Lactams, macrocyclic synthesis

Lactam-based synthesis of complex nucleoside antibiotics and macrocyclic peptides 00PAC1763. 

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

Another example of macrocyclic RCM with a diene-ene was disclosed in 2000 by Meyers and coworkers in the first total synthesis of griseoviridin (223) [ 107]. Griseoviridin is a highly complex member of the family of streptogramin antibiotics, featuring a 23-membered unsaturated bis-lactam core incorporat-... 

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

Rzasa, R. M., Shea, H. A., and Romo, D. (1998). Total synthesis of the novel, immunosuppressive agent (-)-Pateamine A from Mycale sp. Employing a b-lactam-based macrocyclization. J. Am. Chem. Soc. 120, 591—592. 

The stereoselective synthesis of bis-(3-lactams grafted macrocycles has been described [109]. Macrocyclic imine and phenoxy acetyl chloride in the presence of triethylamine produced a diastereomeric mixture of cis macrocyclic bis-(3-lac-tams (Scheme 36) by the Staudinger reaction. 

Taking advantage of the same concept in an intramolecular variant, Romo has documented [78] the synthesis of (—)-panteamine A, Fig. 3, in which a (3-lactam-based macrocyclization is the crucial step to construct the (3-amino macrolactone 33. 

An attractive application of this strategy can be visualized in the synthesis of the tripeptide segment 136, Scheme 44, present in the macrocyclic antibiotic lysobactin 40, Fig. 4. It was reported that p-lactams 131 and 132, upon ring expansion under the NaOCl-TEMPO conditions indicated above, afford NCAs 133 and 134, respectively. Coupling of the NCA 133 with (S)-LeuOMe results in the formation of 135 which upon exposure to 134 provides tripeptide 136 in high overall yield [122],... 

The application of ring closing metathesis for the synthesis of Friedinger lactams was studied by Piscopio et al.4S (Fig. 15), as well as other groups,46 while the formation of macrocycles was accomplished by Blechert s group.47... 

As can be seen from Scheme 2.1, under appropriate equilibrating conditions, the macrocycle will be produced as the thermodynamic product. This dearly appears in the following example (Scheme 2.2). During the synthesis of the 14-membered lactam fluvirudn Bj by Hoveyda and coworkers from diene 1, only the dimer 2 resulting from the head-to-head coupling between the less substituted double bond... 

Immunosuppressant (-)-FK-S06 (2). This 23-membered lactone-lactam resembles cyclosporin A, a macrocyclic polypeptide, in that they both inhibit immune responses to transplantation, but FK-506 seems to be more active. The total synthesis of (- )-FK-506 has been achieved by a process research group at Merck.1 The cyclization to a carboxamide was carried out with Mukaiyama s reagent (1) under high dilution in 81% yield. The most unusual feature of 2 is the presence of a three-keto sequence at C8, C9, and C,(l (hemiketal). 

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