Bromoesters, synthesis

Synthesis The CO2H group spells trouble. We would certainly have to use an ester, but the a-bromoester is too reactive to use with an acetylene. Also there is a danger that the double bond in A will move into conjugation. We can get round all these problems with an epoxide and then oxidise at the end ... 

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

Of interest is a recent report of a rapid synthesis of efaroxin (51), a potent, selective O2 adrenoceptor antagonist, using Darzens Reaction. Accordingly, a-bromoester 48 was condensed with aldehyde 47. The glycidic ester (49) was then hydrogenated to reduce the more labile epoxide bond to give alcohol 50. Subsequent standard transformations subsequently lead to a completed 4-step synthesis of efaroxin. o... 

This procedure has been applied successfully to the synthesis of other a-nitroesters from a-bromoesters,3 as listed below ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate. 

Catalytic one-pot procedure. Since in the described teUuronium ylide olefmation tellurox-ide is formed as a by-product, and the telluroxide is susceptible to reduction by triphenyl phosphite, a catalytic procedure can be employed, providing a practical one-pot synthesis of a, -unsaturated esters and ketones (method E). By this procedure, a catalytic amount of n-dibutyl telluride reacts with the a-bromoester or a-bromoketone, and the formed tel-luronium salt is converted in situ under phase transfer conditions (solid KjCOj/trace HjO) into the ylide, which reacts in turn with the aldehyde, giving the olefin. Since the reaction is performed in the presence of triphenyl phosphite, the formed dibutyl telluroxide is reduced back to the dibutyl telluride, which is then recycled. 

Peterson olefination chemistry based upon tert-butyl fluoroacetate, generated in situ from the corresponding bromoester, has also been used in the synthesis of peptide isosteres [ 176,177]. Equation (58) shows the crucial early steps in the synthesis of an inhibitor of Dipeptidyl Peptidase IV. 

White et al. developed a stereospecific synthesis of Z-olefins, including isotretinoin [84]. Thus, isotretinoin was obtained by a Reformatsky reaction of p-cyclocitral with the C5 bromoester, followed by DIBAL-H lactone reduction, lactol ring opening, selective olefin bond formation with ethyl 4-diethoxyphosphoryl-3-methyl-2-butenoate and further saponification, Fig. (46). 

TV-Hydroxyglycine was obtained in 1896 by acidolysis of the nitrone resulting from the condensation of awd-benzaldoxime 17 with chloroacetic acid 22 N-Alkylation of 17 with a-bromoesters was extended much later to the synthesis of various TV-hydroxyamino acids 23,24 It is notable that syn-benzaldoxime is O-alkylated under the same conditions 25 As substitution of a-bromoacids proceeds with inversion of configuration, Liberek and Palacz 26 prepared H-D-(OH)Phe-OH from (.S )-c/.-bromo-p-phenylpropanoic acid, obtained by HN02 deamination of L-Phe in the presence of KBr. Treatment of nitrone 19 with an TV-hydrox-ylamine salt yields the corresponding TV-hydroxyamino ester 20 (Scheme 5) 24,27 ... 

For the application of this method in the enantioselective total synthesis of heliannuols D and A, see <2000J(P1)1807>. An isomeric mixture of dioxepane 108 was cleaved with iV-bromosuccinimide to give bromoester 109 (Scheme 26) <2003BMC2739>. For the preparation of 108, see Section 13.11.9.2. Ring opening of 109 occurred regioselectively on the least hindered carbon. 

The synthesis of ethyl 2-bromopropanoate (Expt 5.150) illustrates the preparation of an acyl chloride and its ready bromination in the a-position in the presence of red phosphorus. The resulting bromoacyl chloride is converted into the a-bromoester on reaction with an alcohol. 

The formation of the acyl chloride with SOCl2 and the conversion of the a-bromoacyl chloride into the bromoester with MeOH are simple nucleophilic substitutions at the carbonyl group, just like the synthesis of esters from acyl chlorides in Chapter 12. The intermediate stage, the bromination of the very easily enolized acyl chloride, is a typical enol bromination. 

The dehydration product from this aldol product is best made directly by one of the Wlttig variants we discussed earlier. The same bromoester is of course the starting material for the ytid synthesis. 

Synthesis of the synthetically important carbethoxymethylenetriphenylphospho-ranes (Ph3P=CHC02Et and Ph3P=CRC02Et) involves treatment of a-bromoesters... 

The first total synthesis of a sterigmatocystin type structure was reported by Roberts151. The furobenzofuran section73 used in the constmction was the same piece previously encountered95,117,142 in the synthesis of aflatoxin B2 (5). Ullman type coupling152 (pyridine/cuprous chloride) with bromoester (117), and subsequent hydrolysis, gave the diphenyl ether (118). Intramolecular cyclization to form... 

A difficult Stille reaction of bromoester 85 with a stannylpyridine gave the tri-Me ester of enf-thallusin 86 in 54-92% yield, using stoichiometric Pd(PPh3)4.i°9 The use of Cul and water as additives was crucial for the success of this coupling for the synthesis of enf-thallusin 87 (Scheme 5.4.16). 

Bromoesters are valuable intermediates in organic synthesis. They could be employed as building blocks in organic, bioorganic, medicinal, and material chemistry. Two kinds of ionic hquids (2) and (3) in Fig. 12.62 have been directly synthesized from L-prohnol (1) by a simple and convenient method in excellent yields [39]. 

Bao W, Wang Z (2006) An effective synthesis of bromoesters from aromatic aldehydes using tribromide ionic liquid based on f prolinol as reagent and reaction medium under mild conditions. Green Chem 8 1028-1033... 

By the employment of other bromides O-desmethylmycophenolic acid was obtained. Thus, the C7 bromoester methyl 6-bromo-4-methylhex-4-enoate, BrCH2CH=C(Me)CH2CH2C02Me, was prepared from tritylgeraniol which was first converted in several steps to the terminal diol, Malaprade oxidation of which furnished 4-methy-6-trityloxylhex-4-enal. Mild oxidation to, the corresponding acid with silver oxide, formation of the methyl ester with diazomethane and derivation of the required allylic bromide by treatment of the alcohol, liberated from the trityl derivative, with carbon tetrabromide containing triphenylphosphine completed the synthesis. 

In this context the Reformatsky type reaction of Gilman and Specter between a-bromoesters and imines, the lithium enolate-imine condensation and the use of silyl ketene acetals, boron enolates and tin(II) enolates have been successfully utilized in the synthesis of appropriately substituted P-lactams for carbapenem synthesis. 

---