Intramolecular Diels-Alder cyclizations of (E)-1-nitro-1,7,9-decatrienes: Synthesis of the AB ring system of norzoanthamine

Article abstract of DOI:10.1021/ol9904085

Cyclizations of substituted (E)-1-nitro-1,7,9-decatrienes under thermal and Lewis acid conditions have led to the formation of decalin ring systems with excellent endo selectivity. This strategy has been applied to the synthesis of the AB ring system of n

Full text of DOI:10.1021/ol9904085

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1023-1026
Intramolecular Diels−Alder Cyclizations
of (E)-1-Nitro-1,7,9-decatrienes:
Synthesis of the AB Ring System of
Norzoanthamine
David R. Williams* and Todd A. Brugel
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
williamd@indiana.edu
Received December 21, 1999
ABSTRACT
Cyclizations of substituted (E)-1-nitro-1,7,9-decatrienes under thermal and Lewis acid conditions have led to the formation of decalin ring
systems with excellent endo selectivity. This strategy has been applied to the synthesis of the AB ring system of norzoanthamine.
The intramolecular Diels-Alder reaction (IMDA) has been
explored extensively as a valuable tool for organic synthesis.1
Although the thermal intermolecular Diels-Alder reactions
of nitroalkenes with dienes have been widely studied,2
intramolecular examples of this process are remarkably rare.
Kurth has reported the thermal cyclizations of 1-nitro-1,6,8-
decatrienes for the synthesis of perhydroindenes,3 and
Kunesch and Tillequin have recently described the cycload-
dition of a dinitroalkene and tethered furan to produce 3,7-
dinitro-11-oxatricycloundec-9-ene.4 However, the intramo-
lecular Diels-Alder reaction of nitroalkenes has not been
explored as a route to substituted decalin systems. In contrast,
the alternative use of the nitroalkene moiety as a heterodiene
component for formal [4 + 2] intermolecular cyclizations
to provide nitronate intermediates has been systematically
examined by Denmark and co-workers.5 Owing to our efforts
for development of an enantioselective synthesis of the
marine alkaloid norzoanthamine (1),6,7 recent studies have
been focused on a stereocontrolled preparation of the
substituted nonracemic decalone 2. Herein, we describe the
(1) For reviews of the intramolecular Diels-Alder reaction, see: (a)
Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: New York, 1991; Vol. 5, pp 513-550. (b) Craig,
D. Chem. Soc. ReV. 1987, 16, 187. (c) Cigarek, E. Org. React. 1984, 32, 1.
(d) Brieger, G.; Bennet, J. N. Chem. ReV. 1980, 80, 63.
(2) (a) Stoodley, R. J.; Yuen, W.-H. Chem. Commun. 1997, 1371. (b)
Node, M.; Nishide, K.; Imazato, H.; Kurosaki, R.; Inoue, T.; Ikariya, T.
Chem. Commun. 1996, 2559. (c) Ayerbe, M.; Coss´ıo, F. P. Tetrahedron
Lett. 1995, 36, 4447. (d) Ono, N.; Kamimura, A.; Kaji, A. J. Org. Chem.
1988, 53, 251. (e) Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107,
5574.
(3) Kurth, M. J.; O’Brien, M. J.; Hope, H.; Yanuck, M. J. Org. Chem.
1984, 50, 2626.
(4) Sader-Bakaouni, L.; Charton, O.; Kunesch, N.; Tillequin, F. Tetra-
hedron 1998, 54, 1773.
intramolecular Diels-Alder protocol as a key transformation
for the efficient preparation of these bicyclic enones via
subsequent application of the Nef reaction.
10.1021/ol9904085 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/21/2000

Several nitroalkenes were examined as model systems for
our Diels-Alder strategy in order to evaluate issues of
reactivity and stereoselectivity. As shown in Scheme 1,
two diastereomers were detected by 13C and 1H NMR
analysis. Extensive coupling constant and NOE data sup-
ported the stereochemical assignments.
In the case of triene 4d (entry 4), the preexisting
stereogenic center in the tethering chain led to products 5d
and 6d featuring a B-ring chair conformation with the C-3
methyl substituent in an equatorial orientation.13
Scheme 1. Synthesis of (E)-Nitroalkenes 4
Attempts to enhance the endo selectivity through Lewis
acid activation proved difficult. Reactions using a variety
of Lewis acids (AlMe3, BF3‚OEt2, TiCl4, TiCl2(OiPr)2) led
to low yields (<10%) of decalin products. The best results
were achieved using Et2AlCl (entries 5 and 6), which gave
modest yields with significant increases in endo selectivity.
Catalytic quantities of Lewis acid were ineffective in these
studies, while stoichiometric quantities led to considerable
decomposition affording highly polar materials. Decalins 5
and 6 were the only organic-soluble materials observed from
these attempts.
The application of this methodology for norzoanthamine
synthesis required an enantiocontrolled route to enone 2 with
installation of a quaternary carbon at C-12 adjacent to the
trans ring fusion. Oxidation of allylic alcohol 714 (Scheme
2) was followed by Evans aldolization with the Z(O) boron
enolate of 8 to yield syn-alcohol 9.15,16
nitroalkenes 4a-d were prepared through an aldol condensa-
tion of the corresponding aldehydes 3a-d8,9 with nitro-
methane.10 Although the dehydration of these â-hydroxy
adducts is often problematic, a mild procedure using dicyclo-
hexylcarbodiimide, as previously described by Seebach,11
provided good isolated yields (∼60%) of the nitroalkenes.
The dehydration reaction led to nearly exclusive formation
of the E-olefin (g97%), and the nitroalkenes were stable to
procedures of flash silica gel chromatography.
Table 1 shows the results for the thermal and Lewis acid
promoted cycloadditions of trienes 4a-d. Thermal cycliza-
tion of 4a (entry 1) led to a 73:27 ratio of endo/exo products.
This represents a modest increase in endo selectivity
compared to published results with methyl (E,E)-undeca-
2,8,10-trienoate which gave a 51:49 endo/exo ratio of
products (toluene, 155 °C, 45h, 92% yield).8 The increase
in endo selectivity for the nitro case can be attributed to
greater secondary orbital interaction with the more highly
activated nitro-substituted dienophile.12 Thermal cyclizations
of several triene substrates (entries 2-4) showed consistent
trends in endo selectivity and yield. In each experiment, only
Scheme 2. Synthesis of Homoallylic Alcohol 13
Table 1. Diels-Alder Cyclizations of 4a-d
entry
triene
conditionsa
% yieldb
5 endo:6 exoc
1
2
3
4
5
6
4a
4b
4c
4d
4b
4d
A, 89 h
A, 28 h
A, 36 h
A, 42 h
B, 1.5 h
B, 6 h
63
70
72
80
39
38
73:27
70:30
61:39
73:27
89:11
92:8
Oxazolidinone cleavage, protection, and subsequent
Eschenmoser-Claisen rearrangement gave amide 10 as a
a Conditions: A, benzene, 85 °C; B, Et2AlCl (2.0 equiv), CH2Cl2, -78
(5) (a) For a recent publication in this area, see: Denmark, S. E.;
Seierstad, M. J. Org. Chem. 1999, 64, 1610. (b) For a review of tandem [4
+ 2]/[3 + 2] cycloaddition reactions of nitroalkenes, see: Denmark, S. E.;
Thorarensen, A. Chem. ReV. 1996, 96, 137.
1
°C. b Purified yields. c Ratios determined from H NMR (400 MHz) data
of crude mixtures.
1024
Org. Lett., Vol. 2, No. 8, 2000

Scheme 3. Synthesis of (E,E)-Nitrotriene 17
single diastereomer.17 Direct reduction to aldehyde 11 was
desired Diels-Alder precursor 17 in 64% yield following
accomplished using a modified aluminum hydride (11:12
ratio 7.7:1).18 The small quantities of alcohol 12 formed from
over-reduction were readily converted into 1119 for subse-
quent asymmetric allylboration to yield homoallylic alcohol
13.20
silica gel chromatography.
Thermal cyclization of 17 in benzene (reflux, 65 h) led to
a 1:10 ratio of a separable mixture of 18/19 (Scheme 4) in
Installation of the conjugated diene was completed through
a mesylation/elimination sequence to give acetonide 15
(Scheme 3). All reactions in this pathway were generally
straightforward. However, the key intermediate aldehyde 16
was very unstable and particularly prone to â-elimination
of the MOM ether. The mild oxidative cleavage of the diol
resulting from hydrolysis of 15 provided a ready source of
16, which could be used without further purification.
Treatment with nitromethane in the presence of KF afforded
a quantitative aldol condensation. Dehydration gave the
Scheme 4. Diels-Alder Cyclization of (E,E)-Nitrotriene 17
and Completion of the Synthesis of Enone 2
(6) (a) Fukuzawa, S.; Hayashi, Y.; Uemura, D.; Nagatsu, A.; Yamada,
K.; Ijuin, Y. Heterocycl. Commun. 1995, 1, 207. (b) Kuramoto, M.; Hayashi,
K.; Fujitani, Y.; Yamaguchi, K.; Tsuji, T.; Yamada, K.; Ijuin, Y.; Uemura,
D. Tetrahedron Lett. 1997, 38, 5683.
(7) Williams, D. R.; Cortez, G. S. Tetrahedron Lett. 1998, 39, 2675.
(8) Roush, W. R.; Hall, S. E. J. Am. Chem. Soc. 1981, 103, 5200.
(9) Ainswroth, P. J.; Craig, D.; Reader, J. C.; Slawin, A. M. Z.; White,
J. P.; Williams, D. J. Tetrahedron 1995, 51, 11601.
(10) Wollenberg, R. H.; Miller, S. J. Tetrahedron Lett. 1978, 3219.
(11) Knochel, P.; Seebach, D. Synthesis 1982, 1017.
(12) Sauer, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 779.
(13) For related examples of C3-methyl stereocontrol in IMDA cycload-
ditions, see: (a) Williams, D. R.; Gaston, R. D.; Horton, I. B. Tetrahedron
Lett. 1985, 26, 1391. (b) Williams, D. R.; Bremmer, M. L.; Brown, D. L.;
D’Antuono, J. J. Org. Chem. 1985, 50, 2807.
excellent yield (92%). Both cycloadducts arise from the
diastereomeric endo transition states. Cyclization of 17 in
acetonitrile produced a more rapid reaction (7 h at 70 °C)
with a more favorable diastereomeric ratio (95:5) but a
reduced overall yield (66%). Assignment of stereochemistry
(14) Alcohol 7 was synthesized in four steps starting from 3-butyne-1-
ol using the following procedure: (1) PMBOC(NH)CCl3, TfOH, Et2O, rt;
n
(2) BuLi, EtOC(O)Cl, THF, -78 °C to rt; (3) MeCu‚LiI (2 equiv), THF,
-45 °C; (4) LiAlH4, Et2O, 0 °C. For an alternative preparation of alcohol
7, see: Nagano, H.; Nakanishi, E.; Takajo, S.; Sakuma, M.; Kudo, K.
Tetrahedron 1999, 55, 2591.
1
for the two diastereomers was based on H NMR coupling
constants and NOE experiments (Figure 1). MM2* minimi-
zations21 of 18 support the notion that the B-ring twist-boat
(as shown) may provide a significant conformational con-
tribution in order to avoid the 1,3-diaxial interaction of the
corresponding chair.
(15) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83.
1
(16) All new compounds were characterized by H and 13C NMR, IR,
HRMS, and optical rotation where appropriate. Yields are for isolated,
chromatographically pure products.
(17) (a) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. HelV. Chem.
Acta 1964, 47, 2425. (b) Felix, D.; Gschwend-Steen, K.; Wick, A. E.;
Eschenmoser, A. HelV. Chem. Acta 1969, 52, 1030.
(18) (a) Kim, S.; Ahn, K. H. J. Org. Chem. 1984, 49, 1717. (b) Taber,
D. F.; Silverberg, L. J.; Robinson, E. D. J. Am. Chem. Soc. 1991, 113,
6639.
The desired trans-decalin 19 has been efficiently converted
to the desired R,â-unsaturated enone 2 in good yield (72%)
(19) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(20) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(21) Molecular mechanics calculations were performed using the
MacroModel program version 7.0 (MM2* force-field).
Org. Lett., Vol. 2, No. 8, 2000
1025

AB-ring system of the zoanthamine alkaloids. Further efforts
are underway to apply this approach to the synthesis of
norzoanthamine.
Acknowledgment. The authors gratefully acknowledge
the National Institutes of Health (GM-41560) for generous
support of our work. We also thank the Indiana University
College of Arts and Science for a summer fellowship for
T.A.B.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 18, 19, and 2 and
1H NMR data for compounds 5a, 5c, 5d, 6c, and 6d. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. 1H NMR studies of NOE interactions for Diels-Alder
products 18 and 19.
OL9904085
by way of an oxidative Nef reaction.22 In the process, the
C-14/C-15 alkene migrated into conjugation with the C-17
ketone to provide a successful synthesis of the functionalized
(22) Adam, W.; Makosza, M.; Saha-Mo¨eller, C. R.; Zhao, C.-G. Synlett
1998, 1335.
1026
Org. Lett., Vol. 2, No. 8, 2000