A Highly Convergent Total Synthesis of Norhalichondrin B

Abstract

A new synthetic strategy for the total synthesis of norhalichondrin B featuring a highly convergent approach and our recently disclosed reverse approach for the synthesis of cyclic ether structural motifs is disclosed. Resulting in the shortest route to norhalichondrin B disclosed thus far, the reported total synthesis was achieved through the synthesis of two almost equally complex fragments whose coupling and short elaboration sequence featured an essential epimerization of the C16 stereocenter occurring concurrently with a simple acid-induced deprotection, a tactic based on a prior study along the synthetic route. This unprecedented strategy within the halichondrin family of natural products could find practical application to the synthesis of other more or less complex natural or designed halichondrin analogues.

Asymmetric total synthesis of (1S,2S,4S)-β-elemene

“…With 17 in hand, we continued toward the final stage of the total synthesis of (1 S ,2 S ,4 S )-β-elemene ( 3 ) via Wittig olefination. Gratifyingly, treatment of 17 with PPh 3 PCH 2 Br and n -BuLi in THF, 18 gave 3 in 82% yield, completing the first and asymmetric total synthesis of 3 . The 1 H and 13 C NMR spectra of synthetic 3 and its optical rotation (synthetic, [ α ] 20 D = +24.5° ( c 1.0, EtOH); natural, [ α ] 20 D = +36.2° ( c 1.4, EtOH)) were in good agreement with those of the isolated natural product.…”

“…14b, 16 Subsequently, oxidation of 12 with Dess-Martin periodinane (DMP) 17 gave aldehyde 13 in 70% yield. In an attempt to obtain advanced intermediate 14 via Wittig olenation, several reaction conditions (e.g., PPh 3 PCH 2 Br/n-BuLi, TMSCH 2 MgBr) 18 were screened, but none afforded the desired product. Instead, the undesired retro-aldol reaction would occur preferentially to yield 11 in quantitative yield.…”

A unified strategy for the total syntheses of eribulin and a macrolactam analogue of halichondrin B

“…Desilylation of 37 [ N , N , N -tributylbutan-1-aminium fluoride (TBAF)] followed by Dess–Martin oxidation (DMP) of the resulting primary alcohol furnished coveted aldehyde fragment A″ ( 38 ) in 88% overall yield (13 steps from 23 as opposed to 16 steps for fragment A ′ [ 33 ] from the same building block 23 ) ( Scheme 3 ). Coupling of fragment A″ ( 38 ) with fragment IJKLMN ( 8 ) by Nozaki–Hiyama–Kishi reaction ( 25 , 26 , 46 , 47 ) [NiCl 2 /CrCl 2 /ligand (−)- 39 , optimized conditions] followed by cycloetherification (DBU) afforded PMB-protected ester 40 in 56% overall yield. Oxidative cleavage (DDQ, 71% yield) of the PMB protective group within 40 furnished precursor 41 for further advancement to the targeted eribulin molecule ( 3 ) ( Scheme 3 ).…”

“…1 ) ( 25 ) and norhalichondrin B ( 2 ) ( Fig. 1 ) ( 26 ), through our reverse approach to cyclic ether structural motifs (forming the C–O bond first followed by C–C bond construction) and employing convergent synthetic strategies, we now report efficient total syntheses of eribulin ( 3 ) ( Fig. 1 ) and the related macrolactam analog 4 ( Fig.…”

Identification of the Optimal Framework for Nitroxyl Radical/Hydroxylamine in Copper-Cocatalyzed Aerobic Alcohol Oxidation

“…5, 25.8, 21.3, 19.7, 18.1, −5.7 6a Purified by open column chromatography (CHRO-MATOREX-DIOL, EtOAc/hexane = 1/15) to afford 17e as a white solid (224 mg, 0.87 mmol, 87% from 1.00 mmol 16e). 1 H NMR (400 MHz, CDCl 3 ): δ 4.73 (d,1H,J = 5.6 Hz),4.61 (d,1H, J = 9.5 Hz), 4.54 (d, J = 4 Hz, 1H), 4.38 (dd, J = 13.7, 1.9 Hz, 1H), 4.12 (d, J = 13.4 Hz, 1H), 3.99 (d, J = 9.5 Hz, 1H), 1.55 (s, 3H), 1.46 (s, 3H), 1.40 (s, 6H).…”