The first total synthesis of the proposed structure of montiporyne E

Article abstract of DOI:10.1055/s-2006-942441

Montiporyne E, a novel diacetylenic lactam isolated from the stony coral Montipora sp., was shown to exhibit cytotoxicity against certain solid tumor cells. Construction of a suitably functionalized α,β-unsaturated lactam for palladium-catalyzed couplings

Full text of DOI:10.1055/s-2006-942441

PAPER
2319
The First Total Synthesis of the Proposed Structure of Montiporyne E
Total
Synthesis
o
h
f
the Propose
r
d Struct
i
ure of
M
s
ontipory
t
ne
E
ina G. Collison,* Jian Chen, Ryan Walvoord
Department of Chemistry, Rochester Institute of Technology, Rochester, NY 14623, USA
Fax +1(585)4757800; E-mail: cgcsch@rit.edu
Received 16 December 2005; revised 15 March 2006
The genus Montipora is especially rich in acetylenic com-
pounds that have been shown to possess antifungal, anti-
bacterial, ichthyotoxic, and cytotoxic properties.
Biological evaluation of these acetylenic compounds
Abstract: Montiporyne E, a novel diacetylenic lactam isolated
from the stony coral Montipora sp., was shown to exhibit cytotox-
icity against certain solid tumor cells. Construction of a suitably
functionalized a,b-unsaturated lactam for palladium-catalyzed cou-
plings was realized via a Beckmann rearrangement. Subsequent showed that montiporyne E (1) has moderate cytotoxicity
against a small panel of human solid tumor cell lines.4
Sonagoshira coupling with a known alkyne chain efficiently afford-
ed the alleged structure of the natural product.
Based on the analysis of its structure, our retrosynthetic
Key words: synthesis, Beckmann, lactams, coupling reactions,
strategy involved a Sonogashira coupling of a lactam enol
alkynes
triflate 2 with the known diyne side chain 36 (Scheme 1).
The lactam 2 was envisioned as coming from a Beckmann
rearrangement of the commercially available 3-ethoxy-2-
Soft corals have been extensively studied since the 1960s.
In contrast, stony corals (hard coral, scleractinian) have
cyclohexen-1-one (4). Beckmann rearrangements with vi-
nylic halides were often met with poor yields.7 As such,
historically been dismissed by chemists partly based on
we needed to investigate a method that was compatible
the belief that a hard coral would barely produce enough
with a vinyl functional group so that coupling via oxida-
organic extract since it consists mainly of a calcarious
tive addition with a palladium catalyst could follow.
skeleton.1 Recently, however, hard corals have resurfaced
as sources of interesting biologically active natural prod-
OH
HO
ucts.2 Among the marine metabolites often found are a
number of diacetylenic compounds, mostly isolated from
hermaphroditic scleractinian corals such as Montipora
digitata.1,3 Several new diacetylenic compounds found in
the hard coral Montipora sp. were reported,4 two of which
were recently synthesized.5
O
N
N
H
a
N
+
34%
O
OEt
OEt
5
6
7
syn oxime
anti oxime
Scheme 2 Reagents and conditions: a) PPA, 110–120 °C.
O
HN
Initially, Beckmann rearrangement of syn- and anti-
oximes 5 and 6 was attempted with polyphosphoric acid
at 110–120 °C for one hour since it had been reported that
isomerization occurs under these conditions to afford ex-
clusively one desired product, 7 (Scheme 2).7 The result-
ing reaction mixture was extracted with dichloromethane
to give the crude product 7 in 34% yield.
1
Figure 1 Supposed structure of montiporyne E
O
O
PMB
N
O
H
N
Et
OTf
O
2
4
+
1
H
3
Scheme 1 Retrosynthetic analysis of montiporyne E
SYNTHESIS 2006, No. 14, pp 2319–2322
x
x.
x
x
.
2
0
0
6
Advanced online publication: 28.06.2006
DOI: 10.1055/s-2006-942441; Art ID: M08405SS
© Georg Thieme Verlag Stuttgart · New York

2320
C. G. Collison et al.
PAPER
OH
OH
HO
N
N
N
O
Recrystallization
a
+
OEt
OEt
OEt
OEt
4
5
6
5
syn oxime
anti oxime
syn oxime
2
:
1
Scheme 3 Reagents and conditions: a) NH2OH·HCl, NaOAc, EtOH, 55–60 °C, 12 h.
Since b-keto lactam 7 was difficult to extract from water, b-keto lactam 10 in 87% yield. Finally, b-keto lactam 10
and required exorbitant amounts of dichloromethane for was converted to the desired enol triflate 2 in 60% yield
extraction, this method was not practical. In addition, pre- via treatment with trifluoromethane sulfonic anhydride
mature formation of the b-keto lactam complicated our ef- and a sodium hydroxide solution (3 N) in a two-phase sys-
forts to enolize and trap the intermediate since the lactam tem.
nitrogen was not yet protected.
O
Therefore our approach was modified to facilitate protec-
O
PMB
PMB
N
tion of the nitrogen. Commercially available ethoxy-2-cy-
clohexen-1-one (4) was treated with hydroxylamine
hydrochloride and sodium acetate in absolute ethanol. The
solution was heated to 55 °C for two hours to give the de-
sired oxime product.8,9 The solid white product obtained
was a 2:1 mixture of syn/anti-oximes (Scheme 3.)10 The
two isomers could be readily distinguished by their dis-
tinctive olefinic protons: a larger olefinic shift was ob-
served for the syn-oxime relative to the anti-oxime.11
a
N
OTf
2
11
O
H
N
b
OH
1
O
O
N
PMB
H
N
b
a
N
Scheme 5 Reagents and conditions: a) 3, Pd(PPh3)2Cl2, CuI, DMF
(90%); b) CAN, MeCN–H2O (88%).
OEt
OEt
OEt
5
8
9
The Sonogashira coupling12 of the enol triflate 2 with
diyne 3 ensued, when treated with bis(triphenylphos-
phine)palladium(II) dichloride and copper(I) iodide in
DMF, to give the desired coupled product 11 in 90% yield
(Scheme 5).13 Removal of PMB in 11 was achieved via
treatment with CAN in acetonitrile and water at room
temperature14 to afford the presumed structure of monti-
poryne E (1) in 88% yield after purification by column
chromatography.
O
O
PMB
PMB
c
d
N
N
O
OTf
10
2
Scheme 4 Reagents and conditions: a) p-TsCl/Et3N, THF, then
10% K2CO3 (80%); b) PMBCl, NaH, DMF 63%; c) Concd HCl,
EtOH–H2O (87%); d) Tf2O, NaOH (3 N), CH2Cl2 (60%).
1
Comparison of the H and 13C NMR spectral data of the
synthetic sample with those of the natural product sug-
gests they are not identical (Table 1). Despite the spectral
differences, we are confident that we have synthesized the
reported structure of montiporyne E. However, largely
due to the many impurities present in the spectral data of
the isolated natural product, it remains difficult to explain
the observed significant shift discrepancies.15
Beckmann rearrangement was facilitated by p-toluene-
sulfonyl chloride instead of polyphosphoric acid. Since
these conditions were milder, only the syn-oxime could
undergo rearrangement. We treated the recrystallized syn-
oxime 5 with p-toluenesulfonyl chloride and triethyl-
amine to give the lactam 8 in 80% yield (Scheme 4).7 In
addition to spectroscopic techniques, the structure of lac-
tam 8 was characterized by X-ray crystallographic analy-
sis to verify the correct direction of Beckmann
rearrangement.
In summary, an efficient synthetic approach to the pro-
posed structure of the natural product montiporyne E has
been explored. Our synthesis has resulted in a convergent
strategy using a Sonogashira coupling for the connection
of a monosubstituted diacetylenic side chain with a novel
seven-membered lactam enol triflate. All spectral data for
our synthesized compound 1 are in agreement with its
chemical structure.
With the lactam 8 in hand, the nitrogen was then protected
as a p-methoxybenzyl group (PMB). Lactam 8 was treated
with PMBCl to afford PMB-protected lactam 9 in 63%
yield. Next, acidic hydrolysis of 9 gave the corresponding
Synthesis 2006, No. 14, 2319–2322 © Thieme Stuttgart · New York

PAPER
Total Synthesis of the Proposed Structure of Montiporyne E
IR (film): 1680, 1520, 1260 cm–1.
2321
Table 1 Comparisons of the 1H and 13C NMR Data for the Synthetic
and Natural Sample of 1
1H NMR (400 MHz, CDCl3): d = 7.25 (d J = 8.7 Hz, 2 H), 6.86 (d,
J = 8.7 Hz, 2 H), 5.15 (s, 1 H), 4.61 (s, 2 H), 3.81 (s, 3 H), 3.80 (q,
J = 7.0 Hz, 2 H), 3.31 (dd, J = 7.4, 6.0 Hz, 2 H), 2.36 (t, J = 7.3 Hz,
2 H), 1.81–1.75 (m, 2 H), 1.34 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.2, 159.3, 130.8, 129.9, 116.5,
114.3, 96.8, 63.9, 55.6, 50.4, 46.8, 31.1, 27.8, 14.7.
O
HN
3
7
5
LC/MS (APCI+): m/z = 276.0 (M + H).
HRMS (ESI): m/z calcd for C16H21O3N [M+]: 275.1516; found:
1
275.15201.
Position
1H 1
(ppm)
1H Natural
(ppm)
13C 1
(ppm)
13C Natural
(ppm)
N-(p-Methoxybenzyl)azepane-2,4-dione (10)
To a solution of 9 (231 mg, 0.8 mmol) in EtOH (3 mL), was added
H2O (3 mL) and concd HCl (1 mL). The mixture was heated to
50 °C for 2–3 h, then cooled to r.t. The mixture was poured into an
ice bath, neutralized with a 10% solution of K2CO3 (10 mL), and
then extracted with EtOAc (2 × 10 mL). The resulting organic lay-
ers were dried over MgSO4, filtered, and concentrated to give 10 as
a pure yellow oil (180 mg, 87%).
3
5
6
7
6.22
2.58
2.03
3.27
6.60
2.75
1.86
3.35
131.2
32.9
28.2
39.7
115.7
28.2
23.4
42.9
IR (film): 1700, 1650, 1520, 1250 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.24 (d, J = 8.7 Hz, 2 H), 6.87 (d,
J = 8.7 Hz, 2 H), 4.59 (s, 2 H), 3.81 (s, 3 H), 3.61 (s, 2 H), 3.52 (t,
J = 6.0 Hz, 2 H), 2.54 (t, J = 7.1 Hz, 2 H), 1.79 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 203.5, 167.0, 159.2, 129.6 (2 C),
129.2, 114.1 (2 C), 55.2, 52.2, 50.1, 46.2, 41.6, 25.5.
All solvents were freshly distilled before use and anhyd THF and
Et2O were distilled under argon from Na/benzophenone. Chemical
1
shifts in H and 13C NMR spectra are reported relative to residual
solvents. Progress of the reactions were monitored by TLC using
Kodak silica gel 60 F254 pre-coated plates and visualized using UV
lamps or staining with a mixture of p-anisaldehyde/H2SO4/EtOH or
KMnO4/NaOH/K2CO3/H2O. The products were purified by column
chromatography (SiO2). Analytical data of all known compounds
were compared with the literature, and new compounds that were
stable were fully characterized.
HRMS (ESI): m/z calcd for C14H17O3NNa [M + Na]: 270.1101;
found: 270.1093.
Trifluoromethanesulfonic Acid N-(p-Methoxybenzyl)-2-
oxoazepan-4-yl Ester (2)
To a solution of 10 (146 mg, 0.6 mmol) in CH2Cl2 (4 mL) was added
an aq solution of NaOH (3 N, 4 mL), followed by the dropwise ad-
dition of Tf2O (0.2 mL, 1.2 mmol) at 0 °C. The resulting mixture
was slowly warmed to r.t. over 12 h. The mixture was diluted with
CH2Cl2 (10 mL) and the phases separated. The organic phase was
washed with H2O (15 mL) and brine (15 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by col-
umn chromatography to give 2 as a colorless oil (133 mg, 60%).
1H NMR (400 MHz, CDCl3): d = 7.23 (d, J = 8.6 Hz, 2 H), 6.90 (d,
J = 8.6 Hz, 2 H), 6.19 (s, 1 H), 4.61 (s, 2 H), 3.82 (s, 3 H), 3.39 (m,
2 H), 2.65 (t, J = 7.1 Hz, 2 H), 1.89 (m, 2 H).
4-Ethoxy-1,5,6,7-tetrahydroazepin-2-one (8)
To a solution of syn-3-ethoxy-2-cyclohexen-1-one (5; 1.0g, 6.5
mmol) in anhyd THF (25 mL) was added Et3N (1.8 mL) at 0–5 °C,
followed by addition of p-TsCl (1.5 g, 7.8 mmol). After stirring for
an additional 1 h at this temperature, the reaction was quenched with
a 10% solution of K2CO3 (20 mL). After removal of the ice water
bath, the reaction mixture was allowed to warm to r.t. for 1 h. The
solvent was removed under reduced pressure, the residue was neu-
tralized with 1 N HCl and extracted with CH2Cl2 (2 × 15 mL). The
combined organic layers were washed with H2O (30 mL), brine (25
mL), dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography to give the pure prod-
uct 8 as colorless needles (795 mg, 80%);7,11 mp 117–118 °C.
13C NMR (100 MHz, CDCl3): d = 164.0, 159.2, 156.9, 129.6 (2 C),
128.8, 118.8, 113.9 (2 C), 55.2, 50.7, 45.8, 43.4, 31.7, 26.3.
IR (film): 3260, 1680,1580 cm–1.
LC-MS (APCI+): m/z = 380.0 (M + H).
1H NMR (400 MHz, CDCl3): d = 6.08 (br s, 1 H), 5.11 (s, 1 H), 3.82
(q, J = 7.0 Hz, 2 H), 3.29–3.25 (m, 2 H), 2.52 (t, J = 7.0 Hz, 2 H),
2.0–1.96 (m, 2 H), 1.35 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.9, 168.4, 97.0, 63.9, 41.4,
33.1, 27.4, 14.6.
N-(p-Methoxybenzyl)-4-undeca-1,3-diynyl-1,5,6,7-tetra-
hydroazepin-2-one (11)
To a solution of enol triflate 2 (29 mg, 0.08 mmol) and diacetylene
3 (13.6 mg, 0.09 mmol) in DMF (2 mL) was added CuI (2.9 mg, 0.2
mmol) and Pd(PPh3)2Cl2 (5.4 mg, 0.1 mmol), followed by the addi-
tion of Et3N (21.5 mL, 0.15 mmol) at r.t. The solution was stirred for
12 h and then diluted with Et2O (8 mL). The organic phase was
washed with a sat. solution of NaHCO3, a sat. solution of NH4Cl (10
mL), H2O (10 mL), and brine (15 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was purified by col-
umn chromatography to afford 11 as a brown oil (26 mg, 90%).
LC-MS (APCI+): m/z = 156.1 (M + H), 311.0 (2 M + H).
4-Ethoxy-N-(p-methoxybenzyl)-1,5,6,7-tetrahydroazepin-2-one
(9)
To a solution of 8 (50 mg, 0.3 mmol) in anhyd DMF (1 mL), was
added NaH (60%; 15.4 mg, 0.4 mmol) at r.t., followed by the addi-
tion of PMBCl (65 mL, 0.5 mmol). The reaction mixture was stirred
at r.t. for 6 h and then quenched with H2O (5 mL). The mixture was
extracted with EtOAc (2 × 8 mL), the combined organic phases
were washed with brine (10 mL), dried over MgSO4, filtered, and
concentrated. The residue was purified by column chromatography
to give the pure product 9 as a yellow oil (55 mg, 63%).
IR (film): 2920, 2240, 1640, 1510, 1460, 1210 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.25 (d, J = 8.6 Hz, 2 H), 6.89 (d,
J = 8.6 Hz, 2 H), 6.30 (s, 1 H), 4.58 (s, 2 H), 3.78 (s, 3 H), 3.36 (t,
J = 6.20 Hz, 2 H), 2.37 (t, J = 7.1 Hz, 2 H), 2.35 (t, J = 7.5 Hz, 2 H),
1.79 (m, 2 H), 1.55 (m, 2 H), 1.42–1.40 (m, 2 H), 1.34–1.31 (m, 6
H), 0.91 (t, J = 6.6 Hz, 3 H).
Synthesis 2006, No. 14, 2319–2322 © Thieme Stuttgart · New York

2322
C. G. Collison et al.
PAPER
13C NMR (100 MHz, CD3OD): d = 168.3, 159.4, 131.7, 130.6,
129.4, 129.2 (2 C), 113.6 (2 C), 87.1, 77.8, 74.1, 64.0, 54.2, 49.4,
45.5, 31.4, 30.6, 28.4, 28.3, 28.0, 27.8, 22.2, 18.6, 12.9.
HRMS (ESI): m/z calcd for C25H33O2N [M + H]+: 378.2428; found:
378.2413.
(2) For some early examples of metabolites from hard corals,
see: (a) Alam, M.; Sanduja, R.; Welling, G. M. Heterocycles
1988, 27, 719. (b) Higa, T.; Sakai, R. Chem. Lett. 1987,
127. (c) Fusrtani, N.; Asano, M.; Matsunaga, S.; Hashimoto,
K. Comp. Biochem. Physiol., Part B: Biochem. Mol. Biol.
1986, 85, 845. (d) Sanduja, R.; Alam, M.; Wellington, G. E.
J. Chem. Res., Synop. 1986, 450. (e) Sanduja, R.; Martin, G.
E.; Weinheimer, A. J.; Alam, M.; Hossain, M. B.; van der
Helm, D. J. Heterocycl. Chem. 1984, 21, 845.
(3) (a) Coll, J. C.; Bowden, B. F.; Meehan, G. V.; Kong, G. M.;
Carroll, A. R.; Tapiolas, D. M.; Alino, P. M.; Heaton, A.; De
Nys, R.; Leone, P. A.; Maida, M.; Aceret, T. L.; Willis, R.
H.; Babcock, R. C.; Willis, B. L.; Florian, Z.; Clayton, M.
N.; Miller, R. L. Mar. Biol. 1994, 118, 177. (b) Fusetani,
N.; Toyoda, T.; Asai, N.; Matsunga, S.; Maruyama, T. J.
Nat. Prod. 1996, 59, 796.
4-Undeca-1,3-diynyl-1,5,6,7-tetrahydroazepin-2-one (1)
To a solution of 11 (5 mg, 13.3 mol) in H2O (0.2 mL) and MeCN
(0.8 mL), CAN (36 mg, 0.07 mmol) was added at r.t. The mixture
was stirred for 2–5 h, then poured into H2O (5 mL), and extracted
with EtOAc (3 × 5 mL). The combined organic layers were washed
with a sat. solution of NaHCO3 (5 mL), H2O (5 mL), brine (10 mL),
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography to give 1 as a white foam
(3 mg, 88%).
IR (film): 3320–3180, 2220, 1660 cm–1.
(4) (a) Bae, B. H.; Im, K. S.; Choi, W. C.; Hong, J.; Lee, C.-O.;
Choi, J. S.; Son, B. W.; Song, J.-I.; Jung, J. H. J. Nat. Prod.
2000, 63, 1511. (b) Stefani, H. A.; Costa, I. M.; Zeni, G.
Tetrahedron Lett. 1999, 40, 9215.
1H NMR (400 MHz, CD3OD): d = 6.22 (s, 1 H), 3.27 (t, J = 4.4 Hz,
2 H), 2.58 (t, J = 6.9 Hz, 2 H), 2.42 (t, J = 6.9 Hz, 2 H), 2.03 (quin,
J = 6.7 Hz, 2 H), 1.60 (quin, J = 7.2 Hz, 2 H), 1.48–1.44 (m, 2 H),
1.38–1.31 (m, 6 H), 0.95 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CD3OD): d = 170.1, 133.5, 131.0, 87.2, 77.7,
74.4, 64.0, 39.7, 32.9, 31.5, 28.5 (2C), 28.2, 27.8, 22.2, 18.6, 12.9.
(5) Speed, T. J.; Thamattoor, D. M. Tetrahedron Lett. 2002, 43,
367.
(6) Dabdoub, M. J.; Baroni, A. C. M.; Lenardao, E. J.; Gianeti,
T. R.; Hurtado, G. R. Tetrahedron 2001, 57, 4271.
(7) Tamura, Y.; Kita, Y.; Matsutaka, Y.; Terashima, M. Chem.
Pharm. Bull. 1971, 19, 529.
HRMS (ESI): m/z calcd for C17H25ON [M + H]+: 258.1852; found:
258.1857.
(8) Tamura, Y.; Kita, Y.; Matsutaka, Y.; Terashima, M. Chem.
Pharm. Bull. 1971, 19, 523.
(9) Hu, H.; Jagdomann, G. E. Jr.; Hughes, P. F.; Nichols, J. B.
Tetrahedron Lett. 1995, 36, 3659.
(10) The oxime mixture could be recrystallized from EtOH to
give pure syn-oxime 5 in 43% yield.
(11) Tamura, Y.; Kita, Y.; Matsutaka, Y.; Terashima, M. Chem.
Pharm. Bull. 1971, 19, 523.
Acknowledgment
We thank the RIT Department of Chemistry for the start-up funds
for this project and the RIT honors program for an undergraduate
summer research assistantship. We are indebted to Dr. Zecheng
Chen and Dr. Andrew S. Kende of the University of Rochester for
their helpful discussions on the project. We also thank Dr. Sandip
Sur and Dr. Christine Flaschenriem of the University of Rochester
for advanced spectral data of our final compound and the X-ray cry-
stal structure.
(12) (a) Katritzky, A. R.; Yao, J.; Qi, M. J. Org. Chem. 1997, 62,
8201. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 16, 4467.
(13) Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582.
(14) Yamaura, M.; Suzuki, T.; Hashimoto, H.; Yoshimusa, J.;
Okamoto, T.; Shin, C.-G. Bull. Chem. Soc. Jpn. 1985, 58,
1413.
References
(15) The 1H and 13C NMR spectra of natural montiporyne E were
provided by Dr. Jee H. Jung, College of Pharmacy, Pusan
National University, Korea.
(1) Higa, T.; Tanaka, J.; Kohagura, T.; Wauke, T. Chem. Lett.
1990, 145.
Synthesis 2006, No. 14, 2319–2322 © Thieme Stuttgart · New York