Nicotiana rustica, known

in South America as

Mapacho and in Vietnam

as Thuoc Lao (thuốc lào), is a plant in the

Solanaceae family. It is a

very potent variety of

tobacco. The high

concentration of nicotine

in its leaves makes it

useful for creating

organic pesticides.

Nicotiana tabacum, or cultivated

tobacco, is a perennial herbaceous

plant. It is found only in cultivation,

where it is the most commonly grown

of all plants in the Nicotiana genus,

and its leaves are commercially grown

in many countries to be processed

into tobacco. It grows to heights

between 1 to 2 metres. Research is

ongoing into its ancestry among wild

Nicotiana species, but it is believed to

be a hybrid of Nicotiana sylvestris,

Nicotiana tomentosiformis, and

possibly Nicotiana otophora.

(S)-nicotine is the natural compound synthesized by the

tobacco plants. Only a few examples of an

enantioselective synthesis of (S)-Nicotine have been

reported. The isomers are usually separated from a

racemic preparation by recristallisation. A four-step

synthesis of (S)-Nicotine is described here.

RETROSYNTHETIC ANALYSIS

S-NICOTINE

SYNTHESIS: a - Hydroxyketone 3 is obtained by a halogen-lithium exchange of 3-bromopyridine 1 with n-BuLi followed by treatment with the lactone 2. b - The oxidation of the compound 3 to the aldehyde is accomplished with the Swern method: (COCl)2, DMSO, NEt3. c - The desired product 4' is obtained by the reaction of (pyridin-3'-yl)-4-oxobutanone 4 with 2,3,4,6-tetra-O-pivaloyl-b-D-galactopyranosylamine a. d - Acidic hydrolysis of 4' affords optically pure (S)- nornicotine: 1M HCl /MeOH.

An efficient enantioselective synthesis of the non-

natural enantiomer is necessary for the study of its

biological properties and of its metabolism. An example

of a four-step synthesis of (R)-Nicotine is described

here, in which the key step is an intramolecular

hydroboration-cycloalkylation reaction.

2 - Total enantioselective synthesis

of (R)-nicotine

RETROSYNTHETIC ANALYSIS

R-NICOTINE

SYNTHESIS: a - The first step is the allylation of pyridinecarboxaldehyde 1 with 2,2 equivalents of B-allyldiisopinocampheylborane in Et2O at -100°C. The (S)-homoallylicalcool 2 is obtained in 86% yield with an enantiomeric excess of 94%. b - The chiral azide 3 is obtained from alcohol 2 using the Thompson procedure with a 90% yield and without racemisation. DBU (1,2 equivalents), (PhO)2P(O)-N3 (1,2 equivalents), Toluene c - Intramolecular hydroboration-cycloalkylation of the azido-olefin 3. 2,2 equivalents of B(C6H11)2H in THF. This step proceeds by the hydroboration of the double bond of 3 followed by the formation of a boron-nitrogen bond between the azide and the trialkylborane. Finally, ring closure occurs by migration of the borane methylene group to nitrogen-1 with concomitant loss of nitrogen. d - Alkylation of (R)-Nornicotine 4 in (R)-Nicotine. (i) EtOCOCl (1,2 equiv.), Et3N (1,3 equiv.), Et2O (ii) LiAlH4 (1,2 equiv.), THF, 0°C