Halichondrin B:  Synthesis of the C1−C22 Subunit

Abstract

[Reaction: see text]. Two efficient routes to the C1-C22 subunit of halichondrin B are described. The cage ketal 7, which contains 11 asymmetric centers embedded within the ABCDEF-ring framework, was assembled from (+)-conduritol E (27) in 18 steps and 4% overall yield. In a separate route, 7 was also synthesized in 18 steps and 2% overall yield from a derivative of alpha-d-glucoheptonic acid gamma-lactone (62). While the former route installs the fully elaborated C-ring endowed with the correct C12 stereochemistry early in the synthesis, the latter features a late-stage introduction of the C12 stereocenter during the ultimate one-pot Michael addition/ketalization cascade to form the CDE-ring system of the cage. The importance of the C12 stereocenter to the crucial ketalization event is discussed through comparison of these two strategies.

A Reverse Approach to the Total Synthesis of Halichondrin B

“…Having secured all four key fragments ( I , MN , EFG , and A ), the stage was now set for their coupling and further elaboration of the growing molecule toward the targeted halichondrin B ( 1 ). Scheme summarizes the coupling of fragments I ( I ) and MN ( MN ) as effected by Et 3 N and LiCl, leading to ( E )-enone 42 (93% yield), and its elaboration to advanced intermediate 46 . Thus, one-pot desilylation, removal of the acetonide moiety, and intramolecular cyloetherification within the resulting intermediate were sequentially achieved from 42 under a high concentration of HF·py conditions to afford diol 43 as a mixture with its C12 diastereoisomer (90% total yield, 43 :12- epi - 43 ca.…”

Transition metals in organic synthesis: Highlights for the year 2005

“…(221)) [1117,1118], hybrids of d-galactose with 1-deoxynojirimycin analogs [1119], the tetracyclic core of tetrapentalones [1120], 1-epi aglycon of cripowellins A and B [445], gambieric acid [1121], aspercyclide C [524], radicicol and pochonin C [1122], trachelanthamidine [1123], heliannuols G and H [652], (−)-Geismann-Waiss lactone [1124], tuberostemonines [688], (−)-kendomycin [1125], pochonin D [1126], (−)-223A [1127], coleophomones B-D [1128], brevetoxin B [130], garsubellin A [45], fostriecin [48], 11-acetoxy-4-deoxyasbestin D [1129], (+)-cyclophellitol [1130], ␤-C-glycosides [50], zoapatanol [247], deoxymannojirimycin and swainsonine [1131], valienamine [1132], A 3 adenosine recetor agonists [1133], vincantril [810], (−)-perhydrohistrionicotoxin [1134], annonaceous acetogenins [1135], deoxycombrestatin A-4 analogs [1136], (+)-lentiginosine and analogs [1137], N-malayamycin A [1138], (−)-salicylhalamides A and B [938], oxytocin analogs [1139], steroid-like compounds [440], (−)-isoprelaurefucin [338], halichondrin B [1140], (−)-microcarpalide and (+)-lethaloxin [1141,1142], anamarine …”

Total Synthesis of (−)-Platensimycin, a Novel Antibacterial Agent

“…Petasis olefination33 of lactone 15 with Cp 2 TiMe 2 in toluene at 90 °C provided the corresponding enol ether. This product was subjected to hydroboration with 9-BBN followed by oxidation with H 2 O 2 to provide the desired primary alcohol 16 and its diastereomer 17 as a 2:1 mixture in 81% yield 40. It is important to note that reaction times longer than 3 h led to diminished yield due to the isomerization of the double bond.…”