This invention relates to the production of chiral compounds that are useful intermediates in the synthesis of organic molecules for pharmaceutical and industrial applications. More particularly, this invention relates to a practical asymmetric synthesis of general application that employs either enantiomer of pseudoephedrine as a chiral auxiliary.

BACKGROUND OF THE INVENTION

Stereoisomerism is a well known phenomenon in organic chemistry. By definition, stereoisomers are compounds that have the same molecular formula and connectivity, yet differ in the spatial arrangement of their atoms. Enantiomers represent one class of stereoisomers. Enantiomers are pairs of molecules that exist as nonsuperimposable mirror images of one another. Those compounds which cannot be superimposed on their mirror images are also said to be chiral.

A common feature of most chiral organic compounds is the presence of one or more "stereogenic" or asymmetric carbon atoms within the molecule. This invention describes a method for the preparation of a wide variety of such asymmetric carbon centers with predetermined stereochemistry. This invention also relates to novel intermediates useful in the synthesis of a wide variety of compounds with predetermined chirality. Enantiomers are identical with respect to certain physical properties, such as their melting and boiling points. However, they may display profound differences in their chemical properties, particularly within biological systems. For example, it is now believed that the teratogenic effects of the notorious tranquilizer thalidomide are due to only one

enantiomer of the drug; the other enantiomer is believed to be a safe and useful tranquilizer devoid of teratogenic side effects. Consequently, the preparation of pharmaceutical agents as pure enantiomers, uncontaminated by an enantiomeric impurity, is now an overriding concern within the pharmaceutical industry.

One approach to the synthesis of enantiomerically enriched asymmetric compounds is to employ an asymmetric catalyst. For example, United States patents 5,189,177 and 4,943,635 refer to catalysts for the reduction of ketones to form optically active alcohols and are limited to the production of optically active alcohols. Another approach is to employ stoichiometric chiral auxiliaries. An advantage of the use of chiral auxiliaries is that they allow for the facile purification of products to a high degree of diastereomeric purity. By contrast, it is often difficult to further enrich the products of a reaction employing an asymmetric catalyst.

Evans and co-workers have developed a method for the synthesis of enantiomerically enriched molecules that employs one of two chiral oxazolidinones as a "chiral auxiliary." [D.A. Evans et al., J. Am. Chem. Soc. , 1982, 104 1737]. A chiral auxiliary provides an asymmetric environment that dictates the stereochemical outcome of a reaction in a predictable fashion and which, subsequent to the reaction in question, is ideally removed intact for reuse. Disadvantages of the Evans method include the following: (1) the chiral auxiliary is costly when obtained from commercial suppliers, and is difficult to synthesize; (2) the attachment of the chiral auxiliary is difficult relative to the invention disclosed herein; (3) the key step in the Evans method, the alkylation reaction, is restricted to reactive substrates, e.g., those that are allylic or benzylic, or which deliver a methyl group; (4) the products of the Evans alkylation reaction are less versatile with respect to subsequent

transformations versus the invention disclosed herein. In contrast, the asymmetric synthesis disclosed herein employs a chiral auxiliary that is both inexpensive and readily available as either enantiomer. Further, pseudoephedrine amides are reactive towards a variety of important electrophiles, notably ethyl iodide, whereas the method of Evans et al. is far more limited.

Larcheveque and co-workers have developed a method for asymmetric synthesis that uses ephedrine as a chiral auxiliary. [Larcheveque et al., Tetrahedron Lett. , 1978,

3961; Larcheveque et al., J. Orαanometallic Chem.. 1979, 177. 5] . The method referred to in these papers is impractical for a number of reasons. The method fails to produce highly enantiomerically enriched products. Subsequent enrichment is also impractical because the products are oily rather than crystalline. Moreover, Larcheveque et al.'s method depends on the use of a highly carcinogenic solvent, hexamethylphosphoric triamide.

The present invention discloses the use of pseudoephedrine as a chiral auxiliary for the preparation of a wide variety of highly enantiomerically enriched end products. The disclosed asymmetric synthesis yields unprecedented levels of enantiomerically enriched products, which are in turn useful for synthesizing a wide variety of compounds with predetermined stereomeric centers. Moreover, the synthesis is commercially practical. Chiral intermediates synthesized according to the present invention are especially useful for the preparation of pharmaceutical agents which include, for example, chiral amino acids.

SUMMARY OF THE INVENTION

A method for synthesizing enantiomerically enriched chemical intermediates with predetermined chirality is described. The method comprises formation of a pseudoephedrine amide, followed by stereoselective alkylation at the alpha carbon. The chiral auxiliary can then be cleaved off, affording chiral end products useful for further transformations. The enantiomeric excess of the chiral end products may exceed 98%, and the chiral auxiliary can be recovered. Novel amides of pseudoephedrine used in this method are also disclosed.

DETAILED DESCRIPTION

For the purposes of this invention, the following definitions apply:

Adduct - A molecule formed by the chemical addition of two species.

Asymmetric Center - an atom in a molecule about which there is no plane of symmetry. Chiral Auxiliary - an asymmetric molecule which biases a chemical reaction to favor selective formation of one stereoisomer over another.

Chirality - the characteristic of a molecule which cannot be superimposed on its mirror image. A chiral molecule and its mirror image are enantiomers.

Diastereomer - stereoisomers other than enantiomers. Enantiomer - one of a pair of isomeric molecules that are non-superimposable mirror images of one another.

Enantiomeric Excess - the predominance of one enantiomer over the other in a mixture of the two. The degree of enrichment is expressed as the percentage difference of the major enantiomer over the minor one.

Enantiomerically Enriched - when the amount of one enantiomer in a mixture exceeds the amount of the other. Stereoisomers - Molecules which have the same molecular

formula and connectivity, yet differ in the spatial arrangement of their atoms.

The method of this invention employs the chiral auxiliary pseudoephedrine, [α-(1-methylaminoethyl) benzyl alcohol]

(+)-pseudoephedrine (-)-pseudoephedrine

Either the (1S,2S) or (1R,2R) enantiomers of pseudoephedrine may be used as the chiral auxiliary.

In one embodiment, this invention comprises a method of general application for synthesis of a wide variety of compounds of predetermined chirality that are useful in asymmetric synthesis. Briefly, this method involves the acylation of a given enantiomer of pseudoephedrine, followed by alkylation of the alpha carbon of the adduct. The alkylation proceeds in a stereoselective manner and is directed by the chiral auxiliary pseudoephedrine. The amide is transformed into the corresponding chiral carboxylic acid, primary alcohol, aldehyde or ketone, and the chiral auxiliary is recovered.

More specifically, in the first step of this method a carboxylic acid anhydride or carboxylic acid halide or other active acylating agent is condensed with the pseudoephedrine chiral auxiliary to form an amide of pseudoephedrine.

(S, S) Pseudoephedrine Amide The substituent "R" is almost infinitely variable. It is

expected that compounds where R is (CH ₂ ) _n CH ₃ and n is 0-14; R is branched alkyl, R is aromatic (e.g., phenyl, napthyl, heteroaromatic) ; R is alkenyl and R includes a heteroatom such as 0,N,P,S or halogen, can be used. These pseudoephedrine amides are novel compounds, both in racemic and in enantiomerically enriched forms.

For example, the carboxylic acid anhydrides propionic anhydride and hexanoic anhydride were used to synthesize pseudoephedrine propionamide and pseudoephedrine hexanamide, respectively. Methods for the acylation of pseudoephedrine with a wide variety of compounds are known to those ordinarily skilled in synthetic organic chemistry.

In a second step, the pseudoephedrine amide is alkylated at the alpha carbon. Preliminarily, the pseudoephedrine amide is enolized using lithium diisopropylamide at low temperature in tetrahydrofuran. Other bases may be used in place of lithium diisopropylamide, for example, lithium dicyclohexylamide, lithium diethylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide.

It is believed that the factors responsible for the high diastereoselectivity of these alkylations are 1) the highly selective formation of a Z-configured enolate intermediate, and (2) the blocking of a specific π-face of this enolate (determined by the chirality of the pseudoephedrine employed) which leads to alkylation in a highly selective manner from the opposite π-face. The mechanism of the reaction results in a halide leaving group.

Alkylation is carried out in the presence of 6 - 10 equivalents of a lithium halide salt. Lithium chloride is preferred, although it is believed that other halide salts, including lithium bromide, and lithium iodide are also operative. It is further believed that other lithium salts may also be employed. The reaction may be carried out at from -78° C to 0°C, the latter being preferred.

(S, S Alkylated Pseudoephedrine Amide)

Following extractive workup, the alkylated amides are purified by recrystallization or flash column chromatography to afford highly diastereomerically enriched products.

In an alternative embodiment, alkylation is carried out with epoxides. This affords reverse selectivity: eletrophilic attack is at the face of the Z-enolate opposite to that attacked by alkyl halides. It is believed that the mechanism underlying reverse selectivity is intermolecular chelation of lithium alkoxide moiety by the epoxide oxygen; the leaving group being an internal alkoxide. Diastereomeric selectivity in excess of 80 % is observed using ethylene oxide as alkylating agent, without subsequent recrystallization.

Fundamental to this method is the fact that the alkylation reaction produces essentially only one of the two possible isomers at the alkylation center; furthermore, it has been found that any contaminating isomer may be readily removed in a purification step. These products, "alkylated pseudoephedrine amides," are shown to be highly versatile intermediates, exemplified by their transformation into carboxylic acids, ketones, aldehydes, and primary alcohols of broad description. Because the latter transformations proceed without appreciable isomerization at the alkylation center, and because essentially only one configuration is produced at the alkylation center in the alkylation reaction, these carboxylic acid, ketone, aldehyde, and primary alcohol products are formed as highly enantiomerically enriched materials, thus establishing their utility as starting materials for asymmetric synthesis.

Another preferred embodiment of the invention provides a method for synthesis of highly enantiomerically enriched α

a ino acids. The general structure of α amino acids is:

A wide variety of a amino acids can be synthesized using the method of this invention wherein acylation is carried out with

N-BOC (t-butoxycarbonyl) glycine to form diasteriomerically enriched pseudoephedrine glycinamide:

In a second phase of the synthesis, pseudoephedrine glycinamide is alkylated to form an alkylated amide corresponding to the desired amino acid. The diasteriomeric selectivity of the alkylation reaction is excellent, generally providing 90-93% de (diastereomeric excess) with benzylic and allylic halides and 95 to 97% de with primary alkyl iodides. Most of the alkylation products are crystalline solids and yield diasteriomerically pure derivatives after a single recrystallization.

In the third phase of amino acid synthesis, the alkylation products are cleaved from the chiral auxiliary. In the presence of aqueous sodium hydroxide, the amide is readily cleaved, with virtually no racemization. This represents a major advance over existing methodologies in that the free amino acid may be obtained in a direct step from the alkylated product. The resulting aqueous amino acid solutions can be treated with a variety of N-acylating agents to provide highly enantiomerically enriched N-protected (N-BOC or N-FMOC) amino acids which may be used as substrates for solid phase peptide synthesis. Among highly enantiomerically enriched amino acids that have been synthesized with this methodology is the novel

amino acid 2' chloroazatyrosine, a component of the antitumor antibiotic kedarcidin.

More generally, this invention comprises a process for preparing novel diastereomerically enriched compounds of the formula:

'

wherein R and R are different and are each independently P(M) _n where M is O or C and n is 0,1,2 or 3, a C,-C _u straight or branched-chain alkyl group, a C ₂ -C _u straight or branched- chain alkenyl or alkynyl group, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR 1R2 where R1 and R2 are each independently selected from the group consisting of hydrogen, i, C,-C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R where R is C ₁ -C _u straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C→.-C straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo, C,-C ₆ alkylthio, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl, hydroxy, C--C ₆ alkoxy, thio, C ₁ -C ₆ alkylthio, NR R where

R 1 and R2 are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched-chain

alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R ⁴ and NHC0 ₂ R ⁴ where R is C ₁ -C ₁₄ straight or branched-chain alkyl which comprises reacting at about -78°C to 0°C a compound of the formula

wherein R is define above with a compound of the formula R X wherein R is as defined above and X is a leaving group, such as a halide, in the presence of lithium salt and lithium dialkylamide base in a reaction inert solvent. In a preferred embodiment, the process occurs at 0 degrees centigrade in the presence of a molar excess of lithium chloride.

This invention also comprises a process for preparing novel de compounds of the form

wherein R and R are different and are each independently P(M) _n where M is O or C and n is 0,1,2 or 3, a C--C straight or branched-chain alkyl group, a C ₂ -C _H straight or branched- chain alkenyl or alkynyl group, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR R where R and R are each independently selected from the group consisting of hydrogen,

4

C ₁ -C ₆ straight or branched-chain alkyl , C ₃ -C ₈ cycloalkyl , C0 ₂ R and NHC0 ₂ R 4 where R4 is C.,-C ₁₄ straight or branched-chaipn alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C ₁ -C _H straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or

branched-chain alkenyl or alkynyl group, halo, C ₁ -C ₆ alkylthio , heteroaryl , C ₃ -C ₈ cycloalkyl , C ₉ -C ₁₆ bicycloalkyl , aryl , hydroxy, C ₁ -C ₆ alkoxy , thio , C,-C ₆ alkylthio , NR'R ² where

R 1 and R 2 are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R where R ⁴ is C ₁ -C ₁₄ straight or branched-chain alkyl which comprises reacting at about -78°C to 0°C a compound of the formula

wherein R is as defined above with a compound of the formula R X wherein R is as defined above and X is a leaving group, such as a halide, in the presence of lithium salt and lithium dialkylamide base in a reaction inert solvent. In a preferred embodiment, the process occurs at 0 degrees centigrade in the presence of a molar excess of lithium chloride.

This invention also comprises a process for preparing novel ee (enantiomerically enriched) compounds of the form:

HOOCCHRR ³ wherein R and R are different and are each independently P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C ₁ -C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched- chain alkenyl or alkynyl group, C,-C ₆ alkoxy, C ₁ -C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR ¹ R ² where R ¹ and R ² are each independently selected from the group consisting of hydrogen,

4

C ₁ -C ₆ straight or branched-chain alkyl , C ₃ -C ₈ cycloalkyl , C0 ₂ R and NHC0 ₂ R 4 where R 4 is C.,-C ₁₄ straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected

from P (M) _n where M is 0 or C and n is 0 , 1 , 2 or 3 , a C ₁ -C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo , C ₁ -C ₆ alkylthio, heteroaryl , C ₃ -C ₈ cycloalkyl , C ₉ -C ₁₆ bicycloalkyl , aryl , hydroxy, C -C ₆ alkoxy, thio , C,-C ₆ alkylthio, NR R where

R 1 and R 2 are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R ⁴ and NHC0 ₂ R where R ⁴ is C ₁ -C ₁₄ straight or branched-chain alkyl which comprises hydrolyzing a compound of the formula

wherein R and R are as defined above in the presence of a hydroxide in a reaction inert solvent. In a preferred embodiment, the hydroxide is tetrabutylammonium hydroxide.

This invention also comprises a process for preparation of novel ee compounds of the form:

HOOCCHRR ³ wherein R and R are different and are each independently P(M) _n where M is O or C and n is 0,1,2 or 3, a ^-C _u straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched- chain alkenyl or alkynyl group, C,-^ alkoxy, C ₁ -C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR 1R where R1 and R2 are each independently selected from the group consisting of hydrogen, t- C ₁ -C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R ⁴ where R is C^C^ straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected

from P (M) _n where M is 0 or C and n is 0 , 1 , 2 or 3 , a C ₁ -C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group , halo , C,-C ₆ alkylthio, heteroaryl , C ₃ -C ₈ cycloalkyl , C ₉ -C ₁₆ bicycloalkyl , aryl, hydroxy, C,-C ₆ alkoxy, thio, C,-C ₆ alkylthio, NR 1R2 where

R 1 and R2 are each independently selected from the group consisting of hydrogen, C,-C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R ⁴ where R ⁴ is C ₁ -C ₁₄ straight or branched-chain alkyl which comprises hydrolyzing a compound of the formula

wherein R and R are as defined above in the presence of hydroxide in a reaction inert solvent. In a preferred embodiment, the hydroxide is tetrabutylammonium hydroxide. This invention also comprises a process for preparing novel ee compounds of the form:

0

R 5 C "CHRR 3

wherein R and R are different and are each independently

P (M) _n where M is O or C and n is 0 , 1 , 2 or 3 , a C ₁ -C ₁₄ straight or branched-chain alkyl group , a C ₂ -C ₁₄ straight or branched- chain alkenyl or alkynyl group , C ₁ -C ₆ alkoxy , C ₁ -C ₆ alkylthio , halo , hydroxy , heteroaryl , C ₃ -C ₈ cycloalkyl , C ₉ -C ₁₆ bicycloalkyl, aryl or NR 1R2 where R1 and R2 are each independently selected from the group consisting of hydrogen,

4

C ₁ -C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R ⁴ where R ⁴ is C,-C ₁₄ straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio,

heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C ₁ -C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo, C^-C ₆ alkylthio, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl, hydroxy, C _| -C ₆ alkoxy, thio, C,-C ₆ alkylthio, NR1R2 where

R 1 and R2 are each independently selected from the group consisting of hydrogen, C--C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R ⁴ and NHC0 ₂ R ⁴ where R ⁴ is C^C,,, straight or branched-chain alkyl and R is C ₁ -C ₁₄ straight or branched-chain alkyl, aryl, heteroaryl, C ₃ -C ₈ cycloalkyl or C ₉ - C ₁₆ bicycloalkyl wherein when R is heteroaryl it is not bonded through the heteroatom which comprises reacting a compound of the formula

wherein R and R 3 are as defi.ned above with R5X2 where R5 i.s as defined above and X 2 is Li or a lanthanide at about -78°C to

0°C in a reaction inert solvent. In a preferred embodiment RR XX rreeaaccttiioonn iiss aaddddeedd aatt aabboouutt --7788 ddeeggrreeeess centigrade, and the mixture is subsequently warmed to 23°C.

This invention also comprises a process for preparing novel ee compounds of the formula:

wherein R and R are different and are each independently

P(M) _n where M is O or C and n is 0,1,2 or 3, a C.,-C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched- chain alkenyl or alkynyl group, C ₁ -C ₆ alkoxy, C,-C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR R2 where R1 and R2 are each independently selected from the group consisting of hydrogen,

4

C ₁ -C ₆ straight or branched-cham alkyl , C ₃ -C ₈ cycloalkyl , C0 ₂ R

4 4 , and NHC0 ₂ R where R is C ₁ -C _l4 straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C ₁ -C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo, C ₁ -C ₆ alkylthio, heretoaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl, hydroxy, C ₁ -C ₆ alkoxy, thio, C ₁ -C ₆ alkylthio, NR 1R2 where R and R are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R where R is C ₁ -C ₁₄ straight or branched-chain alkyl and R is C^-C straight or branched-chain alkyl, aryl, heteroaryl, C ₃ -C ₈ cycloalkyl or C ₉ - C ₁₆ bicycloalkyl wherein when R is heteroaryl it is not bonded through the heteroatom which comprises reacting a compound of the formula

wherein R and R 3 are as defined above with R5X2 where R5 is as defined above and X is Li or a lanthanide at about -78°C to

5 2

0°C in a reaction inert solvent. In one embodiment the RX at about -78 degrees centigrade, and the mixture subsequently wormed to about 23°C.

This invention also comprises a process for preparing novel ee compounds of the formula:

HOCH ₂ CHRR ³ wherein R and R are different and are each independently P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C ₁ -C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched- chain alkenyl or alkynyl group, C.,-C ₆ alkoxy, C,-C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR 1R2 where R1 and R2 are each independently selected from the group consisting of hydrogen,

C _| -C ₆ straight or branched-chain alkyl , C ₃ -C ₈ cycloalkyl , C0 ₂ R 4

4 4 . and NHC0 ₂ R where R is C -C straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is O or C and n is 0,1,2 or 3, a C,-^ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo, C,-C ₆ alkylthio, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl, hydroxy, C--C ₆ alkoxy, thio, C.,-^ alkylthio, NR ¹ R where R and R are each independently selected from the group consisting of hydrogen, C,-C ₆ straight or branched-chain

₄ 4 alkyl, C ₃ -C ₈ cycloalkyl, CO _z R and NHC0 ₂ R where R is C,-C ₁₄ straight or branched-chain alkyl which comprises reacting a compound of the formula

wherein R and R are as defined above with a secondary organic amine, (C ₁ -C ₆ ) alkyllithium and borane in a reaction inert solvent at about 0°C to 23°C. In a preferred embodiment, the secondary organic amine is pyrrolidine, the (C,-C ₆ ) alkyllithium is n-butyllithium and the reaction inert solvent

is tetrahydrofuran.

This invention also comprises a process for preparing novel ee compounds of the formula:

HOCH ₂ CHRR ³ 3 wherein R is and R are different and are each independently P(M) _n where M is O or C and n is 0,1,2 or 3, a C,-C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched- chain alkenyl or alkynyl group, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR 1R2 where R1 and R2 are each independently selected from the group consisting of hydrogen,

4

C ₁ -C ₆ straight or branched-chain alkyl , C ₃ -C ₈ cycloalkyl , C0 ₂ R

4 4 . and NHC0 ₂ R where R is C,-C ₁₄ straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is O or C and n is 0,1,2 or 3, a C^-C straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo, C ₁ -C ₆ alkylthio, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₁₆ bicycloalkyl, aryl, hydroxy, C ₁ -C ₆ alkoxy, thio, C,-C ₆ alkylthio, NR 1R2 where

R 1 and R2 are each independently selected from the group consisting of hydrogen, C,-C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R where R is C ₁ -C ₁₄ straight or branched-chain alkyl which comprises reacting a compound of the formula

R ³

wherein R and R are as defined above with a secondary organic amine, (C.,-C ₆ ) alkyllithium and borane in a reaction inert

solvent at about 0°C to 23°C. In a preferred embodiment, the secondary organic amine is pyrrolidine, the (C.,-C ₆ ) alkyllithium is n-butyllithium and the reaction inert solvent is tetrahydrofuran.

This invention also comprises a process for preparing novel ee compounds of the formula:

O

I

HCCHRR ²

wherein R and R are different and are each independently P(M) _n where M is O or C and n is 0,1,2 or 3, a C _l -C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched- chain alkenyl or alkynyl group, C ₁ -C ₆ alkoxy, C.-C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR where R ¹ and R ² are each independently selected from the group consisting of hydrogen,

4 ^c ι~ ^C ₆ straight or branched-chain alkyl , C _Z -C _B cycloalkyl , C0 ₂ R

4 4 and NHC0 ₂ R where R is C,-C ₁₄ straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is O or C and n is 0,1,2 or 3, a .-C-^ straight or branched-chain alkyl group, a _z -C _u straight or branched-chain alkenyl or alkynyl group, halo, C ₁ -C ₆ alkylthio, heteroaryl, C ₃ -C ₈ cycloalkyl, ₉ -C^ ₆ bicycloalkyl, aryl, hydroxy, C ₁ -C ₆ alkoxy, thio, C ₁ -C ₆ alkylthio, NR R where R 1 and R2 are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R ⁴ where R is C.,-C _u straight or branched-chain alkyl which comprises reacting a

compound of the formula

wherein R and R are as defined above with the product of a mixture of lithium aluminum hydride and ethyl acetate in a reaction inert solvent at about -78°C to 0°C. In a preferred embodiment, the reaction inert solvent is hexanes or pentane. This invention also comprises a process for preparing novel ee compounds of the formula:

H ?CCHRR

wherein R and R are different and are each independently P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C,-C ₁ straight or branched-chain alkyl group, a C ₂ -C- straight or branched- chain alkenyl or alkynyl group, C,-C ₆ alkoxy, C,-C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C- _ύ bicycloalkyl, aryl or NR 1R2 where R1 and R2 are each independently selected from the group consisting of hydrogen,

4

C _| -C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R where R is C ₁ -C ₁₄ straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C ₁ -C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo, C,-C ₆ alkylthio, heretoaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl, hydroxy, C ₁ -C ₆ alkoxy, thio, C^-C ₆ alkylthio, NR R where

R and R are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R where R is C ₁ -C ₁₄ straight or branched-chain alkyl which comprises reacting a compound of the formula:

wherein R and R are as defined above with the product of a mixture of lithium aluminum hydride and ethyl acetate in a reaction inert solvent at about -78°C to 0°C. In a preferred embodiment, the reaction inert solvent is hexanes or pentane. This invention also comprises a process for the preparation of novel ee compounds of the form:

HOOCCHRR ³ wherein R and R are different and are each independently

P(M) _n where M is O or C and n is 0,1,2 or 3, a C,-^ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched- chain alkenyl or alkynyl group, C ₁ -C ₆ alkoxy, C--C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR R where R ¹ and R are each independently selected from the group consisting of hydrogen,

4

C,-C ₆ straight or branched-chain alkyl , C ₃ -C ₈ cycloalkyl , C0 ₂ R and NHC0 ₂ R 4 where R4 i.s C _l -C ₁₄ straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C ₁ -C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo, C,-C ₆ alkylthio, heretoaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl,

1 2 aryl, hydroxy, C,-C ₆ alkoxy, thio, C,-C ₆ alkylthio, NR R where R and R are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched-chain

4 , alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R where R is C ₁ -C ₁₄ straight or branched-chain alkyl which comprises hydrolyzing a compound of the formula

wherein R and R are as defined above in the presence of acid and water in a reaction inert solvent. In a preferred embodiment, the process is conducted in the presence of sulf ric acid, dioxane and water.

This invention also comprises preparation of novel ee compounds of the form:

HOOCCHRR ³ wherein R and R are different and are each independently

P(M) _n where M is O or C and n is 0,1,2 or 3, a C,-C ₁₄ straight or branched-chain alkyl group, a ₂ -C straight or branched- chain alkenyl or alkynyl group, C.,-C ₆ alkoxy, C,-^ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR 1R where R1 and R2 are each independently selected from the group consisting of hydrogen,

4

C ₁ -C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R ⁴ where R ⁴ is C,-C ₁₄ straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C^C^ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo, C--C ₆ alkylthio, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl,

aryl, hydroxy, C,-C ₆ alkoxy, thio, C.,-C ₆ alkylthio, NR 1R 2 where R and R are each independently selected from the group consisting of hydrogen, C,-^ straight or branched-chain

4 4 4 , alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R where R is C ₁ -C ₁₄ straight or branched-chain alkyl which comprises hydrolyzing a compound of the formula

wherein R and R are as defined above in the presence of acid and water in a reaction inert solvent. In a preferred embodiment, the process is conducted in the presence of sulfuric acid, dioxane and water. In another embodiment, this invention, comprises novel compounds of the form:

wherein R is P (M) _n where M is O or C and n is 0 , 1 , 2 or 3 , a straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group , C ₁ -C ₆ alkoxy, C.,-C ₆ alkylthio , halo , hydroxy, heteroaryl , C ₃ -C ₈ cycloalkyl , C ₉ -C ₁₆ bicycloalkyl, aryl or NR 1R2 where R 1 and R 2 are each independently selected from the group consisting of hydrogen,

4

C.,-C ₆ straight or branched-cham alkyl , C ₃ -C ₈ cycloalkyl , C0 ₂ R

4 4 and NHC0 ₂ R where R is C.-C ₁₄ straight or branched-cham alkyl

where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is 0 or C and n is 0,1,2 or 3, a C,-C ₁₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or branched-chain alkenyl or alkynyl group, halo, C ₁ -C ₆ alkoxy, thio, C--C _ύ alkylthio, NR 1R2 where R1 and R2 are each independently selected from the group consisting of hydrogen,

4

C.,-C ₆ straight or branched-cham alkyl , C ₃ -C ₈ cycloalkyl , C0 ₂ R and NHC0 ₂ R 4 where R4 is C ₁ -C ₁₄ strai.ght or branched-chain alkyl, provided that R is not 1-(S)-methylpentyl or (R)-α- methylbenzyl. In a preferred embodiment, R is methyl, n- butyl, phenyl or benzyl.

In yet another embodiment of this invention, this invention comprises novel de compounds of the form:

wherein R and R are different and are each independently P(M) _n where M is O or C and n is 0,1,2 or 3, a C,-C ₁₄ straight or branched-chain alkyl group, a C _z -C _u straight or branched- chain alkenyl or alkynyl group, C,-C ₆ alkoxy, C,-C ₆ alkylthio, halo, hydroxy, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl or NR 1R2 where R1 and R2 are each independently selected from the group consisting of hydrogen,

4

C,-C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R ⁴ where R ⁴ is C ₁ -C ₁₄ straight or branched-chain alkyl where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heteroaryl, cycloalkyl, bicycloalkyl and aryl are optionally substituted with one or more groups independently selected from P(M) _n where M is O or C and n is 0,1,2 or 3, a 0,-0, ₄ straight or branched-chain alkyl group, a C ₂ -C ₁₄ straight or

branched-chain alkenyl or alkynyl group, halo, C--C ₆ alkylthio, heteroaryl, C ₃ -C ₈ cycloalkyl, C ₉ -C ₁₆ bicycloalkyl, aryl, hydroxy, C^-C _ύ alkoxy, thio, C1-C6 alkylthio, NR 1R2 where

R 1 and R2 are each independently selected from the group consisting of hydrogen, C,-C ₆ straight or branched-chain alkyl, C ₃ -C ₈ cycloalkyl, C0 ₂ R and NHC0 ₂ R where R ⁴ is C _l -C ₁₄ straight or branched-chain alkyl.

These novel compounds are useful in preparing compounds of predetermined chirality according to the method disclosed herein.

EXAMPLES

General Procedures. All nonaqueous reactions were performed in flame-dried glassware fitted with rubber septa under a positive pressure of argon, unless otherwise noted. Air-and moisture-sensitive liquids were transferred via syringe or stainless steel cannula. Deoxygenation of solutions was accomplished by either the freeze-pu p-thaw technique, or evacuating and flushing the solution with argon. Organic solutions were concentrated on a Bϋchi rotary evaporator at 10-20 Torr, unless otherwise specified. Residual solvents were removed under an active vacuum of 0.5 Torr. Flash chromatography was performed using a forced flow with the indicated solvent using JT Baker silica gel (40 mm) . Analytical thin-layer chromatography (TLC) was performed using Merck pre-coated silica gel 60 F-254 plates (0.25 mm, glass-backed, fluorescent at 254 nm) . Instrumentation. Melting points were recorded with a Bϋchi SMP-20 melting point apparatus and are uncorrected. Infrared spectra were recorded with a Perkin Elmer 1600 FTIR spectrometer. Data are represented as follows: frequency of absorption (cm-1) , and intensity of absorption (s=strong, m=medium, w=weak, br=broad) . The 1H NMR spectra were recorded

on a General Electric QE-300 (300 Mhz) NMR spectrometer; peaks are reported in ppm (5 scale) , using the residual solvent peak as reference (CHC13: 7.26, C6D5H: 7.15) . Data are represented as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet, m=multiplet, br=broad) , integration, coupling constants in Hertz. The 13C NMR were obtained on a QE-300 (75.5 Mhz) NMR spectrometer, and are reported in ppm (<5scale) using the solvent peak as reference (CDC13: 77.0, C6D6: 128.0) . Analytical gas-liquid chromatography (GC) was carried out on a Hewlett Packard 5890 gas chromatograph equipped with a splitless mode capillary injection system and a flame ionization detector, using a 25 m x 0.25 mm Alltech Chirasil - Val III chiral fused silica capillary column. Materials. Tetrahydrofuran and diethyl ether were distilled from sodium-benzophenone ketyl. Dichloromethane, hexanes, triethylamine, diisopropylamine, chlorotrimethylsilane, benzene, and toluene were distilled from calcium hydride. C6D6 and CDC13 were dried over activated 3A sieves. Solvents used in the workup and purification of compounds were HPLC-reagent grade or ACS grade and were used without further purification. Lithium chloride was dried under active vacuum for 4 h at 140°C, then transferred to a nitrogen-filled glovebox. The molarity of n- butyllithium was determined by titration with diphenylacetic acid. All alkyl halides were purified immediately prior to use by passage through a short column of basic alumina. All other reagents were used as received.

Method - Preparation of Pseudoephedrine Amides

Pseudoephedrine amides were prepared by condensing pseudoephedrine with the appropriate carboxylic acid anhydride or carboxylic acid chloride in tetrahydrofuran or dichloromethane.

Reaction with the carboxylic acid anhydride involved mixing the carboxylic acid anhydride with a tetrahydrofuran or dichloromethane solution of pseudoephedrine. It is preferred to keep the reaction in an ice bath or water bath since the reaction is exothermic. The pseudoephedrine amides were isolated by quenching the reaction with aqueous bicarbonate, and extracting the amide. Following removal of the solvent, recrystallization afforded analytically pure product.

Reaction with the carboxylic acid chloride involved adding the carboxylic acid chloride to a tetrahydrofuran or dichloromethane solution of pseudoephedrine and triethylamine at 0°C. The pseudoephedrine amides were isolated by quenching the reaction with water, and extracting the amide. Following removal of the solvent, recrystallization afforded analytically pure product.

Example 1

r s- TR* . R* 1 1 -N- ( 2-hydroxy-l-methyl-2-phenylethyl N-methyl propionamide

Into a dry 1 L round-bottomed flask equipped with a magnetic stirrer was added (+) -pseudoephedrine (21.34 g, 129.1 mmol, 1.0 equiv) and tetrahydrofuran (250 Ml) . The flask was placed in a 23°C water bath, and to the well-stirred solution was added propionic anhydride (17.98 g, 138.2 mmol, 1.07 equiv) in 1 Ml portions over several minutes. The solution was stirred for an additional 10 min at 23°C, and then quenched with saturated sodium bicarbonate (400 Ml) , and stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate (250 Ml, 150 Ml, 150 Ml), and the combined organic extracts were dried over sodium sulfate. After the removal of the solvent under reduced pressure, a white solid was obtained. Recrystallization from toluene (125 Ml) afforded the desired propionamide as white crystals (27.19 g, 95% yield): mp 114-115°C; 1H NMR (300 Mhz, C6D6) 66.95-7.45 (m, 5H) , 4.83 (br, 1H) , 4.51 (t, 1H, J = 7.2 Hz), 4.0-4.2 (m, 2H) , 3.6-3.75 (m, 1H) , 2.77 (s, 3H) , 2.40 ( , 2H) , 2.06 (ε, 3H) , 1.73 (m, 2H) , 1.22 (t,3H, J = 7.3 Hz) , 0.9-1.1 (m, 6H) , 0.53 (d, 3H, J = 6.7 Hz) ; 13C NMR (75.5 Mhz, CDC13) 5175.8, 174.8, 142.2, 141.5, 128.3, 128.1, 127.9, 127.4, 126.7, 126.3, 76.1, 75.0, 58.1, 57.7, 32.1, 27.3, 27.6, 26.6, 15.2, 14.2, 9.4, 9.0; FTIR (neat film) cm-1 3380 (br, m) , 2979 (m) , 1621 (s) , 1454 (m) , 1402 (m) , 1053 (m) , 702 (m) ; HRMS (FAB) Calcd for C13H20N02 (MH+) : 222.1495. Found: 222.1490; Anal. Calcd for C13H19N02: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.55; H, 8.50; N, 6.35.

Example 2

ΓS-ΓR*.R*11-N-f2-hvdroxy-l-roethyl-2-phenylethv -N-methyl benzenepropionamide

Into a dry 1 L round-bottomed flask equipped with a magnetic stirrer was added (+) -pseudoephedrine (22.34 g, 135.22 mmol, 1.0 equiv), triethylamine (21.5 Ml, 154 mmol, 1.14 equiv) , and tetrahydrofuran (300 Ml). The solution was cooled to 0°C and hydrocinnamoyl chloride (25.08 g, 148.74 mmol, 1.1 equiv) in tetrahydrofuran (100 Ml) was added via cannula over a 20 minute interval. After 30 minutes, the reaction was quenched with water. The amide was extracted from water (1 L) with ethyl acetate (400 Ml, 120 mL, 120 mL) , and the combined organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, a white solid was obtained, which was recrystallized from 2:1:1 ether/dichloromethane/hexanes (500 mL) affording the hydrocinnamide as white crystals (30.24 g, 75% yield): mp 102-104°C; IH NMR (300 MHz, C6D6) 67.0-7.4 (m, 5H) , 4.59 (br, IH) , 4.48 (t, IH, J = 7.1 Hz), 4.20 (m, IH) , 4.01 (dd, IH, J = 8.4 Hz, 2.4 Hz), 3.66 (m, IH) , 3.15 (m, 2H) , 2.93 (t, 2H, J = 7.7 Hz), 2.79 (s, 3H) , 2.49 (m, 2H) , 2.13 (m, 2H) , 2.02 (s, 3H) , 0.92 (d, 3H, J = 7.0 Hz), 0.49 (d, 3H, J = 6.8 Hz); 13C NMR (75.5 MHz, CDC13) 6174.3, 173.2, 142.2, 141.5, 141.3, 141.1, 128.6, 128.39, 128.36, 128.31, 128.29, 128.2, 127.6, 126.8, 126.4, 126.1, 125.9, 76.3, 75.3, 58.0, 36.1, 35.4, 32.3, 31.5, 31.1, 26.9, 15.2, 14.3; FTIR (neat film) cm-1 3374 (br, m) , 3027 (m) , 1621 (s) , 1495 (m) , 1454 (m) , 1406 (m) , 1118 (m), 1048 (m) , 753 (m) , 701 (m) ; HRMS (FAB) Calcd for C19H24N02 (MH+) : 298.1808; Found: 298.1806.

Example 3

rs-rR*.R*11-N-f2-hvdroxy-l-methyl-2-phenylethyl^-N-methyl hexanamide

In a dry 2 L round-bottomed flask equipped with a magnetic stirrer was added (+) -pseudoephedrine (40.0 g, 242.06 mmol, 1.0 equiv) and tetrahydrofuran (500 mL) , and the mixture was stirred in a 23°C water bath. Hexanoic anhydride (55.51 g, 259 mmol, 1.07 equiv) was added via cannula over a 10 minute interval, and transfer was quantitated with an additional portion of tetrahydrofuran (10 mL) . After 25 minutes, the reaction was quenched with saturated sodium bicarbonate (300 mL) . Volatile components were removed under reduced pressure, and the residue was extracted from water (500 mL) with ethyl acetate (3 x 250 mL) . The organic extracts were dried over sodium sulfate, and after removal of the solvent under reduced pressure, a white solid was obtained, which was recrystallized from 1:1 ether/hexanes (200 mL) to afford the hexanamide as white crystals (58.2 g, 91% yield): mp 62 -63°C; IH NMR (300 MHz, C6D6) 67.0-7.4 (m, 5H) , 4.9 (br, IH) , 4.52 (d, IH, J = 6.9 Hz) , 4.14 (m, IH) , 3.77 (m, IH) , 2.79 (s, 3H) , 2.42 (m, 2H) , 2.13 (ε, 3H) , 1.83 (m, 2H) , 1.59 (qn, 2H, J = 7.6 Hz), 1.1-1.4 (m, 4H) , 0.99 (d, 3H, J = 7.0 Hz) , 0.86 (t, 3H, J = 7.0 Hz) , 0.59 (d, 3H, J = 6.8 Hz) ; 13C NMR (75.5 MHz, CDC13) 6175.2, 174.2, 142.3, 141.6, 128.3, 128.0, 127.8, 127.3, 126.7, 126.2, 76.1, 75.1, 58.2, 57.0,

34.1, 33.4, 32.4, 31.5, 31.3, 26.6, 24.9, 24.5, 22.31, 22.29,

15.2, 14.2, 13.82, 13.79; FTIR (neat film) cm-1 3378 (br, m) , 2956 (m) , 2931 (m) , 2871 (m) , 1618 (s) , 1453 (m) , 1406 ( ) , 1051 (m) , 701 (m) ; HRMS (FAB) Calcd for C16H26N02 (MH+) : 264.1965. Found: 264.1966.

Example 4

rS-TR*. R*11-N-(2-hvdroxy-l-methyl-2-phenylethyl) -N-methyl benzeneacetamide

A dry 1 L round-bottomed flask equipped with a magnetic stirrer was charged (+) -pseudoephedrine (13.92 g, 84.26 mmol, 1.0 equiv) , triethylamine (13.39 mL, 96.06 mmol, 1.14 mmol), and tetrahydrofuran (340 mL) . The solution was cooled to 0°C and phenylacetyl chloride (14.33 g, 92.69 mmol, 1.1 equiv) was added via cannula over a 20 minute interval as a solution in tetrahydrofuran (90 mL) . After 30 minutes, the reaction was quenched with saturated sodium bicarbonate. The amide was extracted from brine (1 L) with ethyl acetate (400 mL, 130 mL, 130 mL) , and the organic extracts were dried over sodium sulfate. After removal of the solvent under reduced presεure, a εolid was obtained. The solid was recrystallized from 2:1:1 ether/ dichloromethane/hexaneε (500 mL) , affording the phenylacetamide (17.90 g, 75% yield) as a white powder: mp 145-146°C; IH NMR (300 MHz, C6D6) 66.9-7.5 (m, 10H) , 4.55 (br, IH) , 4.48 (t, IH, J = 7.1 Hz), 4.11 (m, IH) , 3.95 (m, IH) , 3.83 (m, IH) , 3.78 (s, 2H) , 3.31 (d, 2H, J = 1.3 Hz) , 2.76 (s, 3H) , 2.12 (s, 3H) , 0.95 (d, 3H, J = 7.0 Hz), 0.42 (d, 3H, J = 6.7 HZ); 13C NMR (75.5 MHz, CDC13) 6173.1, 172.2, 142.2, 141.4, 135.5, 134.5, 128.7, 128.64, 128.58, 128.3, 128.1,

127.5, 126.73, 126.68, 126.6, 126.3, 76.2, 75.3, 58.6, 41.8, 41.4, 33.3, 27.0, 15.0, 14.3; FTIR (neat film) cm-1 3393 (br, ) , 1618 (s) , 1494 (m) , 1453 (m) , 1402 (m) ; HRMS (FAB) Calcd for C18H22N02 (MH+) : 284.1652. Found: 284.1646.

Example 5

[S-(R* ,R*) 1-α-chloro-N-(2-hydroxy-l-methyl-2-phenylethyl) -N- methyl acetamide

In a dry round-bottomed flask equipped with a magnetic stirrer and an argon inlet was dissolved chloroacetic anhydride (5.00 g, 30.3 mmol, 1.0 equiv.) in dichloromethane (60 mL) . The solution was cooled to 0°C and a solution of (+) -pseudoephedrine (5.69 g, 33.3 mmol, 1.1 eq) and triethylamine (4.64 ml, 33.3 mmol, 1.1 eq) in dichloromethane (55 mL) was added via cannula. The reaction was stirred at 0°C for 1 hr and was quenched by addition of water. A saturated solution of sodium bicarbonate was added and the resulting layers partitioned. The aqueous layer was back extracted with dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel with ethyl acetate/hexanes as the eluent (25% - 75% gradient) gave [1S- (1R*,2R*)-α-chloro-N-(2-hydroxy-l-methyl-2-phenylethyl) -N- methyl acetamide (6.60g, 90%) as an oil which crystallized on standing. Recrystallization from a minimum volume of ether gave analytically pure product (1:1 mixture of rotamers) : mp 79-81°C; IH NMR (300 MHz, CDC13) 67.28-7.41 (m, 5H) , 4.54-4.63 (m, 1.5H), 4.35 (d, 0.5H, J = 12.4 Hz), 4.07 (d, 0.5H, J = 12.3 Hz), 4.07 (s, IH) , 3.98 (m, 0.5 H) , 3.74 (d(br), 0.5H, J = 4.7 Hz), 3.30 (d, 0.5H, J = 3.2 Hz), 2.94 (s, 3H) , 1.05 (d, 0.5H, J = 6.6 Hz), 1.02 (d, 1.5H, J = 6.8 Hz); 13C NMR (75.5 MHz, CDC13) 6168.2, 168.0, 141.6, 141.1,

128.7, 128.4, 127.9, 126.7, 126.5, 75.8, 75.1, 59.1, 57.7, 42.0, 41.7, 32.0, 27.4, 15.3, 14.0; FTIR (neat film) cm-1 3392, 3030, 2983, 1638. Anal. Calcd. for C ₁₂ H ₁₆ C1N0 ₂ : C, 59.63; H, 6.67; N, 5.79 Found: C:59.61, H, 6.66; N, 5.76.

Example 6

rs-(R*,R*) 1-N2-fbenzyloxycarbonyl) -Nl-(2-hvdroxy-l-methyl -2- phenylethyl)-Nl-methyl glycinamide

In a dry round-bottomed flask equipped with a magnetic stirrer and an argon inlet was dissolved N (benzyloxycarbonyl)-glycine (5.00 g, 23.9 mmol, 1.0 equiv) in dichloromethane (25 mL) . Triethylamine (3.66 mL, 26.3 mmol, 1.1 equiv) was added and the resulting mixture was cooled to 0°C. To the reaction was added dropwise trimethylacetylchloride (2.94 mL, 23.9 mmol, 1.0 equiv). A white precipitate formed and dichloromethane (25 mL) was added to allow efficient stirring. The reaction was stirred for 30 min at 0°C and then a solution of (+)-pseudoephedrine (4.15 g, 25.1 mmol, 1.05 eq) and triethylamine (3.66 L, 26.3 mmol, 1.1 eq) in dichloromethane (40 mL) was added via cannula. The reaction was stirred for 30 min at 0°C. Most of the solvent was removed under reduced pressure and water and saturated sodium bicarbonate were added. The product was extracted with two portions of ethyl acetate and the organic extracts were washed with saturated ammonium chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the

residue by flash chromatography on silica gel with ethyl acetate/hexanes as the eluent (30% - 80% gradient) gave [S- (R*,R*)-N2-(benzyl oxycarbonyl)-Nl-(2-hydroxy-l-methyl-2- phenylethyl)-Nl-methyl glycinamide (6.67g, 78%) as a white foam (1:1 mixture of rotamers) : IH NMR (CDC13, 300 MHz) 6 7.25-7.40 (m, 10H) , 6.04 (m, IH) , 5.09 (2s, 4H) , 4.67 (m, 0.5H), 4.51 (d, 0.5H, J = 4.5 Hz) , 4.49 (d, 0.5H, J = 4.7 Hz), 4.23 (dd, 0.5H, Jl = 16.7 Hz, J2 = 3.8 Hz), 4.15 (s(br), IH) , 4.04 (dd, 0.5H, Jl = 16.5 Hz, J2 = 5.1 Hz) , 3.92 (d, IH, J = 4.3 Hz), 3.77 (m, 0.5H) , 2.88 (s, 1.5H) , 2.77 (s, 1.5H) , 0.94 (d, 1.5H, J = 6.4 Hz) , 0.92 (d, 1.5H, J = 6.3 Hz) ; 13C NMR (CDC13, 75.5 MHz) 6 169.3, 169.0, 156.2, 141.4, 141.1, 136.30, 136.26, 128.4, 128.2, 128.02, 127.95, 127.7, 126.6, 126.5, 75.2, 74.6, 66.5, 57.4, 56.1, 42.9, 42.6, 29.3, 26.8, 14.9, 13.9; FTIR (neat film) cm-1 3405, 3323, 3031, 2980, 1719, 1638.

Method - Alkylation of Pseudoephedrine Amides

The novel process for alkylating pseudoephedrine amides comprised enolizing the amide with lithium diisopropylamide in tetrahydrofuran at -78 ° - 23°C over a period of about 1-2 hours, in the presence of lithium chloride (6-10 equiv) . Reaction of the enolate with alkyl halides at 0°C, over a period of 30 minutes to 1 hour, afforded the alkylated amide. The alkylated amides were isolated by quenching the reaction with ammonium chloride, followed by extraction with ethyl acetate. The amides were then purified by recrystallization or flash column chromatography to afford highly diastereomerically enriched products.

Example 7

dimethyl benzenepropiona ide

A dry 2 L 3-necked round-bottomed flask was equipped with a mechanical stirrer, and charged with lithium chloride (25.0 g, 596 mmol, 6.0 equiv), diisopropylamine (31.3 mL, 224 mmol, 2.25 equiv), and tetrahydrofuran (120 mL) . The suspension was cooled to -78°C, and n-butyllithium (2.43 M in hexanes, 85.1 mL, 207 mmol, 2.08 equiv) was added via cannula. After a brief warming to 0°C, it was recooled to -78°C. [S-[R*,R*]]- N-(2-hydroxy-l-methyl-2-phenylethyl) -N-methyl propionamide (22.0 g, 99.41 mmol, 1.0 equiv) was added as a 0°C solution in tetrahydrofuran (300 L) . The resulting solution was stirred at -78°C for 1 hour, warmed to 0° C for 15 minutes, warmed to 23°C for 5 minutes, and cooled to 0°C. Benzyl bromide (17.74 mL, 149 mmol, 1.5 equiv) was added, and the reaction was stirred at 0°C. The reaction was quenched after 15 minutes with saturated ammonium chloride, and the amide was extracted from saturated ammonium chloride (800 L) with ethyl acetate (500 mL, 150 mL, 150 mL) . The combined organic extracts were dried over sodium sulfate, and after removal of the solvent under reduced pressure, a yellow solid was obtained. Recrystallization from toluene (100 mL) yielded the desired product as a white powder (27.77 g, 90% yield) . GC analysis of the TMS ether indicated a diastereomeric purity of the amide of greater than 99 % de: mp 136-137°C; IH NMR (300 MHz, C6D6) 66.9-7.4 (m, 10 H) , 4.45 (m, IH) , 4.25

(br, IH) , 3.96 (m, IH) , 3.80 (m, IH) , 3.36 (dd, 2H, J = 13.1 Hz, 6.92 Hz), 3.01 (m, IH) , 2.75 (m, IH) , 2.70 (s, 3H) , 2.45-2.59 (m, 3H) , 2.08 (s, 3H) , 1.05 (d, 3H, J = 7.0 Hz), 1.02 (d, 3H, J = 6.5 Hz), 0.83 (d, 3H, J = 7.0 Hz) , 0.59 (d, 3H, J = 6.8 HZ); 13C NMR (75.5 MHz, CDC13) 6178.2, 177.2, 142.3, 141.1, 140.5, 139.9, 129.2, 128.9, 128.6, 128.31, 128.26, 127.5, 126.8, 126.4, 126.2, 76.4, 75.2, 58.0, 40.3, 40.0, 38.9, 38.1, 32.3, 27.1, 17.7, 17.4, 15.5, 14.3; FTIR (neat film) cm-1 3384 (br, m) , 3027 (m) , 2973 (m) , 2932 (m) ,

10 1617 (S) , 1493 (m) , 1453 (m) , 1409 (m) , 1080 (m) , 1050 (m) , 701 (s) ; HRMS (FAB) Calcd for C20H26N02 (MH+) : 312.1965. Found: 312.1972; Anal. Calcd for C20H25NO2: C, 77.14, H, 8.09, N, 4.50. Found: C, 76.87, H, 8.06, N, 4.50.

20

r iS- r iR* tR* , 2R*11-N-(2-hydroxy-l-methyl-2-phenylethyl)-N.2- dimethyl benzenepropionamide

25 A dry 1 L 3-necked round-bottomed flask equipped with a mechanical stirrer was charged with lithium chloride (5.99 g, 141.22 mmol, 6.0 equiv), diisopropylamine (7.42 mL, 52.96 mmol, 2.25 equiv), and tetrahydrofuran (75 mL) . The suspension was cooled to -78°C, and n-butyllithium (1.73 M in ^' 30 hexanes, 28.30 mL, 48.96 mmol, 2.08 equiv)was added via cannula, and the resulting solution was briefly warmed to 0°C, then recooled to -78°C. [S-[R*,R*] ]-N-(2-hydroxy-l-methyl-2- phenylethyl) -N-methyl benzene-propionamide (7.0 g, 23.54 mmol, 1.0 equiv) was added at 0°C as a solution in tetrahydrofuran

35 (75 mL) . The mixture was stirred at -78 °C for 1 h, 0°C for

15 minutes, and 23°C for 5 minutes, then recooled to 0°C. Iodomethane (4.40 mL, 70.61 mmol, 3.0 equiv) was added, and after 45 minutes, the reaction was quenched with saturated ammonium chloride. The amide was extracted from saturated ammonium chloride (400 mL) with ethyl acetate (3 x 140 L) , and upon removal of the solvent under reduced pressure a white solid was obtained. Recrystallization from 1:1 ether/hexanes (60 mL) provided the methylated hydrocinnamide as white crystals (5.89 g, 80% yield) . GC analysis of the TMS ether indicated a diastereomeric purity of the amide of 93 % de: p 79-81°C; IH NMR (300 MHz, C6D6) 66.95-7.4 (m, 10 H) , 5.25 (br, IH) , 4.51 (t, IH, J = 7.0 Hz), 3.97 (m, IH) , 3.75 (m, IH) , 3.15 (m, IH) , 3.06 (m, IH) , 3.02 (m, 2H) , 2.71 (s, 3H) , 2.58 (m, IH) , 2.4 (m, 2H) , 1.93 (s, 3H) , 1.34 (d, 3H, J = 6.3 Hz) , 1.00 (d, 3H, J = 7.0 Hz), 0.93 (d, 3H, J =6.4 Hz), 0.30 (d, 3H, J =6.8 Hz); 13C NMR (75.5 MHz, CDC13) 6178.1, 177.0, 142.3, 141.3, 140.2, 139.9, 128.94, 128.86, 128.6, 128.34, 128.29, 128.2, 127.4, 126.7, 126.3, 126.2, 126.1, 76.1, 75.4, 60.3, 41.2, 40.3, 39.0, 38.2, 33.9, 27.0, 18.2, 17.6, 14.8, 14.2; FTIR (neat film) cm-1 3374 (br, m) , 2974 (m) , 1614 (s) , 1453 (m) , 1080 (m) , 756 (m) , 701 (m) ; HRMS (FAB) Calcd for C20H26NO2 (MH+) : 312.1965. Found: 312.1965.

Example 9

r iS- r iR* tS* , 2R*11 -N- t2-hydroxy-l-methyl-2-phenylethyl) -N . 2- dimethyl hexanamide

A dry 2 L 3-necked round-bottomed flask equipped with a mechanical stirrer was charged with lithium chloride (16.81 g,

396.4 mmol, 6.0 equiv), diisopropylamine (20.83 mL, 148.6 mmol, 2.25 equiv), and tetrahydrofuran (175 mL) . The suspension was cooled to -78°C, and n-butyllithium (1.73 M in hexanes, 79.4 mL, 137.4 mmol, 2.08 equiv) was added via cannula, and the mixture briefly warmed to 0°C, and recooled to -78°C. [S-[R*,R*] ]-N-(2-hydroxy-l-methyl-2-phenylethyl)-N- methyl propionamide (14.62 g, 66.06 mmol, 1.0 equiv) was added as a 0°C solution in tetrahydrofuran (150 mL) , and the reaction was stirred at -78°C for 1 hour, 0°C for 15 minutes, and 23°C for 5 minutes, then cooled back to 0°C. Iodobutane (22.55 mL, 198.2 mmol, 3.0 equiv) was added, and after 90 minutes, the reaction was quenched with saturated ammonium chloride. The amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (500 mL, 150 mL, 150 mL) . The combined organic extracts were dried over sodium sulfate, and after removal of the solvent under reduced pressure a yellow solid was obtained. The solid was recrystallized from hexanes (100 mL) affording the butylated propionamide as white crystals (14.75 g, 80% yield) . GC analysis of the TMS ether indicated a diastereomeric purity of the amide of greater than 99 % de: mp 65.5-66.5°C: IH NMR (300 MHz, C6D6) 67.0-7.45 (m, 5H) , 5.17 (br, IH) , 4.55 (t, IH, J = 7.2 Hz), 4.06 (m, IH) , 3.90 (m, IH) , 2.77 (s, 3H) , 2.70 (m, IH, ) , 2.22 (s, 3H) , 2.17 (m, IH) , 1.70 (m, 2H) , 1.40 ( , IH) , 1.02 (d, 3H, J = 7.2 Hz), 0.99 (d, 3H, J = 6.8 Hz) , 0.85 (3H, J = 7.0 Hz), 0.9-1.25 (m, 9H) , 0.62 (d, 3H, J = 6.8 Hz) ; 13C NMR (75.5 MHz, CDC13) 6179.2, 177.8, 142.6, 141.2, 128.6, 128.3, 128.2, 127.4, 126.8, 126.2, 76.4, 75.4, 59.1, 57.8, 36.5, 35.8, 33.7, 33.4, 29.7, 29.5, 22.9, 22.7, 18.0, 17.3, 15.3, 14.5, 14.1, 14.0; FTIR (neat film) cm-1 3382 (br, m) , 2959 (m) , 2932 (m) , 2872 (m) , 1614 (s) , 1454 (m) , 1109 (m) , 701 (m) ; HRMS (FAB) Calcd for C17H28N02 (MH+) : 278.2121. Found: 278.2124.

Example 10

f lS- r iR* tR*) . 2R*n-N-f2-hvdroxy-l-methyl-2-phenylethyl^-N.2- dimethyl hexanamide.

In a dry 1 L 3-necked round-bottomed flask equipped with a mechanical stirrer was charged lithium chloride (7.73 g, 182.2 mmol, 6.0 equiv), diisopropylamine (9.58 L, 68.34 mmol, 2.25 equiv), and tetrahydrofuran (75 mL) . The suspension was cooled to -78°C, and n-butyllithium (1.71 M in hexanes, 36.94 mL, 63.17 mmol, 2.08 equiv) was added via cannula, and after a brief warming to 0°C, the suspension was recooled to -78°C. [S-[R*,R*] ]-N-(2-hydroxy-l-methyl-2-phenylethyl) -N-methyl hexanamide (8.0 g, 30.37 mmol, 1.0 equiv) was added at 0°C as a solution in tetrahydrofuran (50 mL) , and the solution stirred at -78°C for 1 hour, 0°C for 15 minutes, and 23°C for 5 minutes, and then recooled to -78°C. Iodomethane (5.67 mL, 91.11 mmol, 3.0 equiv) was added, and the reaction was quenched after 6 hours with methanol (7 mL, 5.7 equiv). Volatile components were removed by rotary evaporation, and the amide was extracted from saturated ammonium chloride (400 L) with ethyl acetate (3 x 130 mL) . The combined organic extracts were dried over sodium sulfate, and after removal of the solvent under reduced pressure, a yellow oil was obtained. The oil was purified by flash chromatography (50% ethyl acetate/hexanes) affording the methylated hexanamide (7.49 g, 89% yield) as a yellow oil. GC analysis of the TMS ether indicated a diastereomeric purity of the amide of 96% de. IH NMR (300 MHz, C6D6) 67.0-7.4 (m, 5H, 5.30 (br, IH) , 4.56 (t, IH, J = 6.8 Hz), 4.16 (d, IH, J = 8.6 Hz), 3.95 (m, IH) , 2.82 (s, 3H) , 2.70 (m, IH) , 2.18 (s, 3H) , 1.78 (m, 2H) , 1.1-1.4

(m) , 1.33 (d, 3H, J = 6.7 Hz), 1.08 (d, 3H, J = 7.0 Hz) , 1.0 (m, 3H) , 0.92 (d, 3H, J = 6.8 Hz), 0.87 (t, 3H, J = 6.9 Hz), 0.69 (d, 3H, J = 6.7 Hz); 13C NMR (75.5 MHz, CDC13) 6: 178.9, 177.9, 142.5, 141.5, 128.5, 128.0, 127.3, 126.8, 126.1, 76.3, 75.2, 59.8, 57.9, 36.4, 35.5, 34.2, 33.6, 29.5, 27.0, 22.7, 17.6. 17.3, 15.5, 14.3, 13.9; FTIR (neat film) cm-1: 3382 (br, m) , 2959 (s) , 2932 (s) , 1614 (s) , 1470 (m) , 1112 (m) , 1087 (m) , 1050 (m) , 701 (m) ; HRMS (FAB) Calcd for C17H28N02 (MH+) : 278.2121 Found: 278.2119.

Example 11

phenylethyl) -N-methyl benzeneacetamide

A dry 500 mL round-bottomed flask was charged with lithium chloride (4.24 g, 100 mmol, 10.0 equiv), diisopropylamine (3.1 L, 22.1 mmol, 2.21 equiv), and tetrahydrofuran (35 L) . The suspension was cooled to -78°C, and n-butyllithium (2.04 M in hexanes, 10.20 mL, 20.8 mmol,

2.08 equiv) was added via cannula, and the mixture was briefly warmed to 0°C and then recooled to -78°C. [1S-[1R*, 2R*]]-N- (2-hydroxy-l-methyl-2-phenylethyl) -N-methyl benzeneacetamide (2.83 g, 10.0 mmol, 1.0 equiv) was added as a solution in tetrahydrofuran (50 mL) , and the mixture was stirred at -78°C for 1 hour, 0°C for 10 minutes, and 23°C for 4 minutes, then cooled to 0°C. Ethyl iodide (3.2 mL, 40 mmol, 4.0 equiv) was added, and the reaction was quenched after 40 minutes with saturated ammonium chloride. The amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (3 x

100 mL) , and the combined organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, flash column chromatography (50% ethyl acetate/hexanes) of the oily residue afforded a colorless oil which slowly solidified (2.85 g, 92% yield). GC analysis of the TMS ether indicated a diastereomeric purity of the amide of greater than 98% de: mp 65-66°C; IH NMR (300 MHz, C6D6) 66.9-7.4 (m, 5H) , 4.95 (br, IH) , 4.51 (t, IH, J = 6.9 Hz), 4.03 (m, IH) , 3.82 (m, IH) , 3.11 (dd, IH, J = 7.5 Hz, 7.0 Hz), 2.78 (ε, 3H) , 2.48 (m, 2H) , 2.25 (m, IH) , 2.12 (ε, 3H) , 1.90

(m, IH) , 1.73 (m, 2H) , 0.98 (d, 3H, J = 6.8 Hz), 0.97 (m, 3H) , 0.82 (t, 3H, J = 7.3 Hz), 0.30 (d, 3H, J = 6.5 Hz) ; 13C NMR (75.5 MHZ, CDC13) 6175.4, 174.2, 142.3, 141.3, 140.5, 139.6, 128.8, 128.7, 128.7, 128.3, 128.2, 127.8, 127.7, 127.4, 126.9, 126.7, 126.6, 126.3; FTIR (neat film) cm-1: 3384 (br, m) , 3027 (m) , 2966 (m) , 2932 (m) , 2873 (m) , 1620 (ε) , 1491 (m) , 1453 (m) , 1406 (m) , 761 (m) , 701 (m) ; HRMS (FAB) Calcd for C20H26NO2 (MH+) : 312.1965. Found: 312.1962.

riS-riR*fR* , 2R*11-α-but>/l-N-(2-hydroxy-l-roethyl-2- phenylethyl)-N-methyl benzenepropionamide

A dry 100 mL Schlenk flask was charged with lithium chloride (1.48 g, 35 mmol, 10 equiv), diisopropylamine (1.10 L, 7.88 mmol, 2.25 equiv), and tetrahydrofuran (12 mL) . The suspension was cooled to -78°C and n-butyllithium (2.04 M in hexanes, 3.57 mL, 2.08 equiv) was added, and the mixture was warmed briefly to 0°C, then cooled to -78°C. [S-[R*,R*] ]-N-(2-

hydroxy-l-methyl-2-phenylethyl)-N-methyl benzene-propionamide (0.992 g, 3.5 mmol, 1.0 equiv) was added as a εolution in tetrahydrofuran (12 mL) , and the tranεfer quantitated with an additional portion of tetrahydrofuran (3 mL) . The reaction was stirred at -78°C for 75 minutes, 0°C for 15 minutes, and 23°C for 5 minutes, and then cooled to 0°C. Iodobutane (1.39 L, 12.25 mmol, 3.5 equiv) was added, and the reaction was stirred at 0° for 1 h 30 minutes, then quenched with saturated ammonium chloride. The amide was extracted from saturated ammonium chloride (350 mL) with ethyl acetate (3 x 80 mL) , and the oily residue was chromatographed on silica gel with 40% ethyl acetate/hexanes to afford the butylated hydrocinnamide as a yellow oil (1.03 g, 83% yield). GC analyεiε of the TMS ether indicated a diasteomeric purity of the amide of 98% de: IH NMR (300 MHz, C6D6) 67.0-7.4 (m, 10H) , 5.2 (br, IH) , 4.49 (t, IH, J = 6.9 Hz) , 4.02 (m, IH) , 3.90 (br, IH) , 3.78 (m, IH) , 3.03 (m, 2H) , 2.70 (ε, 3H) , 2.57 (m, 2H) , 2.02 (s, 3H) , 0.93-1.9 (m) , 0.92 (d, 3H, J = 7.0 Hz), 0.84 (t, 3H, J = 7.2 Hz), 0.16 (d, 3H, J = 6.7 Hz); 13C NMR (75.5 MHz, CDC13) 6177.7, 176.7, 142.2, 141.1, 140.2, 139.8, 128.9, 128.6,

128.4, 128.3, 128.2, 128.2, 127.4, 126.8, 126.3, 126.3, 126.1,

75.8, 75.3, 60.0, 58.2, 44.9, 44.2, 39.8, 39.5, 33.6, 33.1,

29.9, 29.5, 22.9, 22.8, 14.4, 14.3, 14.0, 13.9; FTIR (neat film) cm-1 3404 (ε) , 1624 (m) .

Exam le 13

1 -N-methyl benzenepropionamide

A dry 3-necked 2 L round-bottomed flask equipped with a mechanical stirrer was charged with lithium chloride (19.32 g, 455.58 mmol, 6.0 equiv), diisopropyla ine (23.94 L, 170.84 mmol, 2.25 equiv) , and tetrahydrofuran (200 L) . The suspension was cooled to -78°C, and n-butyllithium (2.43 M in hexanes, 64.99 mL, 157.93 mmol, 2.08 equiv) was added, and the mixture was warmed briefly to 0°C, then recooled to -78°C. [S-[R*,R*] ]-N-(2-hydroxy-1-methy1-2-phenylethy1) -N-methyl hexanamide (20.0 g, 75.93 mmol, 1.0 equiv) was added at 0°C as a solution in tetrahydrofuran (150 mL) . The resulting solution was stirred at -78°C for 50 minutes, 0°C for 15 minutes, and 23°C for 5 minutes, and then recooled to 0°C. Benzyl bromide (13.55 mL, 113.90 mmol, 1.5 equiv) was syringed into the reaction mixture and after 40 minutes, the reaction was quenched with saturated ammonium chloride. Most of the volatile components were removed by rotary evaporation, and the amide was extracted from saturated ammonium chloride (700 mL) with ethyl acetate (4 x 150 mL) . The combined organic extracts were dried over sodium sulfate, and after removal of the εolvent under reduced preεεure, a white solid was obtained. Recrystallization from toluene (100 mL) , affording the benzylated hexanamide as white crystals (23.28 g, 87% yield) . GC analysis of the TMS ether indicated a diasteomeric purity of greater than 99% de: mp 120-121°C; IH NMR (300 MHz, C6D6) 67.0-7.45 (m, 10H) , 4.31 (m, IH) , 4.15 (br, IH) , 3.98 (m, IH) , 3.35 (m, IH) , 2.99 (m, IH) , 2.72 (s, 3H) , 2.53-2.67 (m, 2H) , 2.12 (s, 3H) , 1.0-2.0 (m, 6H) , 0.87 (t, 3H, H7, J = 7.0 Hz), 0.73-0.80 (m, 6H) , 0.64 (d, 3H, J = 6.2 Hz); 13C NMR (75.5 MHz, CDC13) 6177.9, 176.6, 142.2, 141.0, 140.5, 139.9, 129.2, 128.9, 128.6, 128.5, 128.3, 128.2, 127.6, 126.9, 126.5, 126.3, 126.2, 76.4, 75.1, 58.2, 57.9, 44.8, 44.0, 39.6, 39.3, 32.9, 32.8. 32.1, 29.8, 29.6, 27.0, 22.8, 15.5, 14.2, 13.9; FTIR (neat film) cm-1 3369 (br, m) , 2958 (m) , 2929 (m) , 1614 (s) , 1493 (m) , 1454 (m) , 1412 (m) , 744 (m) , 700 (s) .

E

fS-fR*fS*l ,R*) 1-α-chloro-N- ( 2-hydroxy-1-methy1-2-phenylethyl) - N-methyl benzenepropionamide

To a dry 50 mL Schlenk flask equipped with a magnetic stirrer was transferred lithium chloride (249 mg, 5.88 mmol, 6.0 equiv) . The flask was evacuated, filled with argon and tetrahydrofuran (2.5 mL) was added. The solvent was vacuum degassed and diisopropylamine (0.302 mL, 2.16 mmol, 2.2 equiv) was added. The solution was cooled to -78°C and a solution of n-butyllithium (1.64 M in hexanes, 1.26 mL, 2.06 mmol, 2.1 equiv) was added. The reaction was warmed to 0°C, stirred for 10 minutes, and recooled to -78°C. A cold (-78°C) solution of [S-(R*,R*) ]-α-chloro-N-(2-hydroxy-1-methy1-2-phenylethyl) -N- methyl acetamide (237 mg, 0.98 mmol, 1.0 equiv, azeotropically dried with toluene) in tetrahydrofuran (3 mL) was added via cannula, and the reaction was stirred for 1 hour at -78°C. The reaction was warmed to -45°C, stirred for 5 minutes and then benzyl bromide (0.175 mL, 1.47 mmol, 1.5 equiv) was added. The reaction was allowed to stir for 1 hr 40 minutes, and was quenched at -45°C by addition of 0.5 M potassium bisulfate. The mixture was warmed to 23°C and the product was extracted with two portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography (with 35% ethyl acetate/hexanes as eluent) gave the product (308 mg, 95%) as an oil which quickly crystallized. The crude product contained an impurity resulting from cyclization to the

corresponding ether (ca 5 %) . Analytically pure product was obtained by recrystallization from a minimum volume of ethyl acetate to give 189 mg (58%) of white crystals (1:1 mixture of rotamers) with a de of > 90% by ¹ H NMR: mp 155-156°C; IH NMR (300 MHz, CDC13) 67.26-7.38 (m, 10H) , 4.83 (dd, 0.5H, J = 8.8 Hz, 5.1 Hz), 4.65 (t, 0.5H, J = 6.9 Hz) , 4.57 (m, IH) , 4.41 (s (br) , 0.5H), 4.12 (m, 0.5H), 3.70 (s(br), 0.5H), 3.46 (dd, 0.5H, J = 13.7 Hz, 7.7 Hz), 3.37 (dd, 0.5H, J = 14.1 Hz, 5.7 Hz), 3.15-3.24 (m, IH) , 2.97 (s, 1.5H), 2.81 (s, 1.5H), 2.23 (d, 0.5H, J = 2.7 Hz), 1.09 (d, 1.5H, J = 6.7 Hz) , 1.07 (d, 1.5H, J = 7.0 Hz); 13C NMR (75.5 MHz, CDC13) 6170.0, 169.5, 141.7, 141.0, 137.4, 136.7, 129.6, 129.5, 128.8, 128.53, 128.47, 128.4, 127.8, 127.1, 126.8, 126.7, 126.4, 126.3, 76.0, 75.4, 58.1, 54.9, 54.8, 40.7, 40.3, 28.0, 15.3, 13.8; FTIR (neat film) cm-1 3388, 3029, 1633; Anal. Calcd for

C19H22C1N02 C, 68.77; H, 6.68; N, 4.22; Found C, 68.75, H,6.69, N, 4.19.

Example 15

rs-(R*CS*) ,R*) -a-fcarbobenzyloxya ino -Nl-(2-hvdroxy-l- methyl-2-phenylethyl)-Nl-methyl benzenepropionamide

To a dry 50 mL Schlenk flask equipped with a magnetic stirrer was transferred lithium chloride (0.221 g, 5.22 mmol, 10 equiv) . The flask was evacuated, filled with argon and tetrahydrofuran (2.5 mL) was added. The solvent was vacuum degasεed and diiεopropylamine (0.234 mL, 1.67 mmol, 3.2 equiv) waε added. The solution was cooled to -78°C and a solution of n-butyllithium (1.64 M in hexanes, 0.986 mL, 1.62 mmol, 3.1

equiv) was added. The reaction was warmed to 0°C, stirred for 10 minutes, and recooled to -78°C. To the reaction was added a solution of [S-(R*,R*) ]-N2-(benzyloxycarbonyl) -Nl-(2- hydroxy-l-methyl-2-phenylethyl) -Nl-methyl glycinamide (0.186 g, 0.522 mmol, 1.0 equiv, azeotropically dried with toluene) in tetrahydrofuran (3 mL) . The reaction was warmed to 0°C and stirred for 1 hour. The reaction was cooled to -45°C and benzyl bromide (0.093 mL, 0.783 mmol, 1.5 equiv) was added. The reaction was stirred at -45°C for 3 hours and was quenched by addition of 0.5 M potassium bisulfate. The mixture was warmed to 23°C and the product extracted with two portions of ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel with ethyl acetate/ hexanes as eluent (20% to 80% gradient) gave the product (171 mg, 73%) as a foam (4:1 mixture of rotamers with a de of > 90% (by HNMR) , * = minor rotamer resonances) , and unalkylated amide (24 mg, 13%): 1HNMR (300 MHz, CDC13) 67.18-7.40 (m, 15H) , 5.52 (d, IH, J = 8.1 Hz), 5.65* (d, IH, J = 9.1 Hz), 4.97-5.16 (m, 2H) , 4.86 (q (obs) , IH, J = 7.5), 4.65 (m, IH) , 4.58* (d, IH, J = 9.1 Hz), 4.49 (d, IH, J = 8.7 Hz), 4.26 (m, IH) , 3.44-3.83 (s (br) , IH) , 3.27* (dd, IH, J = 13.7 Hz, 5.4 Hz), 2.90-3.08 (m, 2H) , 2.61 (s, 3H) , 0.98 (d, 3H, J = 6.6 HZ), 0.79 (d, 3H, J = 6.9 Hz); 13C NMR (75.5 MHz, CDC13) 6173.1, 172.2, 155.8, 155.6, 141.5, 141.2, 136.9, 136.3,

136.2, 136.0, 129.5, 129.3, 129.2, 128.8, 128.7, 128.6, 128.5, 128.34, 128.27, 128.12, 128.10, 128.0, 127.9, 127.81, 127.76, 126.9, 126.7, 126.6, 75.5, 75.1, 66.8, 66.5, 58.2, 56.4, 52.6, 51.8, 39.5, 38.5, 30.3, 27.1, 22.5, 15.4, 13.9; FTIR (neat film) cm-1 3402, 3303, 3030, 1714, 1633.

Method - Hydrolysis of Alkylated Pseudoephedrine Amides to form Chiral Carboxylic Acids of High Enantiomeric Purity

R

The acidic hydrolysis of the alkylated pseudoephedrine amides to the corresponding carboxylic acids with little loss of optical purity was accomplished as follows: The amide was stirred in refluxing aqueous sulfuric acid : dioxane until the reaction was complete, typically for

1-30 h. The mixture was then basified with aqueous sodium hydroxide and washed with dichloromethane to remove liberated pseudoephedrine. The resulting aqueous phase was next acidified and extracted with dichloromethane. These extracts were then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the pure carboxylic acid.

The basic hydrolysis of the alkylated pseudoephedrine amides to the corresponding carboxylic acids with little loss of optical purity was accomplished as follows:

The amide was stirred with 5 equivalents tetrabutylammonium hydroxide in refluxing water: tert-butanol until the reaction was complete, typically 20-24 h. The mixture was then diluted with aqueous sodium hydroxide and washed with diethyl ether to remove liberated pseudoephedrine. The resulting aqueous phase was acidified with aqueous hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. These extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the pure carboxylic acid.

Example 16

18 Λ/H ₂ SQ ₄ :Dioxane reflux

S-α-ethyl benzeneacetic acid

A 50 mL round-bottomed flask was charged with [1S- [1R*(R*) , 2R*] ]-α-ethyl-N-(2-hydroxy-l-methyl-2-phenylethyl)- N-methyl benzeneacetamide (1.2488 g, 4.0 mmol) and 10:8 18 N sulfuric acid : dioxane (18 mL) and the resulting mixture refluxed for 2 h under a Liebig condenser. The mixture was then basified with 50% aqueous sodium hydroxide, and washed with dichloromethane (2 x 50 mL) . The remaining aqueous phase was acidified with 6 N aqueous sulfuric acid and extracted with dichloromethane (3x 50 mL) . These extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford S-α-ethyl benzeneacetic acid (0.6306 g, 96% yield) with an enantiomeric excess of 95% (as determined by chiral GC analysis of the R-α- ethylbenzyl amide of the acid) .

Example 17

A 10 mL recovery flask equipped with a magnetic stirrer was charged with [1S-[1R* (R*) , 2R*] ]-α-ethyl-N-(2-hydroxy-l- methyl-2-phenylethyl) -N-methyl benzeneacetamide (86 mg, 0.28 mmol, 1.0 equiv) and a mixture of tetrabutylammonium hydroxide (0.81g of a 40% aqueous solution, 1.25 mmol, 4.5 equiv) in 4:1 water: tert-butanol (5 mL) , and the resulting mixture

refluxed for 20 h under a Liebig condenser. The reaction was then poured into a separatory funnel with 1 N NaOH (100 L) , and extracted with ether (3 x 10 L) . The aqueous phase was acidified with 3 N HC1, saturated with sodium chloride, and then extracted with ethyl acetate (3 x 15 mL) . The ethyl acetate extracts were washed once with water (5 mL) , dried over sodium sulfate, and the solvent was removed under reduced pressure to provide S-α-ethyl benzeneacetic acid (37.4 g, 82% yield) with an enantiomeric excess of 64% (as determined by chiral GC analysis of the R- -methylbenzyl amide of the acid) .

IH NMR (300 MHZ, CDC13) 7.25 (m, 5H) , 3.41 (t, IH, J = 7.7 Hz), 2.05 ( , IH) , 1.76 (m, IH) , 0.86 (t, 3H, J = 7.4 Hz); 13C NMR (75.5 MHZ, CDC13) 6180.5, 138.3, 128.6, 128.1, 127.4, 53.3, 26.3, 12.1; FTIR (neat film) cm-1 2967 (s, br, OH) , 2683 (m, br) , 1949 (w) , 1871 (w) , 1805 (w) , 1712 (s, C=0) , 1601 (w) , 1496 (m) , 1455 (s) , 1415 (s) , 1286 (s) , 1223 (s) , 1185 (m) , 1082 (w) , 1029 (w) , 942 (m) , 849 (w) , 728 (s) , 698 (s) , 616 (w) , 506 (w) .

A 50 mL round-bottomed flask was charged with [1S- [1R*(S*) , 2R*] ]-N-(2-hydroxy-l-methyl-2-phenylethyl)-N,2- dimethyl benzenepropionic amide (1.2458g, 4.0 mmol) and 10:8 18 N sulfuric acid : dioxane (18 mL) . The resulting mixture was refluxed for 1 h under a Liebig condenser. The mixture was then basified with 50% aqueous sodium hydroxide, and washed with dichloromethane (2 x 50 mL) . The remaining aqueous phase waε acidified with 6 N aqueous sulfuric acid and

extracted with dichloromethane (3 x 50 mL) . These extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford R-α-methyl benzenepropionic acid (0.5719 g, 87% yield) with an enantiomeric excess of 97% (as determined by chiral GC analysis of the R-α-methylbenzyl amide of the acid) .

Exam le 19

A 10 mL recovery flask equipped with a magnetic stirrer was charged with [lS-[1R* (S*) , 2R*] ]-N- (2-hydroxy-l- methyl-2-phenylethyl) -N, 2-dimethyl benzenepropionic amide (75 mg, 0.24 mmol, 1.0 equiv) and a mixture of tetrabutylammonium hydroxide (0.78g of a 40% aqueous solution, 1.21 mmol, 5 equiv) in 4 : 1 water: tert-butanol (5 mL) , and the resulting mixture was refluxed for 22 h under a Liebig condenser. The reaction mixture was basified with 1 N sodium hydroxide (100 mL) , and extracted with ether ( 3 x 10 mL) . The aqueous phase was acidified with 3 N HCl, saturated with sodium chloride, and extracted with ethyl acetate (3 x 15 mL) . The combined ethyl acetate extracts were washed once with water ( 5 mL) , dried over sodium sulfate, filtered, and concentrated to give R-α-methyl benzenepropionic acid (36 mg, 91% yield) with an enantiomeric excess of 94% (as determined by chiral GC analysis of the R-α-methylbenzyl amide of the acid) .

IH NMR (300 MHz, CDC13) 67.25 (m, 5H) , 3.09 (dd, IH, Jl = 6.1 Hz, J2 = 13.1 Hz), 2.75 (m, 2H, H) , 1.18 (d, 3H, J = 6.8 Hz); 13C NMR (75.5 MHz, CDC13) 5182.5, 139.0, 129.0, 128.4, 126.4, 41.2, 39.3, 16.5; FTIR (neat film) cm-1 2976 (s,br,

OH), 2657 (m, br), 1948 (w) , 1877 (w) , 1806 (w) , 1707 (s, C=0), 1496 (m) , 1454 (s) , 1417 (m) , 1294 (s) , 1241 (s) , 1117 (w) , 1082 (w) , 942 (m) , 744 (m) , 700 (s) , 549 (w) .

Example 20

18 NH ₂ SO ₄ :Dioxane reflux

R-2-methyl hexanoic acid

A 50 mL round-bottomed flask was charged with [1S- [1R*(S*) , 2R*] ]-N-(2-hydroxy-l-methyl-2-phenylethyl)-N,2- dimethyl hexanamide (1.1106 g, 4.0 mmol) and 1:1 18 N sulfuric acid : dioxane (16 mL) . The resulting mixture refluxed for 1 h under a Liebig condenser. The mixture was then basified with 50% aqueous sodium hydroxide, and washed with dichloromethane (2 x 50 mL) . The remaining aqueous phaεe waε acidified with 6 N aqueous sulfuric acid and extracted with dichloromethane (3x 50 mL) . These extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced preεεure to afford R-2-methyl hexanoic acid (0.4728 g, 91% yield) with an enantiomeric excess of 97% (as determined by chiral GC analysiε of the R-α-methylbenzyl amide of the acid) .

Example 21

A 10 L recovery flask equipped with a magnetic stirrer was charged with [1S-[1R*(S*) , 2R*] ]-N-(2-hydroxy-l-methyl-2- phenylethyl)-N,2-dimethyl hexanamide (80 mg, 0.29 mmol, 1.0 equiv) and a mixture of tetrabutylammonium hydroxide (0.93 g of a 40% aqueous solution, 1.44 mmol, 5 equiv) in :1 water: tert-butanol (5 mL) and the resulting mixture refluxed for 22 h under a Liebig condenser. The reaction mixture was basified with IN sodium hydroxide (100 mL) , and extracted with ether (3 x 10 mL) . The aqueous phase was acidified with 3 N HC1, saturated with sodium chloride, and extracted with ethyl acetate (3 x 15 mL) . The combined ethyl acetate extracts were washed once with water (5 mL) , dried over sodium sulfate, filtered, and concentrated to give R-2-methyl hexanoic acid (33 mg, 88% yield) with an enantiomeric excess of 93% (as determined by chiral GC analysis of the R-α-methylbenzyl amide of the acid) .

IH NMR (300 MHZ, CDC13) 62.44 (sx, IH, J = 6.9 Hz) , 1.70 (m, IH) , 1.45 (m, IH) , 1.35 (m, 4H) , 1.17 (d, 3H, J = 7.0 Hz) , 0.90 (m, 3H) ; 13C NMR (75.5 MHz, CDC13)6 183.9, 39.4, 33.2, 29.3, 22.6, 16.8, 13.9; FTIR (neat film) cm-1 3028 (s, br, OH), 2959 (Ξ), 2657 (m) , 1712 (s, C=0) , 1467 (ε) , 1417 (m) , 1380 (w) , 1293 (m) , 1239 (s) , 1207 (m) , 1154 (W) , 1102 (w) , 942 (m) , 830 (w) , 792 (w) , 730 (w) , 640 (w) , 555 (w) .

Example 22

18 N H ₂ SO ₄ :Dioxane reflux

R-α-butyl benzenepropionic acid

A 50 mL round-bottomed flask was charged with [1S- [1R*(S*) , 2R*]]-α-butyl-N-(2-hydroxy-l-methyl-2-phenylethyl)- N-methyl benzenepropionamide (1.0624 g, 3.0 mmol) and 1:1 18 N sulfuric acid : dioxane (12 mL) . The resulting mixture was refluxed for 22 h under a Liebig condenser.The mixture was then basified with 50% aqueous sodium hydroxide, and washed with dichloromethane . (2 x 50 mL) . The remaining aqueous phase was acidified with 6 N aqueous sulfuric acid and extracted with dichloromethane (3 x 50 mL) . These extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford R-α-butyl benzenepropionic acid (0.5838 g, 94% yield) with an enantiomeric excess of 96% (as determined by chiral GC analysis of the R-α-methylbenzyl amide of the acid) .

IH NMR (300 MHz, CDC13) 67.30 (m, 5H) , 2.98 (dd, IH, Jl = 7.8 Hz, J2 = 13.5 Hz), 2.70 (m, 2H) , 1.65 (m, IH) , 1.55 (m, IH) , 1.30 (m, 4H) , 0.85 (m, 3H) ; 13C NMR (75.5 MHz, CDC13)6 181.8, 139.1, 128.9, 128.4, 126.4, 47.3, 38.1, 31.4, 29.3, 22.5, 13.9; FTIR (neat film) cm-1 3028 (s,br, OH), 2932 (s) , 2673 (m) , 1945 (w) , 1873 (w) , 1803 (w) , 1711 (s, C=0) , 1604 (w) , 1496 (m) , 1455 (s) , 1417 (m) , 1289 (s) , 1240 (s) , 1205 (m) , 1110 (W) , 1076 (w) , 1030 (w) , 942 (m) , 832 (w) , 792 (w) , 743 (m) , 699 (ε) , 556 (w) . Method - Reduction of Alkylated Pseudoephedrine Amides to form Chiral Primary Alcohols of High Enantiomeric Purity

THF,23°C Reduction of the amide to the alcohol followed the procedure described by Singaram et al. [Tetrahedron Lett. 1993, 3_4, 1091]. The hydride was generated by reacting pyrrolidine with borane-tetrahydrofuran solution at 23°C for 1

hour. Deprotonation with n-butyllithium at 0°C for 30 minutes generated the active hydride species. The amide was added either neat or as a solution in tetrahydrofuran, and stirred at 23°C for several hours. Isolation of the alcohol involved an acidic workup to remove pyrrolidine and pseudoephedrine as their hydrochloride salts, followed by flash chromatography to isolate the alcohol. In some cases it was found that yields could be improved with an additional basic workup, in order to hydrolyze residual borate esters.

(S)-β-butyl benzenepropanol

A dry 25 mL Schlenk flask equipped with a magnetic stirrer was cooled to 0°C, and charged with pyrrolidine (0.142 L, 1.707 mmol, 3.0 equiv) and borane*tetrahydrofuran (1.0 M in tetrahydrofuran, 1.707 mL, 1.707 mmol, 3.0 equiv). The mixture was then warmed to 23°C, and stirred for 1 hour. The mixture was cooled to 0°C, and n-butyllithium (1.73 M in hexanes, 0.99 mL, 1.707 mmol, 3.0 equiv) was added, and the reaction stirred for 35 minutes. [IS-[1R*(R*) ,2R*] ]-α-butyl- N-(2-hydroxy-1-methy1-2-phenylethy1)-N-methy1 benzenepropionamide (0.201 g, 0.569 mmol, 1.0 equiv) was added as a tetrahydrofuran solution (2 mL) , and the reaction was warmed to 23°C and stirred for 3 hours and 5 minutes. The reaction was quenched with 1 N HC1, and the product extracted from 1 N HC1 (100 mL) with ether (4 x 25 mL) . The ether extracts were washed with 1:1 brine/1 N HC1 (2 x 10 mL) , dried over sodium sulfate, and concentrated. The residue was

chromatographed with 25% ethyl acetate/hexanes to afford the alcohol (96 mg, 88% yield) as a colorless oil. Analysis of the Mosher ester indicated an enantiomeric purity of 98% ee: IH NMR (300 MHz, C6D6) 7.0-7.3 (m, 5H) , 3.25 (d, 2H, J = 5.1 Hz), 2.59 (dd, IH, J = 13.5 Hz, 7.6 Hz), 2.48 (dd, IH, J = 13.5 Hz, 6.5 Hz), 1.60 (m, IH) , 1.31 (m, IH) , 1.20 (m, 4H) , 0.84 (m, 3H) ; 13C NMR (75.5 MHz, CDC13) 6140.8, 129.1, 128.1, 125.7, 64.6, 42.4, 37.5, 30.3, 29.0, 22.9, 14.0. FTIR (neat film) cm-1 3342 (br, m) , 3026 (w) , 2955 (ε) , 2928 (m) , 1495 (m) , 1454 (m) , 1050 (m) , 1030 (m) , 742 (m) , 700 (m) .

THF,23°C fR) -β-butyl benzenepropanol

A dry 25 mL Schlenk flask equipped with a magnetic stirrer was cooled to 0°C and charged with pyrrolidine (0.104 mL, 1.242 mmol, 3.0 equiv) and borane*tetrahydrofuran (1.0 M in tetrahydrofuran, 1.242 mL, 1.242 mmol, 3.0 equiv). The mixture Was warmed to 23°C for 1 hour, then recooled to 0°C. n-Butyllithium (1.73 M in hexanes, 0.72 mL, 1.242 mmol, 3.0 equiv) was added, and the reaction was stirred at 0°C for 30 minutes. [1S-[1R*(S*) ,2R*] ]-α-butyl-N-(2-hydroxy-l-methyl-2- phenylethyl) -N-methyl benzenepropionamide (0.146 g, 0.414 mmol, 1.0 equiv) was added as a solution in tetrahydrofuran (2 mL) , and stirred at 23°C for 5 hours. The reaction was quenched with aqueous hydrochloric acid. The product was extracted from 1 N HCl (100 mL) with ether (4 x 25 mL) , and the ether extracts washed with 1:1 brine/1 N HCl (2 x 10 mL) . The ether extracts were dried over sodium sulfate,

concentrated, and the residue was chromatographed with 25% ethyl acetate/hexanes to afford the alcohol (70 mg, 88% yield) as a colorless oil. Analysis of the Mosher ester indicated an enantiomeric purity of approximately 99% ee: IH NMR (300 MHz, C6D6) 7.0-7.3 ( , 5H) , 3.25 (d, 2H, J = 5.1 Hz), 2.59 (dd, IH, J = 13.5 Hz, 7.6 Hz), 2.48 (dd, IH, J = 13.5 Hz, 6.5 Hz), 1.60 (m, IH) , 1.31 (m, IH) , 1.20 (m, 4H) , 0.84 (m, 3H) ; 13C NMR (75.5 MHZ, CDC13)6140.8, 129.1, 128.1, 125.7, 64.6, 42.4, 37.5, 30.3, 29.0, 22.9, 14.0; FTIR (neat film) cm-1 3342 (br, m) , 2955 (s) , 2928 (m) , 1495 (m) , 1454 (m) , 1050 (m) , 1030

fR)-β-methyl benzenepropanol

A dry 100 mL Schlenk flask equipped with a magnetic stirrer was cooled to 0°C and charged with pyrrolidine (0.80 L, 9.63 mmol, 3.0 equiv) and borane-tetrahydrofuran (1.0 M in tetrahydrofuran, 9.63 mL, 9.63 mmol, 3.0 equiv) . The mixture was warmed to 23°C, and stirred for 1 hour. It was recooled to 0°C, and n-butyllithium (1.71 M in hexanes, 5.63 mL, 9.63 mmol, 3.0 equiv) was added, and the reaction was stirred at 0°C for 30 minutes. [IS-[1R* (S*) ,2R*] ]-N-(2-hydroxy-l- methyl-2-phenylethyl) -N, 2-dimethyl benzenepropionamide (1.0 g, 3.21 mmol, 1.0 equiv) was added via cannula aε a solution in tetrahydrofuran (9 mL) , and the transfer quantitated with an additional portion of tetrahydrofuran (1 mL) , and the mixture stirred at 23°C for 6 hours. The reaction was quenched with aqueous hydrochloric acid, and the product was extracted from 1 N HCl (350 mL) with ether (4 x 50 mL) . The ether extracts were washed with 1:1 brine/1 N HCl (2 x 25 mL) , concentrated, and poured into 1 N sodium hydroxide (100 mL) and stirred at 23°C for 30 minutes. The mixture was

extracted with ether (3 x 30 L) , and the ether extracts were washed with 1:1 brine/1 N NaOH (2 x 10 L) , dried over sodium sulfate, and concentrated. Flash column chromatography (35% ether/petroleum ether) afforded the 5 desired alcohol (405 mg, 84% yield) as a colorless oil.

Analysis of the Mosher ester indicated an enantiomeric purity of approximately 99% ee: IH NMR (300 MHz, C6D6) 7.0-7.2 (m, 5H) , 3.15 (m, 2H) , 2.62 (dd, IH, J = 13.3 Hz, 6.2 Hz), 2.22 (dd, IH, J = 13.3 Hz, 8.0 Hz), 1.70 (m, IH) , 0.77 (d, 3H, J = 0 6.7 Hz), 0.62 (t, IH, J = 5.2 Hz) . 13C NMR (75.5 MHz, CDC13)6 140.6, 129.0, 128.2, 125.7, 67.4, 39.6, 37.7, 16.4; FTIR (neat film) cm-1 3332 (s) , 3001 (m) , 2956 (s) , 2922 (s) , 2872 (s) 1603 (m) , 1495 (s) , 1454 (s) , 1378 (m) , 1032 (s) , 986 (m) , 739

(s), 700 (s) 5

(R) -2-methyl-l-hexanol

^* 5 A dry 200 mL Schlenk flask equipped with a magnetic stirrer was cooled to 0°C and charged with pyrrolidine (1.81 L, 21.63 mmol, 3.0 equiv) and borane-tetrahydrofuran (1.0 M in tetrahydrofuran, 21.63 mL, 21.63 mmol, 3.0 equiv). The mixture was warmed to 23°C and stirred for 1 hour. It was 0 recooled to 0°C, and n-butyllithium (1.71 M in hexanes, 12.65 mL, 21.63 mmol, 3.0 equiv) was added, and the reaction was stirred at 0°C for 30 minutes. The ice bath was removed, and [1S-[1R*(S*) , 2R*]]-N-(2-hydroxy-l-methyl-2-phenylethyl)-N,2- dimethyl hexanamide (2.0 g, 7.21 mmol, 1.0 equiv) was added 5 neat, and stirred at 23°C overnight. The reaction was

quenched with aqueous hydrochloric acid, diluted with 1 N HCl (300 mL) , and extracted with ether (4 x 60 mL) . The ether extracts were washed with 1:1 brine/1 N HCl (2 x 15 mL) , and then concentrated. The residue was stirred in 1 N NaOH (100 L) for 30 minutes at 23°C, and extracted with ether (4 x 25 mL) . These ether extracts were washed with 1:1 brine/IN NaOH (2 x 20 mL) , dried over sodium sulfate, and concentrated. Flash chromatography (40% ether/petroleum ether) of the residue afforded the desired alcohol (600 mg, 72% yield) . Analysis of the Mosher ester indicated an enantiomeric purity of approximately 98% ee: IH NMR (300 MHz, C6D6) 63.12-3.26 (m, 2H) , 0.92-1.44 (m, 7H) , 0.87 (t, 3H, J = 6.9 Hz) , 0.83 (d, 3H, J = 6.6 Hz), 0.69 (s, IH) ; 13C NMR (75.5 MHz, CDC13)668.0, 36.0, 33.2, 29.6, 23.4, 16.8, 14.3; FTIR (neat film) cm-1 3339 (br, s) , 2956 (ε) , 2928 (s) , 2873 (ε) , 1468 (m) , 1379 (m) , 1039 (m) .

(S)-β-ethyl benzeneethanol

A dry 200 mL Schlenk flask equipped with a magnetic stirrer was cooled to 0°C and charged with pyrrolidine (1.61 mL, 19.27 mmol, 3.0 equiv) and borane-tetrahydrofuran (1.0 M in tetrahydrofuran, 19.27 mL, 19.27 mmol, 3.0 equiv) . The mixture was warmed to 23°C and stirred for 1 hour, before being recooled to 0°C. n-Butyllithium (1.71 M in hexanes, 11.27 L, 19.27 mmol, 3.0 equiv) was added, and the reaction was stirred at 0°C for 30 minutes. The ice bath was removed, and [1S-[1R*(R*) , 2R*] ]-α-ethyl-N-(2-hydroxy-l-methyl-2- phenylethyl) -N-methyl benzeneacetamide (1.99 g, 7.21 mmol, 1.0

equiv) was added neat, and the reaction was stirred at 23°C overnight. The reaction was quenched with aqueous hydrochloric acid, diluted with 1 N HCl (300 mL) , and extracted with ether (4 x 60 mL) . The ether extracts were washed with 1:1 brine/1 N HCl (2 x 15 mL) , and then concentrated. The residue was stirred in 1 N NaOH (100 mL) for 30 minutes at 23°C, and extracted with ether (4 x 25 mL) . These ether extracts were washed with 1:1 brine/1 N NaOH ( 2 x 20 mL) , , dried over sodium sulfate, and concentrated. Flash chromatography (40% ether/petroleum ether) of the residue afforded the desired alcohol (819 mg, 85% yield) as a colorless oil: IH NMR (300 MHz, C6D6) 67.0-7.2 (m, 5H) , 3.48 (m, 2H) , 2.44 (m, IH) , 1.58-1.65 ( , IH) , 1.36-1.45 (m, IH) , 0.91 (t, IH, J = 5.3 Hz), 0.72 (t, 3H, J = 7.4 Hz) ; 13C NMR (75.5 MHZ, CDC13) 6: 142.2, 128.6, 128.1, 126.6, 67.3, 50.4, 24.9, 11.9; FTIR (neat film) cm-1: 3354 (br, s) , 3028 (m) , 2961 (s) , 2930 (s) , 2874 (s) , 1602 (w) , 1494 (s) , 1454 (s) , 1379 (m) , 1038 (ε) , 760 (ε) , 700 (ε) .

Method - Reduction of Alkylated Pseudoephedrine Amides to form Chiral Aldehydes of High Enantiomeric Purity

Reduction of the amide to the aldehyde followed the procedure described by Brown et al. f ^J - Am. Chem. Soc. 1964, 86. 1089]. The hydride was generated by the addition of ethyl acetate to lithium aluminum hydride in either tetrahydrofuran, hexanes, pentane, or toluene at 0°C over a period of 1-2 hours. Reaction of the hydride with pseudoephedrine amides took place at 0°C in approximately 1 hour. The reaction was quenched by transfer into an aqueous mixture of 1 N hydrochloric acid and trifluoroacetic acid. The acidic workup was necessary for increased yields. The aldehyde was then

isolated following extractive workup and flash chromatography.

Example 28

-78 °→ 0 °C

(R) -α-butyl benzenepropanal

A dry 100 mL Schlenk flask equipped with a magnetic stirrer waε charged with lithium aluminum hydride (0.259 g, 6.48 mmol, 2.3 equiv) in a nitrogen-filled drybox. The hydride was suspended in hexanes (12 mL) , and cooled to 0°C. Ethyl acetate (0.931 mL, 9.53 mmol, 3.38 equiv) waε added by syringe pump over a 1.5 hour interval. Upon completion of addition, the hydride suspension was cooled to -78°C, and [1S- [1R*(S*) ,2R*] ]-α-butyl-N-(2-hydroxy-l-methyl-2-phenylethyl)-N- methyl benzene propionamide (0.996 g, 2.82 mmol, 1.0 equiv) was added as a solution in tetrahydrofuran (8 mL) . The reaction was warmed to 0°C, and stirred for 45 minutes. The reaction was quenched by cannula transfer into a 0°C mixture of trifluoroacetic acid (2.17 mL, 28 mmol, 10 equiv) and 1 N HCl (15 mL) , and the mixture stirred for 5 minuteε. The mixture was poured into 1 N HCl (150 mL) , the layers were partitioned, and the aqueous phase was extracted with ethyl acetate (3 x 25 mL) . The combined organic extracts were basified with saturated sodium bicarbonate (35 mL) , and the flocculent emulsion was filtered through a plug of celite loaded onto a coarse frit. The aqueous layer was removed, and the organic fraction was dried over sodium sulfate, filtered, and concentrated. Flash chromatography (9% ethyl acetate/hexanes) afforded the aldehyde (0.439 g, 82% yield) as

a colorless oil. GC Analysis of the amide derived from coupling (R) -(+)-α-methylbenzylamine with the carboxylic acid (derived from sodium chlorite oxidation of the aldehyde) indicated an enantiomeric purity greater than 97% ee: IH NMR (300 MHz, C6D6)69.34 (d, IH, J = 2.3 Hz), 6.9-7.3 (m, 5H) , 2.71 (dd, IH, J = 13.9 Hz, 7.2 Hz), 2.36 (dd, IH, J = 13.9 Hz, 7.0 Hz), 2.22 (m, IH) , 1.31 ( , IH) , 0.9-1.2 (m, 5H) , 0.74 (m, 3H) ; 13C NMR (75.5 MHz, CDC13) 6 204.7, 138.9, 128.9, 128.5, 126.3, 53.4, 35.0, 29.0, 28.3, 22.7, 13.8; FTIR (neat film) cm-1: 3027 (w) , 2957 (m) , 2930 (m) 2859 (m) , 2713 (w) , 1726 (s) , 1496 (m) , 1454 (m) , 745 (m) , 700 (m) .

Example 29

(S)-α-butyl benzenepropanal

A dry 100 mL Schlenk flask equipped with a magnetic stirrer was charged with lithium aluminum hydride (0.361 g, 9.513 mmol, 2.3 equiv) in a nitrogen-filled drybox. The hydride was suspended in hexanes (18 mL) and cooled to 0°C. Ethyl acetate (1.35 mL, 13.78 mmol, 3.33 equiv) was added over a 1.5 hour period, then the hydride suspension was cooled to -78°C. [1S-[1R*(R*) ,2R*] ]-α-butyl-N-(2-hydroxy-l-methyl-2- phenylethyl)-N-methyl benzenepropionamide (1.46 g, 4.13 mmol, 1.0 equiv) was added in as a solution in tetrahydrofuran (10 mL) , and the reaction was warmed to 0°C. The reaction was stirred for one hour, and quenched with 1 N HCl. Following aqueous workup, flash column chromatography (8% ethyl

acetate/hexanes) afforded the desired aldehyde (669 mg, 85 % yield) as a colorless oil: IH NMR (300 MHz, C6D6) 9.34 (d, IH, J = 2.3 Hz), 6.9-7.3 (m, 5H) , 2.71 (dd, IH, J = 13.9 Hz, 7.2 Hz), 2.36 (dd, IH, J = 13.9 Hz, 7.0 Hz), 2.22 (m, IH) , 1.31 (m, IH) , 0.9-1.2 (m, 5H) , 0.74 (m, 3H) ; 13C NMR (75.5 MHz, CDC13) 6 204.7, 138.9, 128.9, 128.5, 126.3, 53.4, 35.0, 29.0, 28.3, 22.7, 13.8; FTIR (neat film) cm-1 3027 (w) , 2957 (m) , 2930 (m) 2859 (m) , 2713 (w) , 1726 (s) , 1496 (m) , 1454 (m) , 745 (m) , 700 (m) .

Example 30

(R) -α-methyl benzenepropanal

A dry 100 mL Schlenk flask equipped with a magnetic stirrer was charged with lithium aluminum hydride (0.444 g, 11.11 mmol, 2.3 equiv) in a nitrogen-filled drybox. The hydride was suspended in hexanes (26 mL) and cooled to 0°C. Ethyl acetate (1.59 mL, 16.34 mmol, 3.38 equiv) was added by syringe pump over a 1.5 hour period, then the hydride suspension was cooled to -78°C. [1S-[1R* (S*) ,2R*] ]-N-(2- hydroxy-l-methy1-2-phenylethyl) -N,2-dimethyl benzenepropionamide (1.505 g, 4.83 mmol, 1.0 equiv) was added as a solution in tetrahydrofuran (17 mL) , and the reaction warmed to 0°C. The reaction was stirred for 30 minutes, and quenched by cannula transfer into a 23°C solution of 1 N HCl (60 mL) and trifluoroacetic acid (3.7 mL, 48 mmol, 10

equiv) . This solution was stirred for 5 minutes, diluted with 1 N HCl (100 L) , and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) , and the combined organic extracts were basified with saturated sodium bicarbonate (35 mL) . The flocculent emulsion was filtered through celite loaded onto a coarse frit, and the aqueous layer was removed. The aqueous layer was extracted once with ethyl acetate (10 L) , and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Flash chromatography (10% ethyl acetate/hexanes) afforded the aldehyde (0.551 g, 77% yield) as a colorless oil. Analysis of the derived Mosher ester indicated an enantiomeric purity of 93 % ee: IH NMR (300 MHz, C6D6) 69.29 (d, IH, J = 1.2 Hz), 6.8-7.12 (m, 5H) , 2.72 (dd, IH, J = 13.2 Hz, 5.4 Hz), 2.0-2.2 (m, 2H) , 0.69 (d, 3H, J = 6.9 Hz); 13C NMR (75.5 MHz, CDC13) 6 204.3, 138.7, 128.9, 128.4, 126.3, 48.0, 36.5, 13.1. FTIR (neat film) cm-1 3028 (m) , 2971 (m) , 1932 (m) , 2814 (w) , 2716 (w) , 1723 (ε) , 1496 (m) , 1454 (m) , 742 (m) , 701 (s) .

Example 31

(S)-α-ethyl benzeneacetaldehyde

A dry 100 mL Schlenk flask equipped with a magnetic stirrer was charged with lithium aluminum hydride (0.441 g, 11.04 mmol, 2.3 equiv) in a nitrogen-filled drybox. The hydride was suspended in hexanes (21 L) and cooled to 0°C. Ethyl acetate (1.59 mL, 16.23 mmol, 3.38 equiv) was added over

a 1.5 hour period, then the hydride suspension was cooled to -78°C. [1S-[1R*(R*) ,2R*]]-α-ethyl-N-(2-hydroxy-l-methyl-2- phenylethyl) -N-methyl benzeneacetamide (1.495 g, 4.80 mmol, 1.0 equiv) was added in as a solution in tetrahydrofuran (14 mL) , and the reaction was warmed to 0°C. The reaction was stirred for 55 minutes, and quenched by cannula transfer into a 23°C solution of 1 N HCl (60 mL) and trifluoroacetic acid (3.7 mL, 48 mmol, 10 equiv) . The mixture was stirred at 23°C for 5 minutes, diluted with 1 N HCl (100 mL) , and the layers separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) , and the combined organic extracts were basified with saturated sodium bicarbonate (35 mL) , and the flocculent emulsion waε filtered through celite loaded onto a coarse frit. The aqueous layer was removed, and the organic layer dried over sodium sulfate, filtered, and concentrated. Flash chromatography (10% ethyl acetate/hexanes) afforded the desired aldehyde (0.569 g, 80% yield) as a colorless oil. GC analysis of the amide derived by coupling the acid (from oxidation of the aldehyde with sodium chlorite) with (R)-(+) x-methylbenzylamine indicated an enantiomeric purity of the aldehyde of 90 % ee: IH NMR (300 MHz, C6D6) 69.34 (d, IH, J = 1.8 Hz), 6.8-7.15 (m, 5H) , 2.87 (m, IH) , 1.82-1.91 (m, IH) , 1.43-1.53 (m, IH) , 0.66 (d, 3H, J = 7.4 Hz) ; 13C NMR (75.5 MHZ, CDC13)6 200.9, 136.2, 128.9, 128.7, 127.4, 60.7, 22.8, 11.6; FTIR (neat film) cm-1 2966 (m) , 2934 (m) , 2876 (m) , 1727 (s) , 1493 (m) , 1454 (m) , 701 (m) .

(R) -2-methylhexanal

A dry 100 mL Schlenk flask equipped with a magnetic stirrer was charged with lithium aluminum hydride (0.328 g, 8.211 mmol, 2.3 equiv) in a nitrogen-filled drybox. The hydride was suspended in hexanes (16 mL) and cooled to 0°C. Ethyl acetate (1.17 mL, 12.07 mmol, 3.38 equiv) was added over a 1.5 hour period, then the hydride suspension was cooled to -78°C. [1S-[1R*(S*) , 2R*] ]-N-^-hydroxy-l-methyl^- phenylethyl) -N, 2-dimethyl hexanamide (0.99 g, 3.57 mmol, 1.0 equiv) was added as a solution in tetrahydrofuran (9 mL) , and the reaction was warmed to 0°C. The reaction was stirred for 65 minutes, and quenched by cannula transfer into a 23°C solution of IN HCl (45 mL) and trifluoroacetic acid (2.75 mL, 36 mmol, 10 equiv) . The mixture was stirred at 23°C for 5 minutes, diluted with 1 N HCl (100 mL) , and the layers separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) , and the combined organic extracts were basified with saturated sodium bicarbonate (30 mL) , and the flocculent emulsion was filtered through celite loaded onto a coarse frit. GC analysis, using the (R) -(+) -α-methylbenzyl amide of (R) -2-methylhexanoic acid as an internal standard, indicated a yield of 78 ± 3 %. Oxidation of the aldehyde to the carboxylic acid with sodium chlorite, followed by coupling with the (R) -(+) -α-methylbenzylamine and subsequent GC analysis indicated an enantiomeric purity of the 2- methylhexanal of greater than 98% ee: IH NMR (300 MHz, C6D6)59.27 (d, IH, J = 1.8 Hz) , 1.74-1.92 (m, IH) , 0.85-1.15 (m, 6H) , 0.78 (t, 3H, J = 7.0 Hz) , 0.75 (d, 3H, J = 7.0 Hz) . FTIR (neat film) cm-1 2959 (s) , 2926 (s) , 2872 (m) , 1729 (m) , 1455 (m) , 1229 (m) , 1041 (m) .

Method - Addition of Alkyllithium Reagents to Pseudoephedrine Amides to form Chiral Ketones of High Enantiomeric Purity

The preparation of ketones of high optical purity from the pseudoephedrine amides was achieved as follows: Two to four equivalents of an alkyllithium or aryllithium reagent were added to a -78°C ssO.lM mixture of the pseudoephedrine amide in diethyl ether. The mixture was briefly warmed to 0°C and then to 23°C before being cooled again to -78°C and quenched by addition of diisopropylamine followed by 10% glacial acetic acid/diethyl ether. Thiε mixture waε then diluted with ethyl acetate, washed with saturated sodium bicarbonate and water, and concentrated under reduced presεure. This crude concentrate waε purified by flaεh chromatography through silica affording the desired ketone in ca. 90% yield.

Example 33

R-2-methyl-1-phenyl-l-hexanone

To a flame-dried 100 mL round-bottomed flask equipped

with magnetic stir bar was added [1S-[1R* (S*) , 2R*]]-N-(2- hydroxy-l-methyl-2-phenylethyl) -N,2-dimethyl hexanamide (1.0040 g, 3.6 mmol, 1.0 equiv.) . The amide was azeotropically dried under reduced pressure as a solution with toluene (10 mL) and the reaction flask flushed with dry argon. Diethyl ether (36 mL) was added to the residue and the resulting solution cooled to -78°C. Phenyllithium (4.5 mL, 1.94 M, 8.7 mmol, 2.4 equiv.) was added via syringe and the mixture warmed initially to 0°C (10 min) and then to 23°C. TLC (50% ethyl acetate/hexanes) analysiε of the mixture at thiε point showed no starting material. The mixture was cooled again to 0°C and diisopropylamine (0.51 mL, 3.6 mmol, 1.0 equiv.) was added to the mixture, followed 15 min later by 10% acetic acid/diethyl ether (10 mL) . The mixture was extracted with water (50 mL) and the aqueous phase back extracted with ethyl acetate (50 mL) and dichloromethane (2 x 50 mL) . The combined organic phaseε were dried over anhydrouε sodium sulfate, decanted, and concentrated under reduced pressure. Flash chromatography (3 - 5% ethyl acetate/hexanes) of this concentrate then afforded R-2- methyl-1-phenyl-l-hexanone (0.6361 g, 92% yield) aε a slightly yellow oil, with an ee of 92% (as determined by NMR analysis of the Mosher ester derived from the alcohol obtained from reduction of the ketone) : IH NMR (300 MHz, CDC13) 6 7.95 (m, 2H) , 7.50 (m, 3H) , 3.46 (sx, IH, J = 6.8

Hz), 1.80 (m, IH) , 1.45 (m, IH) , 1.30 (m, 4H) , 1.19 (d, 3H, J = 6.9 Hz), 0.87 (m, 3H) ; 13C NMR (75.5 MHz, CDC13) 6 204.5, 136.7, 132.7, 128.6, 128.2, 40.5, 33.4, 29.6, 22.8, 17.2, 13.9; FTIR (neat film) cm-1 3063 (w) , 2959 (ε) , 2859 (s) , 1964 (w) , 1905 (w) , 1817 (w) , 1774 (w) , 1682 (s,), 1596 (m) , 1579 (m) , 1448 (s) , 1376 (m) , 1230 (ε) , 1204 (ε) , 970 (Ξ) , 793 (w) , 704 (s) , 654 (w) .

Example 34

R-2-methyl-l , 3-diphenyl-l-propanone 0

To a flame-dried 100 mL round-bottomed flask equipped with magnetic stir bar was added [1S-[1R* (S*) ,2R*] ]-N-(2- hydroxy-l-methyl-2-phenylethyl) -N, 2-dimethyl benzenepropionamide (1.0143 g, 3.3 mmol, 1.0 equiv.) . The ^' 5 amide was azeotropically dried under reduced pressure as a solution with toluene (12 mL) and the reaction flask flushed with dry argon. Diethyl ether (33 mL) was added to the residue and the resulting slurry cooled to -78°C. Phenyllithium (4.1 mL, 1.94 M, 7.9 mmol, 2.4 equiv.) was added 0 via syringe and the mixture warmed initially to 0°C (15 min) and then to 23°C. TLC (50% ethyl acetate/hexanes) analysis of the mixture at this point showed no starting material. The mixture was cooled again to 0°C and diisopropylamine (0.46 mL, 3.3 mmol, 1.0 equiv.) was added to the mixture, followed 15 5 min later by 10% acetic acid/ diethyl ether (10 mL) . The mixture was extracted with water (50 mL) and the aqueous phase back extracted with ethyl acetate (50 mL) and dichloromethane (2 x 50 mL) . The combined organic phases were dried over anhydrous sodium sulfate, decanted, and concentrated under 0 reduced pressure. Flash chromatography (3 - 10% ethyl acetate/hexanes) of this concentrate then afforded R-2- methyl-l,3-diphenyl-l-propanone (0.6544 g, 90% yield) as a slightly yellow oil with an ee of 92% (as determined by NMR analysis of the Mosher ester derived from the alcohol obtained 5 from reduction of the ketone): IH NMR (300 MHz, CDC13) 6 7.1

- 7.8 (m, 10H) , 3.79 (sx, IH, J = 6.9 Hz) , 3.22 (dd, IH, Jl = 6.3 Hz, J2 = 13.7 Hz) , 2.74 (dd, IH, Jl = 7.9 Hz, J2 = 13.7 ), 1.25 (d, 3H, J = 6.9 Hz); 13C NMR (75.5 MHz, CDC13) 6 203.7, 139.9,136.4, 132.9, 129.1, 128.6, 128.3, 128.2, 126.2, 42.7, 39.3, 17.4; FTIR (neat film) cm-1 3062 (m) , 3026 (m) , 2969 (m) , 1679 (s), 1596 (m) , 1578 ( ) , 1495 ( ) , 1449 (ε) , 1374 (m) , 1281 (m) , 1230 (s) , 1193 (m) , 973 (s) , 740 (m) , 699 (ε) .

R-2-methyl-l-phenyl-3-heptanone

To a flame-dried 100 mL round-bottomed flaεk equipped with magnetic stir bar was added [1S-[1R*(S*) , 2R*]]-N-(2- hydroxy-l-methyl-2-phenylethyl)-N,2-dimethyl benzenepropionamide (1.0374 g, 3.3 mmol, 1.0 equiv.). The amide was azeotropically dried under reduced preεεure as a εolution with toluene (10 mL) and the reaction flask flushed with dry argon. Diethyl ether (33 mL) was added to the residue and the resulting slurry cooled to -78°C. n- Butyllithium (4.5 mL, 1.71 M, 8.7 mmol, 2.3 equiv.) was added via syringe and the mixture warmed initially to 0°C (10 min) and then to 23°C. TLC (50% ethyl acetate/hexanes) analysis of the mixture at this point showed no εtarting material. The mixture was cooled again to 0°C and diisopropylamine (0.47 mL, 3.3 mmol, 1.0 equiv.) added to the mixture, followed 15 min. later by 10% acetic acid/ diethyl ether (10 mL) . The mixture was extracted with water (30 mL) and the aqueouε phaεe back extracted with

ethyl acetate (40 mL) and dichloromethane (2 x 40 mL) . The combined organic phases were dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure. Flash chromatography (5% ethyl acetate/hexanes) of this concentrate then afforded R-2-methyl-l-phenyl-3-heptanone (0.6060 g, 89% yield) as a slightly yellow oil: IH NMR (300 MHz, CDC13) 6 7.20 (m, 5H) , 2.97 (dd, IH, Jl = 7.1 Hz, J2 = 13.2 Hz), 2.83 (sx, IH, J = 7.0 Hz), 2.55 (dd, IH, Jl = 7.3 Hz, J2 13.2 Hz), 2.39 (dt, IH, Jl = 7.3, J2 = 16.9 Hz), 2.25 (dt, IH, Jl= 7.3 Hz, J2 = 16.9 Hz), 1.45 (m, IH) , 1.23 (sx, IH, J = 7.4 Hz), 1.07 (d, 3H, J = 6.9 Hz), 0.85 (t, 3H, J = 7.3 HZ); 13C NMR (75.5 MHz, CDC13) 6214.4, 139.8, 128.9, 128.3, 126.2, 48.1, 41.7, 39.1, 25.6, 22.3, 16.5, 13.9; FTIR (neat film) cm-1 3028 (w) , 2959 (s) , 2932 (ε) , 2873 (m) , 1947 (w) , 1878 (w) , 1805 (w) , 1712 (ε) , 1604 (w) , 1496 (w) , 1454 (m) , 1406 (w) , 1375 (m) , 1130 (w) , 1032 (w) , 992 (w) , 746 (m) , 700 (ε).

Example 36

R-2-butyl-l,3-diphenyl-l-propanone

To a flame-dried 100 mL round-bottomed flaεk equipped with magnetic εtir bar waε added [1S-[1R*(S*) , 2R*] ]-α-butyl- N-(2-hydroxy-l-methyl-2-phenylethyl)-N-methyl benzenepropionamide (1.0860 g, 3.1 mmol, 1.0 equiv.). The amide waε azeotropically dried under reduced pressure as a

solution with toluene (10 mL) and the reaction flask flushed with dry argon. Diethyl ether (30 mL) was added to the residue and the resulting solution cooled to -78°C. Phenyllithium (3.8 mL, 1.94 M, 7.4 mmol, 2.4 equiv.) was added via syringe and the mixture warmed initially to 0° C (10. min) and then to 23°C. TLC (50% ethyl acetate/hexanes) analyεis of the mixture at this point showed no starting material. The mixture waε cooled again to 0°C and diiεopropylamine (0.43 L, 3.1 mmol, 1.0 equiv.) added to the mixture, followed 15 min later by 10% acetic acid/ diethyl ether (10 mL) . The mixture waε extracted with water (50 L) and the aqueous phase back extracted with ethyl acetate (50 mL) and dichloromethane (2 x 50 mL) . The combined organic phaseε were dried over anhydrouε εodium εulfate, decanted, and concentrated under reduced preεεure. Flaεh chromatography (3 - 5% ethyl acetate/hexanes) of thiε concentrate then afforded R-2-butyl-l, 3-diphenyl-l-propanone (0.7704 g, 94% yield) as a slightly yellow oil: IH NMR (300 MHz, CDC13)67.1 - 7.9 (m, 10H) , 3.74 (m, IH) , 3.10 (dd,lH, Jl = 7.7 Hz, J2 = 13.6 Hz ), 2.78 (dd, IH, Jl = 6.5 Hz, J2 = 13.6 Hz), 1.80 (m, IH) , 1.55 (m, IH) , 1.25 (m, 4H) , 0.80 (m, 3H) ; 13C NMR (75.5 MHz, CDC13) 6204.0, 140.0, 137.5, 132.8, 129.0, 128.5, 128.3, 128.1, 126.1, 48.3, 38.2, 32.1, 29.5, 22.8, 13.9; FTIR (neat film) cm-1 3062 (w) , 3027 (m) , 2955 (ε) , 2870 (m) , 1961 (w) , 1898 (w) , 1812 (w) , 1679 (ε) , 1596 (m) , 1581 (w) , 1495 (m) , 1452 (s) , 1374 (w) , 1230 (s) , 1204 (m) , 1179 (w) , 1075 (w) , 1002 (w) , 946 (m) , 751 (m) , 699 (ε) .

Example 37

R-2-butyl-l-phenyl-3-heptanone

To a flame-dried 100 mL round-bottomed flaεk equipped with magnetic εtir bar was added [IS-[1R* (S*) , 2R*] ]-α-butyl- N-(2-hydroxy-l-methyl-2-phenylethyl) -N-methyl benzenepropionamide (1.0012 g, 2.8 mmol, 1.0 equiv.). The amide was azeotropically dried under reduced pressure as a solution with toluene (10 mL) and the reaction flask flushed with dry argon. Diethyl ether (30 mL) was added to the residue and the resulting solution cooled to -78°C. n-

Butyllithium (3.5 mL, 1.71 M, 6.0mmol, 2.1 equiv.) was added via syringe and the mixture warmed initially to 0°C (5 min) and then to 23°C. TLC (50% ethyl acetate/hexanes) analysis of the mixture at this point showed no starting material. The mixture was cooled again to 0°C and diisopropylamine (0.40 mL, 2.8 mmol, 1.0 equiv.) added to the mixture, followed 15 min later by 10% acetic acid/diethyl ether (10 mL) . The mixture was extracted with water (30 mL) and the aqueous phase back extracted with ethyl acetate (30 mL) and dichloromethane (2 x 30 mL) . The combined organic phases were dried over anhydrous sodium sulfate, decanted, and concentrated under reduced presεure. Flash chromatography (2.5 - 10% ethyl acetate/hexanes) of this concentrate then afforded R-2- butyl-l-phenyl-3-heptanone (0.6518 g, 94% yield) aε a εlightly yellow oil: IH NMR (300 MHz, CDC13) 67.20 (m, 5H) , 2.80 (m, 2H) , 2.65 (dd, IH, Jl = 5.0 Hz, J2 = 12.0 Hz) , 2.28 (dt, IH, Jl = 7.3 Hz, J2 = 17.2 Hz) , 2.11 (dt, IH, Jl = 7.3 Hz, J2 = 17.2 Hz) , 1.65 (m, IH) , 1.40 (m, 3H) , 1.25 (m, 6H) , 0.87 (t, 3H, J = 7.0 Hz), 0.81 (t, 3H, J = 7.3 Hz); 13C NMR (75.5 MHz, CDC13) 6214.6, 139.9, 128.9, 126.1, 54.0, 43.4, 38.2, 31.6,

29.5, 25.2, 22.8, 22.2, 13.9, 13.8; FTIR (neat film) cm-1 3028 (m) , 2957 (ε) , 2872 (ε) , 1944 (w) , 1874 (w) , 1803 (w) , 1712 (s, C=0) , 1604 (w) , 1496 (m) , 1455 (s) , 1405 (w) , 1378 (m) , 1255 (w) , 1216 (w) , 1126 (w) , 1055 (w) , 1030 (w) , 973 (w) , 748 (m) , 700 (s) .

Example 38

R-3-(phenylmethyl)-2-heptanone

To a flame-dried 100 mL round-bottomed flask equipped with magnetic stir bar was added [1S-[1R*(S*) , 2R*] ]-α-butyl- N-(2-hydroxy-1-methy1-2-phenylethyl)-N-methyl benzenepropionamide (1.0303 g, 2.9 mmol, 1.0 equiv.). The amide was azeotropically dried under reduced pressure as a solution with toluene (10 mL) and the reaction flaεk fluεhed with dry argon. Diethyl ether (30 mL) waε added to the reεidue and the reεulting εolution cooled to 0°C.

Methyllithium (6.2 mL, 1.3 M, 8.1 mmol, 2.8 equiv.) waε added via εyringe and the mixture warmed to 23°C. TLC (50% ethyl acetate/hexaneε) analyεis of the mixture at this point showed no starting material. The mixture was cooled again to 0°C and diiεopropylamine (0.41 mL, 2.9 mmol, 1.0 equiv.) added to the mixture, followed 15 min later by 10% acetic acid/diethyl ether (10 mL) . The mixture was extracted with water (20 mL) and the aqueous phase back extracted with ethyl acetate (20 mL) and dichloromethane (2 x 20 mL) . The combined organic phaseε were dried over anhydrouε εodium εulfate, decanted, and concentrated under reduced pressure. Flash chromatography (15% ethyl acetate/hexanes) of this concentrate then afforded R-3-(phenylmethyl)-2-heptanone (0.5817 g, 98% yield) as a slightly yellow oil: IH NMR (300 MHz, CDC13)67.2 (m, 5H) , 2.85 (m, 2H) , 2.69 (dd, IH, Jl = 5.1

Hz, J2 = 12.1 Hz), 2.00 (s, 3H) , 1.65 (m, IH) , 1.45 (m, IH) , 1.27 (m, 4H) , 0.88 (t, 3H, J = 6.9 Hz) ; 13C NMR (75.5 MHz, CDC13) 6212.5, 139.6, 128.8, 128.4, 126.2, 54.7, 37.9, 31.4, 30.2, 29.4, 22.7, 13.9; FTIR (neat film) cm-1 3027 (m) , 2931 (ε) , 2858 (s) , 1713 (s) , 1603 (w) , 1496 (m) , 1455 (s) , 1351 (m) , 1162 (m) , 1741 (m) , 700 (s) , 505 (w) .

Method-Analysis of diastereomeric or enantiomeric excesses of alkylated amides, carboxylic acids, alcohols, aldehydes, or ketones.

The diastereomeric purity of the alkylated amides was analyzed by chiral GC analysis of the corresponding trimethylsilyl ether derivatives. The enantiomeric purity of the carboxylic acids waε determined by GC analyεiε of the amides derived by coupling the acids with (R)-(+)-α- methylbenzylamine. The enantiomeric purity of the alcohols was determined by coupling the alcohol with (S) -α-methoxy-α- (trifluoromethyl)phenylacetyl chloride to form the Mosher ester, and analyzing the ratio by NMR. The enantiomeric purity of the aldehydes waε determined either by lithium aluminum hydride or diiεobutylaluminum hydride reduction of the aldehyde to the alcohol followed by formation of the Mosher ester, or oxidation of the aldehyde to the carboxylic acid with sodium chlorite, and coupling with (R) -(+) -α- methylbenzylamine. The enantiomeric purity of the ketones waε determined by lithium aluminum hydride or diisobutylaluminum hydride reduction to the alcohol, followed by formation of the Mosher ester. A general procedure for generating the trimethylsilyl ether of the alkylated amides is aε follows. A dry 10 mL flask equipped with a magnetic stirrer was charged with the alkylated amide (0.1 mmol, 1.0 equiv), and the amide was disεolved in dichloromethane (1.0 " mL) . Triethylamine (0.3 mmol, 3.0 equiv) and chlorotrimethylεilane (0.2 mmol, 2.0

equiv) were added, and the reaction was stirred at 23°C for several hours. The reaction was quenched with water, and the trimethylsilyl ether was extracted with ethyl acetate. A general procedure for coupling a carboxylic acid with (R) - (+) -α-methylbenzylamine is as follows. A dry 10 mL flask equipped with a magnetic stirrer was charged with the acid (0.18 mmol, 1.0 equiv) , (R) -(+) -α-methylbenzylamine (0.25 mmol, 1.4 equiv), 1-hydroxybenzotriazole (0.31 mmol, 1.7 equiv), and dimethylformamide (0.6 mL) . l-(3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

(0.31 mmol, 1.7 equiv) and triethylamine (0.82 mmol, 4.5 equiv) , were added and the reaction waε εtirred overnight at 23°C. The reaction was quenched with 1 N HCl, and the amide was extracted from 1 N HCl with ethyl acetate. A general procedure for coupling an alcohol with Moεher chloride iε as follows. A dry 10 mL flask equipped with a magnetic εtirrer waε charged with α-methoxy-α (trifluoromethyl) phenylacetic acid (0.23 mmol, 2.7 equiv), and the acid waε azeotropically dried with benzene (2 mL) . The residue was dissolved in dichloromethane (1 mL) , and oxalyl chloride (0.19 mmol, 2.3 equiv) and dimethylformamide (catalytic amount) were added, and the mixture was εtirred at 23°C for 1 hour. The mixture waε transferred via cannula into a mixture of dichloromethane (1 mL) , the alcohol (0.08 mmol, 1.0 equiv) , and activated 3 A molecular εieveε, and the mixture was stirred overnight at 23°C (more equivalents of the Mosher chloride are often required for complete reaction of alcohols derived from the ketones) . The reaction mixture was disεolved in ethyl acetate, and extracted with saturated sodium bicarbonate and then IN HCl or saturated ammonium chloride.

A general procedure for aldehyde reduction is as follows. A dry 10 mL flask equipped with a magnetic stirrer was charged with the aldehyde (0.15 mmol, 1.0 equiv), tetrahydrofuran (1.0 mL) , and cooled to -78°C.

Diisobutylaluminum hydride (0.5 mmol, 3.4 equiv) waε added, and the reaction waε warmed to 0° C. The reaction waε stirred at 0°C for 20 minutes and quenched with 1 N HCl, and the product was extracted from 1 N HCl with 1:1 ethyl acetate/hexanes, dried, concentrated, and chromatographed. A general procedure for aldehyde oxidation is aε followε. A 10 mL flaεk equipped with a magnetic stirrer was charged with the aldehyde (0.20 mmol, 1.0 equiv), tert-butanol (4 mL) , and 2-methyl-2-butene (2.0 M in tetrahydrofuran, 1.0 mL, 10 equiv) . The oxidant was prepared by diεεolving εodium chlorite (1.9 mmol, 9.7 equiv) and εodium dihydrogen phosphate (1.44 mmol, 7.4 equiv) in water ( 2 mL) , and pipeting this εolution into the aldehyde mixture. The biphasic mixture was stirred vigorously at 23°C for approximately 1 hour, extracted with dilute sodium bicarbonate, acidified to pH = 2, and extracted with ethyl acetate.

A general procedure for ketone reduction is as followε. A dry 10 mL flask equipped with a magnetic stirrer was charged with the ketone (0.46 mmol, 1.0 equiv) and ether ( 1 mL) , and cooled to 0°C. Lithium aluminum hydride (1.0 M in ether, 0.7 mL, 1.5 equiv) was added, and the mixture waε warmed to 23°C. The reaction was stirred for 1 hour, quenched with water, and extracted with dichloromethane.

Method - Preparation Of Chiral Amino Acids

Pseudoephedrine glycinamide is produced by condensation of either enantiomer of pseudoephedrine with glycine methyl ester in the presence of base (lithium chloride or butylithium) , or by condensation with N-BOC glycine in the presence of trimethylacetylchloride. The enolate is formed by treatment of the glycinamide with lithium diisopylamide or butylithium in the presence of lithium chloride at low temperature (-78 C) followed by warming to 0 C. Introduction

of an alkylating agent produces an alkylated amide in good yield, with excellent diastereoselectivity. Most of the alkylation products are crystalline solids and yield diastereomerically pure derivatives after a single crystallization.

Chiral amino acids may be cleaved from the chiral auxiliary by converting the alkylation products to their respective N protected derivatives, followed by alkaline hydrolysis. When the object of the synthesis is unprotected chiral amino acids, hydrolysis is preferably carried out directly in the absence of acid or base catalyst, by reflux in water. When N-protected amino acids are sought, protecting groups (N-BOC or N-FMOC) are preferably added after alkylation, followed by catalytic alkaline hydrolysis.

Example 39

rs- R ,R 1 l-N-C2-hvdroxy-l-methyl-2-phenylethyl) -N-methyl 2 aminoacetamide (Pseudoephedrine glycinamide)

To a εolution of N-tert-butoxycarbonylglycine (20.Og, 0.114mol) in CH ₂ C1 ₂ (400ml) at 0°C was added triethylamine (19.1ml, 0.137mol, 1.2eq) . To the vigorously stirred reaction mixture was added dropwise trimethylacetylchloride (14.1ml, 0.114mol, l.Oeq). After 5 min, a fine white precipitate was observed. The reaction was stirred for 45 min at 0°C and then a second aliquot of triethylamine (19.1ml, 0.137mol, 1.2eq) was added, followed by addition of (+)- pseudoephedrine (18.9g, 0.114mol, l.Oeq) as a solid. The reaction was stirred for 45min at 0°C. Most of the solvent waε removed in vacuo

and the residue was dissolved in MeOH (200ml) and water (200ml) . The mixture was cooled at 0°C and treated with c. HCl (150ml) and vigorous gas evolution was observed. After 2hr, the methanol was removed in vacuo, and the remaining aqueous was extracted with EtOAc. The organic layer was extracted with 1M HCl. The combined aqueous extracts were cooled to 0°C and basified to pH 12-14 by slow, careful addition of 50% NaOH. The addition rate was moderated to maintain a solution temperature below 45°C. The aqueous was extracted with CH ₂ C1 ₂ (4x) . The pH of the aqueous after the second extraction was found to be 9 and waε readjusted to pH 13 by addition of more 50% NaOH. The combined organic extracts were dried over K ₂ C0 ₃ , filtered and concentrated in vacuo. The residue was dissolved in toluene (200ml) and the solvent removed in vacuo . The oily residue was dissolved in toluene (100ml) , seeded and allowed to stand at 23°C. After the product crystallizes, the recrystallization mixture is cooled to 0°C for lhr before filtration. The filtered crystals were dried in vacuo (0.2mm) at 55°C for 12hr to insure dry product (19.2g, 76%) . Mp. 78-82°C; IR (neat) 3361, 2981, 1633, 1486, 1454, 1312, 1126, 1049, 926, 760, 703; ¹ H NMR (1:1 rotamer ratio, CDCI ₃ ) 7.29-7.40 (m, 5H) , 4.53-4.63 (m, 1.5H), 3.88 (m, 0.5H), 3.72 (d, 0.5H), 3.46 (d, IH, J=16.6), 3.37 (d, 0.5H, J=17.1), 2.97 (ε, 1.5H), 2.79 (ε, 1.5H), 2.11 (ε(br), 3H) , 1.09 (d, 1.5H, J=6.7), 0.99 (d, 1.5H, J=6.7); ¹³ C NMR 174.1, 173.5, 142.3, 142.1, 128.7, 128.5, 127.9, 126.9, 126.7, 75.8, 74.9, 57.5, 57.2, 43.7, 43.4, 30.1, 27.1, 15.3, 14.4; Anal. Calc. for C ₁₂ H _l8 N ₂ 0 ₂ , C, 64.84; H, 8.16; N, 12.60; Found C, 64.54; H, 7.93; N, 12.46.

Example 40

amionacetamide (4.86g, 21.9mmol) in THF (30ml with 10ml wash) was added via cannula over a period of 5min. The reaction was allowed to stir for 20min at -78°C, and the dark yellow solution was then warmed to 0°C and stirred for 20min to give a bright yellow opaque suεpension. To the enolate was added allylbromide (2.08ml, 24.1mmol, l.leq) and the reaction was allowed to stir at 0°C. After 15min, the yellow color had dissipated and TLC analysis indicated nearly complete consumption of starting material. The reaction was quenched by addition of 1M HCl and then extracted with ethyl acetate. The organic layer was washed with 1M HCl and the combined aqueous extracts were cooled in an ice bath and basified to pH13 with NaOH (50%aq) . The aqueous was extracted with four portions of CH ₂ C1 ₂ and the organic extracts were dried over K ₂ C0 ₃ , filtered and concentrated in vacuo to give an oil which was slowly crystallizing. The product was dissolved in hot toluene (40ml) , cooled to -20°C and seeded. The cryεtals that formed were collected and washed with ether to give 3.178g (58%) of 5 as a εingle diaεtereomer. The mother liquor waε concentrated and the residue was purified by chromatography on εilica gel with methanol, triethylamine, dichloromethane (4%, 4%, 92%, reεpectively) as eluent to give 1.70g of additional product aε an oil. The oil waε diεsolved in hot toluene (15ml) , cooled to -20°C and seeded. The crystals that formed were collected and waεhed with ether to give an additional 0.80g (15%) of 5 (Total yield 73% aε a εingle diastereomer) . M.p. 79-83°C; IR (neat) 3256, 3072, 2978, 1632, 1491, 1453, 1109, 1051, 918, 762, 703; ¹ H NMR (3:1 rotamer ratio, *denotes minor rotamer peaks, CDC1 ₃ ) 7.23-7.38 (m, 5H) , 5.64-5.85 (m, IH) , 5.07-5.14 (m, 2H) , 4.55- 4.59 (m, 2H) , 4.03* (m, IH) , 3.69 (m, IH) , 3.65 (dd, IH, J=7.5, 5.3), 2.93 (s, 3H) , 2.87 (s, 3H) , 2.61-2.66* (m, 2H) , 2.13 (m, IH) , 1.03 (d, 3H, J=6.4), 0.96 (d, 3H, J=6.7); ¹³ C NMR 176.1, 175.1*, 142.1, 141.8*, 134.7*, 133.7, 128.5*, 128.2, 128.1*, 127.6, 126.8*, 126.5, 118.1, 117.9*, 75.5, 74.9*, 57.6, 51.2,

crystals that formed were collected and washed with ether to give an additional 0.80g (15%) of 5 (Total yield 73% as a single diastereomer) . M.p. 79-83°C; IR (neat) 3256, 3072, 2978, 1632, 1491, 1453, 1109, 1051, 918, 762, 703; ^ NMR (3:1 5 rotamer ratio, *denotes minor rotamer peaks, CDC1 ₃ ) 7.23-7.38 (m, 5H) , 5.64-5.85 (m, IH) , 5.07-5.14 (m, 2H) , 4.55- 4.59 (m, 2H) , 4.03* (m, IH) , 3.69 (m, IH) , 3.65 (dd, IH, J=7.5, 5.3), 2.93 (s, 3H) , 2.87 (s, 3H) , 2.61-2.66* (m, 2H) , 2.13 (m, IH) , 1.03 (d, 3H, J=6.4), 0.96 (d, 3H, J=6.7); ¹³ C NMR 176.1, 10 175.1*, 142.1, 141.8*, 134.7*, 133.7, 128.5*, 128.2, 128.1*, 127.6, 126.8*, 126.5, 118.1, 117.9*, 75.5, 74.9*, 57.6, 51.2, 51.0*, 39.8*, 39.6, 31.4, 27.0, 15.5*, 13.4; Anal. Calc. for C ₁₅ H ₂₂ N ₂ 0 ₂ , C, 68.67; H, 8.45; N, 10.68; Found C, 68.55; H,

8.55; N, 10.72

15 Example 41

25 rs-rR .R 11-N-(2-hvdroxy-l-methyl-2-phenylethyl)-N-methyl 2-amino 5-pentenamide (Pseudoephedrine Allyl lycinamide)

A solution of azeotropically dried (from toluene) [S- [R ,R ] ]-N-(2-hydroxy-l-methyl-2-phenylethyl) -N-methyl 2-

30 aminoacetamide (289mg, 1.30mmol) in THF (3ml) was transferred to a dry flask containing flame dried LiCI (331mg. 7.80mmol, 6eq) and the total reaction volume was brought to 8ml by addition of additional THF (5ml) . The mixture was cooled to - 78°C and 1.65M BuLi in hexanes (1.54ml, 2.54mmol, 1.95eq) was

35 added slowly and to the inner edge of the flask such that the

alkyllithium was cold when it mixed with the reaction slurry. The reaction was stirred for 20min at -78°C and then the dark yellow mixture was warmed to 0°C. After stirring for 20min, allyliodide (149μ, 1.63mmol, 1.25eq) was added to the bright yellow heterogenious mixture. The color dissipated within lOmin. After 30min, the reaction was quenched by addition of IM HCl and then extracted with ethyl acetate. The organic layer is washed with IM HCl and the combined aqueous extracts were cooled in an ice bath and basified to pH13 with NaOH (50%aq) . The aqueous was extracted with three portions of CH ₂ C1 ₂ and the organic extracts were dried over K ₂ C0 ₃ , filtered and concentrated in vacuo to give 346mg of crude product. A small amount of crude product (lδmg) was reserved for GC analysiε; the remainder waε purified by chromatography on silica gel with methanol, triethylamine, dichloromethane (5%, 5%, 90%, respectively) as eluent to give the allylglycinamide (263mg, 85%) as an oil which crystallized on standing. Example 42

LNaOH, H ₂ 0, reflux 2. FmocCI, NaHC0 ₃

[S-[2S 11-2-f9-fluorenylmethoxycarbonyl) -amino-5- pentenoic acid (N-FMOC-Allylqlvcine)

To a slurry of [S-[R ,R ]-2S ]-N-(2-hydroxy-l-methyl-2- phenylethyl)-N-methyl 2 methyl 2 amino-5-pentenamide (83mg, 316μmol) in H ₂ 0 (2.53ml) was added a solution of NaOH (IM, 633μl, 633μmol 2eq) . The resulting mixture was heated to reflux. After 90min, TLC analysis indicated that the reaction

was complete. The reaction was cooled and pseudoephedrine was observed to crystalize. The reaction mixture was extracted with CH ₂ C1 ₂ (2x) and the organic extracts washed once with H ₂ 0. The aqueous layers were combined and the total volume reduced to approximately 5ml. To the alkaline solution was added solid NaHC0 ₃ (53mg, 633μmol, 2eq) and dioxane (10ml). The resulting solution was cooled to 0°C and treated with FMOCC1 (90mg, 348μmol, l.leq) . The reaction was εtirred for lhr at 0°C and then for 2hr at RT. The reaction was portioned between H ₂ 0 and a mixture of EtOAc and ether (1:1) . The organic extract was washed once with 2% NaHC0 ₃ and the combined aqueous was reextracted with EtOAc/ether (1:1). The second organic extract was again waεhed with 2% NaHC0 ₃ and the combined aqueouε waε carefully acidified with IM HCl to pHl. The product waε extracted with EtOAc (2x) and the organic was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. After azeotroping with toluene (lx) and chloroform (2x) , the product was obtained as a white crystalline εolid (102mg, 96%) . A small amount of the product (5mg) was reserved for analysis, the remainder was recrystallized form EtOAc, hexaneε at 0°C to give 76mg of analytically pure product. Mp. 134.5-136°C; IR (neat) 3408, 3320, 3067, 2952, 1714, 1520, 1450, 1338, 1226, 1052, 925, 759, 740; H NMR (9:1 rotamer ratio, * denoteε minor rotamer peaks, CDCI ₃ ) 10.85 (s(br), IH) , 7.74 (d, 2H, J=7.4), 7.56 (m, 2H) , 7.38 (t, 2H, J=7.3) , 7.29 (t, 2H,

J=7.3), 6.32* (d, IH, J=5.6), 5.65-5.76 (m, IH) , 5.38 (d, IH, J8.0), 5.07-5.19 (m, 2H) , 4.50 (m, IH) , 4.40 (d, 2H, J=7.0), 4.21 (t, IH, J=6.9), 4.15 (m, IH) , 2.57 (m, 2H) , 2.40* (m, 2H) ; ¹³ C NMR 176.5, 155.9, 143.7, 143.6, 143.5, 141.2, 131.7, 131.5*, 127.7, 127.0, 126.7, 125.0, 124.6, 120.0, 119.7,

119.5, 67.6*, 67.2, 53.7*, 53.1, 47.0, 36.3; Anal, Calc, for C ₂₀ H ₁₉ NO ₄ , C, 71.20; H, 5.68; N, 4.15; Found C, 71.12; H, 5.63; N, 4.15.

Example 43

fS-r2S 11-2-(butoxycarbonyl) -amino-5-pentenoic acid (N-BOC-allylglvcine)

To a solution of [S-[R ,R ]-2S ]-N-(2-hydroxy-l-methyl- phenylethyl) -N-methyl 2 amino-5-pentenamide (537mg, 2.05mmol) in H ₂ 0 (4.1ml) was added a solution of NaOH (IM, 4.09ml, 4.09mmol, 2eq) . The resulting mixture waε heated to reflux. After 70min, the reaction was cooled and pseudoephedrine was obεerved to cryεtallize. The reaction mixture was filtered and the solid waε washed with water. Upon drying, 193mg (57%) of pseudoephedrine was recovered. The filtrate was extracted with CH ₂ Cl ₂ (2x) and the organic extracts washed once with H ₂ 0. The aqueous layers were combined and the total volume reduced to approximately 10ml. To the alkaline solution waε added dioxane ^" (10ml) . The reεulting mixture waε cooled to 0°C and di-t-butyldicarbonate (536mg, 2.46mmol, 1.2eq) waε added. The reaction waε stirred for 90min at 0°C. The reaction was extracted with EtOAc and the organic was waεhed with 0.2M NaOH. The combined aqueouε waε carefully acidified with IM HCl to pH2. The aqueouε waε extracted with EtOAc (3x) and the combined organic was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to give the carboxylic acid as an oil (399mg, 91%). IR (neat) 3324, 3081, 2980, 2932, 1715, 1513, 1395, 1369, 1251, 1163, 1053, 1025, 922; ¹ H NMR (2:1 rotamer ratio, * denotes minor rotamer peaks, CDCI ₃ ) 8.86 (ε(br), IH) ,

6.37* (d, IH, J=5.2) , 5.73 (m, IH) , 5.14-5.19 9m, 3H) , 4.40 (m, IH) , 4.19 (m, IH) , 2.57 (m, 2h) , 1.44 (s, 9H) ; ¹³ C NMR176.0, 156.7*, 155.4, 132.1, 119.1, 81.7*, 80.1, 54.2*, 52.7, 36.3, 28.1; Anal. Calc. for C ₁₂ H _l8 N ₂ 0 ₂ , C, 64.84; H, 8.16; N, 12.60; Found C, 64.54; H, 7.93; N, 12.46; Anal. Calc. for C ₁₀ H ₁₇ NO ₄ , C, 55.80; H, 7.96; N, 6.51; Found C, 55.71; H, 8.14; N, 6.56.

Example 44

H ₂ O, reflux

rs-rR ,R 1-2S 1-N-(2-hvdroxy-l-methyl-2-phenylethyl)-N- methyl 2 aminobutanamide (Allylglycine)

Pseudoephedrine allylglycinamide 5 (697mg, 2.59mmol) waε suspended in water (5.20ml) . The mixture was heated to reflux for 9hr, at which point TLC analyεiε indicated that complete hydrolysis had occurred. The reaction was cooled, and the solution was extracted with CH2C12 (2x) . The organic extracts were back extracted with one portion of water. The aqueouε extractε were combined and the water was removed in vacuo to give a white crystalline solid which waε triturated with ethanol, filtered and waεhed with several portions of ethanol. Upon drying (0.2mm), 258mg (87%) of allylglycine was obtained.

Method - pro (S) alkylation with epoxides

Epoxides may also be used as alkylating agents to produce alkylated pseudoephedrine amides with high diastereoselectivity. Electrophilic attack by epoxides is believed to occur at the opposite face of the Z-configured

enolate from that attached by alkyl halideε, illustred in Examples 10 through 15.

Example 45

riS-riR*rs*) ,2R*11-N-(2-Hvdroxy-l-methyl-2-phenylethyl)- 4-hvdroxy-N-2-phenylmethyl butanamide

A dry 25 mL round-bottomed flask equipped with a magnetic stirring bar was charged with lithium chloride (0.576 g, 13.6 mmol, 6.8 equiv), diiεopropylamine (0.60 mL, 4.50 mmol, 2.25 equiv) and tetrahydrofuran (2 mL) . The reεulting εuεpenεion waε cooled to -78°C. A εolution of [S-[R*,R*] ]-N-(2-Hydroxy- l-methyl-2-phenylethyl)-N-methyl benzenepropionamide (0.595 g, 2.00 mmol, 1 equiv) in tetrahydrofuran (5 mL) waε added dropwise to the reaction flask via syringe. Upon completion of the addition the mixture was stirred at -78 °C for 1 h, at 0 °C for 15 min, at 23 °C for 5 min and finally was cooled to 0 °C. Ethylene oxide (0.50 mL, 10.0 mmol, 5.0 equiv) was condensed into a dry 5 mL flaεk via a dry-ice jacketed syringe. After 1 h, saturated aqueouε ammonium chloride solution (10 mL) was added and the reaction mixture was partitioned between water (10 extracted further with 2-20 mL portions of ethyl acetate. The organic extracts were combined and dried over anhydrous sodium sulfate. Removal of the solventε under reduced preεεure afforded a highly viεcous oil. Purification by flash column chromatography (50% ethyl acetate in hexanes) gave 0.656 g (96%) of the desired product as a highly viscous colorleεε oil. Capillary GC analysis of the

corresponding 0,0-diacetate, as described above, established a diastereomeric excesε (de) of 89% for thiε product ¹ H NMR (500 MHz, C ₆ D ₆ ) , 6: 7.36 (d, 2H, J=7.4 Hz, pH) , 7.30 (d. 2H, J=7.4

HZ, PhH) , 7.23 (d, 2H, 7=7.4 Hz, PhH) , 7.20-6.95 (m, 22H, PhH), 6.95 (t, 2H, J=7.4 Hz, PhH), 6.87 (t. IH, J=7.4 Hz,

PhH) , 6.14 (br ε, IH, OH) , 5.30 (br ε, IH, OH) , 5.10 (br s, IH, OH) , 5.04 (br s, IH, OH) , 4.47 (br ε, IH, OH) , 4.29 (br d, IH, J=8.9 Hz, PhCHOH) , 3.98 (dq, IH, J=9.5 , 6.8 Hz, CH ₃ CHN) ,

3.81 (br t, IH, J=9.0 Hz, CH ₂ CH ₂ OH) , 3.74 (m, 2H, CH ₂ CH ₂ OH) , 3.66 (m, IH, CH ₂ CH ₂ OH) , 3.50 (m, IH, COCHCH ₂ ) , 3.14 (m, IH, CH ₃ CHN) , 2.99 (dd, 2H, 7=12.4, 10.4 Hz, PhCH ₂ ) , 2.78 (ε, 3H,

NCH ₃ ) , 2.61 (dd, IH, 7=12.8, 4.5 Hz, PhCH ₂ ) , 2.33 (ε, 3H,

NCH ₃ ) , 2.19 (m, IH, CH ₂ CH ₂ OH) , 2.04 (m, IH, CH ₂ CH ₂ OH) , 1.82 (m, IH, CH ₂ CH ₂ OH) , 1.71 (m, IH, CH ₂ CH ₂ OH) , 0.95 (d, 3H, 7=6.6 Hz, CH ₃ CHN) , 0.88 (d, 3H, 7=6.8 Hz, CH ₃ CHN) , -0.01 (d, 3H, 7=6.6

Hz, CH ₃ CHN) . ¹³ CNMR (125 MHz, C ₆ D ₆ ) , 6: 177.31, 176.20, 143,04, 142.75, 140.48, 140.32, 129.89, 129.41, 128.72, 128.53, 128.41, 127.68, 127.55, 127.37, 137.21, 126.40, 126.31, 75.88, 75.30, 60.73, 60.43, 60.32, 58.73, 58.62, 55.10, 42.17, 41.36, 41.12, 40.35, 39.75, 39.24, 37.54, 36.65, 35.33, 29.53, 26.88,

15.19, 14.79, 14.07. FTIR (neat, cm ^"1 : 3374 (br ε, OH) , 3086 (m) , 3065 (m) , 3033 (m) , 2980 ( ) , 2927 (m) , 2884 (m) , 1767 (m) , 1612 (s, C=0) , 1495 (m) , 1453 (m) , 1123 (m) , 1080 (m) , 1048 (m) , 1027 ( ) , 761 (m) , 703 (m) . HRMS (CI/NH ₃ ) Calcd for C ₂₁ H ₂₇ N0 ₃ (MH+) : 342.2069 Found: 342.2064

Example 46

THF,0°C

rIS-r1R*fS*) .2R*1 I-N-(2-Hvdroxy-l-methyl-2-phenylethyl)- 4-(tert-butyldimethylsiyl) oxy-N-methyl-2-phenylmethyl butanamide

A dry 50 mL round-bottomed flask equipped with a magnetic stirring bar was charged with lithium chloride (1.34 g, 31.7 mmol, 6.0 equiv), diiεoprophylamine (1.47 mL, 11.3 mmol, 2.25 equiv) and tetrahydrofuran (5 mL) . The resulting suspension was cooled to -78 °C and n-butyllithium (2.70 M in hexanes, 3.90 mL, 10.5 mmol, 2.1 equiv) was added via syringe. The suspension was warmed to 0 °C for 15 min, then was cooled to - 78 °C. A solution of [S-[R*,R*] ]-N-(2-Hydroxy-l-methyl-2- phenylethyl) -N-methyl benzenepropionamide (1.49 g, 5.00 mmol, 1 equiv) in tetrahydrofuran (13 mL) waε added dropwise to the reaction flask via syringe. Upon completion of the addition the mixture was εtirred at -78 °C for lh, at 0 °C for 15 min, at 23 °C for 5 min and finally waε cooled to 0 °C, whereupon 2-(tert-butyldimethylsiyl) oxy-l-iodoethane (1.72 g, 6.00 mmol,

1.2 equiv) was added. After 1 h, saturated aqueous ammonium chloride solution (20 mL) waε added and the reaction mixture waε partitioned between water (lOmL) and ethyl acetate (20 mL) . The organic layer waε εeparated and the aqueouε layer waε extracted further with 2-anhydrous sodium sulfate and were concentrated. The residue was purified by flaεh column chromatography (25%) ethyl acetate in hexaneε) to provide 1.97 g (86%) of the desired product as a highly viscous yellow oil. ¹ H NMR (500 MHz, C ₆ D ₆ ) , 6: 7.23 (d, 2H, 7=7.2 Hz, PhH), 7.16

(m, 5H, Phh) , 7.08 (m, 6H, PhH), 6.91 (m, 2H, PhH), 4.51 (t, IH, 7=6.8 Hz, PhCHOH) , 4.21 (dd, IH, 7=9.2, 3.6 Hz, PhCHOH) , 4.12 (br s, IH, OH), 3.89 (m, IH, CH ₃ CHN) , 3.75 (m, IH,

CH _j CHN) , 3.41 (dt, 2H, 7=10.6, 5.0 Hz, CH ₂ CH ₂ OTBS) , 3.22 (dt,

IH, 7=10.0, 3.9 Hz, CH ₂ CH ₂ OTBS) , 3.15 (m, IH, CH ₂ CH ₂ OTBS) , 3.07

(dd, 2H, 7=13.0, 9.6 Hz, PhCH ₂ ) , 2.74 (s, 3H, NCH ₃ ) , 2.70 (dd,

IH, 7=12.8, 4.8 Hz, COCHCH ₂ ) , 2.61 (dd, IH, 7=13.0, 5.1 Hz,

COCHCH ₂ ) , 2.45 (m, IH, COCHCH ₂ ) , 1.89 (m, IH, COCHCH ₂ ) , 1.70 (m, IH, COCHCH ₂ ) , 1.59 (m, IH, COCHCH ₂ ) , 0.96 (s, 9H, OSi(CH ₃ ) ₂ (t-C ₄ H ₉ ) , 0.95 (d, 3H, 7=7.0 Hz, CH ₃ CHN) , 0.93 (d, 3H, J=7.0 Hz, CH ₃ CHN) , 0.89 (s, 9H, OSi (CH ₃ ) ₂ (t-C ₄ H ₉ ) , 0.14 (d, 3H,

7=6.5 Hz, 0.02 (s, 3H, OSi(CH ₃ ) ₂ (t-C ₄ H ₉ ) , -0.04 (s, 3H,

OSi(CH ₃ ) ₂ (t-C ₄ H ₉ ) , -0.07 (ε, 3H, OSi (CH ₃ ) ₂ (t-C ₄ H ₉ ) . ¹³ C NMR (125

MHz, C ₆ D ₆ ) , 6: 176.87, 175.59, 143.57, 142.82, 140.68, 140.47, 129.42, 128.63, 128.56, 127.43, 127.32, 126.84, 126.51, 126.32, 75.86, 75.42, 62.22, 60.65, 60.45, 58.71, 41.21,

40.98, 40.28, 39.36, 36.88, 36.58, 33.81, 26.88, 26.30, 26.06, 18.69, 18.31, 14.87, 14.18, -4.94, -5.09, -5.28. FTIR (neat) , cm ^"1 : 3389 (br ε, OH) , 3072 (w) , 3060 (w) , 3025 (w) , 2955

(ε) , 2931 (s), 2884 (s) , 2861 (ε) , 1948 (w) , 1884 (w) , 1813 (w) , 1619 (s, C=0) , 1455 (s) , 1255 (m) , 1084 (s) , 944 (w) , 838

(m) , 773 (m) , 709 (m) . HRMS (CI/NH ₃ ) Calcd for C ₂₇ H ₄₂ N0 ₃ Si

(MH+) : 456.2934. Found: 456.2943

It εhould be understood that the foregoing examples are merely illustrations of applicant's invention, and εhould be not be conεidered as limitations thereto. The following claims εet forth the εcope of applicant's invention.