Sulfoxide-Controlled SN2′ Displacements between Cyanocuprates and Epoxy Vinyl Sulfoxides

Article abstract of DOI:10.1021/jo000468k

Two short and convergent routes have been devised for the preparation of enantiomerically pure acyclic epoxy vinyl sulfoxides. These substrates undergo highly regio- and stereoselective SN2′ displacements with lithium cyanocuprates to give α′-alkylated, γ-oxygenated Z α,β-unsaturated sulfoxides in moderate to good yields and with good to excellent diastereoselectivities. The absolute configuration of the newly formed carbon-carbon bond is primarily controlled by the chiral sulfur atom, which in a nonreinforcing situation can override the intrinsic anti tendency of the vinyl oxirane moiety and forces the cuprate to undergo syn addition. The hydroxy vinyl sulfoxide functionality of the resulting adducts should allow for subsequent asymmetric transformations thus enhancing the synthetic usefulness of this methodology.

Full text of DOI:10.1021/jo000468k

6462
J . Org. Chem. 2000, 65, 6462-6473
Su lfoxid e-Con tr olled SN2′ Disp la cem en ts betw een Cya n ocu p r a tes
a n d Ep oxy Vin yl Su lfoxid es1
J oseph P. Marino,*,† Laura J . Anna,† Roberto Ferna´ndez de la Pradilla,*,‡
Mar´ıa Victoria Mart´ınez,‡ Carlos Montero,‡ and Alma Viso§
Department of Chemistry, The University of Michigan, Ann Arbor, Michigan 48109-1055, Instituto de
Quı´mica Orga´nica, CSIC, J uan de la Cierva 3, E-28006 Madrid, Spain, and Departamento de Qu´ımica
Orga´nica I, Facultad de Qu´ımicas, Universidad Complutense, E-28040 Madrid, Spain
iqofp19@fresno.csic.es
Received March 28, 2000
Two short and convergent routes have been devised for the preparation of enantiomerically pure
acyclic epoxy vinyl sulfoxides. These substrates undergo highly regio- and stereoselective SN2′
displacements with lithium cyanocuprates to give R′-alkylated, γ-oxygenated Z R,â-unsaturated
sulfoxides in moderate to good yields and with good to excellent diastereoselectivities. The absolute
configuration of the newly formed carbon-carbon bond is primarily controlled by the chiral sulfur
atom, which in a nonreinforcing situation can override the intrinsic anti tendency of the vinyl oxirane
moiety and forces the cuprate to undergo syn addition. The hydroxy vinyl sulfoxide functionality
of the resulting adducts should allow for subsequent asymmetric transformations thus enhancing
the synthetic usefulness of this methodology.
Sch em e 1
The asymmetric construction of carbon-carbon bonds
in acyclic systems remains a challenging area in organic
synthesis.2 Within this field, the SN2′ cleavage of alkenyl
oxiranes by organocopper reagents3 is a valuable meth-
odology primarily due to the high degree of regio- and
stereocontrol observed.4 Previously, we have demon-
strated that copper-mediated SN2′ displacements of acy-
clic allylic mesylates A, activated with a chiral sulfoxide,
proceed with high asymmetric induction and Z-E selec-
tivity to produce enantiomerically pure trisubstituted
vinyl sulfoxides B (Scheme 1).5 As an extension of this
* Corresponding authors. J . P. Marino e-mail: jpmarino@umich.edu.
† The University of Michigan, Ann Arbor.
work we envisioned that the related enantiomerically
pure epoxy vinyl sulfoxides C could be useful substrates
for effecting allylic displacements with organocopper
reagents to produce densely functionalized allylic alcohols
D which maintain the versatile vinyl sulfoxide function-
ality thus allowing for additional enantioselective mani-
pulations.6e-g Moreover, a variety of additional substrate-
directed transformations were readily envisaged for the
‡ Instituto de Qu´ımica Orga´nica.
§ Universidad Complutense.
(1) Taken in part from the M.S. Thesis of M. V. M.; Ph. D. Theses
of C. M. and L. J . A. For a preliminary report, see: Marino, J . P.; Anna,
L. J .; Ferna´ndez de la Pradilla, R.; Mart´ınez, M. V.; Montero, C.; Viso,
A. Tetrahedron Lett. 1996, 37, 8031-8034.
(2) For leading reviews in acyclic stereocontrol, see: (a) Oare, D.
A.; Heathcock, C. H. In Topics in Stereochemistry; Eliel, E. L., Wilen,
S. H., Eds.; Wiley: New York, 1989; Vol. 19, pp 227-407. (b) Evans,
D. A.; Nelson, J . V.; Taber, T. R. In Topics in Stereochemistry; Allinger,
N. L., Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York, 1982; Vol. 13,
pp 1-115. (c) Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46,
1-103. (d) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105-209. (e)
Bartlett, P. A. Tetrahedron 1981, 36, 3-72. (f) Nogradi, N. Stereose-
lective Synthesis; VCH: Weinheim, Germany, 1995. (g) Cox, L. R.; Ley,
S. V. Chem. Soc. Rev. 1998, 27, 301-314. (h) Cha, J . K.; Kim, N.-S.
Chem. Rev. 1995, 96, 1761-1795.
(3) For reviews on organocopper chemistry, see: (a) Krause, N.;
Gerold, N. Angew. Chem., Int. Ed. Engl. 1997, 36, 186-204. (b)
Yamamoto, Y. In Methods Organic Chemistry (Houben Weyl), 4th ed.;
Helmchen, G., Hoffman, R. W., Mulzer, J ., Shauman, E., Eds.; Georg
Thieme Verlag, Stuttgart, Germany, 1995; Vol. E21b, pp 2401-2067.
(c) Lipshutz, B. H. In Advances in Metal-Organic Chemistry; Liebe-
skind, L. S., Ed.; J AI Press: Greenwich, CT, 1995; Vol. 4, pp 1-64.
(d) Lipshutz, B. H. In Organometallics in Synthesis; Schlosser, M., Ed.;
Wiley: Chichester, 1994; pp 283-382. (e) Knochel, P.; Singer, R. D.
Chem. Rev. 1993, 93, 2117-2188. (f) Wipf, P. Synthesis 1993, 537-
557. (f) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
(g) Kozlowski, J . A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, pp 169-198.
(h) Lipshutz, B. H. Synlett 1990, 119-128. (i) Lipshutz, B. H. Synthesis
1987, 325-341. (j) Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986,
25, 947-959, and references therein.
(4) For reviews on SN2′ reactions on vinyl oxiranes, see: (a)
Marshall, J . A. Chem. Rev. 1989, 89, 1503-1511. (b) Magid, R. M.
Tetrahedron 1980, 36, 1901-1930. For recent references on SN2′
displacements on vinyl oxiranes, see: (c) Nagumo, S.; Irie, S.; Akita,
H. Chem. Pharm. Bull. 1996, 44, 675-680. (d) Lipshutz, B. H.; Woo,
K.; Gross, T.; Buzard, D. J .; Tirado, R. Synlett 1997, 477-478. (e) Clive,
D. L. J .; Wickens, P. L.; da Silva, G. V. J . J . Org. Chem. 1995, 60,
5532-5536. (f) Marshall, J . A.; Crute, T. D., III; Hsi, J . D. J . Org. Chem.
1992, 57, 115-123. (g) Marshall, J . A.; Blough, B. E. J . Org. Chem.
1991, 56, 6, 2225-2234. (h) Marshall, J . A.; Blough, B. E. J . Org. Chem.
1990, 55, 1540-1547. (i) Hentemann, M.; Fuchs, P. L Org. Lett. 1999,
1, 355-357. For related SN2′ displacements on vinyl aziridines, see:
(j) Toda, A.; Aoyama, H.; Mimura, N.; Ohno, H.; Fujii, N.; Ibuka, T. J .
Org. Chem. 1998, 63, 7053-7061. (k) Ibuka, T.; Mimura, N.; Ohno,
H.; Nakai, K.; Akaji, M.; Habashita, H.; Tamamura, H.; Miwa, Y.; Taga,
T.; Fujii, N.; Yamamoto Y. J . Org. Chem. 1997, 62, 2982-2991. (l) Wipf,
P.; Henninger, T. C.; Geib, S, J . J . Org. Chem. 1998, 63, 6088-6089.
(m) Wipf, P.; Fritch, P. C. J . Org. Chem. 1994, 59, 4875-4886.
(5) (a) Marino, J . P.; Viso, A.; Lee, J .-D.; Ferna´ndez de la Pradilla,
R.; Ferna´ndez, P.; Rubio, M. B. J . Org. Chem. 1997, 62, 645-653. (b)
Marino, J . P.; Viso, A.; Ferna´ndez de la Pradilla, R.; Ferna´ndez, P. J .
Org. Chem. 1991, 56, 1349-1351.
10.1021/jo000468k CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

Sulfoxide-Controlled SN2′ Displacements
J . Org. Chem., Vol. 65, No. 20, 2000 6463
related enantiopure hydroxy vinyl sulfones,7 readily
accessible in a straightforward manner by oxidation at
sulfur. In this paper, we present a full account of our
research on the preparation of enantiomerically pure
acyclic epoxy vinyl sulfoxides and their highly regio- and
stereoselective SN2′ displacements with cyanocuprates.
In contrast with our previous work,5 the chiral sulfoxide
appears to be the predominant element of anti-syn
stereocontrol.
Sch em e 2
P r ep a r a tion of Su bstr a tes
After evaluating several routes to sulfinyl oxiranes C,8
we envisaged an approach based on the condensation of
enantiomerically pure lithio vinyl sulfoxides with R-func-
tionalized aldehydes and a straightforward functional-
ization of the resulting adducts to effect epoxide forma-
tion.9 While it is known that this condensation takes
place with low diastereoselectivity with nonchiral alde-
hydes, an increase in the steric size of the aldehyde
results in the stereoselective formation of sulfinyl allylic
alcohols in up to 70% de.9f Recently, in our studies
directed toward the formal synthesis of the plant growth
promoter Brassinolide, we described the first example of
double diastereoselection in the condensation of simple
(6) For reviews on synthetic applications of sulfoxides, see: (a)
Carren˜o, M. C. Chem. Rev. 1995, 95, 1717-1760. (b) Walker, A. J .
Tetrahedron: Asymmetry 1992, 3, 961-968. (c) Garc´ıa Ruano, J . L.;
Cid de la Plata, B. Top. Curr. Chem. 1999, 204, 1-126. (d) Procter, D.
J . J . Chem. Soc., Perkin Trans. 1 1999, 641-667. (e) Allin, S. M.; Page,
P. C. B. Org. Prep. Proc. Int. 1998, 30, 145-176. (f) Padwa, A.; Gunn,
D. E., J r.; Osterhout, M. H. Synthesis 1997, 1353-1377. (g) Marino,
J . P. Pure Appl. Chem. 1993, 65, 667-674. For leading references on
applications of vinyl sulfoxides, see: (h) Ferna´ndez de la Pradilla, R.;
Castro, S.; Manzano, P.; Mart´ın-Ortega, M.; Priego, J .; Viso, A.;
Rodr´ıguez, A.; Fonseca, I. J . Org. Chem. 1998, 63, 4954-4966. (i) Adrio,
J .; Carretero, J . C. J . Am. Chem. Soc. 1999, 121, 7411-7412. (j) Priego,
J .; Carretero, J . C. Synlett 1999, 1603-1605. (k) Delouvrie´, B.;
Fensterbank, L.; Lacoˆte, E.; Malacria, M. J . Am. Chem. Soc. 1999, 121,
11395-11401.
(7) Vinyl sulfones are versatile synthetic intermediates. For selected
reviews, see: (a) Simpkins, N. S. Sulphones in Organic Synthesis;
Pergamon Press: Oxford, 1993. (b) Fuchs, P. L.; Braish, T. F. Chem.
Rev. 1986, 86, 903-917. For leading references, see: (c) J ackson, R.
F. W.; Standen S. P.; Clegg, W. J . Chem. Soc., Perkin Trans. 1 1995,
149-156. (d) Garrido, J . L.; Alonso, I.; Carretero, J . C. J . Org. Chem.
1998, 63, 9406-9413. (e) Carretero, J . C.; Go´mez Arraya´s, R. J . Org.
Chem. 1998, 63, 2993-3005. (f) Back, T. G.; Nakajima, K. J . Org.
Chem. 1998, 63, 6566-6571. (g) Caturla, F.; Na´jera, C. Tetrahedron
1998, 54, 11255-11270. (h) Adrio, J .; Carretero, J . C. Tetrahedron
1998, 54, 1601-1614. (i) Enders, D.; Mu¨ller, S. F.; Raabe, G. Angew.
Chem., Int. Ed. Engl. 1999, 38, 195-197. (j) Carretero, J . C.; Go´mez
Arraya´s, R. Synlett 1999, 49-50.
(8) For leading references on the preparation of vinyl oxiranes, see:
(a) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J . Org. Chem.
1998, 63, 2948-2953. (b) Hu, S.; J ayaraman, S.; Oehlshlager, A. C. J .
Org. Chem. 1998, 63, 8843-8849. (c) Ma, S.; Zhao, S. J . Am. Chem.
Soc. 1999, 121, 7943-7944. (d) Ramachandran, P. V.; Krzeminski, M.
P. Tetrahedron Lett. 1999, 40, 7879-7881. For leading references on
synthetic applications of vinyl oxiranes, see: (e) J ung, M. E.; Marquez,
R. Tetrahedron Lett. 1999, 40, 3129-3132. (f) Trost, B. M.; McEachern,
E. J . J . Am. Chem. Soc. 1999, 121, 8649-8650. (g) Murphy, S. T.;
Bencsik, J . R.; J ohnson, C. R. Org. Lett. 1999, 1, 1483-1485. (h) Sasaki,
M.; Inoue, M.; Takamatsu, K.; Tachibana, K. J . Org. Chem. 1999, 64,
9399-9415.
(9) For the original reports on R-metalation of vinyl sulfoxides, see:
(a) Posner, G. H.; Tang, P. W.; Mallamo, J . P. Tetrahedron Lett. 1978,
3995-3998. (b) Okamura, H.; Mitsuhira, Y.; Miura, M.; Takei, H.
Chem. Lett. 1978, 517-520. For the condensation between R-metalated
vinyl sulfoxides and aldehydes, see: (c) Posner, G. H.; Mallamo, J . P.;
Miura, K.; Hulce, M. Pure Appl. Chem. 1981, 53, 2307-2314. (d)
Cheng, H.-C.; Yang, T.-H. Tetrahedron Lett. 1990, 31, 673-676.
Complete selectivity was found in one isolated example. (e) Solladie´,
G.; Moine, G. J . Am. Chem. Soc. 1984, 106, 6097-6098. (f) Fawcett,
J .; House, S.; J enkins, P. R.; Lawrence, N. J .; Russell, D. R. J . Chem.
Soc., Perkin Trans. 1 1993, 67-73. For the intramolecular alkylation
of R-sulfinyl vinyl carbanions, see: (g) Maezaki, N.; Izumi, M.; Yuyama,
S.; Iwata, C.; Tanaka, T. Chem. Commun. 1999, 1825-1826.
enantiomeric lithiated vinyl sulfoxides with a chiral
nonracemic steroidal aldehyde.10 Unfortunately, in this
example the reaction proceeded with moderate diaste-
reoselectivity (20 and 60% de for the mismatched and
matched pairs respectively). However, we hoped that the
use of O-protected R-alkoxy aldehydes or R-halo alde-
hydes could result in an enhanced selectivity and provide
a further understanding of the factors that control the
stereochemical outcome of the process when a chiral
sulfoxide and different chiral R-branched aldehydes are
involved.
Scheme 2 gathers our efforts to prepare the desired
oxiranes from enantiopure R-alkoxy aldehydes 2 and 311,12
and enantiomeric vinyl sulfoxides 1a and 1b.13 These
condensations took place in fair to good yields (52-84%)
but with modest diastereoselectivities (60:40 to 83:17) to
produce diastereomeric alcohols 4 and 5 which were
readily separated by chromatography on silica gel. Ox-
irane formation was then achieved smoothly (68-82%)
by mesylation and fluoride-induced ring closure. The
(10) Marino, J . P.; de Dios, A.; Anna, L. J .; Ferna´ndez de la Pradilla,
R. J . Org. Chem. 1996, 61, 109-117.
(11) Prepared in two steps from the commercially available enan-
tiomerically pure ethyl esters (lactate and mandelate): Massad, S. K.;
Hawkins, L. D.; Baker, D. C. J . Org. Chem. 1983, 48, 5180-5182.
(12) Enantiomerically pure R-alkoxy aldehydes are readily available
by several routes such as glycol cleavage or asymmetric dihydroxylation
of terminal alkenes followed by selective hydroxyl protection and Dess-
Martin oxidation. For recent examples, see: (a) Zhong, Y.-L-; Shing,
T. K. M. J . Org. Chem. 1997, 62, 2622-2624. (b) Li, S.; Pang, J .; Wilson,
W. K.; Schroepfer, G. J ., J r. Tetrahedron: Asymmetry 1999, 10, 1687-
1707.
(13) Prepared in one step from commercially available enantiomeri-
cally pure (+)-menthyl (R)-p-toluensulfinate or (-)-menthyl (S)-p-
toluensulfinate by the method of Craig: Craig, D.; Daniels, K.;
MacKenzie, A. R. Tetrahedron 1993, 49, 11263-11304. Lithiation of
Z vinyl sulfoxides yields E lithio derivatives; there are conflicting
reports on the configurational stability at sulfur in this process, see:
(a) Posner, G. H. In Asymmetric Reactions and Processes in Chemistry;
Eliel, E. L., Otsuka, S., Eds.; ACS Symposium Series No. 185; American
Chemical Society: Washington, DC, 1982; p 142. (b) See refs 9f and
9g.

6464 J . Org. Chem., Vol. 65, No. 20, 2000
Marino et al.
Sch em e 3
results for 9b but produced substantial amounts of
dimeric byproduct 7e′ (ca. 10%), along with the desired
oxirane, 7e.19 This unwanted reaction pathway could be
suppressed by the use of 1.2 equiv of n-BuLi (-78 °C to
room temperature, THF, 5 h). In contrast, phenyl-
substituted chlorohydrins 11b and 12b led smoothly to
the desired oxiranes 7f and 9c, even with a suspension
of KO-t-Bu in THF (1.2 equiv, 0 °C, 30 min), provided
the reaction conditions were carefully controlled.
The structures of sulfinyl diols 4-6, chlorohydrins 11
and 12, and oxiranes 7-9 were tentatively assigned by
spectroscopic methods, primarily by 1H and 13C NMR.
The geometry of our vinyl oxiranes conclusively followed
from the vicinal coupling constants observed for the
oxirane protons (1.8-2.4 Hz for trans isomers and 3.8-
4.0 Hz for cis oxiranes).20 This assignment, coupled with
the known stereochemical course for oxirane formation,
allowed for the unequivocal determination of an anti
configuration for the precursors of trans oxiranes, 7 and
9, derived from the alkoxy aldehyde route. It should be
noted that diastereomeric oxiranes 7 and 9 display
strikingly different chemical shifts for the oxirane protons
(see Experimental Section) and a detailed comparison of
these shifts for oxiranes obtained by either route allowed
for firm structural assignments for chlorohydrins 11 and
12.21 These assignments were later secured by an X-ray
diffraction analysis of the p-nitrobenzoate of 11a , 11a ′.
The stereochemical outcome of these condensations is
consistent with a predominant Cram addition of the vinyl
(17) While at this early stage of the process access to both diaster-
eomeric series (R and â epoxide) was in fact desirable, the possibility
of preparing enantiopure R-halo aldehydes by selective reduction of
the corresponding esters (DIBAL-H in toluene) and in situ condensa-
tion with lithiated alkenyl sulfoxides at low temperature was explored.
Initial attempts performed on racemic R-chloro esters gave very low
conversions (ca. 20%) to the desired chlorohydrins, presumably due to
predominant protonation of the metalated sulfoxide by the acidic
R-hydrogen under these conditions. An improved conversion (ca. 67%)
was observed for racemic R-bromo esters. We believe that, after
optimization, this experimentally challenging protocol could be a
valuable alternative in some cases. Later, to improve the versatility
of this route, the inversion of the allylic hydroxyls to generate syn
chlorohydrins, potential precursors of cis oxiranes was explored. Under
Mitsunobu conditions (Ph3P, C6H5CO2H, DIAD, benzene, rt) 11a and
12a gave clean SN2 inversion albeit not synthetically useful due to a
predominant nonselective SN2′ pathway for 12a or to a low conversion
(43%) for 11a . A straightforward inversion of the mesylate derivative
of 11a with KO2 (Corey, E. J .; Nicolau, K. C.; Shibasaki, M.; Machida,
Y.; Shiner, C. S. Tetrahedron Lett. 1975, 37, 3183-3186) led to a
complex mixture of products.
(18) The desired oxiranes 7e and 9b were obtained in fair yield by
simply allowing the crude condensation mixture to warm to room
temperature; however, separation of these diastereomers by chroma-
tography was exceedingly difficult and therefore we settled for the use
of pure chlorohydrins 11a and 12a . Our initial experiments entailed
addition of solid NaO-t-Bu to a cold (0 °C) solution of 12a in THF.
These conditions, particularly upon scale-up, gave very erratic results
with low yields of oxirane 9b and complex reaction mixtures containing
up to 50% of 1-p-tolylsulfinyl-2-hexene, presumably produced by
fragmentation of 12a . The use of solid KO-t-Bu gave even more complex
reaction mixtures. Fortunately, we found that the use of a preformed
suspension of NaO-t-Bu in THF gave reproducible results.
ability of silyl groups to migrate under basic conditions
between adjacent hydroxyl groups14 allowed for a simple
entry to diastereomeric oxiranes such as 9a by treatment
of 4a with Et3N in refluxing methanol to produce 6 and
subsequent ring closure as described above.
Scheme 3 shows a straightforward alternative ap-
proach to these oxiranes based on the condensation of
lithiated vinyl sulfoxides with readily available racemic
R-halo aldehydes.15 Thus, metalation of enantiopure
alkenyl sulfoxides 1c and 1d 13 and reaction with freshly
distilled racemic 2-chlorohexanal, (()-10,16 afforded a ca.
50:50 mixture of diastereomeric anti chlorohydrins 11
and 12 with high selectivity. A very simple chromato-
graphic separation followed by recrystallization gave good
yields of these adducts (33-38% of each isomer),17 along
with small amounts of unreacted starting material
(<10%, E isomer) and syn chlorohydrins (syn:anti ratio,
ca. 92:8). The preparation of the desired oxiranes, 7 and
9, was then explored. After considerable experimenta-
tion,18 we focused our efforts on the use of a suspension
of NaO-t-Bu in THF (0 °C, 30 min), which gave excellent
(14) (a) J ones, S. S.; Reese, C. B. J . Chem. Soc., Perkin Trans. 1
1979, 2762-2764. (b) Ogilvie, K. K.; Entwistle, D. W. Carbohydr. Res.
1981, 89, 203-210.
(19) Interestingly, this dimer was obtained as a single diastereomer
derived from the stereoselective SN2′ addition of chlorohydrin 11a to
vinyl epoxide 7e. The configuration at C-8 has not been determined.
(20) These are standard values for vicinal coupling constants in
oxiranes. See ref 6h for data of a variety of sulfinyl oxiranes.
(21) Chlorohydrins 11 had a higher chromatographic mobility than
diastereomers 12; this is in agreement with previous findings for
â-hydroxy sulfoxides. See ref 5. See also: (a) Brunet, E.; Garc´ıa Ruano,
J . L.; Mart´ınez, M. C.; Rodr´ıguez, J . H. Tetrahedron 1984, 40, 2023-
2034. (b) Rayner, C. M.; Westwell, A. D. Tetrahedron Lett. 1992, 33,
2409-2412. In an early attempt to secure the relative configuration
of these chlorohydrins, the free radical dehalogenation of 11a and 12a
was explored (Bu3SnH, AIBN, toluene, 100 °C, 4 h), hoping to obtain
sulfinyl alcohols closely related to those described in ref 5. Surprisingly,
good yields of the corresponding enantiomeric sulfonyl chlorohydrins
were obtained.
(15) Enantiopure R-halo aldehydes are relatively difficult to prepare
and particularly prone to undergo racemization under standard
laboratory conditions. For the asymmetric synthesis of nonracemic
R-fluoro aldehydes, see: (a) Davis, F. A.; Kasu, P. V.; Sundarababu,
G.; Qi, H. J . Org. Chem. 1997, 62, 7546-7547. For the synthesis of
related enantiomerically pure R-chloro and R-bromo aldehydes see: (b)
Mart´ın, V. S.; Palazo´n, J . M. Tetrahedron Lett. 1992, 33, 2399-2402.
For protocols to generate these intermediates in situ, see: (c) Bailey,
P. L.; Briggs, A. D.; J ackson, R. F. W.; Pietruska, J . J . Chem. Soc.,
Perkin Trans. 1 1998, 3359-3363. (d) Wang, S.; Howe, G. P.; Mahal,
R. S.; Procter, G. Tetrahedron Lett. 1992, 33, 3351
(16) Prepared in one step by the method of Stevens: Stevens, C. L.;
Farkans, E.; Gillis, B. J . J . Am. Chem. Soc. 1954, 76, 2695-2698.

Sulfoxide-Controlled SN2′ Displacements
J . Org. Chem., Vol. 65, No. 20, 2000 6465
Sch em e 4
contrast, under identical reaction conditions, diastereo-
meric sulfinyl epoxide 9b produced a 4:96 mixture of SN2′
adducts 16a and 15a in excellent yield (Table 1, entry
4). The major products of these displacements, 13a and
15a had remarkably similar spectral features (see below),
and this suggested that a different syn/anti reaction
pathway was operative for each diastereomeric oxirane.
Encouraged by these results, we carried on with the
study to evaluate the scope of the methodology with
respect to the use of different cyanocuprates and to the
range of substituents on the vinyl oxiranes. In this
manner, while EtCuCNLi gave a very high syn selectivity
with 7e in a very clean reaction (Table 1, entry 2), the
use of EtCuCNMgBr afforded lower yields of SN2′ prod-
ucts due to competitive formation of variable amounts
of allene 18b and regioisomeric adducts 17b and 17b′
(Table 1, entries 3 and 5), especially when the cyanocu-
prate was generated from commercial EtMgBr. Nonethe-
less, these processes took place in fair yields and,
remarkably, with anti selectivity for both diastereomeric
oxiranes (5:95 for 9b and 27:73 for 7e, opposite to the
finding for EtCuCNLi, compare Table 1 entries 2 and 3).
The use of aryl copper species was also explored for
oxirane 9b, and not surprisingly,25 a predominant SN2
pathway was found for PhCuCNLi (Table 1, entry 6)
which gave anti adduct 15c. In an effort to improve the
regiochemical outcome of the process we tested a Lewis
acid modified aryl copper reagent, PhCu‚LiBr‚BF3,4c
which gave a clean SN2′ process but just moderately anti
selective (20:80), along with substantial amounts of
starting material and bromohydrin 17e.26
anion to the less hindered face of the carbonyl22 and may
be rationalized in terms of a chelate chairlike transition
state,9f where the aldehyde adopts a Felkin-Ahn rota-
tional conformation,10 with matched and mismatched
pairs for alkoxy aldehydes. In contrast, chloro aldehydes
do not display any measurable double diastereoselection
upon reaction with lithiated vinyl sulfoxides.
The effect of a bulky isopropyl group on the vinyl
moiety of our oxiranes was examined with excellent
results for the reactions between substrates 7a and 9a
and n-BuCuCNLi (Table 1, entries 8 and 13). On the
other hand, the use of EtCuCNMgBr with 7a and 9a
(Table 1, entries 9 and 14) afforded mainly SN2 products
17d and 17d ′27 and allene 18d ; however, the SN2′
pathway showed also an anti selectivity as described
above.
Cu p r a te SN2′ Disp la cem en ts on Ep oxy Vin yl
Su lfoxid es
Our initial task was to establish the viability of the
proposed copper-mediated SN2′ displacements on our
sulfinyl oxiranes. After several preliminary attempts with
Gilman’s reagent (Me2CuLi‚LiI, -78 °C to room temper-
ature) and substrates 7e and 9b (Scheme 4) which led
mainly to diastereomeric mixtures of allene 18b,23 we
focused our efforts on the use of cyanocuprates,24 and the
results obtained are presented in Scheme 4 and Table 1.
Thus, the reaction between oxirane 7e and MeCuCNLi
(6 equiv, Et2O, -78 °C to room temperature, 2 h) gave a
good yield of an 85:15 mixture of SN2′ products 13a and
14a with complete Z selectivity (Table 1, entry 1). In
Entry 10 shows that the geometry of the oxirane does
not have a significant effect on the stereochemical
outcome of the process.28 Finally, phenyl substituted vinyl
sulfoxide 7f gave a smooth syn 1,4 displacement with
n-BuCuCNLi (91:9), further improved (96:4) by lowering
the reaction temperature to -100 °C. Diastereomeric
oxirane 9c gave a clean anti displacement with MeCuCN-
Li but accompanied by a substantial amount of allene
18f, which became the major product when the “higher
order” reagent Me2CuLi‚LiCN was used, along with a
decrease in anti selectivity (Table 1, entries 16 and 17).
In contrast, n-BuCuCNLi gave a high yielding anti
displacement with 9c (Table 1, entry 17).
(22) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191-1223.
Moderate diastereoselectivities have been obtained (dr ) 77:23-88:
12) in favor of anti chlorohydrins (Cram addition mode) in the
condensation between standard nucleophiles and R-chloro aldehydes,
see: (c) Frenking, G.; Ko¨hler, K. F.; Reetz, M. T. Tetrahedron 1991,
43, 9005-9018.
(25) Organocopper reagents with sp2-hybridized ligands often show
a decreased regioselectivity in these processes. See: Marino, J . P.;
Ferna´ndez de la Pradilla, R.; Laborde, E. J . Org. Chem. 1987, 52,
4898-4913.
(23) For a discussion of a related allene formation, see: (a) Ferna´n-
dez de la Pradilla, R.; Rubio, M. B.; Marino, J . P.; Viso, A. Tetrahedron
Lett. 1992, 33, 4985-4988. See also: (b) Delouvrie´, B.; Lacoˆte, E.;
Fensterbank, L.; Malacria, M. Tetrahedron Lett. 1999, 40, 3565-3568.
(c) Satoh, T.; Kuramochi, Y.; Inoue, Y. Tetrahedron Lett. 1999, 40,
8815-8818.
(24) (a) Initial attempts in THF resulted in recovery of starting
material. (b) Cyanocuprates have been the subject of a long standing
controversy regarding structure and reactivity aspects. For a recent
discussion, see: Krause, N. Angew. Chem., Int. Ed. Engl. 1999, 38,
79-80.
(26) In sharp contrast, diastereomeric epoxide 7e showed a different
behavior under identical reaction conditions with aryl copper species
(PhCuCNLi and PhCuLiBr‚BF3). The crude reaction mixtures con-
tained important amounts of starting material and complex mixtures
of Z/ E and syn/anti SN2′ adducts.
(27) The unusually large amount of SN2 products and allene
byproduct obtained in this experiment may be due to the fact that
commercial EtMgBr was used.
(28) Due to the different geometry of the oxirane, the syn-anti
stereochemistry of the SN2′ adduct is opposite to the stereochemical
course.

6466 J . Org. Chem., Vol. 65, No. 20, 2000
Ta ble 1. Rea ction of Ep oxy Vin yl Su lfoxid es w ith Cu p r a tes
Marino et al.
yield (%)b
entry
substrate
R2
R1
RCua
syn SN2′
anti SN2′
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
7e
7e
7e
9b
9b
9b
9b
7a
7a
8a
7f
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Me
Me
Me
n-Bu
n-Bu
Me
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
i-Pr
i-Pr
i-Pr
Ph
MeCuCNLi
EtCuCNLi
EtCuCNMgBr
MeCuCNLi
EtCuCNMgBr
PhCuCNLi
PhCu‚LiBr‚BF3
n-BuCuCNLi
EtCuCNMgBr
MeCuCNLi
n-BuCuCNLi
n-BuCuCNLi
n-BuCuCNLi
EtCuCNMgBr
MeCuCNLi
13a (85)
13b (100)
13b (27)
16a (4)
16b (5)
16c (0)
16c (20)
13c (88)
13d (25)
14e (7)
13f (91)
13f (96)
16d (0)
16e (0)
16f (0)
14a (15)
14b (0)
69
82
56c
93
64d
e
f
68
g
70
82
i
75
j
14b (73)
15a (96)
15b (95)
15c (100)
15c (80)
14c (12)
14d (75)
13e (93)h
14f (9)
7f
Ph
14f (4)
9a
9a
9c
9c
9c
i-Pr
i-Pr
Ph
Ph
Ph
15d (100)
15e (100)
15f (100)
15f (63)
16c (100)m
Me
n-Bu
n-Bu
n-Bu
k
l
87
Me2CuCNLi2
n-BuCuCNLi
16f (37)
15c (0)
a
Cyanocuprates were prepared from CuCN and the corresponding RLi or RMgBr. All experiments were carried out with an excess of
b
the organocuprate (6-9 equiv) in Et2O from -78 °C to room temperature unless otherwise stated. Unoptimized combined yields of pure
SN2′ products. Product ratios were measured by integration of well-separated absorptions of the 1H NMR spectra of the crude reaction
mixtures. c A 10% ratio of 17b and a 25% ratio of 18b were also observed in the 1H NMR spectrum of the reaction mixture. An 8% ratio
d
of 17b′ and an 11% ratio of 18b were also observed in the 1H NMR spectrum of the reaction mixture. e A 30:70 mixture of 15c and 17c
was obtained. The yield was not determined. f BF3‚Et2O was added at -78 °C to a preformed solution of the organocuprate; 13% ratio of
bromohydrin 17e and 19% ratio of starting material were also detected in the 1H NMR spectrum of the reaction mixture. The yield was
not determined. g A 30% ratio of 17d and a 40% ratio of 18d were also observed in the 1H NMR spectrum of the reaction mixture. Combined
h
i
yield 54%. Due to the different geometry of the starting material, 13e is the anti SN2′ product. The reaction was carried out at -100
°C. The yield was not determined. A 50% ratio of 17d ′ was also observed in the 1H NMR spectrum of the reaction mixture. Combined
j
yield 76%. A 41% ratio of 18f was also observed in the 1H NMR spectrum of the reaction mixture. A 67% ratio of 18f was also also
k
l
observed in the 1H NMR spectrum of the reaction mixture. The yield was not determined. In this particular case 16c is the anti SN2′
m
product.
Sch em e 5
The general structure of these SN2′ adducts 13-16 was
1
established readily from their H and 13C NMR spectral
absorptions, including differential NOE experiments. The
Z stereochemistry of the trisubstituted double bond
derives from the chemical shifts found for the proton
attached to the allylic hydroxyl group (H-5 for 15a , 5.10
ppm) particularly deshielded due to the effect of the
sulfinyl moiety relative to related E isomers prepared in
our laboratories.5 Furthermore, in the case of 15a , a 1.1%
NOE enhancement was found for the ortho ArH protons
upon irradiation of H-5. The relative stereochemistry of
the newly created carbon-carbon bond and the sulfoxide
group was deduced by comparison of the spectral char-
acteristics of these adducts with those of related com-
pounds of known structure (Scheme 5).5 A particularly
distinctive feature found was that the methyl group
attached to the allylic position appeared substantially
more shielded in diastereomers 15a and 13a (0.63 and
0.65 ppm) than in 14a and 16a (1.09 and 1.04 ppm). This
is in agreement with the shifts of 0.56 and 1.11 ppm
observed for 19a and 19b.5
These spectroscopic evidences suggested that a differ-
ent anti-syn stereochemical pathway was operative for
identical physical and spectroscopic data to that obtained
each diastereomeric epoxide 7e and 9b. To confirm this
from 13a as described above.30 The structure of the other
hypothesis, we prepared the p-nitrobenzoates of alcohols
SN2′ products was assessed by comparison of key spectral
13a and 15a , 20 and 21, respectively, under standard
absorptions with those of these series.
conditions (p-NO2BzCl, Et3N, cat DMAP, CH2Cl2). On the
other hand, the treatment of 15a with p-nitrobenzoic acid
under Mitsunobu conditions (p-NO2BzOH, DIAD, Ph3P,
SN2′ Cu p r a te Disp la cem en ts on Ep oxy Vin yl
THF),29 led to a good yield of p-nitrobenzoate 20, of
Su lfid es a n d Su lfon es
At this stage we considered that varying the oxidation
state on sulfur to sulfone and sulfide would extend the
scope of the methodology and provide some insight on
the stereochemical outcome of these processes.31,32 Enan-
tiomerically pure sulfonyl oxiranes 22, en t-22, and 23
were obtained in good yields by oxidation of the corre-
(29) (a) Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017-
3020. For reviews, see: (a) Hughes, D. L. Org. React. 1992, 42, 335-
669. (b) Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127-164. The
choice of solvent proved to be critical; polar solvents such as DME or
DMF afforded unreacted starting material and in benzene a 20% ratio
of the desired product was obtained along with an 80% ratio of a
product (2:1 mixture of isomers) of undetermined structure.

Sulfoxide-Controlled SN2′ Displacements
J . Org. Chem., Vol. 65, No. 20, 2000 6467
Sch em e 6
Sch em e 7
resulting vinyllithium reagent was condensed with silyl-
ated lactaldehyde 2a to give a 75:25 mixture of anti
adducts 25 and 26.34 Subsequent mesylation and fluoride-
induced oxirane formation gave enantiomeric alkenyl
sulfides 27 and en t-27.
Scheme 7 and Table 2 gather our survey on these
displacements. The reaction of sulfonyl oxirane 22 with
MeLi gave a complex mixture of E and Z SN2′ products
with low syn-anti stereoselectivity (Table 2, entry 1). A
significant improvement in diastereoselection was ob-
served when MeCu‚AlMe3 was used (Table 2, entry 2)
but unfortunately, although a single Z-SN2′ isomer 28a
was obtained, a 33% ratio of allene 18b was also present
in the reaction mixture. On the other hand, lithium alkyl
cyanocuprates displayed good Z selectivity but with poor
anti stereochemistry (Table 2, entries 3 and 5). The use
of a Grignard derived cyanocuprate (Table 2, entry 4)
resulted in excellent Z anti selectivity but at the expense
of a 27% ratio of E SN2′ product 30b, obtained as a single
diastereomer. Finally sulfide 27 gave a poorly anti
selective displacement with n-BuCuCNLi but with com-
plete Z stereocontrol. These preliminary studies have
established the viability of these processes though some
optimization is still needed.
The general structure of these SN2′ products (28-30)
was derived from their spectral features, as described
above. However, the elucidation of the relative stereo-
chemistry at the allylic centers required some chemical
correlations shown in Scheme 8. Thus, deoxygenation of
15d (TiCl4/Zn) gave sulfide en t-28d ′,35 and oxidation of
15a and 15d gave vinyl sulfones en t-28a and en t-28c,
respectively. Similarly, oxidation of a 60:40 mixture of
14b and 13b gave a 60:40 mixture of sulfones en t-28b
and en t-29b.
sponding sulfoxides 7e, 9b, and 9a with MMPP or
m-CPBA (Scheme 6). On the other hand, iodo vinyl
sulfide 2433 was treated with tert-butyllithium, and the
(30) These assignments are further supported by the following
chemical correlation: oxidation of Z anti adduct 15b (for the oxidation
of E γ-hydroxy R,â-unsaturated sulfoxides, see Guerrero de la Rosa,
V.; Ordo´n˜ez, M.; Alcudia, F.; LLera, J . M. Tetrahedron Lett. 1995, 36,
4889-4892) gave a sulfinyl enone that was reduced with Luche’s
reagent (Gemal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981, 103, 5454-
5459) to produce Z syn adduct 13b with good stereoselectivity (13b:
15b, 86:14). These results suggest that, after optimization, syn adducts
should be available by either syn displacement on oxiranes 7 or anti
displacement on oxiranes 9 followed by oxidation-reduction or Mit-
sunobu protocols. Data for the sulfinyl enone: 1H NMR (200 MHz) δ
0.62-1.75 (m, 21 H), 2.30 (m, 1 H), 2.43 (s, 3 H), 2.85 (m, 2 H), 6.26 (s,
1 H), 7.34 (d, 2 H, J ) 8.4 Hz), 7.83 (d, 2 H, J ) 8.4 Hz).
Resu lts a n d Discu ssion
The Z-selectivity found for these cuprate displacements
may be understood in terms of addition to the more stable
s-trans reactive conformations of the vinyl oxiranes,
dictated by competing allylic 1,2 and 1,3 strains, with
the latter interaction being more severe (Scheme 9).36 In
turn, it is likely that the s-trans conformation proposed
(31) For examples of SN2′ processes on acyclic vinyl sulfones, see:
(a) Auvray, P.; Knochel, P.; Normant, J . F. Tetrahedron 1988, 44,
6095-6106. (b) See also ref 5a .
(32) For examples of SN2′ displacements on cyclic vinyl sulfones,
see: (a) Saddler, J . C.; Fuchs, P. L. J . Am. Chem. Soc. 1981, 103, 2112-
2114. (b) Pan, Y.; Hardinger, S. A.; Fuchs, P. L. Synth. Commun. 1989,
19, 403-416. (c) Pan, Y.; Hutchinson, D. K.; Nautz, M. H.; Fuchs, P.
L. Tetrahedron 1989, 45, 467-478. (d) Ba¨ckvall, J . E.; J untunen, S.
K. J . Org. Chem. 1988, 53, 2398-2400. (e) Braish, T.; Saddler, J . C.;
Fuchs P. L. J . Org. Chem. 1988, 53, 3647-3658. (f) Hardinger, S. A.;
Fuchs, P. L. J . Org. Chem. 1987, 52, 2739-2749. (g) Arjona O.; de
Dios, A.; Ferna´ndez de la Pradilla, R.; Plumet, J .; Viso, A. J . Org. Chem.
1994, 59, 3906-3916. (h) See ref 4i.
(34) The unusual amount of silicon migration product 26 obtained
in this experiment is likely due to the fact that the reaction mixture
was allowed to warm to -20 °C prior to quenching; this procedure was
not optimized.
(35) Although a definitive conclusion cannot be reached due to the
difference in the aryl sulfide substituent (p-tolyl vs phenyl) the allylic
proton of the deoxygenation product en t-28d ′ had identical chemical
shift to the allylic proton of the major isomer of the cuprate addition
28d .
(33) Iodo vinyl sulfide 24 was prepared from (phenylthio)acetylene
(Magriotis, P. A.; Brown J . T. Org. Synth. 1993, 72, 252-264) using
the procedure described: (a) Alexakis, A.; Cahiez, G.; Normant, J . F.;
Villieras, J . Bull. Soc. Chim. Fr. 1977, 693-698. (b) Vermeer, P.; de
Graaf, C.; Meijer, J . Recl. Trav. Chim. Pays-Bas 1974, 93, 24-25.
(36) Hoffman, R. W. Chem. Rev. 1989, 89, 1841-1860.

6468 J . Org. Chem., Vol. 65, No. 20, 2000
Ta ble 2. Rea ction of Or ga n ocu p r a tes w ith Ep oxy Vin yl Su lfon es a n d Su lfid es
Marino et al.
alleneb
entry
substrate
R2
R1
S
RCua
Z anti SN2′
Z syn SN2′
E SN2′
1
22
22
22
en t-22
23
n-Bu
n-Bu
n-Bu
n-Bu
Me
n-Bu
n-Bu
n-Bu
n-Bu
i-Pr
SO2-p-Tol
SO2-p-Tol
SO2-p-Tol
SO2-p-Tol
SO2-p-Tol
SPh
MeLi
MeCu‚AlMe3
MeCuCNLi
EtCuCNMgBr
n-BuCuCNLi
n-BuCuCNLi
28a (30)
28a (67)
28a (63)
28b (63)
28c (70)
28d (60)
29a (30)
29a (0)
29a (37)
29b (0)
29c (30)
29d (40)
30a (40)
2c
3
18b (33)
18b (10)
4d
5d
6
30b (27)
27
Me
i-Pr
a
Cyanocuprates were prepared from CuCN and the corresponding RLi or RMgBr; MeCu was prepared from CuI and MeLi. All
experiments were carried out with an excess of the organocuprate or alkyllithium (6-9 equiv) in Et2O at -78 °C unless otherwise noted.
b
Product ratios were measured by integration of the 1H NMR spectra of the crude reaction mixtures. c The reaction was carried out in
d
THF and AlMe3 was added at -78 °C to a performed solution of the organocopper reagent. For SN2′ products obtained from en t-22 and
23, the relative configuration of the allylic carbons in the displacement products is equal (anti/syn) but opposite to the one shown in
Scheme 7.
Sch em e 8
Sch em e 10
Sch em e 9
Most SN2′ displacements involving cuprates and vinyl
oxiranes take place with high anti facial selectivity,4a and
this preference has been rationalized in terms of orbital
symmetry.38 Our results may be accounted for in terms
of a reinforcing vs nonreinforcing scenario,39 involving
the chiral sulfoxide and the vinyl oxirane moieties. For
lithium cyanocuprates, diastereomers 9 afforded products
consistent with direct addition of the copper reagent anti
to the oxirane and sulfinyl oxygens on conformation I
(Scheme 10), followed by reductive elimination. Alterna-
tively, the remarkable reversal of facial selectivity found
for vinyl oxiranes 7 suggests a nonreinforcing situation
in which the sulfinyl group can override the intrinsic anti
stereochemical bias of the process to produce 1,4 syn
for the vinyl oxirane functionality will influence the
conformational distribution about the C-S bond of the
vinyl sulfoxide moiety, in favor of a CdC/lone pair anti
conformation.37
(38) For mechanistic proposals, see: (a) Corey, E. J .; Boaz, N. W.
Tetrahedron Lett. 1984, 25, 3063-3066. (b) Goering, H. L.; Kantner,
S. S. J . Org. Chem. 1984, 49, 422-426.
(39) Evans, D. A.; Dart, M. J .; Duffy, J . L.; Yang, M. G. J . Am. Chem.
Soc. 1996, 118, 4322-4343.
(37) For a computational treatment of the conformations of R,â-
unsaturated sulfoxides, see: Tiezte, L. F.; Schuffenhauer, A.; Schreiner,
P. R. J . Am. Chem. Soc. 1998, 120, 7952-7958, and references therein.

Sulfoxide-Controlled SN2′ Displacements
J . Org. Chem., Vol. 65, No. 20, 2000 6469
Sch em e 11
a variety of diastereomeric epoxy vinyl sulfoxides that
undergo highly regio- and stereoselective anti or syn SN2′
displacements with lithium alkyl cyanocuprates in accord
with a reinforcing/nonreinforcing scenario with the sul-
foxide being the predominant element for stereocontrol.
This reversal of selectivity under identical reaction
conditions is unprecedented and underlines the extremely
powerful stereocontrolling character of the readily avail-
able and synthetically useful sulfinyl functionality. In
addition, the resulting γ-hydroxy R,â-unsaturated sul-
foxides are ideally suited for further substrate-directed
operations.
Exp er im en ta l Section
Ma ter ia ls An d Meth od s. All reactions were carried out
under a positive pressure of dry argon, using freshly distilled
solvents under anhydrous conditions. Reagents and solvents
were handled by using standard syringe techniques. Hexane,
toluene, CH2Cl2, Et3N, pyridine, and i-Pr2NH were distilled
from CaH2; THF and Et2O were from sodium and benzophe-
none. Crude products were purified by flash chromatography
on Merck 230-400 mesh silica gel with distilled solvents.
Analytical TLC was carried out on Merck (Kieselgel 60F-254)
silica gel plates with detection by UV light, iodine, acidic
vanillin solution, 10% phosphomolybdic acid solution in etha-
nol, or acidic ceric ammonium molybdate solution. Commercial
methyllithium (low halide solution in ether), n-butyllithium
(solution in hexane), and phenyllithium (solution in cyclohex-
ane) were purchased from Aldrich and titrated prior to use.
Ethylmagnesium bromide was prepared from ethyl bromide
and magnesium and titrated prior to use. Copper cyanide,
copper iodide, and copper bromide dimethyl sulfide were
purchased from Aldrich. Copper cyanide was heated at 90-
100 °C in vacuo for 2 h and stored in a desiccator. Cuprate
displacements were carried out in a 0.03-0.17 mmol scale.
PPh3 (hexane), p-NO2BzCl (ether), and p-NO2BzOH (benzene)
were recently recrystallized prior to use. 1H and 13C NMR
spectra were recorded at 200, 300, 360, or 500 MHz using
CDCl3 as solvent and with the residual solvent signal as
internal reference (CDCl3, 7.24 and 77.0 ppm). The following
abbreviations are used to describe peak patterns when ap-
propriate: s (singlet), d (doublet), t (triplet), q (quartet), quint
(quintet), sext (sextuplet), m (multiplet), ap (apparent), br
(broad). Melting points are uncorrected. Optical rotations were
measured at 20 °C using a sodium lamp and in CHCl3 solution.
The vinyl sulfoxides,13 chloroaldehyde,16 lactaldehyde,11 and
mandelaldehyde11 used in this study were prepared by litera-
ture methods.
Gen er a l P r oced u r e for th e Con d en sa tion betw een
Vin yl Su lfoxid es a n d r-F u n ction a lized Ald eh yd es. A
round-bottomed flask was charged with anhydrous THF (7 mL/
mmol of sulfoxide) and 1.6-2.6 equiv of freshly distilled i-Pr2-
NH, and cooled to -78 °C. To the above solution was added
1.5-2.5 equiv respectively of n-BuLi, and the resulting LDA
solution (ca. 0.2-0.4 M) was stirred at this temperature for
10 min. Then, a solution of 1 equiv of vinyl sulfoxide 1 in THF
(2-10 mL/mmol) previously dried over 4 Å sieves was added
dropwise slowly (ca. 8 min/mmol of sulfoxide) to produce a
reddish or yellow solution. After an additional 10 min of
stirring at -78 °C, 1.1-3.5 equiv of freshly chromatographed
or distilled aldehyde in THF (0.6-1.2 mL/mmol of aldehyde)
was added dropwise, and the resulting pale yellow solution
was stirred at this temperature for 15-30 min. The reaction
mixture was quenched at this temperature with a saturated
solution of NH4Cl (4 mL/mmol) and diluted with EtOAc (3 mL/
mmol), and the layers were separated. The aqueous layer was
extracted twice with EtOAc (6 mL/mmol). The combined
organic extracts were concentrated under reduced pressure to
give a crude product which was purified by column chroma-
tography on silica gel using the appropriate mixture of eluents.
Syn th esis of (+)-(2S,3S,SS)-(4E)-2-[(ter t-Bu tyld im eth -
ylsilyl)oxy]-6-m eth yl-4-(p-tolylsu lfin yl)h ep t-4-en -3-ol (4a )
adducts via conformation III.40 On the other hand,
magnesium cyanocuprates display good or modest anti
selectivities upon reaction with diastereomers 9 and 7,
respectively; this is consistent with cuprate addition anti
to both oxygens on chelated conformations II and IV with
the latter being destabilized by steric interactions be-
tween the bulky p-tolyl group and the oxirane carbon.
An alternative rationalization for the results found for
Grignard-derived cyanocuprates and diastereomers 7 is
shown in Scheme 11. It is tempting to speculate about a
more significant participation of SN2 intermediate V,
relative to when lithium cyanocuprates are used, followed
by a suprafacial [1,3] shift and reductive elimination to
produce 14; alternatively, minor products 17 and 18
would derive from V by reductive elimination or â-elim-
ination of the sulfinyl group, respectively. This picture
also accommodates the exclusive obtention of Z SN2′
isomers by admitting some degree of chelation between
the sulfinyl oxygen and magnesium, as well as the loss
of geometric control observed when sulfones, with a
diminished chelating ability, are used.41,42
Con clu sion s
Enantiomerically pure lithiated alkenyl sulfoxides
undergo selective condensations with R-alkoxy and R-chlo-
ro aldehydes. These adducts are readily transformed into
(40) Examples of syn SN2′ displacements involving organocopper
reagents and vinyl oxiranes are scarce and generally involve special
substrates or organocopper reagents. See: (a) Hudlicky, T.; Tian, X.;
Ko¨nigsberger, K.; Rouden, J . J . Org. Chem. 1994, 59, 4037-4039. (b)
Marshall, J . A.; Sedrani, R. J . Org. Chem. 1991, 56, 5496-5498. (c)
Marshall, J . A.; Audia, V. H. J . Org. Chem. 1987, 52, 1106-1113. (d)
See ref 25. (e) Ziegler, F. E.; Cady, M. A. J . Org. Chem. 1981, 46, 122-
128. For a related syn SN2′ displacement on a cyclic epoxy vinyl sulfone
with MeLi, see refs 32a and 32e.
(41) For leading references on sulfonyl participation in chelated
intermediates, see: (a) Yakura, T.; Tanaka, K.; Iwamoto, M.; Nameki,
M.; Ikeda, M. Synlett 1999, 1313-1315. (b) Marcantoni, E.; Cingolani,
S.; Bartoli, G.; Bosco, M.; Sambri, L J . Org. Chem. 1998, 63, 3624-
3630.
(42) We thank one of the reviewers for pointing out the rationaliza-
tions shown in Scheme 10.

6470 J . Org. Chem., Vol. 65, No. 20, 2000
Marino et al.
a n d (+)-(2S,3R,SS)-(4E)-2-[(ter t-Bu tyld im eth ylsilyl)oxy]-
6-m eth yl-4-(p-tolylsu lfin yl)h ep t-4-en -3-ol (5a ). From a Z/E
mixture of vinyl sulfoxide 1a (230 mg, 1.10 mmol, 1 equiv) in
11 mL of THF, 1.6 equiv of LDA in 18 mL of THF and with
(2S)-2-[(tert-Butyldimethylsilyl)oxy]propanal 2 (230 mg, 1.22
mmol, 1.1 equiv) in 1.5 mL of THF following the general
procedure an 83:17 mixture of diastereomeric alcohols 4a and
5a was obtained. Separation by chromatography (30% EtOAc-
hexane) afforded 307 mg (0.77 mmol, 70%) of 4a and 63 mg
(0.16 mmol, 14%) of 5a as yellow oils. Data for 4a : Rf ) 0.46
(30% EtOAc-hexane); [R]20D ) +45.4 (c ) 0.68); 1H NMR (360
MHz) δ -0.01 (s, 3 H), -0.07 (s, 3 H), 0.83 (s, 9 H), 1.03 (d, 6
H, J ) 6.6 Hz), 1.06 (d, 3 H, J ) 6.5 Hz), 2.36 (s, 3 H), 2.88 (d,
1 H, J ) 5.8 Hz), 3.06 (m, 1 H), 3.66 (quint, 1 H, J ) 6.0 Hz),
4.14 (ap t, 1 H, J ) 5.0 Hz), 6.06 (d, 1 H, J ) 10.5 Hz), 7.45 (d,
2 H, J ) 7.9 Hz), 7.49 (d, 2 H, J ) 7.9 Hz); 13C NMR (50 MHz)
δ -4.7, -4.7, 17.9, 18.5, 21.3, 22.2, 22.5, 25.7, 28.2, 70.8, 73.7,
125.8, 129.8, 140.5, 140.6, 141.7, 143.7. Data for 5a : Rf ) 0.57
(30% EtOAc-hexane); [R]20D ) +25.2 (c ) 0.94); 1H NMR (360
MHz) δ 0.09 (s, 6 H), 0.90 (s, 9 H), 0.95 (d, 3 H, J ) 6.3 Hz),
1.09 (d, 6 H, J ) 6.6 Hz), 2.39 (s, 3 H), 2.76 (d, 1 H, J ) 2.8
Hz), 2.83 (m, 1 H), 3.88 (quint, 1 H, J ) 6.3 Hz), 4.20 (dd, 1 H,
J ) 7.7, 2.7 Hz), 6.42 (d, 1 H, J ) 10.7 Hz), 7.29 (d, 2 H, J )
8.1 Hz), 7.47 (d, 2 H, J ) 8.1 Hz); 13C NMR (50 MHz) δ -4.7,
17.7, 18.0, 21.3, 22.1, 22.4, 25.5, 28.6, 69.8, 73.4, 125.1, 129.3,
140.2, 140.7, 141.3, 143.7, 147.4.
(ddd, 1 H, J ) 10.6, 9.6, 2.4 Hz), 4.57 (t, 1 H, J ) 7.8 Hz), 6.08
(t, 1 H, J ) 7.6 Hz), 7.29 (d, 2 H, J ) 8.0 Hz), 7.53 (d, 2 H, J
) 8.3 Hz); 13C NMR (50 MHz) δ 13.8, 13.9, 21.4, 22.1, 22.4,
28.1, 28.7, 30.9, 33.1, 64.2, 73.8, 125.9 (2 C), 130.0 (2 C), 138.9,
140.1, 142.1, 142.3. Partial data for syn chlorohydrin: 1H NMR
(300 MHz) δ 2.90 (m, 1 H), 3.55 (m, 1 H), 4.38 (m, 1 H), 6.67
(t, 1 H, J ) 7.5 Hz). Partial data of syn chlorohydrin: 1H NMR
(300 MHz) δ 2.60 (m, 1 H), 3.55 (m, 1 H), 4.52 (m, 1 H), 6.45
(t, 1 H, J ) 7.5 Hz).
Gen er a l P r oced u r e for th e Syn th esis of Ep oxy Vin yl
Su lfoxid es fr om Alcoh ols 4-6. (a ) Gen er a l P r oced u r e for
Mesyla tion . To a vigorously stirred cold (0 °C) solution of 1
equiv of allylic alcohol in pyridine (20 mL/mmol) was added 3
equiv of Ms2O. The reaction mixture was stirred and warmed
to room temperature over 3 h after which time it was poured
into an ice-cold saturated solution of NaHCO3 and diluted with
CH2Cl2 (100 mL/mmol). The aqueous phase was extracted with
CH2Cl2 (2 times, 20 mL/mmol), and the combined organic
layers were washed sequentially with 10% aqueous HCl (4
times, 20 mL/mmol), water (2 times, 15 mL/mmol), and a
saturated solution of NaCl (20 mL/mmol). Drying over anhy-
drous MgSO4, filtration, and evaporation of the solvents under
reduced pressure afforded a crude product which was used
shortly thereafter for the epoxide formation without further
purification. Formation of the mesylates was checked by IR
1
and H NMR. In some cases, the crude mesylate was purified
Syn th esis of (+)-(2S,3S,SS)-(4E)-3-[(ter t-Bu tyld im eth -
ylsilyl)oxy]-6-m eth yl-4-(p-tolylsu lfin yl)h ep t-4-en -2-ol (6).
To a stirred solution of allylic alcohol 4a (210 mg, 0.53 mmol,
1 equiv) in 8 mL of MeOH at room temperature was added
Et3N (0.025 mL, 0.18 mmol, 0.35 equiv). The reaction mixture
was heated at reflux for 1 h and allowed to cool to room
temperature. A saturated solution of NH4Cl was added, and
the layers were separated. The aqueous layer was extracted
three times with 25 mL of EtOAc, and the combined organic
layers were dried over MgSO4, filtered, and reduced to a
residual oil. The mixture of alcohols was separated by column
chromatography (30% EtOAc-hexane) to afford 80 mg (0.20
mmol, 38%) of 6 as a white solid and 112 mg (0.28 mmol, 53%)
by column chromatography to give pure product. (b) Gen er a l
P r oced u r e for Ep oxid e F or m a tion fr om Mesyla tes. To a
solution of the mesylate derivative in THF (10 mL/mmol) at
room temperature was added 1.5 equiv of n-Bu4NF (1.0 M
solution in THF), and the reaction mixture immediately turned
dark brown. After 5 min the reaction mixture was quenched
with a saturated NH4Cl solution (4 mL/mmol), and the layers
were separated. The aqueous layer was extracted with EtOAc
(3 times, 4 mL/mmol), and the combined organic extracts were
dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude yellow oil residue was purified by column
chromatography to give the pure epoxide.
Syn th esis of th e Mesyla te of (+)-(2S,3S,SS)-(4E)-2-
[(ter t-Bu tyldim eth ylsilyl)oxy]-6-m eth yl-4-(p-tolylsu lfin yl)-
h ep t-4-en -3-ol (4a ′). From alcohol 4a (370 mg, 0.93 mmol, 1
equiv) in 19 mL of pyridine and Ms2O (490 mg, 2.82 mmol, 3
equiv), following the general procedure for mesylation, a crude
product was obtained which was purified by column chroma-
tography (30% EtOAc-hexane) to afford 330 mg (0.69 mmol,
75%) of the pure mesylate 4a ′ as a yellow oil. Data for 4a ′: Rf
of starting material. Data for 6: Rf ) 0.36 (30% EtOAc-
1
hexane); mp 103-106 °C; [R]20 ) +94.1 (c ) 0.29); H NMR
D
(360 MHz) δ -0.06 (s, 3 H), 0.01 (s, 3 H), 0.86 (s, 9 H), 1.01 (d,
3 H, J ) 6.2 Hz), 1.05 (d, 3 H, J ) 6.6 Hz), 1.06 (d, 3 H, J )
6.6 Hz), 1.78 (d, 1 H, J ) 4.5 Hz), 2.37 (s, 3 H), 2.90 (m, 1 H),
3.01 (m, 1 H), 4.32 (d, 1 H, J ) 7.1 Hz), 6.38 (d, 1 H, J ) 10.8
Hz), 7.25 (d, 2 H, J ) 8.0 Hz), 7.53 (d, 2 H, J ) 8.2 Hz); 13C
NMR (90 MHz) δ -5.3, -4.7, 18.0, 19.4, 21.4, 22.1, 22.5, 25.7,
28.1, 69.3, 74.6, 125.7, 129.9, 140.7, 142.0 (2 C), 143.2.
Syn t h esis of (+)-(5R,6S,SS)-(7E)-5-Ch lor o-7-(p -t olyl-
su lfin yl)d od ec-7-en -6-ol (11a ) a n d (-)-(5S,6R,SS)-(7E)-5-
Ch lor o-7-(p-tolylsu lfin yl)d od ec-7-en -6-ol (12a ). From a
Z/ E mixture of vinyl sulfoxide 1c (896 mg, 4.03 mmol, 1 equiv)
in 10 mL of THF with 2.5 equiv of LDA in 28 mL of THF and
with racemic 2-chlorohexanal (1780 mg, 13.12 mmol, 3.25
equiv) in 8 mL of THF, following the general procedure, a 46:
54 mixture of anti chlorohydrins 11a and 12a was obtained.
Chromatographic separation (5-50% EtOAc-hexane) afforded
496 mg (1.39 mmol, 34%) of 11a and 582 mg (1.63 mmol, 40%)
of 12a as yellow oils which were recrystallized from Et2O-
hexane to give white solids. Two minor isomers (syn chloro-
hydrins) were detected in the chromatographic fraction con-
taining 12a . The estimated global syn:anti ratio was approxi-
1
) 0.40 (30% EtOAc-hexane); H NMR (360 MHz) δ 0.002 (s,
3 H), 0.03 (s, 3 H), 0.84 (s, 9 H), 1.04 (d, 3 H, J ) 6.4 Hz), 1.08
(d, 6 H, J ) 6.8 Hz), 2.37 (s, 3 H), 2.61 (s, 3 H), 3.02 (m, 1 H),
3.86 (quint, 1 H, J ) 5.6 Hz), 5.00 (d, 1 H, J ) 5.4 Hz), 6.40
(d, 1 H, J ) 11.0 Hz), 7.29 (d, 2 H, J ) 8.2 Hz), 7.52 (d, 2 H,
J ) 8.2 Hz); 13C NMR (90 MHz) δ -5.1, -4.6, 18.0, 19.3, 21.3,
22.0, 25.8, 28.4, 38.2, 70.1, 80.4, 125.3, 129.9, 138.3, 140.1,
141.8 146.6.
Syn th esis of (+)-(2S,3R,SS)-(4E)-2,3-Ep oxy-6-m eth yl-4-
(p-tolylsu lfin yl)h ep t-4-en e (7a ). From mesylate 4a ′, (177
mg, 0.37 mmol, 1 equiv) in 4 mL of THF and n-Bu4NF (0.56
mL, 0.56 mmol, 1.5 equiv), following the general procedure
for epoxide formation, a crude product was obtained which was
purified by column chromatography (30% EtOAc-hexane) to
afford 89 mg (0.34 mmol, 92%) of pure epoxide 7a as a pale
yellow oil. Data for 7a : Rf ) 0.38 (30% EtOAc-hexane); [R]20
D
1
mately 8:92. Data for 11a : Rf ) 0.38 (30% EtOAc-hexane);
) +166.8 (c ) 1.46); H NMR (300 MHz) δ 1.09 (d, 6 H, J )
1
mp 96-97 °C; [R]20 ) +13.6 (c ) 0.60); H NMR (300 MHz)
6.6 Hz), 1.28 (d, 3 H, J ) 5.1 Hz), 2.39 (s, 3 H), 2.84 (m, 1 H),
3.08 (d, 1 H, J ) 2.2 Hz), 3.12 (qd, 1 H, J ) 5.1, 2.2 Hz), 6.39
(d, 1 H, J ) 10.2 Hz), 7.28 (d, 2 H, J ) 8.2 Hz), 7.56 (d, 2 H,
J ) 8.2 Hz); 13C NMR (75 MHz) δ 17.3, 21.4, 22.5, 27.9, 54.4,
55.2 125.4, 125.5, 129.1, 129.2, 141.4, 142.4; IR (film) 2961,
D
δ 0.84 (t, 3 H, J ) 7.1 Hz), 0.92 (t, 3 H, J ) 7.2 Hz), 1.10-1.60
(m, 9 H), 2.01 (m, 1 H), 2.32 (m, 2 H), 2.40 (s, 3 H), 3.53 (ddd,
1 H, J ) 10.8, 8.4, 2.5 Hz), 4.53 (d, 1 H, J ) 6.5 Hz), 4.68 (dd,
1 H, J ) 8.4, 6.5 Hz), 6.59 (t, 1 H, J ) 7.4 Hz), 7.29 (d, 2 H, J
) 8.1 Hz), 7.52 (d, 2 H, J ) 8.3 Hz); 13C NMR (50 MHz) δ 13.9
(2 C), 21.4, 21.8, 22.4, 27.9, 28.8, 30.8, 32.7, 64.2, 76.0, 124.7
(2 C), 129.8 (2 C), 139.1, 139.6, 141.4, 143.2. Data for 12a : Rf
2869, 1596, 1464, 1083, 1052, 811 cm-1
.
Syn th esis of Ep oxy Vin yl Su lfoxid es fr om Ch lor oh y-
d r in s 11 a n d 12. (A) Syn th esis of (+)-(5S,6R,SS)-(7E)-5,6-
Ep oxy-7-(p-tolylsu lfin yl)d od ec-7-en e (7e). To a cold (-78
°C) solution of chlorohydrin 11a (100 mg, 0.28 mmol, 1 equiv)
in 8 mL of THF, n-BuLi (0.30 mL, 0.42 mmol, 1.5 equiv) was
added dropwise. The reaction mixture was stirred and allowed
) 0.20 (30% EtOAc-hexane); mp 98-100 °C; [R]20 ) -22.2
D
(c ) 0.46); 1H NMR (300 MHz) δ 0.87 (t, 3 H, J ) 7.1 Hz), 0.87
(t, 3 H, J ) 7.2 Hz), 1.20-1.68 (m, 9 H), 1.99 (m, 1 H), 2.30-
2.37 (m, 2 H), 2.39 (s, 3 H), 3.66 (d, 1 H, J ) 7.3 Hz), 3.97

Sulfoxide-Controlled SN2′ Displacements
J . Org. Chem., Vol. 65, No. 20, 2000 6471
to warm to room temperature for 5 h, the reaction was
quenched with 2 mL of a saturated solution of NH4Cl and
diluted with 4 mL of EtOAc, and the layers were separated.
The organic layer was washed with 4 mL of a saturated
solution of NaCl, and the aqueous layer was extracted with 4
mL of EtOAc (3 times). The combined organic layers were dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressured to give a crude product which was purified
by column chromatography on silica gel (CH2Cl2) to afford 61
mg (0.19 mmol, 68%) of 7e as a colorless oil. Data for 7e: Rf
) 0.45 (5% EtOAc-CH2Cl2); [R]20D ) +13.7 (c ) 2.41); 1H NMR
(300 MHz) δ 0.87 (t, 3 H, J ) 7.7 Hz), 0.90 (t, 3 H, J ) 7.3
Hz), 1.24-1.51 (m, 10 H), 2.31 (m, 2 H), 2.37 (s, 3 H), 3.04 (td,
1 H, J ) 5.4, 2.3 Hz), 3.10 (br s, 1 H), 6.53 (td, 1 H, J ) 7.8,
1.2 Hz), 7.25 (d, 2 H, J ) 8.0 Hz), 7.56 (d, 2 H, J ) 8.3 Hz);
13C NMR (50 MHz) δ 13.8 (2 C), 21.4, 22.3, 22.5, 27.8 (2 C),
31.0, 31.5, 53.6, 59.2, 125.5 (2 C), 129.8 (2 C), 135.9, 140.8,
141.0, 141.5.
(B) With Na O-t-Bu or KO-t-Bu . Gen er a l P r oced u r e. A
round-bottomed flask was charged with 1 equiv of chlorohydrin
in THF (20 mL/mmol). The solution was cooled to 0 °C and
under strictly anhydrous conditions, a suspension of 1.2 equiv
of KO-t-Bu or NaO-t-Bu (azeotropically dried with benzene)
in THF (5 mL/mmol) was added dropwise via syringe. The
reaction was stirred at this temperature for 30 min, quenched
with a saturated solution of NH4Cl (20 mL/mmol), and diluted
with EtOAc (10 mL/mmol), and the layers were separated. The
aqueous layer was extracted twice with EtOAc (10 mL/mmol),
and the combined organic extracts were washed twice with a
saturated solution of NaCl (20 mL/mmol), dried over anhy-
drous MgSO4, filtered, and concentrated under reduced pres-
sure to give a crude product, which was purified by column
chromatography on silica gel.
H, J ) 7.8, 0.7 Hz), 7.30 (d, 2 H, J ) 8.0 Hz), 7.72 (d, 2 H, J
) 8.3 Hz); 13C NMR (50 MHz) δ 13.8, 13.9, 21.6, 22.4 (2 C),
27.7 (2 C), 30.7, 31.5, 53.1, 59.1, 127.9 (2 C), 129.7 (2 C), 137.4,
137.5, 144.2, 145.9.
Syn th esis of (-)-(2S,3S)-(4E)-2-[(ter t-Bu tyld im eth ylsi-
lyl)oxy]-6-m eth yl-4-(p h en ylsu lfen yl)h ep t-4-en -3-ol (25)
a n d (+)-(2S,3S)-(4E)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-6-
m eth yl-4-(p h en ylsu lfen yl)h ep t-4-en -2-ol (26). To a cold
(-78 °C) solution of vinyl idodide 24 (204 mg, 0.67 mmol, 1
equiv) in 7 mL of THF was added t-butyllithium (0.78 mL,
1.30 mmol, 1.95 equiv, 1.7 M in hexanes) dropwise. The
resulting dark brown solution was stirred for 5 min, and a
solution of (2S)-2-[(tert-butyldimethylsilyl)oxy]propanal (2)
(125 mg, 0.67 mmol, 1 equiv) in 0.5 mL of THF was then added
dropwise. After an additional 30 min of stirring, the reaction
was allowed to warm to -20 °C at which time 25 mL of water
was added. The aqueous phase was extracted with EtOAc (25
mL) two times, and the combined organic layers were washed
with 25 mL of a saturated solution of NaCl, dried over MgSO4,
filtered, and concentrated under reduced presure to give a
crude product which was purified by column chromatography
on silica gel to afford 140 mg (0.38 mmol, 57%) of 25 and 47
mg (0.13 mmol, 19%) of 26. Data for 25: Rf ) 0.31 (5% EtOAc-
hexane); [R]20 ) -50.7 (c ) 1.61); 1H NMR (360 MHz) δ 0.07
D
(s, 3 H), 0.08 (s, 3 H), 0.89 (s, 9 H), 0.97 (d, 3 H, J ) 6.6 Hz),
1.01 (d, 3 H, J ) 6.6 Hz), 1.14 (d, 3 H, J ) 6.2 Hz), 2.49 (d, 1
H, J ) 7.4 Hz), 2.88 (m, 1 H), 3.97 (m, 1 H), 4.42 (dd, 1 H, J
) 7.4, 5.3 Hz), 5.75 (d, 1 H, J ) 10.2 Hz), 7.29-7.15 (m, 3 H),
7.38 (d, 2 H, J ) 8.0 Hz); 13C NMR (90 MHz) δ -4.7, -4.5,
18.0, 19.3, 22.7, 25.8, 28.5, 70.9, 74.8, 126.1, 128.9, 129.4, 131.1,
133.4, 148.9. Data for 26: Rf ) 0.20 (5% EtOAc-hexane); [R]20
D
) +48.1 (c ) 0.74); 1H NMR (360 MHz) δ 0.09 (s, 3 H), 0.10 (s,
3 H), 0.92 (s, 9 H), 0.93 (d, 6 H, J ) 6.6 Hz), 1.26 (d, 3 H, J )
6.2 Hz), 1.79 (br s, 1 H), 2.77 (m, 1 H), 3.90 (m, 1 H), 4.41 (d,
1 H, J ) 6.8 Hz), 5.25 (d, 1 H, J ) 10.5 Hz), 7.31 (m, 3 H),
7.44 (d, 2 H, J ) 8.1 Hz); 13C NMR (90 MHz) δ -4.9, -4.6,
18.2, 19.0, 22.5, 23.0, 25.8, 28.5, 69.7, 75.8, 127.4, 129.1, 132.8,
134.8, 135.0, 141.1.
Syn th esis of (+)-(5R,6S,SS)-(7E)-5,6-Ep oxy-7-(p-tolyl-
su lfin yl)d od ec-7-en e (9b). From chlorohydrin 12a (50 mg,
0.14 mmol, 1 equiv) in 8 mL of THF with NaO-t-Bu (16 mg,
0.16 mmol, 1.2 equiv) in 3 mL of THF according to the general
procedure 9e was obtained. Purification by chromatography
(5-20% EtOAc-hexane) afforded 40 mg (0.12 mmol, 89%) of
epoxide 9b as a colorless oil. Data for 9b: Rf ) 0.36 (30%
EtOAc-hexane); [R]20D ) +54.4 (c ) 1.43); 1H NMR (300 MHz)
δ 0.80 (t, 3 H, J ) 6.9 Hz), 0.91 (t, 3 H, J ) 7.2 Hz), 1.08-1.52
(m, 10 H), 2.38 (m, 2 H), 2.38 (s, 3 H), 2.49 (td, 1 H, J ) 5.6,
2.3 Hz), 3.21 (d, 1 H, J ) 1.8 Hz), 6.59 (td, 1 H, J ) 7.7, 0.9
Hz), 7.26 (d, 2 H, J ) 8.0 Hz), 7.48 (d, 2 H, J ) 8.2 Hz); 13C
NMR (50 MHz) δ 13.8 (2 C), 21.4, 22.3 (2 C), 27.5, 27.7, 31.1,
31.5, 53.3, 58.3, 125.8 (2 C), 129.9 (2 C), 139.1, 139.6, 140.3,
141.7; IR (film) 2900, 1650, 1600, 1490, 1460, 1380, 1090, 1050,
Syn th esis of th e Mesyla te of (2S,3S)-(4E)-2-[(ter t-Bu -
t yld im et h ylsilyl)oxy]-6-m et h yl-4-(p h en ylsu lfen yl)h ep t -
4-en -3-ol (25′). From alcohol 25 (140 mg, 0.38 mmol, 1 equiv)
in 7.5 mL of pyridine and Ms2O (198 mg, 1.14 mmol, 3 equiv)
following the general procedure of mesylation a crude product
25′ was obtained which was used with no further purification.
1
Data for 25′: Rf ) 0.54 (20% EtOAc-hexane); H NMR (300
MHz) δ 0.09 (s, 3 H), 0.11 (s, 3 H), 1.02 (d, 3 H, J ) 6.5 Hz),
1.04 (d, 3 H, J ) 6.5 Hz), 1.30 (d, 3 H, J ) 7.3 Hz), 2.64 (s, 3
H), 2.91 (m, 1 H), 4.25 (m, 1 H), 5.28 (d, 1 H, J ) 6.9 Hz), 5.89
(d, 1 H, J ) 10.3 Hz), 7.22-7.32 (m, 3 H), 7.43 (d, 2 H, J ) 8.1
Hz); IR (film): 2957, 2859, 1471, 1360, 1254, 1175, 1115, 932,
1010, 810 cm-1
.
Syn th esis of Ep oxy Vin yl Su lfon es by Oxid a tion of
Ep oxy Vin yl Su lfoxid es. Gen er a l P r oced u r e for Oxid a -
tion of Su lfoxid es to Su lfon es w ith MMP P . Monoperox-
yphthalic acid, magnesium salt hexahydrate (MMPP), (1.5
equiv) was added to a cold solution (0 °C) of sulfoxide (1 equiv)
in MeOH (10 mL/mmol). The mixture was stirred, allowed to
warm to room temperature, and monitored by TLC until
starting material disappearance. The solvent was removed
under reduced pressure, the residue was dissolved in EtOAc,
and a 5% aqueous solution of NaHCO3 (5 mL/mmol) was
added. The aqueous layer was extracted with EtOAc (5 mL/
mmol), and the combined organic extracts were washed with
a saturated solution of NaCl (4 mL/mmol), dried over MgSO4,
and concentrated under reduced pressure to give a crude
product which was purified by chromatography on silica gel.
Syn th esis of (+)-(5S,6R)-(7E)-5,6-Ep oxy-7-(p-tolylsu l-
fon yl)d od ec-7-en e (22). From epoxy sulfoxide 7e (12 mg,
0.037 mmol, 1 equiv) in 0.5 mL of methanol and MMPP (27.8
mg, 0.056 mmol, 1.5 equiv) following the general procedure
for oxidation with MMPP (4 h) epoxy sulfone 22 was obtained.
Purification by chromatography (5-10% EtOAc-hexane) af-
forded 8 mg (0.024 mmol, 64%) of 22 as a colorless oil. Data
831 cm-1
.
Syn t h esis of (-)-(2S,3R)-(4E)-2,3-E p oxy-6-m et h yl-4-
(p h en ylsu lfen yl)-4-h ep ten e (27). From the crude mesylate
derivative 25′ in 4 mL of THF and with n-Bu4NF (0.56 mL,
0.56 mmol, 1.5 equiv) following the general procedure for
epoxide formation, a crude product was obtained which was
purified by column chromatography (20% EtOAc-hexane) to
afford 84 mg (0.36 mmol, 94% two steps) of pure epoxide 27
as a colorless oil. Data for 27: Rf ) 0.63 (20% EtOAc-hexane);
1
[R]20 ) -37.8 (c ) 1.09); H NMR (360 MHz) δ 1.07 (d, 6 H,
D
J ) 6.6 Hz), 1.22 (d, 3 H, J ) 5.2 Hz), 2.98 (m, 1 H), 3.09 (dq,
1 H, J ) 5.2, 2.2 Hz), 3.47 (d, 1 H, J ) 2.0 Hz), 6.06 (d, 1 H,
J ) 10.2 Hz), 7.15-7.29 (m, 5 H); 13C NMR (90 MHz) δ 17.2,
22.7, 22.3, 28.8, 54.9, 57.2, 126.0, 127.1, 128.6, 128.8, 136.6,
151.9.
Gen er a l P r oced u r e for SN2′ Ad d ition of Or ga n ocu -
p r a te Rea gen ts to Vin yl Ep oxid es. A round-bottomed flask
was charged with 6-9 equiv of CuCN or CuI in Et2O (50 mL/
mmol) under argon. The resulting suspension was cooled to
the appropriate temperature (0 °C or -20 °C), and the
organolithium or Grignard reagent was added dropwise and
vigorously stirred for 15 min. Upon formation of the organo-
cuprate reagent, this suspension was cooled to -78 °C, a
solution of vinyl epoxide in Et2O (26 mL/mmol) was added
dropwise, and the reaction mixture was slowly allowed to
for 22: Rf ) 0.52 (30% EtOAc-hexane); [R]20 ) +17.4 (c )
D
1
0.70); H NMR (300 MHz) δ 0.86 (t, 3 H, J ) 7.0 Hz), 0.90 (t,
3 H, J ) 7.2 Hz), 1.24-1.48 (m, 10 H), 2.38 (m, 2 H), 2.41 (s,
3 H), 2.74 (td, 1 H, J ) 5.5, 2.3 Hz), 3.28 (m, 1 H), 7.02 (td, 1

6472 J . Org. Chem., Vol. 65, No. 20, 2000
Marino et al.
warm for 30 min. After this time the cold bath was removed,
and the reaction mixture was monitored by TLC until disap-
pearance of starting material. Then, the reaction was quenched
with a saturated solution of Na2S2O4 solution, and the layers
were separated. The aqueous layer was extracted twice with
EtOAc (5 mL/mmol), and the combined organic extracts were
washed twice with a saturated solution of NaCl (5 mL/mmol).
After drying over MgSO4 and concentration under reduced
pressure, the crude product was purified by column chroma-
tography on silica gel using the appropriate mixture of solvents
as eluents. When the reaction was performed with Gilman
cuprates (Me2CuLi) or under not strictly anhydrous conditions,
hydroxy allenes byproducts (as mixtures of diastereomers)
were obtained as major components of the reaction mixture.
Formation of these compounds was also observed when cy-
anocuprates were prepared from Grignard reagents, especially
when commercial EtMgBr was used. Finally, the isolation of
these compounds was difficult in some cases (R1 ) alkyl) due
to its high volatility.
Syn th esis of (-)-(2S,5R,SS)-(3Z)-5-Isop r op yl-4-(p-tolyl-
su lfin yl)n on -3-en -2-ol (13c) a n d (2S,5S,SS)-(3Z)-5-Isop r o-
p yl-4-(p-tolylsu lfin yl)n on -3-en -2-ol (14c). Following the
general procedure, from 7a (40 mg, 0.151 mmol, 1 equiv) with
9 equiv of n-BuCuCNLi preformed at 0 °C, an 88:12 separable
mixture of SN2′ addition products 13c and 14c, was obtained.
Chromatographic separation afforded 33 mg (0.102 mmol, 68%,
combined) of 13c and 14c as colorless oils. Data for 13c: Rf )
0.45 (50% EtOAc-hexane); [R]20D ) -28.1 (c ) 1.26); 1H NMR
(300 MHz) δ 0.57 (d, 3 H, J ) 7.2 Hz), 0.81 (d, 3 H, J ) 6.8
Hz), 0.87 (d, 3 H, J ) 6.8 Hz), 1.01-1.30 (m, 6H), 1.43 (d, 3 H,
J ) 6.2 Hz), 1.82 (m, 1 H), 2.15 (m, 1 H), 2.36 (s, 3 H), 2.57 (br
s, 3 H), 5.35 (dq, 1 H, J ) 8.8. 6.2 Hz), 5.80 (d, 1 H, J ) 8.8
Hz), 7.25 (d, 2 H, J ) 8.2 Hz), 7.56 (d, 2 H, J ) 8.2 Hz); 13C
NMR (75 MHz) δ 13.8, 18.2, 20.9, 21.3, 22.6, 24.7, 28.6, 31.0,
32.7, 41.4, 64.03, 124.9, 129.5, 138.1, 140.6, 141.0, 149.0. Data
for 14c: Rf ) 0.25 (50% EtOAc-hexane); 1H NMR (360 MHz)
δ 0.61 (t, 3 H, J ) 7.3 Hz), 0.86 (d, 3 H, J ) 6.8 Hz), 0.87 (d,
3 H, J ) 6.8 Hz), 0.90-1.15 (m, 6 H), 1.41 (d, 3 H, J ) 6.3
Hz), 1.82 (m, 1 H), 2.12 (m, 1 H), 2.39 (s, 3 H), 2.51 (br s, 1 H),
5.40 (m, 1 H), 5.89 (d, 1 H, J ) 8.7 Hz), 7.28 (d, 2 H, J ) 8.2
Hz), 7.43 (d, 2 H, J ) 8.2 Hz); 13C NMR (90 MHz) δ 13.8, 18.1,
21.2, 21.3, 22.6, 23.0, 28.4, 29.0, 32.2, 41.3, 63.2, 125.0, 129.6,
129.7, 138.7, 139.2, 141.2, 148.3.
Syn th esis of 6,7-Dod eca d ien -5-ol (m ixtu r e of d ia ster -
eom er s) (18b). Following the general procedure, from 7e (18
mg, 0.056 mmol, 1 equiv) with 6 equiv of Me2CuLi‚LiI
preformed at 0 °C, allene 18b (75:25 mixture of diastereomers)
was obtained as the major component of a mixture with traces
of SN2′ addition products after 1 h 30 min. Chromatographic
purification (5-30% EtOAc-hexane) afforded pure products.
Data for allene 18b (major isomer): Rf ) 0.47 (CH2Cl2); 1H
NMR (200 MHz) δ 0.83-0.93 (m, 6 H), 1.29-1.49 (m, 8 H),
1.50-1.62 (m, 2 H), 1.95-2.05 (m, 2 H), 2.30 (m, 1 H), 4.11
(qd, 1 H, J ) 6.1, 2.3 Hz), 5.20 (tt, 1 H, J ) 6.0, 3.0 Hz), 5.27
(qd, 1 H, J ) 6.5, 2.2 Hz); 13C NMR (50 MHz) δ 13.8, 14.0,
22.1, 22.6, 27.6, 28.5, 31.3, 37.3, 69.9, 94.4, 95.9, 202.0. Data
Syn t h esis of (-)-(5S,8R,SS)-(6Z)-8-P h en yl-7-(p -t olyl-
su lfin yl)d od ec-6-en -5-ol (13f) a n d (-)-(5S,8S,SS)-(6Z)-8-
P h en yl-7-(p-tolylsu lfin yl)d od ec-6-en -5-ol (14f). Following
the general procedure, from 7f (53 mg, 0.155 mmol, 1 equiv)
with 9 equiv of n-BuCuCNLi preformed at -20 °C, a not
readily separable 91:9 mixture of SN2′ addition products 13f
and 14f was obtained after 1.25 h. Chromatographic purifica-
tion (5-30% EtOAc-hexane) afforded 51 mg (0.128 mmol, 82%
combined) of pure mixture of products as a colorless oil.
Separation of these isomers required preparative TLC using
50% Et2O-hexane as eluent. When the addition was per-
formed at -100 °C a 96:4 mixture of SN2′ products 13f,14f
was obtained. The yield was not determined. Data for 13f: Rf
) 0.45 (65% Et2O-hexane); [R]20D ) -22.8 (c ) 1.14); 1H NMR
(300 MHz) δ 0.61 (t, 3 H, J ) 7.1 Hz), 0.81-1.70 (m, 15 H),
2.20 (br s, 1 H), 2.38 (s, 3 H), 3.66 (dd, 1H, J ) 9.4, 5.9 Hz),
4.96 (ap q, 1 H, J ) 8.5 Hz), 5.89 (d, 1 H, J ) 8.7 Hz), 7.12-
7.23 (m, 5 H), 7.27 (d, 2 H, J ) 8.1 Hz), 7.58 (d, 2 H, J ) 8.3
Hz); 13C NMR (75 MHz) δ 13.6, 13.9, 21.2, 22.1, 22.4, 27.2,
29.5, 35.4, 37.7, 41.3, 67.5, 124.9 (2 C), 126.2, 127.8 (2 C), 128.3
(2 C), 129.6 (2 C), 138.6, 139.3, 140.9, 142.9, 151.2. Data for
1
for allene 18b (minor isomer): Rf ) 0.40 (CH2Cl2); H NMR
(200 MHz) δ 0.83-0.93 (m, 6 H), 1.29-1.49 (m, 8 H), 1.50-
1.62 (m, 2 H), 1.95-2.05 (m, 2 H), 2.30 (m, 1 H), 4.11 (qd, 1 H,
J ) 6.1, 2.3 Hz), 5.20 (tt, 1 H, J ) 6.0, 3.0 Hz), 5.27 (qd, 1 H,
J ) 6.5, 2.2 Hz); 13C NMR (50 MHz) δ 13.8, 14.0, 22.1, 22.6,
27.6, 28.4, 31.3, 37.2, 70.3, 94.1, 95.7, 202.3.
Syn t h esis of (-)-(5S,8R,SS)-(6Z)-8-Met h yl-7-(p -t olyl-
su lfin yl)d od ec-6-en -5-ol (13a ) a n d (5S,8S,SS)-(6Z)-8-Meth -
yl-7-(p-t olylsu lfin yl)d od ec-6-en -5-ol (14a ). Following the
general procedure, from 7e (43 mg, 0.133 mmol, 1 equiv) with
6 equiv of MeCuCNLi preformed at 0 °C, a not readily
separable 85:15 mixture of SN2′ addition products 13a and 14a
was obtained after 2 h. Chromatographic purification (5-30%
EtOAc-hexane) afforded 31 mg (0.092 mmol, 69% combined)
of products as a white solid. Data for 13a (from an 85:15
mixture of 13a and 14a ): Rf ) 0.25 (30% EtOAc-hexane);
14f: Rf ) 0.48 (65% Et2O-hexane); [R]20 ) -75.6 (c ) 0.26);
D
1H NMR (300 MHz) δ 0.80 (t, 3 H, J ) 7.0 Hz), 0.92, (t, 3 H,
J ) 7.0 Hz), 1.10-1.85 (m, 12 H), 2.00 (br s, 1 H), 2.28 (s, 3
H), 3.65 (dd, 1 H, J ) 8.6, 6.8 Hz), 5.05 (m, 1 H), 6.06 (d, 1 H,
J ) 8.7 Hz), 6.68-6.72 (m, 2 H), 6.97-7.00 (m, 3 H), 7.03 (d,
2 H, J ) 8.1 Hz), 7.30 (d, 2 H, J ) 8.3 Hz); 13C NMR (75 MHz)
δ 13.9, 14.0, 21.2, 22.5 (2 C), 27.4, 29.7, 36.8, 37.8, 41.5, 67.6,
124.8 (2 C), 125.8, 127.5 (2 C), 128.0 (2 C), 129.4 (2 C), 138.1,
138.8, 140.5, 142.3, 150.6.
[R]20 ) -114.3 (c ) 1.75); 1H NMR (300 MHz) δ 0.65 (d, 3 H,
D
J ) 7.0 Hz), 0.87 (t, 3 H, J ) 6.9 Hz), 0.95 (t, 3 H, J ) 7.1 Hz),
1.22-1.80 (m, 12 H), 2.20 (br s, 1 H), 2.40 (s, 3 H), 2.53 (sext,
1 H, J ) 6.9 Hz), 5.06 (td, 1 H, J ) 8.5, 6.7 Hz), 5.88 (d, 1 H,
J ) 8.8 Hz), 7.28 (d, 2 H, J ) 8.1 Hz), 7.59 (d, 2 H, J ) 8.1
Hz); 13C NMR (75 MHz) δ 14.0 (2 C), 21.3, 22.2, 22.5, 22.7,
27.4, 29.3, 29.6, 38.0, 38.1, 67.6, 124.7 (2 C), 129.6 (2 C), 136.7,
139.4, 140.6, 153.4; IR (CCl4) 3360, 2960, 2930, 2860, 1600,
1490, 1460, 1380, 1080, 1015, 790 cm-1. Partial data for 14a
(from an 85:15 mixture of 13a and 14a ): 1H NMR (300 MHz)
δ 1.09 (d, 3 H, J ) 6.9 Hz), 5.87 (d, 2 H, J ) 8.7 Hz).
Syn t h esis of (-)-(5R,8R,SS)-(6Z)-8-Met h yl-7-(p -t olyl-
su lfin yl)d od ec-6-en -5-ol (15a ) a n d (5R,8S,SS)-(6Z)-8-Meth -
yl-7-(p-t olylsu lfin yl)d od ec-6-en -5-ol (16a ). Following the
general procedure, from 9b (45 mg, 0.140 mmol, 1 equiv) with
6 equiv of MeCuCNLi preformed at 0 °C, a separable 96:4
mixture of SN2′ addition products 15a and 16a was obtained
after 1.5 h. Chromatographic purification (5-30% EtOAc-
hexane) afforded 42 mg (0.125 mmol) of 15a and approximately
2 mg (0.006 mmol) of 16a (93% combined) as colorless oils.
Data for 15a : Rf ) 0.37 (30% EtOAc-hexane); [R]20D ) -107.0
(c )1.33); 1H NMR (300 MHz) δ 0.63 (d, 3 H, J ) 6.8 Hz), 0.82
(t, 3 H, J ) 6.7 Hz), 0.93 (t, 3 H, J ) 7.0 Hz), 1.16-1.72 (m, 12
H), 2.37 (s, 3 H), 2.33-2.42 (sext, 1 H, J ) 6.7 Hz), 2.60 (s, 1
H), 5.10 (td, 1 H, J ) 8.2, 4.7 Hz), 5.97 (d, 3 H, J ) 8.4 Hz),
7.26 (d, 2 H, J ) 8.0 Hz), 7.46 (d, 2 H, J ) 8.2 Hz); 13C NMR
(50 MHz) δ 14.0, 21.3, 22.5 (2 C), 22.6, 27.6, 29.4, 30.0, 36.9,
37.8, 66.8, 125.0 (2 C), 129.8 (2 C), 138.3, 139.1, 141.1, 151.3.
Partial data for 16a : Rf ) 0.10 (30% EtOAc-hexane); 1H NMR
(300 MHz): δ 0.65 (t, 3 H, J ) 7.2 Hz), 0.75-1.09 (m, 6 H),
1.04 (d, 3 H, J ) 6.8 Hz), 1.23-1.80 (m, 9 H), 2.33 (sext, 1 H,
Syn t h esis of (-)-(5S,8R,SS)-(6Z)-8-Met h yl-7-(p -t olyl-
su lfin yl)-d od ec-6-en -5-ol (13b). Following the general pro-
cedure, from 7e (10 mg, 0.031 mmol, 1 equiv) with 6 equiv of
EtCuCNLi (prepared from CuCN and EtLi) preformed at -20
°C, SN2′ addition product 13b was obtained after 1 h 30 min
as a single isomer. Chromatographic purification (5-30%
EtOAc-hexane) afforded 9 mg (0.025 mmol, 82%) of 13b as a
colorless oil. Data for 13b: Rf ) 0.24 (20% EtOAc-hexane);
[R]20 ) -73.8 (c ) 0.83); 1H NMR (300 MHz) δ 0.37 (t, 3 H, J
D
) 7.3 Hz), 0.83 (t, 3 H, J ) 6.9 Hz), 0.91 (t, 3 H, J ) 7.0 Hz),
0.99 (m, 2 H), 1.14-1.80 (m, 12 H), 2.28 (quint, 1 H, J ) 6.8
Hz), 2.37 (s, 3 H), 5.05 (td, 1 H, J ) 8.8, 6.7 Hz), 5.78 (d, 1 H,
J ) 8.7 Hz), 7.25 (d, 2 H, J ) 8.0 Hz), 7.56 (d, 2 H, J ) 8.3
Hz); 13C NMR (75 MHz) δ 11.0, 14.0, 21.3, 22.5, 22.8, 27.5,
27.8, 29.0, 35.6, 36.8, 38.0, 67.6, 124.9 (2 C), 129.6 (2 C), 136.6,
139.3, 140.8, 151.5.

Sulfoxide-Controlled SN2′ Displacements
J . Org. Chem., Vol. 65, No. 20, 2000 6473
J ) 6.8 Hz), 2.38 (s, 3 H), 2.66 (br s, 1 H), 5.10 (m, 1 H), 5.96
(d, 1 H, J ) 8.4 Hz), 7.27 (d, 2 H, J ) 8.1 Hz), 7.46 (d, 2 H, J
) 8.2 Hz).
was crystallized from Et2O-hexane to produce a white solid.
Data for 21: Rf ) 0.40 (30% EtOAc-hexane); mp 105-109 °C;
1
[R]20 ) -91.2 (c ) 0.59); H NMR (200 MHz) δ 0.59 (d, 3 Η,
D
Syn th esis of (-)-(5R,8R,SS)-(6Z)-8-Eth yl-7-(p-tolylsu lfi-
n yl)-d od ec-6-en -5-ol (15b), (5R,8S,SS)-(6Z)-8-Eth yl-7-(p-
tolylsu lfin yl)d od ec-6-en -5-ol (16b), a n d (5R,6R,SS)-(7E)-
6-Eth yl-7-(p-tolylsu lfin yl)d od ec-7-en -5-ol (17b′). Following
the general procedure, from 9b (42 mg, 0.130 mmol, 1 equiv)
with 6 equiv of EtCuCNMgBr preformed at -20 °C, an 81:8:
11 mixture of SN2′, SN2 addition products and allene byproduct
(15b,16b):17b′:18b was obtained after 2 h. Chromatographic
separation (CH2Cl2-15% EtOAc-CH2Cl2) afforded 29 mg (0.083
mmol, 64%, combined) of 15b,16b as a separable 95:5 mixture
J ) 6.8 Ηz), 0.72 (t, 3 H, J ) 6.7 Hz), 0.92 (t, 3 H, J ) 6.7 Hz),
1.06-1.49 (m, 10 H), 1.80 (m, 1 H), 1.95 (m, 1 H), 2.37 (s, 3
H), 2.57 (q, 1 H, J ) 6.9 Hz), 5.90 (d, 1 H, J ) 9.2 Hz), 6.44
(m, 1 H), 7.26 (d, 2 H, J ) 8.2 Hz), 7.45 (d, 2 H, J ) 8.2 Hz),
8.24 (ap q, 4 H, J ) 6.3 Hz); 13C NMR (50 MHz) δ 13.9, 14.1,
21.4, 22.5, 22.7, 27.4, 29.2, 29.3, 29.7, 34.6, 38.0, 71.3, 123.5
(2 C), 123.6 (2 C), 124.6 (2 C), 129.8 (2 C), 130.8, 135.6, 139.3,
141.0, 150.6, 155.3, 163.7.
Syn th esis of th e p-Nitr oben zoa te of (-)-(5S,8R,SS)-
(6Z)-8-Meth yl-7-(p-tolylsu lfin yl)dodec-6-en -5-ol (20). From
a not readily separable 85:15 mixture of alcohols 13a and 14a
(12 mg, 0.034 mmol, 1 equiv), Et3N (11 µL, 0.085 mmol, 2.5
equiv), DMAP (2 crystals), and p-nitrobenzoyl chloride (13 mg,
0.068 mmol, 2 equiv), in 0.3 mL of CH2Cl2, following the
general procedure (30 min), a separable 85:15 mixture of
p-nitrobenzoates was obtained. Chromatographic separation
(5-30% EtOAc-hexane) afforded 12 mg (0.027 mmol, 80%)
of 20 as a white solid. Product 20′ was accidentally lost during
purification. Data for 20: Rf ) 0.37 (15% EtOAc-hexane);
of isomers. Data for 15b: Rf ) 0.12 (5% EtOAc-CH2Cl2); [R]20
D
) -50.5 (c ) 1.39); 1H NMR (300 MHz) δ 0.39 (t, 3 H, J ) 7.4
Hz), 0.80 (t, 3 H, J ) 6.8 Hz), 0.92 (t, 3 H, J ) 7.0 Hz), 1.00
(quint, 2 H, J ) 7.3 Hz), 1.17-1.73 (m, 12 H), 2.16 (sext, 1 H,
J ) 6.8 Hz), 2.37 (s, 3 H), 2.85 (d, 1 H, J ) 3.3 Hz), 5.10 (m,
1 H), 5.90 (d, 1 H, J ) 8.3 Hz), 7.25 (d, 2 H, J ) 8.7 Hz), 7.47
(d, 2 H, J ) 8.3 Hz); 13C NMR (75 MHz) δ 10.9, 14.0, 21.3,
22.7, 27.6, 28.0, 29.1, 35.4, 37.0, 66.7, 125.3 (2 C), 129.7 (2 C),
138.3, 139.0, 141.3, 149.1. Partial data for 16b: Rf ) 0.12 (5%
1
[R]20 ) -100.7 (c ) 1.00); 1H NMR (300 MHz) δ 0.52 (d, 3 H,
EtOAc-CH2Cl2); H NMR (300 MHz) δ 0.60 (t, 3 H, J ) 6.7
D
Hz), 5.10 (m, 1 H), 5.78 (d, 1 H, J ) 8.3 Hz). Partial data for
17b′: 1H NMR (200 MHz) δ 6.37 (t, 1 H, J ) 7.3 Hz).
Syn th esis of (-)-(2R,5R,SS)-(3Z)-5-Isop r op yl-4-(p-tolyl-
su lfin yl)n on -3-en -2-ol (15d ). Following the general proce-
dure, from 9a (24 mg, 0.091 mmol, 1 equiv) with 9 equiv of
n-BuCuCNLi preformed at 0 °C, SN2′ addition product 15d
was obtained as a single isomer. Chromatographic purification
(30% EtOAc-hexane) afforded 22 mg of 15d (0.068 mmol, 75%)
as a colorless oil. Data for 15d : Rf ) 0.23 (30% EtOAc-
hexane); [R]20D ) -120.9 (c ) 0.34); 1H NMR (300 MHz) δ 0.35
(m, 2 H), 0.60 (t, 3 H, J ) 7.2 Hz), 0.84 (d, 3 H, J ) 6.8 Hz),
0.87 (d, 3 H, J ) 6.8 Hz), 1.12-1.05 (m, 4 H), 1.40 (d, 3 H, J
) 6.3 Hz), 1.82 (m, 1 H), 2.13 (m, 1 H), 2.39 (s, 3 H), 3.06 (d,
1 H, J ) 2.9 Hz), 5.40 (m, 1 H), 5.88 (d, 1 H, J ) 8.8 Hz), 7.28
(d, 2 H, J ) 8.2 Hz), 7.42 (d, 2 H, J ) 8.2 Hz); 13C NMR (75
MHz) δ 13.9, 18.2, 21.2, 21.3, 22.6, 23.3, 28.6, 29.3, 32.3, 41.5,
63.2, 125.0, 129.6, 139.3, 141.0, 147.6.
J ) 6.9 Hz), 0.86 (t, 3 H, J ) 6.9 Hz), 0.94 (t, 3 H, J ) 7.0 Hz),
1.21-2.05 (m, 12 H), 2.35 (s, 3 H), 2.50 (sext, 1 H, J ) 6.9
Hz), 5.90 (d, 1 H, J ) 9.0 Hz), 6.45 (dt, 1 H, J ) 8.9, 6.7 Hz),
7.24 (d, 2 H, J ) 8.2 Hz), 7.60 (d, 2 H, J ) 8.2 Hz), 8.23 (d, 2
H, J ) 8.9 Hz), 8.31 (d, 2 H, J ) 8.9 Hz); 13C NMR (75 MHz)
δ 13.9, 21.3, 22.2, 22.4, 22.7, 27.1, 29.4, 29.7, 35.0, 38.6, 73.0,
123.6 (2 C), 124.6 (2 C), 129.5 (2 C), 130.8 (2 C), 132.9, 135.6,
138.8, 140.8, 150.7, 154.4, 163.9.
Mitsu n obu P r otocol To Tr a n sfor m Alcoh ol 15a in to
p-Nitr oben zoa te 20. To a cold solution (0 °C) of alcohol 15a
(5 mg, 0.015 mmol, 1 equiv) in 0.5 mL of THF was added
recently recrystallized PPh3 (19 mg, 0.075 mmol, 5 equiv),
p-nitrobenzoic acid (12 mg, 0.075 mmol, 5 equiv), and diiso-
propyl azodicarboxylate (DIAD) (14.7 µL, 0.075 mmol, 5 equiv).
The reaction mixture was stirred and allowed to warm to room
temperature over ca. 1.5 h after which time it was diluted with
7 mL of Et2O and the layers were separated. The organic phase
was washed with 2 mL of a saturated solution of NaHCO3 and
2 mL of a saturated solution of NaCl, dried over MgSO4 and
concentrated under reduced pressure to give a crude product
which was purified by column chromatography to afford 5 mg
(0.010 mmol, 70%) of p-nitrobenzoate 20 as a white solid.
Syn t h esis of (-)-(5R,8R,SS)-(6Z)-8-P h en yl-7-(p-t olyl-
su lfin yl)d od ec-6-en -5-ol (16c). Following the general pro-
cedure, from 9c (57 mg, 0.167 mmol, 1 equiv) with 9 equiv of
n-BuCuCNLi preformed at -20 °C, SN2′ addition product 16c
was obtained as a single isomer after 1 h 30 min. Chromato-
graphic purification (5-20% EtOAc-hexane) afforded 58 mg
(0.146 mmol, 87%) of 9e as a colorless oil. Data for 16c: Rf )
Ack n ow led gm en t. This research was supported by
NIH (CA 22237), DGICYT (AGF98-0805-CO2-02 and
PB96-0822) and CAM (08.5/0046/1998). We thank the
CAM for a doctoral fellowship to C.M. We are grateful
to Professor B. Rodr´ıguez and Dr. J . C. Lo´pez (IQO,
CSIC) for encouragement and support. We thank Dr.
J eff Kampf (Department of Chemistry, The University
of Michigan) for the X-ray analysis of the p-nitroben-
zoate of chlorohydrin 11a .
1
0.25 (30% EtOAc-hexane); [R]20 ) -8.3 (c ) 1.26); H NMR
D
(300 MHz) δ 0.62 (t, 3 H, J ) 7.2 Hz), 0.77-1.77 (m, 15 H),
2.39 (s, 3 H), 2.62 (br s, 1 H), 3.54 (dd, 1 H, J ) 9.4, 5.6 Hz),
5.02 (m, 1 H), 6.01 (d, 1 H, J ) 8.5 Hz), 7.09-7-24 (m, 5 H),
7.27 (d, 2 H, J ) 8.1 Hz), 7.50 (d, 2 H, J ) 8.1 Hz); 13C NMR
(75 MHz) δ 13.7, 14.0, 21.3, 22.1, 22.6, 27.6, 29.5, 36.0, 36.6,
41.2, 66.7, 125.1 (2 C), 216.2, 127.8 (2 C), 128.1, 128.3 (2 C),
129.7 (2 C), 140.2, 141.3, 142.6, 148.7.
Syn th esis of th e p-Nitr oben zoa te of (-)-(5R,8R,SS)-
(6Z)-8-m eth yl-7-(p-tolylsu lfin yl)d od ec-6-en -5-ol (21). From
15a (9 mg, 0.026 mmol, 1 equiv), Et3N (5.6 µL, 0.04 mmol, 1.5
equiv), DMAP, and p-nitrobenzoyl chloride (6.4 mg, 0.034
mmol, 1.3 equiv) in 0.2 mL of CH2Cl2, following the general
procedure (24 h), a crude product was obtained. Subsequent
purification by column chromatography (10% EtOAc-hexane)
afford 9.25 mg (0.019 mmol, 73%) of 21 as a yellow oil which
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O000468K