Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

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Recent Advances in the Syntheses of Fluorinated Amino Acids 227

aldimines and ketoimines bearing a ﬂ uorine - functionality. The corresponding aldimine 113

of triﬂ uoroacetaldehyde undergoes cycloaddition or electrophilic addition with nucleo-

philes. Cycloaddition of 113 with ketene provides highly enantiomerically enriched tri-

ﬂ uoromethylated lactams 114 and 115 , although diastereoselectivity is poor [49] . The

lactams are transformed into syn - 2 - hydroxy - 3 - aminobutanoates 116 and 117 , respectively

(see Scheme 9.24 ).

Figure 9.1 Chiral auxiliary approach. The dotted lines indicate the point of removal of the

chiral auxiliary.

Scheme 9.24

228 Fluorine in Medicinal Chemistry and Chemical Biology

Likewise, imine 118 was transformd into 120 , a mimic of a conformationally rigid

glutamic acid, via cyanide 119 (see Scheme 9.25 ) [50] . 1 - Phenyl - 1,1 - diﬂ uoroacetaldehyde

imine 121 was also used as a precursor of 3,3 - diﬂ uorophenylalanine 123 via cyanide 122 ,

but no diastereoselectivity was observed in the cyanation step (see Scheme 9.26 ) [51] .

The 2 - methoxy group of 2 - methoxy - 1 - phenylethylamine sometimes plays an impor-

tant role in diastereoselection. Thus, imine 125 (X = OMe), which is prepared convention-

ally from imidoyl chloride 124 , undergoes allylation with allylzinc reagent in a

diastereoselective manner ( > 98% de), affording 126 in a high yield. On the other hand,

nonmethoxylated imine 125 (X = H) gives the product with a poor diastereoselectivity

(40% de) (see Scheme 9.27 ). The methoxy group will chelate with the zinc atom tightly,

making the transition state 127 favorable for the stereo - controlled allylation [52, 53] .

However, the effect of the stereoselectivity enhancement by the methoxy group is not

necessarily applicable for the stereochemical outcome of the Strecker - type cyanation of

Scheme 9.25

Scheme 9.26

Recent Advances in the Syntheses of Fluorinated Amino Acids 229

the Schiff base of N - (1 - phenyl - 2 - methoxyethyl)amine with triﬂ uoromethyl ketones since

the reaction of the Schiff base with TMS - cyanide is strongly affected not only by substitu-

ent (X) but also by Lewis acid [54] . Grubbs ’ ring - closing metathesis (RCM) of 126 leads

to cyclohexene skeleton 128 , which is ﬁ nally converted to 1 - amino - 6,6 - diﬂ uorocyclohex-

ane - 1 - carboxylic acid 129 . Fluoride ion - promoted desilylation is useful for the deprotec-

tion of the trimethylsilylethyl group (TMSE) from 2 - (trimethylsilyl)ethyl carboxylate 128

under mild conditions.

9.3.1.2 Chiral Oxazolidines as Auxiliaries

Oxazolidine 130 is a masked aldimine bearing a chiral N - (2 - hydroxy - 1 - phenyl)ethyl

moiety and is readily available from ( R ) - phenylglycinol. Mannich reaction of 130 with

Reformatsky reagent of ethyl bromodiﬂ uoroacetate produces diﬂ uorolactam 131 in high

diastereoselectivity, which is then transformed to enantio - enriched ( S ) - 3 - amino - 2,2 -

diﬂ uoro - 3 - phenylpropanoic acid 133 (see Scheme 9.28 ) [55] .

Oxazolidine 134 is a masked triﬂ uoroacetaldehyde imine that generates in situ the

corresponding imine 135 under Lewis acid catalysis conditions. Lewis acid - catalyzed

reactions of 134 with TMS - cyanide and ketene silylacetal provide adducts 136 in high

yields with good diastereoselectivities (see Scheme 9.29 ) [56] . Conventional chemical

transformation of 137 produces 3 - amino - 4,4,4 - triﬂ uorobutanoic acid 138 . Similarly, tri-

ﬂ uoroacetone oxazolidine 139 is used for the synthesis of 2 - triﬂ uoromethylalanine 142

Scheme 9.27

230 Fluorine in Medicinal Chemistry and Chemical Biology

via 141 . The stereochemistry of C - 2 in 139 does not affect diastereoselectivity in cyanation

to ketimine 140 (see Scheme 9.30 ) [54] .

Oxazolidine 144 obtained from amino alcohol 143 and ethyl triﬂ uoropyruvate is also

a synthetic intermediate for 2 - amino - 2 - triﬂ uoromethylpentanoic acid 145 . Lewis acid -

catalyzed allylation of 144 with allyl silane occurs in excellent yield with a moderate ste-

reoselectivity. Meanwhile, O - tert - butyldimethylsilyl - protected imine 146 gives better

diastereoselectivity although yield is poor (see Scheme 9.31 ) [57] .

A 1 - phenylethylamino moiety is used for diastereomeric control not only in addition

of nucleophiles to N - (1 - phenylethyl)imines but also in diasteroselective Michael addition

to α , β - unsaturated esters. Thus, lithium N - (1 - phenylethyl) - N - benzylamide 148 is employed

for a one - pot tandem Michael addition - ﬂ uorination reaction (see Scheme 9.32 ) [58] . The

reaction provides anti - 3 - amino - 2 - ﬂ uoroesters 149 exclusively, whose diastereoselectivi-

ties (64 – 66% de) to the chiral carbon of the 1 - phenylethyl - group are good enough.

9.3.1.3 (2 R ) - Bornane - 10,2 - sultam as an Auxiliary

Oppolzer ’ s (2 R ) - bornane - 10,2 - sultam 150 is a good auxiliary that transmits its chirality

to the α - carbon of an amide. The reaction of lithium enolate of 151 with the corresponding

Scheme 9.28

Scheme 9.29

Recent Advances in the Syntheses of Fluorinated Amino Acids 231

Scheme 9.30

Scheme 9.31

propargyl bromide affords 152 with excellent diastereoselectivity (see Scheme 9.33 ) [59] .

The subsequent reactions starting from 151 – hydrostannylation, iodine – tin exchange, and

Pd - catalyzed Suzuki – Miyaura coupling with aryl borane of 151 – furnish a total synthesis

of 153 , 5,5 - diaryl - 2 - amino - 4 - pentenoate, a novel class of biologically active molecules

targeted toward the recently cloned glycine reuptake transport system.

The radical perﬂ uoroalkyl - iodination reaction of α , β - unsaturated lactam 154 pro-

ceeds diastereoselectively. The stereospeciﬁ c azide formation and subsequent chemical

transformation of the ( R ) - isomer result in the synthesis of a series of perﬂ uoroalkylated

α - amino acids 156 (see Scheme 9.34 ) [60] .

232 Fluorine in Medicinal Chemistry and Chemical Biology

Scheme 9.32

Scheme 9.33

Scheme 9.34

Recent Advances in the Syntheses of Fluorinated Amino Acids 233

9.3.1.4 2 - Hydroxy - 3 - Pinanone as an Auxiliary

Alkylation of the Schiff base of glycine with 2 - hydroxy - 3 - pinanone proceeds in an

extremely diastereoselective manner. Thus, ﬂ uoro - functionalization on the α - carbon of

the Schiff base followed by hydrolysis provides ﬂ uorinated α - amino acids in a highly

enantiomerically enriched form. 2 - Fluoroethylation and 2 - ﬂ uoroallylation of 157 (see

Scheme 9.35 ) and bromodiﬂ uoromethylation of 161 (see Scheme 9.36 ) give the desired

adducts 158 and 162 , respectively, with excellent diastereoselectivities. Lithium enolate

dimer 160 has been proposed as a reactive intermediate for the stereocontrolled alkylation

[61] . The adducts 158 and 162 were transformed to 4 - ﬂ uoro - 2 - amino acids ( > 96% ee) 159

[61] and 3,3 - diﬂ uoroglutamine 164 [62] , respectively.

Scheme 9.35

Scheme 9.36

234 Fluorine in Medicinal Chemistry and Chemical Biology

Scheme 9.37

9.3.1.5 Oxazolidinone as an Auxiliary

4 - Substituted 2 - oxazolidones 165 are useful chiral auxiliaries for diastereoselective func-

tionalization at the α - carbon of their amide carbonyl group. The α - ﬂ uoroaldehydes 166 were

prepared by a series of reactions: electrophilic ﬂ uorination of the corresponding oxazolidi-

none sodium enolates with N - ﬂ uorobenzenesulfonimine; reductive removal of the auxiliary

with LiBH

; and Dess – Martin oxidation. The aldehydes are so unstable for isolation that they

are converted with ( R ) - p - toluenesulﬁ namide to p - toluenesulﬁ nimines 167 , which are isol-

able and satisfactorily enantio - enriched. Chiral sulﬁ nimine - mediated diastereoselective

Strecker cyanation with aluminum cyanide provided cyanides 168 in excellent diastereose-

lectivity, which were ﬁ nally derived to 3 - ﬂ uoroamino acids 169 (see Scheme 9.37 ) [63] .

Diastereoslective Michael addition of the amino group in the polymer - supported

amino ester 171 to 4,4,4 - triﬂ uorocrotonamide 170 is another application of 4 - substituted

2 - oxazolidone for ﬂ uoroamino acid synthesis (see Scheme 9.38 ) [64] .

9.3.1.6 Chiral Sulﬁ namides as Auxiliaries

Both ( S ) - p - toluenesulﬁ namide 174 [65] and ( R ) - tert - butylsulﬁ namide 182 (see Scheme

9.41 ) [66] are used for amino acid synthesis. Diastereoselective alkylation to their imines

is a key reaction for the creation of chiral amines.

Sulﬁ mines 175 are obtained in excellent yield by Staudinger condensation of sulﬁ n-

amide 174 with triﬂ uoropyruvates. In contrast, and quite surprisingly, the Staudinger

reaction of tert - butylsulﬁ namide 182 with the pyruvates under the same conditions does

not work. Sulﬁ mines 175 are alkylated with Grignard reagents in good yields but with

poor to moderate diastereoselectivities (see Scheme 9.39 ) [67] .

Meanwhile, Reformatsky reaction of sulﬁ nimines 178 with bromodiﬂ uoroacetate

provides the adducts in excellent diastereoselectivities (see Scheme 9.40 ) [68] . The ste-

Recent Advances in the Syntheses of Fluorinated Amino Acids 235

Scheme 9.38

Scheme 9.39

reochemistry of ( S ) at C - 3 and the high diastereoselectivity arise from the six - membered

transition state shown in 181 . The same reaction with the corresponding nonﬂ uorinated

Reformatsky reagent (bromoacetate) provides 3 - aminoester with ( R ) - conﬁ guration at C - 3

for 179b (R = aryl, 76%, 94% de), demonstrating that the ﬂ uorine atoms of Reformatsky

reagent have no effect on the stereochemical outcome of the C – C bond formation. The

acid - catalyzed hydrolysis of the sulﬁ namide 179a produces enantiomerically enriched 3 -

amino - 2,2 - diﬂ uorocarboxylates 180 [68] .

Likewise, tert - butylsulﬁ namide is also used for highly stereocontrolled syntheses of

3 - amino - 2,2 - diﬂ uorocarboxylates 185 (see Scheme 9.41 ) [69] and 2 - phenyl - 3,3,3 - triﬂ uo-

roalanine 189 (see Scheme 9.42 ) [70] . Surprisingly, solvent is signiﬁ cantly effective for

236 Fluorine in Medicinal Chemistry and Chemical Biology

Scheme 9.40

Scheme 9.41

the stereochemical outcome in the Strecker - type cyanation of 187 (see Scheme 9.42 ). The

use of ( R ) - sulﬁ namide provides the cyanide 191 with an opposite stereochemistry. Acid -

catalyzed hydrolysis of sulﬁ namides 184 and 188 generates amines 185 and 189 , respec-

tively. The diﬂ uoroamino acid 185 is incorporated into oligopeptide 186 .

9.3.1.7 Optically Active Aryl Methyl Sulfoxide

The optically active arylsulﬁ nylmethylene moiety plays two important roles in asymmetric

synthesis of optically active amino acids: one is as chiral auxiliary, and the other is as