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auxiliar quiral Salvar

Un auxiliar quirales un grupo o unidad estereogénico que se incorpora temporalmente en un compuestoorgánico para controlar el resultado estereoquímico de la síntesis. [1] [2] La quiralidad presente en el auxiliar puede sesgar la estereoselectividad de una o más reacciones posteriores. El auxiliar puede ser típicamente recuperado para uso futuro.

Esquema general para emplear un auxiliar quiral en síntesis asimétrica La mayoría de las moléculas biológicas y dianas farmacéuticas existen como uno de dos posibles enantiómeros ; en consecuencia, las síntesis químicas de productos naturales y agentes farmacéuticos se diseñan con frecuencia para obtener el objetivo en forma enantioméricamente pura. [3] Los auxiliares quirales son una de las muchas estrategias disponibles para los químicos sintéticos para producir selectivamente el estereoisómero deseado de un compuesto dado. [4] Los auxiliares quirales fueron introducidos por EJ Corey en 1975 [5] con 8fenilmentol quiral y por BM Trost en 1980 con ácido mandélico quiral. El compuesto de mentol es difícil de preparar y, como alternativa, el trans-2-fenil1-ciclohexanol fue introducido por JK Whitesell en 1985. Síntesis asimétrica Los auxiliares quirales se incorporan en rutas sintéticas para controlar la configuración absoluta de los centros estereogénicos. La síntesis de citovaricina de David Evans , considerada un clásico, utiliza auxiliares quirales de oxazolidinona para una reacción de alquilación asimétrica y cuatro

reacciones aldólicas asimétricas, estableciendo la estereoquímica absoluta de nueve estereocentros. [6]

La citovaricina, sintetizada por DA Evans en 1990. Los enlaces azules y rojos indican estereocentros establecidos con el uso de auxiliares quirales. Una transformación estereoselectiva guiada auxiliar típica implica tres pasos: primero, el auxiliar se acopla covalentemente al sustrato; segundo, el compuesto resultante experimenta una o más transformaciones diastereoselectivas; y finalmente, el auxiliar se elimina en condiciones que no causan la racemización de los productos deseados. [4] El costo de emplear auxiliares estequiométricos y la necesidad de gastar pasos sintéticos para agregar y eliminar el auxiliar hace que este enfoque parezca ineficiente. Sin embargo, para muchas transformaciones, la única metodología estereoselectiva disponible se basa en auxiliares quirales. Además, las transformaciones con auxiliares quirales tienden a ser versátiles y muy bien estudiadas, lo que permite el acceso con el tiempo más eficiente a los productos enantioméricamente puros. [2] Además, [7] los productos de reacciones dirigidas auxiliares son diastereómeros , lo que permite su fácil separación por métodos tales como cromatografía en columna o cristalización. 8-phenylmenthol En un ejemplo temprano del uso de un auxiliar quiral en la síntesis asimétrica, EJ Corey y compañeros de trabajo llevaron a cabo una reacción asimétrica de Diels-Alder entre (-) - 8-fenilmentol acrilato éstery 5benciloximetilciclopentadieno. [5] El producto de cicloadición se transfirió a la yodolactona que se muestra a continuación, un intermediario en la síntesis clásica de Corey de las prostaglandinas . Se propone que la cara posterior del acrilato sea bloqueada por el auxiliar, de modo que la cicloadición ocurra en la cara frontal de la olefina.

Cicloadición Diastereoselectiva de Diels-Alder con el (-) - 8-fenilmentol auxiliar quiral en la ruta a las prostaglandinas. (-) - 8-phenylmenthol puede prepararse a partir de cualquier enantiómero de pulegona , [8] aunque ninguna de las rutas es muy eficiente. Debido a la amplia utilidad del auxiliar 8-fenilmentol, compuestos alternativos que se sintetizan más fácilmente, como trans-2-fenil-1ciclohexanol [9] y trans-2- (1-pheyl-1-methylethyl) cyclohexanol [ 10] han sido explorados. 1,1'-Binaphthyl-2,2'-diol (BINOL) El 1,1'-Binaphthyl-2,2'-diol , o BINOL , se ha utilizado como auxiliar quiral para la síntesis asimétrica desde 1983. [11] [12]

(R) -BINOL

Hisashi Yamamoto utilizó por primera vez (R) -BINOL como un auxiliar quiral en la síntesis asimétrica de limoneno , que es un ejemplo de mono- terpenoscíclicos . Se preparó éter monoeril (R) -BINOL mediante la monosililación y alquilación de (R) -BINOL como el auxiliar quiral. Seguido de la reducción con reactivo de organoaluminio, se sintetizó limoneno con bajos rendimientos (29% de rendimiento) y excesos enantioméricos moderados de hasta 64% de ee. [12]

Primera utilización de BINOL como auxiliar quiral.

La preparación de una variedad de R-aminoácidos no comunes enantioméricamente puros se puede lograr mediante la alquilación de derivados de glicina quirales que poseen BINOL axialmente quiral como auxiliar. Ha sido representado por Fuji et al. En base a diferentes electrófilos , el exceso diastereomérico varió de 69% a 86. [13]

Adición diastereoselectiva entre Grignard y aldehído protegido con BINOL

Protegido en la función aldehído con (R) -BINOL, los arilglioxanos reaccionaron diastereoselectivamente con reactivos de Grignard para proporcionar atrolactaldehído protegido con exceso diastereomérico de moderado a excelente y altos rendimientos. [14]

Adición diastereoselectiva entre Grignard y aldehído protegido con BINOL

Trans-2-Fenilciclohexanol

Trans-2-fenilciclohexanol

El trans-2-fenilciclohexanol es un tipo de auxiliar quiral, que fue introducido por primera vez por James K. Whitesell y sus colegas en 1985. Este auxiliar quiral se usó en reacciones de eno del éster de glioxilato derivado. [15]

El trans-2-fenilciclohexanol se usó en la reacción eno como un auxiliar quiral.

En la síntesis total de (-) - Heptemerone B y (-) - Guanacastepene E, unido con trans-2-pheynlcyclohexanol, el glioxilato reaccionó con 2,4-dimethyl-2-pentene, en presencia de cloruro de estaño (IV) , produciendo el anti aducto deseado como el producto principal, junto con una pequeña cantidad de su isómero sin con una relación diastereomérica de 10: 1 . [dieciséis]

El glioxilato reaccionó con 2,4-dimetil-2-pentano con trans-2-fenilciclohexanol como auxiliar quiral

Trans-2-cumylcyclohexanol (TCC) tiene una estructura similar a Trans-2phenylcyclohexanol . En 2015, el grupo Brown publicó un método eficiente en la ciclación oxidativa mediada por permanganato con este tipo de auxiliar quiral. [17]

El trans-2-cumilciclohexanol se utilizó en la ciclación oxidativa mediada por permanganato asimétrico.

Oxazolidinonas Los auxiliares de oxazolidinona , popularizados por David Evans , se han aplicado a muchas transformaciones estereoselectivas , incluidas reacciones aldólicas , [18] reacciones de alquilación , [19] y reacciones de DielsAlder . [20] [21] Las oxazolidinonas se sustituyen en las posiciones 4 y 5. A través del impedimento estérico, los sustituyentes dirigen la dirección de sustitución de varios grupos. El auxiliar se elimina posteriormente, por ejemplo, mediante hidrólisis. Preparación Las oxazolidinonas pueden prepararse a partir de aminoácidos o aminoalcoholes fácilmente disponibles . Un gran número de

oxazolidinonas están disponibles comercialmente, incluidos los cuatro a continuación.

Algunos de los auxiliares quirales de oxazolidinona disponibles comercialmente. La acilación de la oxazolidinona se consigue por desprotonación con n-butillitio y se inactiva con un cloruro de ácido .

Acilación de una oxazolidinona quiral con cloruro de propanoilo . Reacciones de alquilación La desprotonación de la α-carbono de una oxazolidinona imida con una base fuerte tal como diisopropilamida de litio proporciona selectivamente el (Z) - enolato , que puede someterse a estereoselectiva de alquilación .

Alquilación de una imida de oxazolidinona con bromuro de bencilo. Los electrófilos activados, como los haluros alílicos o bencílicos , son sustratos muy buenos. Reacciones de Aldol Las oxazolidinonas quirales se han empleado más ampliamente en reacciones aldólicas estereoselectivas . Soft enolization with the Lewis acid dibutylboron triflate and the base diisopropylethylamine gives the (Z)-enolate, which undergoes a diastereoselective aldol reaction with an aldehyde substrate. The transformation is particularly powerful because it establishes two contiguous stereocenters simultaneously.

Stereoselective Evans aldol reaction. A model for the observed stereoselectivity can be found below. The synstereorelationship between the methyl group and the new secondary alcohol results from a six-membered ring Zimmerman-Traxler transition state, wherein the enolate oxygen and the aldheyde oxygen both coordinate boron. The aldehyde is oriented such that the hydrogen is placed in a pseudo-axial orientation to minimize 1,3-diaxial interactions. The absolute stereochemistry of the two stereocenters is controlled by the chirality in the auxiliary. In the transition structure, the auxiliary carbonyl is oriented away from the enolate oxygen so as to minimize the net dipole of the molecule; one face of the enolate is blocked by the substituent on the chiral auxiliary.

Model for the stereoselectivity of an Evans aldol reaction. Removal A variety of transformations have been developed to facilitate removal of the oxazolidinone auxiliary to generate different synthetically useful functional groups.

Transformation of an oxazolidinone imide to different functional groups. Camphorsultam Camphorsultam, or Oppolzer's sultam, is a typical chiral auxiliary in the asymmetric synthesis.

Camphorsultam

In the total synthesis of manzacidin B, Ohfune group utilized camphorsultam to construct the core oxazolinering asymmetrically. Comparing with oxazolidinone as the chiral auxiliary, camphorsultam had a significant (2S,3R)-selectivity.[22]

The chiral camphorsultam was found to be a superior chiral auxiliary to the oxazolidinone in view of the single asymmetric induction.

Camphorsultam also acts as a chiral auxiliary in Michael addition. Lithium base promoted stereoselective Michael addition of thiols to Nmcthacryloylcamphorsultam produced the corresponding addition products in high diastereoselectivity.[23]

Camphorsultam was used as a chiral auxiliary in Michael addition.

Camphorsultam was used as a chiral auxiliary for the asymmetric Claisen rearrangement. In the presence of butylated hydroxytoluene (BHT) used as a polymerization inhibitor, a toluene solution of the adduct between geraniol and camphorsultam was heated in a sealed tube at 140 °C, to provide mainly the (2R,3S)-isomer as the major rearrangement product in 72% yield, securing the two contiguous stereocenters including the quaternary carbon.[24]

Camphorsultam was used as a chiral auxiliary in Claisen rearrangement.

Pseudoephedrine Both (R,R)- and (S,S)-pseudoephedrine can be used as chiral auxiliaries.[25] Pseudoephedrine is reacted with a carboxylic acid, acid anhydride, or acyl chloride to give a pseudoephedrine amide. The α-proton of the carbonyl compound is easily deprotonated by a nonnucleophilic base to give the enolate, which can further react. The configuration of the addition compound, such as with an alkyl halide, is directed by the methyl group. Thus, any addition product will be anti to the methyl and syn with the hydroxyl group. The pseudoephedrine chiral auxiliary is subsequently removed by cleaving the amide bond with an appropriate nucleophile. Preparation Both enantiomers of pseudoephedrine are commercially available. Racemic pseudoephedrine is marketed as Sudafed and under other brand names as a nasal decongestant. Because pseudoephedrine can be converted to the illicit substance methamphetamine, the purchase of pseudoephedrine for use in academic or industrial research is very regulated. As an alternative, Myers and coworkers recently reported the utility of pseudoephenamine chiral auxiliaries in alkylation reactions.[26]While pseudoephenamine is not readily available from commercial sources, it can be synthesized from other available materials and is not subject to the same regulations as pseudoephedrine.

Pseudoephedrine and pseudoephenamine chiral auxiliaries.

Pseudoephedrine amides are typically prepared by acylation with an acid chloride or acid anhydride.[27]

Acylation of (S,S)-psueodphedrine with an acid anhydride. Alkylation Pseudoephedrine amides undergo deprotonation by a strong base such as lithium diisopropylamide (LDA) to give the corresponding (Z)-enolates. Alkylation of these lithium enolates proceeds with high facial selectivity.

Diastereoselective alkylation of a pseudoephedrine amide. The diastereoselectivity is believed to result from a configuration wherein one face of the lithium enolate is blocked by the secondary lithium alkoxide and the solvent molecules associated with that lithium cation. In accordance with this propsal, it has been observed that the diastereoselctivity of the alkylation step is highly dependent on the amount of lithium chloride present and on the solvent, tetrahydrofuran(THF). Typically, 4 to 6 equivalents of lithium chloride are sufficient to saturate a solution of enolate in THF at the reaction molarity.

Model for the diastereoslective alkylation of a pseudoephedrine amide enolate. One primary advantage of asymmetric alkylation with pseudoephedrine amides is that the amide enolates are typically nucleophilic enough to react with primary and even secondary halides at temperatures ranging from –78 °C to 0 °C. Construction of quaternary carbon centers by alkylation of α-branched amide enolates is also possible, though the addition of DMPU is necessary for less reactive electrophiles.[28]

Removal Conditions have been developed for the transformation of pseudoephedrine amides into enantiomerically enriched carboxylic acids, alcohols, aldehydes, and ketones.

Transformation of pseudoephedrine amides into synthetically useful functional groups. After cleavage, the auxiliary can be recovered and reused. tert-Butanesulfinamide The use of chiral sulfinamide derivatives as chiral auxiliaries has been explored extensively by Jonathan Ellman.[29]

Both enantiomers of tert-butanesulfinamide Preparation Either enantiomer of tert-butanesulfinamide can be reached from tert-butyl disulfide in two steps: a catalytic asymmetric oxidation reaction gives the disulfide monooxidation product in high yield and enantiomeric excess. Treatment of this compound with lithium amide in ammonia affords optically pure inverted product.

Synthesis of tert-butanesulfinamide from readily available 'tert-butyl disulfide Condensation of tert-butanesulfinamide with an aldehyde or ketone proceeds in high yield and affords only the (E)-isomer of the corresponding aldimines and ketimines or N-Sulfinyl imines.

Condensation of tert-butanesulfinamide with aldehydes and ketones Synthesis of chiral amines Addition of a Grignard reagent to a tert-butanesulfinyl aldimine or ketimine results in asymmetric addition to give the branched sulfinamide. The observed stereoselectivity can be rationalized by a six-membered ring transition structure, wherein both oxygen and nitrogen of the sulfinyl imine coordinate magnesium.

Addition of a Grignard reagent to a tert-butanesulfinyl aldimine Removal The auxiliary can be removed from the desired amine by treatment with hydrochloric acid in a protic solvent.

Acidic cleavage of the sulfinamide auxiliary

SAMP/RAMP Alkylation reactions of chiral (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) and (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) hydrazones were developed by Dieter Enders and E.J. Corey.[30][31] Preparation SAMP can be prepared in six steps from (S)-proline, and RAMP can be prepared in six steps from (R)-glutamic acid.

Preparation of SAMP and RAMP from commercially available materials. Alkylation reactions Condensation of SAMP or RAMP with an aldehyde or ketone affords the (E)hydrazine. Deprotonation with lithium diisopropylamide and addition of an alkyl halide affords the alkylated product. The auxiliary can be removed by ozonolysis or hydrolysis.

Condensation, alkylation, and cleavage with SAMP/RAMP chiral auxiliaries Chiral auxiliaries in industry Chiral auxiliaries are generally reliable and versatile, enabling the synthesis of a large number of enantiomerically pure compounds in a time-efficient manner. Consequently, chiral auxiliaries are often the method of choice in the early phases of drug development.[2] Tipranavir The HIV protease inhibitor Tipranavir is marketed for the treatment of AIDS. The first enantioselective medicinal chemistry route to Tipranavir included the conjugate addition of an organocuprate reagent to a chiral Michael acceptor.[32] The chiral oxazolidinone in the Michael acceptor controlled the

stereochemistry of one of two stereocenters in the molecule. The final, commercial route to Tipranavir does not feature a chiral auxiliary; instead, this stereocenter is set by an asymmetric hydrogenation reaction.[33]

Synthetic strategies for setting a key stereocenter in Tipranavir. Atorvastatin The calcium salt of atorvastatin is marketed under the trade name Lipitor for the lowering of blood cholesterol. The first enantioselective medicinal chemistry route to atorvastatin relied on a diastereoselective aldol reaction with a chiral ester to set one of the two alcohol stereocenters.[34]In the commercial route to atorvastatin, this stereocenter is carried forward from readily available isoascorbic acid.[35]

Synthetic strategies for setting a key stereocenter in atorvastatin. See also

 

Example of use of trans-2-Phenyl-1-cyclohexanol as chiral auxiliary: Ojima lactam Valine as a Chiral auxiliary in the Schöllkopf method

References 1. Key Chiral Auxiliary Applications (Second Edition)(ed.: Roos, G.), Academic Press, Boston, 2014. ISBN 978-0-12-417034-6. 2. Glorius, F.; Gnas, Y. (2006). "Chiral Auxiliaries — Principles and Recent Applications". Synthesis. 12: 1899–1930. doi:10.1055/s-2006-942399. 3. Jamali, Fakhreddin (1993). "Chapter 14: Stereochemically Pure Drugs: An Overview". In Wainer, Irving W. Drug Stereochemistry: Analytical Methods and Pharmacology. Marcel Dekker, Inc. pp. 375–382. ISBN 0-8247-8819-2.

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