Stereoselective additions of chiral (E)-crotylsilanes to thionium ions: Asymmetric synthesis of homoallylic thioethers

Article abstract of DOI:10.1021/jo011025z

Stereochemically well-defined homoallylic thioethers 3 are synthesized via Lewis acid promoted condensation reaction between chiral organosilane reagents 2 and in situ generated thionium ions. The stereochemical course of the reaction is consistent with earlier reports concerning crotylsilations of oxonium ions.

Full text of DOI:10.1021/jo011025z

J . Org. Chem. 2002, 67, 1705-1707
1705
Sch em e 1
Ster eoselective Ad d ition s of Ch ir a l
(E)-Cr otylsila n es to Th ion iu m Ion s:
Asym m etr ic Syn th esis of Hom oa llylic
Th ioeth er s
Ping Liu, Eva D. Binnun,† J ennifer V. Schaus,‡
Nicole M. Valentino,† and J ames S. Panek*,§
Department of Chemistry and Center for Streamline
Synthesis, Metcalf Center for Science and Engineering,
590 Commonwealth Avenue, Boston University,
Boston, Massachusetts 02215
Sch em e 2
panek@chem.bu.edu
Received October 24, 2001
resulted in the development of a useful strategy for the
asymmetric construction of homoallylic ethers,8 tetrahy-
drofurans,9 γ-alkoxy-R-amino acid synthons,10 subunits
of many polyketide, and amino acid derived natural
products. Applications have been illustrated with our
syntheses of rutamycin/oligomycin11 and motuporin.12 In
this paper, we report that the Lewis acid promoted
crotylation reactions of chiral (E)-crotylsilanes13 with in
situ generated thionium ions provide stereochemically
well-defined homoallylic thioethers.14 The thioacetals 1,
readily available from the corresponding aldehydes, when
condensed with chiral silane reagents afford under Lewis
acid catalysis syn-homoallylic thioethers 3 with useful
levels of selectivity (Scheme 1).
We began these experiments with the expectation that
the chiral (E)-crotylsilane 2 would show similar charac-
teristics for Lewis acid catalyzed reactions with thio-
acetals as we have previously documented with acetals.7
Thioacetals 1 were prepared according to a procedure
described by Evans and co-workers.15 Treatment of
aldehydes with (phenylthio)trimethylsilane in the pres-
ence of TiCl4 cleanly produced diphenylthioacetal 1
(Scheme 2).
Abstr a ct: Stereochemically well-defined homoallylic thio-
ethers 3 are synthesized via Lewis acid promoted condensa-
tion reaction between chiral organosilane reagents 2 and in
situ generated thionium ions. The stereochemical course of
the reaction is consistent with earlier reports concerning
crotylsilations of oxonium ions.
Thioethers are useful heteroatom functional groups in
organic synthesis.1 An extensive list of methods have
been developed for the preparation of R-sulfenyl carbonyl
compounds,2 R-(R-sulfenyl)alkylated carbonyl compounds,3
vicinal thioether alcohols,4 and vicinal dithioethers.5 A
number of reports have recently appeared that describe
the stereoselective synthesis of thioether derivatives and
their use in asymmetric transformations.6 To further
support this notion Christoffers has recently reported
that chiral bi- and tridentate ligands have been synthe-
sized bearing a thioether moiety as an additional electron
donor.7 As a consequence of the growing importance of
molecules bearing stereogenic C-S bonds, the develop-
ment of a new stereoselective approach to this class of
compounds would constitute a meaningful contribution
to this area. Previous reports from our laboratory have
described the use of chiral (E)-crotylsilanes as carbon
nucleophiles in highly diastereo- and enantioselective
addition reactions to acetals and aldehydes. Those studies
As one of the principle routes to thionium ions, Lewis
acid mediated ionization of thioacetals was surveyed
using five different Lewis acids. A summary of these
experiments describing the addition reaction of organo
silane (R)-2 to diphenylthioacetal 1 is given in Table 1.
In accordance with the observations of Heathcock et al.,11
our experiments have also determined that 1.2-1.5 equiv
of tin tetrachloride (SnCl4) is the most effective Lewis
† Pfizer PREPARE fellows.
‡ Division of Organic Chemistry ACS Graduate Fellow 2001-2002
sponsored by Wyeth-Ayerst.
§ Arthur C. Cope Scholar 2002.
(1) (a) Ohno, A.; Oae, S. Organic Chemistry of Sulfur; Oae, S., Ed.;
Plenum: New York, 1976. (b) Metzner, P.; Thuillier, A. Sulfur Reagents
in Organic Synthesis; Academic Press: London, U.K., 1994.
(2) Enders, D.; Scha¨fer, T.; Mies, W. Tetrahedron 1998, 54, 10239-
10252 and references therein.
(3) Kobayashi, K.; Kawakita, M.; Irisawa, S.; Akamatsu, H.; Sakash-
ita, K.; Morikawa, O.; Konishi, H. Tetrahedron 1998, 54, 2691-2696
and references therein.
(8) (a) Aryl acetals: Panek, J . S.; Yang, M. J . Am. Chem. Soc. 1991,
113, 6594-6600. (b) Heterosubstituted acetals: Panek, J . S.; Yang,
M. J . Org. Chem. 1991, 56, 5755-5758. (c) Masse, C. E.; Panek, J . S.
Chem. Rev. 1995, 95, 1293-1316.
(9) Panek, J . S.; Yang, M. J . Am. Chem. Soc. 1991, 113, 9868-9870.
(10) Panek, J . S.; Yang, M.; Muler, I. J . Org. Chem. 1992, 57, 4063-
4064.
(4) Enders, D.; Piva, O.; Burkamp, F. Tetrahedron 1996, 52, 2893-
(11) Panek, J . S.; J ain, N. F. J . Org. Chem. 2001, 66, 2747-2756.
(12) Hu, T.; Panek, J . S. J . Org. Chem. 1999, 64, 3000-3001.
(13) For the preparation of the chiral silane reagents, see: Beresis,
R. T.; Solomon, J . S.; Yang, M. G.; J ain, N. F.; Panek, J . S. Org. Synth.
1997, 75, 78-88.
(14) Nucleophilic additions of the silyl enol ether and allyltrimeth-
ylsilane to chiral thionium ions have been reported by Heathcock and
Trost: (a) Mori, I.; Bartlett, P. A.; Heathcock, C. H. J . Am. Chem. Soc.
1987, 109, 7199-7200. (b) Mori, I.; Bartlett, P. A.; Heathcock, C. H.
J . Org. Chem. 1990, 55, 5966-5977. (c) Trost, B. M.; Sato, T. J . Am.
Chem. Soc. 1985, 107, 719.
2908 and references therein.
(5) Kondo, T.; Uenoyama, S.; Fujita, K.; Mitsudo, T. J . Am. Chem.
Soc. 1999, 121, 482-483.
(6) For examples, see: (a) Chelucci, G.; Culeddu, N.; Saba, A.;
Valenti, R. Tetrahedron. Asym. 1999, 10, 3537-3546. (b) Selvakumar,
K.; Valentini, M.; Pregosin, P. S.; Albinati, A. Organomet. 1999, 18,
4591-4597. (c) You, S. L.; Zhou, Y. G.; Hou, X. L.; Dai, L. X. J . Chem.
Soc., Chem. Commun. 1998, 2765-2766. (d) Koning, B.; Meetsma, A.;
Kellogg, R. M. J . Org. Chem. 1998, 63, 5533-5540. (e) Montenegro,
E.; Poch, M.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron Lett.
1998, 39, 335-338.
(15) (a) Evans, D. A.; Grim, G. K.; Truesdale, L. K. J . Am. Chem.
Soc. 1975, 97, 3229-3230. (b) Evans, D. A.; Truesdale, L. K.; Grim,
G. K.; Nesbitt, S. L. J . Am. Chem. Soc. 1977, 99, 5009-5017.
(7) Christoffers, J .; Robler, U. Tetrahedron 2001, 57, 1779-1783 and
references there in.
10.1021/jo011025z CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/08/2002

1706 J . Org. Chem., Vol. 67, No. 5, 2002
Notes
Ta ble 1. Lew is Acid P r om oted Ad d ition Rea ction of
Ta ble 2. Sn Cl4-P r om oted Ad d ition Rea ction s of (S)-2 to
Sila n e (R)-2 to Th ioa ceta l 1
Th ioa ceta ls 1
entry Lewis acida
diastereomer ratio (syn/antib) % yieldc
1
2
3
4
5
BF3‚OEt2
TiCl4
SnCl4
SbCl5
TMSOTf
5:1
42
<10
94
43
0
-
7:1
4:1
-
a
All reactions were carried out in CH2Cl2 (0.25-0.3 M) at 0 °C
b
to room temperature using 1.2-1.5 equiv of Lewis acids. Ratios
were determined by 1H NMR on the crude reaction mixtures.
c Yields were based on mixtures of diastereoisomers isolated by
chromatography on SiO2.
acid for promoting the asymmetric addition reaction
between (R)-2 and 1 for the formation of homoallylic
thioether 3.16 As shown in Table 1 (entries 1, 2, and 5),
the use of boron trifluoride etherate (BF3‚OEt2), titanium
tetrachloride (TiCl4), or antimony pentachloride (SbCl5)
resulted in a substantial decrease in reaction rate, and
in one case only, trace amounts (<10%) of the desired
product were detected. Although it is the Lewis acid of
choice in the addition reactions of chiral silane reagents
to oxygen based acetals, TMSOTf failed to deliver any
amount of the desired product (entry 5).7 The optimized
conditions for the Lewis acid-catalyzed asymmetric ad-
dition of the chiral (E)-crotylsilane 2 to thioacetal 1 were
determined to be 1.5 equiv of SnCl4 with methylene
chloride as the solvent for 16 h (0 °C f rt). Several other
useful pieces of information emerged from the above
experiments, which prompted us to further investigate
the utility of the chiral silane reagents in enantioselective
addition reactions. First, the SnCl4-catalyzed reaction
proceeded cleanly and efficiently at room temperature
and was near completion in a matter of hours. Second,
useful levels of diastereoface selectivity were reached
under the described reaction conditions. Third, the
formation of the isolated syn-homoallylic thioether prod-
uct could be rationalized by the use of an anti-SE′ addition
mode and is consistent with oxonium ions, and thus
follows closely our previous work in the area.17 This
notion served as the basis for the assignment of absolute
stereochemistry of the homoallylic thioether.7
Having established reaction conditions, the generality
of this reaction was explored. A summary of experiments
describing the enantioselective addition reactions to a
variety of thioacetals is given in Table 2. As expected on
the basis of the above Lewis acid study, SnCl4 was found
to be most effective and typically afforded high yields of
the homoallylic thioether 3. Acyclic and cyclic aliphatic
thioacetals and aromatic thioacetals are all suitable
substrates for this reaction, although branched aliphatic
substrates generally gave higher levels of selectivity than
aromatic substrates (entries 1-3 vs 4-7). The heteroaro-
matic thioacetals, such as oxazole-, furan-, and pyridine-
derived thioacetals (not shown), did not yield the desired
homoallylic thioethers under the reaction conditions
investigated.
a
All reactions were carried out in CH2Cl2 (0.25-0.3 M) at 0 °C
to room temperature over a 16-h period using 1.5 equiv of SnCl4.
b
Yields were based on mixtures of diastereomers isolated by
chromatography on SiO2. c Ratios were determined by 1H NMR
analysis on the crude reaction mixtures.
For the cases examined in this study, the additions
proceeded with predictable diastereoface selectivity for
the formation of the two stereogenic centers. A trend of
diastereoselectivity has emerged that is consistent with
a stereospecific anti-SE′ pathway as originally docu-
mented by Fleming14 and Kumada18 and which has been
confirmed by Nakai19 and Marshall20 as well as our
laboratory.21 This may be described by an open transition-
state model as illustrated for the silane (S)-2 in Scheme
1. In this arrangement the C-Si bond is positioned anti
to the thionium ion and coplanar to the p-orbital of the
adjacent π-bond allowing stabilization of the emerging
secondary carbocation. The sense of induction is regu-
lated by the absolute configuration at the stereogenic
center bearing the silicon group.18 For example, (S)-silane
2 adds preferentially to the re face of the thionium ion
(Scheme 1) and (R)-2 silane adds to the si face (Table 1).
The relative stereochemistry of the crotylation products
3a -f has been assigned by correlation with the anti-
(18) (a) Hayashi, T.; Konishi, M.; Ito, H.; Kumada, M. J . Am. Chem.
Soc. 1982, 104, 4962-4963. (b) Hayashi, T.; Konishi, M.; Kumada, M.
J . Am. Chem. Soc. 1982, 104, 4963-4965.
(16) All new compounds were isolated as chromatographically pure
materials and exhibited acceptable 1H NMR, 13C NMR, IR, HRMS
spectra data.
(17) (a) Chan, T. H.; Fleming, I. Synthesis 1979, 761-775. (b)
Fleming, I. Chem. Soc. Rev. 1981, 10, 83-99.
(19) Mikani, K.; Kawamoto, K.; Loh, T.-P.; Nakai, T. J . Chem. Soc.,
Chem. Commun. 1990, 1161-1163.
(20) Marshall, J . A.; Wang, X.-J . J . Org. Chem. 1991, 56, 3211-
3213.
(21) Panek, J . S.; Cirillo, P. F. J . Org. Chem. 1993, 58, 294-296.

Notes
J . Org. Chem., Vol. 67, No. 5, 2002 1707
states. 13C NMR were recorded on a 75 MHz spectrometer at
ambient temperature. Chemical shifts are reported in parts per
million relative to chloroform (1H, δ 7.24; 13C, δ 77.0). All 13C
NMR were recorded with complete proton decoupling. Infrared
spectra were recorded on an FT-spectrophotometer. High resolu-
tion mass spectra were obtained in the Boston University Mass
Spectrometry Laboratory. Analytical thin-layer chromatography
was performed on 0.25 mm silica gel 60-F plates. Flash chro-
matography was performed as previously described.22 When
specified as “anhydrous”, solvents were distilled and/or stored
over 4 Å molecular sieves prior to use. Yields refer to chromato-
graphically pure materials unless otherwise stated. DriSolv
DMF was used as supplied. Tin tetrachloride and titanium
tetrachloride were distilled from copper prior to use. All other
reagents were used as supplied by Aldrich and Alfa Aesar. All
reactions were performed under a dry argon or nitrogen atmo-
sphere in oven-dried glassware.
Sch em e 3. Ster eoch em ica l Assign m en ts of 5 via
1H NMR An a lysis
Gen er a l P r oced u r e for th e P r ep a r a tion of Dith ioa cta ls
fr om Ald eh yd es Illu str a ted for 1a (also see ref 12). A solution
of isopropyl aldehyde (1 g, 13.87 mmol) and trimethylsilyl
thiophenol (5.05 g, 27.7 mmol) in CH2Cl2 (0.25 M) was cooled to
0 °C. Freshly distilled TiCl4 (0.95 mL, 6.9 mmol) was added
dropwise, and the solution was allowed to stir at 0 °C for
approximately 45 min. The reaction was quenched with excess
1.0 M HCl, extracted with CH2Cl2, and dried over anhydrous
MgSO4. The crude product was purified via flash chromatogra-
phy (SiO2, 0% f 3% EtOAc/hexanes), affording 74% yield of pure
1a ((3.161 g, 10.3 mmol) as a yellow oil.
homoallylic phenyl sulfide, which was derived from the
syn-homoallylic benzyl ether 4 through a classical SN2
displacement reaction (Scheme 3). The formation of the
major isomer (syn-3c) is consistent with previous studies
from our laboratory concerning the reaction of (E)-
crotylsilanes with unfunctionalized achiral acetals (al-
dehydes) which have demonstrated universal syn-selec-
tivity in the formation of homoallylic ethers7 and alcohols.18
The homoallylic ether 4 was converted to the anti-phenyl
sulfide 7 in a straightforward three-step sequence: (1)
deprotection of the benzyl ether using DDQ, followed by
(2) mesylation of the derived secondary alcohol (MsCl/
Et3N), and (3) SN2 displacement of the mesylate using
the sodium salt of thiophenol afforded the anti-diastere-
omer. This diastereomer displayed different NMR char-
acteristics (i.e., chemical shifts and different three bond
coupling constants when compared to the syn-diastere-
omer 3c. The stereochemistry of the remaining crotyla-
tion products 3a -g is assigned by analogy with 7.
In closing, we have shown that the asymmetric addi-
tions of enantioenriched (E)-crotylsilane reagents to
thionium ions generated through the ionization of the
corresponding thioacetals expands the scope and utility
of our evolving chiral silane-based bond construction
methodology. Further studies concerning the application
of these stereochemically well-defined homoallylic thio-
ethers in organic transformations will be reported as
permitted.
Gen er a l P r oced u r e for th e P r ep a r a tion of Hom oa llylic
Th ioeth er s Illu str a ted for 3a . A solution of isopropyl aldehyde
dithioacetal (126 mg, 0.46 mmol) and (S)-E-crotylsilane (100 mg,
0.38 mmol) in CH2Cl2 (0.25 M) was cooled to 0 °C. Freshly
distilled SnCl4 (0.10 mL, 0.57 mmol) was added dropwise, and
the solution was stirred and allowed to warm to room temper-
ature over a 16-h period. The reaction was quenched with excess
aqueous NaHCO3, extracted with CH2Cl2, and dried over
anhydrous MgSO4. The crude product was purified via flash
chromatography (SiO2 0%f3% EtOAc/hexanes), yielding 94%
of pure 3a (0.134 g, 0.43 mmol) as a yellow oil.
Ack n ow led gm en t. We thank Professor J ohn A.
Porco, J r. (Boston University) for helpful discussions.
Financial support was obtained from NIH (RO1 CA-
56304).
Su p p or tin g In for m a tion Ava ila ble: [R]26D, IR, 1H and
13C NMR, MS spectral data for compounds 1-7, and experi-
mental procedures for the preparation of compounds 4-7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O011025Z
Exp er im en ta l Section
Gen er a l Meth od . 1H NMR spectra were recorded on a 400
MHz spectrometer at ambient temperature unless otherwise
(22) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.