Stereoselective quaternary center construction via atom-transfer radical cyclization using silicon tethers on acyclic precursors

Article abstract of DOI:10.1021/ol901126y

A novel strategy for the stereoselective construction of all-carbon quaternary centers on acyclic molecules using a two-step tandem process is reported. The first step involves an intramolecular and stereoselective atom transfer radical cyclization reacti

Full text of DOI:10.1021/ol901126y

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3148-3151
Stereoselective Quaternary Center
Construction via Atom-Transfer Radical
Cyclization Using Silicon Tethers on
Acyclic Precursors
Martin Duplessis,†,‡ Marie-Eve Waltz,†,‡ Mohammed Bencheqroun,†
Benoit Cardinal-David,*,†,‡ and Yvan Guindon*,†,‡,§
Institut de recherches cliniques de Montre´al (IRCM), Bio-organic Chemistry
Laboratory, 110 aVenue des Pins Ouest, Montre´al, Que´bec, Canada H2W 1R7,
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128, succursale Centre-Ville,
Montre´al, Que´bec, Canada H3C 3J7, and Department of Chemistry, McGill
UniVersity, 801 Sherbrooke Street West, Montre´al, Que´bec, Canada H3A 2K6
yVan.guindon@ircm.qc.ca; b-cardinal-daVid@northwestern.edu
Received May 21, 2009
ABSTRACT
A novel strategy for the stereoselective construction of all-carbon quaternary centers on acyclic molecules using a two-step tandem process
is reported. The first step involves an intramolecular and stereoselective atom transfer radical cyclization reaction from an allyl or vinyl
subunit attached on a silyloxy, serving as a tether, to a tertiary radical r to an ester. A subsequent mild acidic elimination leads stereoselectively
to a quaternary center bearing an allyl or a vinyl in high yield.
The construction of all-carbon stereogenic quaternary centers
is a topic of great importance in chemistry.1 A challenge of
particular interest is the synthesis of stereogenic quaternary
centers proximal to a chiral center on acyclic molecules such
as the 2,3-syn and 2,3-anti allyl (1, 2) or vinyl (3, 4) motifs
as depicted in Figure 1. Indeed, the intrinsic difficulty of
creating quaternary centers is worsened by the presence of
an R tertiary carbon and the increase in steric tensions.
These molecules are otherwise extremely interesting as
potential synthons for the synthesis of natural products. The
presence of an ester or an allyl (or vinyl) on the quaternary
Figure 1. 2,3-syn- and 2,3-anti-ꢀ-hydroxy-R,R-disubstituted ester.
center as well as a hydroxyl on the neighboring carbon offers
a large number of possibilities for further transformations.
Notable scientific contributions toward the synthesis of these
molecules have been realized. Fra¨ter’s anionic alkylation has
led to molecules of general formulas 1 and 2, although in low
yields.2 Mainly, the strong basic conditions required somewhat
limited its use. Similarly, syn and anti motifs (1 and 2) could
† Institut de recherches cliniques de Montréal.
‡ Department of Chemistry, Université de Montréal.
§ Department of Chemistry, McGill University.
(1) For reviews, see: (a) Fuji, K. Chem. ReV. 1993, 93, 2037. (b) Corey,
E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 110, 402. (c)
Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (d)
Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105. (e) Douglas, C. J.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (f) Peterson,
E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11943.
(2) (a) Fra¨ter, G. HelV. Chim. Acta 1979, 62, 2825. (b) Fra¨ter, G.;
Mueller, U.; Guenther, W. Tetrahedron 1984, 40, 1269.
10.1021/ol901126y CCC: $40.75
Published on Web 06/24/2009
 2009 American Chemical Society

be obtained in modest yields through the regioselective opening
of epoxides using an allyltitanium reagent.3
centered radical at C-2 should be delocalized in the ester.
The induced allylic 1,3-strain has therefore to be alleviated
as well as the intramolecular dipole-dipole effect between
the alkoxy and the ester. Consequently, the C-3 hydrogen is
at 30° of the ester while R1 is close to be orthogonal to the
plane of the radical.10 We believe that this is also reflected
in the early transition states of allylation reaction illustrated
in B leading to the syn products. The observed diastereose-
lectivity was unfortunately decreased significantly when R1
was a lower alkyl in the allylation reaction.11 Although
disappointing, the latter results served as a starting point for
our present study and the exciting results reported herein.
Central to this study is our intention to explore intramo-
lecular delivery of a radical trap on a tertiary carbon-centered
free radical while taking advantage of the steric and electronic
factors stated previously. The radical trap was planned to
be linked to the oxygen at C-3 in order to benefit from this
conformational bias.
Although significant advancements have been reported
recently,4 aldol-based strategies have also been limited by
the difficulty of accessing stereoselectively defined tetrasub-
stituted enolates.5 More recently, silyl ketene imine has been
used in the presence of chiral Lewis base and SiCl4 to access
diastereoselectively and enantioselectively the anti motif as
in 2, an aryl group replacing the methyl on the quaternary
center.6 Collectively, these results are exciting for their
potential and serve to illustrate the difficulties in creating
stereogenic quaternary centers.
In the past decade, we have explored the reactivity of carbon-
centered free radicals on acyclic molecules in various transfor-
mations including carbon-carbon bond-forming reactions, as
illustrated in Scheme 1. We have demonstrated that diastereo-
Silicon-based tethers were chosen to link the radical traps
to the oxygen at C-3 (Scheme 2). One should note that this
Scheme 1. Endocyclic Effect vs Acyclic Stereoselection
Scheme 2. Proposed Transition States: 2,3-syn and 2,3-anti
selectivity and high yields could be achieved in many of these
reactions provided that certain conditions are present.7
sequence is different from the previous strategy using
(bromomethyl)dimethylsilyloxy ethers as tethered radical
sources. These stabilized radicals have been involved suc-
cessfully in various cyclizations including cascade reac-
tions.12 In our case, the silyl ether bears the olefin which
will react on the acyclic tertiary radical. Examples of silyloxy
ethers bearing vinyl, allyl, or ethynyl radical traps have been
reported to react to cyclic secondary radicals,13 but only
isolated cases involving secondary acyclic radicals have been
A critical first step en route to realize the objectives
depicted previously was achieved when a radical precursor,
flanked on one hand by an ester and on the other by a
stereogenic center, was reacted with allyltributyltin in the
presence of a bidendate Lewis acid (MgBr2·OEt2 or Me2-
AlCl). Entrapping the radical in a temporary chelated
complex (transition state A, endocyclic effect) allowed the
incoming reagent to attack on the bottom face of the radical
leading to the stereospecific formation of the all-carbon
quaternary centers with the 2,3-anti relative stereochemistry.8
We also observed that the balance of steric and stereo-
electronic effects could influence the ground-state conforma-
tion of these radicals in the absence of Lewis acid (acyclic
stereoselection).9 As illustrated in B, the planar carbon-
(8) For use of allylsilane reagent, see: (a) Guindon, Y.; Gue´rin, B.;
Chabot, C.; Ogilvie, W. W. J. Am. Chem. Soc. 1996, 118, 12528. (b) For
use of allyltin reagent, see: Guérin, B.; Chabot, C.; Mackintosh, N.; Ogilvie,
W. W.; Guindon, Y. Can. J. Chem. 2000, 78, 852.
(9) (a) Guindon, Y.; Lavalle´e, J.-F.; Boisvert, L.; Chabot, C.; Delorme,
D.; Yoakim, C.; Hall, D.; Lemieux, R.; Simoneau, B. Tetrahedron Lett.
1991, 32, 27. (b) Guindon, Y.; Jung, G.; Gue´rin, B.; Ogilvie, W. W. Synlett
1998, 213. (c) Brazeau, J.-F.; Mochirian, P.; Pre´vost, M.; Guindon, Y. J.
Org. Chem. 2009, 74, 64.
(3) Ohno, H.; Hiramatsu, K.; Tanaka, T. Tetrahedron Lett. 2004, 45,
75.
(4) (a) Burke, E. D.; Gleason, J. L. Org. Lett. 2004, 6, 405. (b) Arpin,
A.; Manthorpe, J. M.; Gleason, J. L. Org. Lett. 2006, 8, 1359.
(5) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005.
(6) Denmark, S. E.; Wilson, T. W.; Burke, M. T.; Heemstra, J. R., Jr.
J. Am. Chem. Soc. 2007, 129, 14864.
(10) (a) Giese, B.; Bulliard, M.; Wetterich, F.; Zeitz, H. G.; Rancourt,
J.; Guindon, Y. Tetrahedron Lett. 1993, 34, 5885. (b) Guindon, Y.;
Benchequroun, M.; Bouzide, A. J. Am. Chem. Soc. 2005, 127, 554.
(11) A ratio of 4:1 in favor of syn was obtained when R2 is a methyl
and the allylation reaction done in refluxing hexanes (see ref 8b). In the
case of R2 ) H, the ratio obtained was 6:1. The secondary hydroxyl group
had to be protected in this case in a borinate and a monodentate Lewis acid
used to activate the ester. (Cardinal-David B. Ph.D. Thesis, Universite´ de
Montre´al, 2008).
(7) (a) Cardinal-David, B.; Gue´rin, B.; Guindon, Y. J. Org. Chem. 2005,
70, 776. (b) Cardinal-David, B.; Brazeau, J.-F.; Katsoulis, I.; Guindon, Y.
Curr. Org. Chem. 2006, 10, 1939.
Org. Lett., Vol. 11, No. 14, 2009
3149

described with modest success.14 The strength of our
proposed methodology is the possibility to produce the allyl
or vinyl products (as 1 and 3, Figure 1) selectively. To our
knowledge, neither of the methods described before allows
the stereoselective formation of the syn products efficiently.
Our rationale to study these reactions is illustrated in Scheme
2. Minimization of the allylic 1,3-strain and intramolecular
dipole-dipole effects are both alleviated in transition-state
model C. Rotating the stereogenic center at C-3, in order to
get access to the top face of the radical, leads to unfavorable
transition state D. Two additional destabilizing interactions are
now present: an allylic 1,3-strain between C-R with the ester
and the presence of two bisecting functionalities C-O and C-R
to the incoming double bond. On this basis, one will predict
that the transition state C be of lower energy thus determining
the relative stereochemistry of the quaternary center at C-2
versus the stereogenic center at C-3.
Scheme 3. Regioselectivity of the Radical Cyclization
As stated before, our goal is the transfer of an allyl or a vinyl
to the tertiary radical in order to generate the 2,3-syn stereogenic
quaternary centers using a silicon-tethered radical trap. In order
to reach the necessary cyclic ꢀ-bromosilyloxy intermediates that
would lead to these products, regioselective 7-endo-trig or
5-exo-trig (see E and G, Scheme 3) cyclizations have to be
favored over the competing 6-exo-trig and 6-endo-trig (F and
H) pathways. The corresponding transition states are depicted
in Scheme 3, the orientation of the planar carbon-centered
radicals being consistent to the steric and electronic effects
described above (Scheme 2). A priori it is problematic to predict
the lowest energy transition states in those reactions using the
Baldwin-Beckwith rules.15 Indeed, the presence of silicon in
the cyclizing chain of a number of reactions has generated
different results from the ones expected.16 The increases in bond
lengths of O-Si and C-Si as compared to O-C and C-C
bonds are probable causes of these variances, thus the need to
evaluate those reactions experimentally.17,18
silane bearing a bromide atom to aldehydes activated by a
Lewis acids.19
The silylation reactions were achieved using well-known
conditions. Chlorodimethylallylsilane or chlorodimethylvinyl-
silane was added to CH2Cl2 or DMF solutions of alcohol in
the presence of pyridine or imidazole at room temperature. The
resulting silyloxy ethers (substrates 5a,b to 12a,b and 29a,b to
34a,b) were subsequently isolated in excellent yields.
Solutions of the silyloxy ethers in benzene or toluene20
bearing an allyl (Table 1) or a vinyl (Table 2) subunit were
then exposed to free-radical conditions by adding 0.05 equiv
of a solution of Et3B at 0 °C. For optimal results, we added
at 15-30 min intervals the same quantity of a solution of
Et3B for a period of 4 h or until the reactions were completed
as indicated by TLC.21 A mild acidic treatment leads to the
elimination products and the formation of the quaternary
centers bearing an allyl or a vinyl substituent.
The synthesis in good yields of ꢀ-hydroxy-R-tertiary
bromoesters, our precursors to the silyloxy ethers, have been
realized by adding a mixture of E/Z-tetrasubstituted enoxy-
As seen in Table 1, excellent to fair yields of the 2,3-
syn products, in a ratio greater than 20:1, were obtained.
Indeed, excellent ratios are noted even when lower alkanes
are present (entries 1 and 2) as opposed to our previous
protocol (vide supra). Our reactions are compatible with
the presence of a phenyl group in the R position (entry 3)
and with the usual protecting groups on hydroxyl groups
on C-4 (entries 4 and 5). Of particular importance is the
2,3-syn diastereoselectivity noted regardless of the C-3-C-4
(12) See, for example: (a) Nishiyama, H.; Kitajima, T.; Matsumoto, M.;
Itoh, K. J. Am. Chem. Soc. 1984, 49, 2298. (b) Stork, G.; Kahn, M. J. Am.
Chem. Soc. 1985, 107, 500. (c) Bogen, S.; Malacria, M. J. Am. Chem. Soc.
1996, 118, 3992. (d) Fensterbank, L.; Dhimane, A.-L.; Wu, S.; Lacoˆte, E.;
Bogen, S.; Malacria, M. Tetrahedron 1996, 11405, and references therein.
(e) Blaszykowski, C.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Org.
Lett. 2003, 8, 1341.
(13) Allyl: (a) Shuto, S.; Terauchi, M.; Yahiro, Y.; Abe, H.; Ichikawa,
S.; Matsuda, A. Tetrahedron Lett. 2000, 41, 4151. (b) Kanazaki, M.; Ueno,
Y.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2000, 122, 2422. (c) Terauchi,
M.; Yahiro, Y.; Abe, H.; Ichikawa, S.; Tovey, S. C.; Dedos, S. G.; Taylor,
C. W.; Potter, B. V. L.; Matsuda, A.; Shuto, S. Tetrahedron 2005, 61, 3697.
(d) Shuto, S.; Yahiro, Y.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2000,
65, 5547. (e) Kodama, T.; Shuto, S.; Nomura, M.; Matsuda, A. Chem.sEur.
J. 2001, 7, 2332. (f) Sakaguchi, N.; Hirano, S.; Matsuda, A.; Shuto, S.
Org. Lett. 2006, 8, 3291. (g) Stork, G.; Suk, H. S.; Kim, G. J. Am. Chem.
Soc. 1991, 113, 7054. (h) Xi, Z.; Rong, J.; Chattopadhyaya, J. Tetrahedron
1994, 50, 5255. (i) Sukeda, M.; Ichikawa, S.; Matsuda, A.; Shuto, S. Angew.
Chem., Int. Ed. 2002, 41, 4748. (j) Sukeda, M.; Ichikawa, S.; Matsuda, A.;
Shuto, S. J. Org. Chem. 2003, 68, 3465.
(17) Barton, T. J.; Revis, A. J. Am. Chem. Soc. 1984, 106, 3802.
(18) For references on the ꢀ-silicon effect (also called silicon hyper-
conjugation), see: (a) Ibrahim, M. R.; Jorgensen, W. L. J. Am. Chem. Soc.
1989, 111, 819. (b) Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador,
L. A.; Liu, X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res. 1999, 32, 183. (c)
Chabaud, L.; James, P.; Landais, Y. Eur. J. Org. Chem. 2004, 3173.
(19) Mochirian, P.; Cardinal-David, B.; Gue´rin, B.; Pre´vost, M.;
Guindon, Y. Tetrahedron Lett. 2002, 43, 7067.
(14) Curran, D. P.; Ramamoorthy, P. S. Tetrahedron 1993, 49, 4841.
(15) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc., Chem.
Commun. 1980, 482.
(20) The optimization of this reaction was initially performed in benzene
to avoid benzylic bromination. However, few reactions done in toluene
demonstrate that good yields and excellent diastereoselectivites can be
obtained which represent a great alternative to benzene (entries 1, 4, 5, 7,
and 8 in Table 1 and entry 2 in Table 2).
(16) (a) Wilt, J. W.; Lusztyk, J.; Peeran, M.; Ingold, K. U. J. Am. Chem.
Soc. 1988, 110, 281. (b) Saigo, K.; Tateishi, K.; Hiroshi, A.; Saotome, Y.
J. Org. Chem. 1988, 53, 1572.
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Org. Lett., Vol. 11, No. 14, 2009

alkanes and aryls were compatible with our reactions (entries
1-3) as well as usual protecting groups (entries 4 and 5)
and proximal stereogenic centers (entry 6). The relative syn
stereochemistry of the major compound 45 was proven
through X-ray analysis of a derivative.22
Table 1. Tandem Cyclization-Elimination Reaction-Allylationa
We proposed that, following initiation by Et3B, an intramo-
lecular cyclization occurs followed by atom transfer to give the
corresponding 7-membered ꢀ-bromosilanes (47) which after
elimination gave the corresponding 2,3-syn-allylated products.
Similarly, 5-membered cyclic silyloxy ethers (51a,b) are
proposed intermediates in the vinylation reactions.
Scheme 4. Proof of Structures: 5-exo-trig and 7-endo-trig
a Conditions: Et3B (0.05 equiv) was added every 15-30 min to the
substrate in benzene or toluene at 0 °C until complete conversion by TLC.
Treatment of the reaction mixture with PPTS (0.1 equiv) in MeOH for 1 h
at room temperature led to the product. b Reaction was performed in toluene.
c Reaction was performed in benzene.
relative stereochemistry (entries 6-8). The relative syn
stereochemistry of the major compound 15 (entry 3) was
proven through X-ray analysis of a p-nitrobenzoyl deriva-
tive.22 The relative stereochemistry of the products 24 and
26 (entries 6 and 7) was confirmed through removal of
the protecting groups, lactonization, and further X-ray and
NMR (NOESY) analyses.7a
As seen in Table 2, similar results were noted in the
vinylation reactions. Excellent yields and ratios were obtained
favoring the 2,3-syn isomers, as in 3 (Figure 1). Once again,
The presence of these intermediates (Scheme 4) has been
supported from a number of experimental results, notably
through hydrogen-transfer reactions. Indeed, at the end of
the given allylation or vinylation reactions an equivalent
amount of Bu3SnH was added to the reaction mixtures. As
seen in Scheme 4, 7-membered (48 and 50) and 5-membered
rings (52a,b) were obtained in high yields, attesting to the
presence of the proposed intermediates in these reactions.23
In conclusion, we have described herein the stereospecific
construction of 2,3-syn allyl (as in 1) or vinyl (as in 3)
subunits. The present intramolecular allylation on the tertiary
free radical complement our previous allylation reaction
under the control of the endocyclic effect (vide supra) making
both stereoisomers 1 and 2 (Figure 1) now accessible.
Table 2. Tandem Cyclization-Elimination Reaction-Vinylationa
Acknowledgment. We express our gratitude to the Natural
Sciences and Engineering Research Council of Canada
(NSERC) and the Institut de recherches cliniques de Montre´al
(IRCM) for their financial support. NSERC and FQRNT are
also gratefully acknowledged for Ph.D. and M.Sc. fellow-
ships (B.C.-D. and M.D.).
Supporting Information Available: Experimental pro-
cedures; crystallographic information files; complete spec-
troscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901126Y
a Conditions: Et3B (0.05 equiv) was added every 15-30 min to the
substrate in benzene or toluene, at 0 °C until complete conversion by TLC.
Treatment of the reaction mixture with PPTS (0.1 equiv) in MeOH for 1 h
at room temperature led to the product. b Reaction was performed in toluene.
c Reaction was performed in benzene.
(21) The cyclic intermediates are unstable on silica. The allylated or
vinylated products were observed in these cases.
(22) See the Supporting Information.
(23) See the Supporting Information for more details on the proof of
structure of intermediates 48, 50, and 52a,b.
Org. Lett., Vol. 11, No. 14, 2009
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