Amelia Garcı́a Fraile

Bridgehead-norbornane-derived β-amino alcohol catalysts: structural factors influencing the chirality transfer

Abstract Five new optically active bridgehead-norbornane-derived β-amino alcohols with different substitution patterns have been obtained using a straightforward procedure from commercial (+)-camphor or (−)-fenchone, and tested as chiral catalysts in the enantioselective diethylzinc-addition to benzaldehyde. The obtained results show that chirality transfer is mainly governed by the hydroxyl group and, therefore, by the surroundings of the CO stereocenter. On the other hand, the N- alkyl substitution play an important role by modulating the degree of enantioselectivity.

Synthesis of enantiopure norbornane derivatives. Effect of bridgehead substituent on the π-facial selectivity of the reduction of 2-norbornanones and their oximes

Abstract One of the most important features of the synthesis of camphor-derived compounds is the control of the stereochemistry at the C2 position. According to this, reduction of bridgehead-substituted 2-norbornanones 1 and 2-norbornanoximes 3 has been considered by us as a very convenient method for the preparation of different classes of enantiomerically pure 1,2- and 1,3-difunctionalised norbornane derivatives. Factors controlling the stereoselectivity in these reductions, as well as the role played by the nature of the bridgehead functional groups are discussed.

Synthesis and catalytic activity of 10-(aminomethyl)isoborneol-based catalysts : the role of the c(2)-group on the asymmetric induction

Abstract Five enantiopure C(2)-substituted 10-[(dimethylamino)methyl]isoborneols has been prepared by a novel straightforward camphor-based route, and probed as δ-amino-alcohol ligands for the enantioselective addition of diethylzinc to benzaldehyde. The established route constitutes a divergent model procedure for this class of δ-amino-isoborneol ligands, allowing different substitutions, not only at the nitrogen atom, but also at the more interesting hydroxyl-bearing C(2)–norbornane position. This last synthetic possibility has made possible a study of the role played by the group located at the C(2)–norbornane position on the catalytic activity. New catalyst models and transition-state models for explaining such a role are also proposed and discussed.

From natural camphor to (1R,2S)-2-chloromethyl-3-oxocyclopentanecarboxylic acid: a stereocontrolled approach to enantiopure sarkomycin

The preparation of enantiopure (1R,2S)-2-chloromethyl-3-oxocyclopentanecarboxylic acid 9, an interesting possible precursor of the antitumor agent sarkomycin, from a camphor-derived 3-hydroxymethylnorbornan-2-one is reported. The described procedure constitutes the first stereocontrolled approach to sarkomycin starting from commercially available natural camphor. The procedure takes place in only six steps with a high overall yield (59%). The key-step of the described procedure is the stereocontrolled ring opening of a conveniently functionalized 3-oxonorborn-1-yl triflate under a straightforward basic hydrolysis. The described route constitutes a model procedure for the preparation of other enantiopure C2-substituted 3-oxocyclopentanecarboxylic acids; which are related with the sarkomycin family of antitumor agents.

The role of the substitution pattern on the catalytic activity of chiral bridgehead norbornane-derived β-amino alcohols

The enantioselective addition of diethylzinc to benzaldehyde has been used as standard procedure to test a series of new chiral catalysts derived from norbornane framework. The new ligands are β-amino alcohols possessing both heteroatomic substituents attached to the C(1) and C(2)-endo positions (novel non-coplanar disposition) of a 3,3-dimethylsubstituted norbornane. The results obtained, compared with other previously reported on the related C(2)-exo-7,7-dimethyl series, demonstrate that the relative disposition of the amino, hydroxy and gem-dimethyl groups, as well as the N-alkyl substituents, play an important role on the catalytic activity. Interesting transition-state models have been also proposed in order to explain the observed experimental results.

A new highly efficient synthetic route to enantiopure 10-bromocamphor

Abstract A new enantiospecific synthetic route to the interesting chiral synthetic intermediate 10-bromocamphor starting from readily available camphor is described. The procedure takes place straightforwardly in only three synthetic steps with high overall yield. Mechanistically, two interesting enantiospecific Wagner–Meerwein rearrangements involving 2-norbornyl carbocations take place during the process.

ABOUT THE TIMING OF WAGNER-MEERWEIN AND NAMETKIN REARRANGEMENTS, 6,2-HYDRIDE SHIFT, PROTON ELIMINATION AND CATION TRAPPING IN 2-NORBORNYL CARBOCATIONS

The reaction of different substituted 2-norbornanones 1 with triflic anhydride in the presence of nitriles 6 is carried out in order to study the factors that influence on the different reaction possibilities of 2-norbornyl carbocations. The syntheses of interesting annulated pyrimidine derivatives 10 and conformationally rigid 1,3 disubstituted products are described.

First efficient preparation of enantiopure 10-bromofenchone: the key intermediate to C10-substituted fenchone-derived chiral sources

Abstract The first efficient preparation of enantiopure 10-bromofenchone from commercially available fenchone is described. The synthetic procedure is based on two consecutive Wagner–Meerwein rearrangements of the fenchone skeleton, taking place straightforwardly in only three individual steps with a high overall yield. The ability of the bromine atom to be substituted by other functional groups makes 10-bromofenchone a key intermediate for the preparation of interesting C10-substituted fenchone-derived chiral sources, which are topologically different and analogous to well-known C10-substituted camphor-derived chiral tools.

A new straightforward preparation of enantiopure 10-hydroxycamphor

Abstract The enantiospecific preparation of the interesting chiral source 10-hydroxycamphor from commercially available camphor is described. The synthetic procedure takes place straightforwardly in only three synthetic steps with a high overall yield. The key step of the described route is based on the ability of a 2-methylenenorbornane intermediate to undergo an enantiospecific Wagner–Meerwein rearrangement under electrophilic treatment with m -CPBA.

A new enantiospecific synthetic procedure to the taxoid-intermediate 10-methylenecamphor, and 10-methylenefenchone

Abstract A new straightforward enantiospecific synthetic procedure to both 10-methylenecamphor and 10-methylenefenchone, from (+)-camphor and (−)-fenchone, respectively, is described. 10-Methylenecamphor is the key intermediate in Paquettes approach to taxol and taxusin, whereas 10-methylenefenchone could be a convenient intermediate to a new family of potentially interesting taxoids. The key steps of the described procedure are: (a) stereocontrolled tandem electrophilic carboncarbon double-bond addition-Wagner–Meerwein rearrangement of a camphor- or fenchone-derived 2-methylenenorbornan-1-ol under Eschenmosers salt treatment, and (b) Cope elimination for generation of the vinyl group at the bridgehead norbornane position.