Studies toward the total synthesis of eletefine: An efficient construction of the AB ring system

Article abstract of DOI:10.1016/j.tetlet.2010.08.058

Synthetic studies toward eletefine, a novel stephaoxocane alkaloid, were undertaken in an attempt to provide a general methodology to aid in the synthesis of other novel stephaoxocanes. An efficient construction of the AB ring system with increased functionality is described which presents a flexible approach to synthesizing the C and D rings of eletefine.

Full text of DOI:10.1016/j.tetlet.2010.08.058

Tetrahedron Letters 51 (2010) 5585–5587
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies toward the total synthesis of eletefine: an efficient construction
of the AB ring system
⇑
Jeremy A. Cody , Ijaz Ahmed, Douglas J. Tusch
Department of Chemistry, Rochester Institute of Technology, 85 Lomb Memorial Drive, Rochester, NY 14623-5603, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic studies toward eletefine, a novel stephaoxocane alkaloid, were undertaken in an attempt to
provide a general methodology to aid in the synthesis of other novel stephaoxocanes. An efficient con-
struction of the AB ring system with increased functionality is described which presents a flexible
approach to synthesizing the C and D rings of eletefine.
Received 28 July 2010
Revised 14 August 2010
Accepted 17 August 2010
Available online 22 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
activity and the unusual structures of the family members. Elete-
fine (1) was logically the first member to prepare in our campaign
Isoquinoline alkaloids are an important class of biologically ac-
tive natural products.1 Among this class is the stephaoxocane
family of natural products which consists of eight structurally
interesting compounds (Fig. 1).2–7 The tetracycles contain a re-
mote alcohol stereocenter, an oxygen bridge, and uncommon
unsaturation at the bridgehead carbons. Our synthetic interest
in the stephaoxocanes results from the potential biological
to synthesize members of the stephaoxocane family. Eletefine
was first isolated in 1998 from the roots of Cissampelos glabber-
ima2 harvested in northeastern Brazil and later from the roots
of Stephania longa8 in southern China. Both plant species belong
to the family Menispermacae, members of which have been used
in traditional medicine to treat a wide range of symptoms. The
Cissampelos species have been used to treat symptoms of asthma
and urinary tract infections,8 while S. longa has been used in tra-
ditional Chinese medicine to reduce fever, inflammation, and to
fight dysentery.3
Previous synthetic work on the stephaoxocane skeleton has
been completed by Kaufman, who most recently completed the
synthesis of the carbon skeleton of excentricine without the oxy-
gen bridge or alcohol functionality.9–11 However, to date a success-
ful synthesis of a stephaoxocane has not been achieved. Herein, we
report the successful synthesis of a properly functionalized iso-
quinoline AB rings system and the development of key carbon–car-
bon bond-forming reactions toward our efforts in preparing the CD
rings of eletefine.
OCH3
4
5
4a
C
H3CO
H3CO
H3CO
H3CO
3
6
7
A
B
N
2
N
N
8
1
9
15
13
O
D
O
O
14
10
11
12
OH
OH
stephaoxocane
skeleton (2)
eletefine (1)
stephaoxocanidine (3)
H3CO
H3CO
H3CO
H3CO
H3CO
N
H
NH
NH
H
H3CO
H
H
O
O
O
OH
OH
OH
stephalonganine A (6)
H3CO
OH
2. Results and discussion
stephaoxocanine (4)
H3CO
excentricine (5)
H3CO
H3CO
A retrosynthetic analysis of our proposed route begins by sim-
plifying the novel divinyl oxygen bridge into ynoate 10 (Scheme
1). Therefore, a successful completion of eletefine is envisioned
to be achieved after completing the carbon–carbon bond-forming
reactions at C1 and C8 (stephaoxocane numbering) to join the
top and bottom fragments of the target. The formation of the C1–
C15 bond may be realized using a Sonogashira coupling reaction
NH
NCH3
NCH3
H3CO
H
H3CO
H
H
H
O
O
O
OH
OH
OH
OH
stephalonganine B (7)
stephalonganine C (8)
N-methylexcentricine (9)
Figure 1. The stephaoxocane family of alkaloids.
between c-lactone fragment 11 and isoquinoline 12. Both anionic
and acidic conditions may be proposed to form C8–C9 bond. The
convergent retrosynthetic analysis of eletefine is rapidly dissected
to a c-lactone 11 and an isoquinoline fragment 12.
⇑
Corresponding author. Fax: +1 585 475 7800.
E-mail address: jacsch@rit.edu (J.A. Cody).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.058

5586
J. A. Cody et al. / Tetrahedron Letters 51 (2010) 5585–5587
OCH3
O
OCH3
H3CO
H3CO
H3CO
H3CO
OCH3
OCH3
17
N
1
15
N
8
9
H3CO
H3CO
H3CO
O
H3CO
H3CO
Pd(PPh3)2Cl2
CuI, Et2NH
O
MeO2C
N
N
THF
97 %
OTf
12a
OH
OH
10
H3CO
1
18
OCH3
OCH3
OCH3
O
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
H2, 5% Pd/C
H
O
N
N
N
EtOAc
85-90%
O
O
X
OTf
H3CO
11
12a
X = H
20
19
12b X = Br
Scheme 3. Coupling the model alkyne 17 to triflate 12a using a Sonogashira
reaction.
Scheme 1. Proposed retrosynthetic analysis of eletefine (1).
Construction of the A and B rings of eletefine began with the ami-
dation of commercially available 3,4,5-trimethoxybenzoyl chloride
13 with aminoacetaldehyde dimetyl acetal in CH2Cl2 with diisopro-
pylamine as a base to give moderate yields of amide 14 (Scheme 2).
Amide 14 was in turn cyclized to isoquinoline 15 via a modified
Pomeranz–Fritsch reaction.12 The concentration of the sulfuric
acidic conditions was tuned to effect the cyclization of amide 14
without degradation. Triflation of isoquinolone 15 provided a 6:1
ratio of 12a to 16 in an overall yield of 49–64% from acyl chloride
13. The triflated mixture is the first point of purification in the route.
The N- and O-triflate compounds may be readily separated using sil-
ica gel chromatography. To our knowledge this is the first report of
an N-triflation observed when triflating an isoquinolone.
Currently, a readily available model alkyne fragment 17 is being
used to explore the final stages of the synthetic route, which will
provide des-hydroxyeletefine (20) (Scheme 3). Des-hydroxyelete-
fine is not chiral and may prove to be an interesting analogue for
biological studies. Triflate 12a easily underwent the Sonogashira
coupling reaction with model alkyne 17 in excellent yield. Efforts
to cyclize either alkyne 18 or alkane 19 under acidic conditions
to form the 10-membered ring only hydrolyzed the ester to the
corresponding carboxylic acids. The rigidity of alkyne 18 and in
turn the inherent strain of having three sp2 and two sp carbons
in a 10-membered ring limit the viability of cyclizing alkyne 18.
The cyclization of ester 19 is not limited by strain, but by
entropy.13
DBDMH, DMF
0ºC - RT
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
+
N
N
N
Overnight
Absence of light
50-61%
Br Br
OTf
12a
Br OTf
21
12b
Scheme 4. Bromination of triflate 12a to brominated triflate 12b.
synthesis of eletefine. The bromination of triflate 12a resulted in
a ratio of 3–4:1 of brominated triflate 12b and bis-brominated 21
prior to purification using 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH). Various brominating reagents were explored including
Br2 and NBS, however DBDMH was chosen due to its ease of use
and favorable results.14 Optimization of the bromination condi-
tions led us to utilize 1.5 equiv of DBDMH at 0 °C in the absence
of light (Scheme 4).
Silica gel chromatography provided a mixture of brominated
triflate 12b and dibromo 21 in a 6:1 ratio in acceptable yields. Di-
bromo 21 slowly degrades on silica gel, which explains the differ-
ence in ratios of 12b to 21 and may provide an opportunity for
further degradation and then purification to obtain pure bromi-
nated triflate 12b. Regardless, the mixture of 12b and 21 was used
in the following reaction without detriment, as both provided the
same product. When a mixture of the two compounds underwent
a Sonogashira coupling reaction under mild heating, alkyne 22 was
observed as the product in moderate yields. Interestingly, alkyne
Preparation of a bis-functionalized isoquinolone fragment offers
further opportunities to develop other routes toward the total
OCH3
OCH3 OCH3
DIPEA
H2NCH2CH(OMe)2
H3CO
H3CO
H3CO
OCH3
Cl
NH
H3CO
65-74%
crude yield
O
O
14
13
OCH3
H3CO
N
OCH3
H3CO
H3CO
80% H2SO4
Tf2O
OTf
12a
NH
TEA, CH2Cl2
H3CO
85-97%
crude yield
OCH3
O
49-64%
from 13
H3CO
H3CO
15
N
Tf
O
16
Scheme 2. Synthesis of triflated isoquinolone 12a.

J. A. Cody et al. / Tetrahedron Letters 51 (2010) 5585–5587
5587
OCH3
OCH3
H3CO
H3CO
O
H3CO
24, Pd(PPh3)2Cl2,
OCH3
OCH3
+
N
N
H3CO
H3CO
H3CO
H3CO
CuI, Et2NH
+
X
Br
N
N
THF
H3CO
O
Br OTf
Br Br reflux at 40ºC
H3CO
H3CO
21
12b
32
26
X = OTf or Br
Not Detected
50-55%
6
:
1
Scheme 5. Sonogashira reaction with a mixture of brominated triflate 12b and dibrominated 21.
23 was not observed (Scheme 5). Despite the presence of two hal-
ogenated sites on dibromo 21, the oxidative addition of the palla-
dium complex occurred alpha to the nitrogen atom. This result is
consistent with the results obtained by Stoltz et al. in 2004, where
a single product was observed from a Suzuki coupling reaction
with a dibrominated compound.15
ing. We would also like to thank GlaxoSmithKline for providing an
Undergraduate Fellowship Award to support Douglas Tusch for the
summer of 2008.
Supplementary data
Supplementary data (experimentals for the preparation of com-
pounds 12a–b, 14–18, and 22 including spectral data) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.08.058.
3. Conclusions
In the preparation of isoquinolone 12, a robust route was devel-
oped to prepare triflate 12a in 49–64% yield from commercially
available acid chloride 13 with only one purification step. Also, a
mixture of O-triflate 12a and N-triflate 16 was reported. Currently,
we are surveying a number of different acid chlorides with varying
electronic properties to determine the scope and generality of the
modified Pomeranz–Fritsch reaction to prepare isoquinolones.
Additionally, a useful bis-functionalized isoquinolone 12b inter-
mediate was prepared that can be envisioned to undergo car-
bon–carbon bond formation at the C-1 carbon using Pd coupling
chemistry or at the C-8 carbon with a lithium halogen exchange
reaction followed by addition of a carbon electrophile. Ongoing
work toward the total synthesis of eletefine will take advantage
of the flexibility of bis-functionalized isoquinolone fragment 12b.
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Acknowledgments
We thank the Department of Chemistry and College of Science
of the Rochester Institute of Technology for the facilities and fund-
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