5-Endo-Trig Radical Cyclizations of Bromomethyldimethylsilyl Diisopropylpropargylic Ethers. A Highly Diastereoselective Access to Functionalized Cyclopentanes

Article abstract of DOI:10.1021/jo9904260

An efficient radical sequence involving a 5-exo-dig, a diastereoselective 1,5-H transfer, and a rarely observed in an all-carbon system 5-endo-trig cyclization allows the construction of cyclopentyl derivatives 2 bearing four controlled stereogenic center

Full text of DOI:10.1021/jo9904260

4920
J . Org. Chem. 1999, 64, 4920-4925
5-En d o-Tr ig Ra d ica l Cycliza tion s of Br om om eth yld im eth ylsilyl
Diisop r op ylp r op a r gylic Eth er s. A High ly Dia ster eoselective Access
to F u n ction a lized Cyclop en ta n es
Ste´phane Bogen, Mihaela Gulea, Louis Fensterbank, and Max Malacria*
Laboratoire de Chimie Organique de Synthe`se associe´ au CNRS, Universite´ Pierre et Marie Curie,
4, place J ussieu - Tour 44-54, Case 229, 75252 Paris Cedex 05, France
Received March 9, 1999
An efficient radical sequence involving a 5-exo-dig, a diastereoselective 1,5-H transfer, and a rarely
observed in an all-carbon system 5-endo-trig cyclization allows the construction of cyclopentyl
derivatives 2 bearing four controlled stereogenic centers from diisopropyl precursors 1. Olefins 3
were also isolated as minor side products. The effect of the acetylenic substituent Y has been
investigated, and the scope and the limitations of the cascade have been delineated.
Because of its disfavored nature according to Baldwin’s
highly diastereoselective 1,5-H transfer from a vinyl
radical.11 Thus, when submitted to typical radical cy-
clizations,12 bromomethyldimethylsilyl diisopropylprop-
argylic ether of type 1 gave cyclopentanol derivatives of
type 2 in good yields and as single diastereomers, as well
as olefins 3 (Scheme 2). Full mechanistic details, as well
as the scope and limitations of this new process, have
been determined by varying the acetylenic partner and
are given in this paper.
rules1 and of several reported failures,2 the 5-endo-trig
radical cyclization has long been claimed to be a low-
potential synthetic process. This too simplistic a view has
been recently refuted by some very versatile 5-endo-trig
radical processes involving heteroatomic reacting sys-
tems. The groups of Parsons3 and of Ikeda and Ishibashi4
have, for instance, devised an efficient 5-endo-trig radical
cyclization of N-ethenyl-R-haloamides to form pyrrolidi-
nones and substituted pyroglutamates. The 5-endo clo-
sure of the 2-formylbenzoyl radical has also been shown
to be a particularly facile process.5 Moreover, interesting
examples have included the use of heteroatomic radicals
such as silicon centered,6 generated through a 1,5-H
transfer,7 or sulfur centered.8
Resu lts a n d Discu ssion
1. P r ep a r a tion of th e Ra d ica l Cycliza tion s P r e-
cu r sor s. The precursors 1 have been prepared from the
corresponding alcohols I (Scheme 3) by silylation with
bromomethyldimethylsilylchlorosilane using three dif-
ferent reaction conditions: triethylamine, DMAP in CH2-
Cl2 or imidazole in DMF, or BuLi in THF (see the
Experimental Section). The alcohols I result from the
addition of a lithium acetylide on diisopropyl ketone.
Precursor Ig was obtained in 55% from the condensation
of the magnesium dianion of the diisopropylpropargylic
alcohol with (S)-menthylsulfinate (see the Supporting
Information).
2. Mech a n ism of th e 5-En d o-Tr ig Cycliza tion . This
new reaction was initially discovered with precursor 1a
and gave a mixture of cyclopentane 2a and olefin 3a in
89% overall yield (Scheme 4). An initial 5-exo-dig cycliza-
tion of the R-silyl radical generates a vinyl radical that
exists under two forms: (E)-4 or (Z)-4. The (E)-vinyl
radical intermediate displays a severe 1,3 allylic interac-
tion. No intermolecular stannane reduction or a 1,5(π-
exo)-H-transfer with the acetal C-H-activated bond13
intervenes so that the equilibrium is shifted toward the
(Z)-4 vinyl radical. Only the staggered (Z)-4st vinyl
radical undergoes a remarkably chemoselective 1,5-H
transfer with a nonactivated C-H bond. Indeed, this
diastereoselective 1,5(π-endo)-H takes place so that it
minimizes the interaction between the methyl and the
In comparison, the all-carbon pentenyl system has not
witnessed such a bloom: the 5-endo-trig radical cycliza-
tion has been rarely observed, and most often in low yield,
as illustrated in Scheme 1.9 Recently, we have evidenced
a highly efficient 5-endo-trig cyclization,10 based on a
(1) (a) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734-
736. (b) Baldwin, J . E.; Cutting, J .; Dupont, W.; Kruse, L.; Silberman,
L.; Thomas, R. L. Ibid. 1976, 736-738.
(2) (a) Walling, C.; Pearson, M. S. J . Am. Chem. Soc. 1964, 86, 2262-
2266. (b) Urabe, H.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 1355-
1358. (c) Beckwith, A. L. J .; Boate, D. R. Tetrahedron Lett. 1985, 26,
1761-1764. (d) Curran, D. P.; Chang, C.-T. J . Org. Chem. 1989, 54,
3140-3157.
(3) Baker, S. R.; Parsons, A. F.; Wilson, M. Tetrahedron Lett. 1998,
39, 2815-2818 and references therein.
(4) Ikeda, M.; Ohtani, S.; Yamamoto, T.; Sato, T.; Ishibashi, H. J .
Chem. Soc., Perkin Trans 1 1998, 1763-1768 and references therein.
(5) Mendenhall, G. D.; Protasiewicz, J . D.; Brown, C. E.; Ingold, K.
U.; Lusztyk, J . J . Am. Chem. Soc. 1994, 116, 1718-1724. For related
chemistry, see: Yamamoto, Y.; Ohno, M.; Eguchi, S. J . Am. Chem. Soc.
1995, 117, 9653-9661.
(6) Cai, Y.; Roberts, B. P. J . Chem. Soc., Perkin Trans. 1 1998, 467-
475.
(7) (a) Clive, D. L. J .; Cantin, D. Chem. Commun. 1995, 319-320.
(b) Martinez-Grau, A.; Curran, D. P. J . Org. Chem. 1995, 60, 8332-
8333.
(8) J ournet, M.: Rouillard, A.; Cai, D.; Larsen, R. D. J . Org. Chem.
1997, 62, 8630-8631.
(9) (a) J ulia, M.; Le Goffic, F. Bull. Soc. Chim. Fr. 1965, 1550-1555.
(b) Pines, H.; Sih, N. C.; Rosenfield, D. B. J . Org. Chem. 1966, 31,
2255-2257. (c) Wilt, J . A.; Maravetz, L. L.; Zawadzki, J . F. J . Org.
Chem. 1966, 31, 3018-3025. (d) Bradney, M. A.; Forbes, A. D.; Wood,
J . J . Chem. Soc., Perkin Trans. 2 1973, 1655-1660. (e) Schmalz, H.-
G.; Siegel, S.; Bats, J . W. Angew. Chem., Int. Ed. Engl. 1995, 34, 2383-
2385.
(11) For a similar approach in a heteroatomic version: Gimisis, T.;
Chatgilialoglu, C. J . Org. Chem. 1996, 61, 1908-1909.
(12) For a review on this chemistry: Fensterbank, L.; Malacria, M.;
Sieburth, S. M. Synthesis 1997, 813-854.
(13) Fensterbank, L.; Dhimane, A. L.; Wu, S.; Lacoˆte, E.; Bogen, S.;
Malacria, M. Tetrahedron 1996, 52, 11405-11420.
(10) Bogen, S.; Malacria, M. J . Am. Chem. Soc. 1996, 118, 3992-
3993.
10.1021/jo9904260 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/06/1999

Diastereoselective Access to Functionalized Cyclopentanes
Sch em e 1
J . Org. Chem., Vol. 64, No. 13, 1999 4921
Sch em e 2
with precursors bearing less sterically demanding pro-
pargylic substituents.14
3. Va r yin g th e Acetylen ic P a r tn er . The reaction
was shown to be fairly general (Table 1, entries 1-6)
since good yields of 5-endo products 2 were observed,
generally accompanied by the minor vinylic compound
3, resulting from the 1,5-H transfer followed by an
intermolecular reduction of the methylene radical ana-
logue to 5. Interestingly, even in the case of the mono-
substituted alkyne 1d , the diisopropyl moiety was suf-
ficient to prevent the reduction of the nonhindered vinyl
radical, thereby promoting the 5-endo-trig on an unsub-
stituted position in 55% yield (2d ). In addition, the
olefinic compound 7 was isolated in 20% yield, presum-
ably originating from an initial 6-endo-dig radical cy-
clization.15 This is an unprecedented process in all our
previous studies16 but easily explained here by an un-
substituted pole for the 6-endo attack compared to a
particularly sterically congested 5-exo position (Scheme
5).
Sch em e 3
Ta ble 1
entry
precursor 1, Y
X
5-endo-trig 2, % olefin 3, %
1
2
3
4
5
6
7
1a , (CH2)3CH(OCH2)2 SiMe3
2a , 74
3a , 15
1b, CH2OCPh3
1b, CH2OCPh3
1c, SiMe3
1d , H
1e, t-Bu
1f, Ph
OH
2bOH, 63
2bSi, 64
2c, 69
3bOH, 13
3bSi, 10
3c, 17
SiMe3
SiMe3
SiMe3
SiMe3
Th e ter t-Bu tyl Ca se. When a tert-butyl group was
introduced on the acetylenic partner (precursor 1e), no
vinyl product 3 was detected, suggesting that, because
of the steric bulk, no bimolecular reduction of the
intermediate methylene radical is possible (Scheme 6).
The expected compound 2e was isolated, but the forma-
tion of the (silylmethylidene)cyclopentane 8 was also
observed. Alternatively, employing the bulky tris(tri-
methylsilyl)silane (TTMS) as the radical mediator totally
reversed the 2e:8 ratio and resulted in a breakdown in
the chain transfer, yielding only 29% of cyclization
products (Table 2, entry 2). The yields of 2e and 8 were
found to be dependent on the quantity of AIBN used and
could be increased by utilizing larger quantities of
initiator. Presumably, the steric effects developed by the
tert-butyl and isopropyl groups also prevent the final
reduction from occurring.17 The formation of the het-
erodiquinene 11 (which has been isolated and character-
2d , 55a
2e, 71b
2f, 18c
a
b
6-Endo-dig adduct 7 (20%) was also isolated (Scheme 5). See
Table 2. c Rearranged 4-exo products 12 were also isolated in 63%
yield (Scheme 8).
isopropyl group: eclipsed (Z)-4ec versus staggered (Z)-
4st. Moreover, no deuterium was incorporated on the
vinyl moiety of (Z)-3, suggesting that the hydrogen
transfer is complete. In this single step the stereochem-
istry of the double bond (Z) as well as two new stereogenic
centers are set. The resulting methylene radical 5 can
be reduced to furnish 3a or then it cyclizes according to
the disfavored 5-endo-trig mode of cyclization, placing the
dioxolanyl chain syn to the methyl group and to the C-O
bond. A diastereoselective stannane reduction of the
â-silyl radical 6 installs a cis ring juncture and termi-
nates the sequence. The proposed relative stereochem-
istry of the four new stereogenic centers was confirmed
by an X-ray crystallography of diol 2bOH, obtained from
1b in 63% yield (Table 1, entry 2).
This intriguing 5-endo closure may be rationalized by
a particularly congested transition state, in which the
5-endo-trig cyclization appears as the main way out for
the methylene radical 5. We also feel that a repulsion
effect between the two isopropyl groups modifies the
angle of attack of the 4-pentenyl radical and ensures the
efficiency of the 5-endo-trig cyclization. This was proved
(14) For initial findings, see ref 10. For other confirming examples,
see: Bogen, S.; Gulea, M.; Fensterbank, L.; Malacria, M. To be
published.
(15) For other examples of 6-endo-dig cyclizations, see: (a) Snider,
B. B.; Merritt, J . E.; Dombroski, M. A.; Buckman, B. O. J . Org. Chem.
1991, 56, 5544-5553. (b) Khim, S.-K.; Cederstrom, E.; Ferri, D. C.;
Mariano, P. S. Tetrahedron 1996, 52, 3195-3222. (c) Marco-Contelles,
J .; Bernabe´, M.; Ayala, D.; Sanchez, B. J . Org. Chem. 1994, 59, 1234-
1235. (d) Breithor, M.; Herden, U.; Hoffmann, H. M. R. Tetrahedron
1997, 53, 8401-8420.
(16) With
a dimethyl group, this process is not observed, see:
Magnol, E.; Malacria, M. Tetrahedron Lett. 1986, 27, 2255-2256.
(17) Bogen, S.; Fensterbank, L.; Malacria, M. J . Am. Chem. Soc.
1997, 119, 5037-5038.

4922 J . Org. Chem., Vol. 64, No. 13, 1999
Bogen et al.
Sch em e 4
Ta ble 2
entry H-donor (1.3 equiv) AIBN (equiv)
Sch em e 5
2e:8
yield (%)
1
Bu3SnH
0.3
0.3
0.5
0.7
0.9
1.6
81:19
13:87
12:88
10:90
10:90
10:90
88
29
44
55
65
95
2a
3
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
4
5
6
a
With no methyllithium treatment, heterocycles 10 (3%) and
11 (27%) could also be directly isolated.
Sch em e 7
Sch em e 6
the intermediate â-silyl radical to occur, providing cy-
clopentane 2c in 69% yield.
The â-hydrogen abstraction was further evidenced by
running the reaction with Bu3SnD and in the presence
of 1.6 equiv of AIBN (Scheme 7). A mixture of reduced
5-endo-trig adduct 2eD and vinylsilane 8D was obtained
in a 1:1 ratio, reflecting again that a slower reducing
agent19 favors the â-elimination process. More interest-
ingly, the deuterium incorporation on 2eD was only 82%,
whereas the tin deuteride used was at least 97% en-
riched. Clearly, this suggests that a hydride source, most
likely the tin hydride resulting from the â-elimination,
has been produced in the reaction medium and has
served to reduce 9 into 10.
ized) could be explained by an initial 5-endo-trig process
followed by a rare â-hydrogen atom abstraction.18 It is
worthy of note that this phenomenon is not observed
when the tert-butyl group is replaced by a TMS group.
The longer C-Si bond allows the complete reduction of
(18) (a) Chen, S. H.; Huang, S.; Gao, Q.; Golik, J .; Farina, V. J . Org.
Chem. 1994, 59, 1475-1484. (b) Ripa, L.; Hallsberg, A. J . Org. Chem.
1998, 63, 84-91. (c) Gross, A.; Fensterbank, L.; Bogen, S.; Thouvenot,
R.; Malacria, M. Tetrahedron 1997, 53, 13797-13810.
(19) The kinetic isotope (Bu3SnH/Bu3SnD) for the reduction of the
tert-butyl radical is 2.74; see: Carlsson, D. J .; Ingold, K. U. J . Am.
Chem. Soc. 1968, 90, 7047-7055.

Diastereoselective Access to Functionalized Cyclopentanes
J . Org. Chem., Vol. 64, No. 13, 1999 4923
Sch em e 8
Sch em e 10
explain this complete selectivity. This was the only case
where a 4-exo-trig/5-endo-trig competition occurred.
Sch em e 9
Tow a r d a n Asym m etr ic 5-En d o-Tr ig P r ocess. We
next focused on a potential asymmetric version of the
5-endo-trig cyclization. A sulfur-based chirality source
like a homochiral sulfoxide was first chosen because it
could be readily appended. Moreover, the attachment of
this chiral auxiliary would be only temporary, since after
the 5-endo-trig cyclization the resulting radical 16 should
undergo a â-elimination of the sulfinyl radical (Scheme
10).22
The radical cyclization of the sulfoxide 1g furnished a
complex mixture of products, including the expected diol
15OH bearing no sulfoxide moiety. This diol proved
relatively unstable, and this could partly explain the low
yield observed in this reaction. No ee was detected by
chiral GC on the diol 15OH, as a racemic sample could
be obtained from the radical cyclization of sulfone 1h (in
this case, the presence of 2 equiv of Bu3SnH is neces-
sary).23 This failure in inducing any facial selectivity in
the 1,5-H transfer may be attributed to the distance of
the chiral auxiliary from the isopropyl groups.
We next selected a phosphorus moiety (1i),24 anticipat-
ing that the stereoselectivity, in that case a de, could be
easily estimated by 31P NMR. Three phosphorylated
products were formed in this reaction: two diastereomeric
5-endo-trig adducts 2iM (major) and 2im (minor) in a
1.3:1 ratio, the second diastereomer 2im being difficult
to separate from the olefinic compound 18 (Scheme 11).
The structure for 18 was proposed on the following
grounds: two diastereotopic isopropyl protons, an allylic
ABX system involving coupling with phosphorus: δ 2.95
(dd, J H-H ) 13.7, J P-H ) 10.1 Hz, 1H) and δ 3.23 (dd,
J H-H ) 13.7, J P-H ) 20.1 Hz, 1H) and a vinylic proton
coupled to the phosphorus nucleus (4J P-H ) 5.1 Hz).25 The
ionic formation of the vinylsilane 18 from the heterocycle
19 was deduced from the following data. When the
reaction mixture after treatment with MeLi was quenched
with D2O, the deuterium atom was incorporated at the
Th e P h en yl Ca se. The reaction with the phenylacet-
ylene precursor 1f marked a sharp difference with
previous results. Several products were formed, and we
found it more convenient to directly isolate the hetero-
cycles by adding just 1.5 equiv of methyllithium, which
transforms the tin residues into purely apolar material
(Scheme 8). The 5-endo adduct 2f is now the minor
product (18%). It is accompanied by a mixture of diaster-
eomeric heterocycles 12 (63%). The formation of these
seven-membered rings originates from the following
cascade: 5-exo-dig, 1,5-H transfer, 4-exo-trig, fragmenta-
tion of 13, and reduction of the secondary radical 14. A
deuterium labeling was consistent with this mechanism.
No diastereoselectivity intervenes during the fragmenta-
tion and the final reduction so that the four diastereo-
mers of 12 are produced in an equimolar ratio. The
relative Z-anti stereochemistry was deduced for anti-(Z)-
12 from NOE measurements. This compound was eluted
by flash chromatography in second position, following
probably the anti-(E)-12 isomer. This tentative assign-
ment was based on 13C NMR using γ-gauche effects20
observed for carbons C3 and C5 (Scheme 9), the phenyl
ring shielding alternatively the C3 and the C5 carbons.
Similarly, the following fraction consisted in a mixture
of syn-(Z)- and syn-(E)-12.
Examination of the Dreiding models reveals that the
approach for the 4-exo-trig cyclization21 is not really less
favorable than the one for the 5-endo-trig cyclization. And
only a cyclization under stereoelectronic control, involving
a styryl moiety that activates the 4-exo attack, can
(22) Lacoˆte, E.; Delouvrie´, B.; Fensterbank, L.; Malacria, M. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2116-2118 and references therein.
(23) Van Dort, P. C.; Fuchs, P. L. J . Org. Chem. 1997, 62, 7142-
7147.
(24) For a previous study involving the use of this chiral phosphorus
moiety in cobalt-mediated cycloadditions, see: Slowinski, F.; Aubert,
C.; Malacria, M. Tetrahedron Lett., submitted.
(20) Knorr, R.; Hintermeyer-Hilpert, M.; Bo¨hrer, P. Chem. Ber. 1990,
123, 1137-1141.
(21) For studies concerning the competition between 4-exo-trig and
5-endo-trig cyclization on styryl systems, see: Ikeda, M.; Ohtani, S.;
Yamamoto, T.; Sato, T.; Ishibashi, H. J . Chem. Soc., Perkin Trans. 1
1998, 1763-1768. See also: D’Annibale, A.; Pesce, A.; Resta, S.; Trogolo,
C. Tetrahedron Lett. 1997, 38, 1829-1832.
4
(25) For similar J H-P coupling constants on allylic phosphonates
obtained via
a base-catalyzed isomerization of the corresponding
vinylphosphonates, see: (a) Kiddle, J . J .; Babler, J . H. J . Org. Chem.
1993, 58, 3572-3574. (b) Al Badri, H. Ph.D. Dissertation, Universite´
de Rouen, 1996.

4924 J . Org. Chem., Vol. 64, No. 13, 1999
Bogen et al.
Sch em e 11
allylic position of 18D,26 altering the previous ABX
system to two doublets: δ 2.95 (d, J P-H ) 10.1 Hz, 0.4H)
and δ 3.23 (d, J P-H ) 20.1, 0.6H). Consistent with
literature reports, an anionic isomerization of the vi-
nylphosphine oxide to an allylphosphine oxide takes
place.
of this hydrogen transfer using heteroatomic chiral
auxiliary have been plagued by a too remote position of
the chirality source, lower yields, and a partial radical
â-elimination of the phosphine oxide moiety but could
evolve into valuable phosphorylated carbocycles. We are
now focusing on an approach involving chirality at the
propargylic position. Applications of the 5-endo process
toward the synthesis of polyclic derivatives are also under
investigation.
In addition, the â-elimination adduct 15Si was also
detected (8%). Phosphorus-centered radicals are known
to be particularly stable.27 As far as we are aware,
however, the radical â-elimination of a phosphorus
moiety is an unknown process. Interestingly, when this
cyclization was run with TTMS, the TLC of the crude
product after treatment with MeLi showed only the
presence of 15Si, clearly suggesting that a slower hy-
drogen donor favors this â-elimination process. After
chromatography, an inseparable mixture of the alcohol
15Si and residues from the silane were isolated. This
compound also appears volatile and unstable, and the
amount of â-elimination could not be really assessed.
The slight diastereomeric excess (12% de) observed on
the 5-endo-trig products 2iM and 2im may suggest some
facial diastereoselectivity in the 1,5-H transfer, but this
should be handled with caution, since the â-elimination
process probably modifies the initial ratio.
Facing these issues, a probably too remote chiral
auxiliary and a competitive â-elimination process, we did
not continue in this direction, and we are envisaging
preparing new precursors bearing the chirality at the
propargylic position. Nevertheless, this study showed
that heteroatomic groups were compatible with these
synthetic sequences and could provide intriguing phos-
phorylated cyclopentyl derivatives.
Exp er im en ta l Section
Thin-layer chromatography (TLC) was performed on Merck
silica gel 60 F 254. Silica gel Merck Geduran SI (40-63 µm)
was used for column chromatography using Still’s method.28
Solven ts. Ethyl ether and THF were distilled from sodium-
benzophenone ketyl. Benzene, toluene, dichloromethane, and
triethylamine were distilled from calcium hydride. Chroma-
tography solvents: EE refers to ethyl ether, PE refers to
petroleum ether.
Alcohol Id was purchased from Lancaster.
Typ ica l Silyla tion P r oced u r e. P r oced u r e A. To a 0.5
M CH2Cl2 solution of the propargyl alcohol, in the presence of
0.1 equiv of DMAP and 1.1 equiv of triethylamine, was added
dropwise at 0 °C bromomethyldimethylsilyl chloride (1 equiv).
After completion of the silylation, the reaction mixture was
diluted with CH2Cl2 and washed twice with a saturated NH4-
Cl solution and brine. The organic phase was dried over Na2-
SO4, filtered, and concentrated in vacuo. The crude product
was purified through a rapid filtration over a short pad of silica
gel.
P r oced u r e B. To a 2 M DMF solution of the propargyl
alcohol, in the presence of 2 equiv of imidazole, was added
dropwise at room temperature bromomethyldimethylsilyl chlo-
ride (1.00 equiv). After completion of the silylation (around 1
h), the reaction mixture was diluted with ether and washed
twice with a saturated NH4Cl solution and brine. The organic
phase was dried over Na2SO4, filtered, and concentrated in
Con clu sion
The 5-endo-trig cyclization of bromomethyldimethyl-
silyldiisopropyl propargylic ethers represents one of the
most efficient radical 5-endo-trig involving an all-carbon
4-pentenyl system. This highly unusual process may be
attributed here to a particularly congested transition
state, in which the repulsion between the two isopropyl
groups ensures a favorable angle of attack. It allows the
completely diastereoselective construction of cyclopen-
tanes, bearing four stereogenic centers. The second key
step of the sequence is a diastereoselective 1,5-H transfer
involving a nonactivated but well-disposed methyl on an
isopropyl group. Attempts to control the face selectivity
vacuo. The crude product was purified through
filtration over a short pad of silica gel.
a rapid
P r oced u r e C. To a 0.1 M THF solution of the propargyl
alcohol was added dropwise at -78 °C a 2.3 M solution of
n-BuLi in hexane (1 equiv). After 15 min, bromomethyldimeth-
ylsilyl chloride (1.00 equiv) was added at -78 °C. Then, the
mixture was warmed to room temperature (around 30 min),
diluted with ether, and washed with brine. The organic phase
was dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product was purified through a rapid filtration over
a short pad of silica gel.
Typ ica l P r oced u r e for th e Ra d ica l Cycliza tion of
Br om om eth yld im eth ylsilyl P r op a r gyl Eth er s. A benzene
solution (13.5 mL) of Bu3SnH (360 µL, 1.34 mmol) containing
(26) Some deuterium was incorporated on the methyl of the phos-
phine oxide moiety of 2im .
(27) For an illustration of this, see: Chatgilialoglu, C.; Timokhin,
V. I.; Ballestri, M. J . Org. Chem. 1998, 63, 1327-1329.
(28) Still, W.; Kahn, M.; Mitra, A.J . Org. Chem. 1978, 43, 2923-
2925.

Diastereoselective Access to Functionalized Cyclopentanes
J . Org. Chem., Vol. 64, No. 13, 1999 4925
AIBN (30 mg, 0.18 mmol) was added by a syringe pump over
a period of 6.5 h (2 × 10-4 mol h-1) to a solution of 1 (1.0 mmol)
and AIBN (10 mg, 0.06 mmol) in refluxing benzene (40 mL)
under argon. After completion of the addition, the mixture was
allowed to reflux for an additional 2 h.
Ack n ow led gm en t. S.B. thanks Glaxo-Wellcome for
a grant. M.G. thanks the CNRS for a poste rouge. The
authors are grateful to Isabelle Correia (UPMC) for
NOE measurements, to Franck Slowinski (UPMC) for
providing some phosphorus starting material, to the
COSTD12, and to Dr. C. Chatgilialoglu (CNR Bologna)
for helpful discussions.
Tr ea tm en t w ith Meth yllith iu m . Low chloride methyl-
lithium in ether (5.0 mmol) was added at 0 °C to the reaction
mixture, and stirring was maintained for 30 min under argon.
The organic phase was washed with brine and dried over Na2-
SO4. After evaporation of the solvent, the residue was purified
by column chromatography on silica gel.
Su p p or tin g In for m a tion Ava ila ble: The synthesis and
the spectral data of alcohols (Ia -c and Ie-i) and the spectral
data of the bromomethyldimethylsilyl ethers 1 and of the
cyclization products are reported. 1H NMR spectra for 1d , 1h ,
1i, 3a , the 2bOH and 3bOH mixture, 3bSi, 3c, 10, 11, the
isomers 12, 15OH, 2iM, the 2im and 18 mixture, 2im , the
2im D and 18D mixture, and 15Si, 13C NMR spectra for 2a D,
3a D, 2fD, and the isomers 12D, and a chiral GC spectrum
for 15OH are given. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ta m a o Oxid a tion . The cyclization reaction mixture was
evaporated and dissolved in 15 mL of a 1:1 mixture of MeOH/
THF. To this solution were added KHCO3 (2 mmol), KF (2
mmol), and 30% H2O2 (10-30 mmol). The reaction mixture
was taken to reflux. After completion of the oxidation (moni-
tored by TLC), the reaction mixture was dissolved in ether,
filtered over Celite, washed with brine, and dried over Na2-
SO4. After evaporation of the solvent, the residue was purified
by flash chromatography on silica gel.
J O9904260