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

Подождите немного. Документ загружается.

Recent Advances in the Syntheses of Fluorinated Amino Acids 237

synthon for the hydroxymethyl group. The arylsulﬁ nylmethylene moiety is introduced to,

for example, acyl halides, imines, and imidoyl halides by diastereoselective nucleophilic

addition of arylsulﬁ nylmethyl lithium. Then, nonoxidative desulﬁ nylation followed by

oxidation or conventional desulﬁ nylation leads to the synthesis of enantio - enriched amino

acids (see Scheme 9.43 ).

A typical example is shown in Scheme 9.44 . Arylsulﬁ nylmethyl lithium is

introduced diastereoselectively to imine 193 to give 194 . Then, enantio - enriched

Scheme 9.42

Scheme 9.43

Scheme 9.44

238 Fluorine in Medicinal Chemistry and Chemical Biology

Scheme 9.45

Scheme 9.46

2 - triﬂ uoromethylalanine 195 is synthesized, where arylsulﬁ nyl group is transformed to a

methyl group [71] .

Another example is shown in Scheme 9.45 , in which arylsulﬁ nylmethyl lithium

couples with polyﬂ uoroalkylimidoyl chlorides 197 . Diastereoselective reduction of imine

198 to amine 199 followed by nonoxidative desulﬁ nylative hydroxylation and oxidation

of hydroxymethyl group provides triﬂ uoro - and diﬂ uoroalanines 202 (see Scheme 9.45 )

[72] . The same protocol is applicable for the synthesis of 3,3 - diﬂ uorocyclic amino acids

208 (see Scheme 9.46 ) [72, 73] . The borohydride reduction of sulﬁ nylimine 204 proceeds

with almost complete diastereoselectivity ( > 98% de). The conventional chemical modiﬁ -

Recent Advances in the Syntheses of Fluorinated Amino Acids 239

cation and Grubbs ’ RCM afford bicyclooxazolidone 207 , which is ﬁ nally transformd to

208 . Starting from sulﬁ nylketone 209 , enantiomerically pure diﬂ uoroalanine 213 is syn-

thesized by the same sequence of reactions as shown in Scheme 9.47 [74] . Stereospeciﬁ c

nucleophilic substitution of the hydroxyl group in sulﬁ nyl alcohol 214 [75] with azide ion

and subsequent reduction of the azide group with thiol gave sulﬁ nyl amine 216 . The non-

oxidative desulﬁ nylation followed by oxidation of the hydroxymethyl group afforded

monoﬂ uoroalanine 218 (see Scheme 9.48 ) [76] .

9.3.1.8 Menthyl Group as a Chiral Auxiliary

The menthyl group has often been employed as an easily available chiral auxiliary.

8 - Phenylmenthyl 2 - amino - 3,3 - diﬂ uorocyclopentenecarboxylate 222 prepared from 219

via 221 was hydrogenated diastereoselectively to form cis - 2 - aminocarboxylate 223

(see Scheme 9.49 ) [77] . The higher diastereoselectivity induced by the 8 - phenylmenthyl

group was also observed in ZnI

- catalyzed NaBH

reduction of open - chain β - amino - α , β -

unsaturated esters 224 . In contrast, the unsubstituted menthyl ester was reduced with no

practical diastereoselectivity (see table in Scheme 9.49 ).

Scheme 9.47

Scheme 9.48

240 Fluorine in Medicinal Chemistry and Chemical Biology

A similar approach was employed for the synthesis of racemic m = 1 and higher

members of cyclic β - amino esters 229 starting from 227 (see Scheme 9.50 ) [78] .

The oxazoline moiety is a masked carboxyl group. A chiral oxazoline moiety attached

to enamine 230 confers chirality to the double bond on reduction. Separation of the dia-

stereomers followed by hydrolysis of the oxazoline moiety provide 3 - amino - 4,4 - diﬂ uoro -

or 3 - amino - 4,4,4 - triﬂ uorobutanoates 233 in enantiomerically pure forms (see Scheme

9.51 ) [79] .

Scheme 9.49

Scheme 9.50

Recent Advances in the Syntheses of Fluorinated Amino Acids 241

9.3.2 Building Blocks

Chiral ﬂ uorinated building blocks are in general less readily available, so that ﬂ uoro -

functionalization of available chiral building blocks is one feasible approach for the

asymmetric synthesis of ﬂ uorinated amino acids (see Fig. 9.2 ).

Scheme 9.51

Figure 9.2 Chiral building block approach.

9.3.2.1 Garner ’ s Aldehyde

Garner ’ s aldehyde is readily available from serine. Synthetic processes so far reported for

ﬂ uoroamino acids mostly consist of (1) ﬂ uoro - functionalization of the Garner ’ s aldehyde

at the formyl group, (2) acid - catalyzed hydrolytic opening of the oxazoline ring, and (3)

oxidation of the hydroxymethyl group to a carboxyl group. Reaction of 234 with ethyl 2 -

ﬂ uoro - 2 - phosphonoacetate followed by diastereoselective hydrogenation of 235 provides

monoﬂ uoroester 236 . A sequence of reactions – condensation of 236 with nitromethane,

catalytic reduction of 237a , reaction of 237b with acetimidate, and transformation of the

oxazoline ring to an α - aminocarboxyl moiety – synthesize 4 - ﬂ uoro - L - lysine 238 (see

Scheme 9.52 ) [80] . 4,4 - Diﬂ uoroglutamine 242 is synthesized similarly (see Scheme 9.53 )

[81] .

The aldehyde 234 is also applicable for construction of the proline skeleton. The

oxazoline moiety of 234 was transferred to the N - CHCO

H moiety of the prolines 249 ,

the triﬂ uoromethyl group of which was introduced by cross - coupling of bromide 244 with

triﬂ uoromethyl copper reagent (see Scheme 9.54 ) [82] .

242 Fluorine in Medicinal Chemistry and Chemical Biology

Scheme 9.52

Scheme 9.53

9.3.2.2 ( R ) - 2,3 - O - Isopropylideneglyceraldehyde

( R ) - 2,3 - O - Isopropylideneglyceraldehyde 250 (see Scheme 9.55 ) is also one of the most

readily available chiral building blocks for amino acid synthesis. Here again, a similar

sequence to that with Garner ’ s aldehyde is used: ﬂ uoro - functionalization at the formyl

group and oxidation to carboxyl group of either the secondary or the primary hydroxyl

group involved in the masked glyceraldehydes 250 . The Mitsunobu protocol for transfor-

mation of a hydroxyl group to an amino group is used as a key reaction for synthesis of

ﬂ uorinated amino acids [83] .

In the synthesis of 3 - ﬂ uoroamino acid 256 (Scheme 9.55 ), ﬂ uorination of alcohol 251

= H) with morpho - DAST afforded the desired alcohol only in low yield (10 – 25%).

The same reaction of trimethylsilyl ether 251 (R

= TMS) improved the yield (50%). The

Mitsunobu amination of the secondary hydroxyl group in 254 successfully gives 255 in

89% yield. Starting from 250 , several ﬂ uorinated α - and β - amino acids 257 – 259 have

been prepared [31] .

Recent Advances in the Syntheses of Fluorinated Amino Acids 243

Scheme 9.54

Scheme 9.55

244 Fluorine in Medicinal Chemistry and Chemical Biology

The benzyl imine 260 of aldehyde 250 is an excellent building block for the synthesis

of enantiomerically pure triﬂ uoromethylated isoleucine 264 and valine 265 (see Scheme

9.56 ). The In - mediated alkylation of imine 260 with 4,4,4 - triﬂ uorocrotyl bromide in DMF

proceeds with excellent diastereoselectivity ( > 95% de), affording 261 . In contrast, poor

diastereoselectivity (20% de) is obtained in the same In - mediated aldol reaction of alde-

hyde 250 . The transition state structure 263 is proposed to explain the exclusive stereo-

control [84] .

9.3.2.3 Proline Derivatives

Diastereoselective ﬂ uoro - functionalization of proline derivatives produces ﬂ uorinated pro-

lines. Both enantiomerically pure 4 - triﬂ uoromethyl and 4 - diﬂ uoromethyl prolines 268 and

270 have been prepared (see Scheme 9.57 ) [85] . The key reaction for the stereo - controlled

synthesis is diastereoselective Pd - catalyzed hydrogenation of 267 and 269 .

Nickel(II) complex 271 of the Schiff bases of glycine with o - [ N - α - pycolylamine]be

nzophenone plays two roles in stereocontrolled C – C bond formation; an excellent chiral

auxiliary and a building block. Its diastereoselective Michael addition to 272 occurs

cleanly at the α - position of the glycine moiety, affording 273 almost quantitatively. The

adduct 273 is hydrolyzed by acid - catalysis to give 274 , which is then cyclized to pyroglu-

tamic acid 275 [86] . During the two hydrolysis steps, both o - [ N - α - pycolylamine]benzoph

enone and ( S ) - 5 - phenyl - 2 - oxazolidone can be recovered for recycling (see Scheme

9.58 ).

9.3.3 Other Diastereoselective Syntheses

Other interesting diastereoselective syntheses of ﬂ uorinated amino acids are brieﬂ y sum-

marized in this section.

Tandem alkene metathesis – intramolecular Michael addition of ( R ) - amine 276 pro-

ceeds diastereoselectively, providing pyrrolidines 278 and 279 . These pyrrolidines can be

Scheme 9.56

Recent Advances in the Syntheses of Fluorinated Amino Acids 245

Scheme 9.57

Scheme 9.58

promising precursors of 5 - CF

- prolines and the related amino acids (see Scheme 9.59 )

[87] .

Introduction of a triﬂ uoroethyl group at the α - carbon of the nitro group of 280 by a

sequence of reactions – (1,5 - diazabicyclo[4.3.0]non - 5 - ene) (DBU) - catalyzed alkylation

with triﬂ uoroacetaldehyde hemiacetal in MeCN, dehydration with acetic anhydride – pyri-

dine, and reduction of the C – C double bond with NaBH

– produces 281 . 6 - Triﬂ uoroethyl -

l - lysine 282 can be prepared from 281 (see Scheme 9.60 ) [88] .

Diastereoselective ﬂ uorination of enolate 283 , subsequent epoxidation of 284 , and

separation of diastereomers provide 285 . Activation of epoxy - oxygen with Et

AlCl

and deprotonation from the CHF group in 285 with LDA induces stereospeciﬁ c

246 Fluorine in Medicinal Chemistry and Chemical Biology

cyclopropanation, affording bicyclo product 286 , which is further transformed to bicyclic

α - amino acid 287 (see Scheme 9.61 ) [89] .

9.4 Racemic Amino Acids

In this section, recent advances in the syntheses of racemic ﬂ uorinated amino acids and

the related peptides that involve conceptually new synthetic designs are brieﬂ y

summarized.

Base - catalyzed deprotonation – alkylation of triﬂ uoroalanine is not easy because α -

triﬂ uoromethylated carbanions readily undergo deﬂ uorination in general [90] . Therefore,

α - alkylated triﬂ uoroalanines have been prepared either by alkylation of imines obtained

from triﬂ uoropyruvates [54, 57] or by Strecker cyanation [56] to triﬂ uoroketimines fol-

Scheme 9.59

Scheme 9.60