Transfer of Chirality by the Use of an All Carbon Tether

Article abstract of DOI:10.1021/ol2001182

Methylketone side chains can be used to direct the creation of one or more chiral centers, including quaternary centers, by exploiting the ability of the radical xanthate transfer process to mediate six-membered ring formation.(Figure Presented)

Full text of DOI:10.1021/ol2001182

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1230–1233
Transfer of Chirality by the Use
of an All Carbon Tether
Marie-Gabrielle Braun, Rama Heng, and Samir Z. Zard*
ꢀ
Laboratoire de Synthese Organique, CNRS UMR 7652, Ecole Polytechnique,
91128 Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received January 14, 2011
ABSTRACT
Methylketone side chains can be used to direct the creation of one or more chiral centers, including quaternary centers, by exploiting the ability of
the radical xanthate transfer process to mediate six-membered ring formation.
In a study related to devising a general approach to the
eudesmane class of terpenes,1 represented by general struc-
ture 1 and exemplified by β-eudesmol 2, pygmol 3, and
kikkanol B 4,2 we considered the possibility of combining
the power of the Diels-Alder reaction with that of the radical
chemistry of xanthates in order to control the relative, and
ultimately absolute, stereochemistry around ring B. Our
conception, outlined in simplified form in Scheme 1, hinges
on exploiting the ready accessibility of the cycloadducts
of isoprene such as 5 in enantiopure form3 and using the
methyl ketone to direct a radical carbon-carbon forming
process from the same β-side of the cyclohexene ring.
A temporary tether based on a vicinal hydroxyketone motif,
as in 6 and 7, would allow through oxidative cleavage
the recovery of the methyl ketone in 8, which could then
be easily converted into the isopropyl, isopropenyl, or
dimethylcarbinol side chains found in the eudesmanes.
The nature of substituents R and R0 can be selected in a
manner that allows for the easy construction of ring A.
Furthermore, by starting with functionalized isoprenes
such as 9 or 10, the introduction of a hydroxy group in
position 6, as in pygmol 3, or in position 14, as in kikkanol
B 4, respectively, would become very easy.
The sequence in Scheme 1 represents in fact a transfer
of chirality using a carbon tether. The use of temporary
tethers to control stereochemistry has proven to be a very
powerful strategy in organic synthesis.4 In the case of radical
reactions, Stork and Itoh pioneered a quarter of a century
ago the use of temporary mixed acetal and, especially,
silicon tethers (e.g., 11a and 11b in Scheme 2).5 Their
(4) For reviews, see: (a) Bracegirdle, S.; Anderson, E. A. Chem. Soc.
Rev. 2010, 39, 4114. (b) Gauthier, D. R.; Zandi, K. S.; Shea, K. J.
Tetrahedron 1998, 54, 2289. (c) Fleming, I.; Barbero, A.; Walter, D.
Chem. Rev. 1997, 97, 2063. (d) Fensterbank, L.; Malacria, M.; Sieburth,
S. M. Synthesis 1997, 813. (e) Bols, M.; Skrydstrup, T. Chem. Rev. 1995,
95, 1253. (f) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991,
91, 1237.
(1) Wu, Q.-W.; Yan-Ping Shi, Y.-P.; Jia, Z.-J. Nat. Prod. Rep. 2006,
23, 699.
(2) For a recent discussion of the synthesis of eudesmanes, see:
(a) Chen, K.; Baran, P. S. Nature 2009, 459, 824. (b) Chen, K.; Ishihara,
Y.; Galan, M. M.; Baran, P. S. Tetrahedron 2010, 66, 4738.
(3) For recent reviews on enantioselective Diels-Alder reactions, see:
(5) (a) Stork, G.; Mook, R., Jr.; Biller, S. A.; Rychnovsky, S. D.
J. Am. Chem. Soc. 1983, 105, 3741. (b) Nishiyama, H.; Kitajima, T.;
Matsumoto, M.; Itoh, K. J. Org. Chem. 1984, 49, 2298. (c) Stork, G.;
Kahn, M. J. Am. Chem. Soc. 1985, 107, 500. (d) Stork, G.; Sher, P. M.
J. Am. Chem. Soc. 1986, 108, 303. (e) Stork, G.; Suh, H. S.; Kim, G.
J. Am. Chem. Soc. 1991, 113, 7054. (f) Stork, G.; Kim, G. J. Am. Chem.
Soc. 1992, 114, 1087.
€
(a) Corey, E. J.; Kurti, L. Enantioselective Chemical Synthesis; Direct
Book Publishing: 2010. (b) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48,
2100 and references cited therein.
r
10.1021/ol2001182
Published on Web 02/02/2011
2011 American Chemical Society

Scheme 1
Scheme 3
Scheme 2
In the xanthate transfer process, the reaction of the
intermediate radical with its xanthate precursor is revers-
ible and degenerate. This key property contrasts with most
other radical based methods. It provides the intermediate
radical with an increased lifetime, which hopefully would
allow it to overcome the kinetic barrier of a 6-exo-ring
closure.8 Moreover, by using a stabilized acetonyl radical
in the cyclization step, the undesired competition from the
intramolecular abstraction of an allylic hydrogen should
be curtailed.8h
Our projected approach was implemented by first react-
ing ketone 5 with 1-ethoxyvinyl lithium to give enol ether
21 (Scheme 3). Bromination and displacement with potas-
sium O-ethyl xanthate furnished precursor 6b in a good
overall yield as a 1:1 mixture of epimers. Pleasingly, the
lauroyl peroxide mediated radical ring closure proceeded
smoothly to form the desired [3.2.1] bicyclic structure 23.
Diastereoisomer 23a is presumably the kinetically favored
product, but since the xanthate group exchanges continu-
ously via intermediate radical 22, the more stable epimer
23b with the xanthate in the equatorial position accumu-
lates over time. This is of no consequence for the next
reduction step. Indeed, treatment with triethylammonium
hypophosphite and a small amount of AIBN9 furnished
the reduced material as a separable 1:1 mixture of epimers
24a,b in an 80% overall yield from 6b. Clearly, the
irreversibletransferof thehydrogenatom takesplacesolely
from the least hindered R-side.
approach, relying mostly on stannanes, starts from allylic
alcohols and allows control of the stereochemistry through
the creation of a temporary 5-membered ring anchored to
the hydroxy group as in 14a or 14b and constructed by
a 5-exo-ring closure onto the adjacent alkene. Cleavage
of the linking chain reveals a product, e.g. 15, where the
stereochemistry at one or more chiral centers has been
completely controlled.
In very rare instances involving silicon linkages, it was
observed that a temporary 6-membered ring may be
assembled by a 6-exo- (as in 17 f 18, X = SiMe2) or a
6-endo-cyclization process.6 The main limitation is due to
the relative sluggishness of the cyclization step with respect
to premature reduction of the intermediate radical 17 by
the stannane to give 19a,b. Indeed, in the prototypical
5-hexen-1-yl radical, the 6-endo-cyclization is 50 times
slower than the 5-exo-ring closure.7 A further serious
complication in the 6-exo-mode is the possibility of an
internal abstraction of an allylic hydrogen to give allylic
radical 20a,b.
In order to regenerate the methylketone side chain, we
initially planned to cleave the R-hydroxy-ketone using
periodate. However, only one of the two epimers of 24a,
(8) For reviews of the xanthate transfer chemistry, see: (a) Zard, S. Z.
Angew. Chem., Int. Ed. 1997, 36, 672. (b) Zard, S. Z. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 1, p 90. (c) Quiclet-Sire, B.; Zard, S. Z. Chem.;Eur. J. 2006,
12, 6002. (d) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264,
201. (e) Zard, S. Z. Aust. J. Chem. 2006, 59, 663. (f) Zard, S. Z. Org.
Biomol. Chem. 2007, 5, 205. (g) Quiclet-Sire, B.; Zard, S. Z. Pure Appl.
Chem. ASAP (doi: 10.1351/PAC-CON-10-08-07). (h) Bergeot, O.; Corsi,
C.; El Qacemi, M.; Zard, S. Z. Org. Biomol. Chem. 2006, 4, 278.
(9) (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetrahedron
Lett. 1992, 33, 5709. (b) Boivin, J.; Jrad, R.; Juge, S.; Nguyen, V. T. Org.
Lett. 2003, 5, 1645.
(6) (a) Koreeda, M.; George, I. A. J. Am. Chem. Soc. 1986, 108, 8098.
(b) Koreeda, M.; Hamann, L. G. J. Am. Chem. Soc. 1990, 112, 8175.
Hanessian, S.; Di Fabio, R.; Marcoux, J. F.; Prud’homme, M. J. Org.
Chem. 1990, 55, 3436.
(7) (a) Newcomb, M. In Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 317-336.
(b) Newcomb, M. Tetrahedron 1993, 49, 1151. (c) Beckwith, A. L. J.
Tetrahedron 1981, 37, 3037.
Org. Lett., Vol. 13, No. 5, 2011
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Scheme 4
Scheme 5
alkene moiety could slow down the rate to a level that
would make it synthetically useless.
We were indeed relieved when exposure of xanthate 35b
derived from ketone 33 gave rise to the desired epimeric
mixture of bicyclic product 36a,b following the usual
reduction step (Scheme 4), albeit in a slightly reduced
overall yield (69%). The ring-opening process to regener-
ate the methyl ketone side chain in 37 proceeded normally.
The xanthate in the cyclized product may be readily
converted intonumerousother sulfur groups possessing an
exceptionally rich chemistry.12 Alternatively, another
radical carbon-carbon bond forming process may be per-
formed, before the cutting of the linking chain. Two such
transformations are displayed in Scheme 5. The first
concerns addition of xanthate 23a,b, prepared above as
an epimeric mixture, to allyl trimethylsilane to give deriv-
ative 38, where both the xanthate and the trimethylsilyl
groups may be eliminated by treatment with tetrabutylam-
monium fluoride.13 In this manner, epimeric allyl derivative
39a,b was obtained in 64% overall yield from 6b without
isolation of the intermediates. It could be cleaved by the
abnormal Beckmann rearrangement to furnish 40 cleanly.
While the addition to allyl trimethylsilane represents a
convenient method for introducing an allyl group, numer-
ous other side chains bearing diverse functionalities can be
attached by simply using the corresponding alkene trap.
For example, the separable 1:1 epimeric mixture of bicyclic
compound 41a,b was produced in 50% overall yield from
6b, without isolation of the intermediates, by cyclization,
intermolecular addition to the diethyl acetal of acrolein,
and reductive removal of the xanthate. Cleavage of the
linking chain furnished 42 (70%). The presence of the
masked aldehyde should allow the swift construction of
trans-decalin 43 through deprotection and condensation
of the liberated aldehyde with the acetonitrile side chain.14
It is worth emphasizing that in both products, 40 and 42,
b reacted to give keto acid 25 in 73% yield, while the other
remained unscathed under the usual reaction conditions.
No attempt to use forcing conditions were made, as our
aim was to establish a sequence that would be as mild as
possible. An alternative approach was to perform the scission
by way of an abnormal Beckmann rearrangement.10 To
this end, the epimeric mixture of ketone 24a,b was con-
verted into oxime 26, which was treated with mesyl chlo-
ride in pyridine to give keto nitrile 27 in an 80% overall
yield. The methyl ketone side chain in the starting cyclo-
hexene 5 could thus be used to introduce a cyanomethyl
substituent, while controlling the relative stereochemistry
of two new chiral centers in 27.
The same sequence was applied to the more complex
myrcene derived methyl ketone 28 (Scheme 4). Compound
31a,b, obtained equally efficiently as a separable epimeric
mixture, was cleanly converted into ketone 32 by the same
modified Beckman rearrangement (Scheme 4). Having
established the feasibility of this strategy for the transmis-
sion of chirality, we examined some further extensions.
One important question concerned the possibility of
stereoselectively creating a quaternary center. Placing a
substituent on the alkene terminus where the radical
addition is to take place slows down considerably the rate
of cyclization. For instance, the 5-exo-cyclization of the
5-methyl-5-hexen-1-yl radical is about 40 times slower than
that of the parent 5-hexen-1-yl radical.11 In the case of the
already sluggish 6-exo-cyclization, the substitution on the
(10) (a) Singhal, G. M.; Das, N. B.; Sharma, R. P. J. Chem. Soc.,
Chem. Commun. 1990, 498. (b) Mulijiani, Z.; Desmukh, A. R. A. S.;
Gadre, S. R.; Joshi, V. S. Synth. Commun. 1987, 17, 25. (c) Forrester,
A. R.; Irikawa, H.; Thomson, R. H.; Woo, S.-O.; King, T. J. J. Chem.
Soc., Perkin Trans. 1 1981, 1712. (d) Yates, P.; Wong, J.; McLean, S.
Tetrahedron 1981, 37, 3357. (e) Wakamatsu, T.; Fukui, M.; Ban, Y.
Synthesis 1976, 341. (f) Shoppee, C. W.; Ram, P.; Roy, S. K. J. Chem.
Soc. (C) 1966, 1023. Shoppee, C. W.; Roy, S. K. J. Chem. Soc. 1963,
3774.
(12) Zard, S. Z. In Handbook of RAFT Polymerization; Barner-
Kowollik, C., Ed.; Wiley-VCH: Weinheim, 2008; pp 151-187.
(13) Briggs, M. E.; Zard, S. Z. Synlett 2005, 334.
(11) (a) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc.,
Chem. Commun. 1980, 482. (b) Beckwith, A. L. J.; Blair, A. I.; Phillipou,
G. Tetrahedron Lett. 1974, 2251.
(14) It is interesting to note in this respect that ozonolysis of the olefin
in compound 32 would also give a propionaldehyde side chain that could
condense with the acetonitrile moiety, but this time to give a cis-decalin.
1232
Org. Lett., Vol. 13, No. 5, 2011

Scheme 6
Scheme 7
the abnormal Beckmann rearrangement leading to 54 was
followed by a spontaneous ring-closure to give imine 55,
which then reacted with the excess mesyl chloride to give
sulfonimide 56 in a 60% overall yield. This remarkaby
facile cyclization is no doubt the result of the unbearably
strong steric congestion which forces the enolate of the
ketone into very close proximity to the nitrile group.
While the combination of the Diels-Alder cycloaddi-
tion and the xanthate transfer process constitutes a potent
alliance, the present strategy for remote stereochemical
control is obviously not limited to cyclohexenyl substrates.
Analogous sequences can be accomplished starting with
other ring sizes, as indicated by the transformations in
Scheme 7 starting with ketone 57 and leading ultimately to
products 61 and 63, where the relative stereochemistry
around the cyclopentene ring has been fully controlled. It is
interesting to note that the ring closure is quite stereoselective,
leading to a major diastereoisomer 58 with the relative
stereochemistry indicated. The hydrogen-bonded intermedi-
ate radical 59c is capable of attacking either terminus of the
cyclopentene, but the pathway drawn as 59c0 in the box in
Scheme 7 appears to be preferred. The alternative mode 59c00
suffers from a destabilizing steric replusion between the
methyl group and one of the hydrogens in the ring, as shown.
Insummary, wehavenow inhand a unified, flexible, and
convergent strategy for transmitting the stereochemical
information from a distal acetyl side chain on a cycloalk-
ene. In contrast to the disposable silicon based tethers, all
the elements of the present linking chain are retained in the
product. Moreover, the transfer of the xanthate group
opens up numerous possibilities for subsequent modifica-
tions, including stereoselective carbon-carbon bond for-
mation by an intermolecular radical addition and the
generation of quaternary centers.
a new quaternary center has been created with complete
stereocontrol.
Diels-Alder adducts derived from cyclic dienes such as
cyclopentadiene are also suitable substrates for the remote
stereochemical control using an all carbon tether, as depic-
ted in Scheme 6. Thus, ketone 44 was converted into xanthate
46b,15 which underwent efficient cyclization into separable
epimeric mixture 47a,b and reduction and cleavage to
afford methylketone 49 in good yield.
More interesting is the reaction of xanthate 47a,b with
dichlorovinyl ethyl sulfone leading, after scission of the
linking chain, to product 51, where the xanthate group
has been replaced by an exceedingly useful dichlorovinyl
moiety.16 The dichlorovinyl group, which exclusively from
the least hindered exo face may be further elaborated by
exploiting various transition metal catalyzed couplings, or
converted into a chloroalkyne by treatment with base,17
or into an alkyne by the powerful Corey-Fuchs reaction,18
or cleaved by ozone to the nor-aldehyde.
Another manner of exploiting the presence of the
xanthate group in 47a,b is to exchange it with a bromine
by heating with ethyl bromoisobutyrate in the presence of
stoichiometric amounts of peroxide.19 The bromine atom
in the product, 52a,b, is also delivered from the exo face,
and exposure to base induces the formation of cyclopro-
pane derivative 53a,b in good yield. In this case, however,
(15) The addition of the ethoxyvinyllithium to ketone 44 is surpris-
ingly stereoselective. The addition of isopropylmagnesium iodide to the
corresponding aldehyde has been reported and appears to give only one
epimer, but no comments are given by the authors: Nakazaki, M.;
Naemura, K.; Kondo, Y. J. Org. Chem. 1976, 41, 1229.
(16) Bertrand, F.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem., Int. Ed.
1999, 38, 1943.
Acknowledgment. We dedicate this paper with respect and
admiration to Professor Gilbert Stork (Columbia University).
M.-G.B. thanks Ecole Polytechnique for a scholarship.
(17) Carran, J.; Waschbuch, R.; Marinetti, A.; Savignac, P. Synthesis
1996, 1494.
Supporting Information Available. Experimental proce-
1
(18) For a recent review, see: Habrant, D.; Rauhala, V.; Koskinen,
A. M. P. Chem. Soc. Rev. 2010, 39, 2007. E. J. Corey, E. J.; P. L. Fuchs,
P. L. Tetrahedron Lett. 1972, 3769.
(19) Barbier, F.; Pautrat, F.; Quiclet-Sire, B.; Zard, S. Z. Synlett
2002, 811.
dures, full spectroscopic data, and copies of H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
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