Z-iododienynone 73a in benzene, followed by further
heating for 12 hours, resulted in the formation of a single product
1
in 35% yield. Analysis of H and 13C NMR spectroscopic data
showed clearly that the product had the macrocyclic structure
76a (Scheme 11), resulting from a straightforward 14-endo-dig
cyclisation from the alkyl radical intermediate 74a produced from
73a, followed by H-quench of the resulting vinyl radical 75a.
The analogous macrocyclic ketone 76b was produced (40%) when
the corresponding Z-iododienynone 73b was treated likewise with
Bu3SnH–AIBN. The E-geometry of the newly incorporated alkene
bond in 76 followed conclusively from the magnitude of the
observed couplings between the vicinal olefinic hydrogen atoms,
i.e. J 15 Hz, in the 1H NMR spectrum.
Fig. 1 X-Ray crystal structure of the diol 59.
and 68d were then converted separately into the E- and Z-isomeric
iododienynones 72 and 73 respectively, following chlorination to
69a/c, reduction and oxidation to 69b/d, addition of acetylene
(leading to 70), oxidation to 71, and, finally, chloride–iodide
exchange (Scheme 10) using essentially the same reagents and
We assume that the different outcome following treatment of
73 with Bu3SnH–AIBN, compared to 60, has its origins in the
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preferred conformation of the first-formed macrocyclic radical
intermediate 75. Thus, a favourable conformation in 75 could facil-
itate rapid H-abstraction processes, perhaps involving the methyl
group hydrogens on the adjacent trisubstituted double bond, to
the exclusion of transannular-radical C–C bond forming reactions
found with the corresponding macrocyclic radical intermediate 61
produced from 60. We examined a range of alternative reaction
conditions, designed to promote a cascade of radical cyclisations
producing the ring-D aromatic steroid 7 from 73, but to no avail,
instead only the macrocyclic ketone 76 was obtained. We also
attempted to produce 7 by treatment of the macrocyclic ketone 76
with SmI2 in THF, but only starting material was recovered.
We next studied the outcome of treatment of the corresponding
E-iododienynones 72a and 72b with Bu3SnH–AIBN, and this
was even more interesting and surprising! Thus, treatment of the
methoxyaryl-substituted iododienynone 72b with Bu3SnH–AIBN
in refluxing benzene, followed by work-up and chromatography
gave a 2 : 1 mixture of two diastereoisomers of an oily, chemically
homogenous, polycyclic product in approximately 30% yield.
The separation, and hence identification of these methoxyaryl-
substituted cyclic products proved problematic. The mixture
of diastereoisomers was therefore demethylated, using BBr3 in
CH2Cl2 at −78 ◦C, which led to a 2 : 1 mixture of diastereoisomers
of the corresponding phenols, isolated as a viscous liquid solid.
Crystallisation of the mixture from diethyl ether–pentane gave a
homogenous sample of the major diastereoisomer, as colourless
crystals, suitable for X-ray analysis.
major isomer, was produced when the corresponding des-methoxy
iododienynone 72a was treated with Bu3SnH–AIBN in refluxing
benzene.
The formation of the bridged tricycle 77 from 72 requires
three intramolecular carbon-to-carbon bond-forming processes
involving C-1 and C-11; C-5 and C-10; and C-4 and C-13; in
addition to an intermolecular radical coupling reaction between
C-14 and the benzene used as solvent. It is likely that 77 is produced
from 72 by initial 11-endo-trig cyclisation of the radical precursor
78 leading first to the benzylic radical intermediate 79. Sequential
6-exo-trig (to 80) and 6-exo-dig radical cyclisations, next lead to
the vinyl radical intermediate 81. The radical 81 is then quenched
by coupling to the solvent benzene, producing the benzylidene sub-
stituted tricycle 77, together with a diastereoisomer (Scheme 12).
The differing reactivity of 72 and 73 reflects the importance
of the geometry of the trisubstituted double bonds in these
substrates, permitting 14-endo-trig macrocycliation to 75 with the
Z-isomer 73 and, by contrast, favouring an unforeseen 11-endo-
trig cyclisation (to 79) with the E-isomer 72. Whereas the 14-
ring radical 75 suffers straightforward H-quench producing the
macrocyclic trienone 76, the favoured stereoelectronics present in
the 11-ring radical 79 permit the subsequent radical cyclisations,
leading to 81 via 80 (Scheme 11). Although the addition of carbon
centered radicals to, and the formation of radicals from, benzene
and other aryls is precedented,33 we were somewhat surprised
to encounter this phenomenon in the case leading to 77 from
81. We therefore investigated the outcome of treatment of the
iododienynone 72b with Bu3SnH–AIBN in refluxing heptane at
98 ◦C, in place of benzene. To our satisfaction, we found that
the only product was a 2 : 1 mixture of diastereoisomers of the
angular ring-fused enone 82, analogous to 77b, resulting from
hydrogen, instead of benzene, quench of the presumed vinyl radical
To our surprise, the X-ray crystal structure32 showed that we
had produced the unusual angular 6,6,6-ring fused substituted
aromatic structure 77 as the major product following treatment of
the iododienynone 72b with Bu3SnH–AIBN in refluxing benzene.
A similar 2 : 1 mixture of diastereoisomers, with 77a as the
Scheme 9
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Scheme 10 Reagents and conditions: (i) TBDPSCl, NaH, THF, 2 h, 98%; (ii) 2-mercaptobenzothiazole, PPh3, DEAD, THF, 24 h, 99%; (iii) m-CPBA,
NaHCO3, DCM, −40 ◦C → rt, 12 h, 93%; (iv) NaHMDS, 66, THF, −78 ◦C → rt, 12 h, 38–55%; (v) TBAF, THF, 3 h, 25–52%; (vi) NCS, PPh3, K2CO3,
DCM, 1 h, 85–98%; (vii) DIBAL-H, DCM, −78 ◦C, 4 h, 85–92%; (viii) MnO2, DCM, 20 h, 81–89%; (ix) ≡–MgBr, THF, −78 ◦C → rt, 22 h, 93–99%;
(x) MnO2, DCM, 18 h, 81–88%; (xi) NaI, K2CO3, 2-butanone, 80 ◦C, 24 h, 87–95%.
represent the stereochemistries of the major diastereoisomers of
the angular ring-fused compounds resulting from treatment of 72
with Bu3SnH–AIBN, we have no reliable data, or intelligence, with
which to assign a stereochemistry to the minor diastereoisomers
of 77/81 produced simultaneously in these reactions.
Summary
We have evaluated the scope for two radical-based cascade
reactions involving ynone electrophores towards oestranes and
ring-D aromatic steroids (Scheme 1). Our attempts to carry out
radical-mediated Diels–Alder reactions with the substrates 36 and
47, leading to 38 and 48 respectively, instead led to the unexpected
tetracyclicstructures 44 and 58. Likewise, treatment of the isomeric
iododienynones 72 and 73 with Bu3SnH–AIBN led to either
the macrocycle 76 or to the novel bridged tricycles 77 and 81
Scheme 11
(depending on whether benzene or heptane was used as solvent),
rather than to the anticipated ring-D steroid system 7. Not for
intermediate 81. Although X-ray crystallography and comparative
NMR spectroscopic data established that structures 77 and 82
the first time, therefore, these studies have demonstrated how
interesting and unpredictable some radical reactions can be. This
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Scheme 12
is particularly so when a range of alternative reaction pathways are
presented to radical intermediates by neighbouring functionality
in a constrained environment, as found in the substrates 47 and 73,
in particular. Nevertheless, these same radical reactions frequently
offer the opportunity to elaborate novel and unusual structures
and ring systems not available by more conventional synthetic
methods, e.g. the polycycles 58 and 77.
360 (91 MHz), Bruker AM 400 (101 MHz) or Bruker DRX500
(126 MHz) instrument as dilute solutions in deuterochloroform,
unless otherwise stated. Chemical shifts are reported relative to
residual solvent peaks using a broadband decoupled mode, and
the multiplicities were determined using a DEPT sequence. When
required, 1H–1H COSY spectra were recorded on a Bruker AM
400 (400 MHz) instrument and standard Bruker software with no
modifications. 1H–13C HMQC–HMBC and NOE spectra were
recorded on a Bruker AM 400 (400 MHz) spectrometer. Mass
spectra were recorded on either a VG Autospec, an MM-701CF,
a VG Micromass 7070E or a Micromass LCT spectrometer,
using electron ionisation (EI), electrospray (ESI) or fast atom
bombardment (FAB) techniques.
Microanalytical data were obtained on a Perkin-Elmer 240B
elemental analyser. Flash chromatography was performed using
Merck silica gel 60 as the stationary phase and the solvents
employed were of analytical grade, “petro◦l” used in chromatog-
raphy refers to light petroleum, bp 40–60 C. All reactions were
monitored by thin layer chromatography using aluminium plates
precoated with Merck silica gel 60 F254, which were visualised
with ultraviolet light and then with either acidic alcoholic
vanillin solution, basic potassium permanganate solution, or
acidic anisaldehyde solution. Dry organic solvents were routinely
stored under a nitrogen atmosphere and/or dried over sodium
wire. Dichloromethane was distilled from calcium hydride. Dry
tetrahydrofuran and benzene were distilled from sodium and
benzophenone. Other organic solvents and reagents were purified
Experimental
General details
All melting points were determined using a Kofler hot-stage or
Bibby Stuart Scientific SMP3 apparatus and are uncorrected.
Infrared spectra were obtained on a Perkin-Elmer 1600 series FT-
IR instrument as liquid films or as dilute solutions in spectroscopic
grade chloroform. Proton NMR spectra were recorded on a
Bruker WM 250 (250 MHz), Joel EX 270 (270 MHz), Bruker DPX
360 (360 MHz), Bruker AM 400 (400 MHz) or Bruker DRX500
(500 MHz) spectrometer as dilute solutions in deuterochloroform
at ambient temperature, unless otherwise stated. The chemical
shifts are quoted in parts per million (ppm) relative to residual
solvent peaks, and the multiplicity of each signal is designated
by the following abbreviations: s, singlet, d, doublet, t, triplet,
q, quartet, sx, sextet, br, broad, m, multiplet, app, apparent.
All coupling constants are quoted in Hertz. Carbon-13 NMR
spectra were recorded using a Joel EX 270 (68 MHz), Bruker DPX
1784 | Org. Biomol. Chem., 2007, 5, 1776–1788
This journal is
The Royal Society of Chemistry 2007
©

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by the accepted literature procedures. Solvents were removed in
vacuo at approx. 20 mm Hg using a Bu¨chi rotary evaporator.
Where necessary, reactions requiring anhydrous conditions were
performed in dry solvents in flame-dried or oven-dried apparatus
under a dry nitrogen atmosphere.
8,17-Dioxo-tetracyclo[12,3,01,6,09,14]heptadeca-9,15-diene 58.
A solution of tri-n-butyltin hydride (32 ll, 0.12 mmol), and 2,2ꢀ-
azobis(isobutyronitrile) (1 mg, 0.005 mmol) in dry benzene (3 ml)
was added dropwise over 30 min to a stirred, refluxing solution of
the iodide 47 (37 mg, 0.10 mmol) and 2,2ꢀ-azobis(isobutyronitrile)
(1 mg, 0.005 mmol) in dry, degassed benzene (30 ml), under an
argon atmosphere. The mixture was held at reflux for a further
2 h, then cooled and concentrated in vacuo to leave a yellow oil.
The oil was purified by chromatography on silica, eluting with a
gradient of 10 to 50% ether in light petroleum (bp 40–60 ◦C),
to give the tetracyclic dione 58 (10 mg, 40%) as a colourless
solid, mp 106–108 ◦C (acetone); vmax(film)/cm−1 1694, 1614; dH
2-Oxo-tricyclo[7,4,01,6,09,13]trideca-7-ene 17. A solution of
tri-n-butyltin hydride (0.18 ml, 0.68 mmol), and 2,2ꢀ-
azobis(isobutyronitrile) (4.5 mg, 0.03 mmol) in dry benzene (10 ml)
was added dropwise over 6 h to a stirred, refluxing solution of the
iodide 16b (0.18 g, 0.57 mmol) and 2,2ꢀ-azobis(isobutyronitrile)
(4.5 mg, 0.03 mmol) in dry, degassed benzene (180 ml), under an
argon atmosphere. The mixture was held at reflux for a further
2 h, then cooled and concentrated in vacuo. The residue was
purified by chromatography on silica, eluting with 10% ether in
light petroleum (bp 40–60 ◦C), to give (i) the ynone 16c (7 mg,
6%) (eluted first) as a colourless oil, vmax(film)/cm−1 1682, 1456,
988; dH (360 MHz, CHCl3) 0.90 (3H, t, J 7.4 Hz, CH3), 1.33–
1.46 (2H, m, CH2), 1.76–1.81 (2H, m, CH2), 2.01–2.13 (4H, m,
2 × CH2), 2.61 (2H, t, J 7.4 Hz, CH2CO), 3.22 (1H, s, ≡C–H),
=
(500 MHz, CHCl3) 1.15–1.25 (2H, m, O CCH2CHCH2), 1.33–
=
=
1.44 (2H, m, O CCCHaHb + O CCCCHaHb), 1.50–1.54 (1H,
=
=
m, O CCH2CHCH2CHaHb), 1.63–1.89 (6H, m, O CCCHaHb +
O CCCH2CHaHb + O CCH2CHCH2CHaHb + O CCCCHaHb
+ O CCCCH2CH2), 2.05 (1H, app dq, J 13.1 and 3.8 Hz,
=
=
=
=
=
=
O CCH2CH), 2.12–2.13 (2H, m, O CCH2), 2.21 (1H, td,
=
J 17.1 and 4.1 Hz, O CCCH2CHaHb), 2.30–2.38 (1H, m,
=
=
O CC CHCHaHb), 2.44 (1H, dtt, J 20.3, 5.3 and 1.5 Hz,
O CC CHCHaHb), 6.26 (1H, d, J 5.7 Hz, O CCH ), 7.10
(1H, dd, J 5.3 and 2.8 Hz, O CC CH), 7.61 (1H, d, J 5.7 Hz,
=
=
=
=
=
=
5.47–5.64 (2H, m, 2 × CH), 5.96–6.06 (2H, m, 2 × CH);
dC (68 MHz, CHCl3) 14.1 (q), 22.9 (t), 23.8 (t), 32.0 (t), 35.1
(t), 45.1 (t), 78.8 (d), 81.9 (s), 130.6 (d), 130.7 (d), 132.1 (d),
133.5 (d), 187.7 (s); m/z (EI) 190.1351 (M+, C13H18O requires
190.1358); and (ii) the tricycle 17 (25 mg, 22%) (eluted second)
as a colourless oil, vmax(film)/cm−1 1702, 1168, 896; dH (500 MHz,
=
=
=
=
O CCH CH); dC (91 MHz, CHCl3) 18.6 (t), 23.5 (t), 25.3 (t),
25.7 (t), 29.3 (t), 29.4 (t), 31.1 (t), 37.6 (d), 42.0 (t), 50.1 (s), 54.3
(s), 131.0 (d), 136.6 (s), 139.1 (d), 169.8 (d), 198.4 (s), 214.0 (s);
m/z (EI) 256.1455 (M+, C17H20O2 requires 256.1463).
=
CHCl3) 1.44–1.94 (9H, m), 2.03–2.09 (1H, m, O CCH2CHaHb),
8a,17b - Dihydroxy - tetracyclo[12,3,01,6,09,14]heptadeca - 9,15 -
diene 59. A solution of di-iso-butylaluminium hydride (100 ll)
in dichloromethane (1 M, 0.10 mmol) was added dropwise over
2 min to a stirred solution of the tetracyclic dione 58 (10 mg,
0.04 mmol) in dry dichloromethane (1 ml), at −78 ◦C, under a
=
=
2.21–2.32 (2H, m, O CCHaHb + O CCHCHCHCH2), 2.46–
=
=
=
2.51 (2H, m, O CCHaHb + O CCHCHCH ), 2.60–2.63 (1H,
m, O CCHCHCHCH2), 2.85 (1H, app t, J 6.0 Hz, O CCH),
5.48 (1H, d, J 10.1 Hz, O CCHCHCHCH ), 5.56 (1H, dt, J
10.1 and 3.6 Hz, O CCHCHCH ); dC (100 MHz, CHCl3) 23.8
(t), 24.5 (t), 28.1 (t), 29.5 (t), 31.3 (t), 36.4 (d), 39.5 (d), 40.6 (d),
41.3 (t), 48.8 (d), 127.7 (d), 131.5 (d), 214.9 (s).
=
=
=
=
=
=
◦
nitrogen atmosphere. The mixture was allowed to warm to 0 C
over 2 h and then dichloromethane (5 ml) and water (5 ml) were
added. The organic layer was separated and the aqueous layer was
then re-extracted with dichloromethane (2 × 5 ml). The combined
organic extracts were dried and concentrated in vacuo to leave
a yellow solid, which was purified by chromatography on silica,
eluting with 50% ether in light petroleum (40–60 ◦C), to give the
diol 59 (5 mg, 50%) as colourless crystals, mp 127–130 ◦C (ether);
5,6-Benzo-14-oxa-8-oxo-tricyclo[7,4,11,4,01,9]trideca-2,9-diene
44. A solution of tri-n-butyltin hydride (65 ll, 0.24 mmol),
and 2,2ꢀ-azobis(isobutyronitrile) (1.6 mg, 0.01 mmol) in dry
benzene (5 ml) was added dropwise over 2 min to a stirred,
refluxing solution of the iodide 36 (76 mg, 0.20 mmol) and
2,2ꢀ-azobis(isobutyronitrile) (1.6 mg, 0.01 mmol) in dry, degassed
benzene (66 ml), under an argon atmosphere. The mixture was
held at reflux for a further 4 h, and then cooled and concentrated
in vacuo. The residue was purified by chromatography on silica,
eluting with a gradient of 10 to 30% ether in light petroleum (bp
40–60 ◦C), to give (i) recovered starting material (26 mg, 34%)
(eluted first) as a colourless oil, and (ii) the dihydrofuran 44
(23 mg, 45%) (eluted second) as a colourless oil, which crystallised
upon standing at 0 ◦C; vmax(film)/cm−1 1682, 1632, 751, 736; dH
v
max(film)/cm−1 3390, 1698, 1634, 734; dH (360 MHz, CHCl3) 1.23–
=
1.82 (13H, m), 2.00–2.07 (2H, m, HOCHC CHCH2), 2.10–2.18
(1H, m), 2.25–2.37 (1H, m), 3.98–4.03 (1H, m, HOCHC ), 4.85–
4.86 (1H, m, HOCHCH ), 5.60 (1H, dd, J 5.8 and 2.2 Hz,
HOCHCH CH), 5.81 (1H, dd, J 5.5 and 3.4 Hz, HOCHC CH),
=
=
=
=
=
5.87 (1H, dd, J 5.8 and 2.2 Hz, HOCHCH ); dC (91 MHz, CHCl3)
20.1 (t), 21.1 (t), 24.7 (t), 25.0 (t), 29.7 (t), 31.0 (t), 32.1 (d), 33.3
(t), 39.7 (t), 54.9 (s), 56.1 (s), 70.9 (d), 86.6 (d), 117.8 (d), 132.8 (d),
141.4 (s), 142.4 (d); m/z (EI) 260.1771 (M +, C17H24O2 requires
260.1776).
=
(250 MHz, CHCl3) 1.69–2.00 (4H, m, CHCCH2CH2), 2.12–2.33
(2H, m, O CC CHCH2), 3.33 (1H, d, J 11.7 Hz, O CCHaHb),
4.66 (1H, d, J 11.7 Hz, O CHaHb), 5.89 (1H, app t, J 2.1 Hz,
ArCH), 5.95 (1H, dd, J 5.9 and 1.8 Hz, ArCHCH CH), 6.31
=
=
=
(5E,8E,13Z)-11,12,15,16-Tetrahydro-13-methylbenzo[14]annu-
len-7(10H)-one 76a. A solution of tri-n-butyltin hydride (110 ll,
0.41 mmol) and 2,2ꢀ-azobis(isobutyronitrile) (32 mg, 0.19 mmol) in
degassed benzene (13 ml) was added dropwise, over 8 h, via syringe
pump to a stirred solution of the iodide 73a (127 mg, 0.32 mmol)
and 2,2ꢀ-azobis(isobutyronitrile) (16 mg, 0.10 mmol) in degassed
benzene (130 ml) at 80 ◦C under an argon atmosphere. The mixture
was heated under reflux for a further 12 h, then cooled to room
temperature and concentrated in vacuo. The residue was purified
=
=
=
(1H, dd, J 5.9 and 2.1 Hz, ArCHCH ), 6.44 (1H, t, J 3.6 Hz,
=
=
O CC CH), 7.19–7.29 (4H, m, 4 × ArH); dC (100 MHz, CHCl3)
20.7 (t), 25.3 (t), 36.7 (t), 46.1 (t), 89.5 (s), 89.8 (d), 126.5 (d), 127.3
(d), 127.8 (s), 128.9 (d), 129.1 (d), 133.3 (d), 133.6 (d), 134.9 (d),
138.3 (s), 143.7 (s), 202.2 (s); m/z (EI) 252.1156 (M+, C17H16O2
requires 252.1150).
This journal is
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Org. Biomol. Chem., 2007, 5, 1776–1788 | 1785
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=
by flash column chromatography (5–10% Et2O, 95–90% petrol) on
silica gel to leave the macrocycle 76a (30 mg, 35%) as a colourless
oil, mmax(sol CHCl3)/cm−1, 1644, 1623; dH (400 MHz, CDCl3), 1.63–
J 8.0 and 3.0 Hz, O CCH), 3.38 (1H, dd, J 10.0 and 3.0 Hz,
ArCH), 6.89 (1H, s, PhCH), 7.08–7.43 (9H, m, 9 × ArH); (minor
diastereoisomer) 1.27 (3H, s, CH3), 1.48–1.89 (6H, m), 1.98–2.24
=
=
=
1.76 (2H, m, CH CHCH2CH2), 1.76 (3H, s, CH CCH3), 2.12–
(3H, m), 2.86 (1H, app d, J 10.5 and 1.5 Hz, O CCH), 3.02 (2H,
=
2.20 (4H, m, ArCH2CH2 + CH CHCH2CH2CH2), 2.37 (2H, dtd,
m, ArCH2), 3.34 (1H, dd, J 10.5 and 1.5 Hz, ArCH), 6.71 (1H, s,
PhCH), 7.08–7.43 (9H, m, 9 × ArH); dC (100 MHz, CDCl3) (major
diastereoisomer) 21.4 (t), 24.7 (t), 25.0 (t), 27.6 (q), 30.9 (t), 36.8
(d), 37.1 (t), 43.5 (s), 45.7 (d), 52.4 (d), 125.7 (d), 126.4 (d), 127.5
(d), 127.9 (2C d), 128.0 (d), 129.0 (2C d), 129.1 (d), 135.4 (d), 136.8
(s), 137.0 (s), 139.6 (s), 144.1 (s), 205.7 (s); (minor diastereoisomer)
21.8 (t), 24.0 (t), 24.3 (q), 25.8 (t), 28.7 (t), 40.7 (s), 43.6 (d), 46.0
(t), 46.5 (d), 47.2 (d), 123.3 (d), 125.4 (d), 126.2 (d), 127.8 (2C d),
128.6 (2C d), 128.9 (d), 129.1 (d), 135.1 (d), 136.6 (s), 137.4 (s),
139.5 (s), 142.6 (s), 206.1 (s); m/z (ES) 343.2053 (M + H+, C25H27O
requires 343.2056).
=
J 7.0, 4.5 and 1.5 Hz, CH CHCH2), 2.66 (1H, app dd, J 5.0 and
4.0 Hz, ArCHaHb), 2.67 (1H, app d, J 12.0 Hz, ArCHaHb), 5.37
(1H, t, J 8.0 Hz, CH CCH3), 6.21 (1H, dt, J 16.0 and 1.5 Hz,
O CCH CH), 6.58 (1H, dt, J 16.0 and 4.5 Hz, O CCH CH),
=
=
=
=
=
=
6.73 (1H, d, J 16.5 Hz, ArCH CH), 6.97–7.34 (3H, m, 3 × ArH),
7.70 (1H, dd, J 7.5 and 1.5 Hz, ArH), 7.86 (1H, d, J 16.5Hz,
=
ArCH CH); dC (100 MHz, CDCl3), 23.2 (q), 28.1 (t), 30.1 (t),
31.3 (t), 32.1 (t), 35.3 (t), 123.4 (d), 125.7 (d), 126.9 (d), 127.7 (d),
130.5 (d), 130.6 (d), 130.7 (d), 132.3 (s), 137.7 (s), 142.2 (s), 142.7
(d), 147.7 (d), 197.0 (s); m/z (ES) 289.1566 (M + Na+, C19H22ONa
requires 289.1568).
Benzylidene substituted methoxy bridged tricycle 77b. A so-
lution of tri-n-butyltin hydride (170 ll, 0.61 mmol) and 2,2ꢀ-
azobis(isobutyronitrile) (25 mg, 0.15 mmol) in degassed benzene
(20 ml), was added dropwise over 8 h via syringe pump, to a
stirred solution of the iodide 72b (200 mg, 0.51 mmol) and 2,2ꢀ-
azobis(isobutyronitrile) (50 mg, 0.30 mmol) in degassed benzene
(5E,8E)-11,12,13,14,15,16-Hexahydro-2-methoxy-13-methyl-
benzo[14]annulen-7(10H)-one 76b. A solution of tri-n-butyltin
hydride (85 ll, 0.32 mmol) and 2,2ꢀ-azobis(isobutyronitrile)
(26 mg, 0.16 mmol) in degassed benzene (11 ml) was added
dropwise, over 8 h, via syringe pump to a stirred solution of the
iodide 73b (110 mg, 0.26 mmol) and 2,2ꢀ-azobis(isobutyronitrile)
(13 mg, 0.08 mmol) in degassed benzene (110 ml) at 80 ◦C
under an argon atmosphere. The mixture was heated under
reflux for a further 12 h, then cooled to room temperature and
concentrated in vacuo. The residue was purified by flash column
chromatography (5–10% Et2O, 95–90% pentane) on silica gel to
leave the macrocycle 76b (28 mg, 36%) as a yellow oil, mmax(sol
CHCl3)/cm−1, 1640, 1602; dH (400 MHz, CDCl3), 1.63–1.80 (2H,
◦
(200 ml), at 80 C under an argon atmosphere. The mixture was
heated under reflux for a further 12 h, then allowed to cool to
room temperature and concentrated in vacuo. The residue was
purified by flash column chromatography on silica (2–10% Et2O,
98–90% petrol) to give the bridged tricyclic ketone 77b (45 mg,
30%) as an inseparable mixture of diastereoisomers in a 2 : 1
ratio, as a colourless oil, mmax(sol CHCl3)/cm−1, 1693, 1612; dH
(400 MHz, CDCl3) (major diastereoisomer) 1.39 (3H, s, CH3),
1.47–1.63 (3H, m), 1.69–1.85 (3H, m), 2.01–2.19 (3H, m), 2.67
(1H, app td, J 15.5 and 3.0 Hz, ArCHaHb), 2.89 (1H, app dt, J
15.5 and 3.5 Hz, ArCHaHb), 3.21 (1H, ddd, J 8.0 and 3.0 Hz, and
=
=
m, CH CHCH2CH2), 1.82 (3H, s, CH CCH3), 2.10–2.19 (4H,
m, ArCH2CH2 + CH CHCH2CH2CH2), 2.39 (2H, dtd, J 7.0, 4.0
=
=
and 1.0 Hz, CH CHCH2), 2.66 (2H, app t, J 6.0 Hz, ArCH2),
=
=
3.84 (3H, s, OCH3), 5.38 (1H, t, J 7.5 Hz, CH CCH3), 6.20 (1H,
2.5 Hz, O CCH), 3.32 (1H, dd, J 10.0 and 3.0 Hz, ArCH), 3.80
(3H, s, OCH3), 6.69 (1H, d, J 2.5 Hz, CH3OCCHC), 6.77 (1H, dd,
J 8.5 and 2.5 Hz, CH3OCCHCH), 6.87 (1H, s, PhCH ), 7.17 (1H,
=
=
dt, J 15.5 and 1.0 Hz, O CCH CH), 6.58 (1H, dt, J 15.5 and
=
=
=
=
4.0 Hz, O CCH CH), 6.75 (1H, d, J 16.0 Hz, ArCH CH), 6.79
(1H, d, J 1.5 Hz, CH3OCCHC), 6.84 (1H, dd, J 7.0 and 1.5 Hz,
CH3OCCHCH), 7.55 (1H, d, J 7.0 Hz, CH3OCCHCH), 7.88 (1H,
d, J 8.5 Hz, CH3OCCHCH), 7.26–7.44 (5H, m, 5 × PhH); (minor
diastereoisomer) 1.27 (3H, s, CH3), 1.51–1.82 (6H, m), 1.96–2.19
=
=
d, J 16.0 Hz, ArCH CH); dC (100 MHz, CDCl3), 23.0 (q), 29.0
(3H, m), 2.81 (1H, app d, J 8.5 Hz, O CCH), 3.00 (2H, app t,
J 8.5 Hz, ArCH2), 3.29 (1H, dd, J 8.5 and 1.5 Hz, ArCH), 3.79
(3H, s, OCH3), 6.68 (1H, d, J 3.0 Hz, CH3OCCHC), 6.71 (1H, s,
(t), 30.1 (t), 31.5 (t), 32.1 (t), 35.5 (t), 55.4 (q), 123.3 (d), 125.7 (d),
127.0 (d), 127.7 (d), 130.4 (d), 130.3 (d), 130.8 (d), 132.3 (s), 137.9
(s), 142.1 (s), 142.7 (d), 147.6 (d), 198.3 (s); m/z (ES) 297.1864 (M
+ H+, C20H25O2 requires 297.1854).
=
PhCH ), 6.78 (1H, dd, J 8.5 and 3.0 Hz, CH3OCCHCH), 7.00
(1H, d, J 8.5 Hz, CH3OCCHCH), 7.26–7.38 (5H, m, 5 × PhH);
dC (100 MHz, CDCl3) (major diastereoisomer) 21.4 (t), 24.7 (t),
24.8 (t), 27.6 (q), 31.2 (t), 36.1 (d), 36.9 (t), 43.4 (s), 45.7 (d), 52.6
(d), 55.2 (q), 112.4 (d), 113.3 (d), 127.8 (2C d), 127.9 (d), 128.5
(d), 128.7 (s), 129.0 (2C d), 135.3 (d), 136.9 (s), 140.7 (s), 144.0
(s), 157.4 (s), 205.8 (s); (minor diastereoisomer) 21.8 (t), 23.7 (t),
24.2 (q), 25.9 (t), 29.1 (t), 40.7 (s), 42.9 (d), 46.0 (t), 46.7 (d), 47.3
(d), 55.2 (q), 110.6 (d), 114.4 (d), 124.2 (d), 127.7 (2C d), 127.8
(d), 129.0 (2C d), 131.6 (s), 135.0 (d), 136.6 (s), 138.7 (s), 142.6 (s),
158.0 (s), 206.1 (s); m/z (ES) 373.2155 (M + H+, C26H29O2 requires
373.2162).
Benzylidene substituted bridged tricycle 77a.
A solution
of tri-n-butyltin hydride (107 ll, 0.4 mmol) and 2,2ꢀ-
azobis(isobutyronitrile) (32 mg, 0.2 mmol) in degassed benzene
(13 ml), was added dropwise, over 8 h, via syringe pump to a
stirred solution of the iodide 72a (130 mg, 0.33 mmol) and 2,2ꢀ-
azobis(isobutyronitrile) (16 mg, 0.10 mmol) in degassed benzene
◦
(130 ml), at 80 C under an argon atmosphere. The mixture was
heated under reflux for 12 h, then cooled to room temperature and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica (5–10% Et2O, 95–90% petrol) to give
the bridged tricyclic ketone 77a (38 mg, 35%) as a colourless
oil (inseparable mixture of diastereoisomers in a 2 : 1 ratio);
mmax(sol CHCl3)/cm−1, 1694, 1614; dH (400 MHz, CDCl3), (major
diastereoisomer) 1.40 (3H, s, CH3), 1.48–1.89 (6H, m), 1.98–2.24
(3H, m), 2.68 (1H, app td, J 15.5 and 2.5 Hz, ArCHaHb), 2.94
(1H, app dt, J 15.5 and 3.5 Hz, ArCHaHb), 3.28 (1H, app dt,
Phenolic bridged tricycle 77c. Boron tribromide (50 ll,
0.53 mmol) was added dropwise, to a stirred solution of the
tricycle 77b (50 mg, 0.13 mmol) in dichloromethane (10 ml) at
−78 ◦C, under a nitrogen atmosphere. The solution was warmed
to room temperature slowly over 13 h, and then quenched with
water (50 ml). The separated aqueous phase was extracted with
1786 | Org. Biomol. Chem., 2007, 5, 1776–1788
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©

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dichloromethane (3 × 50 ml) and the combined organic extracts
were dried and concentrated in vacuo. The residue was purified by
flash column chromatography, (10% Et2O, 90% petrol) to give a 2 :
1 mixture of diastereoisomers of the phenol 77c (23 mg, 48%) as a
viscous liquid solid. Crystallisation from diethyl ether and pentane
gave the major diastereoisomer as colourless crystals, mp 195–
196 ◦C; mmax(sol CHCl3)/cm−1, 3597, 1693, 1608; dH (400 MHz,
CDCl3) (major diastereoisomer) 1.39 (3H, s, CH3), 1.46–1.62 (3H,
m), 1.69–1.85 (3H, m), 2.01–2.20 (3H, m), 2.63 (1H, app td, J 15.5
and 3.5 Hz, ArCHaHb), 2.85 (1H, app dt, J 15.5 and 3.0 Hz,
21.5 (t), 23.4 (t), 24.8 (t), 27.0 (q), 31.1 (t), 36.2 (d), 37.0 (t),
43.4 (s), 44.3 (d), 51.2 (d), 55.2 (q), 112.3 (d), 113.3 (d), 119.0 (t),
128.3 (d), 128.6 (s), 140.9 (s), 148.5 (s), 157.4 (s), 205.2 (s); (minor
diastereoisomer) 21.8 (t), 22.3 (t), 24.4 (q), 25.9 (t), 29.1 (t), 40.1
(s), 41.7 (d), 44.7 (t), 46.1 (d), 46.5 (d), 55.3 (q), 110.6 (d), 114.4 (d),
119.7 (t), 127.8 (d), 131.6 (s), 138.7 (s), 146.2 (s), 158.0 (s), 205.3
(s); m/z (ES) 319.1669 (M + Na+, C20H24O2Na requires 319.1674).
Acknowledgements
=
ArCHaHb), 3.19 (1H, app d, J 10.0 Hz, O CCH), 3.31 (1H, dd, J
10.0 and 3.0 Hz, ArCH), 4.71 (1H, br s, OH), 6.62 (1H, d, J 2.5 Hz,
HOCCHC), 6.66 (1H, dd, J 8.5 and 2.5 Hz, HOCCHCH), 6.89
We thank the EPSRC for postgraduate studentships (to DAS and
NMT), and AstraZeneca and Pfizer Ltd for financial support.
We also thank Dr A. J. Blake for X-ray crystal structure
determinations, and Philip Jones and L. Krishnakanath Reddy
for their earlier contributions to this project.
=
(1H, s, PhCH ), 7.11 (1H, d, J 8.5 Hz, HOCCHCH), 7.27–7.36
(3H, m, 3 × PhH), 7.42 (2H, app d, J 7.5 Hz, 2 × PhH); (minor
diastereoisomer) 1.26 (3H, s, CH3), 1.47–1.81 (6H, m), 1.95–2.13
=
(3H, m), 2.79 (1H, app d, J 10.0 Hz, O CCH), 2.93–2.99 (2H,
m, ArCH2), 3.30 (1H, dd, J 10.0 and 2.0 Hz, ArCH), 5.25 (1H,
References
br s, OH), 6.59 (1H, d, J 2.5 Hz, HOCCHC), 6.65 (1H, dd, J 8.5
1 See, for example: F. Marion, J. Coulomb, A. Servais, C. Courillon,
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=
and 2.5 Hz, HOCCHCH), 6.71 (1H, s, PhCH ), 6.92 (1H, d, J
8.5 Hz, HOCCHCH), 7.25–7.39 (5H, m, 5 × PhH); dC (100 MHz,
CDCl3) (major diastereoisomer) 21.4 (t), 24.7 (t), 24.9 (t), 27.6 (q),
31.0 (t), 36.1 (d), 37.0 (t), 43.5 (s), 45.7 (d), 52.6 (d), 113.7 (d),
114.8 (d), 127.8 (2C d), 127.9 (d), 128.7 (d), 128.8 (s), 129.0 (2C d),
135.4 (d), 137.0 (s), 141.0 (s), 144.0 (s), 153.3 (s), 205.9 (s); (minor
diastereoisomer) 21.8 (t), 23.8 (t), 24.3 (q), 25.9 (t), 28.9 (t), 40.7
(s), 43.0 (d), 46.0 (t), 46.8 (d), 47.3 (d), 112.3 (d), 115.7 (d), 127.7
(s), 127.8 (2C d), 128.0 (d), 128.7 (d), 128.9 (2C d), 135.3 (d), 138.1
(s), 139.3 (s), 144.5 (s), 154.1 (s), 206.7 (s); m/z (ES) 359.1999 (M
+ H+, C25H27O2 requires 359.2006).
Methylidene substituted methoxy bridged tricycle 82. A so-
lution of tri-n-butyltin hydride (107 ll, 0.40 mmol) and 2,2ꢀ-
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(14 ml), was added dropwise over 8 h via syringe pump, to a
stirred solution of the iodide 72b (140 mg, 0.33 mmol) and 2,2ꢀ-
azobis(isobutyronitrile) (35 mg, 0.21 mmol) in degassed heptane
◦
6 For example: E. J. Corey and S. Lin, J. Am. Chem. Soc., 1996, 118,
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(140 ml), at 90 C under an argon atmosphere. The mixture was
heated under reflux for a further 12 h, then allowed to cool to room
temperature and concentrated in vacuo. The residue was purified
by flash column chromatography on silica (2–10% Et2O, 98–90%
petrol) to give the bridged tricyclic ketone 82 (18 mg, 18%) as
an inseparable mixture of diastereoisomers in a 2 : 1 ratio, as a
colourless oil, mmax(sol CHCl3)/cm−1, 1695, 1611; dH (400 MHz,
CDCl3), (major diastereoisomer) 1.31 (3H, s, CH3), 1.50–1.83
(6H, m), 1.98–2.14 (3H, m), 2.62 (1H, app td, J 14.5 and 3.0 Hz,
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=
(1H, app dd, J 9.0 and 3.0 Hz, and 2.5 Hz, O CCH), 3.32 (1H,
dd, J 10.5 and 3.0 Hz, ArCH), 3.79 (3H, s, OCH3), 5.43 (1H,
=
=
d, J 1.0 Hz, CHaHb), 6.23 (1H, d, J 1.0 Hz, CHaHb), 6.69
(1H, d, J 2.5 Hz, CH3OCCHC), 6.75 (1H, dd, J 8.5 and 2.5 Hz,
CH3OCCHCH), 7.16 (1H, d, J 8.5 Hz, CH3OCCHCH); (minor
diastereoisomer) 1.20 (3H, s, CH3), 1.55–1.95 (6H, m), 1.98–2.18
=
(3H, m), 2.52 (1H, app d, J 9.0 Hz, O CCH), 2.95 (2H, app t,
J 8.5 Hz, ArCH2), 3.26 (1H, dd, J 9.0 and 1.5 Hz, ArCH), 3.78
=
(3H, s, OCH3), 5.33 (1H, d, J 1.0 Hz, CHaHb), 6.19 (1H, d,
=
J 1.0 Hz, CHaHb), 6.68 (1H, d, J 3.0 Hz, CH3OCCHC), 6.76
(1H, dd, J 8.0 and 3.0 Hz, CH3OCCHCH), 6.98 (1H, d, J 8.0 Hz,
CH3OCCHCH); dC (100 MHz, CDCl3) (major diastereoisomer)
This journal is
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Org. Biomol. Chem., 2007, 5, 1776–1788 | 1787
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1788 | Org. Biomol. Chem., 2007, 5, 1776–1788
This journal is
The Royal Society of Chemistry 2007
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