Ring Analogs

Several investigators have prepared taxol analogs in which the oxetane ring is replaced with an alternate ring. Thus Fenoglio et al, converted 2 -deacetoxyaustrospicatine (5.3.1) into the azetidine derivatives 5.3.4 and 5.3.5 by cyclization of intermediates 5.3.2 and 5.3.3, respectively (202). 

A thietane analog of 7-deoxobaccatin III was prepared from taxine B by Poupat and her colleagues (204). Taxine B was converted to 5.3.8 by standard chemistry, and the thietane ring was constructed through intermediates 5.3.9 and 5.3.10 to give the analog 5.3.11. 

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A similar procedure starting with commercially available piperidine-2-carboxylic acid produced the corresponding six-membered ring analog 88 (2). 

The thiophene ring can be elaborated using standard electrophilic, nucleophilic, and organometallic chemistry. A variety of methods have been developed to exploit the tendency for the thiophene ring (analogous to that of furan and pyrrole) to favor electrophilic substitution and metallation at its a-carbons. Substitution at the p-carbons is more challenging, but this problem can also be solved by utilizing relative reactivity differences. 

The literature preparation (11) of the two-ring analog of strigol (2-RAS) involved reacting the sodium enolate (XIX) with the mesylate (XX) to form 2-RAS (XXI). In our work we found it very difficult to prepare and purify the mesylate. Low yields of 2-RAS contaminated with XVIII resulted. 

Another two ring analog of strigol was prepared in a similar manner from the sodium enolate of a-valerolactone (XXII) and XIV. There is a methyl group at the 5-position of the ring which would correspond to the C-ring of strigol, so the shorthand for this compound is Me-2-RAS (XXIII). Johnson and co-workers (21) had... 

The A-D-ring analog 30a,b (mixture of epimers) has been prepared from the epoxide 3a,b by base catalyzed epoxide cleavage, hydroxymethylenation, and O-alkylation of the butenolide unit using standard conditions. Hydroxymethylenation of keto-ester 7 followed by butenolide addition provided the A-D-ring analog 31. 

Decarboxylation of 16 using the previously described NMP, lithium chloride method provided the dione 32. Selective reduction of the least hindered carbonyl was readily effected using sodium borohydride providing 33. Hydroxymethylenation followed by O-alkylation of the butenolide unit by standard procedures provided the A-B-D-ring analog 34a,b (racemic mixture of epimers). 

Let us now turn to compounds with more than one benzenoid ring. The first species are the isomeric a- and /J-naphthylamincs, 18a and 18b. The archival enthalpies of formation are found to be 157.6 6.9 and 133.8 5.1 kJmol-1. The 24 9 kJmol-1 difference of these two numbers is incompatible with the near-zero difference of the enthalpies of formation for the isomeric naphthols, methyl- and bromonaphthalenes32. Which or either naphthylamine has the correct enthalpy of formation The gas-phase enthalpies of formation of the naphthols differ from their single benzene ring analog, phenol, by 66 kJmol-1 in close agreement with the difference between the methylnaphthalenes and toluene, 63, and between the brominated and parent hydrocarbons, 69 6 and 68 2 kJmol-1 respectively. That is, it is plausibly asserted33 that the difference quantities 17 are nearly constant and equal. 

The decisive step in this reaction is the transannular migration of the N-oxide oxygen atom (86+87). Such an intramolecular attack seems quite plausible, since model studies demonstrate that the oxygen atom of the N—0 group in 86 can approach within 2.6 A of the pseudo-geminal position in the other benzene ring. Analogous intermolecular reactions, such as oxidation of phenols to quinones by N-oxides, are known 87>. 

Since the PK reaction with electron-defident alkynes was also problematic, even when stoichiometric Co2(CO)g was employed, promoters such as trialkylamine N-oxide were required for the reaction to proceed [14]. Alternatively, W(CO)5-THF may be employed semi-catalytically for this class of substrates [9cj. The rhodium catalyst [RhCl(CO)2]2, has shown great versatility for electron-deficient alkynes (Scheme 11.4) the reaction times are much shorter (1-3 h) than those of the usual examples (Tab. 11.3). This rhodium-catalyzed PK reaction may be extended to the synthesis of 6,5-fused ring analogs, as exemplified in the synthesis of bicyclo[4.3.0]nonenone 2o from the 1,7-enyne lo (Eq.4) [13 bj. 

Chloroprocaine Chloroprocaine, the 2-diethylaminoethyl ester of 2-chloro-4-aminoben-zoic acid (2.1.5), is the ortho-chlorinated (in relation to the carbonyl group of the benzene ring) analog of procaine. Synthesis of this drag is accomplished by directly reacting the hydrochloride of the 4-amino-2-chlorbenzoic acid chloride (2.1.4) with hydrochloride of diethylaminoethanol. The hydrochloride of 4-amino-2-chlorbenzoic acid chloride needed for synthesis is synthesized by reacting 2-chloro -aminobenzoic acid with thionyl chloride [5],... 

We shall not go with our analysis beyond the seven-membered rings. For larger ring analogs of the pyrrole type, the interested reader may find relevant material in reviews (75PAC691 78AHC55). 

This similarity between five- and six-membered cyclic hydrocarbons is not surprising, but it is not any longer observed for the three-membered ring analogs, probably because a considerable ring strain introduced by short endocyclic double bonds. 

With both pyr-T and 4-HO-pyr-T, there are two additional ring analogies that are natural companions to 5-MeO-pyr-T. These are the piperidine and the morpholine counterparts, 5-MeO-mor-T and 5-MeO-pip-T. Both compounds are in the literature, and an entry reference to them can be gotten from the "known tryptamines" appendix. Along with the pyrrolidine material I had made a reasonable supply of the amides for these other two, both by way of the 5-methoxyindole and oxalyl chloride procedure given above. With piperidine, there is 5-... 

Although the five-ring analog is easily prepared, it is not useful for the transformation due to the tendency for base-induced decomposition ... 

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