Direct Oxa-Pictet−Spengler Cyclization to the Natural (3a,5)-trans-Stereochemistry in the Syntheses of (+)-7-Deoxyfrenolicin B and (+)-7-Deoxykalafungin

Abstract

The pyranonaphthoquinones (+)-7-deoxyfrenolicin B and (+)-7-deoxykalafungin were synthesized in four steps using an oxa-Pictet-Spengler cyclization that directly provided the natural (3a,5)-trans-substituted dihydronaphthopyrans with high diastereoselectivity. This outcome is in contrast to the unnatural (3a,5)-cis-substituted dihydronaphthopyrans reported under similar conditions for the syntheses of (+)-frenolicin B and (+)-kalafungin. Computational modeling is presented that provides insight into this unusual stereoselectivity.

Novel isochroman-triazoles and thiadiazole hybrids: Design, synthesis and antimicrobial activity

“…The ester was reduced to corresponding phenyl ethanol (2) using a NaBH 4 /MeOH mixture in dry THF [27]. Acid catalyzed oxaPictet-Spengler reaction of (2) with methyl acetoacetate afforded the methyl 2-(6,7,8-trimethoxy-1-methyl-3,4-dihydro-1H-isochromen-1-yl)acetate (3) [28]. FTIR carbonyl stretching at 1731 cm À1 was observed for ester carbonyl and in 1 H NMR characteristic 2H singlet at d 2.93 for CH 2 , 3H singlet at d 2.20 for CH 3 at C-1, besides the multiplets at d 3.95 ppm for CH 2 at C-3, and C-4 and signals for ethyl moiety were noted.…”

Oxa-Pictet–Spengler reaction as key step in the synthesis of novel σ receptor ligands with 2-benzopyran structure

“…OEt 2 , TMSOTf, and Bi(OTf) 3 , 38 and can be applied for the stereoselective synthesis of complex natural products. [39][40][41] In order to broaden the relationships between the structure of 1-aminoalkyl substituted 2-benzopyrans and their  1 affinity and selectivity over the  2 subtype, modifications of the side chain in 3-position and the aminoalkyl part of the compounds were envisaged. In order to get access to a side chain bearing an appropriate substituent, the Oxa-Pictet-Spengler reaction using 3-hydroxy-4- …”

Synthesis of Oxacycles Employing the Oxa‐Pictet–Spengler Reaction: Recent Developments and New Prospects

“…[106] In one case, the oxa-Pictet-Spengler cyclization of the resulting β-hydroxylactone 105 under BF 3 ·Et 2 O assistance in CH 2 Cl 2 furnished the pyranolactones 106 as anti diastereomers, regardless the nature of the aldehyde. [107] Final oxidation with ceric ammonium nitrate (CAN) afforded the anti-pyrano-naphthoquinone lactone 103a. Interestingly, this sequence not only allows access to individual enantiomers of the lactones, but also complements the racemic, syn-selective route (Scheme 13).…”

“…The authors discovered that during the BBr 3 -mediated demethylation (CH 2 Cl 2 , -50°C, 2h) stage, these tetracycles epimerized, presumably as a consequence of enone-dienol tautomerism involving 110, giving diastereomeric mixtures enriched in the anti-diastereomers kalafungin (94) and (-)- The syntheses of (+)-7-deoxyfrenolicin B (97) and (+)-7-deoxykalafungin (95) reported by Eid and co-workers [107] takes place along the same reaction sequence as for 94 and 111 (Scheme 16), where the β,γ-unsaturated ester was prepared in 80 % yield by Heck coupling between 2-bromo-1,4-dimethoxynaphthalene and isobutyl but-3-enoate employing Pd(tBu 3 P) 2 and dicyclohexyl methylamine. The critical oxa-Pictet-Spengler cyclizations which established the stereochemistry of the newly formed stereogenic centre were performed with butyraldehyde (88 % yield) and acetaldehyde (98 % yield) as carbonyl components.…”

“…Computational efforts [107] made on the intermediate oxocarbenium ions derived from 105 and 112 [115] to explain the stereochemical outcome of the reaction evidenced that the geometry and distance of the Z* intermediate which lead to the anti product, are predefined for a favourable eventual ring-forming reaction (Scheme 16). The E* isomer appears to be more stable because it can relieve much of the crowding necessitated by Z*.…”