Construction of a quaternary carbon center via cyclic sulfite

Article abstract of DOI:10.1016/S0040-4039(00)00315-4

Reaction of (S)-2-oxo-4-methyl-4-phenyl-1,3,2-dioxathiolane with triethylaluminum selectively took place at the tertiary carbinol center to give (R)-2-methyl-2-phenyl-1-butanol. Enhanced stereoselectivity was obtained in a nonpolar solvent. Similarly, a series of (S)-4,4-disubstituted-1,3,2- dioxathiolanes reacted with trimethylaluminum to afford the corresponding (R)-2-alkyl-2-phenyl-1-propanols in good yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00315-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2945–2948
Construction of a quaternary carbon center via cyclic sulfite
Nanae Nishimura and Oyo Mitsunobu ∗
Department of Chemistry, College of Science and Engineering, Aoyama Gakuin University, 6-16-1 Chitosedai, Setagayaku,
Tokyo 157-8572, Japan
Received 11 January 2000; revised 16 February 2000; accepted 17 February 2000
Abstract
Reaction of (S)-2-oxo-4-methyl-4-phenyl-1,3,2-dioxathiolane with triethylaluminum selectively took place at
the tertiary carbinol center to give (R)-2-methyl-2-phenyl-1-butanol. Enhanced stereoselectivity was obtained in a
nonpolar solvent. Similarly, a series of (S)-4,4-disubstituted-1,3,2-dioxathiolanes reacted with trimethylaluminum
to afford the corresponding (R)-2-alkyl-2-phenyl-1-propanols in good yields. © 2000 Elsevier Science Ltd. All
rights reserved.
Chiral quaternary carbon centers are widespread in natural products such as steroids, alkaloids and
terpenes.1,2 For the construction of the carbon framework of these compounds, a primary alcohol having a
quaternary carbon atom at the C2 position would be an important building block. However, a few methods
for generating this moiety in an efficient enantioselective manner have been reported.2 As a possible
approach for the construction of this class of compounds, the reaction of nucleophiles with tertiary carbon
electrophiles would be conceivable. However, bimolecular nucleophilic substitution reactions at tertiary
carbon atoms bearing suitable leaving groups are relatively rare processes since competing β-elimination
is usually favored in such systems.
Cyclic sulfites and cyclic sulfates are considered as activated diols.3 Thus, it was reported that
the reaction of 2-oxo-4-phenyl-1,3,2-dioxathiolane (1a) and 2-oxo-4-(tert-butyldiphenylsilylmethyl)-
1,3,2-dioxathiolane (1b) with 3 mol equivalents of Me3Al selectively took place at the secondary
carbinol center to give 2-phenyl-1-propanol (2a) and 3-(tert-butyldiphenylsilyl)-2-methylpropanol (2b),
respectively (Scheme 1).4 A transition state with a carbenium-like character has been proposed to
explain the selectivity observed. It could, therefore, be expected that 2-oxo-4,4-disubstituted-1,3,2-
dioxathiolanes react with aluminum reagents, giving the corresponding primary alcohols having a
quaternary carbon atom at the C2 position.
In this communication, we wish to report the preparation of primary alcohols having quaternary centers
at the C2 position by the regioselective alkylation of tertiary carbon atom of a prim, tert-diol via 1,3,2-
dioxathiolane.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00315-4
tetl 16595

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Scheme 1.
At the outset, cyclohexanespiro-40-(20-oxo-10,30,20-dioxathiolane) (3)5 reacted with 3 mol equivalents
of Me3Al in toluene at 0°C for 1 h to give 1-hydroxymethyl-1-methylcyclohexane (4) in 92% yield
(Scheme 2).
Scheme 2.
In order to confirm the stereochemistry of the reaction, (S)-2-phenylpropane-1,2-diol was converted
into the exo- and endo-isomers of (S)-2-oxo-4-methyl-4-phenyl-1,3,2-dioxathiolane [exo-(S)-5 and endo-
(S)-5],5 which reacted, respectively, with Et3Al at −20°C for 1 h (Scheme 3).
Scheme 3.
When the reaction of exo-(S)-5 was carried out in CH2Cl2, a mixture of (R)- and (S)-2-methyl-2-
phenyl-1-butanol [(R)-6 and (S)-6] was obtained in 84% yield with (R)-isomer:(S)-isomer=1.37:1 (16%
ee) (Table 1, Entry 1).
Table 1
Reaction of 5 with Et3Al at −20°C for 1 h
The stereoselectivity was significantly improved when the reaction was carried out in n-hexane. Thus,
under the same conditions, except for changing the solvent from CH2Cl2 to n-hexane, both endo-(S)-5
and exo-(S)-5 gave (R)-6 in 56% ee (85% yield) and 70% ee (94% yield), respectively (Table 1, Entries
2 and 3). The configuration of the main isomers of these reactions was assigned to be (R) by comparison
of the [α]D of the mixture of the enantiomers obtained with reported [α]D (−5.95 for (R)-2-methyl-2-
phenyl-1-butanol).6
As can be seen from Table 1, enhanced stereoselectivity was obtained in n-hexane. This result would
be explained by assuming a carbenium-ionic character of the transition state. The lower stereoselectivity
observed in endo-5 than that in exo-5 would be rationalized by the formation of a transition state with
extensive bond-breaking (SN1-type transition state) to release the compression energy exerted between
the phenyl group and the complexed S→O group.4

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Next, the reaction of endo- and exo-isomers of 2-oxo-4-phenyl-1,3,2-dioxathiolane, having a series of
alkyl groups in the C4 position [endo-(S)-7 and exo-(S)-7]5 with Me3Al at −20°C for 1 h in n-hexane, was
examined (Scheme 4). When the endo-isomer of 2-oxo-4-phenyl-4-propyl-1,3,2-dioxathiolane [endo-(S)-
7a] was treated with Me3Al, 2-methyl-2-phenylpentanol [(S)-8a] was obtained in 45% ee (97% yield)
(Table 1, Entry 1). The reaction of the exo-isomer [exo-(S)-7a] gave (S)-8a in 48% ee (93% yield)
(Table 2, Entry 2). Similarly, the reaction of the endo- and exo-isomers of 2-oxo-4-butyl-4-phenyl-1,3,2-
dioxathiolane [endo-(S)-7b and exo-(S)-7b] and 2-oxo-4-isopropyl-4-phenyl-1,3,2-dioxathiolane [endo-
(S)-7c and exo-(S)-7c] with Me3Al resulted in the formation of (S)-8b and (S)-8c as main products in
95–98% yields with 35–79% ee (Table 2, Entries 3–6). The effects of the isopropyl group at the C4
position on stereoselectivity have not yet been elucidated.
Scheme 4.
Table 2
Reaction of 7 with Me3Al at −20°C for 1 h
The stereochemical assignment of the major product was made by converting the enantiomer mixture
isolated into the corresponding carboxylic acid with known configration.7 Thus, a 2.83:1 mixture of (S)-
8a and (R)-8a (48% ee) was subjected to Jones oxidation to afford 2-methyl-2-phenylpentanoic acid 9
in 87% yield with [α]D +3.8 (c 2.13, MeOH). The specific rotation observed indicates the major isomer
has (S)-configuration. In a similar way, the stereogenic center of all major products was determined to be
(S), indicating that stereochemical inversion took place in the substitution reaction.
In summary, the reaction of (S)-2-oxo-4-methyl-4-phenyl-1,3,2-dioxathiolane [endo-(S)-5 and exo-(S)-
5] with Et3Al regioselectively took place at the C4 position to afford (R)-2-methyl-2-phenyl-1-butanol (6)
and its (S)-isomer, with the former predominant. Enhanced stereoselectivity was obtained in a nonpolar
solvent. Similarly, a series of (S)-4,4-disubstituted-1,3,2-dioxathiolanes reacted with Me3Al to afford
the corresponding (S)-2-alkyl-2-phenyl-1-propanols [(S)-8] as the major product in good yields, but the
stereoselectivity was moderate (35–79% ee). Although the stereoselectivity of the reaction remains to be
improved, the results described in this paper suggest interesting possibilities for further work.

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Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture of Japan.
References
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