Methoxymethyl methyl ketone

S)- and (+ )-(7 )-l-Amino-2-(methoxymethyl)pyrrolidine- (SAMP and RAMP)-hydrazones derived from methyl ketones and chiral hydrazines are metalated regioselectively at the methyl... 

Cycloadditions.1 Acyclic enones do not usually undergo photochemical l2+2]cycloaddition with alkenes, but this Ti(lV) Lewis acid does promote this cycloaddition in the case of methoxymethyl vinyl ketone and, to a less extent, of methyl vinyl ketone. Usually 2 equiv. of 1 or of TiCl2(0-/-Pr)2 is required. 

The use of hydrazone or enamine derivatives of ketones or aldehydes offers the advantage of stcreocontrol via chelated azaenolates. Extremely useful synthetic methodology, with consistently high anti selectivity, has been developed using azaenolates based on (S)- or (R)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP or RAMP)51 58 (Enders method, see Section 1.5.2.4.2.2.3.). An example which illustrates the efficiency of this type of Michael addition is the addition of the lithium azaenolate of (5 )-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of propanal (R = II) to methyl (E )-2-butenoate to give the nub-isomer (an 1 adduct) in 80% yield with a diastereomeric ratio > 98 2,... 

Alkoxy ketones. These ketones can be prepared by an aldol-type reaction of enol ethers with acetals catalyzed by a trityl salt. Methoxymethyl (MOM) enol ethers are more reactive than methyl enol ethers. 

To a stirred solution of 177 mg (0.57 mmol) of (3S,4S)-3- [2(S )-(methoxymethyl)pyrrolidinyl]carbonyl -3-methyl-3-(l-oxocthyl)-4-phenylcyclohex-l-ene in 5 mL of THF at 0°C are added 1.4 mL (2 mmol) of 1.4M methyllithium in diethyl ether. After 3 h at 0 "C the reaction is quenched by the addition of water. Diethyl ether is added and the organic phase is washed with 10% aq hydrochloric acid, water and brine. After drying over MgS04, filtration and concentration in vacuo, the product is subjected to flash chromatography (silica gel, hexane/cthyl acetate, 2 1) giving the ketone as colorless crystals vield 80 mg (65 %) mp 49-52 CC [a]D +21.5 (c = 0.74. CHCf,). 

Hydrazones prepared from (S)- l-amino-2-(methoxymethyl)pyrrolidine (242) and acyclic ketones have been shown to undergo deprotonation and alkylation with almost complete asymmetric induction at the a-center (79AG(E)397). The ant alarm pheromone, (+)-(5)-4-methyl-3-heptanone (245), was prepared from the metallated hydrazone of diethyl ketone (243) by alkylation with n-propyl iodide and subsequent cleavage of the crude product via its JV-methyl iodide with acid (Scheme 52). The optical purity of the product was >99%. 

Fig. 13.35. Enders RAMP method for the generation of enantiomerically pure a-alky-lated carbonyl compounds RAMP, (/ )-aminoprolinol methyl ether or R-l-amino-2-(methoxymethyl)pyrrolidine. While hydrazones derived from ketones, such as compound E, are methylated at the doubly bound nitrogen, the methyla-tion of the corresponding aldehyde-derived hydrazones preferentially occurs at the nitrogen atom of the heterocycle.

The reductive cyclization protocol was then applied to a suitably A-protected radical precursor to allow further access to the alkaloid calothrixin B. Satisfactorily, 2-indolylacyl radicals derived from A-(methoxymethyl) selenoester 57 underwent cyclization under TTMSS-AIBN conditions with an even higher efficiency than their A-methyl counterparts. The reaction nevertheless followed a different course as, after the radical addition and quinoline rearomatization, pentacyclic phenol 58, a fully aromatic tautomeric form of ketone P, was isolated in 90% yield. The same phenol 58 was isolated although in lower yields (50-70%) using either stannane-AIBN or AIBN-irradiation protocols. 

SYNS KETONE, METHOXYTVIETHYL l-METHYL-2-INDOLYL METHOXYMETHYL l-METHYL-2-INDOLYL KETONE... 

KETONE, 5-INDOUNYL METHYL see ACO320 KETONE, 2-INDOLYL METHOXYMETHYL- see ICW200... 

KETONE, 3-INDOLYL 4-PIPERIDYL see ILG200 KETONE, METHOXYMETHYL l-METHYL-2-INDOLYL see MDX300... 

KETONE, METHOXYMETHYL 3-METHYL-2-INDOLYL- see MDX310 KETONE, 4-(o-METHOXYPHEN YI-)-l-PIPERAZINYLMETHYL 3-PYRIDYL- see KGK130 KETONE, 4-(o-METHOXYPHENYL)PIPERAZINYL... 

Several other examples of stereoselective synthesis of polycyclic ketones, via carbonylative [2 + 2 + 1] cycloaddition of organopalladium compounds derived from norbornene and norbor-nadiene, have been reported53,54,121. These reactions are useful in the synthesis of cyclopen-tanoid compounds, such as dihydrojasmone54 The nickel-catalyzed version of this method was used in a total synthesis of methylenomycin B55 and in the stereoselective synthesis of bicy-clo[3.3.0]oct-l-en-3-one derivatives56. Thus, (E)- or (Z)-9-bromo-l-methoxy-7-nonen-2-yne (5), upon intramolecular carbonylative cyclization promoted by tetracarbonyl nickel, afford the same stereoisomer of methyl 1,2,4,5.6,6a-hexahydro-3-methoxymethyl-2-oxo-l-pentaleneac-etate (6) in 43-50% yield with a relative trans configuration of the H-l and H-6a protons. 

DIALKYLACETIC ACIDS 2-Methyl-4-methoxymethyl-5-phenyl-2-oxazoline. frans-2,3-DlALKYLCYCLOPENTANONES Lithium methyl(vinyl) cuprate. a, a-DIALKYL KETONES Diphenyl disulfide. 

Alkylation of lithiated hydrazones forms the basis of an efficient method for the asymmetric alkylation of aldehydes and ketones, using the optically active hydrazines (5)-l-amino-2-(methoxymethyl)pyrroUdine (SAMP) 59 and its enantiomer (RAMP) as chiral auxiliaries. Deprotonation of the optically active hydra-zones, alkylation and removal of the chiral auxiliary under mild conditions (ozonol-ysis or acid hydrolysis of the A-methyl salt) gives the alkylated aldehyde or ketone with, generally, greater than 95% optical purity. This procedure has been exploited in the asymmetric synthesis of several natural products. Thus, (S)-4-methyl-3-heptanone, the principal alarm pheromone of the leaf-cutting ant Am texana, was prepared from 3-pentanone in very high optical purity as shown in Scheme 1.74. 

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