Bu₂BOTf: A Powerful Tool in Stereoselective Synthesis

Biographical Sketches

Thilo J. Heckrodt was born in 1976; he started to study chemistry in 1997 at the Free University of Berlin, Germany, where he completed his diploma thesis under the supervision of Prof. H.-U. Reissig. After completion of his diploma in 2001, he joined the research group of Prof. J. Mulzer, University of Vienna, Austria and is currently working towards his PhD. He is recipient of a Kekulé fellowship; his research interest is focused on the asymmetric total synthesis of stereochemically complex natural products.

Introduction

In 1980 Mukaiyama et al. published the first synthesis of di-n-butylboryl trifluoromethanesulfonate (Bu₂BOTf) and demonstrated that this Lewis acid is particularly suitable for the generation of vinyloxyboranes (boron enolates). [1] In the presence of a sterically hindered amine base (typically i-Pr₂EtN, Et₃N or 2,6-lutidine) and Bu₂BOTf vinyloxyboranes are conveniently prepared from active methylene-carbonyl containing compounds. The boron enolates turned out to be efficient intermediates for addition to carbonyls in cross-aldol reactions. With unsymmetrical ketones, use of Bu₂BOTf and i-PrEt₂N results in the regioselective formation of the vinyloxyborane at the least hindered carbon. The relative stereochemistry of the new chiral centers formed in the aldol product is a direct consequence of vinyloxyborane enolate geometry with Z-enolates affording the 2,3-syn aldol products and the E-vinyloxyboranes leading to the 2,3-trans isomers. With Bu₂BOTf a remarkably high stereoselectivity towards the Z-enolate is observed which results in highly syn-selective aldol reactions. Probably the greatest utility of this reagent has been in the stereoselective formation of vinyloxyboranes attached to a chiral auxilary. [2] These are typified by the chiral oxazolidinones derived from α-amino alcohols initially developed by Evans. This modern methodology is a powerful tool for the highly enantioselective construction of two new chiral centers in an aldol addition under recycling of the auxilary. Vinyloxyboranes also react with electrophiles other than aldehydes, furthermore it is possible to generate boryl azaenolates with Bu₂BOTf. In the area of macrolactonization Bu₂BOTf has also been used.

Preparation of Bu₂BOTf

Bu₂BOTf is commercially available as a 1 M solution in CH₂Cl₂ or Et₂O. However it is recommended that the reagent is freshly prepared and used pure, as the quality of stored Bu₂BOTf decreases quite rapidly due to its high moisture and air sensitivity. Bu₂BOTf is synthesised from tri-n-butylborane and trifluoromethanesulfonic acid; the product is isolated by vacuum distillation under argon. [1] [3]

Abstracts

(A) In early applications Bu2BOTf was used to form boron enolatates, which undergo diastereoselective aldol additions (syn). The stereoselectivity was found to be dependent on the temperature; the reaction at lower temperature (-78 °C) gave rise to a high stereoselectivity, a fairly good selectivity was observed at room temperature. [1]
(B) Control of the regiochemistry is possible. Only one of the regioisomers of cross-aldols is produced without being accompanied by a detectable amount of the other regioisomers. [1]
(C) The use of a chiral auxiliary attached to the vinyloxy­boranes makes it possible to control the absolute stereochemistry of the new chiral centers formed in the aldol process. This chemistry initially developed by Evans, [2] [4] is nowadays an important tool in stereoselective synthesis and has found wide application in the field of total synthesis.
(D) Vinyloxyboranes also react with electrophiles other than aldehydes. For example chiral bromides can be synthesised stereoselectively using N-bromosuccinimide as the electrophile source. [5]
(E) The formation of boryl azaenolates proceeds smoothly, and they condense with various substituted benzaldehydes to yield β-hydroxy nitrile products. [6] For instance 2-ethylpyridine gives predominantly the 2,3-syn aldol product. [7]
(F) In the presence of 1 equivalent of Bu2BOTf trimethylsilyl ω-trimethylsilyloxycarboxylates cyclize to the corresponding macrolides. [8]

References

1 Inoue T. Mukaiyama T. Bull. Chem. Soc. Jpn.  1980,  53:  174 

2 Evans DA. Bartroli J. Shih TL. J. Am. Chem. Soc.  1981,  103:  2127 

3 Paquette LA. Encyclopedia of Reagents for Organic Synthesis   Vol 3:  John Wiley & Sons; New York: 1995.  p.1596 

4 Evans DA. Gage JR. Org. Synth.  1990,  68:  83 

5 Evans DA. Ellman JA. Dorow RL. Tetrahedron Lett.  1987,  28:  1123 

6 Hamana H. Sugasawa T. Chem. Lett.  1982,  1401 

7 Hamana H. Sugasawa T. Chem. Lett.  1984,  1591 

8 Taniguchi N. Kinoshita H. Inomata K. Kotake H. Chem. Lett.  1984,  1347