Boronic syntheses, stereospecific with

The boronic ester product usually has properties similar to the starting material, and can be treated with additional (dihalomethyl)lithium (LiCHX2) to introduce another stereocenter. Several repetitions are generally possible, as exemplified by the synthesis of L-ribose5. Most syntheses are finished by treatment with hydrogen peroxide, which replaces the boronic ester group stereospecifically by a hydroxy group. 

Hydroboration of terminal acetylenes with boron halides permits the stereospecific synthesis of ( )-l-chloro(or bromo)alk-l-enes919. BBr3 adds to terminal acetylenes in a regio- and stereoselective manner to yield /Lhalovinylboranes, which are very useful syn-thons92a 923. B-bromo- and B-iodo-9 borabicyclo[3.3.1]nonane react similarly924"926. 

The currently available methods for the synthesis of the title compounds are confined to the preparation of homo-1,1-dihalo-1-alkenes 180 while only a few reports are available for mixed 1,1-dihalo-1-alkenes of defined stereochemistry 18u. As the hy-droboration reaction proceeds in a stereospecific manner, the hydroboration-oxi-dation-bromination-debromoboration sequence of 1-chloro-l-alkynes produces selectively (Z)-l-bromo-l -chloro-l-alkenes (Eq. 116),82>. The oxidation with anhydrous trimethylamine oxide of the alkenylborane prior to the addition of bromine is necessary to avoid the competing transfer of one of 1,2-dimethylpropyl group from boron to the adjacent carbon atom. Similar reaction sequence provides 1,1-dibromo-l-alkenes (Eq. 117)182). 

The stereoselective synthesis of (+)-trichodiene was accomplished by K.E. Harding and co-workers. The synthesis of this natural product posed a challenge, since it contains two adjacent quaternary stereocenters. For this reason, they chose a stereospecific electrocyclic reaction, the Nazarov cyclization, as the key ring-forming step to control the stereochemistry. The cyclization precursor was prepared by the Friedel-Crafts acylation of 1,4-dimethyl-1-cyclohexene with the appropriate acid chloride using SnCU as the catalyst. The Nazarov cyclization was not efficient under protic acid catalysis (e.g., TFA), but in the presence of excess boron trifluoride etherate high yield of the cyclized products was obtained. It is important to note that the mildness of the reaction conditions accounts for the fact that both of the products had an intact stereocenter at C2. Under harsher conditions, the formation of the C2-C3 enone was also observed. 

In a stereospecific synthesis of -vinyl sulphides, 1-iodo-alkenylboranes (prepared by hydroborating 1-iodoacetylenes) are reacted with alkylthiomagnesium bromides, after which the boron substituent is removed reductively by treatment with n-butyl-... 

This method was employed in the stereospecific construction of a silyl diene in a synthesis of chlorotri-cholide (Scheme 2.80). The boronic acid partner 2.233 was prepared by hydroboration and hydrolysis. The vinyl iodide was 2.235 prepared by hydroalumination-iodination. The silyl group was included in order to boost stereoselectivity in the later Diels-Alder reaction, but also served to facilitate the synthesis of the vinyl iodide coupling partner. The Suzuki coupling yielded the diene 2.236 with retention of the stereochemistry of both alkenes. Thallium hydroxide was employed as the Lewis base. Thallium-containing Lewis bases have been found to be advantageous in a number of cases, but the toxicity of thallium is a serious concern. 

The utility of (a-haloalkyl)boronic esters in asymmetric synthesis results from a unique combination of several features of their chemistry. A wide variety of products can be obtained in very high stereopurity, and the reactions are compatible with a considerable variety of functional substituents, provided that OH and NH groups are masked. Stereospecific displacement of halide from an (a-haloalkyl)boronic ester with a nucleophile yields an asymmetric boronic ester, which can either be converted stereospecifically into another product such as an alcohol or put into another cycle of reaction with (dihalomethyl)lithium to install additional stereocenters. The general synthetic utility of these boronic esters can best be understood from a detailed outline of the general processes involved. 

The first synthesis of an (a-haloalkyl)boronic ester [8], a free radical addition of a tetrahalomethane, was followed by mechanistic studies that indicated the potential for stereospecific alkylation with Grignard reagents via borate intermediates [9], if only there had been a way to obtain asymmetric examples. The discovery of the efficient reaction of (dichloromethyl)lithium with boronic esters to form (a-chloroalkyl)boron-ic esters by insertion of a CHCl group into the B-C bond opened a new opportunity [10]. Boronic esters of pinanediol, prepared from (+)-a-pinene by osmium tetroxide catalyzed oxidation, were soon found to undergo the insertion reaction with a strong asymmetric bias, with diastereomeric selectivities frequently in the 90-95% range [llj. It was subsequently found that anhydrous zinc chloride promotes the reaction and increases diastereoselectivity to as high as 99.5% in some cases [12]. 

Several types of replacement of halide by metals are known. The only one that appears to have direct utility in asymmetric synthesis is the reaction of (tributylstan-nyl)lithium with (a-chloroalkyl)boronic esters. The replacement is stereospecific and provides a route to a-lithioethers having high enantiopurity [88]. This chemistry is illustrated by the conversion of (S)-DIPED (R)-(l-chloro-2-methylpropyl)boronate (157) into the (S)-tributylstannyl derivative 158 (Scheme 8.38). The displacement is unusually sluggish and was promoted with zinc chloride. Peroxidic deboronation yielded... 

Stereospecific synthesis of c/5-disubstituted or trisubstituted olefins from mono- or di-substituted alkynes can be accomplished via hydroboration to dialkylvinylboranes followed by addition of sodium hydroxide and iodine. By treatment of the vinylborane with cyanogen bromide in methylene chloride solution, the complementary procedure, namely conversion into the /ra 5-olefin, may be effected. In the c/j-producing case, the stereochemistry is believed to be the result of /m 5-elimination of iodide and boron from the intermediate (64). In the corresponding intermediate (65) produced using... 

The reaction of 2-bromo-6-lithiopyridine (13) with trialkylboranes gives intermediate boron compounds which are versatile intermediates for the preparation of unsaturated nitriles (Scheme 9). A stereospecific synthesis of dehydronerol utilizes the dianion of 3-methylbut-2-enoic acid as an isoprene functionality (Scheme 10). Lithium dianions from aj8-unsaturated acids generally undergo alkylation reactions at the a-carbon atom. In contrast the dicopper dianions undergo more selective y-alkylation (62—99%) and this ratio is generally higher than with the corresponding esters. A study of various acids and their alkylation with allyl electrophiles showed that allylic electrophiles unsubstituted at the y-carbon react... 

The additions of allyl-, crotyl-, and prenylborane or -boronate reagents to aldehydes are among the most widely studied, well developed, and powerful reactions in stereoselective synthesis. The additions not only display excellent levels of absolute induction in enantioselective synthesis, but also exhibit superb levels of reagent control in diastereoselective additions. The additions of ( )- or (Z)-crotyl pinacol boronates to aldehydes have been observed to give predominantly 1,2-anti- and 1,2-syn-substituted products, respectively (Scheme 5.3) [31, 50]. The inherent stereospecificity of the reaction is consistent with a closed, cyclic Zimmerman-Traxler transition state structure [51], In the accepted model, coordination of the aldehyde to the allylation reagent results in synergistic activation of both the electrophile and the nucleophile... 

The convenient synthesis of the a-chloro-substituted pinacol-derived boro-nate 46 commences with the hydroboration of propargyl alcohol 57 (Scheme 5.10) [57]. Following protection of the secondary alcohol, hydroboration of the alkyne and transesterification furnishes boronate 59. Treatment of 59 with thionyl chloride stereospecifically installs the a-chloro substituent of 46. 

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