Record Details
Chain extension of boronic esters with stereo- and regio-defined lithiated oxiranes
ScholarsArchive at Oregon State University
| Field | Value |
|---|---|
| Title | Chain extension of boronic esters with stereo- and regio-defined lithiated oxiranes |
| Names |
Alwedi, Embarek
(creator) Blakemore, Paul (advisor) |
| Date Issued | 2014-09-03 (iso8601) |
| Note | Graduation date: 2015 |
| Abstract | The stereospecific reagent-controlled homologation (StReCH) of boronic esters with putative lithiooxiranes generated in situ from appropriate precursors via sulfoxide-lithium exchange, tin-lithium exchange, and direct lithiation is described with an emphasis on the first lithiation technique which allows for the regio- and stereo-specific generation of all types of lithiooxirane isomer. Transient lithiooxiranes[LiCR²(O)CR³R³'] react at low temperature (≤ –30 °C) with boronic esters [R⁰B(OR')₂] to give intermediate ate-complexes that experience 1,2-metallate rearrangement upon warming to room temperature to give chain extended β-alkoxy boronates [R³R³'C(OLi)R⁰R²CB(OR')₂]. Providing the lithiooxirane maintains configurational stability on the time-scale of its interception by the boronic ester, such reactions are anticipated to give anti-like boronate products from cis-lithiooxiranes and syn-like boronate products from trans-lithiooxiranes. Three methods were evaluated to prepare stereodefined scalemic sulfinylepoxides [p-TolS(O)CR²(O)CR³R³'] from enantioenriched sulfoxide containing precursors: (i) a Darzens-type condensation of α-chlorosulfoxides [p-TolS(O)CHR²Cl, R² = H or Me] with aldehydes or ketones, (ii) basic hydrogen peroxide mediated nucleophilic epoxidation of (E)- and (Z)-vinylsulfoxides [p-TolS(O)CR²=CR³R³'] formed via Horner-Wadsworth-Emmons olefination, and (iii) multi-step epoxide formation from the same vinylsulfoxides via vicinal halohydrin formation followed by cyclization. Method (i) led to the production of separable mixtures of cis- and trans-sulfinylepoxides in good overall yield (67-87%, cis:trans ~ 6:1): for non-enolizable carbonyl compounds, epoxide formation mediated by t-BuOK base occurred spontaneously in a single-pot mode; however, a two-step protocol involving LDA mediated chlorohydrin formation followed by t-BuOK mediated cyclization was required to access sulfinylepoxides from enolizable carbonyl compounds. Partial racemization of the α-chlorosulfoxide starting material accompanied epoxide formation via each variant of method (i) (chlorosulfoxide %ee ≥ 95% vs. sulfinylepoxide %ee ~ 85%). Methods (ii) and (iii) were less expedient but resulted in the formation of pure cis-epoxides from cis-vinylsulfoxides and pure trans-epoxides from trans-vinylsulfoxides. Little, if any, racemization accompanied methods (i) and (ii). 3-Substituted sulfinylepoxides were easily obtained from all three methods; however, the formation of unsubstituted and 2-substituted sulfinylepoxides, 2,3-disubstituted, and 2,3,3-trisubstituted sulfinylepoxides could only be successfully achieved via method (i). Lithiooxiranes [LiCR²(O)CR³R³', R² = H or Me; R³/R³'= H/Me, H/n-Pr, H/Ph, H/t-Bu, or Me/Ph] generated by sulfoxide-lithium exchange from the stereodefined sulfinylepoxides (using PhLi or t-BuLi, THF, ≤ –90 °C) were employed for StReCH of boronic esters R⁰-Bpin (R⁰ = BnCH₂, allyl, c-C₆H₁₁, Ph). Addition of TBSOTf to the intermediate ate-complexes gave β-silyloxyboronates which could be converted to vicinal diol monosilylethers upon oxidative work-up with aq. NaOOH. The 2°/2° (4-32%, dr > 98:2), 2°/3° (21-66%, dr ≥ 65:35), and 3°/3° (59-68%, dr ≥ 95:5) vicinal stereodiad containing compounds created in this manner were typically obtained in a highly stereocontrolled manner. In general, and as expected, cis-sulfinylepoxides afforded anti-like stereodiads while trans-sulfinylepoxides gave instead syn-like stereodiads. A deuterium labeling study revealed that sulfinylepoxides with α-H-atoms give StReCH products in low yield (≤32%) because of proton exchange between the transient basic lithiooxirane and its acidic sulfoxide precursor. Due to its apparent configurational instability, LiCMe(O)CHPh afforded anti-like 2°/3° motifs regardless of the cis- or trans-stereochemistry of its sulfinylepoxide precursor. Significant quantities (15-25% yield) of stereochemically pure (E)- or (Z)-tetrasubstituted alkene by-products accompanied the formation of β-hydroxyboronate products from 2,3,3-trisubstituted sulfinylepoxides. The stereochemistry of products was established by NMR spectroscopic (including nOe studies of acetonides derived from vicinal diols) and single-crystal X-ray diffraction methods. Tin-lithium exchange from 2-(tributylstannyl)oxirane was explored as a means to generate the parent lithiooxirane for StReCH of boronic esters. (±)-2-(Tributylstannyl)oxirane was prepared by addition of vinylmagnesium bromide to n-Bu₃SnCl following by m-CPBA mediated epoxidation of the resulting vinyl stannane. Jacobsen's hydrolytic kinetic resolution (HKR) procedure failed to resolve this epoxide and subsequent StReCH studies were conducted with its racemate. Treatment of mixtures of a boronic ester R⁰-Bpin (R⁰ = BnCH₂, allyl) and n-Bu₃SnCH(O)CH₂ with n-BuLi (THF, –90 °C) followed by the addition of TBSOTf and TMEDA, resulted in the formation of the expected chain extended products [TBSOCH₂CHR⁰Bpin] in excellent yield (≥81%).This process was applied to an enantiodivergent synthesis of the carbon skeletons of the pyrrolizidine alkaloids (–)-hastanecine and (+)-dihydroxyheliotridane. Thus, B-allyl pinacol boronate was chain extended with (±)-lithiooxirane using the above method and the resulting racemic β-siloxyboronate further homologated with the enantiopure trans-lithiooxirane generated by deprotonation of (S)-2-[(tert-butyldimethylsilyloxy)ethyl]oxirane with LiTMP (THF, –30 °C). Oxidative work-up afforded a pair of enantiopure epimeric carbinols (in an overall unoptimized yield of 13%) containing all carbon-atoms of the target alkaloids. |
| Genre | Thesis/Dissertation |
| Topic | Lithiated oxiranes in homologation of boronic esters |
| Identifier | http://hdl.handle.net/1957/52283 |
