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auxiliar quiral

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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 8-
fenilmentol 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-fenil-
1-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 5-
benciloximetilciclopentadieno. [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-1-
ciclohexanol [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-2-


phenylcyclohexanol . 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 Diels-
Alder . [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-butil-
litio 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 syn-
stereorelationship 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 N-
mcthacryloylcamphorsultam 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 non-
nucleophilic 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

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