Eschenmoser’s base

Enzymatic hydrolysis of penam 158a with porcine liver esterase (PLE) followed by treatment with Eschenmoser s base (78HCA2851 82T2659) afforded salt 162, which was treated with potassium 2-ethylhexanoate in... 

The half ester of (E -muconic acid (456) was synthesized in three steps as follows Starting from catechol (457), oxidative cleavage with a peracid led to the (Z,Z)-diacid 458, which was monoprotected via lactonization to provide compound 459, and by treatment with Eschenmoser s base the desired monoester 460 was obtained (Scheme 8.15). 

Scheme 8.15 Preparation of half ester 460. Reagents and conditions a) peracid oxidation b) Me3Si(CH2>20H, DCC, DMAP, CH2CI2/DMF, 80% c) Eschenmoser s base, 75%...

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

Further selectivity is needed if the enol component is an unsymmetrical ketone. Some selectivity can be achieved by choice of acid, favouring the more substituted enol, or base, favouring kinetic enolate formation on the less substituted side. The acid 32 was used at a very early stage of Woodward and Eschenmoser s synthesis5 of vitamin Bi2. Standard a -unsaturated carbonyl disconnection revealed unsymmetrical ketone 33 and unenolisable but very electrophilic glyoxylic acid 34 available as its hydrate. In acid solution reaction occurred very selectively indeed. 

Subsequently, the benzotriazole-based equivalent of Eschenmoser s salt, 25, was prepared in our laboratory. Curiously, we found this substrate not only to be considerably less reactive than 23 or 24, but also less reactive than the Eschenmoser s salt/benzotriazole system, suggesting that 25 is not formed in situ by mixing these two reagents. 

Af-Arylsulfonyl-S-ethenyl-S-phenylsulfoximines have been prepared from N-arylsulfonyl-S-methyl-S-phenylsulfoximines by deprotonation and then treatment with Eschenmoser s salt. Treatment of the resulting tertiary amine with an excess of methyl iodide followed by base treatment gave 212a,b in 26-42% overall yields.104,105 Bromination of 212a,b and then elimination with triethylamine gave the a-bromo derivatives 213a,b in 26—32% yields.104... 

A(, -Dimethyl(methylene)iminium salts have been the most widely used class of preformed iminium salts, mainly due to their applications in the synthesis of a,p-unsaturated carbonyl compounds, normally accomplished by subjecting the /V, -dimethyl Mannich base to quatemarization followed by base-induced elimination. Table 3 outlines various counterion forms of /V, -dimethyl(methylene)iminium salts that have been used in Mannich reactions as well as their synthetic precursors. The crystalline iodide (30), known also as Eschenmoser s salt , has seen the most widespread use and is prepared by thermal fragmentation of (iodomethyl)trimethylammonium iodide or, more conveniently, by a variant of the... 

A different approach to a-methylenebutyrolactones is a further development of the chemistry of 2-silyloxycyclopropane carboxylates (393), which, when treated with the trifluoromethanesulphonate analogue of Eschenmoser s salt and a Lewis acid (TMSOTf), are converted into 8-amino-esters (394) and thence lactones (395) following borohydride reduction and elimination.33 Overall yields are reasonable for this multi-step approach. A carbanion based approach to monosubstituted lactones. (390) begins by metallation and regio-selective condensation of ketene dithioacetal (396) with an aldehyde. 

An alternative method for the formation of an a,(3-unsaturated carbonyl compound is the elimination of an initially formed Mannich product. The procedure is particularly effective for the formation of (3,(3-bis(unsubstituted) a, -unsaturated carbonyl compounds. The Mannich product 11 can be formed in the presence of a secondary amine and a non-enolizable aldehyde such as formaldehyde (2.12). The Mannich reaction is a useful carbon-carbon bond-forming reaction and the products have found application in the synthesis of, in particular, alkaloid ring systems. The Mannich product may eliminate under the reaction conditions, or can be alkylated to form the quaternary ammonium salt in order to induce elimination. A convenient variation of this method is the use of Eschenmoser s salt, H2C=NMe2 X. For example, Nicolaou s synthesis of hemibrevetoxin B used this salt in order to introduce the required methylene unit a- to the aldehyde 12 (2.13). The same transformation with the corresponding methyl ester, which is less acidic, requires prior enolization with a strong base (e.g. NaN(SiMe3)2) and subsequent quatemization of the tertiary amine with iodomethane and elimination using DBU. 

C-10 pyrrole Mannich bases of artemisinin have been aceessed as potential anti-malarial agents. Treatment of dihydroartemisinin with N-methylpyrrole in the presence of a Lewis acid gave rise to the C-10 pyrrole analogue. The subsequent Mannich reaction used preformed Eschenmoser s salt to afford the dimethylaminopyrrole, which was an anti-malarial with enhanced water solubility. 

Ring B pyrrole aldehyde (78) and ring C lactam (79) form under base induced condensation and subsequent introduction of sulfur the bicyclic BC thiolactam (80). This bicyclic lactam was coupled by a modification of Eschenmoser s sulfide contraction method 58) with the monocyclic chiral D building block (81) to yield after ester cleavage and complexation with nickel (II) the tricyclic intermediate (82). After hydrogenolytic cleavage of the benzylester in (82) the crude carboxylic acid formed with the ring A pyrrole aldehyde (83) the linear tetrapyrrole... 

A procedure in which the iminium salt shown, A, N-dimethyl(methylene) ammonium trifluoroacetate, is isolated and added separately to an enolate ion allows Mannich bases to be prepared by routes other than those involving acidic media. This procedure is exemplified by entry 4. N,iV-Dimethyl(methylene) ammonium iodide is commercially available as Eschenmoser s salt and is sufficiently electrophilic so as to react directly with enol silyl ethers in neutral media. Ketone enolates have been converted to Mannich bases with Eschen-moser s salt (entry 5). 

The reaction of l-(2-isocyanoaryl)pyrroles with Eschenmoser s salt 147 also goes smoothly with the formation of dimethyl(pyrrolo[l,2-tz]quinoxalin-4-ylmethyl)ammonium iodides 148 (Scheme 3.44), which after treatment with an aqueous solution of NaHCOs readily give quantitative yields of the free bases. In the case of the reactions of l-(2-isocyanophenyl)pyrroles 137a, b with other salts of the iminium type 149 and 151, obtained from secondary amines and aldehydes in the presence of MesSiCl/Nal/EtsN, it was shown that such a synthesis of 4-(l-dialk yl-aminoalkyl)pyrrolo[l,2-ti]quinoxalines 150, 152, and 153 is universal (Kobayashi et al. 2001b). 

A third application of the chenmoser reaction in the synthesis of racemic peihydrogephyrotoxin (76) is based on an extension of the chemistry developed during the pumiliotoxin C synthesis. " Beginning with the bicyclic thiolactam (73), the sulfide-contraction reaction was used to append to the decahydro-isoquinoline a functionalized five-carbon side chain that would later be cyclized and become the a-hy-droxyethylpyrrolidine portion of the molecule. Alkylation of the thiolactam (73) with methyl S-bromolevulinate followed by treatment with the Eschenmoser dual base-thiophile reagent (28) produced the vinylogous carbamate (74) in 81% yield from the starting thiolactam (73 Scheme 17). Reduction of the vinylogous amide (74), followed by equilibration of the amino ketones in the presence of... 

This case history presents only a simple account of one of R.B. Woodward s adventures based on ingenious undentanding of structural features and experimental findings described in the literature. The hydrogenation of porphyrins is still one of the most active subjects in heterocyclic natural products chemistry, and the interested reader may find some modem developments in the publications of A. Eschenmoser (C.Angst, 1980 J.E. Johansen, 1980). 

William Fraser was born in Hamilton. He studied at the other of the two local universities, Strathclyde, where he obtained a first class B.Sc. honors degree in 1986 and Ph.D. in 1989 under the direction of Professor Colin J. Suckling and Professor Hamish C. S. Wood. He was awarded a Royal Society European Exchange Postdoctoral Fellowship and worked in the laboratories of Professor Albert Eschenmoser at the ETH, Zurich. In 1991, he took up his present position as lecturer in medicinal chemistry at Aston University, Birmingham. His scientific interests include nucleoside and nucleic acid chemistry, solid-supported, synthesis, and study of base-modified antigene oligonucleotides targeted to DNA. 

The achiral triene chain of (c//-frans-)-3-demethyl-famesic ester as well as its (6-cir-)-isomer cyclize in the presence of acids to give the decalol derivative with four chiral centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Eschenmoser, 1959 W.S. Johnson, 1968,1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric add catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such adds activate oxygen functions selectively (K.B. Sharpless, 1970). 

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