Stereocontrolled total synthesis of (-)-ephedradine a (orantine)

Article abstract of DOI:10.1021/ja036011k

The stereocontrolled total synthesis of (-)-ephedradine A has been accomplished. The synthesis features an asymmetric C-H insertion reaction, an intramolecular ester-amide exchange reaction, and a Sharpless asymmetric aminohydroxylation reaction. Construction of the complex macrocyclic ring was performed by Ns-strategy and an intramolecular aza-Wittig reaction. Copyright

Full text of DOI:10.1021/ja036011k

Published on Web 06/14/2003
Stereocontrolled Total Synthesis of (-)-Ephedradine A (Orantine)
Wataru Kurosawa, Toshiyuki Kan, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received May 7, 2003; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Scheme 1 a
(-)-Ephedradine A (orantine, 1) is a complex macrocyclic
spermine alkaloid isolated by Hikino and co-workers in 1979 as
one of the hypotensive components of the Chinese traditional drug
“mao-kon.”1,2 While synthesis of racemic O-methylated orantine
(2) was achieved by Wasserman and co-workers in 1985,3 total
synthesis of 1 has not been reported to date. Clearly, construction
of the two macrocyclic rings in the presence of a labile dihydroben-
zofuran moiety constitutes the major challenge in the total synthesis
of 1. Recently, we have developed a highly efficient methodology
for construction of medium- and large-sized cyclic amines via
2-nitrobenzenesulfonamides (Ns-strategy).4,5 We envisioned this
strategy being applied to the construction of the macrocyclic ring
of 1. Herein, we report an efficient total synthesis of (-)-
ephedradine A (1) by the stereocontrolled synthesis of optically
active intermediate 3 and subsequent construction of the macrocyclic
polyamine ring by the Ns-strategy.
a Reagents and conditions: (a) 5, PPh3, DEAD, toluene (80%); (b)
AcNHC6H4SO2N3, DBU, CH3CN; (c) Rh2(S-DOSP)4 (0.3 mol %), CH2Cl2
(63% in two steps); (d) Ba(OH)2‚8H2O, THF/MeOH/H2O (90%).
Scheme 2 a
Recently, we have developed a novel methodology for the
construction of optically active dihydrobenzofuran rings by an
intramolecular C-H insertion reaction.6 According to the protocol,
the cyclization precursor 6 was prepared by condensation of
carboxylic acid 4 with the lactamide-type chiral auxiliary 5 under
Mitsunobu conditions7 and a subsequent diazo transfer reaction
(Scheme 1). Upon treatment of 6 with 0.3 mol % of the Davies
catalyst,8 the C-H insertion reaction proceeded smoothly to afford
exclusively the trans-dihydrobenzofuran 7 in 63% yield (two steps)
and high diastereoselective manner (13:1). Removal of the chiral
auxiliary by hydrolysis and subsequent recrystallization gave the
optically pure carboxylic acid 8.
Direct condensation of 8 with secondary amine derivatives of 9
was unsuccessful due to decomposition of the dihydrobenzofuran
ring brought about by activation of the carboxylic acid 8. After
numerous efforts to construct the amide bond, an intramolecular
ester-amide exchange reaction of 10 was found to be suitable for
the synthesis of 11. Upon treatment of 8 and the alcohol 9 with
DEAD and PPh3, the condensation reaction proceeded smoothly
to provide 10 (Scheme 2). Removal of the Ns group and subsequent
treatment of the secondary amine 10 with dimethylaluminum
chloride9,10 in refluxing CH2Cl2 gave the amide 11 in 67% yield.
a Reagents and conditions: (a) 9, PPh3, DEAD, toluene (96%); (b) PhSH,
K2CO3, DMF/CH3CN, 50 °C (88%); (c) Me2AlCl, CH2Cl2, reflux (67%);
(d) Ac2O, pyr (88%); (e) methyl acrylate, Pd(OAc)2 (6 mol %), P(o-tol)3
(18 mol %), Et3N, DMF, 100 °C (84%); (f) CbzNClNa, K2OsO2(OH)4 (6
mol %), (DHQD)2PHAL (8 mol %), n-PrOH/H2O (66%); (g) PPh3, CCl4,
toluene, 100 °C (87%); (h) Pd/C (20 mol %), HCO2NH4, MeOH, 60 °C;
(i) BnOH, PPh3, DEAD, toluene, 60 °C (61% in two steps); (j) NsCl,
Na2CO3, CH2Cl2/H2O (72%).
Acetylation of the alcohol 11 followed by a conventional Heck
reaction11 with methyl acrylate furnished the cinnamate derivative
12.
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J. AM. CHEM. SOC. 2003, 125, 8112-8113
10.1021/ja036011k CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
With the desired macrocyclic polyamine in hand, we next focused
on the construction of the 13-membered macrolactam ring. The
cyclization precursor 19 bearing an activated ester was prepared
from 18 in a five-step sequence involving deprotection of the acetyl
group, mesylation of the alcohol, displacement of the mesylate with
NaN3, basic hydrolysis of the methyl ester, and condensation of
the resultant carboxylic acid with pentafluorophenol. While genera-
tion of the amine moiety from the azide 19 under hydrogenation
conditions resulted in exclusive dimerization, treatment with PPh3
in refluxing toluene under high-dilution conditions (7.0 mM)
successfully afforded the 13-membered iminoether 21 via the
Staudinger14 and the intramolecular aza-Wittig reactions.15,16 Sub-
sequent hydrolysis of 21 by refluxing in CH3CN-H2O afforded
the desired 13-membered macrolactam 22 in 73% yield (two steps).
Removal of the Ns group and simultaneous cleavage of the Cbz
group and benzyl ether with BCl3 yielded (-)-ephedradine A (1),
the spectral data of which (1H NMR, 13C NMR, IR, and HRMS)
were in full agreement with those of the natural product.1
In conclusion, a stereocontrolled total synthesis of (-)-ephedra-
dine A (1) has been accomplished by a Rh-catalyzed C-H insertion
reaction and a Sharpless asymmetric aminohydroxylation reaction.
Furthermore, our synthesis features construction of all the secondary
amines using the Ns-strategy, including macrocyclization and
formation of the two amide bonds by the intramolecular ester-
amide exchange reaction and the aza-Wittig reaction.
Acknowledgment. We thank Professor Yoshiteru Oshima
(Tohoku University) for providing spectral data of the natural
product. This work was financially supported by CREST, JST, and
a Grant-in-Aid from the Ministry of Education, Science, Sports,
Culture and Technology, Japan.
Supporting Information Available: Experimental details and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) 15, PPh3, DEAD, toluene, 60 °C (95%);
(b) PhSH, KOH, CH3CN, 60 °C (93%); (c) CbzCl, NaHCO3, CH2Cl2/H2O
(91%); (d) CSA, MeOH (94%); (e) NsNH2, DEAD, PPh3, toluene/THF
(quant.); (f) aqueous HF, CH3CN (84%); (g) PPh3, DEAD, toluene (77%);
(h) K2CO3, MeOH/THF (96%); (i) MsCl, Et3N, CH2Cl2, 0 °C; (j) NaN3,
DMF, 60 °C (82% in two steps); (k) LiOH, MeOH/THF/H2O (97%); (l)
pentafluorophenol, WSCD‚HCl, CH2Cl2 (93%); (m) PPh3, toluene, reflux;
(n) CH3CN/H2O, reflux (73% in two steps); (o) PhSH, KOH, CH3CN, 50
°C (75%); (p) BCl3, CH2Cl2, -78 to 0 °C (73%).
References
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in 12 was achieved by the Sharpless asymmetric aminohydroxy-
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