New six-membered rings

In its present form, intermediate 12 is not a viable substrate for the crucial Dieckmann condensation it must undergo prior epimerization at C-16. When intermediate 12 is treated with sodium methoxide in hot methanol, enolization at C-16 occurs and an equilibrium is established between 12 and a diastereomeric substance, intermediate 11. Once formed, 11 can either revert back to 12 through the planar enolate form, or it can participate in a productive cyclization reaction to give a new six-membered ring. Under these conditions, the desired transformations take place with exceptional facility to give, after acidification of the reaction medium, enol ester 10. 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

A particularly important example of the intramolecular aldol reaction is the Robinson annulation, a procedure that constructs a new six-membered ring from a ketone.171 The reaction sequence starts with conjugate addition of the enolate to methyl... 

In the transition state of the electrocyclization of (Z)-l,3,5-hexatriene to 1,3-cyclohexadiene (Scheme 22 entry 1) a new six-membered ring develops analogously... 

In some examples - in contrast to the above cases - an internal nucleophilic attack of a triple bond can occur (in an exo-dig-fasYiion), resulting in the formation of a new six-membered ring. Such conversions are shown in Scheme 29. 

Allenes as versatile synthons including Diels-Alder reactions and especially intramolecular cycloadditions of this type were reviewed by Aso and Kanematsu [338], In some cases of intramolecular Diels-Alder reactions of open-chain starting materials such as 340 [339], 342 [339] and similar acceptor-substituted allenes [156], the formation of two new six-membered rings seems to be favorable if possible (Scheme 7.48). The non-activated cumulated C=C bond of 340 takes part in the [4+ 2]-cycloaddition and hence the necessary reaction temperature is high. On the other hand, the progressive truncation of the tether and the electron deficiency of the allenic C=C bond involved give rise to a remarkable Diels-Alder reactivity of the sulfone 346 generated in situ from sulfoxide 345 [339]. 

It is clear that the CHO group has been lost, presumably in a (3-dicarbonyl cleavage reaction (305-6), and that a condensation has taken place to form a new six membered ring. The order of these two reactions doesn t matter much ... 

Another approach for the construction of rings is to use reactions which start with two acyclic compounds and produce cyclic products. There are many of these processes, but the most used and most useful is the Diels-Alder reaction. This is a reaction between a diene and an olefin to give a new six-membered ring. It is also termed a 4 + 2 cycloaddition because one partner (the diene) containing four 7r electrons adds to a two-electron fragment (the olefin) containing two it electrons to yield a ring. 

Although not described as such, this reactivity of silver as a Lewis acid in C-C bond formation via enamines was already known and actually described in the synthesis of complex indole alkaloids. A A-sulfonyldienamine embedded within a polycyclic indole ring system added to the trimethylsilylated propargyl arm of this system, leading in high yield to a new six-membered ring (Scheme 10.71).110... 

Enolate D of Figure 13.74 is acylated by the ester following the usual mechanism. The bicyclic compound A is a product, which contains a new six-membered ring that has been annulated to an existing ring. 

Often, the Michael addition product is not isolated. Instead, the intramolecular aldol condensation occurs immediately, and the new six-membered ring is formed, as shown in the following equation. (However, when you are attempting to write the product of such a reaction, it is best to first write the product of Michael addition and then write the final product that results from the aldol condensation.)... 

The carbocation adds to the double bond to form a new six-membered ring. 

This sequential process of Michael-aldol reaction leading to a new six-membered ring is known as the Robinson annelation. It was, in fact, Robinson who invented the idea of using a Mannich product in conjugate additions because he wanted to develop this important reaction. There are now thousands of examples used to make all kinds of compounds, especially steroids (Chapter 49). 

The mechanism is the same and a new six-membered ring is formed having one double bond. Now a reaction between a cyclic diene and a nitroalkene. 

The mechanism leads clearly to the first drawing of the product but this is a cage structure and the second drawing is better. The new six-membered ring is outlined in black in both diagrams. Now a more elaborate example to show that quite complex molecules can be quickly assembled with this wonderful reaction. 

The diene has two sets of substituents—inside and outside. The inside one is the bridging CH2 group and it has to end up on one side of the molecule (above in the last diagram) while the two green hydrogens are outside and remain so. In the final diagram they are below the new six-membered ring. 

The remaining case—the cis, trans-diene—is rarer than the first two, but is met sometimes. This is the unsymmetrical case and the two substituents clearly end up on opposite sides of the new six-membered ring. 

Now the diketone is cyclized in HC1 to give a bicyclic enone. A new six-membercd ring has been formed but the old three-membered ring has disappeared. First, an intramolecular aldol reaction closes the new six-membered ring to form an enone and then the stage is set for a fragmentation. 

There are now two possible routes to the final product. Reductive elimination would insert the new alkyne into one of the old C-Co bonds and form a seven-membered ring heterocycle. This could close in an electrocyclic reaction to give the new six-membered ring with the cobalt fused on one side and hence the cobalt complex of the new benzene. 

The Diels-Alder reaction, named for German chemists Otto Diels and Kurt Alder, is an addition reaction between a 1,3-diene and an alkene called a dienophile, to form a new six-membered ring. 

To understand the rule of endo addition, we must first examine Diels-Alder products that result from cyclic 1,3-dienes. When cyclopentadiene reacts with a dienophile such as ethylene, a new six-membered ring forms, and above the ring there is a one atom bridge. This carbon atom originated as the sp hybridized carbon of the diene that was not involved in the reaction. 

Intramolecular Friedel-Crafts acylation formed a product containing a new six-membered ring (in red), which was converted to LSD in several steps. 

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