Synthesis of onychine and formal synthesis of eupolauridine via the vinylogous aza-morita-baylis-hillman reaction

Article abstract of DOI:10.1055/s-0030-1259008

A concise and efficient synthesis of the antimycotic alkaloid onychine was developed, based on the vinylogous aza-Morita-Baylis-Hillman reaction of N-(benzylidene)benzenesulfonamide with methyl 2,4-pentadienoate, followed by intramolecular conjugate addition, Friedel-Crafts acylation, methyl cuprate addition, and aromatization.

Full text of DOI:10.1055/s-0030-1259008

LETTER
2802
Synthesis of Onychine and Formal Synthesis of Eupolauridine via the
Vinylogous Aza-Morita–Baylis–Hillman Reaction
Synthesisof
Onyc
r
hine isten N. Clary, Thomas G. Back*
Department of Chemistry, University of Calgary, Calgary, AB, T2N 1N4, Canada
Fax +1(403)2899488; E-mail: tgback@ucalgary.ca
Received 2 September 2010
We recently reported a novel vinylogous variation of the
aza-Morita–Baylis–Hillman (aza-MBH) reaction,15 in
which suitably activated dienes 4 reacted with imines 3 in
the presence of the nucleophilic catalyst 3-hydroxyquinu-
Abstract: A concise and efficient synthesis of the antimycotic alka-
loid onychine was developed, based on the vinylogous aza-Morita–
Baylis–Hillman reaction of N-(benzylidene)benzenesulfonamide
with methyl 2,4-pentadienoate, followed by intramolecular conju-
gate addition, Friedel–Crafts acylation, methyl cuprate addition, clidine (HQD) to afford products 5.15a,b During these in-
and aromatization.
vestigations, we observed that when the electron-
withdrawing group (EWG) was a sulfonyl or ester moiety,
the aza-MBH adduct cyclized via a base-catalyzed in-
tramolecular conjugate addition to afford tetrahydropyri-
dine derivatives 6. Unfortunately, this cyclization
occurred exclusively from the E-isomers of 5, as the Z-
isomers did not have the appropriate geometry to assume
the required six-membered transition state for intramolec-
ular conjugate addition. Furthermore, the aza-MBH reac-
tions with these EWG typically gave only moderate to low
selectivities, with E/Z ratios ranging from 50:50 to 80:20.
In order to overcome this limitation, we employed a con-
venient in situ photoisomerization of the E/Z mixtures
during the cyclization procedure, resulting in the equili-
bration and ultimate consumption of both geometrical iso-
mers (Scheme 1). We now demonstrate the application of
this methodology to the total synthesis of the alkaloid
onychine (1).
Key Words: alkaloids, onychine, aza-Morita–Baylis–Hillman
reaction, cyclization, cuprates
The 4-azafluorenones are a group of biologically interest-
ing alkaloids found in trees of the family Annonaceae.1
Onychine (1, Figure 1) was the first 4-azafluorenone to be
discovered and was initially isolated from the trunkwood
of the Brazilian tree Onychopetalum amazonicum in
1976.2 The structure originally assigned to onychine1 was
erroneous; however, it was later corrected on the basis of
NMR studies and total synthesis.3 Interestingly, Taylor
and co-workers4 completed the first synthesis of this com-
pound as an intermediate en route to the related alkaloid
eupolauridine (2), before onychine was discovered as a
natural product. It was not until 1979 that Koyama et al.3a
realized that the structures of the Taylor intermediate and
the natural product were identical. Alkaloids 1 and 2 dis-
play antimycotic activity against C. albicans,5,6 as well as
antibacterial activity,6 prompting the development of sev-
eral approaches toward their synthesis. Onychine has been
SO2Ph
EWG
SO2Ph
NH
HQD
DMF
N
EWG
+
Ar
Ar
H
prepared by an enamine triazine cycloaddition,3b
a
3
4
Yb(OTf)3-catalyzed [4+2] cycloaddition,7 a Pummerer–
dipolar cycloaddition cascade,8 an oxidative thermal rear-
rangement of 2-indanone oxime O-crotyl ether,9 zeolite10
or polyphosphoric acid catalyzed11 cyclizations of 2-aryl-
3-nicotinic acid derivatives, Pd(0)-catalyzed cross cou-
pling of aryl-12 or methylboronic acids13 with 2-halopy-
ridines, and via an aza-Wittig reaction.14
base
DMF
hν
EWG
Ar
5
N
SO2Ph
6
hν
(Z)-5
6
(E)-5
EWG = electron-withdrawing group
HQD = 3-hydroxyquinuclidine
N
N
Scheme 1
N
eupolauridine (2)
O
The tetrahydropyridine 7, which we had prepared previ-
ously in two separate steps via Scheme 1,15b was obtained
in an improved one pot reaction from 3 (Ar = Ph) and 4
(EWG = CO2Me) in 73% yield. Its further conversion into
1 was envisaged via an intramolecular Friedel–Crafts re-
action, conjugate addition of a methyl group and desulfo-
nylation–aromatization of the heterocyclic ring. Initial
attempts to perform the Friedel–Crafts cyclization under
onychine (1)
Figure 1
SYNLETT 2010, No. 18, pp 2802–2804
x
x
.x
x
.2
0
1
0
Advanced online publication: 14.10.2010
DOI: 10.1055/s-0030-1259008; Art ID: S05910ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Onychine
2803
acid-catalyzed conditions directly from ester 7 or its par- With the conjugate addition complete, the remaining steps
ent acid proved unsuccessful. Fortunately, treatment of included N-desulfonylation and aromatization. The des-
the corresponding acyl chloride with aluminum trichlo- ulfonylation could be achieved by refluxing 10 with mag-
ride in refluxing 1,2-dichloroethane (DCE) formed the de- nesium in methanol17 containing a catalytic amount of
sired tricycle 8 in 86% yield. Attempts to install the iodine, but also led to the undesired reduction of the ke-
methyl substituent by conjugate addition of the corre- tone. Fortunately, base-catalyzed elimination of the ben-
sponding cuprate resulted in an unexpected ring opening, zenesulfinate anion occurred by heating 10 with DBU in
where double conjugate addition took place with displace- a sand bath at 240 °C for 5 minutes to afford the enamin-
ment of the benzenesulfonamide moiety to provide the one 11 and a small amount of onychine, presumably aris-
dimethylated adduct 9 (Scheme 2). This problem was cir- ing from air oxidation of the enaminone. A more efficient
cumvented by trapping the enolate from the initial conju- one-pot process was developed where the enaminone was
gate addition with trimethylsilyl chloride,16 followed by first formed by solvent-free heating of 10 with DBU at
workup with aqueous HCl to afford the desired product 10 240 °C, followed by refluxing of the crude product 11 in
as a single diastereomer (Scheme 3). The indicated stereo- toluene with DDQ to afford onychine (1) in 84% yield.18
chemistry of 10 is tentatively assigned on the basis of
In conclusion, we have successfully synthesized onychine
in six steps from 3 and 4 in 45% overall yield, based on
our one-pot vinylogous aza-Morita–Baylis–Hillman reac-
tion–cyclization protocol. Since it was previously demon-
NOE experiments, in which irradiation of the proton a to
the keto group (d = 2.18 ppm) resulted in enhancement of
the signals of both the tertiary hydrogen a to the nitrogen
atom (d = 5.54 ppm) and the methyl group (d = 0.97 ppm)
strated that onychine can be converted into eupolauridine
by 2.75% and 1.92%, respectively.
(2),4,9,11 this also represents a formal synthesis of the latter
alkaloid.
SO2Ph
HQD, DMF
DBU, hν
N
+
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
H
73%
MeO2C
4 (EWG = CO2Me)
3 (Ar = Ph)
Acknowledgment
PhO2S
1. 1 M NaOH, THF
2. SOCl2
PhO2S
N
We gratefully acknowledge financial support from the Natural Sci-
ences and Engineering Research Council (NSERC). K.N.C. thanks
NSERC and Alberta Innovates – Technology Futures for postgra-
duate scholarships.
N
3. AlCl3, DCE
86%
CO2Me
O
7
8
References and Notes
Me2CuLi, THF
–78 °C to r.t.
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NHSO2Ph
89%
O
9
Scheme 2
(3) (a) Koyama, J.; Sugita, T.; Suzuta, Y. Heterocycles 1979, 12,
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PhO2S
PhO2S
Me2CuLi, THF
TMSCl
N
N
O
H
–78 °C to r.t.
86%
H
O
8
10
DBU, 240 °C
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N
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toluene, Δ
84%
O
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1
11
Scheme 3
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Synlett 2010, No. 18, 2802–2804 © Thieme Stuttgart · New York

2804
K. N. Clary, T. G. Back
LETTER
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(18) For experimental procedures and characterization data for
new compounds and the final product 1, see the Supporting
Information.
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