A Practical Total Synthesis of Hapalosin, a 12-Membered Cyclic Depsipeptide with Multidrug Resistance-Reversing Activity, by Employing Improved Segment Coupling and Macrolactonization

Abstract

A practical total synthesis of hapalosin, a compound with multidrug resistance-reversing activity, has been carried out using an unprecedented macrolactonization strategy. One of the features of the new approach is the straightforward and fully stereocontrolled access to the key gamma-amino beta-hydroxy carboxylic acid subunit via an efficient acetate aldol addition reaction with N-methyl alpha-aminoaldehydes, which relies on a camphor-derived chiral lithium acetate enolate reagent. The scope of this aldol reaction is investigated and its potential application to the synthesis of other structurally related, biologically relevant compounds illustrated. Remarkably, the chiral tether in the resulting gamma-amino aldol adducts sterically protect the carbonyl group, thus avoiding intramolecular cyclization during the amino group deprotection and the subsequent segment coupling event. After successful segment coupling and smooth, clean release of the chiral auxiliary, a new macrolactonization protocol, based on the principle of double activation of both reactive sites, is applied, which leads to the 12-membered macrolactone hapalosin in unprecedented chemical efficiency.

Reaction ofγ-Hydroxy-N-[1-(dimethylcarbamoyl)ethyl]butanamides under the ‘Direct Amide Cyclization’ Conditions

“…The amide group forms an intermolecular H-bond with the carboxylate carbonyl Scheme 4 4 ) We expected that, in the presence of a better nucleophile, a competition with the attack of Cl À should be possible, which would lead to a mixture of products, but all reactions in the presence of CsI, Bu 4 NI, and PhSNa, respectively, led to the formation of 11 exclusively. 5 ) The structure of 11c has also been established by an X-ray crystal-structure determination. The quality of the crystals and, subsequently, the results of the structure determination were poor, although unambiguous.…”

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…Thus, in target synthesis of biologically active macroheterocycles, after the stage of the formation of unsaturated cycles, the reaction of reduction of multiple bonds follows: exhaustive hydrogenation of C≡C, C=C and C=N bonds over Wilkinson's catalyst, Raney nickel and Pd/C, [6][7][8][9][10][11] reduction of C=N bonds using NaBH 4 or LiAlH 4 [6][7][8][9][10][11][12] and partial hydrogenation of the C-C triple bond to Z-double over Lindlar catalyst [13][14][15][16][17][18] that allow obtaining both isolated bonds, and conjugated systems.…”

“…For example, a method for hydrogenation of a double bond over palladium catalyst has been demonstrated in stereoselective synthesis of macrolactames of fluvirucines B 2-5 (7) showing properties of antibiotics and strong inhibitors of A virus with low toxicity. [19] Construction of the macrocyclic skeleton of species 7 was carried out by the metathesis reaction of acyclic precursor, i.e.…”

Stereoselective synthesis of γ-amino acids

“…Hydroboration of 720 with 9-borabicyclo[3.3.1]nonane (9-BBN) followed by oxidation led to the protected c-amino-b-hydroxy acid 694 in 60% yield (Scheme 180). 272 Ohno et al 273 Recently Palomo et al 276 have described that the addition of the lithium enolate derived from 176 with the chiral amino aldehyde 697 gave the corresponding aldol derivative 726 as a single diastereoisomer in 78% yield, which by cleavage of the Cbz protective group followed by reaction with acyl chloride 727 afforded dipeptide 728 in 78% yield. Deprotection of the tertiary hydroxy group in 728 with TBAF, followed by further selective protection of the secondary carbinol as tert-butyldimethylsilyl (TBS) ether, and oxidative cleavage using cerium ammonium nitrate (CAN) produced dipeptide 729, a key component of Halaposin.…”