Studies of Acyl Nitrene Insertions. A Stereocontrolled Route toward Lankacidin Antibiotics

Abstract

Photochemically generated acyl nitrenes undergo facile addition to 4,5-dihydrofurans 20 and 24b to yield the novel 2-ethoxyoxazolines 21 and 25. The regiocontrolled C=C insertion has provided for introduction of the sterically hindered C-3 amido appendage of the lankacidins 1-4 with high stereoselectivity. High chemoselectivity for the C=C insertion pathway was demonstrated upon production of the acyl nitrene intermediate from azide 33b. Intramolecular competition for allylic C(3)-H insertion versus C=C addition yielded exclusive formation of seven-membered N-acyl aziridines 34a,b. The latent aldehydic functionality of oxazolines such as 21 and 25 is exposed upon a brief hydrolysis, permitting further chemical elaboration. Wittig condensation of the lactol from 25 has led to the synthesis of the lactone fragment 5, containing all of the necessary stereochemistry and functionality for incorporation into the lankacidin antibiotics. The acyl nitrene insertion into 4,5-dihydrofurans affords a route toward unusual beta-amido acids and amino sugar derivatives as shown via stereocontrolled formation of the amidofuranose derivatives 31 and 32. The three-step process of acyl nitrene addition, hydrolysis of the resulting 2,5-dialkoxy oxazoline intermediates, and Wittig carbon chain elongation provides the stereocontrolled formation of novel beta-amido esters.

Biomimetic Synthesis of Lankacidin Antibiotics

“…Although a certain number of lankacidin derivatives have been prepared through enzymatic esterification or sophisticated chemical transformations, these approaches are rather limited, as the modification of the parent structure was found to be difficult due to facile cleavage of the C2–C18 bond upon exposure to even mild acidic or basic conditions. ,, A de novo synthesis arguably provides far greater opportunities and flexibility for discovering new bioactive entities . Over the past three decades, the fragile and congested structure has enticed significant interest from several groups to forge the C2–C18 bond with elaborate functional groups at an early stage in their synthetic blueprint. , Only the Kende group accomplished the landmark synthesis of lankacidin C ( 1 ) with an enormous 34 LLS (longest linear steps) (46 total steps) from two chiral building blocks . Alternatively, a flavin-dependent amine oxidoreductase ( Lkc E) was preliminary identified to biosynthetically participate in the unprecedented intramolecular Mannich-type cyclization (Scheme B). , Kinashi and others also uncovered that polyketide synthases from Streptomyces rochei constructed the entire carbon chain first (such as LC-KA05, 6 ) and that subsequent oxidation at C18 revealed a reactive alkenyl N -acyl imine. − Although the detailed enzymatic underpinnings for this extremely rare ring-forming reaction remain to be clarified (such as involving an enolate-iminium pair 7 ), from a synthetic standpoint, a biomimetic approach would drastically decrease the number of steps if the proper precursor and reaction conditions could be defined.…”

Total Synthesis of Lankacyclinol

“…[6] Our recent studies, stemming from 4,5-dihydrofurans, of tandem acyl nitrene insertions and Wittig reactions have demonstrated a stereocontrolled route to unique b-amido esters. [7] These results have provided the opportunity to address the challenges inherent in a proposed synthesis of 1, particularly with regard to serious issues of acid and base instability and stereochemical concerns. In this communication, we describe the first enantioselective synthesis of (À)-lankacyclinol by a convergent pathway which establishes the relative and absolute configuration as illustrated in 1.…”

“…[12,13] Introduction of the C3-amido appendage was undertaken by the CC insertion of a reactive acyl nitrene with in situ reorganization to a cis-fused bicyclic oxazoline intermediate at room temperature. [7] As illustrated in Scheme 2, photolysis of benzyl azidoformate provided for facile insertion reactions with 8 to deliver the 2-amido furanose derivative 9 in 87 % yield as the product of hydrolysis of the initially formed oxazoline. High diastereoselectivity (95:5) was imparted, to a large extent, by the steric consequences of the C1 substituent in 8.…”

Oxabicyclo[3.2.1]octenes in Organic SynthesisDirect Ring Opening of Oxabicyclo[3.2.1] Systems Employing Silyl Ketene Acetals in Concentrated Solutions of Lithium Perchlorate−Diethyl Ether: Application to the Synthesis of the C(19)−C(27) Fragment of Rifamycin S

“…Acetonide formation and subsequent installation of the C(20) methyl group employing the Fráter−Seebach protocol 13 provided 18 as a single diastereomer. This remarkably selective alkylation can be rationalized by chelation of the benzyloxy group to form the rigid bicyclic structure 19 . Cleavage of the benzyl ether, followed by acetonide formation and reduction of the ester afforded the C(19)−C(27) fragment of Rifamycin S. The spectra of 10 were identical in all respects with those reported in the literature …”