Efficiencies of reductive amination reactions on different solid supports

Topics: Chemical reaction, Peptide synthesis, 1998 Pages: 12 (1714 words) Published: October 12, 2013
TETRAHEDRON
LETTERS

Tetrahedron Letters 39 (1998) 9279-9282

Pergamon

Efficiencies of Reductive Amination Reactions on Different Solid Supports Chinh T Bui, Firas A. Rasoul, Francesca Ercole, Yen Pham and N Joe Maeji* Cluron TechnologiesPry Ltd.. 11 Duerdin Street. Cla.~aon,Vic. 3168, Australia Received 12 August 1998; accepted 1 October 1998

Abstract:
Rreductive amination on resins derivatized with 5-(4-forntyl-3,5-dimethoxyphenoxv)valeric acid linker (Barallv linker, 1) 1 has been reported to be less" effective than on resin derivatized with its" ntonomethoxy analog (2): due to steric hindrance of the extra methoxv fimctional group within the molecule. 3 A study of these linkers indicate that the origins of such data is also related to the spacer and solid support used in the study. Depending on the linker, spacer and solid phase, .yields from 10% to 75% were obtained under exactly the same reaction conditions. © 1998 ElsevierScienceLtd. All rights reserved.

The choice of solid support and linker are important factors for success in solid phase synthesis. ~ Unlike solution phase synthesis, where an optimisation study will result in reproducible reactions, time consuming validation steps usually required in solid phase synthesis may only be specific for a particular solid support s Here, we present a comparative study of reaction rates, yields, and purity to assess the effect of the solid phase and a six bond spacer arm in a model reductive amination.

We compared aminomethylated and
chloromethylated Synphase crowns 6 used with the Multipin method of solid phase synthesis, 7 with aminomethylated (1.0 mmol/g, 500-595 lam, Polymer Laboratories) and chloromethylated (0.99 mmol/g, 400500 Jam, Polymer Laboratories) resin beads. For comparative purposes, we chose resins with relatively large bead sizes as they can be considered individual "reactors" that allow syntheses of many different compounds in common reaction flasks but still allow separation and cleavage to give individual compounds The resins and SynPhase crowns were derivatised with four linkers Aminomethylated supports were derivatised with 5-(4formyl-3,5-dimethoxy-phenoxy) valeric acid (1) and 5-(4-formyl-3-methoxyphenoxy) valeric acid (2) while the chloromethylated supports were derivatised with their corresponding analogues 3 and 4 under previously published conditions w- In principle, supports derivatised with 3 and 4 are functionally identical to 1 and 2 and any differences in outcome can be attributed to the six bond spacer arm.

OMe

OMe

R
1
2

R =
R=

OMe
H

R
3
4

R =
R=

OMe
H

Derivatized crowns and resins were subjected to a reductive amination reaction with benzylamine to give the amine bound linkers 6 (a or b) under identical reaction conditions. 8 The resulting products were acylated with Fmoc-(B)-alanine using previously published conditions to afford 7 (a or b). 9 Under standard cleavage conditions (50% TFA/DCM), all 4 linkers liberated the target amide 8.1° The assigned structure and % purity of 8 were directly obtained by ES-MS H and I-IPLC analysis. 12

0040-4039/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(98)02085-1

9280

OMe

R = H or OMe
SP = Solid phase:
resin or SynPhase
O

I

I
crown

R

I

5a n=l
5b n=O
Benzylamine, NaBH3C N
AcOH, 50% DMF/DCM

OMe

6a n=l
6b n=O
Fmoc-(beta)Alanine,
DIC,
HOBt, 50% DMF/DCM

Fmoc

I
HN

.OMe

\

©

T FA/DCM
~--

N
k~

\

O
O1
1

8

n:l In

~ R

O~... ~

7a

NH

[

7b n=0

Fmoc

Scheme 1. Synthesis of the Model Molecule 8

loo
120

n9

0

1

8o

~.

...............

_ _

60

0
'v

Linker 3
Linker 1
Linker 4

40

20
0

20

40

60

80

100

120

Molar Excess of Benzylamine

Figure 1. % Completion of Reaction vs. Molar Excess of Benzylamine on Resins Derivatized with Linker 1, 3 or 4 (% completion = [FIPLC...

References: Org. Chem. 1990, 55, 3730., Songster, MF.; Vagner J.; Barany, G., Lett. Pept. Sci., 1995, 2, 265.
2. Fivush, M. A.; Willson, T. M. TetrahedronLett, 1997, 38, 7151.
3. Sarantakis, D.; Bicksler, J.J. Tetrahedron Lett, 1997, 38, 7325.
4. Li, W.;Yan, B. J. Org. Chem., 1998, 63, 4092.
5. Burgess, K.; Lim, D. Chem. Commun., 1997, 785.
6. Wendeborn, S.; Beaudegnies, R.; Ang, K H.; Maeji, N J., Biotechnol. Bioeng. (Comb. Chem)., 1998, 61,
89.
7. Geysen, H.M.; Meloen, RH.; Bavteling, SJ. Proc. Natl. Aead. Sci. U.S.A. 1984, 81, 3998. Maeji, N.J.; Bray,
A.M; Valerio R
9 Thompson, L.A; Ellman, JA. ( 'hem. Rev., 1996, 96, 555.
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