Total synthesis of (±)-lennoxamine and (±)-aphanorphine by intramolecular electrophilic aromatic substitution reactions of 2-amidoacroleins

Article abstract of DOI:10.1021/ol016795b

equation presented Intramolecular electrophilic aromatic substitution reactions of 2-amidoacroleins constitute the key steps in the total syntheses of lennoxamine and aphanorphine. The aldehyde moiety of one cyclization product was transformed to a double

Full text of DOI:10.1021/ol016795b

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3923-3925
Total Synthesis of (±)-Lennoxamine and
(±)-Aphanorphine by Intramolecular
Electrophilic Aromatic Substitution
Reactions of 2-Amidoacroleins
James R. Fuchs and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
rlf@chem.psu.edu
Received September 21, 2001
ABSTRACT
Intramolecular electrophilic aromatic substitution reactions of 2-amidoacroleins constitute the key steps in the total syntheses of lennoxamine
and aphanorphine. The aldehyde moiety of one cyclization product was transformed to a double bond, which was then engaged in a radical
cyclization to produce the complete ring system of lennoxamine. The aldehyde functionality of the other cyclization product was converted
to the corresponding mesylate, which underwent intramolecular displacement by a lactam enolate to furnish the ring system of aphanorphine.
We recently reported on a new method for the preparation
of a variety of heterocyclic ring systems that embody a
â-phenethylamine substructure.1 Thus, the 5-amido-4H-1,3-
dioxins 1 and 4 (Scheme 1) were subjected to Lewis acids
to effect catalyzed retrocycloadditions leading to the 2-ami-
doacroleins 2 and 5, respectively, which underwent con-
comitant intramolecular electrophilic aromatic substitution
reactions to afford the desired heterocyclic amides 3 or
lactams 6. We wished to test the utility of this methodology
in the context of natural product synthesis. In particular, the
aldehyde and amide moieties of the cyclization products 3
and 6 were expected to be useful for additional bond/ring
forming reactions. While there exist numerous natural
products of varying complexity that incorporate a â-phen-
ethylamine subunit, we felt that the synthesis of the modest
targets lennoxamine (7)2 and aphanorphine (10)3 would
adequately showcase the versatility of this methodology.
Recorded herein are relatively concise total syntheses of these
natural products by application of this general strategy.
Our retrosynthetic analyses for the construction of len-
noxamine and aphanorphine are outlined in Scheme 2. It was
envisaged that the ring system of lennoxamine would become
Scheme 1
(1) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3349.
10.1021/ol016795b CCC: $20.00 © 2001 American Chemical Society
Published on Web 00/00/0000

We initially examined the total synthesis of lennoxamine.
To that end, the amine 13 was condensed with 1,3-dioxin-
5-one (14),4 and the resultant imine was acylated in the same
reaction flask with the acid chloride 155 to afford the
5-amido-1,3-dioxin 16 (Scheme 3). As expected, the dioxin
Scheme 2
Scheme 3
available by a radical- or palladium-mediated cyclization of
the bromoaryl ring with a C(13)-C(14) enamide. The
enamide, in turn, could be derived from the aldehyde 8 by
oxidative decarboxylation of an intermediate carboxylic acid.
Finally, straightforward application of our cyclization pro-
tocol via 2-amidoacrolein 9 would furnish the tetrahydro-
3-benzazepine 8. The ring system of aphanorphine could be
obtained by either an intramolecular aldol reaction of lactam
aldehyde 11 or internal alkylation of a lactam enolate with
a C(10) alkyl halide or sulfonate derivative. An intramo-
lecular aromatic substitution reaction of 2-amidoacrolein 12
would afford the tetrahydro-3-benzazepine 11. In short, these
two projected syntheses feature the two types of cyclizations
of 2-amidoacroleins (exo vs endo amide), as well as distinct
ways of manipulating the aldehyde functionalities for ad-
ditional ring formations.
16 underwent a Lewis acid catalyzed retrocycloaddition to
the 2-amidoacrolein 9 followed by an aromatic substitution
reaction to afford the desired 3-benzazepine 8. It is of interest
to note that 1H NMR analysis of the amide 8 was complicated
not only by amide rotamers but also atropisomerism around
the aryl-carbonyl single bond.6 Indeed, the atropisomers could
be partially separated by column chromatography but were
found to interconvert upon standing at room temperature.
The aldehyde functionality of 3-benzazepine 8 was converted
to a C(13)-C(14) double bond by oxidation to the corre-
sponding carboxylic acid followed by a Kochi reaction7 to
(2) For the isolation (as a racemate) from Berberis darwinii, see: (a)
Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett.
1984, 25, 599. For previous total syntheses, see: (b) Teitel, S.; Klo¨tzer,
W.; Borgese, J.; Brossi, A. Can. J. Chem. 1972, 50, 2022. (c) Napolitano,
E.; Spinelli, G.; Fiaschi, R.; Marsili, A. J. Chem. Soc., Perkin Trans. 1
1986, 5, 785. (d) Moody, C. J.; Warrellow, G. J. Tetrahedron Lett. 1987,
28, 6089. (e) Koseki, Y.; Nagasaka, T. Chem. Pharm. Bull. 1995, 43, 1604.
(f) Rodriguez, G.; Cid, M. M.; Saa, C.; Castedo, L.; Dominguez, D. J. Org.
Chem. 1996, 61, 2780. (g) Ishibashi, H.; Kawanami, H.; Ikeda, M.; J. Chem.
Soc., Perkin Trans. 1 1997, 817. (h) Rodriguez, G.; Castedo, L.; Dominguez,
D.; Saa, C. Tetrahedron Lett. 1998, 39, 6551. (i) Koseki, Y.; Kusano, S.;
Nagasaka, T. Tetrahedron Lett. 1999, 40, 2169. (j) Couture, A.; Deniau,
E.; Grandclaudon, P.; Hoarau, C. Tetrahedron 2000, 56, 1491. (k)
Ruchirawat, S.; Sahakitpichan, P. Tetrahedron Lett. 2000, 41, 8007.
(3) For the isolation from the blue-green alga Aphanizomenon flos-aquae,
see: (a) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J.
Tetrahedron Lett. 1988, 29, 4381. For previous formal or total syntheses,
see: (b) Takano, S.; Inomata, K.; Sato, T.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1989, 1591. (c) Takano, S.; Inomata, K.; Sato, T.;
Takahashi, M.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1990, 290.
(d) Honda, T.; Yamamoto, A.; Cui, Y.; Tsubuki, M. J. Chem. Soc., Perkin
Trans. 1 1992, 531. (e) Hulme, A. N.; Henry, S. S.; Meyers, A. I. J. Org.
Chem. 1995, 60, 1265. (f) Meyers, A. I.; Schmidt, W.; Santiago, B.
Heterocycles 1995, 40, 525 (g) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry
1995, 6, 893. (h) Hallinan, K. O.; Honda, T. Tetrahedron 1995, 51, 12211.
(i) Node, M.; Imazato, H.; Kurosaki, R.; Kawano, Y.; Inoue, T.; Nishide,
K.; Fuji, K. Heterocycles 1996, 42, 811. (j) Shiotani, S.; Okada, H.;
Nakamata, K.; Yamamoto, T.; Sekino, F. Heterocycles 1996, 43, 1031. (k)
Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8, 371. (l) Shimizu,
M.; Kamikubo, T.; Ogasawara, K. Heterocycles 1997, 46, 21. (m) Tamura,
O.; Yanagimachi, T.; Kobayashi, T.; Ishibashi, H. Org. Lett. 2001, 3, 2427.
(4) Prepared in two steps from tris(hydroxymethyl)aminomethane hy-
drochloride. Hoppe, D.; Schmincke, H.; Kleemann, H.-W. Tetrahedron
1989, 45, 687.
(5) Prepared by treatment of the known 6-bromo-3,4-dimethoxybenzoic
acid with thionyl chloride. Auerbach, J.; Weissman, S. A.; Blacklock, T.
J.; Angeles, M. R.; Hoogsteen, K. Tetrahedron Lett. 1993, 34, 931.
(6) For selected examples of this type of atropisomerism, see: (a)
Cuyegkeng, M. A.; Mannschreck, A. Chem. Ber. 1987, 120, 803. (b) Pirkle,
W. H.; Welch, C. J.; Zych, A. J. J. Chromatogr. 1993, 648, 101. (c)
Thayumanavan, S.; Beak, P.; Curran, D. P. Tetrahedron Lett. 1996, 37,
2899. (d) Clayden, J.; McCarthy, C.; Cumming, J. G. Tetrahedron Lett.
2000, 41, 3279.
(7) For a review, see: (a) Sheldon, R. A.; Kochi, J. K. Org. React. 1972,
19, 279. For oxidative decarboxylation of R-amido acids with lead
tetraacetate, see: (b) Lohmar, R.; Steglich, W. Angew. Chem., Int. Ed. Engl.
1978, 17, 450. (c) Wegmann, H.; Steglich, W. Chem. Ber. 1981, 114, 2580.
(d) Lipinski, C. A.; Aldinger, C. E.; Beyer, T. A.; Bordner, J.; Burdi, D.
F.; Bussolotti, D. L.; Inskeep, P. B.; Siegel, T. W. J. Med. Chem. 1992, 35,
2169. (e) Urban, F. J.; Moore, B. S. J. Heterocycl. Chem. 1992, 29, 431.
(e) Osada, S.; Fumoto, T.; Kodama, H.; Kondo, M. Chem. Lett. 1998, 7,
675. For decarbonylation of R-amino or R-amido activated carboxylic acid
derivatives, see: (f) Herna´ndez, A. S.; Thaler, A.; Castell, J.; Rapoport, H.
J. Org. Chem. 1996, 61, 314 and references therein. (g) Mart´ın-Lo´pez, M.
3924
Org. Lett., Vol. 3, No. 24, 2001

afford the desired enamide 17 (51%, two steps). Finally,
subjection of the aryl bromide 17 to standard free radical
cyclization conditions gave (()-lennoxamine (58%) ac-
companied by debromo 17 in 26% yield, which could not
be attenuated by alternative reducing agents [(Me3Si)3SiH]
and/or syringe pump addition techniques. The spectral
properties of synthetic 7 were identical to those previously
reported.2
Aldehyde 11 was not stable at room temperature for extended
periods of time. Not surprisingly, all attempts to effect a base-
or acid-catalyzed epimerization at C(10) for the purpose of
determining whether the trans stereoisomer is the result of
thermodynamic control vis-a`-vis kinetic, equatorial proto-
nation of the presumed exocyclic aluminum enolate inter-
mediate 21 were unsuccessful. In addition, none of the
desired aldol adduct derived from intramolecular addition
of the lactam enolate of 11 to the aldehyde functionality
could be detected in these experiments. Accordingly, alde-
hyde 11 was directly reduced without purification to afford
the chromatographically stable alcohol 22 in 63% yield for
the two steps. Moreover, subjection of alcohol 22 to KO-t-
Bu in t-BuOH (60 °C, 2 h) gave rise to the epimeric cis
diastereomer of 22 (26:74, cis:trans), suggesting that the
stereoselective production of trans aldehyde 11 is kinetically
controlled. To our delight, the mesylate derivative of alcohol
11 underwent a smooth displacement by the lactam enolate
generated with KO-t-Bu in THF to afford the bridged bicyclic
lactam 23. Straightforward reduction of the lactam moiety
of 23 followed by demethylation of the aryl ether using
established conditions (BBr3, CH2Cl2) then delivered (()-
aphanorphine, whose spectral data were identical to those
reported previously.3
The total synthesis of aphanorphine was initiated by
treatment of the acid chloride 188 with the N-methylimine
19 to afford the 5-amido-1,3-dioxin 20 (Scheme 4). The
Scheme 4
In summary, we have shown that the products derived from
intramolecular electrophilic aromatic substitution reactions
of 2-amidoacroleins facilitate the rapid construction of two
dissimilar natural product ring systems by further transfor-
mation of the post-cyclization aldehyde and amide function-
alities. We expect that the total syntheses of other â-phen-
ethylamine-bearing natural products will also benefit from
this general strategy. These investigations are underway.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM28553).
retrocycloaddition, cyclization of amido dioxin 20 proceeded
smoothly upon treatment with MeAlCl2 in chloroform (rt, 4
h) to afford the aldehyde 11 as a single (trans) diastereomer.
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J.; Rodriquez, R.; Bermejo, F. Tetrahedron 1998, 54, 11623 and references
therein. (h) Mart´ın-Lo´pez, M. J.; Bermejo, F. Tetrahedron 1998, 54, 12379.
(8) Prepared by treatment of the known acid with thionyl chloride. Kubler,
W.; Petrov, O.; Winterfeld, E.; Ernst, L.; Schomburg, D. Tetrahedron 1988,
44, 4388.
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