Chiral vinyl dioxazaborocines in synthesis: Asymmetric cuprate additions to β-boronyl acrylates and vinyl sulfones

Article abstract of DOI:10.1016/S0040-4039(00)00572-4

The first examples of the addition of organometallic reagents to electron deficient boron-substituted olefins are reported. Thus, copper catalysed addition of Grignard reagents to chiral acryloyl and vinysulfonyl dioxazaborocines, followed by oxidative re

Full text of DOI:10.1016/S0040-4039(00)00572-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4235–4238
Chiral vinyl dioxazaborocines in synthesis: asymmetric cuprate
additions to β-boronyl acrylates and vinyl sulfones
Christopher N. Farthing and Stephen P. Marsden ∗
Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, UK
Received 21 March 2000; accepted 4 April 2000
Abstract
The first examples of the addition of organometallic reagents to electron deficient boron-substituted olefins are
reported. Thus, copper catalysed addition of Grignard reagents to chiral acryloyl and vinylsulfonyl dioxazaboro-
cines, followed by oxidative removal of the boron, gives β-hydroxy esters and sulfones with asymmetric inductions
up to 81 and 95% ee, respectively. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; boron and compounds; Grignard reagents; alcohols; Michael reactions.
Asymmetric Michael addition of organometallic nucleophiles to electron deficient olefins is an impor-
tant area of asymmetric synthesis.1–3 The use of chiral auxiliaries to control absolute stereochemistry in
such processes is well documented.1,2 Significant advances have been made in both reagent and catalyst
control of asymmetry through the use of chiral ligands for organocopper reagents, nickel catalysis of
organozinc additions, and rhodium catalysis of organoboronate additions.3,4 The asymmetric addition
of organometallics to acyclic Michael acceptors is particularly challenging and most of the systems
developed thus far place constraints on the substituents tolerated on either the nucleophile or Michael
acceptor if high enantiomeric purities are to be obtained. In this context, efficient chiral auxiliary based
strategies still have a role to play in target synthesis.
We and others have been investigating asymmetric additions to olefins bearing chiral boronyl
functions as stereocontrol elements. Varying degrees of success have been observed in asymmetric
cyclopropanations,5 cycloadditions (Diels–Alder,6 nitrile oxide/olefin7 and nitrone/olefin7a) and radical
additions.6e,8 To the best of our knowledge, the addition of organometallic reagents to electron deficient
boron substituted olefins has not been investigated, although Negishi has reported an alkoxide promoted
Michael-type B–C migration of alkyl groups in β-(dialkylboronyl)acrylates.9 We were intrigued to see if
dioxazaborocines could be used as a stereocontrol element in the addition of organometallics to acrylates
and vinyl sulfones (Fig. 1).
∗
Corresponding author. Tel: (44) 20 7594 5790; fax: (44) 20 7594 5804; e-mail: s.marsden@ic.ac.uk (S. P. Marsden)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00572-4
tetl 16851

4236
Fig. 1.
The major attraction of using boron as an anchor point for a chiral auxiliary is that the versatile
chemistry of the C–B bond10 should allow conversion of the intermediate β-boronyl ester/sulfone to the
corresponding β-hydroxy, β-amino or β-dialkyl compounds. Thus, a single chiral auxiliary would serve
as the synthetic equivalent of a chiral formylacetate,11 iminoylacetate or 3-substituted acrylate. We report
herein the results of our investigations into the addition of cuprates to chiral vinyl dioxazaborocines,
leading to enantio enriched β-hydroxyesters and β-hydroxysulfones in good to excellent optical purity.
Vinyl dioxazaborocine 1a was prepared according to our previous synthesis,7a while dioxazaborocines
1b,c were prepared by condensation of diethanolamine 212 with the appropriate pinacolboronates 3b,c13
in ether at room temperature (Scheme 1). In all cases the product dioxazaborocines precipitated from the
solution as microanalytically pure white solids.
Scheme 1.
Initial investigations focused on determining the optimum conditions for the addition of organometallic
reagents to the dioxazaborocines. Thus, cyclohexylmagnesium chloride was added to dioxazaborocines
1b,c under the conditions shown and, following aqueous work-up of the reaction, the crude material was
treated with sodium perborate to effect the oxidation of the C–B bond to a hydroxyl group. The results
of these preliminary investigations are shown in Scheme 2 and Table 1.
Scheme 2.
From these results it can be seen that the additions proceed smoothly either in the presence or absence
of tricyclohexylphosphine, provided that the Grignard reagent is added slowly to the mixture. Slightly
lower optical purities are obtained in the presence of the phosphine. The use of pre-formed cuprates such
as Bu2CuLi was found to be less effective. Sodium perborate was found to give cleaner oxidations to
the alcohol compared to alternatives such as basic hydrogen peroxide. Significantly, we were also able
to isolate the intermediate boronic acid (entry 5) which was then readily converted to the alcohol 4 with

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Table 1
Optimisation of copper catalysed addition of Grignard reagents to dioxazaborocines 1a–c
identical enantiomeric purity to that obtained without isolation. This will be of use when attempting
interconversions of the C–B bond other than simple oxidation to the hydroxyl group.
We settled upon the optimum conditions for the addition as being the slow (1 hour) addition of three
equivalents of the respective Grignard reagent to the substrate and three equivalents of copper(I) iodide
at −78oC in ether, followed by slow warming to room temperature. The results of the addition of a range
of Grignard reagents to dioxazaborocines 1a–c are shown in Table 2.
Table 2
Copper catalysed addition of Grignard reagents to dioxazaborocines 1a–c
A number of observations can be made regarding these results. Firstly, the greatest degree of asym-
metric induction is observed with vinyl sulfone 1c, while the benzyl acrylate 1b performs better than the
corresponding methyl ester 1a. There are no obvious trends regarding the effects of changing the organic
function of the Grignard reagent. The sense of asymmetric induction was confirmed as being that shown
for entries 1, 3, 4 and 5 by comparison of the sign of the optical rotation of the material obtained with
known literature values.14 The remaining compounds are assigned the same stereochemistry by analogy.
The stereochemical outcome can be rationalised in a similar manner to our results in the addition of
nitrile oxides to vinyl dioxazaborocines,7a namely by assuming the exo-approach of the organometallic

4238
reagent to the olefin in the configuration shown below. Compound 1a has been shown to exist exclusively
in this conformation in the solid state.7a
In summary, we have demonstrated the first addition of organometallic reagents to electron deficient
vinyl boronates, leading to the asymmetric synthesis of a range of β-hydroxyesters and sulfones on
oxidative cleavage of the boronyl function. The versatile chemistry of the C–B bond offers the potential
for these compounds to act as intermediates for the synthesis of β-amino acids and chiral β-branched
acrylates.
Acknowledgements
We thank the Leverhulme Trust for the award of a grant for postdoctoral support (to C.N.F.), and the
Royal Society for additional financial support.
References
1. Schmalz, H.-G. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1990; Vol.
4, pp.199–236.
2. Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771–806.
3. Krause, N. Angew. Chem., Int. Ed. 1998, 37, 283–285.
4. See, for example: Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10,
4047–4056 and references cited therein.
5. (a) Imai, T.; Mineta, H.; Nishida, S. J. Org. Chem. 1990, 55, 4986–4989; (b) Pietruszka, J.; Widenmeyer, M. Synlett. 1997,
977–979; (c) Luithle, J. E. A.; Pietruszka, J.; Witt, A. Chem. Commun. 1998, 2651–2652; (d) Zhou, S.-M.; Deng, M.-Z.;
Xia, L.-J.; Tang, M.-H. Angew. Chem., Int. Ed. 1998, 37, 2845–2847.
6. (a) Wang, X. J. Chem. Soc., Chem. Commun. 1991, 1515–1516; (b) Bonk, J. D.; Avery, M. A. Tetrahedron: Asymmetry
1997, 8, 1149–1152; (c) Renard, P.-Y.; Lallemand, J.-Y. Tetrahedron: Asymmetry 1996, 7, 2523–2524; (d) Mortier, J.;
Vaultier, M.; Plunian, B.; Toupet, L. Heterocycles 1999, 50, 703–711; (e) Guennouni, N.; Rasset, C.; Carboni, B.; Vaultier,
M. Synlett 1992, 581–584.
7. (a) Davies, C. D.; Marsden, S. P.; Stokes, E. S. E. Tetrahedron Lett. 1998, 39, 8513–8516; (b) Jiang, B.; Zhang, A.; Kan, Y.,
Chinese Journal of Chemistry 1999, 17, 293–299; (c) Wallace, R. H.; Zong, K. K. J. Organomet. Chem. 1999, 581, 87–91;
(d) Zhang, A.; Kan, Y.; Zhao, G. L.; Jiang, B. Tetrahedron 2000, 56, 965–970; (e) Davies, C. D.; Marsden, S. P.; Stokes, E.
S. E. Tetrahedron Lett. 2000, 41, 4229–4233.
8. Guennouni, N.; Lhermitte, F.; Cochard, S.; Carboni, B. Tetrahedron 1995, 51, 6999–7018.
9. Negishi, E.-I.; Yoshida, T. J. Am. Chem. Soc. 1973, 95, 6837–6838.
10. Onak, T. Organoborane Chemistry; Academic Press: New York, 1975.
11. The use of β-silyl acrylamides bearing a chiral sultam as a formylacetate equivalent has been reported: Oppolzer, W.; Mills,
R. J.; Pachinger, W. Stevenson, T. Helv. Chim. Acta. 1986, 69, 1542–1545.
12. Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327–9343.
13. Prepared from benzyl propiolate and p-toluenesulfonylacetylene by the general hydroboration procedure of: Martinez-
Fresneda, P.; Vaultier, M. Tetrahedron Lett. 1989, 30, 2929–2932, followed by esterification with pinacol and purification
by chromatography/crystallisation, respectively.
14. Koichi, Y.; Suginata, K.; Yamamoto, Y. J. Chem. Soc., Perkin Trans. 1 1995, 1645–1646.