Synthesis of santiagonamine

Article abstract of DOI:10.1021/ol0711974

The first total synthesis of santiagonamine (1) is achieved in 12 steps from isovanillin. A palladium-catalyzed Ullmann cross-coupling reaction and a photocyclization are the key steps in the synthesis.

Full text of DOI:10.1021/ol0711974

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3255-3257
Synthesis of Santiagonamine
Michael D. Markey, Ying Fu, and T. Ross Kelly*
E.F. Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
ross.kelly@bc.edu
Received May 21, 2007
ABSTRACT
The first total synthesis of santiagonamine (1) is achieved in 12 steps from isovanillin. A palladium-catalyzed Ullmann cross-coupling reaction
and a photocyclization are the key steps in the synthesis.
In 1984, Shamma and colleagues reported1 the isolation and
structure determination of santiagonamine (1). Santiagon-
amine, which was extracted from the stems and branches of
the South American shrub Berberis darwinii Hook and shows
wound-healing properties,2 is the only known examples
naturally occurring or otherwisesof the 10H-[1]benzopy-
rano[5,4,3-hij]isoquinoline ring system. Because of its
structural novelty and the absence of any independent
confirmation of the structure determination,3 the synthesis
of this alkaloid was undertaken. Herein we report the first
synthesis of 1 and the verification of the original structure
assignment.
to originate from manipulation of biaryl 4, with the latter
being secured from an appropriate cross-coupling reaction
Figure 1. Retrosynthetic analysis of santiagonamine (1).
between functionalized monocycles 5 and 6. Both 5 and 6
should be derivable from commerically available material.
The synthesis began (Scheme 1) with conversion of
picolinic acid (7) into the secondary amide 8.4 Ortho-
Retrosynthetic analysis (Figure 1) suggested that attach-
ment of a side-chain equivalent (3) to intermediate 2 would
lead to santiagonamine (1). Intermediate 2 was envisioned
Scheme 1
(1) Valencia, E.; Patra, A.; Freyer, A. J.; Shamma, M.; Fajardo, V.
Tetrahedron Lett. 1984, 25, 3163.
(2) Lewis, W. H.; Stonard, R. J.; Porras-Reyes, B.; Mustoe, T. A.;
Thomas, A. Wound-healing composition. U.S. Patent 5,156,847, 1992.
(3) For earlier synthetic studies stimulated by the structure of santiago-
namine, see: (a) Castedo, L.; Cid, M. M.; Seijas, J. A.; Villaverde, M. C.
Tetrahedron Lett. 1991, 32, 3871. (b) Pave´, G.; Chalard, P.; Viaud-Massuard,
M.-C.; Troin, Y.; Guillaumet, G. Synlett 2003, 987.
10.1021/ol0711974 CCC: $37.00
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lithiation of 8 with n-butyllithium5 (n-BuLi) and subsequent
quenching with iodine supplied the desired specific embodi-
ment (9) of 6.
Scheme 3
Preparation of the unit (12) corresponding to 5 commenced
(Scheme 2) with a previously described procedure6 for the
Scheme 2
iodination of 3-hydroxy-4-methoxybenzaldehyde (isovanillin,
10) to give iodide 11. Protection of the hydroxyl group as
its methoxymethyl (MOM) ether gave the known aldehyde
12, which has also been prepared from 10 by a 3-step route.7
It was anticipated that a palladium-catalyzed Ullmann
cross-coupling reaction8 would prove suitable for forming
the hindered biaryl bond of 4. Exposure of 9 and 12 on a
0.2 mmol scale to palladium and activated copper9 bronze
at 145 °C gave the desired product 14, albeit in only 7%
yield (eq 1).10-12 Efforts to improve the yield of 14 were
unsuccessful.
To complete the ring system, 14 was transformed into
styrene 22 by a Wittig reaction with methylenetri-
phenylphosphorane. Styrene 22 was then subjected to pho-
tocyclization,15 but gave benzo[f]quinoline 23 instead of the
desired benz[h]isoquinoline 24. To overcome this unexpected
result,16 we hoped that by first forming the lactone we could
alter the regioselectivity of the photocyclization.
(11) Although the yield to form 14 was poor, this approach served as an
alternative to our first synthetic approach, where exposure of 9 and 2512 to
palladium and activated copper bronze gave biaryl 26 (eq i) in 29% unopti-
Consequently, we chose to convert aldehyde 12 into an
imine, based on three considerations: imines (i) possess a
history of success in Ullmann reactions,13 (ii) contain a
coordinating lone pair of electrons,14 and (iii) preserve the
benzylic carbon’s oxidation state.
Condensation (Scheme 3) of 12 with cyclohexylamine
gave imine 13. Without purification, 13 was coupled with 9
on a 10 mmol scale to afford, after an aqueous workup, biaryl
14 in 39% yield.
mized yield on a 6 mmol scale. In an effort to complete the synthesis of 1
from 26, we were successful in forming the lactone and hydrolyzing the
N-propyl amide to give carboxylic acid i. However, attempts to advance i
(e.q., by selective reduction of the carboxylic acid with borane reagents)
were unsuccessful. Possibly, the pyridine nitrogen directs the reduction to
the lactone carbonyl in i.
(4) (a) Jo´z´wiak, A.; Brzezin´ski, J. Z.; Płotka, M. W.; Szczes´niak, A. K.;
Malinowski, Z.; Epsztajn, J. Eur. J. Org. Chem. 2004, 3254. (b) Brunner,
H.; Nuber, B.; Prommesberger, M. J. Organomet. Chem. 1996, 523, 179.
(5) Epsztajn, J.; Płotka, M. W.; Grabowska, A. Synth. Commun. 1997,
27, 1075.
(6) Markovich, K. M.; Tantishaiyakul, V.; Hamada, A.; Miller, D. D.;
Romstedt, K. J.; Shams, G.; Shin, Y.; Fraundorfer, P. F.; Doyle, K.; Feller,
D. R. J. Med. Chem. 1992, 35, 466.
(7) Uchida, K.; Yokoshima, S.; Kan, T.; Fukuyama, T. Org. Lett. 2006,
23, 5311 and references cited therein.
(8) For leading references on the Ullmann reaction, see: (a) Ku¨rti, L.;
Czako´, B. Strategic Applications of Named Reactions in Organic Synthesis;
Elsevier: Amsterdam, The Netherlands, 2005; p 466. (b) Nelson, T. D.;
Crouch, R. D. Org. React. 2004, 63, 265. (c) Fanta, P. E. Synthesis 1974,
9. For examples of palladium-catalyzed Ullmann cross-coupling reactions,
see: (d) Shimizu, N.; Kitamura, T.; Watanabe, K.; Yamaguchi, T.; Shigyo,
H.; Ohta, T. Tetrahedron Lett. 1993, 34, 3421. (e) Thompson, W. J.;
Gaudino, J. J. Org. Chem. 1984, 49, 5237. (f) Banwell, M. G.; Lupton, D.
W.; Ma, X.; Renner, J.; Sydnes, M. O. Org. Lett. 2004, 6, 2741. (g) Some,
S.; Dutta, B.; Ray, J. K. Tetrahedron Lett. 2006, 47, 1221.
(12) Iodoamide 25 was available in three steps from 3-hydroxy-4-
methoxybenzoic acid (isovanillic acid). For a synthesis of 25, see: Kelly,
T. R.; Xie, R. L. J. Org. Chem. 1998, 63, 8045.
(13) (a) Sainsbury, M. Tetrahedron 1980, 36, 3327. (b) Stark, L. M.;
Lin, X.-F.; Flippin, L. A. J. Org. Chem. 2000, 65, 3227.
(14) (a) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997,
62, 2312. (b) Ziegler, F. E.; Chliwner, I.; Fowler, K. W.; Kanfer, S. J.;
Kuo, S. J.; Sinha, N. D. J. Am. Chem. Soc. 1980, 102, 790. (c) van Koten,
G.; Leusink, A. J.; Noltes, J. G. J. Chem. Soc. D 1970, 1107.
(15) For a leading reference on photocyclizations, see: (a) Mallory, F.
B.; Mallory, C. W. Org. React. 1984, 30, 1. For related applications on
similar ring systems, see ref 3a and: (b) Veeramani, K.; Paramasivam, K.;
Ramakrishnasubramanian, S.; Shanmugam, P. Synthesis 1978, 855. (c)
Kende, A. S.; Curran, D. P. J. Am. Chem. Soc. 1979, 101, 1857. (d)
McDonald, E.; Martin, R. T. Tetrahedron Lett. 1978, 19, 4723. (e) Padwa,
A.; Doubleday, C.; Mazzu, A. J. Org. Chem. 1977, 42, 3271.
(9) Kleiderer, E. C.; Adams, R. J. Am. Chem. Soc. 1933, 55, 4219.
(10) When performed at 85 °C no biaryl 14 was isolated.
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Org. Lett., Vol. 9, No. 17, 2007

Bromination of 16 at -78 °C with a mixture of triethyl-
amine17 and bromine-1,4-dioxane18 gave bromide 17.19
Cyclization of 17 with trifluoracetic acid in THF gave styrene
lactone 18. The latter, to our delight, underwent smooth and
rapid photocyclization to give bromolactone 19.
Scheme 4
Finally, the side-chain installation began with a Stille
coupling between 19 and allytributyltin to give allyl lactone
20. Transformation of 20 into aldehyde 21 by the action of
osmium tetroxide and sodium periodate20 followed by
reductive amination12 of 21 with dimethylamine and sodium
triacetoxyborohydride secured santiagonamine (1). The
spectra of synthetic 1 are in excellent agreement with those
reported for the natural product.21
In summary, we report the first total synthesis of santi-
agonamine. The synthesis, accomplished in 12 steps (2.6%
overall yield) from commercially available isovanillin, af-
firms the original structure assignment.
Acknowledgment. We thank Dr. M. Shamma1 (Penn-
sylvania State University) for helpful exchange of informa-
tion. We are also grateful to Stepanie M. Ng (Boston College)
for X-ray crystallographic studies.
Supporting Information Available: Experimental pro-
cedures and characterization data for selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Accordingly (Scheme 4), 14 was deprotected with TMSBr
to give phenol 15, which then underwent a Wittig reaction
with methylenetriphenylphosphorane to afford styrene 16.
OL0711974
(16) The photocyclization of ii to a mixture of iii and iv has been re-
(17) When this reaction was performed at room temperature or in the
absence of base there was competing addition of bromine to the vinyl group.
We believe the triethylamine accelerates the rate of ring bromination by
deprotonation of 16 to the corresponding phenoxide.
(18) Finkelstein, B. L. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley: Chichester, UK, 1995; Vol. 1, p 686.
(19) The regioselectivity of the bromination was later proven by an X-ray
crystallographic characterization of 19 (see the Supporting Information).
(20) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
ported.3a We speculate that the failure of 22 to cyclize to 24 may be due to
a repulsive steric interaction between the MOMO and PhHNOC groups
that disfavors a conformation necessary to access the transition state leading
to intermediate v.
(21) Unfortunately, an authentic sample of natural 1 is no longer
available.
Org. Lett., Vol. 9, No. 17, 2007
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