groups have reported their efforts to synthesize the tricyclic
core of these natural products.2-12 But the total synthesis of
these natural products has not been accomplished yet. Herein
we wish to report the first total synthesis of 1.
Our retrosynthetic analysis for 1 is shown in Scheme 1.
Obviously, this compound could be synthesized with tricyclic
â-amino ester 515,16 afforded â-amino ester 6, which was
coupled with 1,4-diiodobenzene catalyzed by CuI at 100 °C
in DMF to provide N-aryl â-amino acid. This acid was
esterified with SOCl2/MeOH to afford 7 in 53% overall yield.
It was notable that this coupling reaction worked at lower
temperature than that required by a typical Ullmann aryl
amination reaction , which implied that, similar to R-amino
acids, the structure of â-amino acid also had an accelerating
effect for Ullmann type aryl amination reaction.17 Next, the
N-aryl â-amino ester 7 was converted into 4-oxoquinoline 8
in four steps: (1) protection of the amino and hydroxy groups
of 7 with acetic anhydride at 100 °C; (2) hydrolysis of the
ester and acetate moieties with aqueous NaOH in methanol;
(3) reprotection of free hydroxy group with acetic anhydride;
(4) conversion of the acid to the acyl chloride and subsequent
intramolecular acylation mediated by AlCl3. Finally, a Pd-
catalyzed carbonylation reaction of aryl iodide 8 followed
by protecting group switch gave 4.
Scheme 1
The alkylation of 4 was carried out at -40 °C using
TfOCH2CH2Br as a coupling agent (Scheme 3). The coupling
product was unstable and directly converted into the azide.
Treatment of this azide with Ph3P/H2O provided the cyclic
imine 9 ([R]20D ) -68.9 (c ) 0.5 in CHCl3)). Reduction of
the imine 9 with NaBH4 in methanol at -40 °C followed
by protection of two amino groups with trifluoroacetic
anhydride afforded the amide 10 and its 4-epimer in a ratio
of 2.8/1. Their stereochemistry was established by NOESY
experiment and further confirmed by X-ray structure analysis
of tetracyclic compound 11, which was obtained as a side
product by deprotection of 10 with TBAF/HOAc and
subsequent cyclization under the assistance of MsCl/Et3N.
Without affecting the N-trifluoroacetyl group, cleavage of
the silyl ether in 10 was achieved under catalysis of TFA in
THF. The alcohol generated was then converted into azide
12 through mesylate. Reduction of the azide moiety of 12
with triphenylphosphine and water followed by deprotection
with HCl/MeOH gave tricyclic triamine 3 as a hydrochloride
salt.
triamine 3 as a key intermediate because the guanylation of
an amine is the most popular method for introducing the
guanidine moiety.13 We envisaged that the pyrrolidine ring
of 3 could be constructed by alkylation and subsequent
reductive amination14 of 2-substituted 4-oxoquinoline 4. The
synthesis of 4 is outlined in Scheme 2, which relied on a
Scheme 2a
The introduction of guanidine moiety into 3 was a
challenging task in this total synthesis because there are only
a few reports on the formation of dialkyl guanidine by
guanylation of a sterically hindered secondary amine.13a-c
Initially, we tried the known methods13a-c to guanylate the
(13) (a) Dodd, D. S.; Wallace, O. B. Tetrahedron Lett. 1998, 39, 5701.
(b) Kearney, P. C.; Fernandez, M.; Flygare, J. A. Tetrahedron Lett. 1998,
39, 2663. (c) Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997, 53,
5291. (d) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J. Org.
Chem. 1998, 63, 3804. (e) Barvian, M. R.; Showalter, H. D. H.; Doherty,
A. M. Tetrahedron Lett. 1997, 38, 6799. (f) Yong, Y. F.; Kowalski, J. A.;
Lipton, M. A. J. Org. Chem. 1997, 62, 1540. (g) Kent, D. R.; Cody, W. L.;
Doherty, A. M. Tetrahedron Lett. 1996, 37, 8711. (h) Ramadas, K.;
Srinivasan, N. Tetrahedron Lett. 1995, 36, 2841. (i) Drake, B.; Patek, M.;
Lebl, M. Synthesis 1994, 579. (j) Burgess, K.; Liu, D.; Ho, K.; Ke, C. J.
Org. Chem. 1994, 59, 2179.
a Reagents and conditions: (i) Pd/C, H2, HCl, MeOH; then Pd/
C, H2, MeOH; (ii) 1,4-diiodobenzene, CuI, K2CO3, DMF, H2O,
100 °C; (iii) SOCl2/MeOH; (iv) Ac2O, 100 °C; (v) aqueous NaOH,
MeOH; (vi) Ac2O, 80 °C; (vii) oxalyl chloride, CH2Cl2, then AlCl3;
(viii) Pd(OAc)2, dppp, CO, MeOH, Et3N, DMF, 80 °C; (ix) HCl,
MeOH; (x) TBDMSCl, DMAP, Et3N, CH2Cl2.
(14) (a) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-
H.; Liao, F.-T.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130. (b)
Hanessian, S.; Raghavan, S. Bioorg. Med. Chem. Lett. 1994, 4.
(15) Ma, D.; Zhang, J. Tetrahedron Lett. 1998, 39, 9067.
(16) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1141.
strategy to build the desired N-aryl â-amino acid skeleton
by a cuprous ion catalyzed coupling reaction of aryl iodide
with â-amino ester. First, deprotection of N,N-disubstituted
(17) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459. The detailed studies for the CuI-catalyzed coupling
reaction of aryl halides with â-amino esters will be published elsewhere.
(11) Nyerges, M.; Fejes, I.; Toke, L. Tetrahedron Lett. 2000, 41, 7951.
(12) Snider, B. B.; O’Hare, S. M. Tetrahedron Lett. 2001, 42, 2455.
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Org. Lett., Vol. 3, No. 14, 2001