Of -thienamycin

In the case of thienamycin (Fig. lb) the absolute stereochemistry at C-5 was unambiguously deterrnined from the ene-lactam (16). The resultant (R)-aspartic acid (17) demonstrated that the absolute stereochemistry at C-5 of thienamycin is (R), corresponding to that found in the C-5 position of both penicillins and cephalosporins. Confirmation of the stereochemical assignments in both thienamycin (2) and the olivanic acid MM 13902 (3, n = 0) has been confirmed by x-ray crystallography (19,21,22). The stmctural determination of the nonsulfated derivatives from S. olivaceus (23), PS-5 (5) (5), the carpetimycins (6), and the asparenomycins (7) followed a similar pattern. 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study stmcture—activity relationships (24). The most interesting class of A/-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while greatiy increasing the chemical stabiUty. Thus /V-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C 2H yN204S, (25) was chosen for clinical evaluation and... 

Formal syntheses of thienamycin (2) from precursors such as carbohydrates (43—45), amino acids (46,47), isoxa2ohdines (48), and tricarbonyliron lactam complexes (49) have also been reported. Many other methods for carbapenem synthesis have been widely reviewed (10,50—52). 

There are several examples of intramolecular reactions of monocyclic /3-lactams with carbenes or carbenoids most of these involve formation of olivanic acid or clavulanic acid derivatives. Thus treatment of the diazo compound (106) with rhodium(II) acetate in benzene under reflux gives (107), an intermediate in the synthesis of thienamycin (80H(14)1305, 80TL2783). 

The strained bicyclic carbapenem framework of thienamycin is the host of three contiguous stereocenters and several heteroatoms (Scheme 1). Removal of the cysteamine side chain affixed to C-2 furnishes /J-keto ester 2 as a possible precursor. The intermolecular attack upon the keto function in 2 by a suitable thiol nucleophile could result in the formation of the natural product after dehydration of the initial tetrahedral adduct. In a most interesting and productive retrosynthetic maneuver, intermediate 2 could be traced in one step to a-diazo keto ester 4. It is important to recognize that diazo compounds, such as 4, are viable precursors to electron-deficient carbenes. In the synthetic direction, transition metal catalyzed decomposition of diazo keto ester 4 could conceivably furnish electron-deficient carbene 3 the intermediacy of 3 is expected to be brief, for it should readily insert into the proximal N-H bond to... 

To complete the synthesis of thienamycin, it only remains to cleave the carbamate and ester functions in 23. Catalytic hydrogenation of 23 accomplishes both of these objectives, and furnishes (+)-thienamycin (1). Synthetic (+)-thienamycin, prepared in this manner, was identical in all respects with natural thienamycin. 

In 1980, a Merck group disclosed the results of a model study which amply demonstrated the efficiency with which the strained bicyclic ring system of thienamycin can be constructed by the carbene insertion cyclization strategy.12 Armed with this important precedent, Merck s process division developed and reported, in the same year, an alternative route to carbene precursor 4.13 Although this alternative approach suffers from the fact that it provides key intermediate 4, and ultimately thienamycin, in racemic form, it is very practical and is amenable to commercial scale production. The details of this interesting route are presented in Schemes 4-6. 

For additional syntheses of thienamycin in both optically active and racemic forms, see (a) Ponsford,... 

Figure 4.62 Synthesis map showing starting materials used for the synthesis of thienamycin.

Reider, P.J. Sc Grabowski, E.J.J. (1982) Total Synthesis of Thienamycin A New Approach from Aspartic Acid. Tetrahedron Letters, 23, 2293-2296. 

Recently Ikegami used the thiol addition reaction in the preparation of optically pure 4-phenylthioazetidin-2-one, the starting material for an elegant ( + )-thienamycin synthesis (58). When 4-phenylsulfonylazetidin-2-one was treated with cinchonidine and thiophenol, the intermediate azetinone underwent a thiol addition reaction and the 4-phenylthioazetidin-2-one was obtained in 54% optical and 96% chemical yield (eq. [13]). Recrystallization of the optically active aze-tidinone allows isolation of the pure enantiomer from the mother liquor. The phenylthio group is eliminated later in the synthesis of thienamycin. 

Fig. 5.18. Base-catalyzed decomposition of imipenem (5.46) initiated by an intermolecular reaction between the ji-lactam and (iminomethyl)amino group. The reaction generates one molecule of thienamycin (5.45) [123].

H. Kropp, J. G. Sundelof, R. Hajdu, F. M. Kahan, Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase I , Antimi-crob. Agents Chemother. 1982, 22, 62-70. 

The discovery of thienamycin created great excitement it is a structurally novel P-lactam antibiotic of outstanding potency and has a remarkable spectrum of activity. It was the broadest spectrum antibiotic of its day. There was, however, a major problem thienamycin is not a stable molecule. Merck scientists were faced with the touchy problem of modifying thienamycin chemically to create a stable molecule while maintaining all its remarkable properties. Following considerable effort, they... 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

This reaction has since been used in a synthesis16 of (+)-thienamycin (4), a potent antibiotic from Streptomyces cattlaya. Thus cyclization of 1 with CHjMgBr resulted mainly in the desired frans-azetidinone 2. Cyclization with DCC favors formation of the undesired cfs-isomer (3). 

This insertion reaction has provided a stereocontrolled synthesis of ( + > thienamycin (3), an important carbapenem antibiotic.5... 

Dehydrobromination. Dehydrobromination with AgF-pyridine was first reported some time ago.1 It has recently proved to be the method of choice in a total synthesis of thienamycin, a carbapenem broad-spectrum antibiotic. I- or example, attempted dehydrobromination of 1 with DBU in DMSO resulted in elimination of HBr and also carbonate to give a mixture (2) of two ene lactams. The desired reaction was effected in 70% yield with AgF in pyridine.2... 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin have been prepared primarily to study structure-activity relationships. 

A synthetic approach that involves the [3.4] bond formation using a carbcnc insertion reaction has been highly successful and is illustrated by the enantioselective synthesis of (+-thienamycin) starting from L-aspaidc acid. C4H7NO4. 

Ratcliffe, R.W and G. Albers-Schonberg The Chemistry of Thienamycin and Other Carbapenem Antibiotics" and I. Ernest. The Penems" in R.B. Morin and M. Gorman, cds.. Chemistry and Biology of ft -Iatcrum Antibiotics. Academic Press, New York, 1982. Chapts. 4 and 5... 

Pure (+)-2 was used for a fairly efficient synthesis of (+)-thienamycin. 

As early as 1977 Pracejus et al. investigated alkaloid-catalyzed addition of thiols to a-phthalimido acrylates, methylene azlactones, and nitroolefins [56a]. In the former approach, protected cysteine derivatives were obtained with up to 54% ee. Mukaiyama and Yamashita found that addition of thiophenol to diisopropyl mal-eate in the presence of cinchonine (10 mol%) proceeds in 95% yield and that the product, (S)-phenylthiosuccinate, was formed with 81% ee [56b]. The latter Michael adduct was used as starting material for preparation of (R)-(+)-3,4-epoxy-1-butanol. In the course of an asymmetric total synthesis of (+)-thienamycin Ike-gami et al. studied the substitution of the phenylsulfonyl substituent in the azetidi-none 69 by thiophenol in the presence of cinchonidine (Scheme 4.34) [56c]. This substitution probably proceeds via the azetinone 70. In this reaction the phenyl-thioazetidinone 71 was obtained in 96% yield and 54% ee. Upon crystallization, the optically pure substitution product 71 was obtained from the mother liquor... 

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