Graduate Thesis Or Dissertation
 

Investigation of Chain Extension Approaches for the Stereoselective Reagent-Controlled Synthesis of alpha-Heteroatom Substituted Alkyl Boronic Esters

公开 Deposited

可下载的内容

下载PDF文件
https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/w37639108

Descriptions

Attribute NameValues
Creator
Abstract
  • Two distinct strategies were explored for the enantioselective synthesis of α-heteroatom substituted alkyl boronic esters by stereoselective reagent-controlled homologation using transient chiral carbenoid reagents CHYMX (Y = heteroatom, X = nucleofuge, M = electrofuge). In the first case, a stereospecific reagent-controlled homologation (sStReCH) approach to α-alkoxyalkylboronates using α-metalated S,O- and O,O-acetals was pursued that necessitated the development of methods to access these carbenoids in stereodefined form and study of their configurational and chemical stability (both classes of carbenoid are known to chain extend alkyl boronic esters). Sulfoxide-metal exchange from dithioorthoformate monooxides was evaluated as a means to access stereodefined α-metalated S,O-acetals. It was discovered that acyclic dithioorthoformate monooxides fragment spontaneously upon their oxidative generation from simple dithioorthoformates [(pTolS)₂CHOR, R = Me, Et]; however, two cyclic dithioorthoformate monooxides, trans and cis 2-isopentoxy-1,3-benzodithiolane-S-oxide (102), were obtained in 85% yield (trans:cis = 96:4) by 3-chloroperoxybenzoic acid mediated oxidation of 2-isopentoxy-1,3-benzodithiolane. Treatment of trans or cis-102 with EtMgCl (in THF at -78 °C) gave configurationally stable (≤ 2.5 h, at -78 °C) stereodefined α-magnesiated S,O-acetals 103 that incorporated D-atoms in a stereospecific manner upon reaction with CD3OD. Carbenoids 103 (M = MgCl) failed to react with all other electrophiles examined (allyl bromide, MeI, MeOTf), except benzaldehyde, and this low nucleophilicity precluded their use in boronic ester chain extension chemistry. α-Lithiated S,O-acetals 103 generated in the same fashion from 102 using PhLi were more reactive than their magnesiated congeners 103 but lacked sufficient configurational stability for applications in sStReCH (epimerization of 103 (M = Li) occurred within 1 min at -78 °C in THF). Direct metalation approaches to stereodefined lithiated S,O- and O,O-acetals were next explored, but ultimately, either acceptably high enantioselectivity was not realized or the organolithiums generated were found to be too chemically unstable for sStReCH applications. For example, kinetic enantioselective lithiation of methoxymethyl p-tolyl thioether (124) with s-butyllithium/(-)-sparteine (PhMe, -78 °C) followed by treatment of the resulting lithiated S,O-acetal [pTolSCH(Li)OMe] with benzaldehyde as a probe electrophile, led to addition products [pTolSCH(OMe)CH(OH)Ph] with low enantiomeric excess [55% yield, dr = 66:34, %ee (major isomer) = 24%, %ee (minor isomer) = 9%]. In another example, lithiation of a thiocarbamate of methoxymethyl mercaptan [i-Pr₂NC(=S)SCH₂OMe] with s-butyllithium and TMEDA (Et₂O, -110 °C) led to a chemically unstable carbenoid that spontaneously extruded methyl thioformate (MeOCHS) to yield putative a-lithio-N,N-diisopropylthioformamide [i-Pr₂NC(=S)Li]. The second strategy explored, and introduced here for the first time, ligand mediated stereoinductive reagent-controlled homologation (iStReCH), deliberately exploits the configurational lability of heteroatom substituted carbenoids and consequently it was more successful. In this case, dynamic kinetic resolution (DKR), or dynamic thermodynamic resolution (DTR), of a racemic configurationally labile carbenoid is effected by an exogenous chiral ligand as the carbenoid is trapped by the boronic ester electrophile. The iStReCH concept was demonstrated for an enantioselective synthesis of α-silylalkylboronates, as follows: (±)-lithio(dimethylphenylsilyl)methyl 2,4,6-triisopropylbenzoate [TIBOCH(Li)SiMe₂Ph], obtained by lithiation of the corresponding silylmethyl TIB ester with t-butyllithium (cumene, -78 °C), was incubated with the chiral BOX ligand 2,2-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl)propane (at -45 °C) before addition of B-phenethyl pinacol boronate at -95 °C. Warming to rt during 18 hours afforded the desired enantioenriched chain extended product (S)-2-[1-(dimethylphenylsilyl)-3-phenylpropyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (69% yield, 57% ee). Ligand mediated iStReCH of B-cyclohexyl (35% yield, 9% ee) and B-sec-butyl [43% yield, dr = 58:42, %ee (major) = 26%, %ee (minor) = 14%] pinacol boronates with the same silylated carbenoid was likewise demonstrated. Enantioselectivity was dependent on the temperature history of the organolithium/ligand complex indicating that the stereoinduction mechanism involves some aspect of DTR.
License
Resource Type
Date Available
Date Issued
Degree Level
Degree Name
Degree Field
Degree Grantor
Commencement Year
Advisor
Committee Member
Academic Affiliation
Non-Academic Affiliation
Subject
权利声明
Publisher
Peer Reviewed
Language
Replaces

关联

Parents:

This work has no parents.

属于 Collection:

单件

缩略图 标题 上传日期 公开度 行动
file details BarsamianAdamL2016.pdf 2017-08-07 公开 下载