Chemical synthesis



The one pot Robinson synthesis of tropinone



Tropine

01. Reducing agents: 
Tropinone when reduced with appropriate reducing agents give tropine. The various reducing agents employed are:

 a. Sodium in ethanol or sodium amalgam can be used for reducing tropinone to pseudotropine.

 b. Catalytic hydrogenation (Pt), electrolytic reduction or Zn/HI can be used to reduce tropinone to tropine.

 c. Complex metal hydrides are the best reducing agents for the preparation of tropine from tropinone in the laboratory. Lithium aluminium hydride and sodium borohydride give a mixture of two, with pseudotropine predominating.



02. Enzymatic process:
The reduction of tropinone  and carbomethoxytropinone is mediated by NADPH-dependent reductase enzymes. All tropane alkaloid containing plant species so far studied possess two tropinone reductase activities, one (TRI) producing tropine and one (TRII) producing pseudotropine. 

T. Hashimoto, K. Nakajima, G. Ongena and Y. Yamada, Plant Physiol., 1992, 100, 836.
K. Nakajima, T. Hashimoto and Y. Yamada, Plant Physiol., 1993, 103, 1465.



Tropinone

01. Tropinone can be synthesized by classic one pot Robinson synthesis. In 1917 Robinson imagined that tropinone could be broken down into three units: succindialdehyde, methylamine, and acetone. He also thought that these units could be joined by means of double Mannich reaction to form tropinone in one step.

Robinson, R. J. Chem. Soc. 1917, 111, 762-768.

R. Robinson, The Structural Relations of Natural Products, Clarendon Press, Oxford, 1955, p. 59.

When the mixture was allowed to stand in water for thirty minutes, tropinone was produced in very small yield. The yield was extremely low due to low acidity of acetone. 

However yield can be improved to 40% by using calcium acetonedicarboxylate or ethyl acetonedicarboxylate instead of acetone. The calcium salt or ester so produced is converted into tropinone by warming with hydrochloric acid.


In acetonedicarboxylic acid, each methylene group is flanked by two carbonyl groups, thus there is a great amount of enol form. Schöpf et al. (1935) have obtained a yield of 70-85% by carrying out the reaction at a pH of 7. 

Mechanism:
  1. Nucleophilic addition of methylamine to succinaldehyde, followed by loss of water to create an imine
  2. Intramolecular addition of the imine to the second aldehyde unit and first ring closure
  3. Intermolecular Mannich reaction of the enolate of acetone dicarboxylate
  4. New enolate formation and new imine formation with loss of water for
  5. Second intramolecular mannich reaction and second ring closure
  6. Loss of 2 carboxylic groups to tropinone


Elming et al. (1958) synthesized tropinone using methylamine hydrochloride, acetonedicarboxylic acid, and generating succindialdehyde in situ by the action of acid on 2,5-dimethoxytetrahydrofuran. The yield was 81%, but in this case physiological conditions were not necessary.

A similar to Robinson synthesis, synthesis of Pseudopelletierine can be helpful for comparison. In tropinone synthesis succindialdehyde is used, while glutaraldehyde is used in the synthesis of Pseudopelletierine.


02. Willstätter synthesis was the first synthesis of tropinone in 1901. It began with cycloheptanone and the final yield was only 0.75%.

R. Willstätter, Annalen., 1903, 317, 204.


03. Decarboxylation of 2-carboxytropinone or 2,4-dicarboxytropinone with concentrated HCl gives Tropinone. Bakers yeast can also be used for this purpose. 


04. Tropinone can also be prepared from 2, 6-cycloheptadienone at a low yield.

Ipratropium Bromide


Scopine

01. For scopine, 6, 7-Dehydrotropinone can be used as a starting material. But to protect the epoxy group in scopine, the ketone group is reduced and esterified. (source)



Ecgonine

1. Ecgonine can be prepared from 2-carbomethoxytropinone, first by reducing it, then hydrolysis.   


2. Tropinone can be used as a starting material for ecgonine synthesis. 
R. Willstätter and W. Müller, Ber. Dtsch. Chem. Ges., 1898, 31, 2655



2-Carbomethoxytropinone


01. Cyclization of 1-methyl-2,5-dicarboethoxypyrrolidine gives 2-Carbomethoxytropinone.
R. Willstatter and M. Bommer, Ann., 422, 15 (1921)
R. Willstiitter and A. Pfannenstiehl, Ann., 422, 1 (1921)


02. 2-Carbomethoxytropinone can be obtained from modified Robinson synthesis. (yield 20%).

German Patent 345,759


03. 2-Carbomethoxytropinone can be produced from Tropinone and carbon dioxide in presence of sodium (or potassium) in benzene (or xylene). Practically dimethyl carbonate is used as a source of carbon dioxide. (yield 70-80%).

N. A. Preobrashenski, M. N. Schtschukina, and R. A. Lapina, Ber., 69,1615 (1936)


04. Willstatter's synthesis proceeds using dipotassium salt of monomethyl beta-ketoglutarate.

R. Willstatter, 0. Wolfes, and H. Miider, Ann., 434, 111 (1923)


05. 2-Carbomethoxytropinone is obtained at a high yield from modified Robinson synthesis.



06. Variation of Willstatter's synthesis using monomethyl beta-ketoglutarate also yields 2-carbomethoxytropinone in satisfactory quantity.

R. Willstiitter and A. Pfannenstiehl, Ann., 422, 1 (1921)
R. Kaushall, J. Indian Chem. SOL, 17,138 (1940)

Cocaine


01. Willstäter´s Preparation

Cocaine was first prepared in 1923 by Willstäter. This synthesis is very remarkable because, although at this time both the relative and the absolute stereochemistry of cocaine were unknown, they were able to prepare this alkaloid in optically active form.



WILLSTÄTTER, R.; WOLFES, O.; MÄDER, H. Annalen 1923, 434, 111

02. Preobrazhenskii´s Preparation

In 1958 a group of Soviet chemists made improvements to Willstäter's synthesis by the in situ generation of the unstable butandial by acidic hydrolysis of dimethoxytetrahydrofuran.



BAZILEVSKAYA, G.I.; BAINOVA, M.S.; GURA, D.V.; DYUMAEV, K.M.; PREOBRAZHENSKII, N.A. Isvest.Vysshikh.Ucheb.Zavedenii, Khim. i Khim.Tekhnol. 1958, 2, 75-81 (Chem.Abstr. 1959, 53, 423h).

BAINOVA, M.S.; BAZILEVSKAYA, G.I.; DYUMAEV, K.M.; PREOBRAZHENSKII, N.A. Zh.Obshch.Khim. 1960, 30, 1120-1123 (Chem.Abstr.1961, 55, 530f)

BAINOVA, M.S.; BAZILEVSKAYA, G.I.; PREOBRAZHENSKII, N.A. Zh.Obshch.Khim. 1960, 30, 3258-3261 (Chem.Abstr. 1961, 55, 21155d)


02. Tufariello synthesis using nitrone

TUFARIELLO, J.J.; TEGELER, J.J.; WONG, S.C.; ALI, S.A. Tetrahedron Lett. 1978, 30, 1733-1736

TUFARIELLO, J.J.; MULLEN, G.B.; TEGELER, J.J.; TRYBULSKI, E.J.; WONG, S.C.; ALI, S.A. J.Am.Chem.Soc. 1979, 101, 2435-2442


04. Carroll´s Preparation

LEWIN, A.H.; NASEREE, T.; CAROLL, F.I. J.Heterocycl.Chem. 1987, 24, 19-21

CARROLL, F.I.; COLEMAN, M.L.; LEWIN, A.H. J.Org.Chem. 1982, 47, 13-19

05. Rapoport´s Preparation

LIN, R.; CASTELLS, J.; RAPOPORT, H. J.Org.Chem. 1998, 63, 4069-4078

PETERSEN, J.S.; FELS, G.; RAPOPORT, H. J.Am.Chem.Soc. 1984, 106, 4539-4547

06. Cha´s Preparation

LEE, J.C.; LEE, K.; CHA, J.K. J.Org.Chem. 2000, 65, 4773-4775

03. Pearson synthesis


Cocaethylene

01. Cocaethylene can be prepared from cocaine and ethanol by an ester exchange reaction.