Synthesis trachelanthamidine

The use of another type of bis(trimethylsilylmethyl)amine leads to the synthesis of l-azabicyclo[m.3.0]alkanes also present in the skeleton of a number of alkaloids as trachelanthamidine, isoretronecanol, and tashiramine.447 451... 

Several syntheses of 1-hydroxymethylpyrrolizidines have been reported. Borch and Ho1 have utilized a reductive cyclization method for their synthesis of ( )-isoretronecanol (6) and ( )-trachelanthamidine (7). The cycloheptenone ester (1), prepared by a novel route (Scheme 1), was reductively aminated to give a mixture of the diastereoisomeric amino-esters (2) and (3) in 48% yield. These esters could not be separated. Oxidative cleavage of the double bond of the esters, followed by reductive cyclization, gave a 35% yield of the pyrrolizidine esters (4) and (5). Separation of these compounds was achieved by preparative t.l.c., and a final reduction step afforded the racemic alkaloids (6) and (7). The second reductive amination process was stereoselective, because reduction of the unseparated ester mixture (4) and (5) gave a 1 2 ratio (g.l.c.) of the 1-hydroxymethylpyrrolizidines. 

Another route to ( )-isoretronecanol (3) and ( )-trachelanthamidine (6) is outlined in Scheme 2.5 This Reporter can hardly agree with the authors extravagant claim that this is the most direct and operationally convenient synthesis [of these bases] yet reported . Unfortunately, the intramolecular alkylation step is not stereospecific, and a mixture of diastereoisomers (4) and (5), in a ratio of 1 4, was formed. This mixture was separated chromatographically, in order to effect the synthesis of the bases (3) and (6). 

Robins and Sakdarat have published full details of their route to optically active (+)- and (—)-forms of isoretronecanol (3), trachelanthamidine (6), and supinidine (8).6 In addition, the synthesis of two new optically active bases (7) and (9) (isolated as its diacetate) is described. 

However, there has been no report on the highly stereoselective chiral synthesis of (- )-trachelanthamidine (100a) and ( + )-epilupinine (enr-lOOd) type alkaloids without the use of a chiral building block, except for Takano s chiral synthesis (33% optical purity) (81H(16)915),... 

Achiwa reported a short synthesis of pyrrolizidine derivatives by the cycloadditions using a nonstabilized azomethine ylide 23 (m = 1) (82CPB3167). When the trimer of 1-pyrroline is treated with a silylmethyl triflate, N-alkylation of the 1-pyrroline takes place. Then the resulting iminium salt is desilylated with fluoride ion in the presence of ethyl acrylate to give ethyl pyrrolizidine-l-carboxylate 295 as a mixture of stereoisomers (28%). After the epimerization of 295 with LDA, the ester moiety is reduced with lithium aluminum hydride in ether to provide (+ )-trachelanthamidine (296). A double bond can be introduced into 295 by a sequence of phenyl-selenylation at the 1-position, oxidation with hydrogen peroxide, and elimination of the selenyl moiety. The 1,2-dehydropyrrolizidine-l-carboxylate 297 is an excellent precursor of (+ )-supinidine (298) and (+)-isoretronecanol (299). Though in poor yield, 297 is directly available by the reaction of 23 with ethyl 3-chloropropenoate. 

This intramolecular reaction proved to be very useful for the synthesis of a number of pyr-rolizidine-based natural products including trachelanthamidine, isoretronecanol, di-hydroxyheliotridane, and mitosane derivatives. ... 

Reductive cyclization has been used in a novel, recent synthesis of the alkaloids ( )-isoretronecanol (22) and ( )-trachelanthamidine (23) by Borch and Ho. Condensation of the dianion derived from methyl acetoacetate with Z-l,4-dichlorobut-2-ene, followed by cyclization with sodium meth-oxide yielded the cycloheptenone ester intermediate (32) (Scheme 2). Reductive amination of this ketoester with sodium cyanoborohydride and ammonium nitrate gave a mixture of the diastereoisomeric aminoesters 33 and 34. Oxidation with osmium tetroxide and periodate, followed by reductive cyclization, again using sodium cyanoborohydride, gave the two pyrrolizidine esters 35 and 36 in a ratio of 1 2 [gas-liquid chromatography (GLC) analysis]. The esters were separated by preparative layer chromatography, and lithium aluminum hydride reduction of the individual esters gave the two pyrrolizidine alkaloids 22 and 23. 

Enantioselective synthesis of (—)trachelanthamidine (127) took place from allylic iodoacetamide (128) by atom-transfer annulation <88JA7536> and functional group transformation. 

Kunec EK, Robins DJ (1989) Pyrrolizidine alkaloid biosynthesis. Synthesis of H-labelled trachelanthamidine and israetronecanol and their incorporation into three pyrrolizidine bases (Necines). J Chtan Soc Perkin Trans 11 1437-1441... 

An interesting solution to the synthesis of the alkaloids ( )-isoretronecanol (44) and ( )-trachelanthamidine (45) is provided by the thermal rearrangement of cyclopropyl imines " as shown in Scheme 75. Alternative syntheses of (-i-)-isoretronecanol and of the related alkaloids (+)-laburnine and (+)-supindine have also been reported.An important reaction used was the regiospecific... 

Robins has outlined an interesting biogenetically patterned synthesis of the pyrrolizidine alkaloid trachelanthamidine (107). The alkaloid, together with its epimer isoretronecanol (112) (- 5%), was produced ( 40%) when homospermidine (106) was incubated with diamine oxidase and catalase at 27 °C in phosphate buffer at pH 7.5 for six days. 

A quite different approach to the pyrrolizidine nucleus starting with pyrrolidine has led to a synthesis of the alkaloids isoretronecanol (19) and trachelanthamidine (20) (Scheme 52). A novel synthesis of A -dehydropyrrolizidinium perchlorate from a-butyrolactone has been reported. The key step is the synthesis of the 2-pyrroline (21) from the butyric acid derivative (Scheme 53). 

An early application of ATRC was reported by the group led by Dceda-Ishibashi in the synthesis of the pyrrolizidine alkaloid (—)-trachelanthamidine (Scheme 25.4). Starting from (5)-prolinol, iodoacetamide 1 was prepared, which underwent an ATRC with triethylborane treatment to give bicyclic lactam 2. 

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