Stereoselectivity acetylides

The direct, stereoselective conversion of alkynes to A-sulfonylazetidin-2-imines 16 by the initial reaction of copper(l) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] cycloaddition of a postulated A-sulfonylketenimine intermediate with a range of imines has been described <06AG(E)3157>. The synthesis of A-alkylated 2-substituted azetidin-3-ones 17 based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates has been... 

Addition of (trimethylsilyl)acetylides to chiral a-aminoalkyl- (413) and a-alkoxyalkyl-(BIGN) (292) nitrones proceeds stereoselectively. Successive desi-lylation (BU4NF, THF) and transformation of the ethynyl group into carboxyl (RuCl3-NaIC>4) led to the synthesis of diastereomerically pure /V-hydroxy-a-amino acids (414) and a-amino acids (415) (Scheme 2.185) (199, 202, 652, 660). 

Starting from 3,4,6-tri-O-benzyl-D-glucal epoxide 93 (Scheme 31), a-C-glycosyl compounds 94 are obtained in good stereoselectivity by treatment with a lithium acetylide and zinc chloride.103... 

The stereospecific reduction of a 2-butyne-l, 4-diol derivative and silver( I)-mediated cyclization of the resulting allene were successively applied to a short total synthesis of (+)-furanomycin 165 (Scheme 4.42) [68], Stereoselective addition of lithium acetylide 161 to Garner s aldehyde in the presence of zinc bromide afforded 162 in 77% yield. The hydroxyl group-directed reduction of 162 with LiAlH4 in Et20 produced the allene 163 stereospecifically. Cyclization followed by subsequent functional group manipulations afforded (+)-furanomycin 165. 

A multi-step reaction sequence was then realized to prepare the precursor (178) for the pivotal macrocyclization reaction. Alternate stepwise chain elongations were achieved according to Schemes 28 and 29. Reaction of the tosylate prepared from the alcohol 162 with lithium acetylide afforded the alkyne 174 (Scheme 28). Following the introduction of a tosylate at the upper branch, a one-carbon chain elongation of the terminal alkyne afforded the methyl alkynoate 175. A methyl cuprate 1,4-addition was used to construct the tri-substituted C double bond stereoselectively. For this purpose, the alkynoate 175 was initially transformed into the Z-configured a,/ -unsat-... 

Thus, the (R)-glycidol (R)-897 was transformed to ethyl (S)-6-benzyloxy-3-methyl-4(E)-hexenoate (S)-899 via addition of acetylide followed by spontaneous isomerization, stereoselective reduction, and Claisen-Johnson rearrangement. The chiral ester (S)-899 was converted to (R)-4-methyl-6-phenylthiohexanol (R)-902. The primary alcohol (R)-902 was then transformed to the terminal acetylene (R)-904, a common intermediate for the synthesis of carbazoquinocins A (272) and D (275). Chain elongation of (R)-904 by two carbon atoms led to (R)-905, the chiral precursor for carbazoquinocin D (275) (639) (Scheme 5.116). 

Stereoselective Alkene Synthesis. Terminal alkynes can also be alkylated by organoboranes. Adducts are formed between a lithium acetylide and a trialkylborane. Reaction with iodine induces migration and results in the formation of the alkylated alkyne.24 25... 

The need for a base additive in this reaction implies the intermediacy of acetylide complexes (Scheme 9.10). As in the Rh(III)-catalyzed reaction, vinylidene acetylide S4 undergoes a-insertion to give the vinyl-iridium intermediate 55. A [l,3]-propargyl/ allenyl metallatropic shift can give rise to the cumulene intermediate 56. The individual steps of Miyaura s proposed mechanism have been established in stoichiometric experiments. In the case of ( )-selective head-to-head dimerization, vinylidene intermediates are not invoked. The authors argue that electron-rich phosphine ligands affect stereoselectivity by favoring alkyne C—H oxidative addition, a step often involved in vinylidene formation. 

Diels-Alder reactions of a -ethenylidenecyclanonesJ These dienophiles (1) are readily obtained by reaction of lithium acetylide with epoxides followed by oxidation, but tend to polymerize when heated. Fortunately catalysts, such as BF3 etherate or ZnCl2, permit Diels-Alder reactions to proceed at low temperatures. This cycloaddition provides a regio- and stereoselective route to spirocylic dienones (2) in fair to good yield. 

Fig. 14.32. Aldehyde alkyne chain elongation via [l,2]-rearrangement of a vinyl carbenoid (Corey—Fuchs procedure). The aldehyde and phosphonium ylide A generated in situ undergo a Wittig olefina-tion and form the 1,1-dibro-moalkene (B). In the second stage, the dibromoalkene is reacted with two equivalents of n-BuLi and the vinyl carbenoid D is formed stereoselectively. The carbenoid undergoes H migration to form the alkyne C. The alkyne C reacts immediately with the second equivalent of n-BuLi to give the lithium acetylide and is reconstituted by reprotonation during aqueous workup.

Fig. 16.31. Stereoselective and stereospecific Pd(0)-cata-lyzed alkenylations of copper acetylides with iodoalkenes at the beginning of a two-step...

Fig. 13.24. Stereoselective and stereospedfic Pd(0)-catalyzed alkenylations of copper acetylides.

Key step of Nicolaou s synthesis is the stereoselective hydrogenation of the unsaturated cyclo-dodecanone 17 which was obtained via intramolecular acetylide-aldehyde condensation of 6. The intermediate (Z)-olefm immediately rearranges to the tricyclic dihydrofuran 18 (Scheme 2). Solely the hydroxyl group at the quaternary carbon atom... 

Addition to cyclohexenones. Lithium acetylides undergo stereoselective axial addition to the carbonyl group of cyclohexenones that are conformationally rigid and free from 1,3-diaxiaI interactions. Thus the enonc 1 reacts with lithium acetylide to give 2 as the only isolable adduct. Addition of ethyllithiuni is not stereoselective. 

The retro-Wittig reaction (i) (Scheme 2.39), with disconnection across the double bond, seems to be an obvious candidate for models containing disubstituted double bonds. In these cases, the steric outcome of the reaction can be easily controlled. An alternative route of disconnection at the vinyl bonds (ii) corresponds to a retro-carbometallation reaction. This disconnection is generally applicable to double bonds with any substitution pattern and is especially useful owing to the high stereoselectivity of the carbometallation step. Route (iii) involves a retrosynthetic dehydrogenation leading to the immediate acetylenic precursor, which can be conventionally disassembled into a parent acetylide and a pair of electrophiles as shown. 

The use of chiral tricarbonyl (Ti -arene) chromium complexes in the highly stereoselective synthesis is well demonstrated. Baldoli et al. have amply demonstrated the application of this strategy in the synthesis of titled compounds. Known chiral ortfto-substituted benzaldehyde tricarbonyl chromium complexes were exposed to lithium acetylide in THE to furnish diastereoselective adducts in good yields (Scheme 21.9). 

Protonation of the acetylide complexes (76) (R = Me, Ph, l-C.oH,) with CFjSOjH at low temperature (-78 °C) has been shown > from H NMR analysis to proceed with high stereoselectivity, giving preferentially (>98% de) the anticlinal diastereomeric vinylidene complexes (77a) (Scheme 11). Analogous Cp methyla-t ons of (76) are similarly stereospecific. This high 1,3 asymmetric induction was... 

The acetylenic nucleosides 130 (B=normal bases, 5-F-Ura, 5-F-Cyt) have been prepared by stereoselective addition of lithium Tms-acetylide to 129, followed by nucleoside formation. The Ura and Cyt compounds had particular antitumour activity. The allofuranosyl analogue 131 of TSAO-T has been prepared, " and 3 -ketonucleosides were treated with JV-methylhydroxylamine, followed by reaction of the nitrones with lithioethyl acetate, to give the spirocyclic compounds 132, also related to TSAO-T. Some other compounds with branches at C-3, prepared in connection with making antisense oligonucleotides, are mentioned in Section 12. 

By the judicious choice of reaction conditions, it is possible to control the regioselectivity and stereoselectivity of acetylide addition to a keto group. For instance, the reaction of the diketone 14 with lithium acetylide in THF at low temperatures gives the C(9)-acetylenic alcohol 75 (Scheme 4) [10], and a stereospecific synthesis of the acetylenic triol 16 is achieved by the condensation of the lithium reagent 77 derived from the isopropenylmethyl (IPM) ether of ( j-3-methylpent-2-en-4-yn-l-ol (18) with the optically active ketone 19, followed by acid-catalysed removal of the protecting groups [11]. Only 3% of the C(6)-diastereoisomer of 16 was detected (Scheme 5). The preparation of 16 is described in Worked Example 2. Table 1 lists a selection of a-hydroxyalkynes that have been prepared from metal acetylides. 

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