Bromolactonizations

Synthesis of (A) started with the combination of 2,4,6-trimethylphenol and allyl bromide to give the or/Ao-allyl dienone. Acid-catalyzed rearrangement and oxidative bydroboration yielded the dienone with a propanol group in porlactone ring were irons in the product as expected (see p. 275). Treatment with aqueous potassium hydroxide gave the epoxy acid, which formed a crystalline salt with (R)-l-(or-naphthyl)ethylamine. This was recrystallized to constant rotation. 

The classic method for controlling stereochemistry is to perform reactions on cyclic substrates. A rather lengthy but nonetheless efficient example in the prostaglandin field uses bicyclic structures for this purpose. Bisacetic acid derivative S is available in five steps from Diels-Alder reaction of trans-piperylene and maleic anhydride followed by side-chain homologation. Bromolactonization locks the molecule as bicyclic intermediate Esterification, reductive dehalogen-... 

Herein we will show a new and simple synthetic method for (S)-4 using asymmetric bromolactonization which has been the most dependable method for the chiral a-a-disubstituted a-hydroxy acids (ref. 3). 

As shown in scheme 1, (S)-amide 2 (ref. 4) obtained from ethyl ester of (S)-proline, chiral auxiliary and 2-substituted-2-propenoic acids 1 are bromolactonized with N-bromosuccinimide (NBS)-DMF, followed by hydrolysis with 6N-HC1 to afford (S)-4. The results are summarized in Table 1. 

As seen in Table 1, (S)-4 are obtained in excellent chemical and optical yields by using the neutral and mild key reaction, the bromolactonization, followed by simple treatment with HCl. 

In view of the absolute configuration and their optical yields (88-96 %), it follows that the precursor of the (S)-4 should be 2a, which are formed highly diastereoselectively. It is likely that the predominant formation of 2a conforms to the mechanism of the bromolactonization, the S-trans transition state (ref. 3). 

To a solution of 2a (1.00 g, 5.46 mmol), (ref. 4) in 10 ml of DMF, a solution of NBS (1.95 g, 10.9 mmol) was added at 0°C and then for 24 hours at room temperature. It was diluted with 400 ml of EtOAc and partitioned. The EtOAc solution was washed with sat. NaHC03 solution (50 x 3 ml), and sat. NaCl solution (50 X 2 ml), and dried over anhyd. MgS04. Filtration and evaporation gave crude bromolactones to which 55 ml of 6N-HC1 was added. After the reaction mixture was refluxed for 24 hours, it was diluted with 55 ml of sat. NaCl solution and extracted with EtOAc (55 x 3 ml). The combined EtOAc solution was washed with... 

Because the reactive intermediate 1277 and methanesulfenyl chloride 1278 are electrophiles, they can react with olefins [72-75]. Thus d -steroids give rise to 6-)9-methylmercapto-zl" -steroids [74]. trans-6-Phenylcyclohex-3-ene-3-carboxyUc add 1291 reacts with DMSO/MesSiBr 16 to form, via 1292, the lactone 1293 in 87% yield, whereas attempted bromolactonization of 1291 affords only 59% 1294 [75] (Scheme 8.29). 

A facile synthesis of 49 was described as follows. When the bromolactone 34 reacted with hydrogen bromide in acetic acid, regioselective cleavage of... 

The absolute configuration of (—)-29 was established by X-ray crystal structure analysis of the bromolactone (89), which was prepared from (—)-29 by bromolactonization with hypobromous acid. It was found that ( )-29 belongs to the d series of carba-sugars, and hence, (+)-29 corresponds to the L series. - ... 

In general, cyclization can be expected in compounds having the potential for formation of five- or six-membered rings. In addition to the more typical bromination reagents, such as those listed in Table 4.2, the combination of trimethylsilyl bromide, a tertiary amine, and DMSO can effect bromolactonization. 

Enantiomerically pure tetrahydro-l//-pyrrolo[2, l -acrylamides derived from proline (see Section 11.11.7.4), are versatile intermediates for the synthesis of natural products or drugs. Compound 86a was submitted to debromination with Bu3SnH followed by ring opening in KOH and further reduction with BHj to give diol 89 that was then easily transformed into (A)-4-(2,2,4-trimethyl-l,3-dioxolan-4-yl)-lT>utanol 90, a key intermediate for )-frontalin, <2002TA155>,... 

A series of enantiomerically pure tetrahydro-l//-pyrrolo[2,l-c][l,4]oxazine-l,4(3//)-diones 86a-d have been prepared by bromolactonization of acrylamides derived from proline mediated by NBS (Equation 5). These compounds... 

A trans-acetoxy elimination was described (210) for the 2-bromodeoxyal-dono-1,4-lactone 33b, induced by NaHS03, to afford the butenolide 162a. However, the C-2 epimeric bromolactone 33a, undergoes a trans-fi-bromo-acetoxy elimination to produce (211) butenolide 162b. 

The bromolactonization product 470 was obtained by the reaction of y-monoalkyl-substituted allenoates 467 with NBS in H20 or Br2 at room temperature. Here the carbonyl oxygen served as an intramolecular nucleophile. The Z-isomer of the bro-mohydroxylation product was also formed in 4% yield (R Me, R2 = H) [211, 213, 214], The absence of the Z-isomer may be ascribed to the easy conversion of the E-isomer to butenolide 470. 

NBS is a source of Br+. It reacts with alkenes to give bromonium ions. Then both C-Br bonds need to be replaced by C-0 bonds by single inversions, since the trans stereochemistry of the double bond is retained in the epoxide. Under these acidic conditions the bromonium ion is opened intramolecularly by the acid carbonyl O, with inversion at one center loss of H+ gives a bromolactone. 

The hitherto preferred method for preparation of the butenolide is that of Price and Judge, which can be modified (by extraction of the bromolactone with methylene chloride and elimination of hydrogen bromide with triethylamine or preferably with diisopropylethyl amine in toluene at 70°C) to give routinely 60% or greater overall yield on a 6-mol scale. However, the large amount of... 

In the context of the synthesis of carbohydrate-based amphiphilic (alkylsulfanyl) polyols, Beaupere and co-workers explored the access to 5- and 6-alkylsulfanyl derivatives of pentono- and hexonolactones and their corresponding 1-(alkylsulfanyl) pentitol or l-(alkylsulfanyl)hexitol [38, 39]. Bromolactones 27 and 30 were treated... 

To summarize, crystalline l,4-dideoxy-l,4-imino-hexitols are readily prepared from 2,6-dibromo-2,6-dideoxy-hexonolactones in gram quantities without any use of chromatographic separations. The bromolactones may, prior to treatment with aqueous ammonia, either be converted into the 2,3-epoxides by treatment with KF or K2CO3 in acetone, or may be reduced with sodium borohydride in water to give the bromodeoxyhexitols. 

Ring closure of the amino-bromolactones 34 and 39 was now performed. Based on our experience with the reaction of bromolactones with different... 

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