Highly stereoselective synthesis of optically active oxazolinyl oxiranes from azaenolates of a chiral 2-chloromethyloxazoline

Article abstract of DOI:10.1016/S0040-4039(00)00809-1

Boron and titanium azaenolates 2 and 4, generated at 0°C and -100°C, respectively, from the optically active chloromethyloxazoline 1, have been found to couple with aliphatic ketones in a highly diastereoselective fashion ending up with the formation of optically active oxazolinyl oxiranes 3. Less stereoselective was the reaction with aromatic ketones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00809-1

Tetrahedron Letters 41 (2000) 5295±5298
Highly stereoselective synthesis of optically active oxazolinyl
oxiranes from azaenolates of a chiral 2-chloromethyloxazoline
Saverio Florio,* Vito Capriati and Renzo Luisi
CNR, Centro di Studio sulle Metodologie Innovative di Sintesi Organiche, Dipartimento Farmaco-Chimico,
Á
Universita di Bari, Via E. Orabona 4, I-70125 Bari, Italy
Received 19 April 2000; accepted 16 May 2000
Abstract
Boron and titanium azaenolates 2 and 4, generated at 0ꢀC and ^100ꢀC, respectively, from the optically
active chloromethyloxazoline 1, have been found to couple with aliphatic ketones in a highly diastereo-
selective fashion ending up with the formation of optically active oxazolinyl oxiranes 3. Less stereoselective
was the reaction with aromatic ketones. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: boron azaenolate; titanium azaenolate; chiral oxazolines; chiral oxiranyl oxazolines.
The chemistry of azaenolates of 2-alkyloxazolines, which are extremely useful intermediates in
synthetic organic chemistry, has been rather exhaustively investigated with pivotal and fundamental
achievements from Meyers' research group.1 In comparison, azaenolates of heterosubstituted
2-alkyloxazolines have been studied much less.2 Recent results from our laboratory had proved
that azaenolates of chloroalkyloxazolines couple eciently with carbonyl compounds3 and imines4
to produce oxazolinyl oxiranes, and then formyl oxiranes by elaboration of the oxazolinyl
ring, and aziridines, respectively. In particular, we had found that lithium azaenolates couple
with carbonyl compounds with poor diastereoselection,5 whereas boron azaenolates react with
very high and opposite diastereoselection depending upon the ligands on the boron atom.6
However, we disappointingly found that boron azaenolates of 1, generated at ^78ꢀC, do not
couple with aliphatic enolizable ketones probably due to the competing ketone enolization
which interferes with the enolization of the chloromethyloxazoline in the generation step of the
boron azaenolate.
In the present paper we wish to report that under proper experimental conditions boron aza-
enolates of the chiral, non-racemic, chloromethyloxazoline 1 also couple eciently and highly
diastereoselectively with enolizable ketones. We also report on the coupling of titanium azaenolates.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00809-1

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Treatment of a dichloromethane solution of (4S,5S)-2-chloromethyl-4-methoxymethyl-5-
phenyl-2-oxazoline 1 (prepared by chlorination6 8 of commercially available (4S,5S)-2-methyl-4-
methoxymethyl-5-phenyl-2-oxazoline) with Bu2BOTf/NEt3 at 0ꢀC (1 h) and subsequent addition
of 3-pentanone after 1.5 h a€orded diastereomeric chlorohydrins, which, without isolation, were
converted, under basic conditions (NaOH/iPrOH), into oxazolinyl epoxides 3 in high yield and
with excellent diastereoselection (dr=97:3) (Table 1).
Table 1
Reaction of 1, via boron azaenolates 2a/2b, with ketones
The diastereomeric ratio was determined by gas-chromatography (the main stereoisomer
1
showed the lower retention time) and was con®rmed by H NMR (500 MHZ) (usually on the
basis of the chemical shift and the integral of the characteristic doublet of each of the two dia-
stereomeric oxazoline ring hydrogens at C-5 in the range of 5.0±5.5 ppm: the main isomer had the
higher ꢀ value). Equally highly diastereoselective was the aldol-type reaction of the dibutyl boron
azaenolate 2a with other aliphatic ketones (Table 1). It was interesting to observe that the direction
of diastereoselection did not change when the same boron azaenolate 2a was prepared to 0ꢀC,
cooled to ±78ꢀC and reacted with the ketone (cyclohexanone).
A lower diastereoselection, but showing similar trends, was observed in the coupling reaction
of the boron azaenolate 2b (prepared from 1 and 9-BBNOTf) at 0ꢀC (Table 1). This result seemed
intriguing as we had previously found that the aldol-type reaction of the dibutyl boron azaenolate
2a with aromatic ketones proceeded with high and opposite diastereoselection with respect to
the boron azaenolate 2b.6 This had been ascribed to the coordination of the boron atom by
the methoxymethyl group present on the C4 of the oxazoline ring,6 thus driving the carbonyl

5297
to attack the carbanionic center preferentially from the same side of the methoxymethyl appendage.
The di€erent behavior observed with aliphatic ketones could be tentatively explained in terms of
a competition between the coordination of the boron atom by the methoxymethyl group and the
carbonyl compound. The aliphatic ketones (at least those used in the present work) being stronger
Lewis bases than the aromatic ketones, one could envisage a weak interaction between the boron
atom and the methoxymethyl group with no e€ect on the stereoselection. It is also useful to point
out that when the reaction of 2a and 2b with an aromatic ketone (benzophenone) was carried out
at 0ꢀC, the measured diastereoselection was exactly the same as for the reaction performed at
^78ꢀC.
We have also studied the stereochemical aspects of the aldol-type reaction of the titanium
azaenolate of chloromethyl oxazoline 1. Oxazoline 1 was treated with LDA at ±100ꢀC. The
lithium azaenolate was then transmetalated with titanium tetraisopropoxide Ti(iPrO)4. The
resulting titanium azaenolate 4 was treated with cyclobutanone and then with NaOH in iPrOH
a€ording the oxazolinyl epoxide in good yield and excellent diastereoselection, the direction of
stereoselection being the same of the dibutyl boron azaenolate 2a (Table 2).
Equally highly diastereoselective was the reaction of 4 with other aliphatic ketones (Table 2).
No reaction took place when 2,2,4,4-tetramethyl-3-pentanone was used as the electrophile,
probably for steric reasons. In contrast, the reaction of 4 with aromatic ketones occurred with
very poor or no stereoselection.
Table 2
Reaction of 1, via titanium azaenolate 4, with ketones
In conclusion, in this paper we report a highly stereoselective synthesis of oxazolinyl oxiranes,
which are potentially useful synthetic intermediates, based on the coupling reaction of boron and
titanium azenolates, easily available from the chiral oxazoline 1, with ketones. More work is
under way in order to razionalize the observed stereoselection.

5298
Acknowledgements
Work carried out in the framework of the National Project `Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni' supported by the Ministero dell'Universita e della Ricerca Scienti®ca
e Tecnologica, Rome, and by the University of Bari. We also thank the Italian CNR for
®nancial support.
References
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