Yohimbine analog

The Danishefsky group has examined the uncatalyzed and Lewis adic-catalyzed cycloadditions of highly oxygenated dienes with simple imines in preparation of yohimbine analogs and the indolizidine alkaloid ipalbi-dine (Scheme 2-VII). What is quite interesting is that some of these dienes are sufficiently reactive that catalysis was not necessary with neutral imines. Also, the reaction seems to show excellent facial stereoselectivity with respect to the imine. 

Szantay also utilized the Dieckmann cyclization strategy to prepare other 18-hydroxy yohimbine analogs (Scheme 3.46) (53). For example, Wadsworth-Emmons condensation of tetracyclic ketone 281 followed by hydrogenation provided diester 289. Dieckmann cyclization of 289 then afforded the epimeric pentacyclic esters 290 and 291. Treatment of 291 with sodium methoxide effected epimerization to the desired C(18)a methoxy epimer 290. Sodium... 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

Szdntay and co-workers (254) have synthesized all four possible stereoisomers of 18-hydroxyyohimbine and a number of stereoisomeric raunescine analogs having normal yohimbine skeletons. 

With the structure of quinamine firmly established, its other reactions can now be considered (Chart II), all of which proceed via VIII. When the alkaloid was refluxed with acetic anhydride or acetyl chloride, acetyl-apoquinamine (O-acetyl-d3- 14-cinchonamine, XII), picrate, mp 143° was obtained. The change may be formulated, quinamine VIII-XII, with the last step being a special case of a general reaction of hydroxy-indolenines (20). The analogous transformation can be realized very easily when 7-hydroxy-7/f-yohimbine methiodide (X) is boiled in methanol (21). 

The arbitrary classification of Rauwolfia alkaloids (91) is simplified here, and it is slightly different from a recent arrangement (92). The Rauwolfia alkaloids can all be regarded as yohimbinoid derivatives as shown in Chart I, viz. the yohimbines (all yohimbine isomers) 18-hydroxyyohimbines (reserpine-type alkaloids) ring E heterocycles and their anhydronium analogs (ajmalicine, serpentine) ajmaline-type (which includes sarpagine) and compounds of unknown constitution. 

Epimerization at C-3 to the extent of about 15% takes place when yohimbine is heated for prolonged times in acetic acid. The reverse epimerization is a practical one (8) and has been utilized in the analogous transformation of reserpine into isoreserpine (9). 

Pyrone-6-carboxylate 139 (Scheme 35) was shown to undergo an IMDA reaction to afford dihydrobenzofuranone 141, upon elimination of CO2 from the initially formed cycloadduct 140 <85CL151>. Analogously, the amide 142 produced 143, which was a key intermediate in syntheses of the natural products ( )-reserpine and ( )-yohimbine... 

EUP288196, 1989USP4960891, 1991USP5229387, 1991USP5231181). It should be noted that the structural analog of a-yohimbine, viz., 6-methoxy-A-methylsulfonyl-6//-isoquinolino[2,l- ][l,6]naphthyridine (57, / = MeO, 7 2=MeS02, the preparation... 

Finally, analogy for the cleavage of ring C of the yohimbine skeleton at... 

FIGURE 15.32 (a) Replacement of ester ether oxygen by a fluoro-nitrogen (b) Exo-endo amidine in place of a carboxylic ester functionality (c) iV-methylsulfonamide analog of a-yohimbine (rauwolsdne). 

Some R. a. have valuable pharmacological properties. They may act centrally (e.g. see Reserpine) or peripherally (e g. see Yohimbine, Ajmaline). In addition to the pure alkaloids or their synthetic analogs, extracts of the drug Radix Rauwolfiae and combination preparations are also used. The drug has been known since early times in Indian folk medicine, and its systematic investigation began in 1930. 

Analogs of nicotine and anabasine in which the pyridine ring has been replaced by quinuclidine (XXI a and both diastereoisomers of XX lb) show hypotensive effects when given i.v. to dogs. The hydrazide of yohimboic acid, which is considerably less toxic than the methyl ester (yohimbine), causes prolonged hypotension at I mg/kg (i.v.) in chioralosed dogs. ... 

In the present state of biogenetic theory, it cannot be assumed that the combination of the ten carbon precursor and tryptophan must always lead to a basic compound. The recent isolation of certain aspidosperma alkaloids which owe their basicity and therefore the reason they were isolated to the indoline nitrogen may mean inter alia that the analogous yohimbine derivative (lactam carbonyl group at C-5 in Chart 2.3) is also a natural product. 

The absolute stereochemistry of the group depended on a number of arguments. For C-3 it is based on a comparison of the molecular rotation differences between the bases and their dehydro and tetradehydro derivatives with analogous yohimbine derivatives. For C-15 on the conversion of dihydrocorynantheol and dihydrocinchonamine into the same quaternary salt. Dihydro-cinchonamine had previously been prepared from cinchonine by a route which did not affect the stereochemistry at C-15. 

Intermediate 285 was then employed successfully to access (+)-yohimbine (282) (Scheme 6.46A) [141]. Hiemstra s synthesis of this challenging target employed the phosphoric acid 143a-catalyzed Pictet-Spengler reaction of aldehyde 286 and tryptamine derivative 287 to install the tertiary stereogenic center in 84% ee (Scheme 6.46B). Intermediate 288 was then converted to yohimbine (282) by analogy to Jacobsen s report [142]. 

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