Highly diastereoselective formation of spirocyclic compounds via 1,5-hydrogen transfer: A total synthesis of (-)-erythrodiene

Article abstract of DOI:10.1021/ol051426r

(Chemical Equation Presented) A highly stereoselective synthesis of (-)-erythrodiene starting from 4-isopropylcyclohexanone is described. The key reactions are an asymmetric methoxycarbonylation of the starting ketone and a highly diastereoselective radical cascade involving addition of a phenylthiyl radical to a terminal alkyne followed by a 1,5-hydrogen transfer and a 5-exo-cyclization.

Full text of DOI:10.1021/ol051426r

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4103-4106
Highly Diastereoselective Formation of
Spirocyclic Compounds via
1,5-Hydrogen Transfer: A Total
Synthesis of (−)-Erythrodiene
Mathilde Lachia, Fabrice De´ne`s, Florent Beaufils, and Philippe Renaud*
Departement fu¨r Chemie und Biochemie, UniVersita¨t Bern, Freiestrasse 3,
3012 Bern, Switzerland
philippe.renaud@ioc.unibe.ch
Received June 20, 2005
ABSTRACT
A highly stereoselective synthesis of (−)-erythrodiene starting from 4-isopropylcyclohexanone is described. The key reactions are an asymmetric
methoxycarbonylation of the starting ketone and a highly diastereoselective radical cascade involving addition of a phenylthiyl radical to a
terminal alkyne followed by a 1,5-hydrogen transfer and a 5-exo-cyclization.
(+)-Spirojatamol 1 and (-)-erythrodiene 2 (Figure 1) are
structurally closely related sesquiterpenoids isolated from the
Indian plant Nardostachys jatamansi (spirojatamol, 1)1 and
This rare spirobicyclo[4.5]decane skeleton has attracted much
attention over the past 10 years, and several groups have
developed different strategies to achieve the formation of
the key spiro center.3
Racemic erythrodiene has been prepared by Fukumoto and
Eilbracht.4 Forsyth reported the first enantioselective syn-
thesis of (-)-erythrodiene starting from (-)-perillyl alcohol
using an intramolecular carbomercuration reaction (Scheme
1, eq 1).5 This approach gives a low stereocontrol at the spiro
quaternary center. Later, Oppolzer reported a second ap-
proach of both enantiomers starting either from (-)-menthene
or from (-)-perillyl alcohol based on a palladium-catalyzed
zinc-ene reaction as key step (Scheme 1, eq 2).6
Figure 1. Two sesquiterpenes: (+)-spirojatamol and (-)-eryth-
rodiene.
(3) Srikrishna, A.; Vijaykumar, D.; Reddy, T. J. Tetrahedron 1997, 53
(4), 1439.
(4) Tokunaga, Y.; Yagihashi, M.; Ihara, M.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. 1 1997, (3), 189. Tokunaga, Y.; Yagihashi, M.; Ihara, M.;
Fukumoto, K. J. Chem. Soc., Chem. Commun. 1995, (9), 955. Sattelkau,
T.; Eilbracht, P. Tetrahedron Lett. 1998, 39, 9647.
(5) Huang, H.; Forsyth, C. J. J. Org. Chem. 1995, 60, 2773.
(6) Oppolzer, W.; Flachsmann, F. Tetrahedron Lett. 1998, 39, 5019.
Oppolzer, W.; Flachsmann, F. HelV. Chim. Acta 2001, 84, 416. For a related
strategy starting from an allyl sulfone, see: Deng, K. Ph.D. Thesis, etd-
10252004-171707, University of Pittsburgh, 2004.
Caribbean gorgonian octocoral Erythropodium caribaeorum
(erythrodiene, 2).2 They present the same carbon skeleton
and differ only by their absolute configuration and by the
hydration of the exocyclic alkene on the five-membered ring.
(1) Bagchi, A.; Oshima, Y.; Hikino, H. Tetrahedron 1990, 46, 1523.
(2) Pathirana, C.; Fenical, W.; Corcoran, E.; Clardy, J. Tetrahedron Lett.
1993, 34, 3371.
10.1021/ol051426r CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/24/2005

envisage a shorter access to this building block by desym-
metrization of the 4-isopropylcyclohexanone 5.
Scheme 1. Key Steps in Previous Syntheses of
(-)-Erythrodiene by Forsyth5 and Oppolzer6
The control of the stereochemistry of the radical cascade
process was expected to be the key point of this process. To
study this reaction and particularly its stereocontrol, we
prepared the racemic tert-butyl analogue 6 from the com-
mercially available 4-tert-butylcyclohexanone (see the Sup-
porting Informations).
The thiophenol-mediated spirocyclization was run with
cis-6 under our standard conditions [PhSH (2 equiv), AIBN
(2 equiv)] in tert-butyl alcohol as solvent (Scheme 4, eq 4).7
Scheme 4
During the course of our studies on the development of
tin-free radical reactions, we reported recently that thiophenol
proved to be a very efficient reagent to generate alkenyl
radicals and achieve 1,5-hydrogen transfer-cyclization
cascade.7 This reaction offers an easy access to spirocyclic
ketones as depicted in Scheme 2 (eq 3).8 Based on these
Scheme 2. Thiophenol-Mediated Preparation of Spicrocyclic
Ketones8
The diastereoselectivity of the reaction was monitored by
GC/MS (see the Supporting Information for details).9 A good
yield (90%) was obtained, but the stereocontrol is low and
in favor of the undesired diastereomer cis-7 (Table 1, entry
1).
results, we decided to demonstrate the utility of this reaction
for the synthesis of natural products. We describe here a short
and efficient synthesis of (-)-erythrodiene and a formal
synthesis of (-)-spirojatamol.
Table 1. Diastereoselectivity in Different Solvents
(Scheme 4, Eq 4)
solvent
T (°C)
init
yield (%)
trans/cisa
1
2
3
4
tert-BuOH
MeOH
MeOH/H2O
c-C6H12
85
65
90
80
AIBN
V-501
V-501
AIBN
90
85
70
92
40:60
62:38
36:64
56:44
Scheme 3. Retrosynthesis of (-)-Erythrodiene
a Four diastereomers were detected by GC/MS; see the Supporting
Information for details.9
When MeOH was used as solvent with the water-soluble
initiator [V-501 ) 4,4′-azobis(4-cyanovaleric acid)], trans-7
was the major product but the stereoselectivity remains low
(entry 2, 85% yield, trans/cis 62:38). The selectivity was
reversed when a mixture MeOH/H2O was used (entry 3,
70%, trans/cis 36:64). Finally, reaction in cyclohexane at
The retrosynthetic analysis is depicted in Scheme 3. (-)-
Erythrodiene will be prepared from the spirocyclic ketone 3
via methylenation of the ketone and elimination of the sulfide
after sulfoxidation. The key reaction is the formation of the
sulfide 3 from the cyclohexanone 4. The control of the
stereochemistry at the spiro center is a key issue for the
success of this approach. The ketone 4 has aldready been
prepared by Forsyth from perillyl alcohol.5 However, we
(9) The four possible diastereomers were observed by GC analysis
(column Macherey-Nagel optima delta 3 (30 m), 40 °C (1 min) to 280
°C, 6°/min. The first (tret ) 40.54 min) and third (tret ) 40.92 min)
diastereomers to elute possess the trans relative configuration in the six-
membered ring. The second (tret ) 40.79 min) and the fourth (tret ) 41.56
min) are cis configured. Only the stereoselectivity of the six-membered
ring is relevant for the synthesis of (-)-erythrodiene (trans relative
configuration is required) and will be discussed within this paper. The second
center of chirality is not controlled (dr between 1:1 and 2:1).
(7) Beaufils, F.; De´ne`s, F.; Renaud, P. Org. Lett. 2004, 6, 2563.
(8) Beaufils, F.; De´ne`s, F.; Becattini, B.; Schenk, K.; Renaud, P. AdV.
Synth. Catal. 2005, in press.
4104
Org. Lett., Vol. 7, No. 19, 2005

80 °C (Table 1, entry 4) gives an almost equimolar mixture
of both trans- and cis-7 in excellent yield (92%). No clear
trend related to solvent polarity or ability to make hydrogen
bonding could be deduced from these experiments. However,
a correlation with the reaction temperature seems to be
present: the cis isomer is favored at high temperature and
the trans one at low temperature.
material plays a role in the efficiency of the H-abstraction
step and in the stereochemical outcome of the reaction.
Indeed, depending on the relative configuration of 6, the
hydrogen atom to be abstracted occupies either an axial (cis-
6) or an equatorial (trans-6) position.
Interestingly, the results obtained with trans-6 at 85 °C
in t-BuOH (Scheme 6, trans/cis 43:57) or at 25 °C in
The effect of the temperature was further investigated in
apolar solvents such as cyclohexane (Table 2, entries 1-3)
Scheme 6
Table 2. Diastereoselectivity in Cyclohexane or Chlorobenzene
at Different Temperatures (Scheme 4, Eq 4)
T (°C)
solvent
yield (%)
trans/cis
1
2
3
4
25a
50a
80
c-C6H12
c-C6H12
c-C6H12
C6H5Cl
80
90
92
72
98:2
82:18
56:44
27:73
120
a Sunlamp irradiation.
cyclohexane under sunlamp irradiation (Scheme 6, trans/
cis 99:1) are within experimental error identical with those
obtained with cis-6 (Table 1, entry 1, and Table 2, entry 1,
respectively). These results demonstrate that both the axial
and the equatorial hydrogen atoms are efficiently abstracted
by the alkenyl radical and that a fast conformational
equilibrium of the radical is occurring before cyclization even
at 25 °C.
The study of the model system demonstrates that good
yield and stereocontrol can be achieved during the key radical
abstraction-cyclization process. Moreover, the configuration
at C(2) of the cyclohexanone precursor does not have to be
controlled since both the cis and trans precursors are leading
to the same trans spiro product. With this information in
hand, it was then possible to examine the total synthesis of
(-)-erythrodiene.
The desired precursor for the synthesis of (-)-erythrodiene
is prepared ina few steps from monoprotected 1,4-cyclo-
hexadione 9 (Scheme 7). Wittig olefination afforded the
exocyclic alkene derivative in 60% yield. After hydrogena-
tion of the alkene and hydrolysis of the acetal, the 4-iso-
propylcyclohexanone 5 was obtained in 94% yield for the
two steps. Deprotonation of 5 with lithium N,N-bis[(R)-1-
phenylethyl]amide10,11 in THF at -100 °C produced after
reaction with methylcyanocarbonate12,13 the optically pure
â-keto ester (-)-10 (82% yield, ee g 94%,14 enol form).
Alkylation of 10 with 5-iodopent-1-yne and subsequent
Krapcho decarboxylation furnished the desired precursor (-)-
cis-4 (70% yield for the two steps, 96% ee).
and chlorobenzene (entry 4). A dramatic temperature effect
is observed: at 25 °C (entry 1), the reaction affords trans-7
with an excellent stereoselectivity and good yield (trans/cis
98:2, 80% yield). This stereochemical outcome is best
explained by the transition state depicted in Scheme 4 where
a new axial C-C bond is formed. This transition state is
presumably favored by stereoelectronic effects. At 50 °C
(entry 2), a 82:18 trans/cis mixture of diastereomer is
obtained. A nearly 1:1 mixture is obtained at 80 °C (entry
3), and a clear inversion of stereochemistry is observed at
120 °C (entry 4, trans/cis 27:73). Further experiments are
in progress to determine if the reaction is under strict kinetic
control or partially reversible at high temperature.
To prove the relative configuration of 7, the mixture of
diastereomers (dr 60:38:1:1) of the reaction run at 25 °C
was oxidized to the corresponding sulfoxide with m-CPBA
and engaged in a thermal elimination leading to the exo-
methylene derivative 8 (dr 98:2) (Scheme 5). Comparison
Scheme 5
(10) For a reviews on asymmetric synthesis using chiral lithium amide
bases, see: Cox, P. J.; Simpkins, N. S. Tetrahedron: Asymmetry 1991, 2,
1. Majewski, M. AdV. Asym. Synthesis 1998, 3, 39. O’Brien, P. J. Chem.
Soc., Perkin Trans. 1 1998, 1439.
(11) For pioneering work with lithium N,N-bis[(R)-phenylethyl]amide,
see: Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1980, 45, 755. Simpkins,
N. S. J. Chem. Soc., Chem. Commun. 1986, 88. Cain, C. M.; Coumbarides,
G.; Cousins, R. P. C.; Simpkins, N. S. Tetrahedron 1990, 46, 523. For the
effect of LiCl, see: Bunn, B. J.; Simpkins, N. S. J. Org. Chem. 1993, 58,
533.
of 1H and 13C NMR spectra of 8 with the isopropyl analogue
described by Forsyth5 allowed unambiguous attribution of
trans relative configuration to the major isomer of 8.
The presence of the bulky tert-butyl substituent freezes
the conformation of the disubstituted cyclohexanone 6. So
far, all experiments were run with the cis-6. It was therefore
of high interest to examine if the configuration of the starting
(12) Majewski, M.; Lazny, R. J. Org. Chem. 1995, 50, 6825.
(13) Corey, E. J.; Bush-Petersen, J. Tetrahedron Lett. 2000, 41, 6941.
Org. Lett., Vol. 7, No. 19, 2005
4105

Scheme 7. Synthesis of the Precursor for the
(-)-Erythrodiene
Scheme 8. Radical Spirocyclization Leading to the Optically
Pure (-)-Erythrodiene
successfully applied to the preparation of spirocyclic com-
pounds. This tin-free procedure proved to be efficient at room
temperature using sunlamp irradiation of an AIBN containing
solution to initiate the process. At this temperature, the
reaction is highly diastereoselective. The temperature was
found to have a strong influence on the stereoselectivity of
the reaction, and inversion of the stereochemical outcome
was even observed at high temperature. The presence of the
phenylthio moiety in the cyclized product is particularly
attractive for further functionalization as demonstrated by a
concise asymmetric synthesis of (-)-erythrodiene. Interest-
ingly, this synthesis is the first one that does not use a chiral
building block approach. The two chiral centers have been
introduced via highly enantioselective deprotonation and
radical H-abstraction-cyclization processes.
The thiophenol-mediated 1,5-hydrogen transfer-cycliza-
tion process is conducted with (-)-cis-4 in cyclohexane at
25 °C under sunlamp irradiation. The desired spirocyclic
derivative is obtained in 65% yield as a mixture of four
diastereomers (dr 67:31:1:1, trans/cis 98:2). After oxidation
of the sulfide with m-CPBA (96% yield) and thermal
elimination (microwave heating, DMSO, 180 °C, 30 min,
70% yield), the corresponding exo-methylene spirocycle (-)-
11 is isolated as a single diastereoisomer. Methylenation
following a reported procedure5 affords the optically pure
(-)-erythodiene 2 in 70% yield (Scheme 8). The synthesis
of (-)-erythrodiene 2 from the 4-isopropylcyclohexanone 5
requires seven steps and gives a global yield of 18%. Since
the ketone intermediate (-)-11 has been converted into the
nonnatural (-)-spirojatamol 1,5 our synthesis represents also
a formal synthesis this compound.
Acknowledgment. We thank the Swiss National Science
Foundation (Grant No. 20-103627), the Roche Foundation
(postdoctoral fellowship to F.D.), and the University of Berne
for support of this work. We are very grateful to A. Saxer
for determination of enantiomeric excesses by GC.
Supporting Information Available: Experimental pro-
cedures and product characterization for all compounds
mentioned in this paper. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, we have demonstrated that the thiophenol-
mediated radical translocation-cyclization process can be
(14) The enantiomeric excess was determined by GC on a chiral
column: stationary phase: 50% octakis-(2,3-O-di-n-butyl-6-O-tert-butyl-
dimethylsilyl)-γ-cyclodextrin in PS 086; temperature 100 °C.
OL051426R
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Org. Lett., Vol. 7, No. 19, 2005