Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ¹²‐Prostaglandin J₃

Abstract

Re‐investigation of the l‐proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14 % to a 29 % isolated yield on a multi‐gram scale (32 % NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic utility of this enal intermediate has been further demonstrated through the total synthesis of Δ12‐prostaglandin J3, a compound with known anti‐leukemic properties.

Access to a Key Building Block for the Prostaglandin Family via Stereocontrolled Organocatalytic Baeyer–Villiger Oxidation

“…[1,2] So far, there have been more than 20 drugs related to prostaglandins marketed, some of which, such as latanoprost, have become billion-dollar drugs. [5,6] Elegant contributions to the total synthesis of PGJ compounds have also been made by Nicolaou, Carreira, and Stoltz. [5,6] Elegant contributions to the total synthesis of PGJ compounds have also been made by Nicolaou, Carreira, and Stoltz.…”

Prostaglandin Total Synthesis Enabled by the Organocatalytic Dimerization of Succinaldehyde

“…In summary, we have developed a simple-yet-complex organocatalysed aldol dimerization of succinaldehyde that delivers enal 6 in 29 % yield, 99 : 1 e.r., and on decagram scale. [32] We have utilized this key intermediate in the total synthesis of a wide range of medicinally relevant prostaglandins, and in almost half the number of steps previously reported. [21,32,34,38] We have also been able to demonstrate the versatility of enal 6 by successfully applying it to the total synthesis of stable prostacyclin and thromboxane analogues, [42] again in considerably fewer steps.…”

“…In order to improve our process, we started a further reoptimization campaign, re-evaluating both aldol reaction steps in the enal synthesis. [32] Initial re-optimization studies (Table 2) demonstrated a slight increase in yield from standard conditions (14 %, entry 1) by switching the solvent from THF to acetonitrile (MeCN) (16 %, entry 2), and a further increase by diluting the concentration of the first aldol step (19 %, entry 3). However, at this stage we observed complications during purification of enal 6, where a drop in isolated yield was observed (19 % NMR yield !9% isolated yield) due to the formation of Scheme 12.…”

“…Re-optimization of the synthesis of enal 6. [a] [32] prompted us to reinvestigate aqueous work-ups. [33] Using this strategy, full recovery of enal 6 could be effected with just 3 × ethyl acetate extractions of the reaction mixture from an aqueous solution of Na 2 SO 4 (17 % w/w).…”

“…Ultimately, the process could be scaled up 100 × from 0.5 g (5.81 mmol) to 50 g (581 mmol) of succinaldehyde with minimal drop in yield: 31 % (0.14 g enal 6) on 0.5 g scale and 29 % (12.8 g enal 6) on 50 g scale (entry 9). [32]…”