Antibiotics thienamycin

Ketene has also been used on a large scale for C-acetylation in the synthesis of the carbapenem antibiotic thienamycin [59995-64-1] (86,87). 

Table 4.29 summarizes the metrics for 4 plans to the antibiotic thienamycin and Figure 4.62 shows the corresponding synthesis map with starting materials used. The two Melillo and Reider variants by Merck co-workers are the better performers however each plan has certain attributes that are not found in the other. The slightly shorter Reider plan has a higher overall reaction yield though it has a similar atom economy and overall kernel RME to the Melillo plan. Further optimization would be required to result in all optimum metrics occurring in the same plan. 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

The medicinally important )3-lactam antibiotic thienamycin (34) has stimulated several investigations into the application of the aldol reaction for the introduction of the hydroxyethyl moiety with the indicated Cg and Cg stereochemistry (29,30). Low-temperature enolization (LDA, THF) of either 35 (29a,b) or 36 (30) and subsequent condensation with excess acetaldehyde afforded the illustrated kinetic aldol adducts (eqs. [22] and [23]). In both examples the modest levels of threo diastereoselection are comparable to related data for unhindered cyclic ketone lithium enolates. Related condensations on the penam nucleus have also been reported (31). 

Other P-lactam antibiotics have revolutionized our understanding of the structure-activity relationships in this large group of antibiotics. Thienamycin (9.53), discovered in 1976, is a broad-spectrum antibiotic of high activity. It is lactamase resistant because of its hydroxyethyl side chain but is not absorbed orally as it is highly polar. Unfortunately,... 

This method has been used to prepare the antibiotic thienamycin. The magnesium enolate of the /3-lactam was prepared from the 6-iodo derivative in THF (equation 9/ . 

The formal total synthesis of the novel /3-lactam antibiotic thienamycin has been accomplished from an isoxazoline derivative generated by [3 + 2] dipolar cycloaddition <79H(l2)l 183). Reaction of the nitrile oxide derived from 3-nitropropanal dimethyl acetal with methyl crotonate gave the isoxazoline (477) regio- and stereo-selectively. The isoxazoline was converted to amino ester (478) by hydrogenation and then to /3-lactam (479) by ester saponification and ring closure with DCC. Treatment of (479) with p-nitrobenzyl chloroformate and reaction of the derived acetal (480) with excess N-p-nitrobenzyloxycar-bonylcysteamine gave thioacetal (481), a compound which has previously been converted into ( )-(8S )-thienamycin (Scheme 106). 

A formal total synthesis of the early carbapenem antibiotics thienamycin 217 and PS-5 218 from an acyclic amino acid derivative has been reported <1996JOC2413>. For a cycloaddition process from acyclic compounds, see Section... 

Trimethylsilyl-l,3-dithianes can also serve as masked carboxyl groups. The principle is exemplified by the transformations shown in Scheme 2.124 that form part of a synthesis of the [Uactam antibiotic Thienamycin.252... 

The original Lonza synthesis [1, 2] of (d)-(+)-biotin 1 (outlined in Fig. 1) was designed around the critical diastereoselective hydrogenation of the tetrasubstituted double bond in imidazolinone 2 to the desired 3aS,6aR isomer 3. This strategy was a natural consequence of the experience gained with an analogous diastereoselective hydrogenation in the synthesis of an intermediate for the Merck antibiotic thienamycine (see Fig. 2). 

This compound was used in an asymmetric synthesis25 of the antibiotic thienamycin 138. The A-allyl group was removed with Pd(0) catalysis to give 134 and the /-butyl ester hydrolysed to give the redrawn acid 135. Cyclisation by the pyridyldisulhde reagent gave the 3-lactam core 137 of the antibiotic 138. 

As a step in the synthesis of a higher homologue of the antibiotic thienamycin, the closure of the pyridine ring is effected by warming the diazo ester (793) with rhodium(II) acetate (review of rhodium-catalysed reactions [3928]) the product (79.6, R = H) is more easily isolated and purified as its O-tosyl derivative (79.6, R = Ts). Intramolecular homolytk cyclization (the Pschorr reaction) of the diazonium salt of N-methylbenzanilide gives moderate yields which are comparable with those given by the pyrolytic cyclization of the 2-iodo analogue (see Chapter 90, Section II.2 [2303]). 

R = SCH2CH2OCONH2, X = Na) [94392-35-5] (22) have been documented. Similady, synthesis of the carhapenem antibiotic thienamycin [59995-64-1]... 

For some diazo transfer reactions, a more lipophilic azide than mesyl or 4-toluenesulfonyl azide, is preferred. This is the case, for instance, in the Merck process for the synthesis of the )ff-lactam antibiotic thienamycin (Lx)racarbef), in which benzenesulfonyl azide with an dodecyl substitutent on the benzene ring is used (Salzmann et al., 1980 Reider and Grabowski, 1982 Bodurow et al., 1989 Reider, 1993). We will discuss the chemistry of the Merck process in Section 8.7. 

Methylcorrinoids are competent for the efficient methylation of alkyl radicals. Thermolysis of 2 -bis(ethoxycarbonyl)propylcobalamin and methylcobalamin at 70 °C led to formation of cob(II)alamin and the organic products 2-ethyl-2-methylmalonic acid diethyl ester and 2,2-dimethylmalonic acid diethyl ester. The former product was generated with quantitative deuterium incorporation from CDsCobjllljalamin. The proposed mechanism involves homolytic substitution on methylcob(III)alamin by the 2 -bis(ethoxycarbonyl)propyl radical, resulting in net methyl-radical abstraction, a process calculated to be highly exothermic (A7/ -201 kJmoK ). The stereochemical course of the reaction should result in net inversion at the methyl carbon, although this has not been demonstrated. The reaction may serve as a precedent for several biosynthetic methylations, such as the antibiotic thienamycin synthesis. ... 

Insertion of carbenes into other bonds, particularly O—H and N—H bonds, has found worthwhile application in organic synthesis. Both inter- and intramolecular reactions are possible to give ethers, amines or amides. Intramolecular O—H insertion of the carbene, generated from the diazoketone 105, gave rise to the seven-membered cycUc ether 106 (4.84). In a synthesis of the -lactam antibiotic thienamycin, intramolecular N—H insertion of the carbene, formed from the diazoketone 107, was a key step to give the -lactam 108 (4.85). 

A new antibiotic, thienamycin (107a), has been isolated from the culture of... 

The generality of this method is indicated by its recent application in the synthesis of various antibiotics (thienamycin, epithienamy-cin, antibiotics PS-5 and PS-6 333, clavulanic acid,. ..) [83-84]. These new 3-lactam antibiotics display an exceptionally potent and broad-spectrum antibacterial activity against Gram-positive bacteria, including 3-lactamase-producing organisms. 

Full details of the synthesis of the B-lactam antibiotic (+)-thienamycin (255), which uses the reaction between the n-allyltri-carbonyliron lactone complex (261) and benzylamine, leading to the... 

The discovery of a new type of P-lactam antibiotic, thienamycin (7), was reported in 1976 [6]. However, the molecule itself is chemically unstable. Derivatising the amino group in the cystamine side chain to a less nucleophilic species increases the stability of the molecule by preventing intermolecular aminolysis of the azetidinone nucleus. 

Trapping by nucleophiles such as alcohols, which can also be drawn as insertion into the O-H bond, is a useful process. Cyclic ethers can be formed under very mild conditions (Scheme 8.136). Similarly, amines and other nitrogen derivatives can be employed to trap the carbene, most notably in the commercial synthesis of the antibiotic thienamycin in which a five-membered ring is annulated onto an existing p-lactam 8.507 (Scheme 8.137). °... 

Metal-catalysed decompositions of diazo-esters to carbenoid intermediates are well known, and commonly used in synthesis. A recent application to the total synthesis of the important antibiotic (+)-thienamycin is impressive in that formation of the highly strained bicyclic jS-lactam was achieved in essentially quantitative yield by treatment of (7) with a catalytic amount of rhodium(ll) acetate in benzene at 80 °C (Scheme 24). Further elaboration of the ketonic product afforded the natural compound. " ... 

Reaction of ferralactones with amines provides ferralactams. This method has been used for the synthesis of the lactam antibiotic ( )-thienamycin, for example. ... 

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