Macrolactams preparation

Bis-4-arylidene-5(4//)-oxazolones are easily obtained from aromatic dialdehydes by the Erlenmeyer synthesis. Such bis(oxazolones) react with a,co-diamines to provide a convenient approach to macrolactams.Tandem Erlenmeyer condensation-macrolactamization (TECM) has been used to prepare analogues of naturally occurring, biologically active cyclic peptides such as bastadin-5. 

This method of amide synthesis has been applied to the construction of natural amide alkaloids and macrolactam alkaloids. Diamide (612) was prepared from the corresponding diacid (611) and then reacted with spermide to give a mixture of codonocarpine (613) and its isomer (614 Scheme 136). 

Cycloamidation has been used extensively to prepare 17-membered cycloisodityrosines. The acyclic biaryl ether precursors were prepared by methods including the Ullmann reaction 2-5 and nucleophilic aromatic substitution (SNAr)J6 7 Since these methods have all been used intramolecularly in cyclization reactions, they will be discussed in Sections 9.5.3 and 9.5.4. Evans and co-workers employed the pentafluorophenyl ester method of macrolactamization 8] to prepare 11, an intermediate in their total synthesis of OF4949-III (7) (Scheme 2)J3 In this case, the acidic removal of a Boc group was employed to release the cyclization substrate, although hydrogenolysis of a Z group is also effective 3 ... 

Macrolactamization has limitations. All macrolactamization methods studied to date are ineffective at forming 14-membered cycloisodityrosines of the type found in deoxy-bouvardin (2) and RA-VII (3).[1° In addition, macrolactamization was not successful at preparing 16-membered rings that are structurally similar to cycloisodityrosines, such as the type found in the vancomycin family of glycopeptide antibiotics.[11 12 ... 

J. A. Macrolactamization via Pd Jt-allyl alkylation. Preparation of CGS25155 a 10-mem-bered lactam neutral endopeptidase 24.11 inhibitor. J. Org. Chem. 1995, 60, 6595-6598. Bonnet, B. Pie, G. Duhamel, L. Competition between metalation and halogen—lithium exchange in halovinylic acetals. Synlett 1996, 221-224. 

RCM has also been used as the final step in a preparation of macrolactams as cyclic peptidomimetics (104), with simultaneous release from a Merrifield resin (Scheme 23, cyclative cleavage) [222]. 

Macrolactamization Carboxylic esters containing polyamine units undergo cyclization facilitated by preorganization with Sb(OEt)j. Based on the ready preparation of a phenyl-substituted 17-membered lactam by this method in 90% yield, synthesis of several spermine alkaloids (verbacine, verbaskine, and verbascenine) is achieved in a straightforward manner. 

The catalytic properties of DABCO (or other tertiary amines) attain preparative significance in the intramolecular version of the addition of a protic, nucleophilic group to an activated dieneketene to produce macrolides or macrolactams by photolactonization or photolactamization, respectively. 

In later work, Helquist and co-workers" evaluated much of their overall synthetic strategy to 1226 in a model smdy. Cleavage of the silyl ether in 1234 and esterification of the resulting alcohol with a protected D-alanine furnished 1235 in excellent yield (Scheme 1.314). The requisite 4-oxazolecarboxylic acid, 1237 was readily prepared in two steps from 1236 and 957. After cleavage of the Boc group, 1235 was coupled with 1237, followed by Swern oxidation, to produce the advanced model target 1238 in 45% overall yield. The authors noted that the experimental conditions to prepare the appropriate protected precursor of 1226 and subsequent macrolactamization were in progress. 

C44H69NO12, Mr 804.04, prisms, mp. 127-129°C, [ajj, -84.4° (CHCI3), a macrolactam lactone produced by Streptomyces tsukubaensis, in which a long-chain hy-droxycarboxylic acid is cyclized with L- pipecoUc acid as bridging unit. FK-506 is structurally related to rapamycin and has been prepared synthetically. It exhibits immunosuppressive activity by suppression of cell-mediated and humoral immune responses. It has been available in Japan since 1993, in Europe and USA since 1996 under the name Prograf tacrolimus) for use in transplantation medicine to suppress rejection reactions. FK-506 is also effective in the treatment of autoimmune diseases, e. g., multiple sclerosis, psoriasis, or rheumatoid arthritis. 

The macrolactam 13.1.9 was prepared by Botta and Corelli and their collaborators, based on the observation that an analog lacking the taxol side chain had moderate antiproliferative activity 419). Regrettably 13.1.9, with the taxol side chain in place, did not show any enhanced activity. 

The synthesis of MK-7009 based on a through process via Heck reaction-hydrogenation-macrolactamization was next explored (Scheme 4) [14]. Two key chiral building blocks were readily prepared from commercially available... 

The macrolactamization strategy for the closure of the 14-membered D ring, previously developed from model structures, was applied to the dia-zatricychc acid 96 to afford tetracyclic lactam 97. Acid 96, which already incorporates the required functionalized 11-carbon chain at C-9, was prepared in four steps from the enantiopure alcohol 64 oxidation of the C-3... 

Ill was prepared by condensation of ethylbromopyruvate with thioamide 110. Utilizing these oxazole and thiazole derivatives, sequential couplings of 109 and 111 and then 112 and 113 with EDCI-N-hydroxybenzotriazole (HOBt) (EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) in basic medium afforded the linear precursor 114. Deprotection followed by macrolactamization with FDPP/DIPEA afforded dendroamide A 106 in 91% yield. 

Schiff base 1 with 5-iodo-2-methoxybenzyl bromide and CsOH H2O under the influence of PTC 1 and subsequent acid hydrolysis provided the amino acid hydrochloride 18 in 86% yield with 96% ee. Similar to Lepine and Zhu s strategy, the synthesis diverged at this point, and two substituted phenylalanine derivatives 19 and 20 were prepared. Then, the boronate 19 and the free iode acid 20 were coupled to give the biaryl acid 21 without epimerization. After derivatization of 21 to dipeptide 22, ring closure to the macrolactam 23 was achieved using HATU/HOAt" under the pseudo—high-dUution condition. Deprotection of all the functional groups and reduction of the azide moiety furnished 11. 

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