Asymmetric synthesis of (+)-hypusine.

Article abstract of DOI:10.1021/ol016959o

Wittig reaction of (triphenylphosphoranylidene)acetonitrile with the lactone carbonyl of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (3) and subsequent reduction generates morpholinylethylamine dihydrochloride (5) in

Full text of DOI:10.1021/ol016959o

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4287-4289
Asymmetric Synthesis of (+)-Hypusine
Rajendra P. Jain, Brian K. Albrecht, Duane E. DeMong, and Robert M. Williams*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
rmw@chem.colostate.edu
Received October 26, 2001
ABSTRACT
Wittig reaction of (triphenylphosphoranylidene)acetonitrile with the lactone carbonyl of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-
tetrahydro-4H-1,4-oxazin-2-one (3) and subsequent reduction generates morpholinylethylamine dihydrochloride (5) in quantitative yield and
with excellent diastereoselectivity. Compound 5 was readily converted into hypusine dihydrochloride (1‚2HCl) in overall 53% yield.
(+)-Hypusine (1) (Hpu, (2S,9R)-2,11-diamino-9-hydroxy-
7-azaundecanoic acid) is an unusual naturally occurring
amino acid that was first isolated from extracts of bovine
brain in 1971 by Shiba et al.,1 who also established its
absolute configuration in 1982.2 (+)-Hypusine (1) is formally
a conjugate of hydroxyputrescine (2, Figure 1) and lysine.1
red blood cells and determined the amino acid sequence
around the single hypusine residue (Hpu) as Thr-Gly-Hpu-
His-Gly-His-Ala-Lys. Recently, eIF-5A has been shown to
play a key role in the replication of human immunodeficiency
virus-1 (HIV-1).5
Synthesis of a reagent that enables the incorporation of
hypusine into peptide sequences has also recently been
reported.6
A number of approaches have been reported in the
literature for the synthesis of hypusine, including (1) N-
alkylation of a L-lysine fragment with a 4-amino-1-bromo-
2-butanol derivative;2 (2) reductive amination of a hydroxy-
putrescine fragment with a 2-amino-6-oxo-hexanoic acid
derivative;7 (3) reductive amination of a L-lysine fragment
with a 4-amino-2-hydroxy-butyraldehyde derivative;8 and (4)
N-alkylation of a L-lysine fragment with epichlorohydrin,
subsequent displacement of chloride with cyanide, and
reduction.9 In most of these approaches, L-lysine was utilized
as a key substrate.
Figure 1. Structures of hypusine (1) and hydroxyputrescine (2).
In 1983, Folk and co-workers3 found that a precursor protein
of eukaryotic initiation factor 5A (eIF-5A, formerly known
as eIF-4D), found in all animal cells, undergoes posttrans-
lational modification in growing cells to form hypusine. In
1986, Park et al.4 isolated the eIF-5A protein from human
(4) Park, M. H.; Liu, T.-Y.; Neece, S. H.; Swiggard, W. J. J. Biol. Chem.
1986, 261, 14515-14519.
(5) Bevec, D.; Jaksche, H.; Oft, M.; Wo¨hl, T.; Himmelspach, M.; Pacher,
A.; Schebesta, M.; Koettnitz, K.; Dobrovnik, M.; Csonga, R.; Lottspeich,
F.; Hauber, J. Science 1996, 271, 1858-1860.
(1) Shiba, T.; Mizote, H.; Kaneko, T.; Nakajima, T.; Kakimoto, Y.; Sano,
I.; Biochim. Biophys. Acta 1971, 244, 523-531.
(6) Bergeron, R. J.; Ludin, C.; Mu¨ller, R.; Smith, R. E.; Phanstiel, O.,
IV. J. Org. Chem. 1997, 62, 3285-3290.
(2) Shiba, T.; Akiyama, H.; Umeda, I.; Okada, S.; Wakamiya, T. Bull.
Chem. Soc. Jpn. 1982, 55, 899-903.
(7) (a) Tice, C. M.; Ganem, B. J. Org. Chem. 1983, 48, 5043-5048. (b)
Knapp, S.; Hale, J. J.; Bastos, M.; Molina, A.; Chen, K. Y. J. Org. Chem.
1992, 57, 6239-6256.
(3) Cooper, H. L.; Park, M. J.; Folk, J. E.; Safer, B.; Braverman, R.
Proc. Natl. Acad. Sci. U.S.A. 1983, 80, 1854-1857.
(8) Tice, C. M.; Ganem, B. J. Org. Chem. 1983, 48, 5048-5050.
10.1021/ol016959o CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/04/2001

Scheme 1
Scheme 2a
a Reagents and conditions: (a) 120 psi H2, PdCl2, MeOH,
concentrated HCl, rt, 100%; (b) THF, 2 M NaOH, reflux; then
Cbz2O, rt, 70%.
Herein, we report a concise method for the synthesis of
(+)-hypusine by employing (5R,6S)-4-(benzyloxycarbonyl)-
5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (3)10 as
a starting material. This approach involves a de novo
synthesis of both the L-lysine fragment and the hydroxy-
putrescine moiety and is amenable to the site-specific
incorporation of stable and/or radioisotopes.
The relative and absolute stereochemistry of the newly
created stereogenic center in the major diastereomer of 5
1
was determined as R by H NMR NOE measurements that
revealed a syn-relationship of the protons at C2, C5, and C6
of the oxazine ring. The high degree of asymmetric induction
in the reduction step can be explained by adsorption on the
catalyst surface and subsequent hydrogenation of the double
bond from the sterically less hindered face of the molecule.
Selective protection of primary amine in 5 was achieved
by treatment of 5 with Cbz2O (1 equiv, THF/2 M NaOH)
yielding the desired monoprotected morpholine 6 in 70%
yield (Scheme 2).
Compound 6 is a protected version of hydroxyputrescine
2 and may be suitable for related applications in the
regioselective coupling of this fragment to other amino acids.
The conversion of 6 into (+)-hypusine (1) required N-
alkylation of the morpholine nitrogen in 6 with an electro-
philic L-lysine fragment. The desired L-lysine fragment 7
required for this coupling reaction was easily synthesized
by the glycine enolate alkylation method19 by using the
commercially available antipode of 310 and 1,4-diiodobutane,
as reported previously by our group20 (Scheme 3).
As shown in Scheme 1, Wittig reaction of (triphenylphos-
phoranylidene)acetonitrile11 with the lactone carbonyl group
of 3 (xylene, 210 °C, 2.5 h) generated the adduct 4 in
quantitative yield. This species is reasonably presumed to
arise via tautomerization of the initial olefination product A
to the thermodynamically more stable trisubstituted olefin.
Although a few isolated cases of stabilized Wittig olefinations
of lactones and esters have appeared in the literature, this
condensation is an underutilized reaction in synthetic organic
chemistry.12-18 Wittig reactions of stabilized ylides with the
carbonyl groups of lactones,12 esters,13 thioesters,14 anhy-
drides,15 thioanhydrides,16 amides17 and imides18 have been
reported in the literature, but many of these systems were
intramolecular ring-closure reactions. Attempts to conduct
the reaction at lower temperatures (in toluene or xylene at
reflux) required longer reaction times and incomplete
transformations with poor yields of 4.
Hydrogenation of 4 with PdCl2 (30 mol %, 120 psi of H2,
MeOH, 4 equiv concentrated HCl, rt, 72 h) resulted in the
formation of desired all syn-substituted oxazine 5 in es-
sentially quantitative yield and with >95:5 diastereomeric
Scheme 3a
1
ratio (by H NMR, Scheme 2).
(9) Bergeron, R. J.; Xia, M. X. B.; Phanstiel, O., IV. J. Org. Chem. 1993,
58, 6804-6806.
(10) The requisite diphenyloxazinone and its antipode are commercially
available from Aldrich Chemical Co.: catalog no. 33185-6 (CAS registry
no. 105228-46-4). The antipode: catalog no. 33187-2 (CAS registry no.
100516-54-9).
(11) Trippet, S.; Walker, D. M. J. Chem. Soc. 1959, 3874-3876.
(12) (a) Brennan, J.; Murphy, P. J. Tetrahedron Lett. 1988, 29, 2063-
2066. (b) Lakhrissi, M.; Taillefumier, C.; Chaouch, A.; Didierjean, C.;
Aubry, A.; Chapleur, Y. Tetrahedron Lett. 1998, 39, 6457-6460. (c)
Sabitha, G.; Reddy, M. M.; Srinivas, D.; Yadov, J. S. Tetrahedron Lett.
1999, 40, 165-166.
(13) Begasse, B.; Hercouet, A.; Corre, M. L. Tetrahedron Lett. 1979,
2149-2150.
(14) (a) Ernest, I.; Gosteli, J.; Greengrass, C. W.; Holick, W.; Jackman,
D. E.; Pfaendler, H. R.; Woodward, R. B. J. Am. Chem. Soc. 1978, 100,
8214-8222. (b) Ponsford, R. J.; Roberts, P. M.; Southgate, R. J. Chem.
Soc., Chem. Commun. 1979, 847-848.
(15) (a) Gara, A. P.; Massy-Westropp, R. A.; Reynolds, G. D. Tetrahe-
dron Lett. 1969, 4171-4172. (b) Kayser, M. M.; Hatt, K. L.; Yu, H.;
Hooper, D. L. Can. J. Chem. 1993, 1010-1021.
a Reagents and conditions: (a) 6, N,N-diisopropylethylamine,
xylene, reflux, 78%; (b) 80 psi H2, PdCl2, THF/H2O, 80-85 °C,
98%.
(16) Flitsch, W.; Schwiezer, J.; Strunk, U. Liebigs. Ann. Chem. 1975,
1967-1970.
(17) See ref 12c.
(18) Flitsch, W.; Kappenberg, F. Chem. Ber. 1978, 111, 2396-2400.
4288
Org. Lett., Vol. 3, No. 26, 2001

Treatment of 6 with 7 in the presence of N,N-diisopro-
pylethylamine in xylene at reflux (2.5 h) generated the
desired coupling product 8 in 78% yield. Complete hydro-
genolysis of 8 with PdCl2 (6 equiv, THF/H2O, 80 psi of H2,
80-85 °C, 6 h) resulted in the formation of (+)-hypusine
(1) in essentially quantitative yield as its dihydrochloride salt
([R]25D ) +7.3 (c 0.52, 6M HCl); lit.9 [R]23D ) +7.6 (c 0.5,
6 M HCl)). The spectral data for this substance matched that
reported in the literature for hypusine.2,7-9
mercially available,10 the present method can provide access
to all four stereoisomers of hypusine. Current efforts are
focused on extending the stabilized Wittig homologation on
the oxazinones to other amino acid-derived natural products
and alkaloids.
Acknowledgment. This work was supported by National
Science Foundation (grant CHE 9731947).
In summary, we have demonstrated a concise, asymmetric,
and stereocontrolled method for the synthesis of (+)-
hypusine. Since both antipodes of oxazinone 3 are com-
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) For review see: Williams, R. M. Aldrichimica Acta 1992, 25, 11-
25.
(20) Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113, 9276-
9286.
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