On the configurational stability of α-lithiated sulfurated styrene oxides: Synthetic and mechanistic aspects

Article abstract of DOI:10.1080/10426507.2010.524180

The configurational stability of some sulfurated styrene oxides has been investigated. Chemical studies have shown that in THF at 157 K α-lithiated ortho-and paraphenylthiostyrene oxides are configurationally unstable and undergo a fast racemization on the time scale of the reaction, whereas α-lithiated meta-phenylthiostyrene oxide retains its stereochemical integrity for at least 60 min. The deprotonation-trapping methodology has also been employed for the preparation of a sulfurated β-aminoalcohol effective for the fight against phytopathogenic fungi. Copyright Taylor and Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.524180

Phosphorus, Sulfur, and Silicon, 186:1274–1277, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.524180
ON THE CONFIGURATIONAL STABILITY OF α-LITHIATED
SULFURATED STYRENE OXIDES: SYNTHETIC AND
MECHANISTIC ASPECTS
Vito Capriati, Mariangela Dammacco, Saverio Florio,
Filippo M. Perna, and Antonio Salomone
Dipartimento Farmaco-Chimico, Universita` di Bari “Aldo Moro,” Consorzio
Interuniversitario Nazionale Metodologie e Processi Innovativi di Sintesi
(C.I.N.M.P.I.S.), Bari, Italy
Abstract The configurational stability of some sulfurated styrene oxides has been inves-
tigated. Chemical studies have shown that in THF at 157 K α-lithiated ortho- and para-
phenylthiostyrene oxides are configurationally unstable and undergo a fast racemization on
the time scale of the reaction, whereas α-lithiated meta-phenylthiostyrene oxide retains its
stereochemical integrity for at least 60 min. The deprotonation-trapping methodology has also
been employed for the preparation of a sulfurated β-aminoalcohol effective for the fight against
phytopathogenic fungi.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Configurational stability; oxiranyllithiums; racemization; sulfurated styrene oxides
INTRODUCTION
α-Lithiated aryloxiranes are a useful class of chiral organometallic compounds that
currently are of increasing interest not only for their employment as building blocks for
asymmetric synthesis, but also for their intriguing behavior as “lithium carbenoids” that
triggers mechanistic investigations.1
In contrast to enantioenriched styrene-, phenylpropylene-, and stilbene oxides, which
could be lithiated at the benzylic position in THF (within the range 175–213 K) and
stereospecifically trapped with electrophiles,2 it has been quite recently reported that enan-
tioenriched ortho-tolylsulfinyl-3 and trifluoromethyl-styrene oxides4 undergo racemization
soon after their deprotonation in THF, the latter at a different rate depending on the relative
position of the trifluoromethyl group on the phenyl ring. In this article, we report the effect
of the phenylthio group, ortho-, meta-, and para-positioned on the phenyl ring of styrene
oxide, on the configurational stability of the corresponding lithiated derivatives.
Received 2 July 2010; accepted 13 September 2010.
Address correspondence to Antonio Salomone, Dipartimento Farmaco-Chimico, Universita` di Bari “Aldo
Moro,” Consorzio Interuniversitario Nazionale Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.I.S.), Via
E. Orabona 4, I-70125, Bari, Italy. E-mail: antoniosalomone@libero.it
1274

α-LITHIATED SULFURATED STYRENE OXIDES
1275
RESULTS AND DISCUSSION
(R)-o-Phenylthiostyrene oxide 4 was prepared in three steps by the reaction of ortho-
bromobenzaldehyde 1 with dimethylsulfonium methylide in DMSO (Corey–Chaykovsky
epoxidation)5 to give epoxide ( )-2 (60% yield), which was then subjected to a hydrolytic
kinetic resolution (HKR) according to the Jacobsen6 protocol [48 h, yield 25%, 98:2
enantiomeric ratio (er)] (Scheme 1). With optically active epoxide (R)-27 in hand, a bromine-
lithium exchange (n-BuLi, −98 ◦C, THF) was performed followed by a coupling reaction
with S-phenyl benzenethiosulphonate 3 to give sulfurated epoxide (R)-4 in 50% yield and
98:2 er (Scheme 1).
Scheme 1
o-Phenylthiostyrene oxide (R)-4 was deprotonated at 157 K with s-BuLi (2 equiv) in
THF, with a reaction time of 10 s, followed by MeOD quenching (Scheme 2). Racemization
of (R)-4 was found to proceed very quickly since 4-D was recovered with 61:39 er (HPLC
analysis), but with a high deuterium incorporation at the benzylic position (> 98%D,
1H NMR analysis of the crude reaction mixture). A similar deprotonation–deuteration
experiment was also performed at a higher temperature (175 K); after MeOD quenching,
however, the oxirane 4-D (>95%D) was recovered completely racemic. Therefore, the
presence of an ortho-positioned phenylthio-group induces configurational instability in the
corresponding 4-Li intermediate, also at very low temperature (157 K) in THF.
Scheme 2
Next we turned our attention to investigating lithiation of meta-phenylthiostyrene
oxide (R)-58 (98:2 er) (Scheme 3) at 175 K. After a lithiation time of 60 min, the addition
of MeOD essentially gave (R)-5-D (95%D) with the same optical purity of the starting
oxirane. This result is consistent with a configurational stability of the chiral organolithium
(R)-5-Li on the time scale of the reaction at 175 K in THF (Scheme 3).

1276
V. CAPRIATI ET AL.
Scheme 3
Finally, deprotonation of optically active (S)-6 (er = 98:2)8 (s-BuLi, THF, 175 K),
followed by MeOD quenching after 10 s, gave the deuterated product 6-D in a 68:32 er.
Such a result is also consistent with a configurationally instability of oxiranyllithium 6-Li
under the experimental conditions described above (Scheme 4).9
Scheme 4
The synthesis of an industrially relevant antifungal agent10 such as 9 was also set up
in a few steps (Scheme 5). Deprotonation of ( )-7 with s-BuLi/THF at 175 K, followed by
MeI quenching, afforded ( )-8. A regioselective ring-opening reaction of the so-formed
α,α-disubstituted epoxide promoted by 1-adamantylamine lead to the target molecule ( )-9
in 45% overall yield (Scheme 5).
Scheme 5

α-LITHIATED SULFURATED STYRENE OXIDES
1277
CONCLUSIONS
In conclusion, an investigation on the configurational stability of some lithiated
sulfurated styrene oxide derivatives has been carried out. α-Lithiated ortho- and para-
phenylthiostyrene oxides 4-Li and 6-Li proved to be configurationally unstable at 175 K
in THF on the time scale of the reaction, whereas α-lithiated meta-phenylthiostyrene oxide
5-Li could be, indeed, stereospecifically generated and deuterated after a reaction time
as long as 60 min. Strong conjugative interactions involving the low-lying 3-D orbitals
of the sulfur-containing substituent ortho- and para-positioned on the phenyl ring may
contribute to the oxiranyllithium’s chemical stability in THF, thus triggering an extensive
racemization also with short reaction time. In fact, when the phenylthio substituent is
meta-positioned, and thus not able to conjugate with the reaction center, the corresponding
lithiated intermediate was configurationally stable.
A lithiation–methylation sequence performed on oxirane 7, followed by a regioselec-
tive ring-opening reaction of α,α-disubstituted oxirane 8 with 1-adamanthylamine, allowed
the preparation of 9, which is a powerful antifungal agent. Such a methodology exploits the
nucleophilic character of α-lithiated sulfurated epoxides as key intermediates in the forma-
tion of quaternary carbinol centers. An asymmetric synthesis of 9 is currently underway in
our lab, and results will be reported in due course.
REFERENCES
1. (a) Capriati, V.; Florio, S.; Luisi, R. Chem. Rev. 2008, 108, 1918–1942; (b) Capriati, V.; Florio,
S.; Perna, F. M.; Salomone, A.; Abbotto, A.; Amedjkouh, M.; Nilsson Lill, S. O. Chem. Eur. J.
2009, 15, 7958–7979; (c) Capriati, V.; Florio, S. Chem. Eur. J. 2010, 16, 4152–4162.
2. Capriati, V.; Florio, S.; Luisi, R. Synlett 2005, 9, 1359–1369.
3. Capriati, V.; Florio, S.; Luisi, R.; Salomone, A.; Tocco, M. G.; Mart´ın Castro, A. M.; Garc´ıa
Ruano, J. L.; Torrente, E. Tetrahedron 2009, 65, 383–388.
4. Capriati, V.; Florio, S.; Perna, F. M.; Salomone, A. Chem. Eur. J. 2010, 16, 9778–9788.
5. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–1364.
6. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow,
M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307–1315.
7. Absolute configuration of o-, m-, and p-bromostyrene oxides was assigned on the basis of the
sign of their optical rotation, as reported in: Matsumoto, K.; Kubo, T.; Katsuki, T. Chem. Eur.
J. 2009, 15, 6573–6575. The absolute configuration of o-, m-, p-phenylthiostyrene oxides is the
same of their bromo precursors.
8. (R)-meta- and (S)-para-phenylthiostyrene oxides 5 and 6 were prepared starting from the corre-
sponding meta- and para-bromobenzaldehydes as shown for epoxide (R)-4.
9. By comparison, a sulfinyl substituent also causes extensive epimerization from the ortho-position
at the benzylic carbon of the epoxide, whereas meta- and para-sulfinyl-substituted styrene oxides
undergo exclusive hydrogen/lithium exchange ortho to the sulfinyl group when treated with
LDA/THF, with the epoxide stereochemistry remaining unaffected (see Ref. 3). This is in line
with the fact that sulfoxides, in contrast with sulfides, are, indeed, more powerful directed ortho
metalation groups by virtue of better coordination and acidifying effects (see also Clayden, J. In
Organolithium: Selectivity for Synthesis; Pergamon: Amsterdam, 2002, p. 47). However, while
in the case of the sulfenyl-substituted styrene oxide, the epoxide successfully strives with such a
functional group to bind the lithium thus facilitating benzylic deprotonation (complex-induced
proximity effect, see Ref. 1b), a similar competition with the epoxide ring does not occur with
sulfinyl derivatives.
10. Wehner, V.; Braun, P.; Sachse, B. Substituted β-hydroxyethylamine fungicides, DE Patent
4210569, 1993.

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