A method for the net contra-thermodynamic isomerization of cyclic trisubstituted alkenes

Article abstract of DOI:10.1021/ol4018744

A simple sequence for the net contra-thermodynamic isomerization of cyclic trisubstituted alkenes is reported consisting of a radical addition of p-chlorothiophenol, followed by oxidation to the sulfoxide and thermal syn-elimination to give the least substituted isomeric cycloalkene.

Full text of DOI:10.1021/ol4018744

ORGANIC
LETTERS
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Vol. XX, No. XX
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A Method for the Net Contra-
thermodynamic Isomerization of Cyclic
Trisubstituted Alkenes
€
Raphael F. Guignard, Laurent Petit, and Samir Z. Zard*
ꢀ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique,
91128 Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received July 4, 2013
ABSTRACT
A simple sequence for the net contra-thermodynamic isomerization of cyclic trisubstituted alkenes is reported consisting of a radical addition of
p-chlorothiophenol, followed by oxidation to the sulfoxide and thermal syn-elimination to give the least substituted isomeric cycloalkene.
As part of an ongoing project aimed at the synthesis of
pseudopteroxazole 1 and other structurally related natural
products, we were faced with the difficult task of control-
ling the relative stereochemistry at C-4 and C-7 (Figure 1).
While attempting to overcome this synthetic hurdle, we
devised a practical, reasonably general procedure for con-
verting a cyclic trisubstituted alkene into the thermodynami-
cally less stable disubstituted isomer. Our preliminary results
are described herein.
with the serrulatane backbone. Pseudopteroxazole 1 has a
strong inhibitory activity against Mycobacterium tubercu-
losis H37Rv (97% at 12.5 mg/mL).3
Pseudopteroxazole1 is a diterpenoid alkaloid possessing
the amphilectane skeleton found in the pseudopterosins,
but where the catechol subunit has been replaced by an
uncommon benzoxazole.1 The amphilectosins have a seco-
pseudopterosin structure and were recently shown to be
key biosynthetic intermediates.2 Seco-pseudopteroxazole3
and erogorgiaene 4 are two other related natural products
Figure 1. Pseudopteroxazole and related natural products.
(1) (a) Rodriguez, A.; Ramirez, C.; Rodriguez, I.; Gonzalez, E. Org.
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Glaser, K. B. Life Sci. 1998, 62, 401. (d) Duque, C.; Puyana, M.;
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The intricate structure of these substances as well as the
interesting biological activity profile of several members
has elicited sustained synthetic activity in this area over the
past two decades.4
ꢁ
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Mayer, A. M. S.; Sanchez, J. A.; Ortega, E.; Gonzalez, J. J. Nat. Prod.
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Mulzer, J. Top. Curr. Chem. 2005, 244, 1.
Our synthetic plan hinged on the use of two successive
radical reactions to assemble rapidly most of the serrulatane
framework, as illustrated by the model transformations
in Scheme 1 (DLP = lauroyl peroxide).5 The relatively
(2) Ferns, T. A.; Kerr, R. G. J. Org. Chem. 2005, 70, 6152.
(3) Rodriguez, A.; Ramirez, C. J. Nat. Prod. 2001, 64, 100.
r
10.1021/ol4018744
XXXX American Chemical Society

group on C-7 with the correct trans relationship with respect
to the side chain on C-4 (pseudopteroxazole numbering).
The simpler model 13 was readily prepared by the
sequence outlined in Scheme 1. Not surprisingly, catalytic
reduction furnished the unwantedcisderivative 14through
delivery of the hydrogen from the least hindered face of the
molecule.6 Following precedents by Thompson and by
Nichols,7 weattempted the reduction on the freealcohol15
in a noncoordinating solvent under various conditions,
in the hope that the hydroxyl group would chelate the
palladium and direct the approach of the hydrogen from
the same side and therefore lead to the desired trans
product 16. Unfortunately, our efforts were all in vain.
Another, more fruitful approach relied on an elegant
procedure devised by McCombie and co-workers,4l,m
whereby an intramolecular delivery of hydride is accom-
plished from the correct face by using an internal siloxane.
Indeed, exposure of compound 17 to trifluoroacetic acid
followed by treatment with tetrabutylammonium fluoride
afforded the desired epimer 16 as the major product.
Scheme 1
Scheme 2
efficient addition and cyclization of xanthate 5 to citronel-
lene derived epoxide 6 to give tetralone 7 crisply encapsu-
lates our strategy and underscores the mild and tolerant
nature of the radical process.5a The next stage in this study
called for developing a way to install the missing methyl
Having secured one potential solution, we undertook the
exploration of a conceptually different and possibly more
general route, since it does not require the presence of a well-
positioned hydroxyl group on the side chain. Another
practical drawback of the internal hydride transfer we
sought to avoid is the need to work under high dilution
(0.005 M) and to add the trifluoroacetic acid (10 equiv) very
slowly over 10 h. In our alternative approach, control of
the relative stereochemistry would be achieved by using the
presence of the substituent on C-4 to direct the radical
addition of a thiol to the alkene in 19 from the opposite side
to give intermediate carbon radical 20 (Scheme 2).8 Because
of its proximity, the newly introduced sulfide should exert a
greater influence on the course of the hydrogen atom transfer
and favor the formation of the desired diastereoisomer 21.
Removal of the sulfide would then complete the sequence.
In the event, the outcome was not as clear-cut as initially
hoped. After some experimentation, we found that the
(4) (a) Johnson, T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 123,
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(d) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581. (e) Harmata, M.;
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F.; Pfaltz, A. Org. Lett. 2004, 6, 2023. (g) Broka, C. A.; Chan, S.;
Peterson, B. J. Org. Chem. 1988, 53, 1584. (h) Corey, E. J.; Lazerwith,
S. E. J. Am. Chem. Soc. 1998, 120, 12777. (i) Kocienski, P. J.; Pontiroli,
A.; Qun, L. J. Chem. Soc., Perkin Trans. 1 2001, 2356. (j) Buszek, K. R.;
Bixby, D. L. Tetrahedron Lett. 1995, 36, 9129. (k) Harrowven, D. C.;
Tyte, M. J. Tetrahedron Lett. 2004, 45, 2089. (l) McCombie, S. W.; Cox,
B.; Lin, S.-I.; Ganguly, A. K. Tetrahedron Lett. 1991, 32, 2083. (m)
McCombie, S. W.; Cox, B.; Ganguly, A. K. Tetrahedron Lett. 1991, 32,
2087. (n) Majdalani, A.; Schmalz, H.-G. Synlett 1997, 1303. (o)
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Lolsberg, W.; Werle, S.; Neudorfl, J. M.; Schmalz, H. G. Org. Lett.
2012, 14, 5996. (p) Cooksey, J. P.; Kocienski, P. J.; Schmidt, A. W.;
Snaddon, T. N.; Kilner, C. A. Synthesis 2012, 44, 2779. (q) Mans, D. J.;
Cox, G. A.; Rajanbabu, T. V. J. Am. Chem. Soc. 2011, 133, 5776.
(5) (a) Petit, L.; Zard, S. Z. Chem. Commun. 2010, 46, 5148. For
earlier examples of tetralone formation using xanthate chemistry, see:
(b) Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1997, 38,
1759. (c) Cordero-Vargas, A.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett.
(6) Tippett, L. M.; Massywestropp, R. A. Aust. J. Chem. 1993, 46,
945.
(7) (a) Thompson, H. W. J. Org. Chem. 1971, 36, 2577. (b) Chambers,
J. J.; Parrish, J. C.; Jensen, N. H.; Kurrasch-Orbaugh, D. M.; Marona-
Lewicka, D.; Nichols, D. E. J. Med. Chem. 2003, 46, 3526.
(8) For a recent review on the radical addition of thiols to alkenes,
see: Hoyle, C. E; Bowman, C. N. Angew. Chem., Int. Ed. 2010, 49, 1540.
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2003, 5, 3717. (d) Cordero-Vargas, A.; Perez-Martin, I.; Quiclet-Sire, B.;
Zard, S. Z. Org. Biomol. Chem. 2004, 2, 3018. For a review on the
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S. Z. Pure Appl. Chem. 2011, 83, 519.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Net Contra-thermodynamic Isomerization of
Cycloalkenes
Scheme 3
Scheme 4
radical addition of the thiol was best accomplished photo-
chemically using visible light and benzophenone as the
photoinitiator. While the chemical yield of the addition was
satisfactory, the stereoselectivity was only moderate albeit
in the desired direction. A typical example is displayed in
Scheme 3. Thus, irradiation with a tungsten-halogen lamp
of a solution of 23 and benzophenone in ethyl acetate at
0 °C furnished a 1.0:0.39:0.14:0.05 ratio of isomers 24aÀd
in a combined yield of 68%.
Attempts to improve the stereoselectivity by modifying
the steric bulk of the thiol or that of the side chain either
had only a marginal effect or resulted in a poor chemical
yield. To further complicate matters, the various diaste-
reoisomers were essentially inseparable by normal column
chromatography. Clearly, in the present case, the opposing
steric effects of the sulfide group and the side chain on C-4
were of comparable magnitude, resulting in the formation
of only moderately interesting isomeric mixtures. One
possible explanation is that the arylthiyl group occupies
a pseudoequatorial position, whereas the diethoxymethyl
side chain prefers a pseudoaxial disposition as in 25b in
order to relieve the allylic strain due to repulsion with the
neighboring aromatic hydrogen present in 25a.6 This axial
orientation causes a significant shielding of the β-face and
counteracts the directing effect of the arylthiyl group.
Nevertheless, the addition of a thiol to cyclic trisubsti-
tuted alkenes could be more usefully stereoselective in
other structures, and this indeed would furnish a practical
method for the isomerization of trisubstituted cyclic al-
kenes into the thermodynamically less stable isomers.
This conjecture is summarized in Scheme 4. Thus, the
overall anti addition of p-chlorothiophenol to the requisite
Org. Lett., Vol. XX, No. XX, XXXX
C

cycloalkane 26 should give rise to sulfide 27 as the major
product. Oxidation would lead to a sulfoxide 28 that
can syn-eliminate only from the methylene side and not
from the methine side, since the hydrogen atom in the
latter case is on the opposite side of the ring and cannot
therefore participate in a syn-elimination. The choice
of p-chlorothiophenol was dictated by the fact that it is
crystalline at room temperature, cheap, and much less
difficult to handle than the parent thiophenol.
Scheme 5
We tested this sequence on a number of different
structures. Our results are collected in the Table 1.
Fused dihydronaphthalenes and one example of a benzo-
cycloheptene were successfully isomerized, as indicated
by examples 29aÀg. 1-p-Methoxyphenyl-cyclopentene,
-cyclohexene, and -cycloheptene could also be isomerized
(examples 29hÀj). In the last case, the stereoselectivity
was only modest, presumably because of the greater
flexibility of the ring and the consequent diminished
differentiation of the two faces. It must be remembered
that the hydrogen atom transfer process from thiols is
anexceedingly fastprocesswitha relatively early transition
state and consequently a lesser sensitivity to steric
hindrance.9 Finally, cyclohexene derivatives lacking an
aromatic substituent (which normally facilitates the
radical addition step) were shown to be also viable sub-
strates, as demonstrated by examples 29kÀl. The isomeric
ratio indicated for compounds 29aÀl reflects as expected
the diastereoisomeric ratio of the precusor sulfides
27aÀl.
observed in equimolar amounts in the NMR spectrum of
the crude reaction mixture.
In summary, we have described a straightforward, mild
method for converting a cyclic trisubstituted alkene into
the lessstabledisubstitutedisomer, using cheap and readily
available reagents. Such net contra-thermodynamic shifts
of an alkene in a ring would normally require multistep
sequences, such as an anti-Markovnikov hydration via
hydroborationÀoxidation followed by tosylation or mesy-
lation of the resulting alcohol and E2 elimination (the
photodeconjugation of enones is, however, one important
exception). Many of the isomerized cycloalkenes in Table 1
would be very difficult to obtain by other routes, especially
the rather sensitive 1,4-dihydronaphthalenes. Indeed, the
possibility of accessing less stable cycloalkenes allows for
synthetic planning not hitherto practical.
In the case of enol acetate 26m, the radical addition was
efficient but the alkene arising from elimination of the
sulfoxide underwent spontaneous aromatization to naph-
thalene 30 under the reaction conditions (Scheme 5).
Interestingly, enamine 26n led to a 4:1 mixture of the
tertiary amine 31 and the hydrolyzed product 32. The
reduced product 31 presumably arises from the Markovnikov
addition of the thiol onto the electron-rich enamine fol-
lowed by the homolytic cleavage of the newly formed
carbonÀsulfur bond and reduction of the corresponding
radical (Scheme 5). Unfortunately, the addition of a base
did not prevent this reaction. Finally, N-acetylenamine
26o underwent quantitative transformation into vinyl
sulfide 35, most likely by Markovnikov addition followed
by elimination of N-benzylacetamide. The latter could be
Acknowledgment. This paper is respectfully dedicated
to Dr. Issam Hanna (Ecole Polytechnique). We thank
Laboratoires Servier and Ecole Polytechnique for scholar-
ships to L.P. and R.G., respectively.
Supporting Information Available. Experimental proce-
1
dures, full spectroscopic data, and copies of H and 13C
(9) The rate constant for hydrogen atom abstraction from thiophenol
: (a)
Newcomb, N.; Glenn, A. G. J. Am. Chem. Soc. 1989, 111, 275. (b)
Franz, J. A.; Bushaw, B. A.; Alnajjar, M. S. J. Am. Chem. Soc. 1989, 111,
268.
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
by a carbon centered radical is of the order of 108 MÀ1 sÀ1
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX