Retrosynthetic Analysis and Strategy

Retrosynthetic cleavage of the A13,14 double bond in 6 significantly simplifies the side-chain appendage attached to C-l2 and affords aldehyde 7 and ketophosphonate 8 as potential precursors. In the synthetic direction, a Homer-Wadsworth-Emmons reaction10 would appear to provide a very simple means of joining intermediates 7 and 8 with concomitant formation of the requisite trans C13-C14 olefin. Retrosynthetic simplification of aldehyde 7 provides intermediate 9, a molecular assembly commonly known as the Corey lactone. 

The retrosynthetic maneuvers that we have addressed thus far have only resulted in simplification of the vicinal side-chain substituents appended to carbons 8 and 12 we have yet to address the marked stereochemical complexity of the cyclopentane nucleus of 

PGF2a- The cyclopentane ring of the Corey lactone (9) is the host of four contiguous stereogenic centers. Retrosynthetic simplification of 9 provides 10, a construct which is more complex than 9 Nevertheless, intermediate 10 possesses structural features that satisfy the requirement for the iodolactonization transform. The iodolactone in 10 constitutes the retron for the iodolactonization transform.11 Cleavage of the indicated bonds in 10 sacrifices two of the five stereocenters and provides unsaturated carboxylic acid 

To clarify the relationship between intermediate 11 and its predecessor, intermediate 12, it is instructive to recognize the correspondence between the C-ll hydroxyl group and the C-6 carboxyl group in 11. Thus, even though the structural relationship between intermediates 11 and 12 may not appear to be close, subjection of 

Bicyclic ketone 13 is a pivotal intermediate in Corey s approach to the prostaglandins. Buried within 13 is the five-membered ring of PGF2a, albeit in an undeveloped form. It would appear that a particularly direct approach to the synthesis of 13 would involve a [4+2] cycloaddition reaction between substituted cyclopentadiene 15 and ketene. Unfortunately, however, ketene itself is not a suit- 

Anticipating that the central pentacyclic core of ecteinascidin 743 (1) would need to be constmcted prior to the formation of either the ten-membered lactone (ring F) or its appended tetrahydroisoquino- 

Based on inductive effects, EWG satC-2andC-4 hinder reaction, while EDG s at C-3 and C-5 significantly accelerate the reaction 

based on these final simplifications, the synthesis of ecteinascidin 743 (1) has been reduced to the creation of two building blocks of relatively similar complexity (38 and 39), each bearing only one stereogenic center and a protected amine. In principle, the latter elements could result in both fragments from the asym- 

As has been demonstrated through countless examples of this rearrangement process in chemical synthesis, the migration reaction that converts an intermediate such as 46 into 47 always proceeds with retention of stereochemical configuration. Thus, follow- 

Having now appended both tetrahydroisoquinoline systems onto the central C-ring piperazine, the only major synthetic objective remaining to complete the total synthesis of ecteinascidin 743 (1) was the formation of the ten-membered macrocyclic F-ring lactone through the envisioned biomimetic o-quinone methide capture. Before this operation could be explored, however, several func- 

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