Preparation of (3S)-N,N-1,7-bis-tert-butoxycarbonyl-3-hydroxyspermidine in high enantiomeric purity

Full text of DOI:10.1021/jo991061m

J . Org. Chem. 1999, 64, 8741-8742
8741
Sch em e 1
P r ep a r a tion of (3S)-N,N-1,7-Bis-ter t-
bu toxyca r bon yl-3-h yd r oxysp er m id in e in
High En a n tiom er ic P u r ity
D. Scott Coffey, Andrew I. McDonald, and
Larry E. Overman*
Department of Chemistry, 516 Rowland Hall, University of
California, Irvine, California 92697-2025
Received J uly 1, 1999
Although polyamines are structural features of many
natural products,1 3-hydroxyspermidine (1) is rare, being
found only in the crambescidin family of guanidinium
alkaloids.2 During our recent total syntheses of 13,14,-
15-isocrambescidin 800 (3)3 and crambescidin 800 (4),4
we required a practical way to prepare suitably protected
3-hydroxyspermidines in high enantiopurity. Ponasik and
Ganem had previously reported the only synthesis of the
3-hydroxyspermidine unit, albeit in racemic form.5 Herein
we describe a convenient, high-yielding procedure for
preparing (3S)-N,N-1,7-bis-tert-butoxycarbonyl-3-hydrox-
yspermidine (2).
ously used this precursor to fashion the diaminobutanol
unit of (+)-hypusine.6 Reaction of [N-(tert-butoxycarbo-
nyl)-3-aminopropyl]benzylamine (6)7 and 5 (97% ee) at
room temperature for 24 h and then heating the resulting
crude chlorohydrin at reflux in acetonitrile in the pres-
ence of KCN and 18-crown-66a provided â-hydroxy nitrile
7 in 85% yield. However, 19F NMR analysis of the (R)-
R-methoxy-R-(trifluoromethyl)phenylacetate [(R)-MTPA]8
derivative revealed that 7 had been generated in only
50-60% ee. To confirm that racemization had occurred
in the second step, chlorohydrin 8 was isolated and shown
to have high enantiopurity (>95% ee).8 Thus, competitive
formation of achiral azetidinium salt 9 in refluxing
acetonitrile during the second step was undoubtedly the
cause of the partial epimerization observed in forming
7.6c,910
In their synthesis of hypusine, Bergeron and co-
workers solved the racemization problem by preparing
the N-benzyloxycarbonyl derivative of the chlorohydrin
intermediate prior to reaction with cyanide.6c An alter-
nate solution would be to avoid formation of azetidinium
salt 9 during the conversion of 8 f 7. We reasoned that
simply switching to a nonpolar solvent for the cyanide
displacement step would accomplish this goal. To this
end, a solution of [N-(tert-butoxycarbonyl)-3-aminopropyl]-
benzylamine (6) and (R)-epichlorohydrin (5) was main-
tained at room temperature for 24 h, and the resulting
crude chlorohydrin was heated at 70 °C in toluene with
a slight excess of tetrabutylammonium cyanide for 5 h
to give 7 in 80% yield (Scheme 2). Gratifyingly, the
enantiomeric purity of 7 formed in this way was ∼97%
ee.8 Selective reduction of the nitrile group of 7 with
(R)-Epichlorohydrin (5) is an obvious starting material
for preparing the (S)-1,4-diamino-2-butanol fragment of
2 (Scheme 1), since Bergeron and co-workers had previ-
(6) (a) Bergeron, R. J .; Xia, M. X. B.; Phanstiel IV, O. J . Org. Chem.
1993, 58, 6804-6806. (b) Bergeron, R. J .; Ludin, C.; Mu¨ller, R.; Smith,
R. E., Phanstiel IV, O. J . Org. Chem. 1997, 62, 3285-3290. (c)
Bergeron, R. J .; Weimar, W. R.; Mu¨ller, R.; Zimmerman, C. O.;
McCosar, B. H.; Yao, H.; Smith, R. E. J . Med. Chem. 1998, 41, 3888-
3900.
(1) (a) Scha¨fer, A.; Benz, H.; Fiedler, W.; Guggisberg, A.; Bienz, S.;
Hesse, M. Alkaloids (Academic Press) 1994, 45, 1-125. (b) Guggisberg,
A.; Hesse, M. Alkaloids (Academic Press) 1983, 22, 85-188. (c) Ganem,
B. Acc. Chem. Res. 1982, 15, 290-298.
(2) (a) J ares-Erijman, E. A.; Sakai, R.; Rinehart, K. L. J . Org. Chem.
1991, 56, 5712-5715. (b) J ares-Erijman, E. A.; Ingrum, A. L.; Carney,
J . R.; Rinehart, K. L.; Sakai, R. J . Org. Chem. 1993, 58, 4805-4808.
(c) Tavares, R.; Daloze, D.; Braekman, J . C.; Hajdu, E.; Muricy, G.;
Van Soest, R. W. M. Biochem. Syst. Ecol. 1994, 22, 645-646. (d)
Berlinck, R. G. S.; Braekman, J . C.; Daloze, D.; Bruno, I.; Riccio, R.;
Ferri, S.; Spampinato, S.; Speroni, E. J . Nat. Prod. 1993, 56, 1007-
1015.
(3) Coffey, D. S.; McDonald, A. I.; Overman, L. E.; Stappenbeck, F.
J . Am. Chem. Soc. 1999, 121, 6944-6945.
(4) Coffey, D. S.; McDonald, A. I.; Overman, L. E.; Rabinowitz, M.
H.; Renhowe, P. A. To be submitted for publication.
(5) Ponasik, J . A.; Ganem, B. Tetrahedron Lett. 1995, 36, 9109-
9112.
(7) Bergeron, R. J .; Garlich, J . R.; Stolowich, N. J . J . Org. Chem.
1984, 49, 2997-3001.
(8) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
519. (b) MTPA esters were prepared by the method of Ward: Ward,
D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165-7166.
(9) The intermediacy of azetidinium salts in reactions of 1-chloro-
3-dialkylamino-2-propanol derivatives with nucleophiles, including
cyanide, is well-known.10
(10) (a) Gaertner, V. R. J . Org. Chem. 1968, 33, 523-530. (b)
Gaertner, V. R. Tetrahedron Lett. 1967, 343-347. (c) Beaulieu, P. L.;
Wernic, D. J . Org. Chem. 1996, 61, 3635-3645. (c) For a review of
azetidines and azetidinium cations, see: Cromwell, N. H.; Phillips, B.
Chem. Rev. 1979, 79, 331-358.
10.1021/jo991061m CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/16/1999

8742 J . Org. Chem., Vol. 64, No. 23, 1999
Notes
155.9, 138.0, 128.8, 128.4, 127.3, 117.3, 79.0, 64.0, 59.0, 58.9,
Sch em e 2
51.7, 38.3, 28.3, 27.1, 23.2 ppm; IR (film) 3371, 2252, 1694 cm-1
;
[R]25D +41.7, [R]25577 +43.4, [R]25546 +49.5, [R]25435 +85.0, [R]25
405
+102 (c 1.6, CHCl3). Anal. Calcd for C19H29O3N3: C, 65.68; H,
8.41; N, 12.09. Found: C, 65.57; H, 8.49; N, 12.03.
Following the general procedure of Ward,8b 7 was treated with
(S)-R-methoxy-R-(trifluoromethyl)phenylacetic acid chloride [(S)-
MTPACl] to give the corresponding (R)-MTPA ester. Analysis
by 19F NMR showed a ratio of approximately 74:1 of 7-(R)-MTPA
and ent-7-(R)-MTPA13 corresponding to 97% ee. Diagnostic 19F
NMR (400 MHz, CDCl3) signals:14 7-(R)-MTPA, δ -71.4; ent-7-
(R)-MTPA, δ -71.6.
(2S)-1-[N-Ben zyl-N-[3-(ter t-bu toxycar bon yl)am in opr opyl]-
a m in o]-4-(ter t-(bu toxyca r bon yl)a m in obu ta n -2-ol (10). A
solution of 7 (400 mg, 1.15 mmol) and Et2O (5 mL) was added
dropwise to a stirring suspension of LiAlH4 (180 mg, 4.74 mmol)
and Et2O (15 mL) at 0 °C. After 1 h, H2O (180 µL), 3 N NaOH
(180 µL), and H2O (540 µL) were added sequentially to the
reaction mixture. The resulting mixture was filtered through a
pad of Celite and concentrated, and the resulting colorless oil
was used without further purification.
lithium aluminum hydride at 0 °C, followed by treatment
of the resulting primary amine with di-tert-butyl dicar-
bonate (BOC2O), provided 10 in 91% yield. Standard
hydrogenolysis of the benzyl group of 10 then delivered
2 in nearly quantitative yield.
In summary, a convenient procedure for preparing bis-
BOC derivative 2 of (S)-3-hydroxyspermidine in high
enantiopurity from commercially available (R)-epichlo-
rohydrin (5) has been developed. This first enantiospecific
synthesis of the (S)-3-hydroxyspermidine unit proceeds
in 72% yield from 5 by way of two isolated and purified
intermediates. Partial racemization in generating â-hy-
droxy nitrile intermediate 7 was prevented by carrying
out the displacement reaction of 1-chloro-3-dialkylamino-
2-propanol 8 with cyanide in toluene. Since epichlorohy-
drin is a common precursor of diverse 1-dialkylamino-2-
propanol derivatives, performing the nucleophilic displace-
ment of 1-chloro-3-dialkylamino-2-propanol intermedi-
ates in a nonpolar solvent should be a useful tactic for
enantiospecific synthesis of other epichlorohydrin-derived
amino alcohols.
A mixture of this crude primary amine, BOC2O (310 mg, 1.4
mmol), CH2Cl2 (5 mL), and saturated aqueous NaHCO3 (5 mL)
was stirred at room temperature for 1 h. The reaction mixture
was then poured into Et2O (20 mL), and the layers were
separated. The organic layer was washed with brine (5 mL),
dried (MgSO4), and concentrated. The residual oil was purified
by flash chromatography (1:1 hexanes-EtOAc) to provide 470
mg (91%) of 10 as a colorless oil: 1H NMR (500 MHz, CDCl3) δ
7.20-7.29 (m, 5 H), 5.15 (s, 1 H), 4.88 (s, 1 H), 3.66-3.74 (m, 2
H), 3.58 (s, 1 H), 3.30-3.39 (m, 2 H), 3.06-3.15 (m, 3 H), 2.53-
2.59 (m, 1 H), 2.35-2.42 (m, 3 H), 1.52-1.62 (m, 4 H), 1.34 (s,
18 H); 13C NMR (75 MHz, CDCl3) 156.2, 155.9, 138.4, 128.9,
128.3, 127.2, 78.8, 66.2, 60.2, 58.8, 51.4, 38.5, 37.9, 34.4, 28.3,
27.1 ppm; IR (film) 3354, 1694 cm-1; [R]25D +42.3, [R]25577 +44.3,
[R]25
+49.7, [R]25
+88.2 (c 3.5, CHCl3). Anal. Calcd for
546
435
C
24H41O5N3: C, 63.83; H, 9.15; N, 9.30. Found: C, 63.87; H, 9.22;
N, 9.22.
(2S)-1-[N-[3-(ter t-bu toxyca r bon yl)a m in op r op yl]a m in o]-
4-(ter t-bu toxyca r bon yl)a m in obu ta n -2-ol (2). A mixture of 10
(120 mg, 0.27 mmol), 10% Pd/C (20 mg), and MeOH (5 mL) was
maintained at room temperature under 1 atm of H2 for 5 h. The
mixture was then filtered through a plug of Celite, the plug was
washed with MeOH (20 mL), and the eluent was concentrated
to yield 96 mg (99%) of 2 as a colorless oil that was sufficiently
pure to be employed directly in our syntheses of 3 and 4.3,4 For
characterization purposes, a sample of 2 was purified by flash
chromatography (9:1 CHCl3-MeOH) to give a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 5.16 (s, 1 H), 5.06 (s, 1 H), 3.69-3.71
(m, 1 H), 3.34-3.36 (m, 1 H), 3.10-3.20 (m, 3 H), 2.96 (br s, 2
H), 2.59-2.69 (m, 3 H), 2.47-2.51 (m, 1 H), 1.53-1.64 (m, 3 H),
1.39-1.50 (m, 19 H); 13C NMR (125 MHz, CDCl3) 156.6, 156.2,
79.1, 79.0, 67.4, 55.2, 46.8, 38.5, 37.4, 35.0, 29.9, 28.3 ppm; IR
(film) 3344, 1694 cm-1; HRMS (FAB) (MH) m/z 362.2653
Exp er im en ta l Section
Gen er a l Meth id s. (R)- and (S)-epichlorohydrin (97% ee) were
purchased from Aldrich Chemical Co. Dry THF, Et2O, and CH2-
Cl2 were filtered through
a
column charged with Al2O3.11
Triethylamine (Et3N), pyridine, diisopropylethylamine, diiso-
propylamine, and acetonitrile were distilled from CaH2 at
atmospheric pressure. Silica gel (0.040-0.063) by Merck was
used for flash chromatography. Microanalyses were performed
by Atlantic Microlabs, Atlanta, GA. Other general experimental
details have been described.12
(3S)-4-N-Ben zyl-N-[3-(ter t-bu toxyca r bon yl)a m in op r op y-
l]a m in e-3-h yd r oxybu tyr on itr ile (7). (R)-Epichlorohydrin (5,
310 µL, 4.0 mmol) and [N-(tert-butoxycarbonyl)-3-aminopropyl]-
benzylamine (6, 1.00 g, 3.78 mmol) were mixed and maintained
at room temperature for 24 h. Tetra-n-butylammonium cyanide
(1.22 g, 4.54 mmol) and toluene (19 mL) were then added, and
the resulting solution was heated at 70 °C for 5 h. The solution
was allowed to cool to room temperature and then partitioned
between EtOAc (100 mL) and brine (40 mL). The organic phase
was dried (MgSO4), filtered and concentrated. The resulting
crude oil was purified by flash chromatography (7:3 hexanes-
EtOAc f 6:4 hexanes-EtOAc) to give 1.05 g (80%) of nitrile 7
as a clear oil: 1H NMR (500 MHz, CDCl3) δ 7.23-7.32 (m, 5 H),
4.81 (s, 1H), 3.84-3.89 (m, 1 H), 3.69 (d, J ) 13.4 Hz, 1 H), 3.49
(d, J ) 13.4 Hz, 1 H), 3.09-3.11 (m, 2 H) 2.38-2.60 (m, 7 H),
1.61-1.67 (m, 2 H), 1.41 (s, 9 H); 13C NMR (125 MHz, CDCl3)
(362.2655 calcd for C17H36N3O5); [R]25 +9.8, [R]25
+10.2,
D
577
[R]25 +11.4, [R]25 +18.2, [R]25 +21.1 (c 2.0, CHCl3).
546
435
405
Ack n ow led gm en t. This research was supported by
a grant from NIH NHLBIS (HL-25854), through an NIH
Postdoctoral Fellowship to D.S.C. (CA-75616) and a
graduate fellowship to A.I.M. from Pfizer. NMR and
mass spectra were determined at UCI using instru-
ments acquired with the assistance of NSF and NIH
shared instrumentation grants.
J O991061M
(11) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518-1520.
(12) Metais, E.; Overman, L. E.; Rodriguez, M. I.; Stearns, B. A. J .
Org. Chem. 1997, 62, 9210-9216.
(13) Prepared from 6 and (S)-epichlorohydrin.
(14) 19
F
NMR spectra were calibrated using fluorobenzene
(δ -113.1) as an internal standard.