Synthesis of -isoretronecanol

Scheme 13. Retrosynthetic Analysis and Synthesis of Isoretronecanol 37a b NH4C1, xylene c CH3OH, HC1 d LAH then Raney Ni (No yields)...

Tufariello has reviewed his strategy for the synthesis of alkaloids (including necine bases) using the 1,3-dipolar cycloaddition of nitrones to alkenes.5 This work began with the synthesis of ( )-supinidine (7) from 1-pyrroline 1-oxide (see these Reports, Vol. 2, Ch. 4). A related approach has been used by Iwashita et al. in their synthesis of ( )-isoretronecanol (5).6 The stereochemistry of the exo-product (8), formed by regiospecific 1,3-dipolar cycloaddition of 1-pyrroline 1-oxide to dihydrofuran (Scheme 2), was confirmed by its conversion into... 

The stereochemical aspect of these cyclizations has been investigated. They have been found to be non-stereoselectives.342 On the contrary, diastereoselective 1-azabicyclo-alkanes have been prepared in the same way, the stereochemistry being dependent upon the size of the ring formed, namely, 1,5-cis and 1,6-trans.343 This methodology has been applied to the synthesis of ( )-isoretronecanol, ( )-epilupinine344 and retronecanol.345... 

Pandey, G., Devi Reddy, G., and Chakrabarti, D. (1996) Stereoselectivity in the photoinduced electron transfer (PET) promoted intramolecular cyclisations of l-alkenyl-2-silyl-piperidines and -pyrrolidines rapid construction of 1-azabicyclo [m.n.o] alkanes and stereoselective synthesis of ( )-isoretronecanol and ( )-epilupinine. Journal of the Chemical Society, Perkin Transactions 1, 219-224. 

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. 

Cyclization of a h-amino alcohol to a pyrrolidine. This reaction was used in the final steps of a synthesis of isoretronecanol (4) from the 5-amino alcohol (2), prepared as shown in equation (I). 

A transannular reaction has been successfully applied to the stereo-specific synthesis of (+ )-isoretronecanol (22) by Leonard and Sato. The... 

Addition of the titanium enolate of Af-acetyl-4-isopropyl-l,3-thiazohdme-2-thione 150 to the A-acyl iminium ions from 151 furnishes the corresponding Mannich-type adducts 152 and 153 with good diastereoselectivity <05JOC4214>. A similar diastereoselective addition of the titanium enolate derived from Af-4-chlorobutyryl-l,3-thiazolidine-2-thione 154 to A -Boc-2-methoxypyrrohdine 155 has been used to provide 2-substituted pyrrolidine 156, a key intermediate in the synthesis of (+)-isoretronecanol <05TL2691>. 

A new, stereospecific synthesis of (+)-isoretronecanol, by a transannular route, has been developed by Leonard et al. Dieckmann cyclisation of NN-bis-(y-ethoxycarbonylpropyl)benzylamine gave ethyl l-benzyl-5-oxo-l-azacyclo-octane-4-carboxylate (20), whose perchlorate was shown to possess a bicyclic structure. Hydrogenation of this perchlorate in ethanol, using palladised charcoal catalyst, afforded ethyl ( )-isoretronecanolate perchlorate (22) as sole product, presumably by stereospecific addition of hydrogen at the less hindered face of the intermediate debenzylated immonium ion (21). Reduction of the free base corresponding to (22), by means of lithium aluminium hydride, gave (+ )-isoretronecanol (23), the stereochemical purity of which was shown by g.l.c. analysis to be >98%. 

Hart DJ, Tsai Y-M (1984) a-Acylamino radical cyclizations synthesis of isoretronecanol. J Am Chem Soc 106 8209-8217... 

As mentioned in an earlier section in this Report, free-radical carbon-carbon bond-forming processes are becoming increasingly important in synthesis, and this year they have proved themselves particularly useful for the synthesis of pyrrolizidine alkaloids. Thus, Hart and his group have now applied their intramolecular tin hydride generated ot-acylamino radical to alkyne cyclization [viz. (97) - (98)] and to the synthesis of (-)-dehydrohastanecine (99), (+)-heliotridene (100), and (+)-hastanecine (101). In addition, free radical in mechanism is the photochemical cyclization of the -acylpyrrolidine (102) to the pyrrolizidene (103), a key intermediate in a synthesis of ( )-isoretronecanol (104). 

Das, S., Kumar, J.S.D., Shivaramayya, K., and George, M.V., Formation of lactams via photoelectron-transfer catalyzed reactions of N-aUylamines with a,P-unsaturated esters. Tetrahedron, 52,3425,1996. (a) Bertrand, S., Glapski, C, Hoffmann, N., and Pete, J-P., Highly efficient photochemical addition of tertiary amines to electron deficient alkenes. Diastereoselective addition to (5R)-5-menthyloxy-2(5ff]-furanone. Tetrahedron Lett., 40, 3169, 1999 (b) Bertrand, S., Hoflfrnann, N., and Pete, J-P., Stereoselective radical addition of tertiary amines to (5R)-5-menthyloxy-2[5H]-furanone application to the enantioselective synthesis of (-)-isoretronecanol and (-l-)-labumine. Tetrahedron Lett., 40,3173,1999 (c) Farrant, E. and Mann, J., Novel synthesis of the indoUzidine alkaloid skeleton with appropriate functionality and stereochemistry for use as a chiral scaffold, /. Chem. Soc., Perkin Trans. 1,1083,1997. 

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... 

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. 

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. 

Anodendrine (17) and alloanodendrine (18) are a pair of zwitterionic alkaloids whose structure was determined by a combination of physical and chemical methods. The synthesis of the former was achieved by treating the methyl ester of labrnninic acid with isopentenyl bromide and hydrolysing the product. The alio base was similarly prepared from (+ )-isoretronecanolic acid (12). 

An interesting two-step procedure has been reported which allows the stereospecific synthesis of the racemate (3) in 80% overall yield. AT-Formyl-L-proline, prepared from L-proline and acetic-formic anhydride, is treated with ethyl propiolate in acetic anhydride to give the ester (4), the cycloaddition presumably proceeding via the dipolar intermediate (5). Hydrogenation of (4) in the presence of palladized charcoal affords the stereochemically pure ethyl ( )-isoretrone-canolate (3), which on reduction provides (+ )-isoretronecanol (6). Since the ester (3) can be efficiently epimerized at C-1 this synthesis also affords a convenient route to the pseudoheliotridine series. 

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... 

Allylsilanes have been used in heterocycle preparation, and in the synthesis of the Prelog-Ljerassi lactone, (+)-mosembrine, such hydroxylactams as (+)-isoretronecanol and ( )-epilupinine, while oxidation to give -silyl enones is used in the preparation of... 

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