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

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Fluorinated Moieties for Replacement

of Amide and Peptide Bonds

Takeo Taguchi and Hikaru Yanai

10.1 Introduction

Chemical modiﬁ cations of peptides to improve their biological activity, in vivo stability

or bioavailability have been studied extensively [1, 2] . As one of the promising approaches,

replacement of a speciﬁ c amide bond in the target peptide molecule by an appropriate

amide bond surrogate can not only bring about enhanced recognition by the target enzyme,

which induces the parent peptide to exhibit biological responses, but also facilitate pepti-

dase resistance, conformational control or increase of the lipophilicity of the target peptide

(see Figure 10.1 ) [1, 2] .

Isosteric amide replacements are commonly shown using the symbol Ψ [ ], where

the Ψ indicates the absence of an amide bond and the structure that is replacing the amide

is shown in the brackets. The alkene dipeptide isostere Ψ [CH = CH], which is conforma-

tionally ﬁ xed and enzymatically nonhydrolyzable (peptidase resistance), has been well

studied because of its close similarity to the amide bond with regard to the steric demand,

bond lengths, and bond angles, as described in Chapter 1 [3] . However, the low polarity

of the alkene moiety compared with the amide bond, as well as the small dipole moment

and the lack of ability to form hydrogen bonds are quite different characteristics of

Ψ [CH = CH] as a replacement of the amide bond. Introduction of ﬂ uorine into the double

bond remarkably changes the electronic nature of the double bond to one much closer

to that of the amide bond, while still keeping steric similarity [4 – 7] . In addition to the

ﬂ uoro - oleﬁ n dipeptide isostere Ψ [CF = CH], several types of ﬂ uorinated moieties such

Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima

258 Fluorine in Medicinal Chemistry and Chemical Biology

as triﬂ uoromethyl - oleﬁ n Ψ [C(CF

) = CH], triﬂ uoromethylamine Ψ [CH(CF

) - NH] and

diﬂ uoroethylene Ψ [CF

- CH

] have been developed as dipeptide isosteres. In this chapter,

recent achievements in ﬂ uoro - oleﬁ n Ψ [CF = CH] and triﬂ uoromethyl - oleﬁ n Ψ [C(CF

) = CH]

dipeptide isosteres are reviewed. Developing bioorganic chemistry of ﬂ uoroarenes as

replacement for nucleoside bases is also brieﬂ y described.

10.2 Fluoro - oleﬁ ns Ψ [CF = CH] as Dipeptide Isosteres

10.2.1 Synthetic Methods

As described above, the ﬂ uoro - oleﬁ ns are the most studied ﬂ uorinated peptide mimetics.

For the synthesis of the ﬂ uoro - oleﬁ n Ψ [CF = CH] dipeptide isostere or the depsipeptide

isostere (5 - hydroxy derivative, see Figure 10.2 ), stereochemical control of the oleﬁ n con-

ﬁ guration (either E or Z ) and the relative stereochemistry of the two chiral centers at C - 2

and C - 5 (either syn or anti ) is a major issue to be solved. Furthermore, the use of readily

available starting material is also important. Since the pioneering work by Allmenginger

et al . in the early 1990s [8] , many research groups, as described in this section, have con-

tributed to this development of facile synthetic methods for ﬂ uorinated dipeptide isosteres,

in particular for optically pure forms, but this subject is still challenging. In this section

are summarized (i) synthetic methods mainly focused on the oleﬁ nation reactions of car-

Figure 10.1 Various peptide bond mimics.

Fluorinated Moieties for Replacement of Amide and Peptide Bonds 259

bonyl compounds and related reactions, (ii) utilization of ﬂ uoroalkenyl building blocks,

and (iii) application to the modiﬁ cations of the target peptides of biological interest.

10.2.1.1 Utilization of Organophosphorus and Organosilyl Reagents

The Honor – Wadsworth – Emmons (HWE) reaction of α - ﬂ uoro - α - phosphonoacetate 1 with

aldehydes or ketones, providing α - ﬂ uoro - α , β - unsaturated carbonyl compounds, is one of

commonest methods for ﬂ uoro - oleﬁ ns having suitable functionality for further elaboration

to the target molecules (see equation 1, Scheme 10.1 ) [9] . The stereochemical outcome of

this reaction with both aliphatic and aromatic aldehydes is generally excellent, giving rise

Figure 10.2 Replacement of amide bonds by ( Z ) - ﬂ uoro - oleﬁ ns.

Scheme 10.1

260 Fluorine in Medicinal Chemistry and Chemical Biology

to the ( E ) - isomer. In contrast, the Wittig reaction of phosphorane 3 (Bu

P = CFCO

Et) with

aldehyde proceeds in nonstereoselective manner (see equation 2, Scheme 10.1 ). The reac-

tions of the dianion of α - ﬂ uoro - α - phosphonoacetic acid 4 , with aromatic aldehydes give

Z - isomers exclusively, while those with aliphatic aldehydes are nonstereoselective (see

equation 3, Scheme 10.1 ) [10] . Sano and Nagao reported the Z - selective synthesis through

acylation of 1 with acyl chloride, followed by NaBH

reduction of the ketone group (see

equation 4, Scheme 10.1 ) [11] . Falck and Mioskowski reported a high yield and Z - selec-

tive synthesis of α - haloacrylates by the Cr(II) - mediated Reformatsky type reaction of tri-

haloacetate, including dibromoﬂ uoroacetate 5 for ﬂ uoro derivatives, with aldehydes (see

equation 5, Scheme 10.1 ) [12] .

Allmenginger reported the preparation of Phe - ψ [( E ) - CF = CH] - Gly in racemic form

via E - selective HWE reaction, yielding α - ﬂ uoroenoate 7 . Conversion of the ( E ) - aldehyde

8 to N - silylimine, followed by the addition of the Grignard reagent afforded amine 9

without isomerization of the double bond (see Scheme 10.2 ) [13] .

The HWE reaction of (EtO)

P(O)CHFCO

Et ( 1 ) with ketones proceeds in nonselec-

tive manner. For example, Augustyns reported the HWE reaction of 1 with cyclopentanone

derivative 10 to give a mixture of α - ﬂ uoroenoate 11a ( E / Z = 1.3: 1), which, after separa-

tion of isomers, was converted to N - alkyl Gly - ψ [CF = C] - Pro - CN ( 14 ) for their SAR studies

on dipeptidyl peptidase (DPP) inhibitors (see Scheme 10.3 ) [14] . In this synthesis, conver-

sion of amide 12 to amine 13 was achieved by LiAlH

reduction of the imidoyl derivative

formed by treating 12 with POCl

. Without this pre - treatment, LiAlH

reduction of 12

gave 13 in very low yield because of several side - reactions (see Scheme 10.3 ).

For the preparation of Gly - ψ - [CF = CH] - Pro in relation to the study of cyclophilin

A inhibitors, Welch and co - workers employed the Peterson reaction of α - ﬂ uoro - α -

trimethylsilyl acetate ( 15a,b ) with ketone 10 . E / Z selectivity was found to be inﬂ uenced

by the ester part of the acetate (see Scheme 10.4 ) [15] . The reaction of tert - butyl ester 15a

gave almost an equal amount of the isomers ( 11b , E : Z = 1 : 1.1), while moderate E

selectivity was observed when trimethylphenyl ester 15b was used ( 11c , E : Z = 6 : 1).

Conversion of ester Z - 11b to amino derivative 16 was achieved via the Mitsunobu reaction

of phthalimide with the alcohol formed by the DIBAL - H reduction of Z - 11b .

Scheme 10.2

Fluorinated Moieties for Replacement of Amide and Peptide Bonds 261

Scheme 10.3

Scheme 10.4

10.2.1.2 Ring Opening Reaction of Oxygenated Chloroﬂ uorocyclopropanes to

( Z ) - α - Fluoroenal

Under acidic conditions, α - ﬂ uoro - α , β - unsaturated aldehydes form the thermodynamically

stable Z - isomer. For the preparation of ( Z ) - aldehyde 19 , acid hydrolysis of pyrane deriva-

tive 18 , whose oleﬁ n - conﬁ guration corresponds to the E conﬁ guration, was affected due

to facile isomerization under the reaction conditions. Pyrane 18 was obtained by chloro-

ﬂ uorocarbene addition to dihydrofuran under phase - transfer conditions (see Scheme 10.5 )

[13] . ( Z ) - Aldehyde 19 was converted to Ph - ψ [( Z ) - CF = CH] - Gly ( 20 ) using the same reac-

tions for the preparation of the ( E ) - isomer as described above (see Scheme 10.2 ).

262 Fluorine in Medicinal Chemistry and Chemical Biology

Carbene addition to an E / Z mixture of vinyl ether 21 , followed by solvolysis of the

resultant cyclopropane 22 afforded ( Z ) - α - ﬂ uoroenal 23 (Scheme 10.6 ) [16] . ( Z ) - α - Fluo-

roenal 23 was used for the preparation of Substance P analogues containing a Phe - Ψ [( Z ) -

CF = CH] - Gly dipeptide unit as described next.

10.2.1.3 Imidate [3,3] - Sigmatropic Rearrangement

Transposition of an allylic hydroxyl group into an amino group through [3,3] - sigmatropic

rearrangement is well known as the Overmann rearrangement, which has been applied to

the total synthesis of a variety of nitrogen - containing natural products. In general, the

rearrangement proceeds via a six - membered chair - like transition state, resulting in a

perfect chirality transfer of the stereogenic center at the allylic hydroxyl moiety. For the

synthesis of a Phe - Ψ [( Z ) - CF = CH] - Gly dipeptide unit in optically pure form to be applied

to Substance P analogues, Allemendinger employed enantioselective aldol reactions of

chiral enolates 24 and 25 with ( Z ) - α - ﬂ uoroenal 23 , giving rise to both enantiomers ( R ) - 26

and ( S ) - 26 , respectively, with high optical purities (see Scheme 10.7 ) [16] .

Enantiomerically pure imidate 27 was subjected to thermal rearrangement at 140 ° C

to give the desired amide derivative 28 in good yield, retaining the optical purity of 26

(see Scheme 10.8 ). Jones oxidation of the primary alcohol to carboxylic acid afforded

dipeptide isostere 29 in optically pure form, which was applied to the preparation of Sub-

stance P analogues 30 [16] . It should be noted that nonﬂ uorinated analogues easily undergo

isomerization of the double bond to form α , β - unsaturated amides, while the ﬂ uorinated

double bond in these compounds and the corresponding intermediates is stable under basic

and acidic conditions employed, reﬂ ecting the stabilizing effect of ﬂ uorine on the double

bond [17] .

Scheme 10.5

Scheme 10.6

Fluorinated Moieties for Replacement of Amide and Peptide Bonds 263

Scheme 10.7

Scheme 10.8

For the synthesis of ﬂ uoro - oleﬁ n dipeptide isosteres corresponding to dipeptides

consisting of two chiral amino acids in stereochemically pure forms with respect to both

the conﬁ guration of the C – C double bond and the chiral centers at C - 2 and C - 5, we

reported the imidate rearrangement route starting from optically pure aldehydes derived

from, for example, commercially available ester 31 (see Scheme 10.9 ) [18] . Indium - medi-

ated diﬂ uoroallylation of aldehyde 32 gave diﬂ uorohomoallyl alcohol 33 as a mixture of

diastereomers, which were separated by column chromatography. In the presence of CuI

(20 mol%), Grignard reaction of 32 with diﬂ uorohomoallyl alcohol 33 afforded allylic

substitution product 34 in a highly Z - selective manner, wherein both aliphatic and aromatic

Grignard reagents can be employed. Scheme 10.9 illustrates a typical example. The

imidate rearrangement of syn - 34c led to the formation of syn - 35c and the subsequent

conversion to the carboxylic acid proceeded smoothly to give Leu - Ψ [CF = CH] - Ala ( syn -

36c ) without any loss in optical purity. This method has some generality since a variety

of Grignard reagents can be used for the preparation of ﬂ uoroallyl alcohols 34 from 33 .

Alternatively, the starting chiral aldehydes, such as 32 , could also be readily prepared by

hydroxymethylation of carboxylic acid derivatives using a chiral auxiliary protocol [19] .

264 Fluorine in Medicinal Chemistry and Chemical Biology

Preparation of N - Ac - Glu - Ψ [CF = CH] - Ala was also reported using the imidate rearrange-

ment protocol [20] .

10.2.1.4 Aldolization of Fluorooxaloacetate

Bartlett and Otake employed aldol reaction of an in - situ - generated ﬂ uorooxaloacetate with

a chiral aldehyde derived from 37 to prepare α - ﬂ uoroenoate 38 . Stereoselectivity was

moderate ( Z : E = 2.3 : 1), with preferential formation of the Z - isomer (see Scheme 10.10 )

[19] . Further elaboration led to the preparation of tripeptide analogues, Cbz - Gly - Ψ [( Z ) -

CF = CH] - Leu - Xaa ( 39 ).

10.2.1.5 Sulfoxide - elimination Reaction

Alkylation of the anion of α - ﬂ uoro - α - phenylsulﬁ nylacetate 40 with an alkyl halide, fol-

lowed by thermal syn - elimination of sulﬁ nic acid, gave α - ﬂ uoroenoate 41 in Z - selective

manner (see Scheme 10.11 ) [21] .

10.2.1.6 Deﬂ uorinative Allylic Substitution and Related Reactions

Reaction of γ , γ - diﬂ uoro - α , β - enoate derivatives 42 with Me

CuLi (5 equivalents), followed

by aqueous work - up afford the reductive deﬂ uorination product 44 without forming the

α - methylated product. It is postulated that enolate intermediate 43 reacts with alkyl halide

smoothly and regioselectively to give the desired α - alkylated product 45 (see Scheme

10.12 ) [22, 23] . The reaction proceeded in an excellently Z - selective manner.

Otaka and Fujii demonstrated that alkyl transfer from Me

CuLi can be promoted by

air oxidation of intermediate 43 (see Scheme 10.13 ) [24] .

Scheme 10.9

Fluorinated Moieties for Replacement of Amide and Peptide Bonds 265

Scheme 10.10

Scheme 10.11

Scheme 10.12

266 Fluorine in Medicinal Chemistry and Chemical Biology

Although Me

CuLi - mediated reductive deﬂ uorination of 42 , followed by α - alkylation

with alkyl halide, gave product 45 in high yield and in Z - selective manner, the relative

stereochemistry at C - 5 and C - 2 was not controlled (see Scheme 10.12 ). For the stereo -

controlled alkylation at C - 2, a chiral auxiliary at the carboxyl moiety was used, and rela-

tively high diastereoselectivity was realized in the case of camphorsultam derivative 46

(see Scheme 10.14 ) [23] .

For the preparation of chiral nonracemic dipeptide isosteres, Otaka and Fujii also

reported the use of camphorsultam derivative 49 , which was prepared in optically pure

form through the Reformatsky reaction of BrCF

Et with a chiral imine (see Scheme

10.15 ) [25] .

Scheme 10.13

Scheme 10.14

Scheme 10.15