698
J . Org. Chem. 1999, 64, 698-699
Sch em e 1
Mild Oxid a tive Clea va ge of Bor a n e-Am in e
Ad d u cts fr om Am id e Red u ction s: Efficien t
Solu tion - a n d Solid -P h a se Syn th esis of
N-Alk yla m in o Acid s a n d Ch ir a l Oligoa m in es
Dennis G. Hall,* Carmen Laplante,
Sukhdev Manku, and J eevan Nagendran
Department of Chemistry, University of Alberta,
Edmonton, Alberta T6G 2G2, Canada
Received November 19, 1998
Unsymmetrical secondary amines such as oligoamines
and N-alkylamino acids possess a wide range of biological
properties and potential applications in drug discovery.1 For
instance, N-alkylamino acids are useful intermediates in the
solid-phase organic synthesis (SPOS) of small-molecule
libraries.2 They are generally synthesized by reductive
alkylation of primary amines,3 a rather capricious reaction
particularly inefficient with small unbranched aliphatic
aldehydes, such as formaldehyde, which tend to give over-
alkylation and cross-linking.4 Alternatively, the reduction
of amides6 and peptides7 with diborane is a very general
method for the synthesis of secondary amines in the solution
phase. However, traditional workup procedures effect cleav-
age of the resulting borane-amine adducts under strongly
acidic conditions (e.g., refluxing aqueous 1 N HCl). Such
treatment is clearly not desirable in SPOS as most resin
linkers would be incompatible.8 Similarly, the use of a basic
workup to dissociate borane-amine adducts by ligand
exchange9 usually requires extended reaction times and
temperatures higher than ambient.10,11
Ta ble 1. Solid -P h a se Syn th esis of N-Alk yla m in o Acid s 5a
a
Typical scale 0.1-0.5 g. Obtained and characterized as triflu-
b
oroacetate salts. Crude yield of product according to the loading
level of starting commercial resin (pre-amino acid loaded). c De-
termined by 1H NMR and RP-HPLC.19 Obtained as a free alcohol
d
(cleavage cocktail containing 2% EDT).
Herein, we report on a mild and highly practical workup
procedure for the synthesis of secondary amines from the
diborane reduction of secondary amides. It employs iodine
to promote the fast oxidative cleavage of borane-amine
adducts. This preliminary account discloses the solution- and
solid-phase synthesis of N-alkylamino acids that are difficult
to obtain by reductive amination, and chiral oligoamines
derived from peptides. When performed on solid-support,
this mild method prevents premature release of products
from acid-sensitive resins and provides free secondary
amines that can be further derivatized.
As shown in Scheme 1, the complete reduction of a
secondary amide such as the N-acylamino acids 1 requires
six hydride equivalents and leads to an aminoborane bo-
rane-amine intermediate (2) that must be cleaved cleanly
to afford the desired secondary amine 4.6 Whereas aminobo-
rane moieties are easily protolyzed,12 borane-amine adducts
(e.g., 3) are extremely robust.13 However, it has been
suggested that they can be titrated with iodine in a process
that ultimately liberates the amine.14 We have adapted this
method to resin-bound or sensitive substrates by using a
buffered solvent system to trap the released hydriodic acid.
As shown in Table 1, diverse N-acylamino acids attached to
Wang 1% DVB polystyrene resin were monoalkylated suc-
cessfully. Typically, resin-bound N-formyl amino acids 1a -d
were treated with diborane (3.0-3.5 equiv) at 55 °C for 6 h,
while other N-acyl derivatives (1e-g) required slightly more
rigorous conditions (3.5-4.0 equiv BH3, 65 °C, 6-12 h). As
expected, the 4-alkoxybenzyl ester linker (Wang) is highly
* To whom correspondence should be addressed. Tel: (780) 492-3141.
Fax: (780) 492-8231. E-mail: dennis.hall@ualberta.ca.
(1) For instance, N-methylamino acids are important constituents of the
therapeutically promising class of N-methylated peptides. Recent ex-
ample: Schmidt, R.; Kalman, A.; Chung, N. N.; Lemieux, C.; Horvath, C.;
Schiller, P. W. Int. J . Pept. Protein Res. 1995, 46, 47.
(2) For reviews, see: (a) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996,
96, 555. (b) Balkenhohl, F.; von dem Bussche-Hu¨nnefeld, C.; Lansky, A.;
Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288.
(3) For selected examples, see: (a) Gordon, D. W.; Steele, J . Bioorg. Med.
Chem. Lett. 1995, 5, 47. (b) Matthews, J .; Rivero, R. A. J . Org. Chem. 1997,
62, 6090. (c) Bilodeau, M. T.; Cunningham, A. M. J . Org. Chem. 1998, 63,
2800. (d) Matthews, J .; Rivero, R. A. J . Org. Chem. 1998, 63, 4808.
(4) Alternatively, two groups recently reported a three-step sequence for
amino acid N-methylation centered either on base-promoted alkylation5a
or on the Mitsunobu reaction5b of sulfonamide derivatives. The scope of these
methods, however, was not demonstrated beyond N-methylation.
(5) (a) Miller, S. C.; Scanlan, T. S. J . Am. Chem. Soc. 1997, 119, 2301.
(b) Yang, L.; Chiu, K. Tetrahedron Lett. 1997, 38, 7307.
(6) (a) Brown, H. C.; Heim, P. J . Org. Chem. 1973, 38, 912. (b) Brown,
H. C.; Narasimhan, S.; Choi, Y. M. Synthesis 1981, 441. (c) Krishnamurthy,
S. Tetrahedron Lett. 1982, 23, 3315. (d) Bonnat, M.; Hercouet, A.; Le Corre,
M. Synth. Commun. 1991, 21, 1579.
(7) (a) Roeske, R. W.; Weitl, F. L.; Prasad, K. U.; Thompson, R. M. J .
Org. Chem. 1976, 41, 1260. (b) Northrop, R. C., J r.; Russ, P. L. J . Org. Chem.
1977, 42, 4148. (c) Chu, K. S.; Negrete, G. R.; Konopelski, J . P. J . Org.
Chem. 1991, 56, 5196. (d) Cuervo, J . H.; Weitl, F.; Ostresh, J . M.; Hamashin,
V. T.; Hannah, A. L.; Houghten, R. A. In Peptides 1994, Proceedings of the
23rd European Peptide Symposium; Maia, H. L. S., Ed.; ESCOM: Leiden,
1995; p 465.
(8) For an example of a solid-phase synthesis of triamines from peptides
on Merrifield resin, see: Nefzi, A.; Ostresh, J . M.; Meyer, J .-P.; Houghten,
R. A. Tetrahedron Lett. 1997, 38, 931. Therein, acidic cleavage of borane-
amine adducts is carried out with 1 M HCl/MeOH (65 °C, >12 h). Also,
with this support, product cleavage with HF requires special equipment.
(9) (a) Reetz, T. J . Am. Chem. Soc. 1960, 82, 5039. (b) Baldwin, R. A.;
Washburn, R. M. J . Org. Chem. 1961, 26, 3549. (c) Young, D. E.; McAchran,
G. E.; Shore, S. G. J . Am. Chem. Soc. 1966, 88, 4390.
(10) For examples of amide reductions, see: (a) Paikoff, S. J .; Wilson, T.
E.; Cho, C. Y.; Schultz, P. G. Tetrahedron Lett. 1996, 37, 5653. (b) Brown,
P. J .; Hurley, K. P.; Stuart, L. W.; Willson, T. M. Synthesis 1997, 778.
(11) For a recent example of peptide reduction/piperidine treatment on
methylbenzhydrylamine polystyrene resin followed by HF cleavage, see:
Ostresh, J . M.; Schoner, C. C.; Hamashin, V. T.; Nefzi, A.; Meyer, J .-P.;
Houghten, R. A. J . Org. Chem. 1998, 63, 8622.
(12) Steinberg, H.; Brotherton, R. J . Organoboron Chemistry; J ohn Wiley
and Sons: New York, 1966; Vol. 2.
(13) (a) Lane, C. F. Aldrichim. Acta 1973, 6, 51. (b) Hutchins, R. O.;
Learn, K.; Nazer, B.; Pytlewski, D. Org. Prep. Proc. Int. 1984, 16, 335.
(14) (a) Douglass, J . E. J . Am. Chem. Soc. 1964, 86, 5431. (b) Ryschke-
witsch, G. E. J . Am. Chem. Soc. 1967, 89, 3145.
10.1021/jo982290w CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/12/1999