Total Synthesis of Salicylihalamides A and B

Abstract

The paper illustrates two efficient routes to macrolactone 19 containing a 3-(para-methoxybenzyloxy)propyl side chain at C-15. The chiral center at C-15 was introduced by a Noyori reduction of keto ester 5. The intermediate common to both routes, aldehyde 8, was prepared from keto ester 5. The subsequent chain extension utilized Evans aldol reactions. The first route leads to the alkene 14, which was used, after hydroboration, for a Suzuki cross-coupling reaction with vinyl iodide 15. The derived seco acid 18 was converted into the macrolactone 19 by a Mitsunobu lactonization by using immobilized triphenylphosphine. Alternatively, an aldol reaction of 8 with the 4-pentenoyl derivative 20 was used to prepare alkene 26. This building block led to ester 28, which could also be converted into macrolactone 19 by the classical ring-closing metathesis. After conversion of the C-15 side chain to the corresponding aldehyde, the enamide was introduced through hemiaminal formation and formal elimination of water. Separation of the double-bond isomers and removal of the silyl protecting groups provided salicylihalamides A (E)-1 and B (Z)-1.

Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs)

“…122 Another variant of the Mitsunobu reaction was reported to affect the closure of a 13-membered lactone in the presence of supported triphenylphosphine in low yield (10%) but was recently more successful in the formal synthesis of salicylihalamides (206, Scheme 7c). 119,123 The intramolecular Mitsunobu cyclization between the sulphonamide and benzylic hydroxyl in 212 (derived from amino acid 207 through a series of reactions, as depicted in Scheme 7d) furnished enantiomerically pure benzannulated mediumring thio-ethers of the type 213 in 69% yield, as depicted in Scheme 7d. 124 Macrocyclization of cyclization precursor 214 under Mitsunobu conditions (DEAD, PPh 3 , toluene, 0 C) gave rise to benzolactone 215 in 78% yield (Scheme 7e).…”

A Practical Approach to Synthesize the C(9) –C(24) Fragment of (+)‐Discodermolide

“…12 To obtain the aldehyde 12, Smith and coworkers employed Weinreb transamidation of 7 in the presence of Me 3 Al, however, Me 3 Al is a dangerous and not readily available reagent due to its pyrophoric properties.…”

Synthesis of Natural Products Containing Macrocycles by Alkene Ring‐Closing Metathesis

“…In addition, aigialomycin D (7), zeranol (25), zeralenone (28), and the pochonins (16, 19, 22) share the basic skeleton consisting of a 14-membered ring lactone that includes a 1,2-phenylene. The major contribution in this field was achieved by Danishefsky et al who, despite the relative similarity of the target molecules, have developed a wide variety of synthetic strategies and conditions.…”

“…Zeranol ( Mitsunobu/RCM strategy, Suzuki cross-coupling, Stille cross-coupling are the three general approaches for the synthesis of salicylihalamides A (34) and B (35) [25]. After a thorough optimization, the best reaction conditions involved the use of [Ru]-II (10 mol%) in toluene at 70 • C for 2 hours (Scheme 5.8).…”