A flexible, unified radical-based approach to polycyclic structures

Article abstract of DOI:10.1039/c1ob00024a

Cis- and trans-decalins, trans-perhydroazulenes, and [5.3.1]-bicyclo- undecanone scaffolds can be readily constructed starting from unsaturated ketones and using the degenerative xanthate transfer technology to accomplish unusual and otherwise difficult r

Full text of DOI:10.1039/c1ob00024a

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 3396
www.rsc.org/obc
PAPER
A flexible, unified radical-based approach to polycyclic structures†‡
Rama Heng and Samir Z. Zard*
Received 5th January 2011, Accepted 9th February 2011
DOI: 10.1039/c1ob00024a
Cis- and trans-decalins, trans-perhydroazulenes, and [5.3.1]-bicyclo-undecanone scaffolds can be readily
constructed starting from unsaturated ketones and using the degenerative xanthate transfer technology
to accomplish unusual and otherwise difficult radical cyclisations.
Introduction
Terpenes exhibit an astonishing diversity of structures. The
intricate polycyclic carbon framework decorated with various
oxygen-based functional groups found in many members of this
large family of natural products has attracted much attention
from synthetic organic chemists.1 Some examples are displayed
in Fig. 1. Essentially all the techniques for ring construction have
been employed in the course of these synthetic endeavours. While
the advent of efficient and practical metathesis catalysts has all
but solved most of the difficulties associated with the formation
of rings of nearly all sizes,2 it still seemed worthwhile exploring
other routes to polycyclic scaffolds containing six-, seven-, and
eight-membered rings, since these arrangements are quite frequent
in terpenes. The possibility of introducing different substitution
patterns in comparison with previous approaches could in some
cases simplify the synthetic planning.
Radical reactions have had a strong impact on the synthesis
Fig. 1 Examples of polycyclic terpenes.
of terpenes, especially as regards the formation of five-membered
rings. In this respect, the spectacular and pioneering synthesis
of hirsutene, a linear triquinane, by Curran and co-workers,3
may be considered as an important milestone. The efficiency of
radical-based methods for the formation of polyquinanes and
other terpenes containing cyclopentane motifs derives from the
fast rate of the 5-exo ring closure, allowing the cyclisation step,
under judicious experimental conditions, to compete successfully
with premature capture of the uncyclised radical.
This can be seen in Scheme 1 for the case of the now classical
stannane mediated processes.4 In the case of the parent 5-hexen-1-
yl radical 1, the 5-exo ring closure leading to 3 is sufficiently rapid
to overtake undesired bimolecular reduction by the stannane to
give 2, as long as medium is dilute or the stannane is added slowly,
Scheme 1 General outline of radical cyclisations.
either drop-wise or by the use of a syringe pump, so as to keep
its concentration low. Furthermore, the 5-exo cyclisation is fifty
times faster than the corresponding 6-endo cyclisation, so that
competition from the latter mode is generally minimal. In contrast,
the formation of a 6-membered ring 6 (n = 1) from 4 (n = 1) by
a 6-exo closure is hampered by the intrinsically sluggish rate of
cyclisation favouring premature reduction to give 5 (n = 1), and
by a serious competition both from the 7-endo mode leading to
7 (n = 1) and from an allylic hydrogen abstraction leading to 8
(n = 1).5 Clearly, access to six-membered rings by either a 6-endo
Laboratoire de Synthe`se Organique (CNRS UMR 7652), Ecole Polytech-
nique, 91128, Palaiseau, France. E-mail: zard@poly.polytechnique.fr; Fax: +
33 16933 5972; Tel: 33 16933 5971
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob00024a
‡ This paper is dedicated with respect to the memory of our dear friend,
Professor Athel L. J. Beckwith.
3396 | Org. Biomol. Chem., 2011, 9, 3396–3404
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
or a 6-exo radical ring closure is a much more risky strategy. The
situation for the construction of seven-membered and especially
eight-membered rings (6, 7, n = 2, 3) is even more difficult and
problematic. Consequently, successful examples in this category
are far less frequent.5,6
We now report what appears to be a reasonably general
approach to polycyclic structures featuring the direct formation
of six-, seven-, and eight-membered rings. It hinges on providing
the radical with sufficient lifetime to undergo slow cyclisation
processes and on using stabilised acetonyl radicals to limit the
untoward competing allylic hydrogen abstraction.
Results and discussion
We have developed over the past years the reversible addition-
fragmentation-transfer of xanthates and related derivatives.7 In
this system, depicted in simplified form in Scheme 2, the reaction of
radicals R∑ with their xanthate precursor 9 is a degenerate process
that not only does not consume radicals R∑, but the adducts, 10,
are rather un-reactive species and act as a convenient reservoir
for radicals R∑. This eliminates a major competing pathway and
provides the radicals with a much longer effective lifetime, even
under concentrated conditions. This is in stark contrast to most
other radical methods, and especially those based on triorganotin
hydrides. It becomes now possible to contemplate accomplishing
more difficult radical transformations, such as an intermolecular
addition to an un-activated alkene 11 to give a new xanthate 12,
as shown on Scheme 2.
Scheme 3 A convergent access to decalins.
eventually the substituents on the cyclohexenone ring (including
its size). (b) In the likely event the intermediate adduct radical
16 reacts faster with the xanthate precursor 15 than undergo
the desired cyclisation, this will be of no consequence, since the
xanthate exchange process is reversible and it is always possible
to go back to radical 16 under conditions more propitious for
ring closure. (c) There are no readily accessible allylic hydrogens
that can cause radical translocation, and competition from a 7-
endo pathway is very unlikely because of the unacceptable strain
in attaining the transition state. (d) The presence of the xanthate
in the final product is a very valuable synthetic asset, since it can
be modified in almost infinite ways through the exceedingly rich
chemistry of sulfur-based functional groups.8 (e) Finally, no heavy
metals are involved, and the reagents and starting materials are
readily available.
The synthesis of xanthate 15 could be accomplished readily
in 79% overall yield from 2-cyclohexenone. Its addition to
vinyl pivalate and concomitant cyclisation proceeded reasonably
efficiently, considering the number of discrete steps involved, to
give adduct 20 as a mixture of epimers 20a and 20b (85 : 15) in
42% yield (Scheme 4). Both had the cis-decalin framework and
differed only in the stereochemistry of the carbon bearing the
pivaloyloxy group. The cis-junction could be ascertained from the
small coupling constant of the hydrogen atom at the junction
with that on the carbon bearing the xanthate group, indicating
an equatorial disposition for both. The formation of a cis-decalin
is in line with earlier observations.9 NMR analysis also indicated
that in the major product, the pivaloyloxy group occupies an exo-
equatorial position, and in both compounds the xanthate group
stood in what appears to be the less hindered exo-axial position. In
an equatorial orientation, the bulky O-neopentyl xanthate would
come into conflict with the axial substituent (hydrogen or pivalate)
on the adjacent ring on C-6 (Scheme 4).
Scheme 2 Simplified mechanism for the xanthate transfer process.
Formation of six-membered rings
For our first approach to decalin structures, we exploited this prop-
erty and considered the general route outlined in Scheme 3. Thus,
starting from a cyclohexenone, addition of 1-ethoxy-vinyllithium
would give enol ether 13, which should be easily brominated
to afford bromoketone 14. Displacement of the bromine with
readily available sodium O-neopentyl xanthate would lead to
the required precursor 15, which, hopefully, would undergo the
desired exo cyclisation to give decalin 19. The choice of the O-
neopentyl xanthate over the more ubiquitous O-ethyl derivative
was dictated by its simpler NMR signature and consequently easier
determination of isomeric ratios. The advantages of this strategy
are numerous: (a) It is highly flexible and convergent, and diversity
can be easily introduced by simply modifying the alkene partner or
By using a symmetrical 1,1-disubstituted alkenes 21 and 23 as
the olefinic trap, only one isomer of the corresponding cyclised
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3396–3404 | 3397
©

View Article Online
Scheme 5 Silicon substituted cis-decalins.
strategy is to modify the structure of the starting material and to
rely on an intramolecular process, as pictured in Scheme 6.
Scheme 4 Examples of cis-decalin syntheses.
products 22 and 24 were observed, albeit in modest yields. This
nevertheless simplified parts of the NMR spectra and allowed us
to confirm that the xanthate group occupies the axial position and
that the ring junction is indeed of the cis-type. For convenience, the
liquid 2-ethyl-butene 21 was used instead of the more volatile but
more interesting isobutene, which would have required the use of
pressure resistant sealed tubes. Isobutene would have furnished
decalins with a geminal dimethyl motifs frequently found in
terpenes.1
No attempts were made to improve the yields, but it is
nonetheless noteworthy that quaternary centres could be so easily
introduced. The limits of this strategy were however uncovered
when the addition-cyclisation was attempted using trimethyl
vinylsilane as the olefinic component (Scheme 5). While the first
addition proceeded efficiently to give the expected adduct 25 in
68% yield, no conditions could be found to induce a clean ring-
closure into 26, either with transfer of the xanthate group or
with concomitant reduction. This is in contrast to the sequence
involving the homologous allyl trimethylsilane, where addition
and reductive cyclisation could be accomplished in an overall yield
of 65% by treatment of the crude product 27 from the addition
step with a stoichiometric amount of peroxide in refluxing 2-
propanol.10
Scheme 6 Synthesis of trans-decalins.
Addition of 1-ethoxy-vinyllithum to 2-allylcyclohexanone 29
took place from the least hindered side to give the cis-alcohol 30.
Bromination furnished bromoketone 31 and displacement with
potassium O-ethyl xanthate provided the desired precursor 32
in 65% overall yield. Because of the relative trans-disposition of
the allyl side-chain and the radical bearing acetyl unit, as well
Another limitation of the present approach is the difficulty
in introducing a substituent in position-7. With a few notable
exceptions, 1,2-substituted alkenes tend to be poor partners in
intermolecular radical additions. The placement of a substituent on
position-7 has therefore to be done at a later stage. An alternative
3398 | Org. Biomol. Chem., 2011, 9, 3396–3404
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
as the existence of a somewhat rigidifying hydrogen bonding
between the hydroxy and ketone groups, it was not obvious
from the outset if the ring closure of radical 33 would proceed
by a 7-endo mode to 34 or by a 6-exo route to 35, or both.
In the event, only the 6-exo-derived product 36 was observed
upon exposure of xanthate 32 to the action of the peroxide. It
was obtained in 60% yield as a 4 : 1 mixture of epimers. The
relative configuration was established by repeating the lauroyl
mediated cyclisation of xanthate 32 and reducing the crude
product with triethylammonium hypophosphite to give the same
4 : 1 ratio of methyldecalinone 37 in 54% overall yield (Scheme 6).11
Examination of the NMR spectra revealed for the major epimer
a large 12–13 Hz coupling constant between the hydrogen on C-7
and the axial H on C-8, indicating an axial disposition for the
former. The methyl group must therefore be equatorial, as in 37e.
For the minor epimer, a 6–7 Hz coupling constant was observed
between the hydrogen on C-7 and the axial H on C-8, indicating an
equatorial disposition for the former, as in 37a. Interestingly, when
xanthate 32 was exposed to triethylammonium hypophosphite
and AIBN in refluxing dioxane, the cyclised-reduced material 37
was obtained directly in 50% yield along with reduced, but un-
cyclised product 38 (observed by NMR but not quantified). The
yield of compound 37 was higher (66%) when the slower reducing
combination of 2-propanol and stoichiometric amounts of lauroyl
peroxide was used for the simultaneous cyclisation and reductive
dexanthylation.
Scheme 7 Synthesis of a perhydroazulene.
Formation of seven-membered rings
decisive advantages of the xanthate technology when dealing with
sluggish radical transformations, such as the 7-endo cyclisation.
As our study was in progress, Ollivier, Santelli, and their co-
workers reported the 6-endo cyclisation of xanthate 44 into trans-
hydrindane 45 in good yield, as part of their synthetic work
on steroids.12 This gratifying result clearly demonstrates that the
same strategy may be employed to access both hydrindanes and
perhydroazulenes.
In the light of these observations, it became interesting to see
if a trans-hydrindane could be made by the same approach.
To this end, 2-allylcyclopentanone 39 was prepared from 2-
methoxycarbonyl-cyclopentanone, as shown in Scheme 7, and
subjected to the usual sequence leading to xanthate 40a,b in 56%
overall yield without purification of the intermediates. In this
case, the addition of the 1-ethoxy-vinyllithium did not proceed
with high stereoselectivity and significant amounts of the trans-
isomer 40b were observed. Exposure of xanthate 40a to lauroyl
peroxide in refluxing ethyl acetate did not afford any hydrindane
product but gave instead perhydroazulenone 41, which, without
purification, was reduced with hypophosphite into ketone 42 in
73% overall yield. In this system, clearly, the 7-endo ring-closure
mode is favoured over the 6-exo pathway. The perhydroazulene
system is a central architecture in numerous terpene families:
guainolides, pseudoguainolides, carotanes, aromadendranes, etc.,
with hundreds of members (e.g. a-guaiene and confertin in Fig.
1). The present approach to this motif is straightforward and very
concise.
In order to have a feel for the rate of the 7-endo cyclisation,
we subjected xanthate 40a to the action of triethylammonium
hypophosphite. Under these conditions, a 1 : 2 mixture of per-
hydroazulenone 42 and reduced but uncyclised material 43 was
obtained in 95% combined yield. By using the slower reducing 2-
propanol/lauroyl peroxide, an improved ratio of 1 : 1 of 42:43 was
produced in equally good combined yield (87%). The application
of the xanthate transfer process prior to performing the reduction
is clearly a superior tactic, for it ensures that little or no premature
reduction takes place. This example highlights the unique and
B Formation of eight-membered rings
We finally considered the more difficult case of constructing
eight-membered rings, which are also common in terpenes (e.g.
basmanes, taxanes, fusicoccanes etc.). In a model study, we had
found that it was possible using the xanthate transfer to form the
eight-membered ring present in pleuromutilin (Fig. 1),13 but we
had built on a fairly rigid template, which made the ring-closure
easier. It was not therefore obvious that success could be attained
on a more flexible framework, such as 47b, prepared in the usual
manner from well-known ketone 46. The directing effect of the
allyl group was less effective in this case, and an almost equal yield
of epimers 47a and 47b were obtained from the ionic sequence
(Scheme 8).
Radical 48 derived from xanthate 47b exists mostly in the
chair conformation, where the two bulkiest substituents are in
the less congested equatorial orientation. In this disposition, the
radical is too far from the alkene and cannot undergo the desired
addition. For cyclisation to occur, the radical has to adopt the less
stable conformation with the reacting partners in a 1,3-diaxial
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3396–3404 | 3399
©

View Article Online
Experimental
General details
Anhydrous THF was obtained by distillation from sodium-
benzophenone under nitrogen. Infrared spectra were recorded as
solutions in CCl4 using CaF2 cells, on a Perkin–Elmer FT 1600.
Absorption maxima (nmax) are reported in wavenumbers (cm1)
and only selected peaks are reported. Magnetic resonance spectra
were recorded at ambient temperature on a Bruker AMX 400
instrument. Proton magnetic resonance spectra (1H NMR) were
recorded at 400 MHz and coupling constants (J) are reported to
0.5 Hz. Carbon magnetic resonance spectra (13C NMR) were
recorded at 100.6 MHz. Chemical shifts (dH, dC) are quoted in
parts per million (ppm) and are referenced to the residual solvent
peak. High-resolution mass spectra were recorded by positive
electron impact ionization (EI +) at 70 eV on a JEOL JMS-
GCmate II mass spectrometer. The quoted masses are accurate
to 5 ppm.
General procedure A for the synthesis of the xanthates
To a stirred solution of ethyl vinyl ether (5 n mmol) in freshly
distilled THF (2 n ml) under nitrogen and at - 78 ◦C, was added
drop-wise over 10 min tert-butyl lithium (~1.35 M in pentane,
2 n mmol). After 15 more minutes, the acetone/dry ice bath was
replaced by a water/ice bath, and stirring was kept for 15 min.
The flask was cooled back to - 78 ◦C, and a solution of the
cycloalkanone (n mmol) in distilled THF (2 n ml) was added
drop-wise over 10 min. The mixture was allowed to warm up to
room temperature, and stirred for an additional 2 h. Saturated
ammonium chloride and diethyl ether were added to quench the
reaction. The aqueous layer was then extracted with diethyl ether,
and the combined organic layers were washed with brine, dried,
and then concentrated under reduced pressure, yielding pure ethyl
vinyl ether adduct.
The ethyl vinyl ether adduct (n mmol) was then dissolved in
a mixture of acetonitrile/water (9 : 1) (2 n mL) under nitrogen
in an ice water bath, and a solution of N-bromosuccinimide
(1.1 n mmol) in acetonitrile/water (9 : 1) (2 n mL) was then added.
Stirring was kept for 20 more minutes, and the mixture was then
partitioned between diethyl ether and water. The organic layer
was then washed with brine, and dried over anhydrous MgSO4.
Filtration and removal of the solvent under reduced pressure, gave
the a-bromoketone.
Scheme 8 Example of an 8-endo cyclisation.
arrangement that is propitious for interaction, but also more
crowded (Scheme 8). This adds a further constraint to an already
sluggish transformation. We were therefore relieved to find that
despite the unfavourable equilibrium, the ring closure did take
place in acceptable yield. Thus treatment of 47b with lauroyl
peroxide followed by reductive dexanthylation with hypophosphite
afforded [5.3.1]-bicyclo-undecanone 50 in 53% overall yield. It
is interesting to note that direct reductive cyclisation using 2-
propanol/lauroyl peroxide furnished only a small yield (24%) of
bicylic ketone 50; the major product was methyl ketone 51 (63%)
arising from premature hydrogen atom abstraction by radical 48.
This illustrates another instance where proceeding by way of the
xanthate transfer product, 49 in this case, circumvents premature
reduction and allows the desired radical cyclisation to take place
satisfactorily.
Conclusions
The crude bromoketone (n mmol) was then stirred in acetone
(1.5 n mL) under nitrogen at 0 ◦C, and sodium O-neopentyl
xanthate or potassium O-ethyl xanthate (1.2 n mmol) was then
added. After one hour at 0 ◦C, the mixture was partitioned between
diethyl ether and water. Brine was added to the aqueous layer,
which was then extracted twice with diethyl ether. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and the solvent removed in vacuo to afford the
crude xanthate, which was purified by chromatography.
This preliminary study provides the outlines of what appears to be
a very powerful, yet concise and highly flexible, approach to both
fused and bridged polycyclic structures, with various combinations
of five-, six-, seven-, and eight-membered rings. The relatively long
lifetime of radicals generated through the degenerative xanthate
transfer process provides a convenient and experimentally very
practical method for overcoming the limitations imposed by in-
trinsically slow radical transformations, and opens thus numerous
synthetic opportunities. In the examples shown, the xanthate
group was reductively removed to simplify characterisation, but
its presence in the cyclised product, in addition to the very
useful vicinal hydroxy-ketone moiety, constitutes a tremendous
springboard for the introduction of further substituents and
functional groups.
O-(2,2-Dimethyl-propyl)-S-[2-(1-hydroxy-cyclohex-2-enyl)-2-oxo-
ethyl] dithiocarbonate 15
Following general procedure A, the sequence was carried out using
2-cyclohexenone (1.5 mL, 15 mmol) and sodium O-neopentyl
3400 | Org. Biomol. Chem., 2011, 9, 3396–3404
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
xanthate. The crude xanthate was purified by column chromatog-
raphy using petroleum ether/ethyl acetate (9/1) as the eluent to
give pure xanthate 15 in 79% yield, dH (400 MHz, CDCl3) 6.20
(ddd, J = 2.7 Hz, J = 4.9 Hz, J = 9.8 Hz, 1H, CH CHC(OH)),
5.67 (td, J = 2.7 Hz, J = 9.8 Hz, 1H, CH CHC(OSi)), 4.40 (d,
J = 17.6 Hz, 1H, OCH2), 4.31 (d, J = 17.6 Hz, 1H, OCH2), 4.26
(s, 2H, SCH2), 3.47 (s, 1H, OH), 1.9–2.3 (m, 3H), 1.7–1.9 (m,
3H), 1.02 (s, 9H, CH2C(CH3)3); dC (100.6 MHz, CDCl3) 213.5
(C S), 205.9 (C O), 134.5 (CH CH), 125.7 (CH CH), 84.1
(OCH2), 76.5 (CqOH), 41.6 (SCH2), 33.6 (CH2CH2CH2), 31.8
(CH2C(CH3)3), 26.5 (C(CH3)3), 24.7, 18.0 (CH2CH2CH2); nmax
(CCl4)/cm-1 3494, 1722, 1227, 1068. HRMS (EI +), Found: M+,
302.1009. C14H22O3S2 requires M+, 302.1010.
J = 3.4 Hz, 1H, C(O)CH2eq), 2.18 (s, 1H, SCHCHeq), 1.90–2.15
(m, 3H, CH2-CH2-CH2, C(Et)2-CH2), 1.75–1.90 (m, 2H, CH2-
CH2-CH2, C(Et)2-CH2), 1.50–1.65 (m, 4H, 2 ¥ CH2-CH3), 1.35–
1.45 (m, 1H, CH2-CH2-CH2, C(Et)2-CH2), 1.17–1.32 (m, 2H,
CH2-CH2-CH2, C(Et)2-CH2), 1.00 (s, 9H, C(CH3)3), 0.94 (t, J =
7.4 Hz, 3H, CH2CH3), 0.76 (t, J = 7.5 Hz, 3H, CH2CH3); dC
(100.6 MHz, CDCl3) 217.1, 213.5 (C O, C S), 83.0 (COH),
76.5 (OCH2), 52.1 (SCH), 44.4 (SCHCH), 40.9 (C(Et)2), 33.9,
33.6, 30.3, 29.9, 29.1, 28.0, 15.9 (CH2CH2C O, CH2CH2CH2, 2 ¥
CH2CH3), 31.7 (C(CH3)3), 26.5 (C(CH3)3), 8.2, 8.0 (2 ¥ CH2CH3);
nmax (CCl4)/cm-1 3485, 1714, 1208, 1069. HRMS (EI +), Found:
M+, 386.1957. C20H34O3S2 requires, M+, 386.1949.
1-Acetoxymethyl-8-(2,2-dimethyl-propoxythiocar-bonylsulfanyl)-
4a-hydroxy-4-oxo-decahydro-naphthalen-1-ylmethyl acetate 24
General procedure B for the intermolecular addition and cyclisation
A solution of the xanthate (n mmol) and olefin (generally 3n or
4n mmol), in ethyl acetate (n mL), was refluxed under nitrogen
for 15 min. Dilauroyl peroxide (DLP) was then added in portions
of 5% every 90 min, until the reaction was over. The excess olefin
and the solvent were then removed in vacuo, giving crude adduct
compound. The crude was then diluted in ethyl acetate (10n mL),
and after being refluxed for 15 min under nitrogen, dilauroyl
peroxide was added in portions of 5% every 90 min, until complete
consumption of the starting material. Evaporation of the solvent
gave the crude cyclised compound.
Following general procedure B, the reaction was carried out using
xanthate 15 (76 mg, 0.25 mmol), acetic acid 2-acetoxymethyl-allyl
ester (172 mg, 1 mmol) as the olefin, and DLP (total of 75 mol%).
The crude product was purified by column chromatography using
petroleum ether/ethyl acetate (7/3) as eluent to give bicyclic
product 24 in 37% yield, dH (400 MHz, CDCl3) 4.70 (d, J = 11.5 Hz,
1H, CH2OAc), 4.64 (m, 1H, SCH), 4.1–4.3 (m, 5H, 2 ¥ CH2OAc,
SC(S)OCH2), 2.76 (dt, J = 5.1 Hz, J = 14.8 Hz, 1H, CH2-CH2ax),
2.4–2.5 (m, 2H, SCH-CH, CH2-CH2eq), 2.14 (s, 3H, CH3CO), 2.05
(s, 3H, CH3CO), 2.2 (m, 1H) + 1.7 (m, 1H) (SCHCH2), 2.0–2.1
(m, 2H, CH2), 1.6 (m, 1H) + 1.45 (m, 1H) (CH2), 1.2–1.3 (m,
2H, CH2), 1.00 (s, 9H, C(CH3)3); dC (100.6 MHz, CDCl3) 216.6,
211.9 (C O, C S), 170.7, 170.5 (2 ¥ O–C O), 83.3 (OCH2),
75.8 (COH), 67.5, 63.2 (2 ¥ OCH2), 51.6 (SCH-CH), 44.3 (SCH),
42.3 (Cq(CH2OAc)2), 34.1, 32.8, 29.6, 28.9 (2 ¥ CH2-CH2), 31.8
(CH2C(CH3)3), 26.5 (C(CH3)3), 20.85, 20.81 (2 ¥ CH3CO), 15.8
(CH2CHS); nmax (CCl4)/cm-1 3480, 1749, 1718, 1223, 1069. HRMS
(EI +), Found: M+, 474.1761. C22H34O7S2 requires, M+, 474.1746.
8-(2,2-Dimethyl-propoxythiocarbonylsulfanyl)-4a-hydroxy-4-oxo-
decahydro-naphthalen-1-yl 2,2-dimethyl-propionate 20
Following general procedure B, the reaction was carried out using
xanthate 15 (106 mg, 0.35 mmol), vinylpivalate (77 mL, 0.52 mmol)
as the olefin, and DLP (15 mol% at first, then 30 mol%). The
crude product was purified by column chromatography using
toluene/diethyl ether (97.5/2.5) as eluent to give bicyclic product
20 in 42% yield (mixed with 15% of axial pivalate), dH (400 MHz,
CDCl3) 5.37 (dt, J = 4.4 Hz, J = 11.2 Hz, 1H, CHaxOPiv), 4.35
(m, 1H, CHeqS), 4.19–4.28 (m, 2H, OCH2), 3.98 (s, 1H, OH),
2.74 (dt, J = 4.6 Hz, J = 14.9 Hz, 1H, COCH(ax)2), 2.54 (ddd,
J = 2.6 Hz, J = 6.1 Hz, J = 14.9 Hz, 1H, COCH(eq)2), 2.25–2.42
(m, 2H), 2.0–2.15 (m, 2H), 1.88–1.98 (m, 1H), 1.78–1.88 (m, 1H),
1.62–1.72 (m, 1H), 1.27–1.30 (m, 1H), 1.25 (s, 9H, C(CH3)3), 1.00
(s, 9H, C(CH3)3); dC (100.6 MHz, CDCl3) 217.3, 210.6 (C O,
O-(2,2-Dimethyl-propyl)-S-[4-(1-hydroxy-cyclohex-2-enyl)-4-oxo-
1-trimethylsilanyl-butyl] dithiocarbonate 25
Following the first part of general procedure B, the reaction was
carried out using xanthate 15 (302 mg, 1 mmol), DLP (30 mol%),
and vinyltrimethylsilane (1.5 mL, 10 mmol) as the olefin. The crude
product was purified by column chromatography using petroleum
ether/ethyl acetate (9/1) as eluent to give bicyclic product 25 in
68% yield as a 1 : 1 mixture of two diastereoisomers, dH (400 MHz,
CDCl3) 6.09 (ddd, J = 2.5 Hz, J = 5.2 Hz, J = 9.9 Hz, 1H, CH CH-
CH2, isomers 1/2), 5.45 (m, J = 9.9 Hz (d), 1H, CH CH-CH2,
isomers 1/2), 4.20–4.34 (m, 2H, SCSOCH2, isomers 1/2), 3.91,
3.89 (s, 1H, OH, isomers 1/2), 3.17 (dt, J = 3.8 Hz, J = 10.9 Hz,
1H, CHSi, isomers 1/2), 2.65–2.80 (m, 2H, CH2C O, isomers
1/2), 2.10–2.20, 1.95–2.08, 1.56–1.82 (m, 8H, CH2-CH2-CH2,
CH2CHSi, isomers 1/2), 1.00 (s, 9H, C(CH3)3, isomers 1/2), 0.10
(s, 9H, Si(CH3)3, isomers 1/2). dC (100.6 MHz, CDCl3) 216.7,
213.2 (C O, C S, isomers 1/2), 133.6,133.5, (C C, isomers
1/2), 126.13, 126.08 (C C, isomers 1/2), 83.6 (OCH2, isomers
1/2), 75.9 (COH, isomers 1/2), 36.2, 36.1 (CHSi, isomers 1/2),
34.9, 34.7 (CH2C O, isomers 1/2), 33.4, 33.3 (CH2, isomers 1/2),
31.9 (C(CH3)3, isomers 1/2), 26.5 (C(CH3)3, isomers 1/2), 24.8,
24.9 (CH2, isomers 1/2), 24.70, 24.69 (CH2, isomers 1/2), 18.1
(CH2, isomers 1/2), - 2.70, - 2.73 (Si(CH3)3), isomers 1/2); IR
C
S), 178.1 (O-C O), 83.2 (OCH2), 76.2 (COH), 68.3, 52.5,
44.9 (CH- CH- CH), 38.9 (COC(CH3)3), 33.7, 32.7, 30.4 (CH2),
31.7 (CH2C(CH3)3), 27.3 (CH2), 26.5 (CH2C(CH3)3), 25.8, 16.8
(CH2); nmax (CCl4)/cm-1 3482, 1725, 1215, 1067, 1150. HRMS (EI
+), Found: M+, 430.1851. C21H34O5S2 requires: M+, 430.1848.
S-(8,8-Diethyl-4a-hydroxy-5-oxo-decahydronaphthalen-1-yl)-O-
(2,2-dimethyl-propyl) dithiocarbonate 22
Following general procedure B, the reaction was carried out
using xanthate 15 (302 mg, 1.0 mmol), 2-ethyl-but-1-ene (490 mL,
4.0 mmol) as the olefin, and DLP (first 25 mol%, then 15 mol%).
The crude product was purified by column chromatography using
petroleum ether/diethyl ether (9/1) as eluent to give bicyclic
product 22 in 43% yield, dH (400 MHz, CDCl3) 4.39 (m, 1H,
SCHeq), 4.24 (m, 2H, OCH2), 3.83 (s, 1H, OH), 2.61 (dt, J =
4.7 Hz, J = 14.5 Hz, 1H, C(O)CH2ax), 2.38 (dt, J = 14.2 Hz,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3396–3404 | 3401
©

View Article Online
nmax (CCl4)/cm-1 3479, 1708, 1213, 1067. HRMS (EI +), Found:
O-Ethyl-S-(4a-hydroxy-4-oxo-decahydro-naphthalen-2-ylmethyl)
dithiocarbonate 36
M+, 402.1719. C19H34O3S2Si requires: M+, 402.1719.
General procedure C for the reductive cyclisation in isopropanol
Following general procedure D, the reaction was carried out using
xanthate 32 (150 mg, 0.5 mmol), and DLP (15 mol%), to give
crude cyclic compound 36. This crude material was purified by
column chromatography using petroleum ether/diethyl ether (8/2)
as eluent to give bicyclic product 36 in 60% overall yield as a 4 : 1
mixture of two diastereoisomers, dH (400 MHz, CDCl3) 4.63 (q,
J = 7.1 Hz, 1H, OCH2, isomers 1/2), 3.29 (dd, J = 6.7 Hz, J =
13.4 Hz, 1H, COCHax, isomer 2), 3.14 (d, J = 6.6 Hz, 2H, CH2S,
isomer 1), 3.06 (dd, J = 1.3 Hz, J = 7.8 Hz, 2H, CH2S, isomer 2),
2.8 (t, J = 12.9 Hz, 1H, COCHax, isomer 1), 2.47–2.56 (m, 1H,
COCHeq, isomer 2), 2.32–2.39 (m, 1H, COCHeq, isomer 1), 1.92–
2.22 (m, 2H, OH, CHCH2CH(CH2)4, isomers 1/2), 1.43–1.74 (m,
10H, CHCH2CH(CH2)4, isomers 1/2), 1.40 (t, J = 7.1 Hz, 3H,
OCH2CH3,isomers 1/2), 1.16–1.26 (m, 1H, CHCH2CH(CH2)4,
isomers 1/2); dC (100.6 MHz, CDCl3) 214.3, 211.3 (C O, C S),
76.0 (COH, isomer 2), 65.2 (COH, isomer 1), 70.1 (OCH2,
isomers 1/2), 44.6 (CHCOH, isomer 1), 42.7 (COCH2CHCH2,
isomer 1), 41.8 (COCH2CHCH2, isomer 1), 41.2 (COCH2CHCH2,
isomer 2), 41.1 (CHCOH, isomer 2), 38.9 (COCH2CHCH2, isomer
2), 37.9 (CHCH2S, isomer 1), 35.4 (CHCH2S, isomer 2), 33.0
((CH2)4CHCH2, isomer 1), 31.03 ((CH2)4CHCH2, isomer 1), 30.97
((CH2)4CHCH2, isomer 2), 30.4 ((CH2)4CHCH2, isomer 2), 27.22
((CH2)4CHCH2, isomer 1), 27.18 ((CH2)4CHCH2, isomer 2), 25.35
((CH2)4CHCH2, isomers 1/2), 20.8 ((CH2)4CHCH2, isomers 1/2),
13.7 (OCH2CH3, isomers 1/2); nmax (CCl4)/cm-1 3603, 1720, 1220,
1051. HRMS (EI +), Found: M+, 302.1022. C14H22O3S2requires:
M+, 302.1011,.
A solution of the xanthate (n mmol) in isopropanol (10 n ml)
was refluxed under nitrogen for 15 min. Dilauroyl peroxide was
then added in portion of 20% every 60 min, until the reaction was
complete. The solvent was then removed in vacuo, giving the crude
cyclic compound.
8a-Hydroxy-4-trimethylsilanylmethyl-octahydronaphthalen-1-one
28
Following the first part of general procedure B, the addition
reaction was carried out using xanthate 15 (135 mg, 0.45 mmol),
allyltrimethylsilane (572 mL, 3.6 mmol) as the olefin, and DLP
(15 mol%), giving crude adduct 27. Without purification, this
adduct was then transformed following general procedure C. The
crude product was purified by column chromatography using
petroleum ether/ethyl acetate (97.5/2.5) as eluent to give bicyclic
product 22 in 65% overall yield, dH (400 MHz, CDCl3) 3.93 (s, 1H,
OH), 2.66 (dt, J = 6.0 Hz, J = 14.4 Hz, 1H, CH2C O), 2.43 (ddd,
J = 2.4 Hz, J = 4.2 Hz, J = 14.1 Hz, 1H, CH2C O), 2.13–2.20 (m,
1H, CH2), 2.06–2.13 (m, 1H, CHCH2Si), 1.90 (dt, J = 4.4 Hz, J =
13.0 Hz, 1H, CH2C(OH)), 1.57–1.84 (m, 4H, 2 ¥ CH2), 1.46–1.54
(m, 1H, CH2), 1.40–1.44 (m, 1H, CHC(OH)), 1.34–1.40 (m, 1H,
CH2), 1.25–1.34 (m, 2H, CH2), 0.91 (dd, J = 2.6 Hz, J = 14.9 Hz,
1H, CH2Si), 0.23 (dd, J = 10.2 Hz, J = 14.9 Hz, 1H, CH2Si),
0.06 (s, 9H, Si(CH3)3); dC (100.6 MHz, CDCl3) 214.3 (C O),
77.7 (C-OH), 52.0 (CH-COH), 37.1, 35.2, 32.2 (3 ¥ CH2), 32.0
(CHCH2Si), 22.6, 21.2, 20.4, 19.7 (4 ¥ CH2), - 0.45 (Si(CH3)3);
n
max (CCl4)/cm-1 3486, 1711. HRMS (EI +), Found: M+, 254.1706.
8a-Hydroxy-3-methyl-octahydro-naphthalen-1-one 37e and 37a
C14H26O2Si requires: M+, 254.1702.
Following general procedure C for the reductive intramolecular
cyclisation in isopropanol, the reaction was carried out using
xanthate 32 (90 mg, 0.30 mmol). This crude material was purified
by column chromatography using petroleum ether/diethyl ether
(85/15) as eluent to give epimers 37e and 37a.
Epimer 37e (53% yield), dH (400 MHz, CDCl3) 2.77 (t, J =
12.8 Hz, 1H, CH2(ax)C O), 2.23 (ddd, J = 1.6 Hz, J = 4.1 Hz,
J = 12.7 Hz, 1H, CH2(eq)C O), 1.4–1.9, 1.24 (m, 13H), 1.01 (d,
J = 6.5 Hz, 3H, CH3); dC (100.6 MHz, CDCl3) 212.4 (C O),
75.3 (C-OH), 45.7 (CH2), 45.3 (CH-COH), 36.0 (CH2), 34.1 (CH-
CH3), 31.2, 27.4, 25.5 (3 ¥ CH2), 22.3 (CH3), 20.9 (CH2); nmax
(CCl4)/cm-1 3604, 1719. HRMS (EI +), Found: M+, 182.1315.
C11H18O2 requires: M+, 182.1307.
Epimer 37a (13% yield), dH (400 MHz, CDCl3) 3.27 (dd, J =
6.5 Hz, J = 12.8 Hz, 1H, CH2(ax)C O), 2.34–2.45 (m, 2H), 1.96–
2.04 (m, 2H), 1.35–1.75 (m, 8H), 1.15–1.35 (m, 2H), 0.97 (d, J =
7.3 Hz, 3H, CH3); dC (100.6 MHz, CDCl3) 77.2 (C-OH), 43.7
(CH2), 40.8 (CH-COH), 33.3, 31.2 (2 ¥ CH2), 30.5 (CH-CH3),
27.4, 25.5, 21.0 (3 ¥ CH2), 19.3 (CH3); nmax (CCl4)/cm-1 3604,
1719. HRMS (EI +), Found: M+, 182.1315. C11H18O2requires:
M+, 182.1307.
S-[2-(2-allyl-1-hydroxy-cyclohexyl)-2-oxo-ethyl]-O-ethyl
Dithiocarbonate 32
Following general procedure A for the formation of xanthate,
the reaction was carried out using 2-allyl-cyclohexanone (1.38 g,
10 mmol), and potassium O-ethyl xanthate, to give crude xanthate
32. This compound was purified by column chromatography using
petroleum ether/diethyl ether (9/1) as eluent to give pure xanthate
32 in 65% overall yield, dH (400 MHz, CDCl3) 5.71 (m, 1H,
CH CH2), 4.97–5.01 (m, 2H, CH CH2), 4.65 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.41 (d, J = 17.7 Hz, 1H, SCH2), 4.33 (d, J = 17.7 Hz,
1H, SCH2), 3.21 (s, 1H, OH), 1.85–1.95, 1.62–1.82, 1.28–1.36
(m, 11H, CH2-CH2-CH2-CH2-CH-CH2), 1.42 (t, J = 7.1 Hz, 3H,
CH2CH3); dC (100.6 MHz, CDCl3) 213.3 (C S), 207.6 (C O),
136.3 (CH CH2), 116.8 (CH CH2), 81.5 (COH), 70.8 (OCH2),
42.3 (SCH2), 42.1 (CH-COH), 36.3, 35.5, 26.7, 25.4, 20.7 (5 ¥
CH2), 13.7 (CH2CH3); nmax (CCl4)/cm-1 3490, 1717, 1229, 1054.
HRMS (EI +), Found: M+, 302.1001. C14H22O3S2 requires: M+,
302.1011.
General procedure D for the radical cyclisation
A solution of xanthate (n mmol) in ethyl acetate (10 n ml) was
refluxed under nitrogen for 15 min. Dilauroyl peroxide was then
added in portions of 5 mol% every 90 min, until the reaction was
complete. The solvent was then removed in vacuo, giving crude
cyclic compound.
2-Allylcyclopentanone 39
Methyl-2-oxocyclopentane carboxylate (2.6 mL, 20 mmol), was
stirred in acetone (50 mL) with dry potassium carbonate (11 g,
80 mmol) and allyl bromide (9 mL, 100 mmol). The mixture was
3402 | Org. Biomol. Chem., 2011, 9, 3396–3404
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
heated under reflux for 4 h. After filtration of the excess of salt,
water was added, and the mixture was extracted several times with
ethyl acetate. The organic layers were then washed with water,
brine, dried, and the solvent was removed under reduced pressure,
giving allylated cyclopentanone of sufficient purity for the next
step. This material was heated under reflux for 150 min in methanol
(48 mL) with a solution of hydrochloric acid (6N; 24 mL). Once
the reaction was complete, the mixture was partitioned between
diethyl ether and water. The organic layer was then washed with
water and brine, dried over anhydrous magnesium sulfate, and
the solvent removed under reduced pressure, giving previously
described,14 pure 2-allylcyclopentanone 39 in 95% yield.
3a-Hydroxy-octahydroazulen-4-one 42
Following general procedure D, the reaction was carried out using
xanthate 40a (58 mg, 0.2 mmol), and DLP (15 mol%), giving
crude cyclic compound 41. Without purification, this compound
was reduced following general procedure E. The crude product was
purified by column chromatography using petroleum ether/ethyl
acetate (85/15) as eluent to give pure title compound 42 in 73%
overall yield, dH (400 MHz, CDCl3) 2.74 (td, J = 4.8 Hz, J =
14.6 Hz, 1H, COCH2), 2.55 (m, 1H, COCH2), 2.27 (ddd, J =
8.0 Hz, J = 10.6 Hz, J = 13.9 Hz, 1H, CH2C-OH), 2.11 (s, 1H,
OH), 1.5–1.9/1.20–1.36 (m, 12H); dC (100.6 MHz, CDCl3) 214.6
(C O), 87.8 (C-OH), 48.1 (CH), 41.4 (CH2CO), 37.3, 30.8, 28.3,
27.9, 23.4, 20.8 (6 ¥ CH2); nmax (CCl4)/cm-1 3618, 1702. HRMS
(EI +),Found: M+, 168.1146. C10H16O2requires: M+, 168.1150.
S-[2-(2-allyl-1-hydroxy-cyclopentyl)-2-oxo-ethyl]-O-ethyl
dithiocarbonate 40a and 40b
S-[2-(3-Allyl-1-hydroxy-4,4-dimethylcyclohexyl)-2-oxoethyl]-O-
Following general procedure A, the reaction was carried out
using cyclopentanone 39 (980 mg, 5 mmol), potassium O-ethyl
xanthate and NCS (instead of NBS), to give crude xanthate
40. This compound was purified by column chromatography
using petroleum ether/diethyl ether (9/1) as eluent to give pure
xanthates 40a and 40b.
Xanthate 40a (45% yield), dH (400 MHz, CDCl3) 5.69 (tdd, J =
7.1 Hz, J = 10.1 Hz, J = 17.2 Hz, 1H, CH CH2), 5.02 (dd, J =
1.5 Hz, J = 17.1 Hz, 1H, CH CH(cis)2), 4.94 (dd, J = 1.1 Hz, J =
10.1 Hz, 1H, CH CH(trans)2), 4.63 (q, J = 7.1 Hz, 2H, OCH2CH3),
4.31 (s, 2H, SCH2), 3.02 (s, 1H, OH), 2.35 (ddd, J = 7.6 Hz, J =
11.0 Hz, J = 14. 6 Hz, 1H), 2.12–2.26 (m, 1H), 2.05–2.15 (m, 2H),
1.87–2.05 (m, 2H), 1.67–1.86 (m, 2H), 1.50–1.62 (m, 1H), 1.41 (t,
J = 7.1 Hz, 3H, CH2CH3); dC (100.6 MHz, CDCl3) 213.3 (C S),
207.1 (C O), 136.8 (CH CH2), 116.2 (CH CH2), 88.0 (COH),
70.8 (OCH2), 48.6 (CHC(OH)), 41.9 (SCH2), 39.8, 33.1, 30.4, 22.7
(4 ¥ CH2), 13.7 (CH2CH3); nmax (CCl4)/cm-1 3504, 1714, 1227,
1052. HRMS (EI +), Found: M+, 288.0854. C13H20O3S2requires:
M+, 288.0854.
Xanthate 40b (11% yield), dH (400 MHz, CDCl3) 5.71 (tdd, J =
6.7 Hz, J = 10.2 Hz, J = 17.0 Hz, 1H, CH CH2), 4.95–5.04 (m,
2H, CH CH2), 4.63 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.51 (d, J =
17.6 Hz, 1H, SCH2), 4.23 (d, J = 17.6 Hz, 1H, SCH2), 2.7–3.0,
(1H, OH), 2.2–2.3 (m, 1H), 1.97–2.17 (m, 3H), 1.72–1.90 (m, 4H),
1.47–1.60 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H, CH2CH3); dC (100.6
MHz, CDCl3) 213.7 (C S), 206.9 (C O), 136.7 (CH CH2),
116.3 (CH CH2), 89.5 (COH), 70.7 (OCH2), 52.2 (CHC(OH)),
44.0 (SCH2), 38.5, 34.5, 30.5, 21.7 (4 ¥ CH2), 13.7 (CH2CH3); nmax
(CCl4)/cm-1 3504, 1714, 1227, 1052. HRMS (EI +),Found: M+,
288.0854. C13H20O3S2 requires: M+, 288.0854.
ethyl dithiocarbonate 47a and 47b
Following general procedure A, the reaction was carried out
using 3-allyl-4,4-dimethylcyclohexanone (830 mg, 5 mmol), and
potassium O-ethyl xanthate, to give crude xanthate 47a and 47b as
a 3 to 2 mixture of two diastereoisomers, which could be separated
by column chromatography using petroleum ether/diethyl ether
(8/2) as the eluent.
Xanthate 47a, 26% yield, dH (400 MHz, CDCl3) 5.65–5.80 (m,
1H, CH CH2), 4.90–4.94 (m, 2H, CH CH2), 4.56 (q, J = 7.2 Hz,
2H, OCH2CH3), 4.31 (s, 2H, SCH2), 3.12 (s, 1H, OH), 2.32 (m,
1H), 1.88 (dt, J = 4.1 Hz, J = 13.8 Hz, 1H), 1.51–1.69, 1.40–
1.50 (m, 6H), 1.34 (t, J = 7.2 Hz, 3H, CH2CH3), 1.27 (td, J =
3.3 Hz, J = 13.5 Hz, 1H), 0.95 (s, 3H, C(CH3)2), 0.80 (s, 3H,
C(CH3)2); dC (100.6 MHz, CDCl3) 214.1 (C S), 204.7 (C O),
138.0 (CH CH2), 116.1 (CH CH2), 78.6 (COH), 70.7 (OCH2),
41.6 (SCH2), 42.2 (CH), 36.1, 34.9 (3 ¥ CH2), 32.2 (C(CH3)2), 31.8
(CH2), 29.1, 18.4 (C(CH3)2), 13.8 (CH2CH3); nmax (CCl4)/cm-1
3490, 1719, 1228, 1053. HRMS (EI +), Found: M+, 330.1321.
C16H26O3S2 requires: M+, 330.1324.
Xanthate 47b, 39% yield, dH (400 MHz, CDCl3) 5.65–5.80 (m,
1H, CH CH2), 4.90–4.94 (m, 2H, CH CH2), 4.56 (q, J = 7.2 Hz,
2H, OCH2CH3), 4.40 (d, J = 17.7 Hz, 1H, SCH2), 4.34 (d, J =
17.7 Hz, 1H, SCH2), 3.12 (s, 1H, OH), 2.14 (ddd, J = 2.4 Hz, J =
3.6 Hz, J = 13.6 Hz, 1H), 2.05 (dtd, J = 2.4 Hz, J = 4.1 Hz, J =
13.3 Hz, 1H), 1.51–1.69, 1.40–1.50 (m, 6H), 1.42 (t, J = 7.1 Hz, 3H,
CH2CH3), 1.27 (td, J = 3.3 Hz, J = 13.5 Hz, 1H, CH2-CH2/CH2-
CH-CH2), 0.95 (s, 3H, C(CH3)2), 0.86 (s, 3H, C(CH3)2); dC (100.6
MHz, CDCl3) 213.0 (C S), 207.4 (C O), 137.6 (CH CH2),
115.8 (CH CH2), 79.3 (COH), 70.4 (OCH2), 41.5 (SCH2), 40.0
(CH), 35.8, 35.0, 34.3 (3 ¥ CH2), 32.3 (C(CH3)2), 30.1 (CH2), 29.7,
18.2 (C(CH3)2), 13.5 (CH2CH3); nmax (CCl4)/cm-1 3490, 1719,
1228, 1053. HRMS (EI +), Found: M+, 330.1321. C16H26O3S2
requires: M+, 330.1324.
General procedure E for the reduction of the xanthates with H3PO2
A solution of the xanthate (n mmol), triethylamine (5.5 n mmol),
and hypophosphorous acid (50% in water; 5 n mmol) in dioxane
(12.5 n mL) was refluxed under nitrogen for 15 min. AIBN
(0.15 n mmol) in dioxane (0.4 n mL) was then added to the
solution, and reflux was kept for an additional one hour under
nitrogen. The resulting mixture was partitioned between ethyl
acetate and water. The organic layer was then washed with
brine, dried over anhydrous MgSO4, filtered, and the solvent was
removed in vacuo, giving the crude reduced product.
1-Hydroxy-8,8-dimethylbicyclo[5.3.1]undecan-2-one 50
Following general procedure D, the reaction was carried out using
xanthate 47b (30 mg, 0.09 mmol), and DLP (15 mol%), giving
crude bicyclic xanthate 49, which was then reduced following
general procedure E into bicyclic 50. Purification by column
chromatography using petroleum ether/diethyl ether (8/2) as
eluent gave compound 50 in 53% overall yield, dH (400 MHz,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3396–3404 | 3403
©

View Article Online
CDCl3) 3.12 (ddd, J = 3.9 Hz, J = 11.5 Hz, J = 13.7 Hz, 1H,
CH2C O), 2.43 (td, J = 2.8 Hz, J = 14.2 Hz, 1H, CH2C O),
2.18–2.25 (m, 2H), 1.94–2.08 (m, 2H), 1.82–1.94 (m, 2H), 1.6–
1.8 (m, 2H), 1.52–1.60 (m, 1H), 1.25–1.50 (m, 3H), 1.18–1.25 (m,
1H), 1.12 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.64–0.76 (m, 1H);
dC (100.6 MHz, CDCl3) 212.8 (C O), 74.5 (C-OH), 42.4 (CH),
36.4 (CH2), 32.6 (C(CH3)2), 31.8, 31.4, 31.1, 29.1 (4 ¥ CH2), 28.3
(CH3), 27.4 (CH2), 27.3 (CH3), 24.2 (CH2); nmax (CCl4)/cm-1 3589,
1709. HRMS (EI +), Found: M+, 210.1625. C13H22O2 requires: M+,
210.1620.
2 C. Samojlowicz, M. Bieniek and K. Grela, Chem. Rev., 2009, 109, 3708;
M. R. Buchmeister, Chem. Rev., 2009, 109, 303 and references there
cited.
3 D. P. Curran and D. M. Rakiewicz, J. Am. Chem. Soc., 1985, 107, 1448.
4 B. Giese, B. Kopping, T. Go¨bel, J. Dickhaut, G. Thoma, K. J. Kulicke
and F. Trach, Org. React., 1995, 48, 301For examples of recent radical
annulations, see:; B. Mitasev and J. A. Porco Jr., Org. Lett., 2009, 11,
2285; P. Panchaud and P. Renaud, J. Org. Chem., 2004, 69, 3205; W.
Zhang, Z. Luo, C. H.-T. Chen and D. P. Curran, J. Am. Chem. Soc.,
2002, 124, 10443; Q. Zhang, A. Rivkin and D. P. Curran, J. Am. Chem.
Soc., 2002, 124, 5774; K. Takasu, H. Ohsato, J. Kuroyanagi and M.
Ihara, J. Org. Chem., 2002, 67, 6001.
5 M. Newcomb in Radicals in Organic Synthesis, P. Renaud and M. P.
Sibi, eds; Wiley-VCH, Weinheim, 2001, Vol. 1, 317–336; M. Newcomb,
Tetrahedron, 1993, 49, 1151; A. L. J. Beckwith, Tetrahedron, 1981, 37,
3073.
1-(3-Allyl-1-hydroxy-4,4-dimethyl-cyclohexyl)-ethanone (51)
6 A. Srikrishna, Unusual Radical Cyclizations in Radicals in Organic
Synthesis, P. Renaud and M. P. Sibi, Eds, Wiley-VCH, Weinheim, 2001;
Vol. 2, pp.151–187.
7 For reviews of the xanthate transfer, see: S. Z. Zard, Angew. Chem., Int.
Ed. Engl., 1997, 36, 672; S. Z. Zard, Xanthates and Related Derivatives
as Radical Precursors in Radicals in Organic Synthesis, P. Renaud, M. P.
Sibi, Eds, Wiley-VCH, Weinheim, 2001; Vol. 1, pp. 90–108; B. Quiclet-
Sire and S. Z. Zard, Top. Curr. Chem., 2006, 264, 201; B. Quiclet-Sire
and S. Z. Zard, Chem.–Eur. J., 2006, 12, 6002; B. Quiclet-Sire and S. Z.
Zard, Pure Appl. Chem., 2011, 83, 519.
Following general procedure C, the reaction was carried out
using xanthate 47b (100 mg, 0.3 mmol), to give 51 mixed with
bicyclic compound 50. Purification of the crude mixture by column
chromatography using petroleum ether/diethyl ether (8/2) as
eluent gave compound 51 in 63%, overall yield, dH (400 MHz,
CDCl3) 5.69 (dddd, J = 5.3 Hz, J = 8.4 Hz, J = 9.4 Hz, J = 13.8 Hz,
CH CH2), 4.93–5.00 (m, 2H, CH CH2), 2.36–2.44 (m, 1H),
2.34 (t, J = 7.5 Hz, 1H), 1.88 (dt, J = 4.2 Hz, J = 13.4 Hz, 1H), 1.68–
1.77 (m, 1H), 1.58–1.68 (m, 2H), 1.42–1.48 (m, 2H), 1.28–1.37 (m,
2H), 1.01 (s, 3H, CH3), 0.87 (s, 3H, CH3); dC (100.6 MHz, CDCl3)
212.6 (C O), 138.0 (CH CH2), 115.8 (CH CH2), 78.6 (COH),
40.2 (CHC(Me)2), 36.2 (C(OH)CH2CH), 34.9 (CH2CqCHCH2),
34.6 (CH2CqCHCH2), 32.5 (C(CH3)2), 29.98 (CH2CH2C(OH),
29.92, 23.7, 18.5 (CH3CO, C(CH3)2); nmax (CCl4)/cm-1 1712.
HRMS (EI +), Found: M+, 210.1614. C13H22O2 requires: M+,
210.1620.
8 S. Z. Zard in Handbook of RAFT Polymerization, C. Barner-Kowollik,
ed., Wiley-VCH, Weinheim, 2008, 151–187.
9 G. Stork and R. Mah, Heterocycles, 1989, 28, 723; T. Kaoudi, L. D.
Miranda and S. Z. Zard, Org. Lett., 2001, 3, 3125; G. Binot, B. Quiclet-
Sire, T. Saleh and S. Z. Zard, Synlett, 2003, 382.
10 A. Liard, B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett., 1996, 37,
5877.
11 D. H. R. Barton, D. O. Jang and J. Cs Jaszberenyi, Tetrahedron Lett.,
1992, 33, 5709; J. Boivin, R. Jrad, S. Juge and V. T. Nguyen, Org. Lett.,
2003, 5, 1645.
12 R. Rodriguez, A.-S. Chapelon, C. Ollivier and M. Santelli, Tetrahedron,
2009, 65, 7001 Interestingly, the xanthate transfer was the only method
that provided good yields of cyclised product (M. Santelli, private
communication).
13 E. Bacque´, F. Pautrat and S. Z. Zard, Org. Lett., 2003, 5, 325.
14 A. L. J. Beckwith, D. M. O’Shea and S. W. Westwood, J. Am. Chem.
Soc., 1988, 110, 2565; T. Hirao, T. Fujii and Y. Ohshiro, Tetrahedron,
1994, 50, 10207.
Notes and references
1 Comprehensive Natural Products Chemistry. Isoprenoids, Including
Carotenoids and Steroids D. E. Cane, Ed., Elsevier, Oxford, 1999; Vol.
2.
3404 | Org. Biomol. Chem., 2011, 9, 3396–3404
This journal is
The Royal Society of Chemistry 2011
©