Bromohydrin epoxide synthesis

The successful implementation of this strategy involves the synthesis of a suitable trapping agent. Hence, trapping agent 130 was synthesized in the manner outlined in Scheme 29 via the cyclization of the bromohydrin epoxide 127 under similar conditions to those described by McDonald and co-workers [30]. 

The products of bromination in water are called bromohydrins. They can be treated with base, which deprotonates the alcohol. A rapid intramolecular Sjyj2 reaction follows bromide is expelled as a leaving group and an epoxide is formed. This can be a useful alternative synthesis of epoxides avoiding peroxy-acids. 

The conversion of a diol or bromohydrin to the corresponding epoxide is a well-known and useful method. Recently two methods have been reported that significantly add to this chemistry. A synthesis of a key component of the natural product neocarzinostatin has been reported <07OL45>. In this work, an allenyl zinc bromide was added to a propargylic ketone to provide a chlorohydrin stereoselectively. Treatment of the chlorohydrin with base provided the epoxide. 

In their synthesis of (+)-narciclasine 26, Elango and Yan performed a stereocontrolled epoxide formation via the bromohydrins 25. Following concomitant ring closure and N-piperonylation, treatment with catalytic SnCh affected intramolecular arene-epoxide coupling (Scheme 16) <2002JOC6954>. 

Transesterification can be used to cleave the acyl group from an ester to release the alcohol. The mildness of the reaction conditions enables chemoselective transformation. A siloxy group /S to a ketone group was not eliminated (Eq. 225) [524], and formation of an epoxide from the unprotected bromohydrin did not occur (Eq. 226) [525]. Similarly, in the synthesis of an avermectin derivative, delactonization was carried out by the titanium-based method as shown in Eq. (227) [526]. 

The addition of halogens and hydroxyls across double bonds leads to halohydrins, which are useful intermediates, especially for the synthesis of epoxides. Such additions are achieved by treatment of alkenes with N-bromoacetamide [1104] or iV-brontosuccinintide [746] in aqueous media and give products of anti addition. On heating with alkalies, bromohydrins... 

During the enantioselective total synthesis of (-)-coriolin, I. Kuwajima and co-workers used a Darzens-type reaction to construct the spiro epoxide moiety on the triquinane skeleton. Interestingly, the usual Darzens condensation where the a-bromoketone was condensed with paraformaldehyde yielded a bromohydrin in which the hydroxymethyl group was introduced from the concave face of the molecule. This bromohydrin upon treatment with DBU gave the undesired stereochemistry at C3 (found in 3-ep/-coriolin). To obtain the correct stereochemistry at C3, the substituents were introduced in a reverse manner. It was also necessary to enhance the reactivity of the enolate with potassium pinacolate by generating a labile potassium enolate in the presence of NIS. The in situ formed iodohydrin, then cyclized to the spiro epoxide having the desired stereochemistry at C3. 

Similar bromohydrin interconversions were demonstrated in sugar-based epoxide rearrangements. The unsaturated aldehydes formed in these reactions are useful for further elaboration, as shown in a recent synthesis of botryodiplodin. 

Stereoselectivity comes from a stereospecific syn or anti addition to an alkene of fixed and known geometry. These last reactions, applied to cyclohexene, lead to anti bromohydrin 14 while epoxidation occurs stereospecifically and syn. It doesn t matter which end of the epoxide 12 or bromonium ion 13 is attacked by the nucleophile anti addition occurs in both cases since inversion is demanded by the mechanism of the SN2 reaction. Cyclohexene must be Z but in open chain compounds syn addition to the -isomer would lead to the same diastereoisomer of the product as anti addition to the Z-isomer. In this chapter we explore more advanced versions of these reactions in which usually several types of selectivity will be combined and show how they are used in synthesis. 

For an example of epoxide formation from a bromohydrin, taken from a synthesis of (-)-coriolin, see Mizuno, H. Domon, K. Masuya, K. Tanino, K. Kuwajima, 1.1. Org. Chem., 1999, 64, 2648. 

Homochiral epoxides are versatile intermediates for the synthesis of a variety of natural products. The four-carbon bifiinctional chiron (i )-l- erNbutyldimethylsilyl-3,4-epoxybut-l-yne (228) is conveniently prepared from 141 as shown in Scheme 53. The conversion of 141 to chloride 225 followed by base-induced chloride elimination in liquid ammonia proceeds without any detectable epimerization (as determined by both hplc and nmr analysis of the corresponding Mosher ester) to provide the i -alcohol 226 in good yield. Subsequent silyl protection followed by treatment with boron tribromide results in a highly stereoselective bromination, together with simultaneous debenzylation to the bromohydrin 227, which under mild basic conditions is converted to epoxide 228. The optical purity of 228 (ee = 99%) demonstrates the high selectivity in this new bromination reaction [80,81]. 

One of the most potent frameworks for the synthesis of two contiguous stereochemically defined asymmetric centers is the chiral epoxy functionality. Prepared in molar-scale quantity from dimethyl L-tartrate (la), bromohydrin 860 is a shelf-storable solid that undergoes selective reduction at the a-hydroxy ester function with borane-dimethylsulfide complex in the presence of catalytic sodium borohydride to provide a 4 1 mixture of methyl (2S,3S)-2-bromo-3,4-dihydroxybutanoate (861) and methyl (2i, 3i )-3-bromo-2,4-dihydroxybutanoate (862). Without purification this mixture is treated with ert-butyldimethylsilylchloride and then exposed to sodium methoxide, which results in conversion to the single epoxide methyl (2i, 3iS)-4-( err-butyldimethylsilyloxy)-2,3-epoxybutanoate (863) in 95% yield and with 99% optical purity (Scheme 188). 

As outlined in Scheme 6, isovanillin (35) was converted to aryl iodide 36 via MOM-protection, protection of the aldehyde, and subsequent iodination. Hydrolysis of the acetal and Wittig olefination delivered phenol 37 after exposure of the intermediate aldehyde to methanolic hydrochloric acid. Epoxide 41, the coupling partner of phenol 37 in the key Tsuji-Trost-reaction, was synthesized from benzoic acid following a procedure developed by Fukuyama for the synthesis of strychnine [62]. Birch reduction of benzoic acid with subsequent isomerization of one double bond into conjugation was followed by esterification and bromohydrin formation (40). The ester was reduced and the bromohydrin was treated with base to provide the epoxide. Silylation concluded the preparation of epoxide 41, the coupling partner for iodide 37, and both fragments were reacted in the presence of palladium to attain iodide 38. 

Dihydropyridine 429 was next used for the synthesis of methyl glycoside of 5-amino-5-deoxy-DL-ido-hexopiperidonose (445). In the first step, 429 was reacted with N-bromosuccinimide to afford two bromoacetates (439 and 440). The first bromoacetate (429) was deacetylated to the bromohydrin 441. Reaction with silver oxide followed by acetylation gave a rearranged diacetate 442 (which was certainly preceded by an epoxide). The 1-0-acetyl group in 442 could be readily replaced by a methoxy group to form 443. C -hydroxylation of the... 

The P-bromohydrin was formed according to the procedure described by Zeng using epoxide 4 (55 mg, 0.15 mmol), MgBr2-THF (0.60 mL, 1.08 mmol, prepared in situ from Mg (88 mg, 3.60 mmol) and 1,2-dibromoethane (0.31 mL, 3.60 mmol) in THF (2.0 mL)). Reaction mixture was stirred at room temperature for 30 min, quenched with saturated NH4CI solution, extracted twice with EtOAc, dried over anhydrous Na2S04 and the solvent was removed in vacuo to yield 18 as a colourless oil (68 mg). Pure by crude H-NMR. Analytical data identical to attempted synthesis of 3a. 

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