New homochiral ketoalcohols from aldol reactions of (+)-isomenthone and reversal of diastereoselectivity

Synthesis, Stereostructure, and Conformations of Novel Bi- and Trifunctional (+)-Isomenthone Derivatives

“…Carbon−carbon bond formation to the kinetic enolate of menthone (at C6) is generally not diastereospecific, and most elaborations from menthone have thus been at the carbonyl group. We have previously shown that aldol reactions of (+)-isomenthone ( 1 ) with a wide range of aldehydes are all completely diastereospecific in C−C formation to C6 with the same sense of diastereocontrol at the new C6 center (to 2 and/or 3 ) (Scheme ) . This offers the potential of elaborating isomenthone into bi- and trifunctional ligands by elaboration at both the terpene carbonyl and at the α methylene, without complications from generating mixtures of ring diastereomers.…”

“…While the new C6 stereocenter is introduced with complete control, Re or Si selectivity for addition to the carbonyl group of either alkyl or aryl aldehydes is in most cases not specific, providing threo/erythro mixtures, though in some cases, a single (threo) diastereomer is obtained. The diastereoselectivity can be affected by modifying conditions; separation of diastereomers, if desired, is achievable through chromatography or crystallization …”

Novel isomenthone-derived 1,3-diol ligands identified through parallel synthesis and screening catalyse an asymmetric aldol reactionElectronic supplementary information (ESI) available: HPLC data for Mukaiyama aldol products. NMR data for a pure reference sample of Mukaiyama aldol product, independently prepared selected examples of isomenthone aldol constituents and the diols included in the ligand array. See http://www.rsc.org/suppdata/cc/b2/b212769p/

“…7 We envisaged that isomenthone chemistry could be extended to (2)-isopinocamphone as a pseudo-enantiomeric analogue. 8 We had previously established that (+)-isomenthone 1 undergoes aldol reactions which are diastereoselective at C6 with universally exclusive R configuration to give 2 (established through a series of X-ray structure analyses) (Scheme 1). The side chain centre is obtained with variable diastereoselectivity dependent on the structure of R, and also the conditions employed.…”

“…The side chain centre is obtained with variable diastereoselectivity dependent on the structure of R, and also the conditions employed. 8,9 To evaluate the facility for different elaborations from this entry point, several new types of isomenthyl derivatives have been prepared both through reactions at the ring carbonyl (variable diastereoselectivity § ) and through elaboration of the side chain hydroxy functionality. 9 This offers the possibility of generating diverse ligand structures from this scaffold, based on:…”

“…The products were analyzed by chiral HPLC, † † and as shown in Table 1 four ligand systems catalyzed the reaction with 87-90% e.e. (entries 1,4,8,9). Clearly, parallel evaluation could be iteratively employed to screen other reaction parameters such as solvent, ligand and catalyst loadings and ratio for further optimization for these ligands, or for other ligand sets using this same basic protocol.…”