Asymmetric synthesis of α-branched primary amines on solid support via novel hydrazine resins

Article abstract of DOI:10.1021/ol015721x

Matrix presented Two novel chiral hydrazine resins for asymmetric solid-phase synthesis have been developed. The enantiopure β-methoxyamino auxiliaries, derived from frans-4-hydroxy-(S) -proline and (R) -leucine, were attached to Merrifield resin and transformed into their corresponding hydrazines. Immobilization of various aldehydes, followed by 1,2-addition of organolithium reagents to the resulting enantiopure hydrazones and reductive cleavage from the solid support, furnished α-branched amines, which were isolated as their corresponding amides in good overall yields and enantiomeric excesses of up to 86%.

Full text of DOI:10.1021/ol015721x

ORGANIC
LETTERS
2001
Vol. 3, No. 8
1241-1244
Asymmetric Synthesis of r-Branched
Primary Amines on Solid Support via
Novel Hydrazine Resins
Dieter Enders,* Jan H. Kirchhoff, Johannes Ko1bberling,† and Thomas H. Peiffer†
Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen Hochschule
Aachen, Professor-Pirlet-Strasse 1, D-52074 Aachen, Germany
enders@rwth-aachen.de
Received February 17, 2001
ABSTRACT
Two novel chiral hydrazine resins for asymmetric solid-phase synthesis have been developed. The enantiopure â-methoxyamino auxiliaries,
derived from trans-4-hydroxy-(S)-proline and (R)-leucine, were attached to Merrifield resin and transformed into their corresponding hydrazines.
Immobilization of various aldehydes, followed by 1,2-addition of organolithium reagents to the resulting enantiopure hydrazones and reductive
cleavage from the solid support, furnished r-branched amines, which were isolated as their corresponding amides in good overall yields and
enantiomeric excesses of up to 86%.
The synthesis of chiral, R-branched amines is of great
importance in the preparation of compounds for therapeutical
use, since a large number of primary amines show biological
activity.1 Moreover, the R-branched amine moiety is incor-
porated into many compounds such as amino acids or
alkaloids encountered in medicinal chemistry.2 Although the
enantio- and diastereoselective synthesis of this class of
compounds in liquid phase is well-known and has been
extensively reviewed,3 rather few efforts have been made to
transform these methodologies to the solid phase. Especially,
asymmetric syntheses on solid support have not been studied
extensively.
Starting with the pioneering work of Kawana et al.,4 the
application of polymer-bound chiral auxiliaries has been
focused thus far on the asymmetric R-alkylation of ke-
tones5 and amides,6 the Ugi four-component condensation
(4-CC),7and reactions with polymer-bound sulfoximines8 and
(3) (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Kobayashi, S.; Ishitani, H.
Chem. ReV. 1999, 99, 1069.
† Synthesis of the SAMP-resin.
(1) (a) Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.;
Umeyama, H.; Ishida, T.; Kiso, Y. J. Med. Chem. 1990, 33, 2707. (b)
Kempf, D. J.; Norbeck, D. W.; Codacovi, L. M.; Wang, X. C.; Kohlbrenner,
W. E.; Wideburg, N. E.; Paul, D. A.; Knigge, M. F.; Vasavanonda, S.;
Craig-Kennard, A.; Rosenbrook, W., Jr.; Clement, J. J.; Plattner, J. J.;
Erickson, J. J. Med. Chem. 1990, 33, 2687. (c) Pirie, D. K.; Welch, W. M.;
Weeks, P. D.; Volkmann, R. A. Tetrahedron Lett. 1986, 27, 1549.
(2) (a) Volkmann, R. A. In ComprehensiVe Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 1, Chapter 1.12, p 335.
(b) Kleinmann, E. F.; Volkmann, R. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter
4.3, p 975.
(4) (a) Kawana, M.; Emoto, S. Tetrahedron Lett. 1972, 13, 4855. (b)
Kawana, M.; Emoto, S. Bull. Chem. Soc. Jpn. 1974, 47, 160.
(5) (a) Worster, P. M.; McArthur, C. R.; Jiang, J. L.; Leznoff, C. C.
Angew. Chem. Int. Ed. Engl. 1979, 18, 221; Angew. Chem. 1979, 91, 255.
(b) McArthur, C. R.; Worster, P. M.; Jiang, J.-L.; Leznoff, C. C. Can. J.
Chem. 1982, 60, 1836. (c) Enders, D.; Ko¨bberling, J. Manuscript in
preparation.
(6) (a) Moon, H. S.; Schore, N. E.; Kurth, M. J. J. Org. Chem. 1992,
57, 6088. (b) Moon, H. S.; Schore, N. E.; Kurth, M. J. Tetrahedron Lett.
1994, 35, 8915.
(7) Oertel, K.; Zech, G.; Kunz, H. Angew. Chem. 2000, 112, 1489;
Angew. Chem., Int. Ed. 2000, 39, 1431.
10.1021/ol015721x CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/22/2001

oxazolidinones.9 Such immobilized auxiliaries offer some
advantages over their application in liquid phase, including
the ease of workup, the easy recovery and potential recycling
of the expensive reagents, and the isolation of reaction
products by simple filtration. In addition, the microenviron-
ment of the polymeric backbone could lead to an improved
stereoselectivity for a given transformation.
Scheme 1. Synthesis of Chiral Amines (S,R)-4 and (R)-6a
To the best of our knowledge there have been only three
reports of the enantioselective synthesis of R-branched
amines employing a polymer-bound chiral catalyst or reagent,
respectively. Soai et al.10 described the enantioselective
addition of dialkylzinc compounds to the C-N double bond
of N-diphenylphosphinylimines, catalyzed by polystyrene-
supported N,N-dialkylnorephedrins. The enantioselective
allylation of N-(trimethylsilyl)benzaldehyde imines using a
polymer-supported chiral allylboron reagent for the synthesis
of homoallylamines has been reported by Itsuno et al.11 The
same group described the use of a chiral imine attached to
a soluble polystyrene polymer, affording after oxidative
degradation of the chiral auxiliary a homoallylic amine.12
Although good to excellent enantiomeric excesses are
obtained with these protocols, all methods are restricted to
aromatic electrophiles which are not commercially available
and therefore have to be synthesized in liquid phase. In
addition, stoichiometric amounts of catalyst or boron reagent,
respectively, are required and the latter two examples are
limited to allylic nucleophiles.
a (a) SOCl2, MeOH, 0 °C f rt; (b) BzCl, DMAP, NEt3, CH2Cl2,
0 °C f rt; (c) TBSCl, imidazole, DMF; (d) LiAlH4, THF, ∆; (e)
NaH, MeI, THF, ∆; (f) H2, Pd/C, 4 bar, EtOH, 60 °C; (g) Trt-Br,
NEt3, CH2Cl2, rt; (h) TBAF, THF, rt; (i) NaH, MeI, THF; ∆; (j)
H2, Pd(OH)2/C, 4 bar, MeOH, rt.
We present here the first application of two novel chiral
hydrazine resins in the asymmetric solid-phase synthesis of
nonracemic R-branched primary amines, enabling the 1,2-
addition of both aliphatic and aromatic nucleophiles to
polymer-bound aliphatic and aromatic aldehyde hydrazones.
For the synthesis of the chiral hydrazine resins, the
enantiopure â-methoxyamines (S,R)-4 and (R)-6 had to be
attached to a polymeric support. The synthesis of these two
chiral auxiliaries starts from readily available amino acid
hydroxy proline [(S,R)-1] and N,N-dibenzylleucinol (R)-5
(Scheme 1).
Esterification of hydroxy proline [(S,R)-1]13 and protection
of both the amine and hydroxyl functionality led to the
formation of (S,R)-2, which upon reduction with lithium
aluminum hydride and subsequent methylation furnished the
benzyl-protected amine (S,R)-3. After removal of the benzyl
group, treatment with trityl bromide, and cleavage of the silyl
ether, the enantiopure â-methoxyamine (S,R)-4 was obtained
in excellent yield (62% over eight steps) on a 30 g scale
with only one chromatographic purification needed after the
final step. Deprotonation of alcohol (R)-514 and methylation,
followed by hydrogenolysis of the benzyl groups, furnished
â-methoxyamine (R)-6 in 81% yield.
The attachment of the chiral amines to Merrifield resin
(7) was achieved via nucleophilic substitution of the chlorine
by deprotonated alcohol (S,R)-4, followed by removal of the
trityl group, yielding (S)-2-methoxymethylpyrrolidin (SMP)15
analogue (S,R)-8 (SMP-resin), while amine (R)-6 was
coupled through nucleophilic substitution by the amine
moiety leading to (R)-methoxyleucinol (RML)-resin [(R)-9]
(Scheme 2).
The immobilized secondary amines (S,R)-8 and (R)-9 were
obtained in 66% and quantitative yield, respectively, judged
by elemental analysis.
(8) Hachtel, J.; Gais, H. J. Eur. J. Org. Chem. 2000, 1457.
(9) (a) Allin, S. M.; Shuttleworth, S. J. Tetrahedron Lett. 1996, 37, 8023.
(b) Phoon, C. W.; Abell, C. Tetrahedron Lett. 1998, 39, 2655. (c) Purandare,
V.; Natarajan, S. Tetrahedron Lett. 1997, 38, 8777. (d) Burgess, K.; Lim,
D. J. Chem. Soc., Chem. Commun. 1997, 785. (e) Bew, S. P.; Bull, S. D.;
Davies, S. G. Tetrahedron Lett. 2000, 41, 7577. (f) Reggelin, M.; Brenig,
V. Tetrahedron Lett. 1996, 37, 6851. (g) Reggelin, M.; Brenig, V.; Zur, C.
Org. Lett. 2000, 2, 531. (h) Reggelin, M.; Brenig, V.; Welcker, R.
Tetrahedron Lett. 1998, 39, 4801.
(10) (a) Soai, K.; Suzuki, T.; Shono, T. J. Chem. Soc., Chem. Commun.
1994, 317. (b) Suzuki, T.; Shibata, T.; Soai, K. J. Chem. Soc., Perkin Trans.
1 1997, 2757. (c) Suzuki, T.; Narisada, N.; Shibata, T.; Soai, K. Polym.
AdV. Technol. 1999, 10, 30.
(11) El-Shehawy, A. A.; Abdelaal, M. Y.; Watanabe, K.; Ito, K.; Itsuno,
S. Tetrahedron: Asymmetry 1997, 8, 1731.
Nitrosation of these polymer-bound amines was conducted
under standard conditions16 with excess tert-butylnitrite in
yields > 95% (elemental analysis). In the last step of the
synthesis, nitrosamine resins (S,R)-10 and (R)-11 were treated
with excess diisobutylaluminum hydride (DIBAL-H), af-
fording hydrazine resins17 (S,R)-12 (SAMP-resin) and (R)-
13 (RAML-resin) in 93 and 81%, respectively. The loading
(14) Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61, 3635.
(15) For a review see: Enders, D.; Klatt, M. Synthesis 1996, 1403.
(16) Kirchhoff, J. H.; Bra¨se, S.; Enders, D. J. Comb. Chem. 2001, 3, 71.
(17) Kirchhoff, J. H.; Ko¨bberling, J.; Bra¨se, S.; Enders, D. German Patent
Application 100 07 704.8, 2000.
(12) Itsuno, S.; El-Shehawy, A. A.; Abdelaal, M. Y.; Ito, K. New J. Chem.
1998, 775.
(13) Guttsman, S. HelV. Chim. Acta 1961, 44, 721.
1242
Org. Lett., Vol. 3, No. 8, 2001

Scheme 2. Preparation of Chiral Hydrazine Resins (S,R)-12
and (R)-13a
Scheme 3. Formation of R-Branched Amides (R)- or (S)-19a
a (a) (S,R)-4 (2.5 equiv), KH, DMF, 50 °C; (b) TFA/CH2Cl2 (1:
10), then NEt3; (c) (R)-6 (4 equie), n-TBAI, DMF, 80 °C; (d)
t-BuONO, THF, ∆; (e) DIBAL-H, THF, 50 °C.
of the linker resins was determined by condensation with
nitrogen-containing aldehydes such as p-nitrobenzaldehyde
and subsequent elemental analysis of the hydrazone resins,
indicating a loading of 0.52 mmol‚g-1 [(S,R)-12] and 0.54
mmol‚g-1 [(R)-13], respectively.
a (a) R1CHO, THF, MS 4 Å, rt; (b) R2Li, THF, -100 °C f rt,
then H2O; (c) BH3‚THF, THF, ∆, then HClaq, rt, then extraction;
(d) R3COCl, NEt3, DMAP, CH2Cl2, 0 °C f rt.
With these linkers in hand, representing immobilized
analogues of the SAMP18 and (R)-methoxyleucinol19 auxil-
iary, we were able to synthesize a series of enantiomerically
enriched R-branched amines on solid support (Scheme 3).
First, coupling of resins (S,R)-12 and (R)-13 with excess
aliphatic and aromatic aldehydes led to the formation of
chiral resin-bound hydrazones 14 and 15. Stereoselective
addition of different carbon nucleophiles to the C-N double
bond was achieved by treatment of the hydrazone resins with
7 (aliphatic nucleophile) or 10 (PhLi) equiv of organolithium
reagent at -100 °C in THF. After warming to room
temperature and subsequent hydrolysis, the hydrazine resins
16 and 17 were obtained with loadings ranging from 70 to
90% according to the nitrogen content determined by
elemental analysis.
treated with excess borane-tetrahydrofuran complex (BH3‚
THF) according to standard procedures developed in our
group.20 Hydrolysis with 3 M hydrochloric acid, followed
by filtration and extraction procedures, furnished the enan-
tiomerically enriched (R)- and (S)-amines 18 in yields of 30-
70% on the basis of hydrazine resins (S,R)-12 and (R)-13
and initial purities of 50-70% (1H NMR).
Further purification and determination of the enantiomeric
excess was achieved by protection of the amine functionality
as their corresponding amides. Thus, the reaction of crude
amines with benzoyl chloride or acetyl chloride in the
presence of triethylamine and catalytic amounts of DMAP
furnished, after chromatography, (R)- and (S)-amides 19 in
moderate to good enantiomeric excesses and yields (Table
1).
For the release of the R-branched primary amines via N-N
bond cleavage, the trisubstituted hydrazines 16 and 17 were
(18) (a) Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933. (b)
Enders, D.; Klatt, M. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.: Wiley&Sons: Chichester, 1995; Vol. 1, p 178.
(19) Meyers, A. I.; Poindexter, G. S.; Brich, Z. J. Org. Chem. 1978, 43,
892.
(20) Enders, D.; Lochtmann, R.; Meiers, M.; Mu¨ller, S.; Lazny, R. Synlett
1998, 1182.
Org. Lett., Vol. 3, No. 8, 2001
1243

hydrazone (entry 5) furnished amide (R)-19c in lower
enantiomeric excess (50%) and yield (28%). This drawback
can be circumvented by the use of the SAMP-resin, which
yields (S)-19c in good enantiomeric purity (ee ) 81%). Also
the addition of aliphatic organolithium reagents to an
aliphatic hydrazone (entry 2 and 4) proceeds with good
asymmetric inductions and chemical yields. Moreover, this
linker enables the addition of n-butyllithium to an aromatic
system (entry 8) in moderate enantioselectivity (ee ) 66%).
The (R)-leucine resin obtained after N-N bond cleavage
with BH3‚THF (Scheme 3) could be successfully recycled
to the hydrazine linker (R)-13 following the nitrosation/
reduction protocol (Scheme 2). The so-generated hydrazine
resin (loading 0.24 mmol‚g-1) was still suitable for aldehyde
attachment. However, no further investigations in the asym-
metric 1,2-addition were attempted.
Table 1. Asymmetric Synthesis of Amides 19
In conclusion, two novel chiral hydrazine resins have been
developed and successfully employed in the asymmetric
synthesis of R-branched primary amines on solid support.
The methodology enables the synthesis of the acyl-protected
title compounds starting from readily available substrates in
good yields (24-51% over four steps) and moderate to good
enantiomeric excesses (50-86%). In addition, this protocol
shows great flexibility regarding aliphatic and aromatic
nucleophiles and hydrazones.
a The enantiomeric excess was determined by chiral HPLC. b Absolute
configuration based on the assumption that linker (S,R)-12 leads to the same
enantiomer as the SAMP-auxiliary in liquid phase. c Each compound was
characterized by 1H NMR and mass spectroscopic analysis. The yields refer
to the loading of resins (S,R)-12 and (R)-13.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Leibniz Prize, Sonder-
forschungbereich 380, TFB 11). We thank Degussa AG,
BASF AG, Bayer AG, and Wacker Silan for the donation
of chemicals.
As shown in Table 1, both enantiomers of amides 19a-c
can be obtained by choosing either the SAMP-resin (S,R)-
12 or the RAML-resin (R)-13, respectively. For the addition
of aliphatic nucleophiles to aliphatic aldehyde hydrazones
(entries 1 and 3), the employment of the RAML-resin results
in the formation of the desired products in good enantiomeric
excesses (78, 86%) and yields (51, 35%). However, due to
the lower reactivity of aromatic nucleophiles, the addition
of phenyllithium to aliphatic 3-phenylpropanal aldehyde
Supporting Information Available: Experimental pro-
cedures and characterizations for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL015721X
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Org. Lett., Vol. 3, No. 8, 2001