Tải bản đầy đủ - 0 (trang)
V. RESINS AND LINKERS FOR HYDROXYL AND GENERATION OF AMINO FUNCTION

V. RESINS AND LINKERS FOR HYDROXYL AND GENERATION OF AMINO FUNCTION

Tải bản đầy đủ - 0trang

Figure 12



p-Benzyloxybenzylamine (BOBA) 48 is a new class of an amine

support and was prepared from Merrifield resin in two steps [56]. BOBA

resin was treated with an aldehyde in the presence of an acid to give an

imine that subsequently reacted with Yb(OTf )3-catalyzed silyl enolates

(Scheme 18). Cleavage with trimethylsilyl triflate (TMSOTf) or 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave either phenols or

amines, respectively.

9-Phenylfluoren-9-yl polystyrene (Phfl) based resin 49 was applied in

the solid-phase synthesis of hydroxyl and amino functions [57,58]. This

resin has higher acid stability compared to the structurally similar trityl

resin. Final release of the product is accomplished with TFA in high purity

(Scheme 19).

Trialkylsilane resin (PS-DES) 50 was incorporated for solid-phase

glycosylation by anchoring a glycosyl donor via their corresponding thiophenyl ether or h-glucopyranosyl fluorides (Scheme 20) [59]. Disaccharides



Scheme 17



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 18



were prepared by reaction with a glycosyl acceptor followed by cleavage

with acetic acid (AcOH).

Phenols were constructed form novel serine-derived handle 51,

which was stable to acids (TFA) and bases (pyridine) (Scheme 21) [60].

The final products were released from the support by fluoride ion.

A variety of cleavage conditions have been reported for the release

of amines from a solid support. Triazene linker 52 prepared from

Merrifield resin in three steps was used for the solid-phase synthesis of

aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic

conditions and the amino products were released in high yields upon

treatment with mild acids. Alternatively, base labile linker 53 synthesized

from a-bromo-p-toluic acid in two steps was used to anchor amino

functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of

the thioether to the sulfone with m-chloroperbenzoic acid followed by helimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A

linker based on 1-(4,4V-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde)

primary amine protecting group was developed for attaching amino

functions (Scheme 24) [65]. Linker 54 was stable to both acidic and

basic conditions and the final products were cleaved from the resin by

treatment with hydrazine or transamination with n-propylamine.



Scheme 19



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 20



REM linker 55 (regenerated after cleavage, functionalized by

Michael addition) is a traceless handle for anchoring secondary amines

(Fig. 13) [64]. Tertiary amines were prepared on this linker via basedinduced Hofmann elimination of the subsequent quaternary ammonium

salt. An analogous vinyl sulfone linker was prepared from Merrifield resin

to perform the identical synthetic strategy (Scheme 25) [65]. Similar to

REM, vinyl sulfone handle 56 was regenerated following cleavage, but

was more stable to acids and nucleophiles such as Grignard reagents than

the former. An extension to the vinyl sulfone theme was demonstrated by

inserting a carbamate function at the anchoring position for the assembly

of 2- and 2,4-substituted pyrrolidines (Scheme 26) [66]. The acid stable,

base labile (final cleavage accomplished with NaOMe) support 57 was

used for N-acyliminium ion reactions.



Scheme 21



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 22



Scheme 23



Scheme 24



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Figure 13



Scheme 25



Scheme 26



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 27



N-Protected amines were assembled on solid-phase via sulfonamidebased handle 58 (Scheme 27) [67]. Tertiary sulfonamides were generated

upon reaction with allylic, benzylic and primary alcohols under Mitsunobu conditions. Secondary amines were released from the support using

mild nucleophilic conditions such as treatment with thiophenol and

potassium carbonate.

A versatile approach for the solid-phase synthesis of aminopyridazines used the anchoring of 3,6-dichloropyridazine to resin-bound

thiophenol 59 (Scheme 28) [68]. Treatment with nucleophilic amines

released the aminopyridazine products from the solid support without

further oxidation.

Traceless linker 60 based on a benzotriazole scaffold was reacted with

amines and aldehydes to produce Mannich-type amine products [69]. Final

product release was achieved by treatment with Grignard reagents

(Scheme 29).



Scheme 28



Scheme 29



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Figure 14



VI. RESINS AND LINKERS FOR HYDROXAMIC

GENERATION OF ACID FUNCTIONS

Hydroxamic acids are an important class of compounds targeted as potential therapeutic agents. N-Fmoc-aminooxy-2-chlorotrityl polystyrene

resin 61 allowed the synthesis and subsequent cleavage under mild conditions of both peptidyl and small molecule hydroxamic acids (Fig. 14)

[70]. An alternative hydroxylamine linkage 62 was prepared from trityl

chloride resin and N-hydroxyphthalimide followed by treatment with

hydrazine at room temperature (Scheme 30) [71]. A series of hydroxamic

acids were prepared by the addition of substituted succinic anhydrides to

the resin followed by coupling with a variety of amines, and cleavage with

HCOOH-THF(1:3).



Scheme 30



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



VII. RESINS AND LINKERS FOR GENERATION

OF SULFONAMIDE, UREA, AND

GUANIDINE FUNCTIONS

Aminosulfonyl ureas were constructed from a sulfonylcarbamate linkage (Scheme 31) [72]. Reaction of chlorosulfonyl isocyanate (CSI) with

Wang resin provided a chlorosulfonylcarbamate 63 which was then

converted to substituted amino sulfonylcarbamate compounds by reaction with excess amines. The final aminosulfonyl urea products were

cleaved from the resin by treatment with amines in HF at reflux

temperature for overnight.

Urea libraries were assembled via thiophenoxy carbonyl linker 64

readily available in two steps from Merrifield resin (Scheme 32) [73].

Treatment of this linker with primary or secondary amines, followed by

basic cleavage with amines generated the ureas. An alternative

approach for the synthesis of ureas was to treat p-nitrobenzophenone

oxime resin with phosgene to give p-nitrophenyl(polystyrene)ketoxime

(Phoxime resin) 65 [74]. The addition of primary amines to the

phosgenated oxime linker gave a resin-bound carbamate. Ureas were

genated by reaction with a second set of amines at temperatures greater

than 80jC (Scheme 33).

Traditional SPPS anchors the peptide to the support via the acarboxylic acid of the C-terminal residue. Novel sulfonyl linker 66 was

prepared to side-chain anchor the guanidine function of arginine

(Scheme 34) [75]. To demonstrate the utility of the linker, tripeptide

H-Phe-Arg-Ala-OMe was assembled in which amino acids were

extended to the anchoring residue in both the C- and N-terminal

directions. HF cleavage released the peptide from the support. Small

molecules containing guanidines were constructed from carbonylimidazole handle 67 generated from Wang resin (Scheme 35) [76]. Treatment

of the carbonylimidazole linker with thiourea basic conditions afforded



Scheme 31



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Tài liệu bạn tìm kiếm đã sẵn sàng tải về

V. RESINS AND LINKERS FOR HYDROXYL AND GENERATION OF AMINO FUNCTION

Tải bản đầy đủ ngay(0 tr)

×