Total Synthesis of (+)-Manzamine A

Abstract

A novel synthetic route to (+)-manzamine A was developed. It highlights an amazingly efficient construction of a highly strained 15-membered ring across a cyclohexenone ring with the aim of installing the requisite functionalities in a completely stereocontrolled manner. Other key features include a stereoselective Diels-Alder reaction of an optically active butenolide, construction of the 15-membered ring by intramolecular Mitsunobu reaction of a nosyl amide, [3,3]-sigmatropic rearrangement of allyl cyanate for stereoselective introduction of nitrogen functionality at a sterically congested position, and a ring-closing metathesis in the presence of labile functional groups.

Neurotrophic Natural Products: Chemistry and Biology

“…[182] Among them, manzamine A ( 195 ) [183] displays a broad biological profile that includes anticancer, antibacterial, insecticidal, antimalarial, anti-inflammatory, and anti-HIV activities. [184] In addition, manzamines A ( 195 ), E ( 197 ), F ( 198 ), and 8-hydroxymanzamine A ( 196 ) were shown to exhibit potent neuritogenic activities in Neuro 2A cells at concentrations as low as 1 μM (Figure 11). [185] Furthermore, it was proposed that 195 could act through the same mechanism reported for lactacystin ( 1 ).…”

“…[184] An intermolecular Diels–Alder reaction between the Danishefskydiene-like motif 207 and chiral butenolide 208 provided the B ring of 209 . Subsequently, a well-designed [3,3] sigmatropic rearrangement of allyl cyanate 210 furnished the desired pyrrolidine motif of 211 .…”

Chemoenzymatic Synthesis of Advanced Intermediates for Formal Total Syntheses of Tetrodotoxin

“…Theallylic alcohol moiety in 14 can also be installed directly on 7 by means of aWittig olefination, [15] albeit in lower yield. Upon dehydration of 15 with TFAA and Hünigs base, [16] af acile [3,3]-sigmatropic rearrangement took place to yield an isocyanate intermediate,w hich, upon treatment with lithium tert-butoxide,f urnished Fukuyamasc arbamate 2 in 56 %y ield (Scheme 2) in six steps from 6 (Fukuyamas work: a ½ 24 D ¼ + 108 8 (c = 0.97, CHCl 3 ); this work: a ½ 22 D ¼ + 9.88 8 (c = 1.0, CHCl 3 )). Both the E and Z isomers of 14 converge to the same Boc-protected amine 2.I nt heir approach to TTX, Fukuyama and co-workers utilized the Z isomer of 15 as the rearrangement precursor (see Scheme S1).…”

Total Synthesis of (−)‐Tetrodotoxin and 11‐norTTX‐6(R)‐ol

“…Then itrogen group was stereoselectively installed via [3,3]-sigmatropic rearrangement of allylic cyanate.T he rearrangement precursor was prepared from allylic alcohol 24 through carbamoylation. Upon dehydration of 25 with TFAA and Hunigs base, [13] afacile rearrangement took place to give asterically hindered isocyanate,w hich, through treatment with t-butoxide,f urnished carbamate 26.T he resultant terminal alkene was selectively converted into aldehyde 27 through Osmediated dihydroxylation and oxidative cleavage with lead tetraacetate.T he addition of alkynyl magnesium bromide to aldehyde 27 furnished propargyl alcohol as as ingle diastereomer.T he stereochemical outcome was rationalized in terms of the chelation model 28,a sd epicted in the brackets, where the magnesium acetylide approaches from the less hindered side. [4h] After partial reduction of the alkyne, desilylative elimination of p-toluenesulfinate through treatment with CsF yielded the cis-a,b-unsaturated oxime without isomerization of the double bond.…”