PSEUDOEPHEDRINE 1

Pseudoephedrine product, which is easily removed by crystallization or flash col- umn chromatography. Because intramolecular O→N acyl trans- fer within pseudoephedrine β-amino esters occurs rapidly, and

CH3 because the N-acyl form is strongly favored under neutral or ba- H sic conditions,3 products arising from (mono)acylation on oxygen N rather than nitrogen are not observed. OH CH3 Pseudoephedrine amides undergo efficient and highly diastere- oselective alkylation reactions with a wide range of alkyl halides as 1S,2S-(+) substrates (Table 2).2 Alkylation of pseudoephedrine amides is ac- [90-82-4] complished by dianion formation with lithium diisopropylamide InChI = 1/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10- (LDA) in tetrahydrofuran (THF) in the presence of lithium chlo- 12H,1-2H3/t8-,10+/m0/s1 ride (6 equiv), followed by the addition of an alkylating agent.4 InChIKey = KWGRBVOPPLSCSI-WCBMZHEXBE The use of lithium chloride leads to a substantial acceleration 1R,2R-(−) in the rate of alkylation and is essential for complete reaction. [321-97-1] C10H15ON (MW 165.24) In addition, O-alkylation of the secondary hydroxyl group of the InChI = 1/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10- pseudoephedrine auxiliary is suppressed in the presence of lithium 12H,1-2H3/t8-,10+/m1/s1 chloride. Although the specific role of lithium chloride in the reac- InChIKey = KWGRBVOPPLSCSI-SCZZXKLOBW tion is not known, there is ample precedent in the literature, notably in the work of Seebach and co-workers, documenting the benefi- (reagent used as a practical chiral auxiliary for asymmetric cial influence of lithium chloride in enolate alkylation reactions. synthesis) These studies suggest that lithium chloride modifies the aggrega- 5–8 Alternate Name: α-[1-(methylamino)ethyl] benzenemethanol; - tion state, and thereby the reactivity of an enolate in solution. ephedrine; isoephedrine. ◦ Table 2 Diastereoselective alkylation of pseudoephedrine amides Physical Data: mp 118–120 C. with alkyl halides Solubility: sparingly soluble in water, soluble in ether, alcohol, and many other organic solvents. CH3 O Form Supplied in: white crystalline solid; widely available. 1. LDA, LiCl, THF R Purity: recrystallization from water. N 2. R'X Handling, Storage, and Precaution: stable; combustible; incom- OH CH3 patible with strong oxidizing agents; eye, skin, and respiratory CH3 O −1 irritant; toxicity (oral) rat LD50: 660 mg kg . R N

OH CH3 R' Asymmetric Alkylation. d-Pseudoephedrine ([1S,2S]-(+)) is R R'X Isolated de (%) Isolated yield (%) a commodity chemical employed in over-the-counter medications CH3 n-BuI ≥99 80 with annual worldwide production in excess of 300 metric tons. CH3 BOMBr 98 80 The enantiomer, l-pseudoephedrine, is also readily available in t-Bu BnBr ≥99 84 bulk and is inexpensive. Pseudoephedrine has been shown to be 2-Thiophene CH3I 95 88 highly effective as a chiral auxiliary in asymmetric alkylation reactions.1,2 Treatment of either enantiomer of pseudoephedrine A useful mnemonic for deriving the preferred diastereomer with carboxylic acid chlorides and anhydrides leads to efficient formed in the alkylation reaction of pseudoephedrine amide eno- and selective N-acylation to form the corresponding tertiary amide lates with alkyl halides is as follows: the alkyl halide enters from derivatives (Table 1).2 Typically, the only by-product in the acy- the same face as the methyl group of the pseudoephedrine auxil- lation reactions is a small amount (<5%) of the N,O-diacylated iary when the (putative) (Z)-enolate is drawn in a planar, extended conformation (eq 1).1

Table 1 Preparation of pseudoephedrine amides

O 1. LDA, LiCl CH3 O CH3 CH3 O THF R R H X R N 2. R′X N N base OH CH3 OH CH3 OH CH3 (S, S)-pseudoephedrine

R X Isolated yield (%)

CH3 RCH2CO2 95 CH3 O 1, 4-syn (1) CH3 CH3O 89 R i-Pr Cl 92 N ′ 3-Pyridyl t-BuCO2 72 OH CH3 R

Avoid Skin Contact with All Reagents 2 PSEUDOEPHEDRINE

Table 3 Diastereoselcetive alkylation of pseudoephedrine amides β-branced electrophiles

O O O CH 1. LDA, LiCl, THF R R ψ 3 ψ + ψ X 2. RI, 23 °C X X CH3 CH3 A B

Xψ = pseudoephedrine auxiliary RI Product Ratio of A:B Isolated yield (%) O

IPhXψ+ Ph 142:1 93

CH3 CH3 CH3 CH3 CH3 (matched) O

IPhXψ– Ph 1:70 96

CH3 CH3 CH3 CH3 CH3 (mismatched) O

IPhXψ+ Ph 66:1 93

CH3 CH3 CH3 CH3 CH3 (mismatched) O

IPhXψ– Ph 1:199 94

CH3 CH3 CH3 CH3 CH3 (matched)

The superior nucleophilicity and excellent thermal stability of Table 4 Diastereoselective alkylation of pseudoephedrine amides pseudoephedrine amide enolates make possible alkylation reac- with matched epoxides tions with substrates that are ordinarily unreactive with the cor- responding ester and imide-derived enolates, such as β-branched CH3 O primary alkyl iodides.2 Also, alkylation reactions of pseudoephe- R 1. LDA, LiCl N 2. O drine amide enolates with chiral β-branched primary alkyl iodides H proceed with high diastereoselectivity for both the matched and OH CH3 mismatched cases (Table 3).9 R′ Epoxides can also be used as substrates in pseudoephedrine amide enolate alkylation reactions, but react with opposite di- CH3 O R′ astereofacial selectivity (suggesting a change in mechanism, pro- N posed to involve delivery of the epoxide electrophile by coordina- OH CH3 ROH tion to a side-chain associated lithium ion), and are more limited in scope (Tables 4 and 5).10 1,3-syn A pictorial representation of the opposing diastereoselectivities R ′ Isolated de (%) Isolated yield (%) of alkyl halides and epoxides is shown in Figure 1.10 A similar R CH 93 88 electrophile dependence upon diastereoselectivity was first noted 3 CH3 CH 96 84 in the alkylation of prolinol amide enolates.11 3 CH2OTBS Bn ≥95 86 Although alkylation reactions of pseudoephedrine amide eno- C6H6 Bn CH OBn ≥95 87 lates are successful with a broad range of electrophiles, a few 2 problematic substrates have been identified. Among these are secondary alkyl halides, such as cyclohexyl bromide, and alkyl halides that are both β-branched and β-alkoxy substituted.2 However, there is evidence that the thermal stability of pseu- Compounds), amino (described in detail in the section Synthe- doephedrine amide enolates may be such that extended reaction sis of α-Amino Acids), and 2-pyridyl groups,2 undergo highly times at ambient temperature, or even heating, may be tolerated; diastereoselective alkylation reactions. However, to date, no gen- both approaches have led to successful alkylation reactions with eral solution has emerged for the diastereoselective alkylation of problematic electrophiles (eqs 2, 3, and 4).12,2,13 pseudoephedrine amides with an α-oxygenated substituent. Eno- Pseudoephedrine amides with a wide variety of α-substituents, lization of pseudoephedrine α-hydroxyacetamide with 3.2 equiv including aryl,1 branched alkyl,14 chloro,1,2 fluoro (described in of LDA furnishes a presumed trianion, with partial decomposition detail in the section Asymmetric Synthesis of Organofluorine of the starting material. Alkylation of the resulting enolate (1.65

A list of General Abbreviations appears on the front Endpapers PSEUDOEPHEDRINE 3 equiv) with benzyl bromide (limiting reagent) then produces the derivatives of α-hydroxyacetamide has been examined in a search corresponding C-benzylated product with 82% de (eq 5).2 for an alternative alkylation substrate [TBS, TBDPS, THP, Bn, BOM, Piv, and methyl(1-methoxyethyl)], none has provided satis- factory results nor offered any improvement over pseudoephedrine Table 5 Diastereoselective alkylation of pseudephedrine amides 2 with mismatched epoxides α-hydroxyacetamide itself.

CH3 O CH3 O 1. LDA, LiCl, THF CH R 1. LDA, LiCl 3 N 2. OTBS N 2. O R′ OH CH3 I OH CH3 CH3 H 61% after 46 h at 45 °C

CH3 O R′ CH O N 3 OTBS (3) OH CH3 ROH N 1,3-anti OH CH3 CH3 CH3

R R′ Isolated de (%) Isolated yield (%) 99% de CH3 CH3 73 86 CH3 O CH3 CH2OTBS 12 78 1. LDA, LiCl, THF Bn C H 46 72 6 6 N Bn 36 80 2. 2-Iodopropane CH2OBn 23 °C → reflux OH CH3 OCH3 52%

O(CH2)3OCH3 Epoxides

CH3 O

N OH CH H OLi 3 Pr-i H OCH3 (4) H3C OLi > N 95% de O(CH2)3OCH3 CH H3C 3 H CH O 3 1. LDA, LiCl, THF OH N 2. BnBr 84% OH CH3 Alkyl Halides CH3 O OH (5) Figure 1 N

OH CH3 Bn 82% de CH3 O 1. LDA, LiCl, THF CH3 α,β-Unsaturated pseudoephedrine amides undergo γ-deproton- N 2. OPMB ation when subjected to standard conditions for pseudoephedrine OH CH3 I CH3 amide enolate formation. The resulting enolate can be α-alkylated 68% after 3 d with high diastereoselectivity to provide β,γ-unsaturated alky- at 23 °C lated products (eq 6).15

CH3 OCH3 CH3 O 1. LDA, LiCl, THF OPMB (2) N N CH3 2. EtI OH CH 93% OH CH3 CH3 CH3 3

~13:1 CH3 O

The diastereoselectivity of the reaction is lower than that ob- N CH3 (6) tained in benzylations of pseudoephedrine amide enolates lacking OH CH3 the α-hydroxyl group. Although an extensive series of O-protected CH3

Avoid Skin Contact with All Reagents 4 PSEUDOEPHEDRINE

Transformations of Alkylated Pseudoephedrine Amides. Addition of alkyllithium reagents to pseudoephedrine amides Alkylation products of pseudoephedrine amides are readily trans- leads to the formation of enantiomerically enriched ketones1,2,21 formed in a single operation into highly enantiomerically en- (eqs 9 and 10).19,20 The protocol developed to transform alkylated riched carboxylic acids, aldehydes, ketones, lactones or primary pseudoephedrine amides into ketones was optimized to avoid pre- alcohols.1,2 Alkylated pseudoephedrine amides can be hydrolyzed mature breakdown of the tetrahedral intermediate generated fol- under acidic or basic conditions to form carboxylic acids. Sim- lowing addition of the organolithium species to the amide.23 ply heating a pseudoephedrine amide at reflux in a 1:1 mixture of sulfuric acid (9–18 N) and dioxane affords the correspond- CH3 O ing carboxylic acid in excellent chemical yield with little or no n-BuLi, Et2O 16 CH3 epimerization (eq 7). Under these conditions, the substrate ini- N –78 0 °C → tially undergoes a rapid N O acyl transfer reaction followed by OH CH3 Bn 88% rate-limiting hydrolysis of the resulting β-ammonium ester inter- 3,17 mediate to form the carboxylic acid. ≥ 99% de O

H3C CH3 (9) CH3 O H2SO4, dioxane Bn N Ph reflux ≥ 95% ee OH CH3 CH3 83% O ≥ 99% de HO Ph (7) 1. Li

CH3 97% ee H3CO OCH3 CH3 O Basic conditions for the hydrolysis of pseudoephedrine amides H3C typically involve heating the substrate with tetra-n-butylammo- N 2. (+)-DIPCl, THF nium hydroxide in a mixture of tert-butyl alcohol and water OH CH3 CH3 (55%, two steps) (Table 6).1,2 Where the expense of tetra-n-butylammonium hy- droxide is a consideration, or in cases where the product car- CH3 boxylic acid is poorly soluble in ether (making extractive removal HO of tetra-n-butylammonium salts difficult), an alternative procedure employing sodium hydroxide in a mixture of water, methanol, and (10) tert-butyl alcohol can be used. The mechanism of the base-induced hydrolysis reaction is believed to involve initial rate-limiting in- CH3O OCH3 tramolecular N→O acyl transfer, followed by rapid saponification of the resulting β-amino ester.3 H3C Reduction of pseudoephedrine amides with metal amide-borane Table 6 Basic hydrolysis of pseudoephedrine amides complexes,1 and lithium amidotrihydroborate (LAB) in particu- lar,2,24 furnishes the corresponding primary alcohols in high yield. CH3 O O In the initial report, LAB was prepared by deprotonation of the R 5 equiv n-Bu4NOH R 25 N HO commercial, solid reagent borane–ammonia complex, using 1:4 t-BuOH:H O, reflux 24 2 ′ slightly less than 1 equiv of butyllithium as base (eq 11). In OH CH3 R′ R more recent work,9 an improved preparation of the reagent has R R′ Isolated ee (%) Isolated yield (%) been developed that uses 1 equiv of LDA as base in the reaction 26 CH3 Bn 94 93 (eq 12). The greater efficiency of reductions using LDA as base CH3 BOM 69 92 is attributed to the propensity of n-butyllithium to form butylboron n-Bu CH3 93 88 side-products in the reaction and, ultimately, butylboron alkoxide Ph Et 64 82 products that are difficult to hydrolyze.

CH3 O Pseudoephedrine amides can be converted directly into highly n-BuLi, BH3•NH3 1,2 N enantiomerically enriched aldehydes using Brown and Tsuka- THF, 23 °C 18 19,20 moto’s lithium triethoxyaluminum hydride reagent (eq 8). OH CH3 CH2CH3 90%

³ 99% de CH3 O LiAlH(OEt)3 O hexanes, THF (11) CH3 CH (8) N 3 –78 0 °C H HO OH CH3 Bn Bn 76% CH2CH3 ≥ 99% de 95% ee 90% ee

A list of General Abbreviations appears on the front Endpapers PSEUDOEPHEDRINE 5

H3CCH3 glycinamide hydrate entails the direct treatment of glycine methyl CH3 O ester hydrochloride with lithium tert-butoxide.38 This procedure is CH LDA, BH3•NH3 N 3 advantageous because it obviates the need to use the hygroscopic THF, 0 °C reagent lithium chloride and it eliminates difficulties associated OH CH3 91% with the handling of the free-base form of glycine methyl ester, CH3 which is prone to polymerization. H3CCH3 Enolization of pseudoephedrine glycinamide is complicated by the presence of two other acidic sites in the molecule: the sec- CH3 HO (12) ondary hydroxyl group and the primary amino group. The eno- lization protocol originally reported requires the addition of a carefully measured amount of LDA to a thoroughly dried so- CH3 lution of pseudoephedrine glycinamide and lithium chloride.37 The strict use of less than 2 equiv of base avoided partial cleav- age of the auxiliary from pseudoephedrine glycinamide. Several γ,δ-Unsaturated pseudoephedrine amides are efficiently con- practical laboratory-scale preparations of enantiomerically en- verted into γ-lactones by cleavage of the auxiliary through halo- riched α-amino acids, including l-azatyrosine39 and l-allylglycine lactonization reactions (eqs 13 and 14).27,28 (eq 15),40 have been executed based on this methodology.

CH3 O CH CH3 O N 3 NBS, HOAc 1. LDA, LiCl, THF NH2 2. Allyl bromide OH CH3 CH3 THF, H2O N 66 _ 71% 80% OH CH3 F O CH3 O NH2 (15) O N

CH3 (13) OH CH3 F

Br CH3 ≥ 99% de

A modified procedure has since been developed that involves CH3 O O 38 I2 the direct alkylation of pseudoephedrine glycinamide hydrate. CH3 H3C (14) N THF, H2O O In this operationally simpler procedure, excess lithium hexam- ethyldisilazide (LHMDS) is added to a solution of anhydrous OH CH3 95% I lithium chloride and pseudoephedrine glycinamide hydrate. In situ generation of LHMDS•LiCl from lithium metal, hexamethyldis- 12:1 ilazane (HMDS), and hexyl chloride can also been used for the enolization and subsequent alkylation of pseudoephedrine glyci- The efficiency and practicality of pseudoephedrine-based namide hydrate.38 These procedures for the alkylation of pseu- asymmetric alkylation reactions has been exploited in synthe- doephedrine glycinamide reliably afford good yields of alky- ses of several complex natural products, including cylindrocyclo- lated products (Table 7). The procedure employing commercial 22,29 30 15 31 phane A, fumonisin B2, pironetin, epothilones A and B, LHMDS has been used in the total synthesis of saframycin A salicylihalamide A,32 6,7-dideoxysqualestatin H5,33 saframycin (eq 16).34,35 A,34,35 and terpestacin.28 Alkylation of pseudoephedrine sarcosinamide can be used to prepare enantiomerically enriched N-methyl-α-amino acids.36,37 Synthesis of α-Amino Acids. The diastereoselective alky- Anhydrous pseudoephedrine sarcosinamide has been prepared lation of enolates derived from pseudoephedrine glycinamide by the addition of sarcosine methyl ester to a mixture of pseu- has been shown to be an effective method for the prepara- doephedrine, lithium chloride, and lithium methoxide. In contrast tion of α-amino acids of high enantiomeric purity.36,37 Pseu- to the preparation of pseudoephedrine glycinamide, the amount doephedrine glycinamide hydrate can be easily prepared in a sin- of dipeptide by-product produced in the reaction is minimal, per- gle step by the condensation of pseudoephedrine with the free- haps due to the increased steric hindrance of the N-methyl group of base form of glycine methyl ester in the presence of lithium chlo- sarcosine. Thus, pure anhydrous pseudoephedrine sarcosinamide ride and base (n-butyllithium36 or lithium methoxide37). The pri- can be obtained from the crude acylation reaction mixture by pre- mary by-product in the reaction is the dipeptide pseudoephedrine cipitation from toluene and subsequent drying. Like anhydrous glycylglycinamide, formed to the extent of < 10%. The crude acy- pseudoephedrine glycinamide, anhydrous pseudoephedrine sar- lation reaction mixture can be directly purified by selective crystal- cosinamide can be handled in the atmosphere for brief periods lization of pseudoephedrine glycinamide hydrate from hot aque- without consequence, but should be stored with scrupulous avoid- ous tetrahydrofuran. An improved preparation of pseudoephedrine ance of moisture to prevent hydration.

Avoid Skin Contact with All Reagents 6 PSEUDOEPHEDRINE

Table 7 Alkylation of pseudoephedrine glycinamide hydrate The alkylation of anhydrous pseudoephedrine sarcosinamide is similar to the alkylation of anhydrous pseudoephedrine glyci- namide, with one important experimental modification, wherein 1. LHMDS (3.2 equiv), THF the reaction is conducted in the presence of 1 equiv of N- CH O 3 LiCl (3.2 equiv), 0 °C methylethanolamine. The optimum conditions for alkylation of NH2 N 2. RX, 0 °C anhydrous pseudoephedrine sarcosinamide involve the addition of n-butyllithium or LDA (2.95 equiv) to a suspension of an- OH CH3 •H2O hydrous pseudoephedrine sarcosinamide (1 equiv), anhydrous CH3 O lithium chloride (6.00 equiv), and N-methylethanolamine (1.00 NH2 − ◦ N equiv) in THF at 78 C, followed by warming the resulting slurry to 0 ◦C and the addition of an alkylating agent (1.1–1.5 OH CH3 R equiv) (eq 17).37 The presence of N-methylethanolamine in the Isolated Isolated alkylation reaction is necessary to achieve reproducible diastere- RX LHMDS de (%) yield (%) oselectivity and may function by facilitating anionic equilibration. Commercial solution Many functional groups are stable under conditions for the CH =CHCH Br 93 86 2 2 (1.0 M in THF) alkylation of pseudoephedrine glycinamide enolates, including aryl benzenesulfonate esters (eq 18),39 tert-butyl carbamate and Generated in situ tert-butyl carbonate groups (eq 19),41 tert-butyldimethylsilyl CH2=CHCH2Br 93 82 (Li, HMDS, n-HexCl) ethers,42 benzyl ethers,37 tert-butyl ethers,37 methoxymethyl ethers,36 and alkyl chlorides.36 The stereochemistry of the alky- O Commercial solution lation reactions of pseudoephedrine glycinamide and pseudoe- 97 65 (1.0 M in THF) phedrine sarcosinamide is the same as that observed in alkylations O I of simple N-acyl derivatives of pseudoephedrine.

O Generated in situ 96 62 CH3 O O (Li, HMDS, n-HexCl) 1. LDA, LiCl, THF I NH N 2 2. N I OH CH3 CH O 1. LHMDS, THF OSO2Ph 3 LiCl, 0 °C 92% NH N 2 2. OTBS OH CH3 • H2O Br CH3 O

CH3O OCH3 NH N 2 CH3 OH CH3 N (18) 80%

OSO2Ph CH O 3 90 _ 91% de NH N 2 (16) CH3 O OH CH3 OTBS 1. LDA, LiCl, THF NH2 N 2. CH3O OCH3 Br N OH CH3 CH 3 CH3 BocHN OBoc 97% de 60%

CH3 O 1. n-BuLi, LiCl, THF CH3 O NH2 HO(CH2)2NHCH3 N (19) NHCH3 N 2. BnBr OH CH3 69% N OH CH3 CH3 CH3 O BocHN OBoc NHCH3 (17) N >10:1

OHCH3 Bn Hydrolysis reactions of alkylated pseudoephedrine glycina- 99% de mides are more rapid than the hydrolysis of pseudoephedrine

A list of General Abbreviations appears on the front Endpapers PSEUDOEPHEDRINE 7 amides without α-amino groups. It is believed that this reflects groups within the adducts using trifluoroacetic acid (TFA) and the inductive influence of the amino group, enhancing the elec- hydrogenolysis of the resulting α-hydrazino derivatives then pro- trophilicity of the amide group.37 It is significant that this rate vides α-amino acids in good yield following acidic hydrolysis and enhancement is not accompanied by an increased rate of racemiza- ion exchange chromatography (eq 20).43 tion. Typically, alkaline hydrolysis of the alkylation products oc- curs upon heating at reflux in aqueous sodium hydroxide solution (0.5 M, 2 equiv).36 Upon cooling, the pseudoephedrine auxiliary is OCH3 easily recovered by extraction of the aqueous product slurry with OCH3 CH3 O 1. LDA, THF, –78 °C dichloromethane (typically, 96% of the pseudoephedrine auxiliary 2. DTBAD, –105 °C is recovered, and 83–86% after one recrystallization from water). N OCH3 90% After extraction of the auxiliary, the alkaline aqueous product so- OH CH3 lution can be treated with an acylating agent to furnish the cor- responding N-protected α-amino acid derivative directly. N-tert- OCH Butoxycarbonyl (N-Boc) and N-(9-fluorenylmethoxy)-carbonyl 3 (N-Fmoc) protected α-amino acids are prepared efficiently by this OCH3 1. TFA, DCM CH3 O 2. H , Raney Ni method (Table 8).37 Free α-amino acids can be obtained simply 2 3. 4 M H SO by refluxing the alkylation products in pure water. Extraction of N OCH3 2 4 dioxane, reflux the aqueous reaction mixture with dichloromethane, lyophiliza- OH CH3 N(Boc)NHBoc 4. DOWEX 50 tion of the aqueous layer, and trituration of the solid residue with >95% de 71% ethanol (to remove any remaining pseudoephedrine) then provides the pure α-amino acids (Table 9).36 OCH3 OCH O 3 Table 8 Basic hydrolysis of pseudoephedrine amides followed by (20) N-protection HO OCH3

NH2 CH O O 3 >99% ee NH 1. NaOH NHX N 2 HO 2. Boc2O or FmocCl OH CH3 R R Recently, the bis(methylthio)methylene imine of pseudoeph- R X Isolated ee (%) Isolated yield (%) edrine glycinamide was shown to undergo diastereoselective alky- ◦ CH3CH2 Boc ≥99 97 lation at 23 C with lithium tert-butoxide or sodium ethoxide as 44 CH3CH2 Fmoc ≥99 99 base and various alkyl halides as electrophiles (eq 21). This pro- (CH3)2CHCH2 Boc ≥99 97 cedure was used to prepare enantiomerically enriched α-amino MOMO Fmoc 96 73 acids. Alkylation reactions of pseudoephedrine amides offer many practical advantages over existing procedures for the asymmet- ClN CH2 ric construction of α-amino acids. These include the high crys- tallinity of many pseudoephedrine amides, the low cost of pseu- Table 9 Hydrolysis of pseudophedrine amides in water doephedrine, the high diastereoselectivity of the alkylation reac- tions, a simple protocol for recovering the auxiliary, and the ease

CH3 O O of hydrolytic, racemization-free removal of the chiral auxiliary. H2O, reflux The methodology is also advantageous because it requires no pro- NH2 NH2 N HO tecting group for the α-amine. Thus, in many instances, alkylation OH CH3 R R of pseudoephedrine glycinamide has been deemed the method of choice for the preparation of enantiomerically enriched α-amino R Isolated ee (%) Isolated yield (%) acids in quantity (eq 22).45 ≥ CH2=CHCH2 99 87 ≥ c-C3H5CH2 98 79 ≥ (CH3)3SiCH2 99 77 ≥ CH3 O 2-CH3OC6H4CH2 99 71 LiOt-Bu, BnBr N SCH3 N THF, 23 °C

OHCH3 SCH3 60% The asymmetric amination of pseudoephedrine amide enolates has been introduced as an alternative method for the synthesis of α-amino acids.43 Lithium enolates, generated by the addition CH3 O N SCH3 (21) of LDA to pseudoephedrine amides, can be efficiently aminated N with di-tert-butyl azodicarboxylate (DTBAD). The amination re- OHCH3 Bn SCH3 action is complete within a few minutes at low temperature and does not require the use of lithium chloride. Cleavage of the Boc 90% de

Avoid Skin Contact with All Reagents 8 PSEUDOEPHEDRINE

CH3 O 1. LDA, LiCl, THF; An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe- NH prenylbromide drine-based arylacetamide and paraformaldehyde has been used N 2 53 2. H2O, reflux to prepare enantiomerically pure isoflavanones. OH CH3 63% Table 10 Mannich reaction of pseudoephedrine propionamide CH3 enolate with p-(methoxy)phenyl aldimides CO2H (22) H3C CH3 O 1. LDA, LiCl, THF, –78 °C NH2 CH N 3 2. RCH=NPMP, THF, 0 °C 94% ee OH CH3 PMP CH3 O HN

β-Amino Acids. Pseudoephedrine has been used as a chi- N R ral auxiliary for the preparation of both α-substituted and α,β- OH CH3 CH3 disubstituted β-amino acids. Alkylation of β-alanine was shown Major diastereomer to furnish an efficient, inexpensive, and enantioselective route to anti/syn anti/anti*a α-alkyl β-amino acids (eq 23).46 R Yield (%) Ph >99/1 >99/1 86 2-furyl >99/1 >99/1 80 >99/1 >99/1 69 CH3 O 1. LHMDS, LiCl, THF t-Bu –5 0 °C; CH3CH2I N NH2 a 2. H2O, reflux Ratio of major anti diastereomer (shown) to doubly OH CH3 74% epimeric minor anti diastereomer.

O Table 11 Pseudophedrine-based asymmetric aldol reactions

HO NH2 (23) 1. LDA, THF, –78 °C CH3 O CH2CH3 2. Cp2ZrCl2, THF, –78 °C CH3 94% ee N 3. RCHO, THF, –105 °C OH CH3

In addition, the lithium enolate derived from pseudoephedrine CH3 O OH propionamide has been shown to undergo highly diastereose- N R lective Mannich reactions with p-(methoxy)phenyl aldimines to OH CH3 CH3 form enantiomerically enriched α,β-disubstituted β-amino acids Major diastereomer (Table 10).47 As observed in alkylation reactions using alkyl hali- des as electrophiles, lithium chloride is necessary for the reac- R syn/anti syn/syn*a Yield (%) tion of aldimines. With respect to the enolate, the stereochem- Ph 94/6 >99/1 90 istry of the alkylation reactions is the same as that observed with Et 96/4 >99/1 90 alkyl halides; reactions of p-(methoxy)phenyl aldimines are fur- i-Pr >99/1 >99/1 94 ther characterized by a preference for the formation of 2,3-anti aRatio of major syn diastereomer (shown) to doubly products, a unique and highly useful feature of these reactions. epimeric minor syn diastereomer.

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition re- Asymmetric Synthesis of Organofluorine Compounds. actions, providing enantiomerically enriched β-hydroxy acids, Asymmetric alkylation of fluorinated pseudoephedrine amides esters, ketones, and their derivatives (Table 11).48,49 The opti- has been employed to synthesize a variety of enantiomerically mized procedure for the reaction requires enolization of the pseu- enriched α-fluoro carboxylic acid derivatives. Pseudoephedrine α- doephedrine amide substrate with LDA followed by transmeta- fluoroacetamide, a nonvolatile, crystalline compound, can be read- ◦ lation with 2 equiv of ZrCp2Cl2 at −78 C and addition of the ily prepared by the acylation of pseudoephedrine with ethyl fluo- aldehyde electrophile at −105 ◦C. It is noteworthy that the re- roacetate. (CAUTION: Fluoroacetic acid and derivatives of fluo- action did not require the addition of lithium chloride to favor roacetic acid are exceedingly toxic, causing convulsions and ven- product formation as is necessary in many other pseudoephedrine tricular fibrillation upon inhalation and should be used only under amide enolate alkylation reactions. The stereochemistry of the adequate supervision and in an appropriate fume hood. Although alkylation is the same as that observed with alkyl halides and the the specific toxicities of pseudoephedrine α-fluoroacetamide and formation of the 2,3-syn aldol adduct is favored. The tendency of other fluorinated pseudoephedrine derivatives are unknown, ex- zirconium enolates to form syn aldol products has been previously treme caution in their preparation and handling is urged.) Pseu- reported.50,51,52 The β-hydroxy amide products obtained can be doephedrine α-fluoroacetamide can be enolized with LHMDS in readily transformed into the corresponding acids, esters, and ke- the presence of anhydrous lithium chloride and the resulting eno- tones as reported with other alkylated pseudoephedrine amides. late can be efficiently trapped with reactive electrophiles, such

A list of General Abbreviations appears on the front Endpapers PSEUDOEPHEDRINE 9 as benzyl bromide, to form the corresponding alkylated products of the four possible diastereomeric conjugate addition products with high diastereoselectivity (eq 24).54 Interestingly, enolization (eq 25).55 These products were demonstrated to be stereoisomeric at the β-carbon, and had the same configuration at the α-carbon, that expected based upon addition of simple alkyl halides to the Z-enolate derived from pseudoephedrine α-fluoroacetamide. CH3 O Inductive activation of the amide by the adjacent fluorine atom LHMDS, LiCl F allows for the basic hydrolysis of the amide bond under relatively N THF mild conditions (warming to ∼75 ◦C in a biphasic solution of 2 N OH CH 3 sodium hydroxide in a 2:2:1 mixture of water, tert-butyl alcohol, and methanol) to form carboxylic acids with high enantiomeric excess (eq 26).54 CH3 OLi BnBr F N 87% CH O 3 t OLi CH3 NaOH, -BuOH CH3 N CH3OH, H2O, 75 °C Z-enolate OH CH3 F 91% ≥ CH3 O 99% de O Bn (24) CH3 (26) N HO OH CH3 F F ≥99% de 98% ee

Alkylation of pseudoephedrine α-fluoropropionamide can be of pseudoephedrine α-fluoroacetamide with LDA in the presence used to prepare enantiomerically enriched tertiary alkyl fluo- 56 of anhydrous lithium chloride and subsequent trapping of the re- ride centers (eq 27). In contrast to the alkylation of pseu- sulting enolate with reactive electrophiles resulted in the formation doephedrine α-fluoroacetamide, alkylation of pseudoephedrine α- of alkylated products with diminished diastereoselectivity. The fluoropropionamide proceeds with high diastereoselectivity when basis for the improved selectivity in alkylations conducted with LDA in used as the base in the reaction and low diastereoselec- LHMDS versus LDA is not known; however, the stereochemistry tivity when LHMDS is used. In these reactions, deprotonation of of enolate formation is proposed to be the selectivity-determining pseudoephedrine α-fluoropropionamide with LDA, proposed to step in these reactions. Presumably, the enolization of pseu- occur under kinetic control, is believed to form the corresponding doephedrine α-fluoroacetamide with LHMDS, be it kinetically E-enolate. Electrophilic attack by alkyl halides then occurs oppo- or thermodynamically controlled, exhibits a strong preference for site the enolate π-face occupied by the side-chain alkoxide group, the Z-configuration. The stereochemistry of the subsequent alky- as observed with other pseudoephedrine amide enolates. lation reaction is then consistent with the model proposed for the alkylation of simple N-acyl derivatives of pseudoephedrine. Un- CH3 O like other pseudoephedrine amide enolates, the enolate derived LDA, LiCl CH3 from pseudoephedrine α-fluoroacetamide exhibits limited ther- N THF ∼− ◦ mal stability above 40 C and, as a consequence, alkylation OH CH3 F reactions with relatively unreactive electrophiles, such as ethyl iodide, proceed poorly. However, Michael addition with 1-nitro- 3-phenyl-1-propene does occur, even at −78 ◦C, forming two CH3 OLi BnBr CH N 3 1. LHMDS, LiCl 71% CH3 O THF, –78 °C OLi CH3 F F N 2. H E-enolate Ph NO OH CH3 2 H CH3 O 65% CH3 N (27) OH CH FBn Ph 3 CH3 O NO ≥99% de N 2 (25)

OH CH3 F Related Reagents. Prolinol; Ephedrine; Oxazolidinones; 1.7:1 anti:syn Camphorsultams; Camphor-derived Auxiliaries; Oxazolines.

Avoid Skin Contact with All Reagents 10 PSEUDOEPHEDRINE

1. Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L., J. Am. Chem. Soc. 31. Bode, J. W.; Carreira, E. M., J. Am. Chem. Soc. 2001, 123, 3611. 1994, 116, 9361. 32. Snider, B. B.; Song, F., Org. Lett. 2001, 3, 1817. 2. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; 33. Martin, S. F.; Naito, S., J. Org. Chem. 1998, 63, 7592. J. Am. Chem. Soc. 1997 119 Gleason, J. L., , , 6496. 34. Myers, A. G.; Kung, D. W.; Zhong, B.; Movassaghi, M.; Kwon, S., J. 3. Welsh, L. H., J. Am. Chem. Soc. 1947, 69, 128. Am. Chem. Soc. 1999, 121, 8401. 4. Myers, A. G.; Yang, B. H., Org. Synth. 1999, 77, 22. 35. Myers, A. G.; Kung, D. W., J. Am. Chem. Soc. 1999, 121, 10828. 5. Seebach, D.; Bossler, H.; Gründler, H.; Shoda, S.-I., Helv. Chim. Acta. 36. Myers, A. G.; Gleason, J. L.; Yoon, T., J. Am. Chem. Soc. 1995, 117, 1991, 74, 197. 8488. 6. Miller, S. A.; Griffiths, S. L.; Seebach, D., Helv. Chim. Acta. 1993, 76, 37. Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W., J. Am. Chem. Soc. 563. 1997, 119, 656. 7. Bossler, H.; Seebach, D., Helv. Chim. Acta. 1994, 77, 1124. 38. Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W., J. Org. Chem. 1999, 8. Rück, K., Angew. Chem., Int. Ed. Engl. 1995, 34, 433. 64, 3322. 9. Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J., Synlett 1997, 457. 39. Myers, A. G.; Gleason, J. L., J. Org. Chem. 1996, 61, 813. 10. Myers, A. G.; McKinstry, L., J. Org. Chem. 1996, 61, 2428. 40. Myers, A. G.; Gleason, J. L., Org. Synth. 1999, 76, 57. 11. Askin, D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.; Shinkai, I., 41. Sinha Roy, R.; Imperiali, B., Tetrahedron Lett. 1996, 37, 2129. Tetrahedron Lett. 1988, 29, 4245. 42. Kearney, P. C.; Nowak, M. W.; Zhong, W.; Silverman, S. K.; Lester, H. 12. Lee, D.-H.; Rho, M.-D., Tetrahedron Lett. 2000, 41, 2573. A.; Dougherty, D. A., Mol. Pharmacol. 1996, 50, 1401. 13. Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fässler, A., Tetrahedron Lett. 43. Vicario, J. L.; Badía, D.; Domínguez, E.; Crespo, A.; Carrillo, L.; 2000, 41, 10091. Anakabe, E., Tetrahedron Lett. 1999, 40, 7123. 14. Ravn, M. M.; Coates, R. M.; Jetter, R.; Croteau, R. B., Chem. Commun. 44. Guillena, G.; Nájera, C., Tetrahedron: Asymmetry 2001, 12, 181. 1998, 21. 45. Smith, A. B., III; Benowitz, A. B.; Favor, D. A.; Sprengeler, P. A.; 15. Keck, G. E.; Knutson, C. E.; Wiles, S. A., Org. Lett. 2001, 3, 707. Hirschmann, R., Tetrahedron Lett. 1997, 38, 3809. 16. Bach, J.; Galobardes, M.; Garcia, J.; Romea, P.; Tey, C.; Urpí, F.; 46. Nagula, G.; Huber, V. J.; Lum, C.; Goodman, B. A., Org. Lett. 2000, 2, Vilarrasa, J., Tetrahedron Lett. 1998, 39, 6765. 3527. 17. Mitchell, W., J. Chem. Soc. 1940, 1153. 47. Vicario, J. L.; Badía, D.; Carrillo, L., Org. Lett. 2001, 3, 773. 18. Brown, H. C.; Tsukamoto, A., J. Am. Chem. Soc. 1964, 86, 1089. 48. Vicario, J. L.; Badía, D.; Domínguez, E.; Carrillo, L., Tetrahedron Lett. 19. Myers, A. G.; Yang, B. H.; Chen, H., Org. Synth. 1999, 77, 29. 1998, 39, 9267. 20. Paterson, I.; Febner, K.; Finlay, M. R. V., Tetrahedron Lett. 1997, 38, 49. Vicario, J. L.; Badía, D.; Domínguez, E.; Rodríguez, M.; Carrillo, L., J. 4301. Org. Chem. 2000, 65, 3754. 21. Martín, M.; Mas, G.; Urpí, F.; Vilarrasa, J., Angew. Chem., Int. Ed. Engl. 50. Evans, D. A.; McGee, L. R., Tetrahedron Lett. 1980, 21, 3975. 1999, 38, 3086. 51. Katsuki, T.; Yamaguchi, M., Tetrahedron Lett. 1985, 26, 5807. 22. Smith, A. B., Jr; Kozmin, S. A.; Adams, C. M.; Paone, D. V., J. Am. 52. Murphy, P. J.; Procter, G.; Russell, A. T., Tetrahedron Lett. 1987, 28, Chem. Soc. 2000, 122, 4984. 2037. 23. Myers, A. G.; Yoon, T., Tetrahedron Lett. 1995, 36, 9429. 53. Vicario, J. L.; Badía, D.; Domínguez, E.; Rodríguez, M.; Carrillo, L., 24. Myers, A. G.; Yang, B. H.; Kopecky, D. J., Tetrahedron Lett. 1996, 37, Tetrahedron Lett. 2000, 41, 8297. 3623. 54. Myers, A. G.; McKinstry, L.; Barbay, J. K.; Gleason, J. L., Tetrahedron 25. Andrews, G. C.; Crawford, T. C., Tetrahedron Lett. 1980, 21, 693. Lett. 1998, 39, 1335. 26. Whitlock, G. A.; Carreira, E. M., Helv. Chim. Acta. 2000, 83, 2007. 55. Myers, A. G.; Barbay, J. K.; Zhong, B., J. Am. Chem. Soc. 2001, 123, 27. Dragovich, P. S.; Prins, T. J.; Zhou, R.; Fuhrman, S. A.; Patick, A. K.; 7207. Matthews, D. A.; Ford, C. E.; Meador, J. W., Jr; Ferre, R. A.; Worland, 56. Myers, A. G.; McKinstry, L.; Gleason, J. L., Tetrahedron Lett. 1997, 38, S. T., J. Med. Chem. 1999, 42, 1203. 7037. 28. Myers, A. G.; Siu, M.; Ren, F., J. Am. Chem. Soc. 2002, 124, 4230. 29. Smith, A. B., III; Kozmin, S. A.; Paone, D. V., J. Am. Chem. Soc. 1999, Andrew G.Myers & Mark G.Charest 121, 7423. Harvard University, Cambridge, MA, USA 30. Shi, Y.; Peng, L. F.; Kishi, Y., J. Org. Chem. 1997, 62, 5666.

A list of General Abbreviations appears on the front Endpapers