Halolactonization synthesis

Tran orm-based or long-range strategies The retrosynthetic analysis is directed toward the application of powerful synthesis transforms. Functional groups are introduced into the target compound in order to establish the retion of a certain goal transform (e.g., the transform for the Diels-Alder reaction, Robinson annulation, Birch reduction, halolactonization, etc.). 

Terashima et al. 231) reported an asymmetric halolactonization reaction. This highly stereoselective reaction permits the synthesis of intermediates for the preparation of chiral a,a-disubstituted a-hydroxycarboxylic acids (227)231c), a-hydroxyketones (228) 231c), functionalized epoxides (229) 231d,e) and natural products 231h,j). Only amino acids have so far been used as a source of the chiral information in the asymmetric halolactonization reaction. Again, the best results have been obtained by using cyclic imino acid enantiomers, namely proline. 

In the total synthesis of an anthracycline antibiotic, the key step was an asymmetric halolactonization reaction. The corresponding bromolactones were formed with high stereoselectivity (d.s. > 90%). (S)-Proline was used as chiral auxiliary. 

Several recent reviews have included specific types of electrophilic cyclofunctionalization reactions.1 Important areas covered in these reviews are halolactonization u cyclofunctionalization of unsaturated hydroxy compounds to form tetrahydrofurans and tetrahydropyrans lb cyclofunctionalization of unsaturated amino compounds lc cyclofunctionalization of unsaturated sulfur and phosphorus compounds ld lf electrophilic heterocyclization of unconjugated dienes 1 synthesis of y-butyrolactones 1 h synthesis of functionalized dihydro- and tetrahydro-furans lj cyclofunctionalization using selenium reagents lk lm stereocontrol in synthesis of acyclic systems 1" stereoselectivity in cyclofunctionalizations lP and cyclofunctionalizations in the synthesis of a-methylenelactones.lq Previous reference works have also addressed this topic.2... 

As mentioned earlier in the discussion of cyclizations leading to (3-lactones, the (3-lactones formed from halolactonization of 1,4-dihydrobenzoic acids readily rearrange to produce bridged ring y-lac-tones.19 In some cases, the substitution pattern favors formation of the y-lactone even under conditions of kinetic control (equation 23).20 Synthesis of a variety of y-lactones by iodolactonization of dihydroben-zoic acid derivatives has been reported recently by Hart (equation 24).91 Attempted iodolactonization of the acid in the case where R = H resulted primarily in an oxidative decarboxylation however, iodolactonization was effected using the amide derivative. 

The asymmetric halolactonization reactions of unsaturated L-proline amides, developed by Terashima and coworkers,184 has been extended to a-alkyl acrylic acid derivatives (equation 75 and Table 21).185 This allows for the synthesis of either enantiomer of an a-methyl-a-hydroxy acid using L-proline as the auxiliary. Less successful approaches to asymmetric induction with a chiral auxiliary include iodolac-... 

Ma S, Wu B, Shi Z (2004) An efficient synthesis of 4-halo-5-hydroxyfuran-2(5H)-ones via the sequential halolactonization and y-hydroxylation of 4-aryl-2, 3-alkadienoic acids. J Org Chem 69 1429-1431... 

The halolactonization of amide derivatives has been successfully employed in the synthesis of a number of 2,4-Pww-disubstituted y-lactones32. 

Synthesis of Morpholin-2,5-diones via Diastereoselective Halolactonization Mediated by L-Proline Derivatives... 

By analogy to the halolactonization reaction, the synthesis of cyclic iodocarbonates has been studied with the aim of functionalizing a double bond under regio- and stereocontrol, starting from allylic or homoallylic alcohols. These heterocyclic intermediates are employed for the synthesis of epoxy alcohols, diols and triols. 

A related route to a-hydroxyalkanoic acids is illustrated by the synthesis of / (-)-2-hydroxy-2-methylbutyric acid (407) from (5)(-)-tigloylproline (403). The initial step of halolactonization of 403 with N-bromosuccini-mide in DMF proceeds stereospecifically to give 405 (94.5%) and 407 (5.5%). Debromination of 405 to 409 with tributyltin hydride in benzene, followed by hydrolysis, gave the desired compound 410 (77TL1005 79T2337, 79T2345). 

Halolactonizations have been used extensively for achieving high degrees of functionalization in a regio- and stereo-controlled manner. The conversion of (284) into (285 equation 101) is a key step in Corey s prostaglandin synthesis to prepare the central intermediate (286). For p,7-unsaturated acids like (287) the P-lactone (288) is formed under kinetic control, which then equilibrates to the 7-lactone isomer (2 9 equation 102). ... 

The first total synthesis of (+)-stenine has been accomplished in the laboratory of D.J. Hart/ The key steps were an intramolecular DIels-Alder reaction, an amidine variant of the Curtius rearrangement, an Eschenmoser-Clalsen rearrangement, a halolactonization, and a Keck allylation. The allylic alcohol precursor and A/,A/-dimethylacetamide dimethyl acetal was heated to reflux in xylenes for 4h to afford the desired amide in 93% isolated yield. The transition state most likely adopted a boatlike conformation. 

Haloetherification is closely related to halolactonization although it is used less often. Its main application is the diastereoselective synthesis of synthetically useful substituted tetrahy-drofurans. The mechanism of the asymmetry transfer of the reaction has been investigated using a transition-structure model based on AM1 calculations167. The strong correlation between model and experimental results makes the proposed rationale extremely attractive. 

The chiral allylic carbamate (249) reacts with NBS in DMSO-HjO with high 1,2-relative asymmetric induction, via carbonyl participation, to give the chiral 3-oxo-l,l-disubstituted per-hydropyrrolo[l,2-c]oxazole (250) in a particular case of halolactonization used in the synthesis of the pumiliotoxin A alkaloids class <82TL4887, 84JA4192>. Similar reactions of halonium-initiated cyclization using brominium dicollidine perchlorate have been studied <83JA654>. 

Kim and co-workers have also applied this radical cyclization to construct a furan skeleton from MBH derivatives. As shown in Scheme 4.81, the products 252 of radical cyclization were subjected to a sequence steps involving hydrolysis, halolactonization and spontaneous decarboxylation, and, thus, a facile synthetic method for the synthesis of 3,4-disubstituted 2,5-dihydrofurans 254... 

Lactones, cyclic esters such as compound A, are prepared by halolactonization, an addition reaction to an aikene. For example, iodolactonization of B forms lactone C, a key Intermediate In the synthesis of prostaglandin PGp2a (Section 4.15). Draw a stepwise mechanism for this addition reaction. 

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