Total synthesis of the marine alkaloids Caulibugulones A and D

Article abstract of DOI:10.1016/j.tet.2014.12.059

Total synthesis of the marine cytotoxic alkaloids Caulibugulones A and D is accomplished in three steps with an overall yield of 60-62% from easily accessible starting materials. The key features include isoquinoline-5,8-diol core construction by ammonia mediated iminoannulation of 2-ethynyl-3,6-dihydroxybenzaldehyde, and subsequent in situ oxidation followed by oxidative amination.

Full text of DOI:10.1016/j.tet.2014.12.059

Tetrahedron 71 (2015) 801e804
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Total synthesis of the marine alkaloids Caulibugulones A and D
*
K.S. Prakash, Rajagopal Nagarajan
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Total synthesis of the marine cytotoxic alkaloids Caulibugulones A and D is accomplished in three steps
with an overall yield of 60e62% from easily accessible starting materials. The key features include
isoquinoline-5,8-diol core construction by ammonia mediated iminoannulation of 2-ethynyl-3,6-
dihydroxybenzaldehyde, and subsequent in situ oxidation followed by oxidative amination.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 25 November 2014
Received in revised form 13 December 2014
Accepted 15 December 2014
Available online 19 December 2014
Keywords:
Marine alkaloids
Total synthesis
Iminoannulation
Caulibugulones
Oxidative amination
1. Introduction
Caulibugulones AeF (Fig. 1, 1e6) are isoquinoline quinone al-
kaloids,1 isolated from an extract of the marine bryozoan Caulibu-
gula intermis collected in the Indo-Pacific off Palau, by Milanowski
and co-workers in 2004.2 Compounds 1e6 were found to have
interesting cytotoxic activity (IC50 of 0.03e1.67
mg/mL) against
murine tumour cells.2 Valderrama et al. reported the synthesis of 4-
methoxycarbonyl-3-methylisoquinoline-5,8-quinone (which con-
tains the Caulibugulone core) and their analogues, which expressed
valuable in vitro cytotoxic activity against MRC-5 (healthy lung
fibroblasts) and human cancer cell lines: AGS (gastric), SK-MES-1
(lung), J82 (bladder) and HL-60 (leukaemia).3 The Brission group
reported that Caulibugulones are selective in vitro inhibitor of the
Cdc25 family of cell cycle-controlling protein phosphatases.4
However, to the best of our knowledge, there are only three
reports on the synthesis of Caulibugulones.5e7 In 2004, Tamagnan
et al. reported the first total synthesis of Caulibugulones from 5,8-
isoquinolinedione, which was prepared 30% overall yield from 5-
aminoisoquinoline.5 In the same year, Wipf and co-workers re-
ported the synthesis of 1e6 from oxidation of 5-
hydroxyisoquinoline by iodobenzene bis(trifluoroacetate) PIFA in
a H2O/EtOH and the subsequent in situ addition of methylamine,
and they reported that compounds 1e6 are potent and selective
inhibitors of the dual specificity phosphatase Cdc25B.6 Most re-
cently, Caulibugulones AeD were synthesized in six steps starting
Fig. 1. Structure of Caulibugulones AeF (IC50 are expressed in
mg/mL against the
murine tumour cell line).2
from 2,5-dimethoxybenzaldehyde. The key intermediate 5,8-
dimethoxyisoquinoline was prepared from PomeranzeFritsch re-
action of N-(2,5-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-2-
nitrobenzenesulfonamide.7 We planned a different efficient and
simple route for the synthesis of key intermediate 5,8-
dihydroxyisoquinoline by utilizing ammonia-mediated imi-
noannulation of the corresponding 1,2-alkynylaldehyde.
2. Results and discussion
The significant biological activity and very few methods for the
synthesis of Caulibugulones5e7 prompted us to find a new approach
* Corresponding author. Tel.: þ91 40 23134831; fax: þ91 40 23012460; e-mail
addresses: rnsc@uohyd.ernet.in, naga_indole@yahoo.co.in (R. Nagarajan).
http://dx.doi.org/10.1016/j.tet.2014.12.059
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

802
K.S. Prakash, R. Nagarajan / Tetrahedron 71 (2015) 801e804
towards the synthesis of these marine alkaloids. We recently re-
ported the first total synthesis of the marine alkaloid Mansour-
amycin D via iminoannulation.8 We herein report a simple and
concise total synthesis of Caulibugulones A and D via iminoannu-
lation with an overall yield of 62% and 60% over three steps from an
easily accessible known starting material. Fig. 2 shows the retro-
synthetic analysis for the synthesis of 1 and 4. Caulibugulone A and
D (1 and 4) are the direct products of aminolysis of isoquinoline-
5,8-dione (5) with methylamine and 2-aminoethanol, respectively.
In addition, Caulibugulone A (1) would be extended to Caulibugu-
lone B (2) C (3) and E (5) by halogenation using NBS or NCS or
imination.6 The dione 7 could easily be synthesized from the 5,8-
dihydroxyisoquinoline 8. The formation of protected 5,8-
Caulibugulone A (1) in a yield of 82% over the two steps (Scheme 1).
Caulibugulone D (4) was also synthesized with 80% yield from
dione 7 by aminolysis with ethanolamine (2 equiv) in DME. The
structure of Caulibugulone D (4) was unambiguously confirmed by
single-crystal X-ray diffraction analysis,13 the ORTEP of 4 is shown
in Fig. 3.
dihydroxyisoquinoline from corresponding alkynylaldehyde
9
would be the key step in this report. The alkynylaldehyde 9 would
be accessed from Sonogashira cross coupling9 of bromoaldehyde 10
with trimethylsilylacetylene followed by removal of trimethylsilyl
group.
Scheme 1. Total synthesis of Caulibugulones A and D.
Fig. 2. Retrosynthetic analysis of Caulibugulones AeD.
2-Bromo-3,6-bis(methoxymethoxy)benzaldehyde (11) was
readily prepared by bromination, followed by MOM protection of
2,5-dihydroxybenzaldehyde in 82% yield over two steps.10 The se-
lection of the MOM group was designed to be easily tailored to
provide isoquinoline-5,8-diol. Then, Sonogashira coupling of 11
with trimethylsilylacetylene in the presence of
4 mol % of
Fig. 3. ORTEP diagram of Caulibugulone D (4).
PdCl2(PPh3)2, 2 mol % of CuI provided the coupled product 12 as
pale yellow oil in 90% yield. With compound 12 in hand, the re-
action was proceeded with the trimethylsilyl (TMS) group, because
we anticipated its removal after cyclization under K2CO3 in ethanol
reaction condition. The cyclization underwent smoothly with an
excess of aqueous ammonia (27% ammonia in water), 2 equiv of
K2CO3, in ethanol under reflux conditions and gave the expected
product 5,8-bis(methoxymethoxy)isoquinoline (13) in 84% yield. In
a parallel study, we attempted the synthesis of 13 by Larock imi-
noannulation11 via preparation of tert-butyl imine of 12, followed
by copper catalyzed cyclization, but this was unsuccessful.
The regioselective oxidative amination of 7 and formation of the
major isomer is explained by the resonance stabilization of com-
pound 7.5 C-7 position of isoquinoline-5,8-dione is more favourable
for oxidative amination than C-6 and so that the required
regioisomer was formed as a sole product. With Caulibugulone A in
hand, it would be converted into Caulibugulones B (2), C (3) and E
(5) potentially by following the previously reported studies by Wipf
and co-workers6 (Fig. 4).
The completion of total synthesis of Caulibugulones A (1) and D
(4) is shown in Scheme 1. Compound 13 is further subjected to
removal of the MOM group by treating with THF/H2O/concd HCl
(6:2:1 ratio) with heating at 50 ꢀC to afford the required iso-
quinoline-5,8-diol, which was further converted into isoquinoline-
5,8-dione (7) by in situ oxidation. Unfortunately, the dione 7 has
insufficient stability, the next step was proceeded after a water
work up and sodium bicarbonate wash without further purification
and isolation of 7. This observation is consistent with the previous
literature reports on difficulties of isolating and characterizing of
14.6,7 Therefore, crude compound 7 is directly subjected to ami-
nolysis12 using 3 equiv of methylamine (33 wt % in ethanol). After
complete conversion as monitored by TLC (1 h), the product was
purified by column chromatography using silica gel to afford
Fig. 4. Formal synthesis of Caulibugulones B, C and E.

K.S. Prakash, R. Nagarajan / Tetrahedron 71 (2015) 801e804
803
Thus, we have completed the total synthesis of Caulibugulones
A and D with overall yields of 62% and 60%, respectively, the highest
overall yields so far. NMR and high-resolution mass data of the
synthesized compounds (1 and 4) are in full accordance with nat-
ural Caulibugulones A (1) and D (4). Spectroscopic data comparison
is given in Tables S1 and S2 (see Supplementary data).
NMR (100 MHz, TMS, CDCl3)
117.3,107.1 (aromatic C), 96.9, 96.0, 95.6, 56.4, 0.2 (aliphatic C) HRMS
(ESI-MS) calcd for C16H22O5Si: 345.1134 (MþNa), found: 345.1131.
d
: 190.4,153.8,152.9,127.2,122.6,117.6,
4.2.2. 5,8-Bis(methoxymethoxy)isoquinoline (13). An oven-dried
10 mL round-bottomed flask equipped with a Teflon-coated mag-
netic stirring bar was charged with 3,6-bis(methoxymethoxy)-2-
(2-(trimethylsilyl)ethynyl)benzaldehyde (12) (100 mg, 0.31 mmol)
and K2CO3 (128 mg, 0.93 mmol), 2 mL of ethanol and excess of
aqueous ammonia (0.5 mL) (27% ammonia in water). The reaction
mixture was allowed to stir under reflux for 2 h. The complete
conversion of starting material was observed (TLC). Then, the re-
action mixture was allowed to cool to room temperature and
extracted with CHCl3 (2ꢁ10 mL). The organic layer was washed
with 10 mL of water and 5 mL of brine, dried over anhydrous so-
dium sulfate and solvent was removed under reduced pressure. The
crude product was purified by column chromatography on silica gel
(eluent: 10% ethyl acetate in hexanes). The product was eluted in
10% eluent as a thick pale yellow liquid (65 mg) in 84% yield.
Rf¼0.20 (20% ethyl acetate in hexanes). IR (neat): 2954, 2827, 1625,
3. Conclusion
In summary, we have disclosed a concise synthesis of Caulibu-
gulones A (1) and D (4) via three steps with overall yields of 62%
and 60%, respectively. Noteworthy features of this synthesis in-
clude; (a) the effective preparation of isoquinoline-5,8-diol core via
ammonia mediated iminoannulation, (b) in situ oxidation and
regioselective oxidative amination, (c) generally excellent yield, (d)
overall operational simplicity, (e) Caulibugulones B, C and E (2, 3
and 5) can easily be synthesized from Caulibugulone A (1) by fol-
lowing the literature procedure. (f) The protocol presented herein
potentially allows the preparation of biologically active Caulibu-
gulones for further biological screening and evaluation.
1575, 1491, 1453, 1375, 1273, 1110, 1024, 920, 821, 716 cmꢂ1
NMR (400 MHz, TMS, CDCl3)
;
1H
4. Experimental section
4.1. General information
d: 9.63 (s, 1H), 8.59 (d, J¼5.6 Hz, 1H),
7.97 (d, J¼6.0 Hz, 1H), 7.22 (d, J¼8.4 Hz, 1H), 7.09 (d, J¼8.4 Hz, 1H),
5.38 (s, 2H), 5.34 (s, 2H), 3.56 (s, 3H), 3.55 (s, 3H); 13C NMR
(100 MHz, TMS, CDCl3) d: 148.3, 147.2, 146.5, 143.3, 129.5, 114.5,
112.6, 109.1 (aromatic C), 95.3, 95.1, 56.3, 56.2 (aliphatic C); HRMS
(ESI-MS) calcd for C13H15NO4: 250.1079 (MþH), found: 250.1075.
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, or at 500 and 125 MHz, respectively. Chemical shifts
are calculated in parts per million (ppm) downfield from TMS (
d
¼0)
for 1H NMR, and relative to the central CDCl3 resonance (
d
¼77.00)
4.2.3. Caulibugulone A (1). An oven-dried 10 mL round-bottomed
flask equipped with a Teflon-coated magnetic stirring bar was
charged with 5,8-bis(methoxymethoxy)isoquinoline (13) (50 mg,
0.20 mmol) in 1 mL THF. Solution of THF, H2O and concd HCl (6:4:1
ratio) (1 mL) was added dropwisely to the reaction mixture. Then
reaction mixture was allowed to stir at 50 ꢀC for 2 h. The reaction
mass turned in dark yellow colour after 30 min. The complete
conversion observed by TLC. The solvent THF was removed under
reduced pressure. The resultant residue was extracted with ethyl
acetate (2ꢁ10 mL), washed with saturated sodium bicarbonate
solution, water, brine and concentrated under reduced pressure.
This crude material (red colour residue) was then taken for next
step without further purification. The residue was diluted with
2 mL of 1,2-dimethoxymethane (1,2-DME). The reaction mixture
was then cooled to 0 ꢀC and 33 wt % absolute ethanolic solution of
methylamine (0.6 mL, 0.06 mmol) was added dropwise. Then it was
allowed to stir at room temperature. After 2 h complete conversion
was observed in TLC. After removing the solvent under reduced
pressure, the reaction mixture was poured in 10 mL of water and
extracted with ethyl acetate (2ꢁ20 mL). The organic layer was
washed with water (10 mL) and brine (5 mL), dried over anhydrous
sodium sulfate and the solvent was removed under reduced pres-
sure. The crude product was purified by column chromatography
(eluent: 20% ethyl acetate in hexanes). The product was eluted in
20% eluent as a red solid (31 mg) in 82% yield. Rf¼0.37 (20% ethyl
acetate in hexanes). Mp 218e220 ꢀC; IR (neat): 3371, 2958, 2922,
2852, 2362, 1733, 1683, 1603, 1585, 1362, 1261, 1078, 797 cmꢂ1; 1H
and CD3CN (
d
¼118.20) for 13C NMR. Data are presented as follows:
chemical shift, multiplicity (br s¼broad singlet, s¼singlet,
d¼doublet, t¼triplet, dt¼doublet of triplet), coupling constant in
hertz (Hz) and integration. IR spectra were recorded on FT/IR-5700
instrument. TOF and quadrupole mass analyzer types are used for
the HRMS measurements. Melting points were measured in open
capillary tubes and are uncorrected. All the obtained products were
purified by column chromatography using silica gel (100e200
mesh). All reaction solvents used were of GR grade and used
without drying unless mentioned. All other commercial reagents
were used as received.
The starting material 2-bromo-3,6-bis(methoxymethoxy)benz-
aldehyde (11) was prepared as reported.8
4.2. General procedure
4.2.1. 3,6-Bis(methoxymethoxy)-2-(2-(trimethylsilyl)ethynyl)benzal-
dehyde (12). An oven-dried 50 mL Schlenk tube equipped with
a Teflon-coated magnetic stirring bar is charged with 2-bromo-3,6-
bis(methoxymethoxy)benzaldehyde (11) (1 g, 3.2 mmol), CuI
(12 mg, 2 mol %) and PdCl2(PPh3)2 (91 mg, 4 mol %), freshly distilled
triethylamine (0.5 mL), dry THF (4 mL) and trimethylsilylacetylene
(1.8 mL, 12.8 mmol) was added under nitrogen atmosphere and the
resulting mixture was heated at 70 ꢀC. After 18 h, the complete
conversion of starting material was observed by TLC. The reaction
mixture was cooled to room temperature, it was diluted with 50 mL
of CHCl3 and filtered through Celite bed. Then, water (10 mL) was
added to the diluted solution, which was then extracted with CHCl3
(2ꢁ50 mL). The combined organic layer was dried with anhydrous
Na2SO4 and concentrated under vacuum and purified by column
chromatography on silica gel (eluent: 5% ethyl acetate in hexanes) to
afford the 3,6-bis(methoxymethoxy)-2-(2-(trimethylsilyl)ethynyl)
benzaldehyde (12) as a viscous oil (0.95 g) in 90% yield. Rf¼0.41 (20%
ethyl acetate in hexanes). IR (neat): 2925, 2853, 2154, 1698, 1576,
NMR (500 MHz, TMS, CDCl3)
7.84 (d, J¼5.0 Hz, 1H), 6.02 (br s, 1H), 5.75 (s, 1H), 2.89 (d, J¼5.0 Hz,
3H); 13C NMR (125 MHz, TMS, CDCl3)
: 181.2, 180.9, 156.3, 148.8,
d
: 9.19 (s, 1H), 8.94 (d, J¼5.0 Hz, 1H),
d
147.9, 139.3, 124.2, 119.0, 101.2 (aromatic C), 29.2 (aliphatic C);
HRMS (ESI-MS) calcd for C10H8N2O2: 189.0664 (MþH), found:
189.0661. Rf value and other spectroscopic properties were found to
be identical with the Caulibugulone A reported earlier.5e7
1468, 1441, 1393, 1000, 922, 752 cmꢂ1
CDCl3)
: 10.59 (s, 1H), 7.25 (d, J¼9.2 Hz, 1H), 7.15 (d, J¼9.2 Hz, 1H),
5.22 (s, 2H), 5.21 (s, 2H), 3.56 (s, 3H), 3.51 (s, 3H), 0.29 (s, 9H); 13C
;
1H NMR (400 MHz, TMS,
4.2.4. Caulibugulone D (4). Same experimental protocol as adopted
in the synthesis of Caulibugulone A (1) was followed. To a solution
of THF, H2O and concd HCl (6:4:1 ratio) (1 mL),
d

804
K.S. Prakash, R. Nagarajan / Tetrahedron 71 (2015) 801e804
5,8-bis(methoxymethoxy)isoquinoline (13) (50 mg, 0.20 mmol) in
1 mL THF was added dropwise. Resulting residue was diluted with
2 mL of 1,2-dimethoxymethane. The reaction mixture was then
cooled to 0 ꢀC and 2-aminoethanol (36 mg, 0.60 mmol) in 1 mL of 1,2-
DME was added dropwise. Then it was allowed to stir at room tem-
perature. After 2 h, complete conversion was observed in TLC. After
removing the solvent in reduced pressure, the reaction mixture was
poured in 10 mL of water and extracted with ethyl acetate (2ꢁ20 mL).
The organic layer was washed with water (10 mL) and brine (5 mL),
dried over anhydrous sodium sulfate and the solvent was removed
under reduced pressure. The crude product was purified by column
chromatography (eluent: 40% ethyl acetate in hexanes). The product
was eluted in 40% eluent as an orange solid (35 mg) in 80% yield.
Rf¼0.42 (95:5 ethyl acetate/methanol). Mp 180e182 ꢀC; IR (neat):
3312, 3193, 3015, 2973, 1689, 1633,1594,1561, 1524,1354, 1327, 1101,
References and notes
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991, 753 cmꢂ1; 1H NMR (500 MHz, TMS, CD3CN)
d: 9.16 (s, 1H), 8.97
9. For reviews on Sonogashira cross coupling, see: (a) Sonogashira, K. In Com-
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(d, J¼5.0 Hz,1H), 7.81 (d, J¼5.0 Hz,1H), 6.57 (br s,1H), 5.83(s,1H), 3.71
(t, J¼5.5 Hz, 2H), 3.31 (dt, J¼5.0, 5.5 Hz, 2H); 13C NMR (125 MHz, TMS,
CD3CN) d: 182.3, 181.5, 156.9, 149.6, 148.2, 140.0, 125.5, 119.2, 101.4
10. Little, A.; Porco, J. A., Jr. Org. Lett. 2012, 14, 2862.
(aromatic C), 59.7, 45.3 (aliphatic C); HRMS (ESI-MS) calcd for
11. Selective examples of iminoannulation, see: (a) Roesch, K. R.; Zhang, H.; Larock,
R. C. J. Org. Chem. 2001, 66, 8042; (b) Roesch, K. R.; Larock, R. C. J. Org. Chem.
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C
11H10N2O3: 219.0769 (MþH), found: 219.0768.
Rf value and other spectroscopic properties were found to be
€
€
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identical with the Caulibugulone D reported earlier.5e7
Acknowledgements
The authors thank Department of Science and Technology,
Ministry of Science and Technology, New Delhi for financial assis-
tance (Project Number: SR/S1/OC-70/2008) and for the single-
crystal X-ray Diffractometer facility in our school. K.S.P. thanks
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S.; Rhee, H.-K.; Park, H. J.; Lee, I.-K.; Lee, S. K.; Suh, M.-E.; Lee, H. J.; Ryu, C.-K.;
Choo, H.-Y. P. Bioorg. Med. Chem. 2007, 15, 451; (c) Joseph, P. K.; Joullie, M. M. J.
Med. Chem. 1964, 7, 801; (d) Lazo, J. S.; Aslan, D. C.; Southwick, E. C.; Cooley, K.
A.; Ducruet, A. P.; Joo, B.; Vogt, A.; Wipf, P. J. Med. Chem. 2001, 44, 4042; (e)
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University Grants Commission, India for
Fellowship.
a Senior Research
Supplementary data
13. The CCDC deposition number for Caulibugulone D (4) is 1026827. Formula:
C
11H10N2O3. Unit cell parameters: a¼4.054(4); b¼10.691(10); c¼23.15(2), space
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.12.059.
group: P-1.