Remarkable Effect of a Silicon Group on the Stereoselectivity of Radical 5-exo-Trig Cyclizations

Article abstract of DOI:10.1021/ol036025v

(Matrix presented) Sulfonyl radical mediated 5-exo-trig cyclization of chiral 3-silylhepta-1,6-dienes has been shown to provide cyclopentanes having up to four stereogenic centers with an unexpectedly high level of stereocontrol.

Full text of DOI:10.1021/ol036025v

ORGANIC
LETTERS
2004
Vol. 6, No. 3
325-328
Remarkable Effect of a Silicon Group on
the Stereoselectivity of Radical
5-exo-Trig Cyclizations
Philippe James and Yannick Landais*
UniVersite´ Bordeaux-I, Laboratoire de Chimie Organique et Organome´tallique, 351,
Cours de la Libe´ration, 33405 Talence Cedex, France
y.landais@lcoo.u-bordeaux1.fr
Received October 16, 2003
ABSTRACT
Sulfonyl radical mediated 5-exo-trig cyclization of chiral 3-silylhepta-1,6-dienes has been shown to provide cyclopentanes having up to four
stereogenic centers with an unexpectedly high level of stereocontrol.
Five-membered-ring carbocycles are a common structural
unit in natural products of biological interest and can be
assembled in a number of ways (i.e. 1-2, Scheme 1).1 We
Our strategy relied on a sequential tosyl radical addition,
5-exo-trig cyclization, â-fragmentation. This process is
known to provide five-membered-ring skeletons under mild
conditions with generally high efficiency.2 Excellent control
of the C1-C2 relative configuration is usually observed but
the control of the C2-C3 configuration has remained a
challenging task to achieve.3
Scheme 1. Natural Products Containing Cyclopentanes
A few examples on the application of this strategy to the
synthesis of heterocyclic analogues have been reported,
effectively revealing that only low to moderate levels of
stereocontrol could be attained.3 Recent studies on inter-
molecular radical functionalization of chiral allylsilanes,
however, convinced us that a silicon group at the stereogenic
center might be a decisive element for the stereocontrol in
this radical process.4 So far, to our knowledge, this issue
has not been addressed. We describe here our preliminary
(2) (a) Bertrand, M.-P.; De Riggi, I.; Lesueur, C.; Gastaldi, S.; Nouguier,
R.; Jaime, C.; Virgili, A. J. Org. Chem. 1995, 60, 6040-6045. (b) Wang,
C.; Russell, G. A. J. Org. Chem. 1999, 64, 2346-2352. (c) Harvey, I. W.;
Philips, E. D.; Whitham, G. H. Tetrahedron 1997, 53, 6493-6508. (d)
Harvey, I. W.; Whitham, G. H. J. Chem. Soc., Perkin Trans. 1 1993, 185-
190. (e) Harvey, I. W.; Whitham, G. H. J. Chem. Soc., Perkin Trans. 1
1993, 191-196.
recently started an investigation on the construction of
polysubstituted cyclopentane skeletons of type 3, based on
the cyclization of dienes 4 having a chiral allylsilane moiety.
(3) (a) Bertrand, M.-P.; Gastaldi, S.; Nouguier, R. Tetrahedron Lett. 1996,
37, 1229-1232. (b) Bertrand, M.-P.; Gastaldi, S.; Nouguier, R. Tetrahedron
1998, 54, 12829-12840. (c) Nouguier, R.; Gastaldi, S.; Stien, D.; Bertrand,
M.-P.; Renaud, P. Tetrahedron Lett. 1999, 40, 3371-3374. (d) Denes, F.;
Chemla, F.; Normant, J. F. Angew. Chem., Int. Ed. 2003, 47, 4043-4046.
(1) (a) Herndon, J. W. Tetrahedron 2000, 56, 1257-1280. (b) Hartley,
R. C.; Caldwell, S. T. J. Chem. Soc., Perkin Trans. 1 2000, 477-501. (c)
Hassner, A.; Ghera, E.; Yechezkel, T.; Kleiman, V.; Balasubramanian, T.;
Ostercamp, D. Pure Appl. Chem. 2000, 72, 1671-1683.
10.1021/ol036025v CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/13/2004

results on the sulfonyl radical cyclizations of chiral allyl-
silanes such as 4, and demonstrate that this approach provides
an efficient and highly stereocontrolled access to polysub-
stituted five-membered-ring carbocycles 3.
Chiral racemic allylsilanes were easily prepared by using
the following sequences. For instance, 1,6-diene 8 was
prepared in 6 steps from allylsilane 5 (Scheme 2). Metalation
diastereomer anti-11,9 which was sulfonylated as above,
affording the required allylic sulfone 12 in reasonable yield
as a unique stereoisomer.
We first investigated the radical cyclization by treating
allylsilane 8 with a catalytic amount of p-TolSO2SePh in
the presence of AIBN (Table 1, entry 1). A mixture of two
Table 1. Sulfonyl Radical Mediated 5-exo-Trig Cyclization of
Dienes 8 and 12
Scheme 2. Preparation of Allylsilane 8
entry diene solvent T (°C) time (h) 13/14d yielde (%)
1
2
3
4
5
6
8
8
8
8
12
12
C6H6
C6H6
CCl4
CHCl3
CHCl3
80a
16
-15
-50b
-50b
10
4
2.5
0.5
0.5
3.5
86:14
96:4
98:2
>99:<1
95:5
>99:<1
69
77
85
85
72
56
of 5 and coupling with oxetane afforded an inseparable 2:1
R/γ mixture5 of alcohols 6 which were directly oxidized into
the corresponding aldehydes. Separation of the major alde-
hyde followed by Wittig-Horner olefination and reduction
of the resulting R,â-unsaturated ester with DIBAH led to
the allylic alcohol, which was protected as its acetate 7.
Palladium-catalyzed sulfonylation6 of 7 finally led to the
required (E)-allylic sulfone 8.
A second model 12, having an additional stereogenic
center, was prepared starting from vinylsilane 97 (Scheme
3). 9 was submitted to Johnson-Ireland rearrangement to
provide the â-silylester 10.8 The enolate of 10 was then
alkylated with (E)-1,4-dibromobut-2-ene to give a unique
CH2Cl2 -78c
a AIBN was used as initiator. b 0.25 equiv of p-TolSO2SePh. c 0.5 equiv
of p-TolSO2SePh. d Ratio estimated from GC analysis of the crude reaction
mixture. e Yield of isolated major diastereomer.
diastereomers 13a and 14a was thus obtained in a reasonable
yield with moderate diastereocontrol. H NMR (NOESY)
1
of the purified products showed that the major isomer 13a
had the C1-C2-C3 trans-cis stereochemistry, while the
minor 14a had the trans-trans stereochemistry, indicating that,
as expected, the C1-C2 relative configuration was totally
controlled during the process. A better yield and selectivity
was then obtained at room temperature, by irradiation of the
mixture with a sunlamp (entry 2). Lowering the temperature
and using CHCl3 or CH2Cl2 as solvents eventually led to a
complete control of the stereochemistry of the three stereo-
genic centers, with only the isomer 13a detectable by GC
analysis (entry 4). Parallel studies were performed on
substrate 12 which showed a similar behavior. Cyclopentane
Scheme 3. Preparation of Allylsilane 12
(4) (a) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2002, 4, 4257-
4260. (b) Porter, N. A.; Zhang, G.; Reed, A. D. Tetrahedron Lett. 2000,
41, 5773-5777.
(5) Schaumann, E.; Kirschning, A.; Narjes, F. J. Org. Chem. 1991, 56,
717-723.
(6) Inomata, K.; Yamamoto, T.; Kotake, H. Chem. Lett. 1981, 1357-
1360.
(7) Kahle, K.; Murphy, P. J.; Scott, J.; Tamagni, R. J. Chem. Soc., Perkin
Trans. 1 1997, 997-999.
(8) Ward, R. A.; Procter G. Tetrahedron 1995, 51, 12821-12836.
(9) Panek, J. S.; Beresis, R.; Xu F.; Yang M. J. Org. Chem. 1991, 56,
7341-7344.
326
Org. Lett., Vol. 6, No. 3, 2004

13b having four contiguous stereocenters was obtained as a
unique stereoisomer when irradiation was performed at -50
or -78 °C (entries 5 and 6).10 Interestingly, cyclizations of
8 and 12 were complete within 0.5 h at -50 °C, leading to
high yield of the cyclized products, in contrast with literature
reports on similar cyclizations, where long reaction times
are usually observed (vide infra).
els.15 Applied to our case, these models effectively provide
a good basis for understanding the sense of the stereoinduc-
tion (Figure 1). The major isomer is likely to be formed
We then extended our study to simple acyclic precursors
15 and 17,11 to test the generalization of the strategy to other
allylic systems (Scheme 4). Surprisingly, 15 led, after 14 to
Scheme 4. Cyclization of Precursors 15 and 17
Figure 1. Beckwith-Houk transition state models for 5-exo-trig
cyclization of 8, 12, and 17.
through a chairlike transition state A, in which the bulky
silicon group prefers the pseudoequatorial position. The
minor isomer could then be formed through a boatlike TS
B, which is higher in energy due to higher torsional strain.16
Interestingly, the electron-rich C-Si bond is nearly aligned
with the incipient C-C bond and is thus able to stabilize
the partial positive charge developing at the â-center. This
is reminiscent of the well-known â-silicon effect17 and may
explain both the unusual rate and the level of stereocontrol
of the process. Steric and electronic effects would thus
reinforce one another in cyclizations of models 8 and 12
having an allylic silicon group. Electronic effects are
probably operating in the case of alcohol 17. Major cyclo-
pentane 18a is likely to be formed through a TS similar to
A, in which the OH group at C2 would prefer the pseudoaxial
position to avoid destabilizing interactions between the
C2-O bond and the partial positive charge developing at
C1.18
24 h, to a mixture of four stereoisomers in good yield but
with low stereocontrol.12 When the reaction was performed
at lower temperature (-78 °C), only traces of the cyclized
product 16 were observed after 8 h of irradiation. On the
opposite side, allylic alcohol 17 afforded, after 2 h at -50
°C, a mixture of cyclopentanes 18a,b in reasonable yield
but again with modest diastereocontrol. Interestingly, the all-
cis isomer 18a was obtained as the major isomer, thus
providing an access to the complementary stereochemistry
to that of the silylated analogues.13
We thus noticed that under analogous conditions, cycliza-
tion of allylsilanes 8 and 12 was faster than that of analogues
having a methyl, a hydroxy, or simply no allylic substituent.
This may be mainly attributed to the known reactivity of
allylsilanes toward electrophiles.14 p-TolSO2 radical is elec-
trophilic in nature and is thus likely to react efficiently with
electron-rich allylsilanes.
Finally, cyclopentanes 13 can be elaborated further in a
simple way, using the pendant olefinic moiety and the
sulfonyl function. This is illustrated below with the efficient
preparation of the tricyclic ketone 19 (Scheme 5). Alkylation
Stereocontrol in these 5-exo-trig cyclizations is usually
rationalized by using Beckwith-Houk transition state mod-
(10) Best results were obtained at -50 °C, using 0.25 equiv of p-TolSO2-
SePh (entries 4 and 5). As shown in entry 6, use of 0.5 equiv of p-TolSO2-
SePh at -78 °C slightly increased the diastereoselectivity, but at the expense
of the yield.
(11) 15 and 17 were prepared in 6 and 4 steps from (R)-(-)-citronellene
and hexa-1,5-diene, respectively (see Supporting Information).
(12) Cyclization of the achiral analogue of 15, lacking the allylic Me
group, provided a 3:1 cis/trans ratio at best, in good agreement with earlier
reports.2
(13) A silicon group may be used as a masked hydroxy group, see: Jones,
G. R.; Landais, Y. Tetrahedron 1996, 52, 7599-7662.
(14) Fleming, I.; Dunogue`s, J.; Smithers, R. Org. React. 1989, 37, 57-
575.
(15) (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985,
26, 373-376. (b) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985,
41, 3925-3941. (c) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987,
52, 959-974. (d) Beckwith, A. L. J.; Zimmermann, J. J. Org. Chem. 1991,
56, 5791-5796.
(16) Boatlike conformation B with a SiR3 group in the pseudoequatorial
position has been preferred over a chairlike conformation with the bulky
silicon group in the pseudoaxial position.
(17) Lambert, J. B. Tetrahedron 1990, 46, 2677-2689 and references
therein.
(18) In TS A, a pseudoequatorial σC2-H bond, which is a better electron
donor than the σC-O bond would be aligned with the incipient C-C bond
and thus stabilize more efficiently the developing positive charge at C1.
Org. Lett., Vol. 6, No. 3, 2004
327

of allylsilanes such as 8 and 12 provides an efficient and
highly stereocontrolled access to polysubstituted cyclo-
pentanes. This work illustrates further the unique role of a
silyl group in the control of the stereochemistry of radical
processes.4,21 Cyclizations of related substrates having dif-
ferent substituents on the chain are currently underway.
Application of this methodology to the synthesis of natural
products is also in progress and will be reported in due
course.
Scheme 5. Functionalization of Cyclopentane 13a
Acknowledgment. This work was supported by CNRS
and the Institut Universitaire de France. P.J. thanks the
Ministe`re de l’Education et de la Recherche for a fellowship.
of 13a with a TMS-protected propargylic bromide led to the
desired enyne as a mixture of two stereoisomers. Pauson-
Khand cyclization19 of the resulting enynes led in turn to
ketone 19, with the stereochemistry as shown (NOESY), as
a 3:1 mixture of diastereomers.20
In summary, we have demonstrated that tosyl radical
sequential addition-5-exo-trig cyclization-â-fragmentation
Supporting Information Available: Representative ex-
perimental procedures including product characterization,
preparation, and cyclizations of precursors 8, 12, 15, and
17. This material is available free of charge via the Internet
at http://pubs.acs.org.
(19) (a) Schore, N. E. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford, UK, 1991; Vol.
5, p 1037. (b) Breczinski, P. M.; Stumpf, A.; Hope, H.; Krafft, M. E.;
Casalnuovo, J. A.; Schore, N. E. Tetrahedron 1999, 55, 6797-6812.
(20) Removal of the sulfonyl group led to a single isomer, indicating
that stereochemistry at the ring junction is totally controlled during the
Pauson-Khand reaction.
OL036025V
(21) (a) Masterson, D. S.; Porter, N. A. Org. Lett. 2002, 4, 4253-4256.
(b) Angelaud, R.; Landais, Y. Tetrahedron Lett. 1997, 38, 233-236. (c)
Hart, D. J.; Krishnamurthy, R. J. Org. Chem. 1992, 57, 4457-4470.
328
Org. Lett., Vol. 6, No. 3, 2004