Regiochemical control by remote substituents. A direct synthesis of tetrangulol

Article abstract of DOI:10.1055/s-2001-12331

Diels-Alder reactions of quinones 4 and 10 exhibit remarkable regioselectivity. This selectivity plus a novel phosphazine-mediated cyclization has led to a six-step synthesis of tretrangulol.

Full text of DOI:10.1055/s-2001-12331

LETTER
521
Regiochemical Control by Remote Substituents. A Direct Synthesis of
Tetrangulol
George A. Kraus,a* Ning Zhang,a Alex Melekhov,a Jan H. Jensenb*
a Department of Chemistry, Iowa State University, Ames, IA 50011
Fax 515-294-0105; E-mail: gakraus@iastate.edu
b Department of Chemistry, The University of Iowa, Iowa City, IA 52242
Fax 319-335-1270; E-mail: jan-jensen@uiowa.edu
Received 14 February 2001
quinone such as 4 would, either by a steric or electronic
effect, attenuate the directing effect of the carbonyl group
at C-4. In order to test this hypothesis, quinone 4 was syn-
thesized using an intramolecular SnCl4-mediated cycliza-
tion of a hydroxy benzoquinone.5 The Diels-Alder adduct
was produced by the addition of two equivalents of 1-tri-
methylsilyloxybutadiene (5) to quinone 4 at -78 °C fol-
lowed by warming to ambient temperature. The solvent
was removed and the residue was oxidized using the Jones
reagent.6 The product 6 was purified by column chroma-
tography. No other quinone-containing products were de-
tected. The regiochemistry of 6 was confirmed by a X-ray
structure determination.7
Abstract: Diels-Alder reactions of quinones 4 and 10 exhibit re-
markable regioselectivity. This selectivity plus a novel phospha-
zine-mediated cyclization has led to a six-step synthesis of tretran-
gulol.
Key words: Diels-Alder reaction, regioselective cycloaddition,
phosphazine, quinone
Recently, natural products researchers determined the
structures of several tetracyclic and hexacyclic aromatic
compounds which are angularly fused. Some of these
compounds such as tetrangulol (1), 6-hydroxytetrangulol
(2), and benaphthamycin (3) exhibit significant biological
activity.1 Recently, 6-hydroxytetrangulol was reported to
be a CPP32 protease inducer.2
OMe
OMe
MeO
O
OMe
MeO
OMe
O
5
O
Me
OH
4
OTMS
HO
OH
HO
CH3
O
O
Jones
oxidation
O
HO
O
O
4
6
Scheme 1
OMe OH
HO
O
R
3
1: R = H
2: R = OH
In view of the successful production of 6, we developed a
route to 1 starting with quinone 7. Treatment of quinone 7
with commercially available 3,5-dimethylanisole and
stannic chloride8 followed by reductive methylation pro-
vided a separable 4:1 mixture of biphenyls 8 and 9 in 35%
yield from 7.
Figure 1
Thomson has recorded a total synthesis of 1; and Krohn
and Snieckus have reported innovative chemistry related
to the synthesis of angularly fused ring systems.3 These
compounds present significant challenges for the control
of regiochemistry on carbons that are distant from one an-
other. This challenge is similar to that encountered in lin-
early fused anthracyclines.4 However, the presence of the
angular fusion might confer opportunities for selectivity
not available in linear systems. In our approach, the angu-
larly fused ring system is regioselectively assembled by a
strategy that takes advantage of the proximity of function-
al groups enforced by the angular fusion. This permits a
strategy that is direct and significantly different from the
previously reported approaches to these compounds.
MeO
1.
Me
MeO
OMe
Me
+
Me
OMe
OMe
O
O
Me
Me
CHO
Me
CHO
2. K2CO3
MeI
CHO
OMe
OMe
9
8
4:1
7
Scheme 2
Cyclization of 8 was not possible using bases such as lith-
ium diisopropylamide and potassium tert-butoxide.9,10
Phenanthrene 10 was eventually prepared in 62% yield
using P4-t-Bu, a novel phosphazine base.11 AgO oxidation
The key question in our approach to this system was
whether the substituent at C-5 of a 1,4-phenanthrene-
Synlett 2001 No. 4, 521–522 ISSN 0936-5214 © Thieme Stuttgart · New York

522
G. A. Kraus et al.
LETTER
then afforded phenanthrenequinone 11 in 55% yield. The
reaction of 11 with 5 provided an adduct that was treated
with Jones reagent to produce O-methyl tetrangulol 12 in
78% yield. The structure of this compound was confirmed
by X-ray spectroscopy. Demethylation using trimethyl-
silyl iodide afforded 112 in 81% yield.
References and Notes
(1) Rohr, J.; Thiericke, R. Natural Product Reports 1992, 9, 103.
Isolation of tetrangulol: Kunstmann, M. P.; Mitscher, L. A. J.
Org. Chem. 1966, 31, 2920.
(2) Yamashita, N.; Harada, T.; Shin-Ya, K.; Seto, H. J. Antibiot.
1998, 51, 79.
(3) Brown, P. M.; Thomson, R. H. J. Chem. Soc. Perkin 1 1976,
997. Krohn, K.; Khanbabaee, K. Liebigs Ann. Chem. 1994,
1109. Katsuura, K.; Snieckus, V. Can. J. Chem. 1987, 65, 124.
Krohn, K.; Loock, U.; Paavilainen, K.; Hausen, B. M.;
Schmalle, H. W.; Kiesele, H. ARKIVOC 2000, 1, 954.
(4) Krohn, K.; Tetrahedron 1990, 46, 291.
MeO
OMe
Me
MeO
O
Me
tBuN=P---N=P(NMe2)3
AgO
3
8
(5) Kraus, G. A.; Melekhov, A. J. Org. Chem 1999, 64, 1720.
(6) The Diels-Alder/Jones oxidation sequence had been
employed in our regioselective synthesis of frenolicin B:
Kraus, G. A.; Jun, L.; Gordon, M.; Jensen, J. J. Am. Chem. Soc
1993, 115, 5859. Kraus, G. A.; Li, J.; Gordon, M.; Jensen, J.
H. J. Org. Chem. 1995, 60, 1154.
OMe
O
10
11
Scheme 3
(7) Guzei, I. A.; Melekhov, A.; Kraus, G. A. Acta Cryst. 1999,
C55, 620.
(8) Kuser, P.; Inderbitzin, M.; Brauchli, J.; Eugster, C. H. Helv.
Chimica Acta 1971, 54, 980.
(9) Base/aryl ester Magnus, P.; Eisenbeis, S. A.; Magnus, N. A.
J. Chem. Soc. Chem. Comm. 1994, 1545. See also: Brandao,
M. A. F.; Oliveira, A. B; Snieckus, V. Tetrahedron Lett. 1993,
34, 2437.
(10) Light/t-BuOK: deKoning, C. B.; Michael, J. P.; Rousseau, A.
L. Tetrahedron Lett. 1998, 39, 8725.
MeO
O
Me
HO
CH3
O
O
OTMS
TMSI
(5)
Jones
1
oxidation
O
11
HO
12
Scheme 4
(11) Kraus, G. A.; Zhang, N.; Verkade, J. G.; Nagarajan, M.;
Kisanga, P. B. Org. Lett. 2000, 2, 2409.
(12) Matsumoto, T.; Sohma, T.; Yamaguchi, H.; Kurata, S.;
Suzuki, K. Tetrahedron 1995, 51, 7347.
The reactions of 4 and 11 demonstrate that substituents re-
mote from the atoms undergoing cycloaddition can exert
a profound effect on the regiochemical outcome of the re-
action. This strategy should be applicable to many natural
products bearing angularly-fused ring systems. The mech-
anistic rationale for this remarkable selectivity is also un-
der investigation.
(13) Spectra for tetrangulol:
1H NMR (CDCl3): 12.28 (s, 1H), 11.28 (s, 1H), 8.36-8.33 (d,
1H, J = 8.4 Hz), 8.18-8.15 (d, 1H, J = 8.4 Hz), 7.89-7.86 (d,
1H, J = 7.6 Hz), 7.73-7.68 (t, 1H, J = 8.0 Hz), 7.36-7.33 (d,
1H, J = 8.4 Hz), 7.28 (s, 1H), 7.17 (s, 1H), 2.51 (s, 3H). 13
C
NMR (CDCl3): 189.9, 188.1, 161.8, 155.4, 142.2, 139.3,
137.9, 137.1, 135.0, 135.0, 132.6, 125.0, 122.1, 121.51, 121.5,
120.4, 120.3, 114.8, 21.5. IR (KBr): 1637, 1618 cm-1. MS
(CI): m/z = 305 (M+1). HRMS: found: 304.0741 calcd.
304.0736.
Acknowledgement
GK thanks the Environmental Protection Agency and the Iowa State
University Center for Advanced Technology Development for par-
tial support of this research. The calculations by JHJ were perfor-
med on workstations provided by the University of Iowa
Biosciences Initiative Pilot Grant Program.
Article Identifier:
1437-2096,E;2001,0,04,0521,0522,ftx,en;S00201ST.pdf
Synlett 2001, No. 4, 521–522 ISSN 0936-5214 © Thieme Stuttgart · New York