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

Recent Advances in the Syntheses of Fluorinated Amino Acids 247

lowed by hydrolysis. π - Allyl palladium 291 is strongly electrophilic, so that it can trap

the enolate of 288 to give α - allylated triﬂ uoroalanine 290 in excellent yields (see Scheme

9.62 ) [91] .

Stereospeciﬁ c nucleophilic substitution of the hydroxyl group in sec - triﬂ uoromethyl

alcohols with nucleophiles is one of the promising approaches for synthesis of optically

active triﬂ uoromethylated tertiary carbon skeletons, since enantiomerically enriched sec -

triﬂ uoromethylalcohols are readily available [92] . However, the S

N

2 reaction with carbon

nucleophiles has never been developed, although the reactions with heteroatom nucleo-

philes are known [92] . Only the intramolecular stereospeciﬁ c cyclopropanation has been

employed for the syntheses of racemic triﬂ uoromethylated coronamic acids 294 and 297 ,

as shown in Scheme 9.63 [93] . It is noteworthy that the stereochemistry for the cyclopro-

panation is governed by electrostatic repulsion between the triﬂ uoromethyl group and the

electronic charge on ortho - positions in the aryl group rather than by steric repulsion

between the two substituents [94] .

Scheme 9.61

Scheme 9.62

248 Fluorine in Medicinal Chemistry and Chemical Biology

Imines 299 of triﬂ uoropyruvates are so strongly electrophilic that they undergo spon-

taneous ene - type carbon – carbon bond formation between 298 and 299 on their being

mixed, as shown in Scheme 9.64 . α - Triﬂ uoromethylated tryptophan and its related amino

esters 300 have been prepared (see Scheme 9.64 ) [95] .

Copper - catalyzed thermal reaction of diazo - triﬂ uoropyruvate 301 with aryl aldehydes

in the presence of SbBu

3

provides alkenes 302 , which are transformed to racemic amino

acids 304 (see Scheme 9.65 ) [96] . Antimony ylide 305 is proposed as an intermediate.

Dipeptides are mostly prepared by the condensation of two amino acids, in which a

carboxyl group of one of the amino acids must be activated by condensation - promoting

reagents. Noncondensation synthesis of triﬂ uoroalanine dipeptides is shown in Scheme

9.66 [97] . Pentaﬂ uoroenamine 306 reacts with the amino group of amino esters in DMF

at 0 ° C within 1 hour, affording triﬂ uoroalanine dipeptides in a one - pot synthesis. The

overall reactions involve addition of amino ester to 306 , dehydroﬂ uorination of 308 , and

acid - catalyzed hydrolysis of imidoylﬂ uorides 309 . Enamine 306 is readily prepared in 95%

yield by magnesium - promoted deﬂ uorination of the corresponding hexaﬂ uoroacetone

imine. Enamine 306 is strongly electrophilic and reacts spontaneously with even a weak

nucleophile such as an amino ester due to the electron - withdrawing nature of both CF

2

and CF

3

groups [98] and is highly chemoselective since it accepts the amino group of

Scheme 9.63

Scheme 9.64

Recent Advances in the Syntheses of Fluorinated Amino Acids 249

serine and tyrosine without protecting the hydroxyl group. The same protocol is applicable

for the synthesis of diﬂ uoroproline dipeptides of 312 from 310 [99] .

9.5 Conclusions

Recent advances in the syntheses of ﬂ uorinated amino acids have been summarized on

the basis of the strategies for creating chiral centers in target amino acids: (1) enantioselec-

tive, (2) diastereoselective, and (3) racemic syntheses. Remarkable progress in ﬂ uorinating

reagents and ﬂ uoro - functionalization methodologies; the commercial availability of

Scheme 9.65

Scheme 9.66

250 Fluorine in Medicinal Chemistry and Chemical Biology

ﬂ uorinated building blocks; and easy accessibility of computer - based information on the

chemistry and science of organoﬂ uorine compounds along with the well - collected and

well - arranged reference books recently published [100] – all of these increase the potential

for synthesis of desirable ﬂ uorinated amino acids.

References

(a) Babu , I. R. , Hamill , E. K. and Kumar , K. ( 2004 ) A highly stereospeciﬁ c and efﬁ cient syn-

thesis of homopentaﬂ uorophenylalanine . J. Org. Chem. , 69 , 5468 – 5470 ; (b) Wang , P. , Tang ,

Y. and Tirrell , D. A. Incorporation of Triﬂ uoroisoleucine into proteins in vivo . ( 2003 ) J. Am.

Chem. Soc. , 125 , 6900 – 6906 .

(a) Soloshonok V. A. (ed.) ( 2005 ) Fluorine - containing amino acids and peptides: ﬂ uorinated

synthons for life sciences . in Fluorine - containing Synthons , ACS Symposium Series 911 ,

American Chemical Society , Washington, D.C. ; (b) Soloshonok , V. A. , Mikami , K. , Yamazaki ,

T . , et al. (eds) ( 2006 ) New biological application , in Current Fluoroorganic Chemistry , ACS

Symposium Series 949 , American Chemical Society , Washington, D.C. ; (c) Filler , R. and

Kobayashi , Y. ( 1982 ) Biomedicinal Aspects of Fluorine Chemistry , Kodansha, Ltd. , Tokyo ;

(d) Ishikawa , N. (ed.) ( 1987 ) Synthesis and Speciality of Organoﬂ uorine Compounds , CMC ,

Tokyo ; (e) Ishikawa , N. (ed.) ( 1990 ) Biologically Active Organoﬂ uorine Compounds , CMC :

Tokyo ; (f) Welch , J. T. and Eswarakrishnan , S. ( 1991 ) Fluorine in Bioorganic Chemistry , John

Wiley & Sons, Inc ., New York ; (g) Ojima , I. , McCarthy , J. R. and Welch , J. T. (eds) ( 1996 )

Biomedical Frontiers of Fluorine Chemistry , ACS Symposium Series 639 , American Chemical

Society , Washington, D.C.

(a) Ondetti , M. A. ; Cushman , D. W. and Rubin , B. ( 1977 ) Design of speciﬁ c inhibitors of

angiotensin - converting enzyme: new class of orally active antihypertensive agents . Science ,

196 , 441 – 444 ; (b) Cushman , D. W. , Cheung , H. S. , Sabo , E. F. and Ondetti , M. A. ( 1977 )

Design of potent competitive inhibitors of angiotensin - converting enzyme. Carboxyalkanoyl

and mercaptoalkanoyl amino acids . Biochemistry , 16 , 5484 – 5491 ; (c) Kollonitsch , J. , Perkins ,

L. M. and Patchett , A. A. , et al. ( 1978 ) Selective inhibitors of biosynthesis of aminergic neu-

rotransmitters . Nature , 274 , 906 – 908 . (d) Wyvratt , M. J. , Tristram , E. W. , Ikeler , T. J. , et al.

( 1984 ) Reductive amination of ethyl 2 - oxo - 4 - phenylbutanoate with l - alanyl - l - proline. Syn-

thesis of enalapril maleate . J. Org. Chem. , 49 , 2816 – 2819 .

Kukhar , V. P. and Soloshonok , V. A. ( 1995 ) Fluorine - Containing Amino Acids: Synthesis and

Properties , John Wiley & Sons, Inc ., New York .

Qiu , X. - L. , Meng , W. - D. and Qing , F. - L. ( 2004 ) Synthesis of ﬂ uorinated amino acids . Tetra-

hedron , 60 , 6711 – 6743 . This is the most up - to - date review on the synthesis of ﬂ uorinated

amino acids.

(a) Liu , M. and Sibi , M. P. Recent advances in the stereoselective synthesis of β - amino acids .

( 2002 ) Tetrahedron , 58 , 7991 – 8035 ; (b) Ojima , I. , Inoue , T. and Chakravarty , S. Enantiopure

ﬂ uorine - containing taxoids: potent anticancer agents and versatile probes for biomedical prob-

lems . ( 1999 ) J. Fluorine Chem. , 97 , 3 – 10 ; (c) Uneyama , K. ( 1999 ) Asymmetric synthesis of

ﬂ uoro - amino acids , in Enantiocontrolled Synthesis of Fluoro - Organic Compounds (ed. V. A.

Soloshonok ), John Wiley & Sons, Ltd , Chichester , pp. 3914 – 3918 ; (d) Uneyama , K. , Katagiri ,

T. and Amii , H. New approaches to stereoselective synthesis of ﬂ uorinated amino acids . ( 2002 )

J. Synth. Org. Chem. Jpn , 60 , 1069 – 1075 ; (e) Welch , J. T. Tetrahedron report number 221,

Advances in the Preparation of Biologically Active Organoﬂ uorine Compounds . ( 1987 ) Tet-

rahedron , 43 , 3123 – 3197 .

1.

2.

3.

4.

5.

6.

Recent Advances in the Syntheses of Fluorinated Amino Acids 251

(a) Petasis , N. A. and Zavialov , I. A. ( 1997 ) A new and practical synthesis of α - amino acids

from alkenyl boronic acids . J. Am. Chem. Soc. , 119 , 445 – 446 ; (b) Petasis , N. A. and Zavialov , I.

A. ( 1997 ) A new synthesis of α - arylglycines from aryl boronic acids . Tetrahedron , 53 , 16463 –

16470 ; (c) Petasis , N. A. and Zavialov , I. A. ( 1998 ) Highly stereocontrolled one - step synthesis

of anti - β - amino alcohols from organoboronic acids, amines, and α - hydroxy aldehydes . J. Am.

Chem. Soc. , 120 , 11798 – 11799 ; (d) Petasis , N. A. and Boral , A. ( 2001 ) One - step three - compo-

nent reaction among organoboronic acids, amines and salicylaldehydes . Tetrahedron Lett. , 42 ,

5395 – 5342 ; (e) Petasis , N. A. and Patal , Z. D. ( 2000 ) Synthesis of piperazinones and benzopi-

perazinones from 1,2 - diamines and organoboronic acids . Tetrahedron Lett. , 41 , 9607 – 9611 .

Prakash , G. K. S. , Mandal , M. , Schweizer , S. , et al. ( 2002 ) Stereoselective synthesis of anti -

α - (diﬂ uoromethyl) - β - amino alcohols by boronic acid based three - component condensation.

Stereoselective preparation of (2 S ,3 R ) - diﬂ uorothreonine . J. Org. Chem. , 67 , 3718 – 3723 .

Watanabe , H. , Hashizume , Y. and Uneyama , K. ( 1992 ) Homologation of triﬂ uoroacetimidoyl

iodides by palladium - catalyzed carbonylation. An approach to α - amino perﬂ uoroalkanoic

acids . Tetrahedron Lett. , 33 , 4333 – 4336 .

Amii , H. , Kishikawa , Y. , Kageyama , K. and Uneyama , K. ( 2000 ) Palladium - catalyzed tert -

butoxycarbonylation of triﬂ uoroacetimidoyl iodides . J. Org. Chem. , 65 , 34043 – 34408 .

Abe , H. , Amii , H. and Uneyama , K. ( 2001 ) Pd - catalyzed asymmetric hydrogenation of α - ﬂ uo-

rinated iminoesters in ﬂ uorinated alcohol: a new and catalytic enantioselective synthesis of

ﬂ uoro α - amino acid derivatives . Org. Lett. , 3 , 313 – 315 .

Sakai , T. , Yan , F. , Kashino , S. and Uneyama , K. ( 1996 ) Asymmetric reduction of 2 - ( N - ary-

limino) - 3,3,3 - triﬂ uoropropanoic acid esters leading to enantiomerically enriched 3,3,3 - triﬂ uo-

roalanine . Tetrahedron , 52 , 233 – 244 .

Suzuki , A. , Mae , M. , Amii , H. and Uneyama , K. ( 2004 ) Catalytic route to the synthesis of

optically active β , β - diﬂ uoroglutamic acid and β , β - diﬂ uoroproline derivatives . J. Org. Chem. ,

69 , 5132 – 5134 .

Demir , A. S. , Sesenoglu , O. and Gercek - Arkin , Z. ( 2001 ) An asymmetric synthesis of both

enantiomers of 2,2,2 - triﬂ uoro - 1 - furan - 2 - yl - ethylamine and 3,3,3 - triﬂ uoroalanine from 2,2,2 -

triﬂ uoro - 1 - furan - 2 - yl - ethanone . Tetrahedron Asymmetry , 12 , 2309 – 2313 .

Kubryk , M. and Hansen , K. B. ( 2006 ) Application of the asymmetric hydrogenation of

enamines to the preparation of a beta - amino acid pharmacophore . Tetrahedron Asymmetry , 17 ,

205 – 209 .

Jiang , Z. - X , Qin , Y. - Y. and Qing , F. - L. ( 2003 ) Asymmetric synthesis of both enantiomers of

anti - 4,4,4 - triﬂ uorothreonine and 2 - amino - 4,4,4 - triﬂ uorobutanoic acid . J. Org. Chem. , 68 ,

7544 – 7547 .

Kobayashi , S. and Ishitani , H. ( 1999 ) Catalytic enantioselective addition to imines . Chem. Rev. ,

99 , 1069 – 1094 .

C ó rdova , A. , Nots , W. , Zhong , G. , et al. ( 2002 ) A highly enantioselective amino acid - catalyzed

route to functionalized α - amino acids . J. Am. Chem. Soc. , 124 , 1842 – 1843 .

Reviews on phase - transfer catalysis for the syntheses of α - amino acids. (a) Ooi , T. and Maruoka ,

K. ( 2004 ) Asymmetric organocatalysis of structurally well - deﬁ ned chiral quaternary ammonium

ﬂ uorides . Acc. Chem. Res. , 37 , 526 – 533 ; (b) Maruoka , K. and Ooi , T. ( 2003 ) Enantioselective

amino acid synthesis by chiral phase - transfer catalysis . Chem. Rev. , 103 , 3013 – 3028 ; (c) Ooi ,

T. and Maruoka , K. ( 2003 ) Enantioselective synthesis of α - amino acids by chiral phase - transfer

catalysis . Yuki Gosei Kagaku Kyokaishi (J. Synth. Org. Chem.) 61 , 1195 – 1206 .

Jew , S. - S. , Jeong , B. - S. , Yoo , M. - S. , et al. ( 2001 ) Synthesis and application of dimeric Cin-

chona alkaloid phase - transfer catalysts: α , α ′ - bis[ O (9) - allylcinchonidinium] - o , m , or p - xylene

dibromide. Chem. Commun. 1244 – 1245 .

Ramachandran , P. V. , Madhi , S. and O ’ Donnell , M. J. ( 2007 ) Synthesis of ﬂ uorinated glutamic

acid derivatives via vinylalumination . J. Fluorine Chem. , 128 , 78 – 83 .

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

252 Fluorine in Medicinal Chemistry and Chemical Biology

(a) Soloshonok , V. A. , Ono , T. and Soloshonok , I. V. ( 1997 ) Enantioselective biomimetic

transamination of β - keto carboxylic acid derivatives. An efﬁ cient asymmetric synthesis of β -

(ﬂ uoroalkyl) - β - amino acids . J. Org. Chem. , 62 , 7538 – 7539 ; (b) Soloshonok , V. A. , Ohkura ,

H. and Yasumoto , M. ( 2006 ) Operationally convenient asymmetric synthesis of ( S ) - and ( R ) -

3 - amino - 4,4,4 - triﬂ uorobutanoic acid . J. Fluorine Chem. , 127 , 924 – 929 ; (c) Soloshonok , V. A. ,

Ohkura , H. and Yasumoto , M. ( 2006 ) Operationally convenient asymmetric synthesis of ( S ) -

and ( R ) - 3 - amino - 4,4,4 - triﬂ uorobutanoic acid . J. Fluorine Chem. , 127 , 930 – 935 .

Uneyama , K. ( 2006 ) Discussion on unique chemical phenomena of highly ﬂ uorinated carbonyl

and imino compounds , Organoﬂ uorine Chemistry , Blackwell Publishing , Oxford , pp. 31 – 36 .

Soloshonok , V. A. and Kuklar , V. P. ( 1997 ) Biomimetic transamination of α - keto perﬂ uoro-

carboxylic esters. An efﬁ cient preparative synthesis of β , β , β - triﬂ uoroalanine . Tetrahedron , 53 ,

8307 – 8314 .

Li , G. and van der Donk , W. A. ( 2007 ) Efﬁ cient synthesis of suitably protected β - diﬂ uoroala-

nine and γ - diﬂ uorothreonine from l - ascorbic acid . Org. Lett. , 9 , 41 – 44 .

For scope of ﬂ uorination with DAST, see ref. 23 , pp. 233 – 239 .

Doi , M. , Nishi , Y. , Kiritoshi , N. , et al. ( 2002 ) Simple and efﬁ cient syntheses of Boc - and

Fmoc - protected 4( R ) - and 4( S ) - ﬂ uoroproline solely from 4( R ) - hydroxyproline . Tetrahedron ,

58 , 8453 – 8459 .

Raines , R. T. ( 2006 ) Hyperstable collagen based on 4 - ﬂ uoroproline residues , in Current Fluo-

roorganic Chemistry , ACS Symposium Series 949 , American Chemical Society , Washington,

D.C.

(a) Katagiri , T. and Uneyama , K. ( 2003 ) Stereospeciﬁ c substitution at α - carbon to triﬂ uoro-

methyl group: application to optically active ﬂ uorinated amino acid syntheses . Chirality , 15 ,

4 – 9 ; (b) Katagiri , T. , Uneyama , K. ( 2005 ) Functional group transformation at α - carbon to tri-

ﬂ uoromethyl group , in Fluorine - containing Synthons , ACS Symposium Series 911 , American

Chemical Society , Washington, D.C.

Konno , T. , Daitoh , T. , Ishihara , T. and Yamanaka , H. ( 2001 ) A novel and expedient synthesis

of optically active ﬂ uoroalkylated amino acids via palladium - catalyzed allylic rearrangement

and Ireland - Claisen rearrangement . Tetrahedron Asymmetry , 12 , 2743 – 2748 .

Fokina , N. A. , Kornilov , A. M. , Kulik , I. B. and Kukhar , V. P. ( 2002 ) Towards optically pure

mono - and diﬂ uorinated amino acids: common methodology based on ( R ) - 2,3 - O - isopropyli-

deneglyceraldehyde . Synthesis , 2589 – 2596 .

Xing , X. , Fichera , A. and Kumar , K. ( 2001 ) A novel synthesis of enantiomerically pure

5,5,5,5 ′ ,5 ′ ,5 ′ - hexaﬂ uoroleucine . Org. Lett. , 3 , 1285 – 1286 .

Meffre , P. , Dave , R. H. , Leroy , J. and Badet , B. ( 2001 ) A concise synthesis of l - 4,4 -

diﬂ uoroglutamine . Tetrahedron Lett. , 42 , 8625 – 8627 .

Anderson , J. T. , Toogood , P. L. and Marsh , E. N. G. ( 2002 ) A short and efﬁ cient synthesis of

l - 5,5,5,5 ′ ,5 ′ ,5 ′ - hexaﬂ uoroleucine from N - Cbz - l - serine . Org. Lett. , 4 , 4281 – 4283 .

Ding , Y. , Wang , J. , Abbound , K. A. , et al. ( 2001 ) Synthesis of l - 4,4 - diﬂ uoroglutamic acid via

nucleophilic addition to a chiral aldehyde . J. Org. Chem. , 66 , 6381 – 6388 .

(a) Lubell , W. and Rapoport , H. ( 1989 ) Surrogates for chiral aminomalondialdehyde. Synthesis

of N - (9 - phenylﬂ uoren - 9 - yl)serinal and N - (9 - phenylﬂ uoren - 9 - yl)vinylglycinal . J. Org. Chem. ,

54 , 3824 – 3831 ; (b) Lubell , W. and Rapoport , H. ( 1987 ) Conﬁ gurational stability of N -

protected α - amino aldehydes . J. Am. Chem. Soc. , 109 , 236 – 239 ; (c) Lubell , W. D. , Jamison ,

T. F. and Rapoport , H. ( 1990 ) N - (9 - phenylﬂ uoren - 9 - yl) - α - amino ketones and N - (9 - phenylﬂ uo-

ren - 9 - yl) - α - amino aldehydes as chiral educts for the synthesis of optically pure 4 - alkyl - 3 -

hydroxy - 2 - amino acids. Synthesis of the C - 9 amino acid MeBmt present in cyclosporin .

J. Org. Chem. , 55 , 3511 – 3522 .

Lal , G. S. , Pez , G. P. and Syvret , R. G. ( 1996 ) Electrophilic N – F ﬂ uorinating agents . Chem.

Rev. , 96 , 1737 – 1755 .

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

Recent Advances in the Syntheses of Fluorinated Amino Acids 253

Konas , D. W. and Coward , J. K. ( 1999 ) Synthesis of l - 4,4 - diﬂ uoroglutamic acid via electro-

philic diﬂ uorination of a lactam . Org. Lett. , 1 , 2105 – 2107 .

Qiu , J. and Silverman , R. B. ( 2000 ) A new class of conformationally rigid analogs of 4 - amino -

5 - halopentanoic acids, potent inactivators of γ - aminobutyric acid aminotransferase . J. Med.

Chem. , 43 , 706 – 720 .

Very few examples of retention: (a) Kozikowski , A. P. , Powis , G. , Fauq , A. H. , et al. ( 1994 )

Synthesis and biological activity of the d - 3 - deoxy - 3 - ﬂ uoro and d - 3 - chloro - 3 - deoxy analogs of

phosphatidylinositol . J. Org. Chem. , 59 , 963 – 971 ; (b) Gharbaoui , T. , Legraverend , M. ,

Ludwing , O. , et al. ( 1995 ) Synthesis of new carbocyclic oxetanocin analogs . Tetrahedron , 51 ,

1641 – 1652 .

Katagiri , T. and Uneyama , K. ( 2000 ) Chemistry of TFPO . J. Fluorine Chem. , 105 , 285 – 293 .

Schaus , S. E. , Brandes , B. D. , Larrow , J. F. , et al. ( 2002 ) Highly selective hydrolytic kinetic

resolution of terminal epoxides catalyzed by chiral (salen)CoIII complexes. Practical synthesis

of enantioenriched terminal epoxides and 1,2 - diols . J. Am. Chem. Soc. , 124 , 1307 – 1315 .

(a) Yamauchi , Y. , Kawate , T. , Katagiri , T. and Uneyama , K. ( 2003 ) Triﬂ uoromethyl - stabilized

optically active oxiranyl and aziridinyl anions for stereospeciﬁ c syntheses of triﬂ uoromethyl-

ated compounds . Tetrahedron 59 , 9839 – 9847 ; (b) Yamauchi , Y. , Katagiri , T. and Uneyama ,

K. ( 2002 ) The ﬁ rst generation and stereospeciﬁ c alkylation of α - triﬂ uoromethyl oxiranyl anion .

Org. Lett. , 4 , 173 – 176 .

Yamauchi , Y. , Kawate , T. , Katagiri , T. and Uneyama , K. ( 2003 ) Generation and reactions of

α - triﬂ uoromethyl stabilized aziridinyl anion, a general synthetic precursor for stereospeciﬁ c

construction of α - amino - α - triﬂ uoromethylated quaternary carbon . Tetrahedron Lett. , 44 ,

6319 – 6322 .

Kirihara , M. , Kawasaki , M. , Takuwa , T. , et al. ( 2003 ) Efﬁ cient synthesis of ( R ) - and ( S ) - 1 -

amino - 2,2 - diﬂ uorocyclopropanecarboxylic acid via lipase - catalyzed desymmetrization of pro-

chiral precursors . Tetrahedron Asymmetry , 14 , 1753 – 1761 .

Prati , F. , Moretti , I. , Forni , A. , et al. ( 1998 ) Synthesis and stereodirected N - halogenation of

trans - 3 - triﬂ uoromethyl - 2 - methoxycarbonylaziridine . J. Fluorine Chem. , 89 , 177 – 181 .

Davoli , P. , Forni , A. , Franciosi , C. , et al. ( 1999 ) Stereoselective synthesis of ﬂ uorinated β -

amino acids from ethyl trans - N - benzyl - 3 - triﬂ uoromethylaziridine - 2 - carboxylate . Tetrahedron

Asymmetry , 10 , 2361 – 2371 .

Kuznetsova , L. , Ungureanu , I. M. , Pepe , A. , et al. ( 2004 ) Triﬂ uoromethyl - and diﬂ uoromethyl -

β - lactams as useful building blocks for the synthesis of ﬂ uorinated amino acids, dipeptides,

and ﬂ uoro - taxoids . J. Fluorine Chem. , 125 , 487 – 500 .

Abouabdellah , A. , Begue , J - P. , Bonnet - Delpon , D. and Nga , T. T. T. ( 1997 ) Diastereoselective

Synthesis of the Nonracemic Methyl syn - (3 - Fluoroalkyl)isoserinates . J. Org. Chem. , 62 ,

8826 – 8833 .

Ito , H. , Saito , A. , Kakuuchi , A. and Taguchi , T. ( 1999 ) Synthesis of 2 - ﬂ uoro analog of

6 - aminonorbornane - 2 ,6 - dicarboxylic acid: a conformationally rigid glutamic acid derivative .

Tetrahedron , 55 , 12741 – 12750 .

Schlosser , M. , Brugger , N. , Schmidt , W. and Amrhein , N. ( 2004 ) β , β - Diﬂ uoro analogs of α -

oxo - β - phenylpropionic acid and phenylalanine . Tetrahedron , 60 , 7731 – 7742 .

Fustero , S. , Sanchez - Rosello , M. , Rodrigo , V. , et al. ( 2006 ) Asymmetric synthesis of new

β , β - diﬂ uorinated cyclic quaternary α - amino acid derivatives . Org. Lett. , 8 , 4129 – 4132 .

Osipov , S. N. , Artyushin , O. I. , Kolomiets , A. F. , et al. ( 2001 ) Synthesis of racemic cyclic

amino acids; Synthesis of ﬂ uorine - containing cyclic α - amino acid and α - amino phosphonate

derivatives by alkene metathesis . Eur. J. Org. Chem. , 3891 – 3897 .

Huguenot , F. and Brigaud , T. ( 2006 ) Concise synthesis of enantiopure α - triﬂ uoromethyl ala-

nines, diamines, and amino alcohols via the Strecker - type reaction . J. Org. Chem. , 71 ,

7075 – 7078 .

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

254 Fluorine in Medicinal Chemistry and Chemical Biology

Marcotte , S. , Pannecoucke , X. , Feasson , C. and Quirion , J. - C. ( 1999 ) Enantioselective synthe-

sis of α , α - diﬂ uoro - β - amino acid and 3,3 - diﬂ uoroazetidin - 2 - one via the Reformatskii - type

reaction of ethyl bromodiﬂ uoroacetate with chiral 1,3 - oxazolidines . J. Org. Chem. , 64 ,

8461 – 8464 .

(a) Lebouvier , N. , Laroche , C. , Huguenot , F. and Brigaud , T. ( 2002 ) Lewis acid activation of

chiral 2 - triﬂ uoromethyl - 1,3 - oxazolidines. Application to the stereoselective synthesis of tri-

ﬂ uoromethylated amines, α - and β - amino acids . Tetrahedron Lett. , 43 , 2827 – 2830 ; (b) Hugue-

not , F. and Brigaud , T. ( 2006 ) Convenient asymmetric synthesis of β - triﬂ uoromethyl - β - amino

acid, β - amino ketones, and γ - amino alcohols via Reformatsky and Mannich - type reactions

from 2 - triﬂ uoromethyl - 1,3 - oxazolidines . J. Org. Chem. , 71 , 2159 – 2162 .

Chaume , G. , Van Severen , M - C. , Marinkovic , S. and Brigaud , T. ( 2006 ) Straightforward syn-

thesis of ( S ) - and ( R ) - α - triﬂ uoromethyl proline from chiral oxazolidines derived from ethyl

triﬂ uoropyruvate . Org. Lett. , 8 , 6123 – 6126 .

Andrews , P. C. , Bhaskar , V. , Bromﬁ eld , K. M. , et al. ( 2004 ) Stereoselective synthesis of β -

amino - α - ﬂ uoro esters via diastereoselective ﬂ uorination of enantiopure β - amino enolates .

Synlett , 5 , 791 – 794 .

Isaac , M. , Slassi , A. , Da Silva , K. and Xin T. ( 2001 ) Synthesis of chiral and geometrically

deﬁ ned 5,5 - diaryl - 2 - amino - 4 - pentenoates: novel amino acid derivatives . Tetrahedron Lett. , 42 ,

2957 – 2960 .

Yajima , T. and Nagano , H. ( 2007 ) Photoinduced diastereoselective addition of perﬂ uoroalkyl

iodides to acrylic acid derivatives for the synthesis of ﬂ uorinated amino acids . Org. Lett. , 9 ,

2513 – 2515 .

Laue , K. W. , Kroger , S. , Wegelius , E. ad Haufe , G. ( 2000 ) Stereoselective synthesis of

γ - ﬂ uorinated α - amino acids using 2 - hydroxy - 3 - pinanone as an auxiliary . Eur. J. Org. Chem. ,

3737 – 3743 .

Katagiri , T. , Handa , M. , Matsukawa , Y. , et al. ( 2001 ) Efﬁ cient synthesis of an optically pure

β - bromo - β , β - diﬂ uoroalanine derivative, a general precursor for β , β - diﬂ uoroamino acids . Tet-

rahedron Asymmetry , 12 , 1303 – 1311 .

Davis , F. A. , Srirajan , V. and Titus , D. D. ( 1999 ) Efﬁ cient asymmetric synthesis of β - ﬂ uoro

α - amino acids . J. Org. Chem. , 64 , 6931 – 6934 .

(a) Volonterio , A. , Bravo , P. , Moussier , N. and Zanda , M. ( 2000 ) Solid - phase synthesis of

partially - modiﬁ ed retro and retro - inverso - ψ [NHCH(CF

3

)] - peptides . Tetrahedron. Lett. , 41 ,

6517 – 6520 ; (b) Volonterio , A. , Chiva , G. , Fustero , S. , et al. ( 2003 ) Stereocontrolled solid -

phase synthesis of ﬂ uorinated partially - modiﬁ ed retropeptides via tandem aza - Michael/enolate -

protonation . Tetrahedron Lett. , 44 , 7019 – 7022 ; (c) Volonterio , A. , Bravo , P. and Zanda , M.

( 2000 ) Synthesis of partially modiﬁ ed retro and retroinverso - ψ [NHCH(CF

3

)] - peptides . Org.

Lett. , 2 , 1827 – 1830 ; (d) Volonterio , A. , Bravo , P. and Zanda , M. ( 2001 ) Solution/solid - phase

synthesis of partially modiﬁ ed retro - ψ [NHCH(CF

3

)] - peptidyl hydroxamates . Tetrahedron

Lett. , 42 , 3141 – 3144 .

Davis , E. A. , Reddy , R. E. , Szewezyk , J. M. , et al. ( 1997 ) Asymmetric synthesis and properties

of sulﬁ nimines (thiooxime S - oxides) . J. Org. Chem. , 62 , 2555 – 2563 .

(a) Cogan , D. A. , Liu , G. , Kim , K. , et al. ( 1998 ) Catalytic asymmetric oxidation of tert - butyl

disulﬁ de. Synthesis of tert - butanesulﬁ namides, tert - butyl sulfoxides, and tert - butanesul-

ﬁ nimines . J. Am. Chem. Soc. , 120 , 8011 – 8018 ; (b) Backes B. J. , Dragoli , D. R. and Ellman ,

J. A. ( 1999 ) Chiral N - acyl - tert - butanesulﬁ namides: the “ safety - catch ” principle applied to

diastereoselective enolate alkylations . J. Org. Chem. , 64 , 5472 – 5478 .

Asensio , A. , Bravo , P. , Crucianelli , M. , et al. ( 2001 ) Synthesis of nonracemic α - triﬂ uoromethyl

α - amino acids from sulﬁ nimines of triﬂ uoropyruvate . Eur. J. Org. Chem. , 1449 – 1458 .

(a) Soloshonok , V. A. , Ohkura , H. , Sorochinsky , A. , et al. ( 2002 ) Convenient, large - scale

asymmetric synthesis of β - aryl - substituted α , α - diﬂ uoro - β - amino acids . Tetrahedron Lett. , 43 ,

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

Recent Advances in the Syntheses of Fluorinated Amino Acids 255

5445 – 5448 ; (b) Sorochinsky , A. , Voloshin , N. , Markovsky , A. , et al. ( 2003 ) Convenient asym-

metric synthesis of β - substituted α , α - diﬂ uoro - β - amino acids via Reformatskii reaction between

Davis ’ N - sulﬁ nylimines and ethyl bromodiﬂ uoroacetate . J. Org. Chem. , 68 , 7448 – 7454 .

Staas , D. D. , Savage , K. L. , Homnick , C. F. , et al. ( 2002 ) Asymmetric synthesis of α , α -

diﬂ uoro - β - amino acid derivatives from enantiomerically pure N - tert - butylsulﬁ nimines . J. Org.

Chem. , 67 , 8276 – 8279 .

Wang , H. , Zhao , X. , Li , Y. and Lu , L. ( 2006 ) Solvent - controlled asymmetric Strecker reaction:

stereoselective synthesis of α - triﬂ uoromethylated α - amino acids . Org. Lett. , 8 , 1379 – 1381 .

Bravo , P. , Capelli , S. , Meille , S. V. , et al. ( 1994 ) Synthesis of optically pure ( R ) - and ( S ) - α -

triﬂ uoromethylalanine . Tetrahedron Asymmetry , 5 , 2009 – 2018 .

Fustero , S. , Navorro , A. , Pina , B. , et al. ( 2001 ) Enantioselective synthesis of ﬂ uorinated α -

amino acids and derivatives in combination with ring - closing metathesis: intramolecular π -

stacking interactions as a source of stereocontrol . Org. Lett. , 3 , 2621 – 2624 .

Fustero , S. , Sanz - Cervera , J. F. , del Pozo , C. and Acena , J. L. ( 2006 ) Nitrogen - containing

organoﬂ uorine compounds , in Current Fluoroorganic Chemistry , ACS Symposium Series 949 ,

American Chemical Society , Washington, D.C.

Arnone , A. , Bravo , P. , Capelli , S. , et al. ( 1996 ) New versatile ﬂ uorinated chiral building blocks:

synthesis and reactivity of optically pure α - (ﬂ uoroalkyl) - β - sulﬁ nylenamines . J. Org. Chem. ,

61 , 3375 – 3387 .

Bravo , P. and Resnati , G. ( 1987 ) An efﬁ cient approach to enantiomerically pure ﬂ uorhydrins .

Tetrahedron Lett. , 28 , 4865 – 4866 .

Bravo , P. , Cavicchio , G. , Crucianelli , M. , et al. ( 1997 ) Stereoselective synthesis of the anti-

bacterial 3 - ﬂ uoro - d - alanine . Tetrahedron Asymmetry , 8 , 2811 – 2815 .

(a) Fustero , S. , Sanchez - Rosello , M. , Sanz - Cervera , J. F. , et al. ( 2006 ) Asymmetric synthesis

of ﬂ uorinated cyclic β - amino acid derivatives through cross metathesis . Org. Lett. , 8 , 4633 –

4636 ; (b) Fustero , S. , Pina , B. , Savalert , E. , et al. ( 2002 ) New strategy for the stereoselective

synthesis of ﬂ uorinated β - amino acids . J. Org. Chem. , 67 , 4667 – 4674 .

Fustero , S. , Bartolome , A. , Sanz - Cervera , J. F. , et al. ( 2003 ) Diastereoselective synthesis of

ﬂ uorinated, seven - membered β - amino acid derivatives via ring - closing metathesis . Org. Lett. ,

5 , 2523 – 2526 .

Fustero , S. , Salavert , E. , Pina , B. , et al. ( 2001 ) Novel strategy for the synthesis of ﬂ uorinated

β - amino acid derivatives from ∆ 2 - oxazolines . Tetrahedron , 57 , 6475 – 6486 .

Hallinan , E. A , Kramer , S. W. , Houdek , S. C. , et al. ( 2003 ) 4 - Fluorinated l - lysine analogs as

selective i - NOS inhibitors: methodology for introducing ﬂ uorine into the lysine side chain .

Org. Biomol. Chem. , 1 , 3527 – 3534 .

Konas , D. W. , Pankuch , J. and Coward , J. K. ( 2002 ) The synthesis of (2 S ) - 4,4 - diﬂ uoroglutamyl

γ - peptides based on Garner ’ s aldehyde and ﬂ uoro - Reformatskii chemistry . Synthesis ,

2616 – 2626 .

Qiu , X. - L and Qing , F. - L. ( 2002 ) Synthesis of Boc - protected cis - and trans - 4 - triﬂ uoromethyl -

d - prolines . J. Chem. Soc., Perkin Trans. , 1 , 2052 – 2057 .

(a) Kolb , M. , Barth , J. , Heydt , J. - G. and Jung , M. J. ( 1987 ) Synthesis and evaluation of mono - ,

di - , and triﬂ uoroethenyl - GABA derivatives as GABA - T inhibitors . J. Med. Chem. , 30 , 267 –

272 ; (b) Bey , P. , Ducep , J. R. and Schirlin , D. ( 1984 ) Alkylation of malonates or Schiff base

anions with dichloroﬂ uoromethane as a route to a - chloroﬂ uoromethyl or α - ﬂ uoromethyl α -

amino acids . Tetrahedron Lett. , 25 , 5657 – 5660 ; (c) Bravo , P. , Cavicchio , G. , Crucianelli , M. ,

et al. ( 1997 ) Stereoselective synthesis of the antibacterial 3 - ﬂ uoro - d - alanine . Tetrahedron

Asymmetry , 16 , 2811 – 2815 .

Chen , Q , Qiu , X - L. and Qing , F - L. ( 2006 ) Indium - mediated diastereoselective allylation of

d - and l - glyceraldimines with 4 - bromo - 1,1,1 - triﬂ uoro - 2 - butene: Highly stereoselective syn-

thesis of 4,4,4 - triﬂ uoroisoleucines and 4,4,4 - triﬂ uorovaline . J. Org. Chem. , 71 , 3762 – 3767 .

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

256 Fluorine in Medicinal Chemistry and Chemical Biology

Qiu , X. - L. and Qing , F. - L. ( 2002 ) Practical synthesis of Boc - protected cis - 4 - triﬂ uoromethyl

and cis - 4 - diﬂ uoromethyl - l - prolines . J. Org. Chem. , 67 , 7162 – 7164 .

Soloshonok , V. A. , Cai , C. and Hruby , V. J. ( 2000 ) A practical asymmetric synthesis of enan-

tiomerically pure 3 - substituted pyroglutamic acids and related compounds . Angew. Chem. Int.

Ed. , 39 , 2172 – 2175 .

Fustero , S. , Jimenez , D. , Sanchez - Rosello , M. and del Pozo , C. ( 2007 ) Microwave - assisted

tandem cross metathesis intramolecular aza - Michael reaction: an easy entry to cyclic β - amino

carbonyl derivatives . J. Am. Chem. Soc. , 129 , 6700 – 6701 .

Hallinan , E. A. , Dorn , C. R. , Moore , W. M. , et al. ( 2003 ) The synthesis of 6 - triﬂ uoroethyl - l -

lysine: a method to introduce functionality at C - 6 of l - lysine . Tetrahedron Lett. , 44 ,

7345 – 7347 .

Yoshikawa , N. , Tan , L. , Yasuda , N. , et al. ( 2004 ) Enantioselective syntheses of

bicyclo[3.1.0]hexane carboxylic acid derivatives by intramolecular cyclopropanation . Tetrahe-

dron Lett. , 45 , 7261 – 7264 .

Uneyama , K. , Katagiri , T. and Amii , H. ( 2008 ) The chemistry of α - triﬂ uoromethylated carb-

anions is discussed. Acc. Chem. Res. , 41 , 817 – 829 .

Konno , T. , Kanda , M. , Ishihara , T. and Yamanaka , H. ( 2005 ) A novel synthesis of ﬂ uorine -

containing quaternary amino acid derivatives via palladium - catalyzed allylation reaction. J.

Fluorine Chem. , 126 , 1517 – 1523 .

Katagiri T. and Uneyama , K. ( 2003 ) Stereospeciﬁ c substitution at α - carbon to triﬂ uoromethyl

group: application to optically active ﬂ uorinated amino acid syntheses . Chirality , 15 , 4 – 9 .

Katagiri , T , Irie , M. and Uneyama , K. ( 2000 ) Syntheses of optically active triﬂ uoronorcoron-

amic acids . Org. Lett. , 2 , 2423 – 2425 .

Katagiri , T. , Yamaji , S. , Handa , M. , et al. ( 2001 ) Diastereoselectivity controlled by electrostatic

repulsion between the negative charge on a triﬂ uoromethyl group and that on aromatic rings .

Chem. Commun. , 2054 – 2055 .

Osipov , S. N. , Kova , N. M. K. , Kolomiets , A. F. , et al. ( 2001 ) α - Fluoromethyl tryptophans via

imino ene reaction . Synlett , 1287 – 1289 .

Pang , W. , Zhu , S. , Jiang , H. and Zhu , S. ( 2006 ) Transition metal - catalyzed formation of CF

3

-

substituted β - unsaturated alkene and the synthesis of α - triﬂ uoromethyl - substituted β - amino

ester . Tetrahedron , 62 , 11760 – 11765 .

Guo , Y. , Fujiwara , K. and Uneyama , K. ( 2006 ) A novel route to dipeptides via noncondensation

of amino acids: 2 - Aminoperﬂ uoropropene as a synthon for triﬂ uoroalanine dipeptides . Org.

Lett. , 8 , 827 – 829 .

The synthetic scope and mechanistic aspect of reactions of diﬂ uoromethylene compounds are

summarized in ref. 23 , pp 112 – 121 .

Guo , Y. , Fujiwara , K. , Amii , H. and Uneyama , K. ( 2007 ) Selective deﬂ uorination approach to

N - Cbz - 3,3 - diﬂ uoro - 2 - diﬂ uoromethylenepyrrolidine and its application to 3,3 - diﬂ uoroproline

dipeptide synthesis . J. Org. Chem. , 72 , 8523 – 8526 .

(a) Hiyama , T. ( 2000 ) Organoﬂ uorine Comounds , Springer - Verlag , Berlin ; (b) Chambers D.

R. ( 2004 ) Fluorine in Organic Chemistry , Blackwell Publishing , Oxford ; (c) Kirsh , P. ( 2004 )

Modern Fluoroorganic Chemistry , Wiley - VCH Verlag GmbH , Weinheim ; (d) Uneyama , K.

( 2006 ) Organoﬂ uorine Chemistry , Blackwell Publishing , Oxford .

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

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

Подождите немного. Документ загружается.