Concise synthesis of the Hasubanan Alkaloid (±)-cepharatine A using a Suzuki coupling reaction to effect o,p -phenolic coupling

Article abstract of DOI:10.1021/ol402302k

Suzuki coupling of 10 and 11 resulted in 9, which was O-alkylated to provide 12. Treatment of 12 with CsF in DMF resulted in the formation of the completed core structure 13 in a single step. Reductive amination of 13 completed the synthesis of (±)-cepharatine A, 4.

Full text of DOI:10.1021/ol402302k

ORGANIC
LETTERS
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Vol. XX, No. XX
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Concise Synthesis of the Hasubanan
Alkaloid (()-Cepharatine A Using a Suzuki
Coupling Reaction To Effect o,p-Phenolic
Coupling
Philip Magnus* and Charles Seipp
Department of Chemistry and Biochemistry, University of Texas at Austin,
1 University Station A5300, Austin, Texas 78712, United States
p.magnus@mail.utexas.edu
Received August 12, 2013
ABSTRACT
Suzuki coupling of 10 and 11 resulted in 9, which was O-alkylated to provide 12. Treatment of 12 with CsF in DMF resulted in the formation of the
completed core structure 13 in a single step. Reductive amination of 13 completed the synthesis of (()-cepharatine A, 4.
The hasubanan alkaloids, exemplified by the structures
of hasubanonine 1 and cepharamine 2,1 have attracted the
attention of synthetic organic chemists because of their
obvious structural relationship to morphine 3 (opioid),
Figure 1.2aꢀd,3aꢀ3c
Recently, the structures of the cepharatines A (4), B (6),
C (5), and D (7), Figure2, havebeenreported,4 and thishas
generated a successful enantioselective synthesis of cephar-
atines A, C, and D.5
In 2009 we reported a new strategy for the synthesis of
codeine and galanthamine that involved a Suzuki reaction
Figure 1. Structures of hasubanonine 1, cepharamine 2, and
morphine 3.
(1) Matsui, M. The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1988; Vol. 33, pp 307ꢀ347(see also earlier vols. 13 and 16).
(2) (a) (()-Cepharamine synthesis: Inubushi, Y.; Ibuka, T.; Kitano,
M. Tetrahedron Lett. 1969, 1611–1614. (b) (()-Hasubanonine synthesis:
Ibuka, T.; Tanaka, K.; Inubushi, Y. Tetrahedron Lett. 1970, 13, 1393–
1396. (c) (þ)-Cepharamine Synthesis: Schultz, A. G.; Wang, A. J. Am.
Chem. Soc. 1998, 120, 8259–8260. (d) (ꢀ)-Hasubanonine synthesis:
Herzon, S. B.; Calandra, N. A.; King, S. A. Angew. Chem., Int. Ed.
2011, 50, 8863–8866.
(3) (a) (ꢀ)-Acutumine synthesis: Li, F.; Tartakoff, S. S.; Castle, S. L.
J. Am. Chem. Soc. 2009, 131, 6674–6675. (b) Li, F.; Tartakoff, S. S.;
Castle, S. L. J. Org. Chem. 2009, 74, 9082–9093. (c) Jones, S. B.; He, L.;
Castle, S. L. L. Org. Lett. 2006, 8, 3757–3760.
to establish the key o,p-phenolic coupling structural feature,
followed by intramolecular phenol alkylation resulting in a
cross conjugated cyclohexa-2,5-dienone.6 Application of
this concise strategy leads to the retrosynthetic pathway
for the construction of cepharatine A 4, Scheme 1.
It was anticipated that construction of the adduct 9 by a
Suzuki coupling reaction would solve the o,p-phenolic
coupling problem, Scheme 2 (formation of the blue
biaryl bond). Intramolecular alkylation of 9 (formation
(4) He, L.; Zhang, Y.-H.; Guan, H.-Y.; Zhang, J.-X.; Sun, Q.-Y.;
Hao, X.-J. J. Nat. Prod. 2011, 74, 181–184.
(5) Chuang, K. V.; Navarro, R.; Reisman, S. E. Angew. Chem., Int.
Ed. 2011, 50, 9447–9451.
(6) Magnus, P.; Sane, N.; Fauber, B. P.; Lynch, V. J. Am. Chem. Soc.
2009, 131, 16045–16047.
r
10.1021/ol402302k
XXXX American Chemical Society

Scheme 2. Conversion of 10 into Cepharatine A
Figure 2. Structures of cepharatines A, B, C, and D respectively.
Scheme 1. Retrosynthetic Strategy for the Construction of
o,p-Phenol Coupling Intermediate 8 from 9
of the red bond) leads to the cross conjugated cyclohexa-
2,5-dienone 8. The enolizable C-9 methyl group in 8 is
poised to undergo condensation with the C-10 aldehyde to
give cepharatine A 4 after reductive amination and acidic
treatment. It is noteworthy that, in principle, this strategy
forms the phenathrenone skeleton directly in the correct
oxidation state. Castle adopted a Suzuki coupling strategy
to form the biaryl bond and subsequent RCM to establish
the C9ꢀC10 double bond.3aꢀc
the crude product was treated with aqueous 1 M HCl to
give cepharatine A (42%).
The synthesis of (()-cepharatine A proceeds in 7 steps
from commercially available 2-methoxy-5-methylphenol
in 16% overall yield. The key transformation was the
conversion of 12 into 13, where the C-15 and C9ꢀC10
carbonꢀcarbon bonds are formed in a single step.
Treatment of the boronic ester derivative 11 (available in
three steps from 2-methoxy-5-methylphenol in overall
78% yield; see Supporting Information for its synthesis)
with 2-bromo-isovanillin 10 under Suzuki coupling reac-
tion conditions provided 9 (70%), Scheme 2. The final two
carbon atoms were obtained from bromination of ethyl
vinyl ether and exposure of 9 to the in situ generated
dibromide in the presence of iPr2NEt resulting in 12 (89%).
When 12 was treated with CsF in DMF at 80 °C it was
converted into 8 (colorless), which on further warming to
130 °C generated a bright yellow solution characteristic of
the fully conjugated chromophore associated with the
cepharatines (λmax 388 nm). After workup 13 was isolated
as a canary yellow solid (mp 147ꢀ150 °C), and its structure
was confirmed by single crystal X-ray crystallography. To
complete the synthesis 13 was reductively aminated, and
Acknowledgment. The Welch Foundation (Chair F-0018)
is thanked for their support of this work. Dr. Vince Lynch,
Department of Chemistry, University of Texas at Austin, is
thanked for the X-ray structure determination of 13.
Supporting Information Available. Complete experi-
mental details and compound characterization. This in-
formation is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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