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In the preceding paper, we described the synthesis of the vancomycin-related M(4-6)(5-7) bicyclic subunit 3 (Scheme 1), 1,2 a structural motif common to all members of this family of antibiotics exemplified by vancomycin aglycon (1). 3 Herein we describe the first synthesis of the vancomycin-related heptapeptide nucleus and the transformation of this intermediate to orienticin C (bis-dechlorovancomycin) aglycon (2). 4Our original strategy for the construction of the biaryl ethercontaining rings was based on a successful study that demonstrated that these macrocycles, in the absence of the biarylcontaining M(5-7) ring, could be constructed through a Tl(III)mediated oxidative cyclization. 5 In the current plan, the N-terminal tripeptide 4 incorporating the 4,4′-dimethoxydiphenylmethyl (Ddm)-protected asparagine was employed for the construction of the final M(2-4) macrocyclic subunit. The selection of this protecting group was predicated on its favorable impact on epimerization during the fragment coupling, 6 on suppression of the aspartate-iso-aspartate rearrangement, 6 and on protection of this residue during selective derivatization of the N-methyl amide at the end of the synthesis. Given the complexity of these natural products, orienticin C aglycon (2) 4 was chosen as our initial target.Deprotection of the Boc-protected bicyclic tetrapeptide 3 (30% TFA, DMS, CH 2 Cl 2 , 0°C) and fragment coupling with the N-terminal tripeptide 4 7 was carried out under standard conditions (1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), THF, 0°C) to afford heptapeptide 5 in excellent yield with no detectable epimerization (Scheme 1). Removal of the ring-2 allyl ether provided 6, which was cyclized under the optimized conditions developed for the M(2-4)(4-6) bicycle 5 (Tl(NO 3 ) 3 ‚3H 2 O, 30:1 CH 2 Cl 2 /MeOH, room temperature (rt); CrCl 2 , 0°C) to provide the desired tricycle 7 in approximately 20% yield as an inseparable mixture with two other unidentifiable byproducts. In spite of an extensive reevaluation of this methodology, no improvement in yield for this critical transformation could be achieved. We conclude that the enhanced rigidity of the biaryl-containing M(4-6)(5-7) bicycle, in comparison to that of the M(4-6) monocyclic counterpart employed in the model studies, 5,8 could be responsible for the failure of this transformation. A detailed investigation of this reaction will be published elsewhere. 9 Rather than proceeding with a substandard cyclization step, other diaryl ether-forming macrocyclization strategies were considered. On the basis of the existing precedent provided by Beugelmans, Rao, and Boger, 10 the nitroaromatic-based S N -Ar methodology was evaluated. Accordingly, the refunctionalization of bicyclic tetrapeptide 3 to phenol 8 was undertaken (Scheme 2). Protection of the ring-4 phenol as its derived allyl ether and subsequent deprotonation of the six amidic and alcoholic hydrogens with MeMgCl (18 equiv, THF/Et 2 O, 0°C, 2 h) was followed by lit...

Retinoids 1-5 have been identified as potent RXR agonists for evaluation in the treatment of non-insulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1-5 have been developed. The core tetrahydronaphthalene 7, employed in the synthesis of 1 and 2, was prepared in 98% yield using an AlCl(3)-catalyzed (0.03 equiv) Friedel-Crafts alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel-Crafts acylation of 7 with chloromethylnicotinate 9 was developed to prepare ketone 10 in 68% yield. Chelate-controlled addition of MeMgCl to 10 followed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis of 1 in 33% yield. FeCl(3)-catalyzed (0.05 equiv) Friedel-Crafts acylation of 7 with chloromethylterephthalate 14 afforded ketone 15 in 81% yield. Saponification of 15 and reaction with 50% aqueous NH(2)OH in AcOH afforded a 9:1 mixture of cis and trans oximes, from which the desired cis-oxime 2 was isolated in 43% yield. The core bromo-dihydronaphthalene 29 required for the synthesis of 3-5 was prepared by a Shapiro reaction. Transmetalation of 29 and reaction with Weinreb amides 30b or 36 afforded ketones 32 and 37, which were converted into 3-5 using chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids 41 and 42 with vinyl triflate 43 provided an alternative approach to the synthesis of this class of compounds.

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