Anti SN2 Research Articles

Regio- and stereoselective SN2′ reaction of an allylic picolinate in the synthesis of LY426965

Allylic substitution of secondary γ,γ-disubstituted allylic picolinates with ArMgBr-based copper reagents was applied to the synthesis of LY426965. Reduction of (R)-6-(PMB-oxy)-3-hexyn-2-ol of 93% ee (PMB = p-MeOC6H4CH2) using Red-Al gave (R,Z)-4-iodo-5-(PMB-oxy)hex-3-en-2-ol, which was later converted to the Me-substituted allylic picolinate by Pd-catalyzed coupling with MeZnI followed by esterification with picolinic acid. Allylic substitution with PhMgBr/Cu(acac)2 proceeded with high anti SN2′ selectivity (99%). Ozonolysis, addition of c-Hex-MgBr to the resulting aldehyde, and reductive amination with the piperazine derivative afforded LY426965.

Synthesis of the Verapamil Intermediate through the Quaternary Carbon-Constructing Allylic Substitution

In the present study, the key secondary allylic picolinate was synthesized via Pd(PPh3)4-catalyzed coupling of the TBS ether of (R,Z)-4-iodo-5-methylhex-3-en-2-ol with allyl-MgBr. Allylic substitution of the picolinate with the copper reagent derived from 3,4-(MeO)2C6H3MgBr and Cu(acac)2 in a 2:1 ratio afforded the anti SN2′ product with complete chirality transfer and 91% regioselectivity. Synthetic manipulation of the olefin moiety led to the nitrile group, generating the intermediate for the synthesis of (S)-verapamil.

Allylic Substitution of Esters Derived from 2-Bromocyclohex-2-enol with Aryl Copper Reagents and Synthetic Utilization of the Derived anti SN2′ Products

Allylic substitution of esters derived from 2-bromocyclohex-2-enol with PhMgBr-based copper reagent was investigated to find high anti SN2′ selectivity with the diethyl phosphate, whereas other esters such as picolinate, acetate, and mesylate resulted in partial racemization or recovery of the starting esters. This protocol was applied to the copper reagent derived from 2-Me-4-MeOC6H3MgBr and CuBr·SMe2 and the olefin part of the anti SN2′ product was cleaved for a synthesis of patchouli alcohol.

Highly efficient substitution of allylic picolinates with copper reagents derived from aryl-, alkenyl-, furyl-, and thienyl-lithiums

Substitution of optically active allylic picolinate, cis R1-CH(OC(O)(2-Py))CHCHR2 (R1=(CH2)2Ph, R2=CH2OTBS), with phenylcopper reagents derived from salt free PhLi (2equiv) and CuBr·Me2S (2 and 1equiv, respectively) was highly promoted by MgBr2 (3equiv), producing anti SN2′ product regio- and stereoselectively. This reagent system was proven to be general with several picolinates (R1, R2: Ph(CH2)2, PMBO(CH2)3, Me, TBSOCH2, PMBOCH2, c-Hex). Furthermore, aryl copper reagents prepared from ArLi, which was in turn prepared by Li–halogen exchange, was proven to be compatible with the substitution in the presence of larger quantity of MgBr2 than that of LiX coproduced by the exchange. Substitution was not interfered with the steric hindrance on aryl coppers (Ar: 2-MeOC6H4, 2,6-(MOMO)2-4-MeC6H2, 2,6-Me2C6H3, etc.). Similarly, stereodefined cis and trans alkenyl, furyl, and thienyl reagents gave the corresponding anti SN2′ products efficiently.

Formation of Chiral C(sp3)−C(sp) Bond by Allylic Substitution of Secondary Allylic Picolinates and Alkynyl Copper Reagents

To establish allylic substitution of secondary allylic alcohol derivatives with alkynyl copper reagents, allylic esters bearing the (2-pyridine)CO2-, (2-pyrazine)CO2-, (EtO)2PO2-, C6F5CO2-, o-(Ph2P)C6H4CO2-, MeOCO2-, or AcO- group were examined. First, picolinate (R1 = Me, R2 = CH2OPMB) was subjected to reaction with (TMS-C[triple bond]C)2CuLi.LiBr at 0degreesC. Although no substitution took place, MgBr2 (3 equiv) was found to promote the reaction to produce the anti SN2' product in 93% yield with 94% regioselectivity and 99% chirality transfer. In contrast, substitution of the other esters with the copper reagent in the presence of MgBr2 were less reactive ((2-pyrazine)CO2-) or marginally reactive (other cases). Generality of the substitution using picolinates was established with five picolinates (R1 = Me, Ph(CH2)2, PMBO(CH2)3; R2 = Me, CH2OPMB, CH2OTBS, C5H11, c-C6H11) and seven alkynyl copper reagents (R3 = TMS, Ph, p-TBSOC6H4, p- and o-MeOC6H4, p-MeC6H4, p-FC6H4), furnishing anti SN2' products in 61-93% yields with high regioselectivity (usually >90%) and high chirality transfer (usually >95%). In addition, transformation of the products was briefly studied.

Picolinoxy Group, a New Leaving Group for anti SN2′ Selective Allylic Substitution with Aryl Anions Based on Grignard Reagents

The picolinoxy group was found to be an extremely powerful leaving group for allylic substitution with aryl nucleophiles derived from ArMgBr and CuBr*Me2S. The substitution proceeds with anti SN2' pathway and with high chirality transfer. The electron-withdrawing effect of the pyridyl group and chelation to MgBr2 are likely the origin of success. Results suggesting these effects were obtained.

Development of copper-mediated allylation of γ-activated-α,β-unsaturated lactam toward peptide mimetic synthesis

Reactions of γ-activated-α,β-unsaturated lactams with allylboronate in the presence of LiO i-Pr and CuX (stoichiometric or catalytic amount) proceed in an anti-S N2′ manner to yield α-allylated compounds that serve as a potential synthetic intermediate for cis-aminoacyl-Pro mimetics.

Preparation of α‐Substituted γ‐Alkoxyallylstannanes from β‐Tributylstannyl Acrolein Acetals: Scope of the Method and Primary Rationalization of the Obtained Results.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Construction of Optically Active CF3‐Containing Quaternary Carbon Centers via Stereospecific SN2′ Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly Diastereoselective Allylic Azide Formation and Isomerization. Synthesis of 3(2‘-Amino)-β-lactams

The stereoselective anti SN2' attack of NaN3 to 3-alkenyl-3-bromo-azetidin-2-ones gave a mixture of diastereomeric azides in fast equilibrium. The [3,3]-sigmatropic rearrangement of allylic azides occurred with complete stereocontrol, allowing the equilibrium to be directed preferentially toward the (E)- or (Z)-isomer, useful precursors of 3(2'-amino)-beta-lactams. [reaction: see text]

Concise Synthesis of trans‐ and cis‐3,4‐Disubstituted Piperidines Based on Regio‐ and Stereoselective Allylation of Cyclopentenyl Esters.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective synthesis of alpha-ionone derivatives using an anti S(N)2' substitution of functionalized zinc organometallics.

[reaction: see text] The allylic substitution of sterically hindered (2-iodocycloalkyl)phosphates proceeds with complete anti S(N)2' stereoselectivity with mixed diorganozincs of the type RZnCH(2)SiMe(3) in the presence of CuCN.2LiCl. Only the group R of the copper-zinc reagent is transferred in the allylic substitution. This method was used to prepare odoriferous substances such as (R)-alpha-ionone in 97% ee and (R)-dihydro-alpha-ionone in 98% ee.

Stereoselective SN2‐Substitutions Using Polyfunctional Lithium Arylcuprates Prepared by an Iodine—Copper Exchange.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly stereoselective anti SN2' substitutions of (Z)-allylic pentafluorobenzoates with polyfunctionalized zinc-copper reagents.

[reaction: see text] Allylic substitution reactions of zinc-copper organometallics on (Z)-allylic pentafluorobenzoates proceed with very high regioselectivity and excellent anti selectivity. The high fidelity in transfer of stereochemical information allowed a short synthesis of (+)-ibuprofen (97% ee).

Mitsunobu Reaction of Unbiased Cyclic Allylic Alcohols.

The stereochemical inversion of unbiased allylic alcohols using triphenylphosphine, diethyl azodicarboxylate, and benzoic acid, commonly known as the Mitsunobu reaction, was studied in three different solvents with specific attention toward the product composition. The results generated for the Mitsunobu reaction of (R)-3-deuterio-2-cyclohexen-1-ol and the cis and trans isomers of 1-deuterio-5-methyl-2-cyclohexen-1-ol, 1-deuterio-5-tert-butyl-2-cyclohexen-1-ol, and optically active cis and trans 5-isopropyl-2-methyl-2-cyclohexen-1-ol all gave similar product distributions with respect to inversion and retention at the carbinol center as well-as syn and anti S(N)2' type addition when THF or benzene was used as the solvent (CH(2)Cl(2) gave less selective product distributions). Interestingly, it was found that the quasi-equatorial and quasi-axial nature of the starting allylic alcohol does not appear to affect the product distribution for this reaction, nor does methyl substitution at the central carbon of the allylic alcohol. In all cases, significant amounts (8-28%) of non-S(N)2 type products were detected for these sterically unbiased allylic alcohols; only 72-77% of the product was from S(N)2 type reaction when sterically undemanding (R)-3-deuterio-2-cyclohexen-1-ol was subjected to Mitsunobu conditions.

Reaction of Enohexopyranoside Acetates with Lithium Dimethylcuprate(I) and Its Application to Synthesis of Prelog-Djerassi Lactone

Abstract In the reaction of two 2-O-acetyl-3-enohexopyranosides and four 4-O-acetyl-2-enohexopyranosides including 2-C-methyl and 4-C-methyl derivatives, respectively, with lithium dimethylcuprate(I), anti SN2′ substitution was proved to be preferential, giving the corresponding C-methylated derivatives. On the other hand, SN2 substitution occurred in the reaction of the 2-enopyranoside without methyl branch and d-glucal triacetate.