Oxidative workup

A cursory inspection of key intermediate 8 (see Scheme 1) reveals that it possesses both vicinal and remote stereochemical relationships. To cope with the stereochemical challenge posed by this intermediate and to enhance overall efficiency, a convergent approach featuring the union of optically active intermediates 18 and 19 was adopted. Scheme 5a illustrates the synthesis of intermediate 18. Thus, oxidative cleavage of the trisubstituted olefin of (/ )-citronellic acid benzyl ester (28) with ozone, followed by oxidative workup with Jones reagent, affords a carboxylic acid which can be oxidatively decarboxylated to 29 with lead tetraacetate and copper(n) acetate. Saponification of the benzyl ester in 29 with potassium hydroxide provides an unsaturated carboxylic acid which undergoes smooth conversion to trans iodolactone 30 on treatment with iodine in acetonitrile at -15 °C (89% yield from 29).24 The diastereoselectivity of the thermodynamically controlled iodolacto-nization reaction is approximately 20 1 in favor of the more stable trans iodolactone 30. 

A synthetically useful virtue of enol triflates is that they are amenable to palladium-catalyzed carbon-carbon bond-forming reactions under mild conditions. When a solution of enol triflate 21 and tetrakis(triphenylphosphine)palladium(o) in benzene is treated with a mixture of terminal alkyne 17, n-propylamine, and cuprous iodide,17 intermediate 22 is formed in 76-84% yield. Although a partial hydrogenation of the alkyne in 22 could conceivably secure the formation of the cis C1-C2 olefin, a chemoselective hydrobora-tion/protonation sequence was found to be a much more reliable and suitable alternative. Thus, sequential hydroboration of the alkyne 22 with dicyclohexylborane, protonolysis, oxidative workup, and hydrolysis of the oxabicyclo[2.2.2]octyl ester protecting group gives dienic carboxylic acid 15 in a yield of 86% from 22. 

The conversion of a thiolactone to a cyclic ether can also be used as a key step in the synthesis of functionalized, stereochemically complex oxacycles (see 64—>66, Scheme 13). Nucleophilic addition of the indicated higher order cuprate reagent to the C-S double bond in thiolactone 64 furnishes a tetrahedral thiolate ion which undergoes smooth conversion to didehydrooxepane 65 upon treatment with 1,4-diiodobutane and the non-nucleophilic base 1,2,2,6,6-pentamethylpiperidine (pempidine).27 Regio- and diastereoselective hydroboration of 65 then gives alcohol 66 in 89 % yield after oxidative workup. Versatile vinylstannanes can also be accessed from thiolactones.28 For example, treatment of bis(thiolactone) 67 with... 

The first of the nudeophilic ring-opening reactions of vinylaziridines discussed in this section is diborane reduction, developed by Laurent and coworkers in 1976 (Scheme 2.24). Treatment of N-unsubstituted vinylaziridines 89 with B2H6 gives allyl amines 92 by SN2 reduction via cyclic intermediates 90 [40]. In contrast, treatment with 9-BBN gives 2-(hydroxyethyl)aziridines 93 after oxidative workup (Scheme 2.25) [41]. 

Isopinocampheyl(l-isopinocampheyl-2-octenyl)borinic acid (1), available with a diastereomer-ic purity of approximately 80 85% de, reacts smoothly with aldehydes at —15 °C in tetrahy-drofuran to provide a homoallylic alcohol with 79-85% ee after oxidative workup (30% hydrogen peroxide, 40 °C)6. 

Achiral ketones, for example, 3-pentanone, can be converted predominantly into (Z)-boron enolates [(Z)/( )>97 3] by treatment with (- )-diisopinocampheylboron triflate. Subsequent addition to aldehydes, followed by an oxidative workup procedure, delivers /i-hydroxy ketones with a diastcrcomeric ratio of 95 5 to 98 2 (synjanli) and the xpn-products with 66 to 93% ee33. 

An entry to. yyrt-2-methoxy-3-hydroxycarboxylic acids is also opened using similar methodology. Thus the norephedrine derived (4/ ,5S)-3-(2-methoxy-l-oxoethyl)-4-methyl-5-phenyl-1,3-oxazolidine-2-one 23105a, as well as the phenylalanine derived (4S)-4-benzyl-3-(2-methoxy-l-oxoethyl)-l,3-oxazolidin-2-one 25105b, can be added to aldehydes via the boron enolates to give, after oxidative workup, the adducts in a stereoselective manner (d.r. 96 4, main product/sum of all others). Subsequent methanolysis affords the methyl esters. 

Nanaomycin A 103 and deoxyfrenolicin 108 are members of a group of naphthoquinone antibiotics based on the isochroman skeleton. The therapeutic potential of these natural products has attracted considerable attention, and different approaches towards their synthesis have been reported [65,66]. The key step in the total synthesis of racemic nanaomycin A 103 is the chemo-and regioselective benzannulation reaction of carbene complex 101 and allylacety-lene 100 to give allyl-substituted naphthoquinone 102 after oxidative workup in 52% yield [65] (Scheme 47). The allyl functionality is crucial for a subsequent intramolecular alkoxycarbonylation to build up the isochroman structure. However, modest yields and the long sequence required to introduce the... 

Alkynes are reactive toward hydroboration reagents. The most useful procedures involve addition of a disubstituted borane to the alkyne, which avoids complications that occur with borane and lead to polymeric structures. Catechol borane is a particularly useful reagent for hydroboration of alkynes.212 Protonolysis of the adduct with acetic acid results in reduction of the alkyne to the corresponding cw-alkene. Oxidative workup with hydrogen peroxide gives ketones via enol intermediates. 

Scheme 12.19 illustrates some cases in which ozonolysis reactions have been used in the course of syntheses. Entries 1 to 4 are examples of use of ozonolysis to introduce carbonyl groups under reductive workup. Entries 5 and 6 involve oxidative workup and give dicarboxylic acid products. The reaction in Entry 7 is an example of direct generation of a methyl ester by methoxide trapping. 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

After successful installation of the first two stereocenters, our attention was focused on elaboration of the terminal alkene in 64 (Scheme 6.9). Treatment with disiamylborane followed by oxidative workup afforded primary alcohol 65 in good yield (70-85 %). A side product containing a mixture of two diastereomers (66) was also observed and resulted from conjugate addition of the alkoxide formed during basic workup onto the unsaturated ester. Maintaining the temperature at 0 °C by a slow, dropwise quench during the oxidative workup was necessary to minimize the amount of the undesired cyclization product (66). Subsequent oxidation of the primary alcohol 65 using Dess-Martin periodinane [28] and a Pinnick oxidation afforded carboxylic acid 67 [29]. 

The quantum yield for formation of 20, R=6-C(CH3)3, from 14, R=4-C(CH3)3, via photolysis in fer -butyl alcohol and oxidative workup, has been determined as (1.2 0.1) X 10 2 4 ). Quantum yields for formation of various other N-hydroxy-2-indolinones from appropriately substituted 2-nitro-fer -butylben-zenes fall into the range 1.1 X 10 to 2.2 X 10 and thus are of the same order of magnitude as the disappearance quantum yield reported for nitrobenzene in 2-propanol... 

There are a wide number of reports regarding nucleophilic aromatic substitution a to nitrogen in 1,10-phenanthro-line 48. Eor example, the aryllithium reagent 49 adds to 1,10-phenanthroline 48 and on oxidative workup yields... 

Among the reducing agents for the reductive workup, peroxide is a common oxidative workup. 

Various prochiral olefins are hydroborated by Rh complexes of BINAP or DIOP in up to 96% optical yield (30h, 31). Oxidation of the products provides a convenient way to produce optically active alcohols. Reaction of styrene and catecholborane in the presence of a BINAP-Rh complex at low temperature forms, after oxidative workup, 1-phenylethyl alcohol in 96% ee (Scheme 11) (31). Double stereodifferentiation occurs in the BINAP-Rh catalyzed reaction of 4-methoxy-styrene and an ephedrine-derived chiral borane (32). 

Use ol a stronger reducing agent such as lithium aluminum hydride or sodium borohydride would generate the corresponding alcohols. whereas an oxidative workup with hydrogen peroxide would cause the carbonyl compounds to be oxidized in situ to carboxylic acids. 

Asymmetric induction of central chirality at a carbon atom was achieved by an intramolecular enantioposition-selective asymmetric cross-coupling [12]. Treatment of the prochiral bisbo-rane 46, which was prepared from the alkenyl triflate 45 and 2 equiv. of 9-BBN with 20 mol % of Pd/(S)-(/ )-BPPFOAc (48) catalyst generated in situ in THF, brings about intramolecular Suzuki coupling. The following oxidative workup and p-nitrobcnzoylation affords the chiral cyclopentane derivative (R)-47 in 58% yield and 28% ee (Scheme 8F.14). 

While die above reactions will provide carboxylic acid products, each has problems associated with it. The cleavage of olefins to carboxylic acids [reaction (7.1)] can be carried out using potassium permanganate or by ozonolysis at low temperature followed by oxidative workup with hydrogen peroxide. Neither of diese mediods is very useful since only symmetric olefins provide a single carboxylic acid product. Unsymmetrical olefins give a mixture of two acids which must be separated. Furthermore the most useful synthetic processes are those which build up structures, whereas these reactions are degradative in nature. 

Our persistence with the boron-mediated aldol reaction of 4 and 5 was rewarded when the reaction was conducted without recourse to the usual oxidative workup. Other work conducted by our group had shown that oxidative cleavage of certain aldol borinates under standard conditions (H2O2, pH 7 buffer, H20/Me0H) led to poor yields of the aldol products. In the case of 44, the oxidative step was omitted and the reaction mixture was placed directly on silica gel and then eluted to afford aldol adduct 44 in excellent yield (89%) and with improved diastereoselectivity (90 10 ds) relative to the corresponding lithium conditions.17... 

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