Sequencing a ring

In this reaction sequence a ring is reductive 1> cleaved and a protect ing-g roup operation is accomplished. 

Briefly, B-ring THP 64 was prepared from 65 (which took several steps to prepare) using a 13 reaction sequence. A-ring THP 63 was prepared in 16 steps from known compound 66 via key intermediates 67 and 68. 

This sequence of Michael reaction and cyclisation is known as tile Robinson annelation since it makes a ring. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

A carbon atom in a ring can be a chirality center if it bears two different sub stituents and the path traced around the ring from that carbon m one direction is differ ent from that traced m the other The carbon atom that bears the methyl group m 1 2 epoxypropane for example is a chirality center The sequence of groups is O—CH2 as one proceeds clockwise around the ring from that atom but is CH2—O m the counter clockwise direction Similarly C 4 is a chirality center m limonene... 

Anions of heterocyclics may attack heterocumulenes to set up systems which can incorporate new atom sequences into the ring by nucleophilic attack on a ring site (such as a carbonyl group). Scheme 32 gives an example (80AG(E)466). 

While an aromatic A-ring does not interfere with this sequence, isolated double bonds will react with hypobromous acid. 

Amino-3-alkyl derivatives of474 have been prepared and found to undergo facile nucleophilic 5-substitution with methanolic hydrazine (65°, 4 hr, 75% yield), hydroxide ion (20°, 3 hr, 75% yield), or pro-panolic benzylamine (100°, 5 hr, 80% yield). The first two reactions may proceed by a ring-opening and reclosure sequence. ... 

When the nitrogen is part of a ring, as for example in iV-methylpyrolidine 10, the olefinic product resulting from one elimination step still contains the nitrogen as a tertiary amino group. A second quaternization/elimination sequence is then necessary to eliminate the nitrogen function from the molecule as final product a diene is then obtained ... 

With the polycyclic framework of the natural product intact, the completion of the total synthesis only requires a short sequence of reactions. At this juncture, the decision was made to address the problem of reconstituting the A-ring lactone. It was hoped that a selective oxidation of the A-ring allylic ether could be achieved. 

Benzofurazan (8), on irradiation in benzene solution, undergoes a complex sequence of ring openings and rearrangements to yield, in situ, the cyanobutadienylcarbonylnitrene 9 which is trapped by the solvent to give ultimately the 1 //-azcpinc 10 as the major product.125... 

Interconversion of - and Z-macrocycles in metathesis reactions proceeds via a ring-opening metathesis/ring-closing metathesis sequence thus, more... 

AnGwer> This compound (31) i nearly a ring-opened version of (26) so a similar sequence will bo satisfactory ... 

In another example, a sequence of methylation-elimination-hydroxymethylation was used to install the functionality pattern found in the A-ring of taxol. The hydrazone dianion was generated and methylated at low temperature. The hydrazone was then deprotonated again using excess n-butyllithium and allowed to warm to room temperature, at which point formation of the vinyllithium occurred. Reaction with paraformaldehyde generated the desired product.290... 

The key cyclization in Step B-2 was followed by a sequence of steps that effected a ring expansion via a carbene addition and cyclopropyl halide solvolysis. The products of Steps E and F are interesting in that the tricyclic structures are largely converted to tetracyclic derivatives by intramolecular aldol reactions. The extraneous bond was broken in Step G. First a diol was formed by NaBH4 reduction and this was converted via the lithium alkoxide to a monomesylate. The resulting (3-hydroxy mesylate is capable of a concerted fragmentation, which occurred on treatment with potassium f-butoxide. 

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