Total synthesis of (±) aspidostomide B, C, regioisomeric N-methyl aspidostomide D and their derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.151040

A full account of the total synthesis of aspidostomide B, C, their analogues and our synthetic efforts towards the synthesis of aspidostomide D, which led to the synthesis of regioisomeric N-methyl aspidostomide D, its analogues via epoxide opening strategy is presented. The synthesis of regioisomeric N-methyl aspidostomide D involves an efficient, five-step sequence, with 36.3% overall yield, starting from 3,4,5-tribromo-1H-pyrrole-2-carboxylic acid. The key features of this protocol are intramolecular cyclization, dehydration, oxidation, and a Lewis acid-mediated regioselective epoxide ring opening by C-3 position of 2,5-dibromo-1H-indole to furnish the title compounds.

Full text of DOI:10.1016/j.tetlet.2019.151040

Tetrahedron Letters 60 (2019) 151040
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of ( ) aspidostomide B, C, regioisomeric N-methyl
aspidostomide D and their derivatives
⇑
Mulla Althafh Hussain, Faiz Ahmed Khan
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana 502285, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A full account of the total synthesis of aspidostomide B, C, their analogues and our synthetic efforts
towards the synthesis of aspidostomide D, which led to the synthesis of regioisomeric N-methyl aspidos-
tomide D, its analogues via epoxide opening strategy is presented. The synthesis of regioisomeric N-
methyl aspidostomide D involves an efficient, five-step sequence, with 36.3% overall yield, starting from
3,4,5-tribromo-1H-pyrrole-2-carboxylic acid. The key features of this protocol are intramolecular cycliza-
tion, dehydration, oxidation, and a Lewis acid-mediated regioselective epoxide ring opening by C-3 posi-
tion of 2,5-dibromo-1H-indole to furnish the title compounds.
Received 15 July 2019
Revised 9 August 2019
Accepted 11 August 2019
Available online 12 August 2019
Keywords:
Natural products
Cyclization
Ó 2019 Elsevier Ltd. All rights reserved.
Epoxide opening
Total synthesis
Introduction
Aspidostoma giganteum. These compounds have dibromotyrosine
or bromotryptophan structural moieties, which forms either linear
Natural products are chemical substances which are derived
from natural sources such as plants, animals or microorganism,
which have been used traditionally as drugs, drug candidates or
lead compounds for novel drugs [1]. Natural products are also an
attractive source for generating new anti-bacterial compounds.
Marine natural products consist of several halogenated metabo-
lites which have shown antibacterial properties. Bryozoans are a
rich source of biologically active compounds which have been
studied extensively over the past few years.
Bromopyrrole is a privileged structure that frequently occurs in
marine natural products and pharmaceuticals, many of which
exhibit simple to the complex structure and display an extraordi-
narily broad range of biological activities [2]. For example,
longamide B, hanishin [3], agesamides A, B [4], mukanadins A-C
[5], slagenins B and C [6], agelamadins A, B and F [7], agelastatin
A-F [8].
amides or cyclic amides with a bromopyrrole carboxylic acid as a
common structural motif [9].
Because of these diverse molecular architectures and prominent
biological activities, our group became interested in the synthesis
of marine natural products and their analogues. In our ongoing
studies, we recently reported syntheses of brominated marine nat-
ural products wilsoniamine A, B, amathamide D, F, convolutamine
F, H and lutamide A, C [10], and ianthelliformisamines A-C, their
analogues as well as antibacterial evaluation [11]. As a continua-
tion, we aimed to synthesize aspidostomide D (1) which eventually
led to the synthesis of regioisomeric N-methyl aspidostomide D
through epoxide opening strategy and total synthesis of aspidosto-
mide B, C and their analogues have been synthesized.
Results and discussion
Recently Palermo and co-workers have isolated bromopyrrole
containing natural products such as aspidostomides D, E, F and
Aspidostomide D contains a 6,7,8-tribromopyrrolo[1,2-a]pyra-
zin-1(2H)-one moiety which is connected to C-3 position of 2,5
dibromo-1H-indole 11r [12]. Retrosynthetic analysis for aspidosto-
mide D 1 is shown in Scheme 1. Epoxide 9 was identified as a suit-
able building block. It was envisaged that the target 1 and its
regioisomer 1a could be secured via an epoxide ring opening of 9
with the nucleophilic C-3 position of 2,5-dibromo-1H-indole 11r
in presence of Lewis acids. Epoxide could be derived via oxidation
of alkene 8, obtained by dehydration of cyclized product 7. Trans-
aspidazide
A (1–4, Fig. 1) from the Patagonian bryozoan
⇑
Corresponding author.
E-mail address: faiz@iith.ac.in (F.A. Khan).
https://doi.org/10.1016/j.tetlet.2019.151040
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
M.A. Hussain, F.A. Khan / Tetrahedron Letters 60 (2019) 151040
Fig. 1. Structures of the aspidostomides B-E and aspidazide A (1–4).
Scheme 1. Retrosynthetic analysis of aspidostomide D and its regioisomer.
Scheme 2. Synthesis of regioisomeric N-methyl aspidostomide D. Reaction conditions: (a) oxalyl chloride (3.5 mmol, 7 equiv) DMF (15 mg, 0.4 equiv), amino acetaldehyde
dimethyl acetal (0.650 mmol, 1.3 equiv), pyridine (1.25 mmol, 2.5 equiv), CH2Cl2, 0 °C - rt, 14 h, (87%). (b) 2 N HCl (2.5 equiv), acetone, rt, 16 h, (94%). (c) CF3COOH, 80 °C, 1 h,
(94%). (d) NaH 60% dispersion in mineral oil (1.61 mmol, 2 equiv), MeI (3.2 mmol, 3 equiv), DMSO, 0 °C - rt, 12 h, (83%). (e) i, mCPBA, 65–75% (0.389 mmol, 1.5 equiv), NaHCO3
(0.779 mmol, 3.0 equiv), CH2Cl2, 0 °C - rt, 2 h. ii, LiClO4 (0.249 mmol, 1.0 equiv), 2,5-dibromo-1H-indole 11r, (0.249 mmol, 1.0 equiv), CH3CN, 80 °C, 6 h, 57% (over two steps).

M.A. Hussain, F.A. Khan / Tetrahedron Letters 60 (2019) 151040
3
formation of 5 through routine amine coupling followed by hydrol-
ysis and intramolecular cyclization of the resulting amide 6 would
furnish 7.
a solvent at 80 °C to obtain 8. Attempts to transform 8 to epoxide
9 under usual conditions such as mCPBA/NaHCO3 and oxone/
NaHCO3 were unsuccessful. However, converting the free amide
NH in 8 to the corresponding N-methyl derivative 8a by treating
with NaH/MeI followed by epoxidation with mCPBA and ring open-
ing of fragile crude epoxide in the presence of LiClO4, furnished 1a
in good yield (57%, over two steps), as single regioisomeric ring
opening product.
As depicted in Scheme 2, the synthesis commenced by an amine
coupling between 3,4,5-tribromo-1H-pyrrole-2-carboxylic acid 5
and amino acetaldehyde dimethyl acetal. Preparation of 5 was
accomplished from the commercially available pyrrole-2-carbox-
aldehyde according to modified literature protocol via oxidation
with Ag2O followed by bromination reaction with Br2/AcOH [13].
The coupling reaction initially furnished poor yield (33%) of ami-
de 6 with DCC/DMAP which was significantly improved (87%) by
performing the reaction with oxalyl chloride and catalytic amount
of DMF in presence of amino acetaldehyde dimethyl acetal and
pyridine [14]. Preparation of 7 from 6 was accomplished in good
yield (94%) via in situ hydrolysis followed by cyclisation using
2 M HCl/acetone [14] at ambient temperature. Initially, the dehy-
dration reaction was performed using TsCl/Et3N which gave poor
yield (14%) of the desired product. A significant improvement
(94%) was achieved by performing the reaction with TFA [15] as
We anticipated that Lewis acid catalyzed epoxide opening of
compound 9 would give us a mixture of both regioisomers 1 and
1a via path ‘a and b’ respectively as shown in Scheme 1. We
assumed that both the nitrogen lone pairs will not interfere in
the reaction as pyrrole nitrogen lone pair is involved in aromaticity
whereas amide nitrogen lone pair is in resonance with a keto
group. But contrary to our expectation, we observed selectively
one regioisomer 1a.
The structural assignment for 1a was based on 1H, 13C NMR and
HRMS data which was further supported by 2D NMR correlations
(Fig. 2).
An unambiguous structural proof was obtained by performing a
single crystal X-ray analysis of the corresponding acylated pro-
duct 10, prepared by performing the acylation reaction of 1a with
Ac2O in presence of DMAP/Et3N/CH2Cl2 [16] in good yield (Fig. 3).
Based on the product formed, we proposed a plausible mecha-
nism to explain the observed selectivity as depicted in Scheme 3.
Amide nitrogen is possibly assisting the epoxide opening followed
by nucleophilic attack of C-3 position of 2,5-dibromo-1H-indole
11r followed by aromatization leading to compound 1a.
Additionally, we have synthesized a variety of different regioi-
someric N-methyl aspidostomide D analogues 1a-s (a total of 19
analogues, as shown in Scheme 4) by employing various indole
derivatives 11a-s, having different substitutions. The same reaction
procedure as for 1a (vide supra) was used to obtain moderate to
good yields, as shown in Scheme 4. The indole derivatives 11a-s
were synthesized by using Suzuki cross-coupling [12,18].
Aspidostomides B and C contain a dibromotyrosine moiety
which is connected with bromopyrrole carboxylic acid via amide
functionality.
Fig. 2. HMBC, NOESY and COSY correlation of 1a.
Retrosynthetic analysis of our approach for aspidostomides B
and C is shown in Scheme 5. Intermediate 12 or 12a was identified
as a suitable building block. It was imagined that the target 3 and
3a could be secured via demethylation of 12 or 12a. Intermediate
12 or 12a could be derived via routine acid amine coupling of 13
with a bromopyrrole carboxylic acid. Amino alcohol 13 could be
Fig. 3. X-ray crystal structure of compound 10 [17].
Scheme 3. Proposed mechanism for the synthesis of regioisomeric N-methyl aspidostomide D.

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M.A. Hussain, F.A. Khan / Tetrahedron Letters 60 (2019) 151040
Scheme 4. Synthesis of a regioisomeric N-methyl aspidostomide D and its analogues. Reaction conditions: LiClO4 (1.0 equiv), indole derivatives 11a-s (1.0 equiv), epoxide 9
(1.0 equiv), anhydrous CH3CN, 80 °C, 2.5–12 h, under nitrogen atmosphere.

M.A. Hussain, F.A. Khan / Tetrahedron Letters 60 (2019) 151040
5
ture of acetone, water (4:1) to furnish compound 17 in 90% yield.
The bromo group in 15 was replaced with NaN3 to furnish 14 in
nearly quantitative yield. Reduction of 14 with PPh3 in MeOH at
80 °C was accomplished in excellent yield to obtain 13 [10].
Amidation of the free –NH2 in 13 with 4,5-dibromo pyrrole
carboxylic acid and 3,4,5-tribromo pyrrole carboxylic acid by
using EDC.HCl/HOBt [11] in CH2Cl2, at 0 °C to room temperature
gave the corresponding amide products 12 and 12a in good yield
(75 and 80%, respectively). Attempts to transform 12 and 12a to
3 and 3a under nucleophilic demethylation conditions such as
CH3SNa/DMF, NaHMDS/HMPA were unsuccessful. A significant
transformation of 12 or 12a to 3 or 3a was accomplished by per-
forming reaction with BBr3/CH2Cl2 at À78 °C to obtain the desired
products in good yield (89 and 90%, respectively).
Scheme 5. Retrosynthetic analysis of aspidostomide B and C.
Additionally, we have synthesized a variety of O-methyl aspi-
dostomide B and C their analogues 12c-q (a total of 15 analogues,
as shown in Scheme 7) by employing various acid derivatives 18a-
o, having different substitutions. The same reaction procedure as
for 12 or 12a (vide supra) was used to obtain good yields, as shown
in Scheme 7.
derived via azidation of 15 followed by reduction. Conversion of 16
to 15 through bromohydrin of the resulting alkene would furnish
15.
In summary, we have synthesized a regioisomeric N-methyl
aspidostomide D 1a via regioselective epoxide ring opening reac-
tion with 2,5-dibromo-1H-indole 11r in presence of LiClO4. This
strategy was extended to synthesize a variety of synthetic regioiso-
meric N-methyl aspidostomide D analogues, by varying indole
derivatives. First total synthesis of aspidostomide B, C and their
analogues has been reported.
As depicted in Scheme 6, the synthesis of aspidostomide B and C
was commenced by the preparation of known aldehyde 17 from
commercially accessible 4-hydroxy benzaldehyde as reported ear-
lier.[19] The aldehyde 17 was treated CH3P(C6H5)Br in presence of
KOtBu under Wittig olefination conditions to furnish olefin 16 in
82% yield. The olefin was subjected to bromohydroxylation in pres-
ence of NBS and a catalytic amount of ammonium acetate in a mix-
Scheme 6. Synthesis of ( ) aspidostomide B and C.

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M.A. Hussain, F.A. Khan / Tetrahedron Letters 60 (2019) 151040
Scheme 7. Synthesis of O-methyl aspidostomide B & C analogues. Reaction conditions: EDC.HCl (2.1 equiv), HOBt (2.3 equiv), corresponding derivatives 12c-q (1.2 equiv),
compound 13 (1.0 equiv), anhydrous CH2Cl2, 0 °C to rt, 12 h.
[2] (a) C.-X. Zhuo, X. Zhang, S. -Li. You, ACS Catal. 6 (2016) 5307–5310;
Acknowledgment
(b) A. Grube, E. Lichte, M. Kock, J. Nat. Prod. 69 (2006) 125–127;
(c) I.C. Pina, K.N. White, G. Cabrera, E. Rivero, P. Crews, J. Nat. Prod. 70 (2007)
613–617;
(d) B. Jiang, J.-F. Liu, S.-Y. Zhao, Org. Lett. 22 (2002) 3951–3953;
(e) M. Kuramoto, N. Miyake, Y. Ishimaru, N. Ono, H. Uno, Org. Lett. 10 (2008)
5465–5468;
F.A.K. gratefully acknowledges to D.S.T for financial support. M.
A.H. thanks CSIR for fellowship.
(f) J.P. Kennedy, J.T. Brogan, C.W. Lindsley, J. Nat. Prod. 71 (2008) 1783–1786;
(g) V. Bhardwaj, D. Gumber, V. Abbot, S. Dhiman, P. Sharma, RSC Adv. 5 (2015)
15233–15266.
Appendix A. Supplementary data
[3] (a) D.-G. Zhao, Y.-Y. Ma, W. Peng, A.-Y. Zhou, Y. Zhang, L. Ding, Z. Du, K. Zhang,
Bioorganic Med. Chem. lett. 26 (2016) 6–8;
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151040.
(b) G. Cheng, X. Wang, H. Bao, C. Cheng, N. Liu, Y. Hu, Org. Lett. 14 (2012)
1062–1065;
(c) J. Patel, N.P. Leon, F. Minassian, Y. Vallee, J. Org. Chem. 70 (2005) 9081–
9084;
References
(d) Z. Shiokawa, S. Inuki, K. Fukase, Y. Fujimoto, Synlett 27 (2016) 616–620.
[4] (a) M. Tsuda, T. Yasuda, E. Fukushi, J. Kawabata, M. Sekiguchi, J. Fromont, J.
Kobayashi, Org. Lett. 8 (2006) 4235–4238;
(b) S.-J. Lee, S.-H. Youn, C.-W. Cho, Org. Biomol. Chem. 9 (2011) 7734–7741.
[5] H. Uemoto, M. Tsuda, J. Kobayashi, J. Nat. Prod. 62 (1999) 1581–1583.
[6] (a) A.C.B. Sosa, K. Yakushijin, D.-A. Horne, Org. Lett. 2 (2000) 3443–3444;
(b) B. Jiang, J.-F. Liu, S.-Y. Zhao, J. Org. Chem. 68 (2003) 2376–2384.
[1] (a) D.J. Newman, G.M. Cragg, K.M. Snader 1981–2002 J. Nat. Prod. 66 (2003)
1022–1037;
(b) A. Gosslau, S. Li, C.-T. Ho, K.Y. Chen, N.E. Rawson, Mol. Nutr. Food Res. 55
(2011) 74–82;
(c) F.E. Koehn, G.T. Carter, Nat. Rev. Drug Discov. 4 (2005) 206–220;
(d) A.A. Siddiqui, F. Iram, S. Siddiqui, K. Sahu, Int. J. Drug Dev. Res. 6 (2014)
172–204.

M.A. Hussain, F.A. Khan / Tetrahedron Letters 60 (2019) 151040
7
[7] (a) T. Kusama, N. Tanaka, K. Sakai, T. Gonoi, J. Fromont, Y. Kashiwada, J.
Kobayashi, Org. Lett. 16 (2014) 3916–3918;
(b) T. Kusama, N. Tanaka, Y. Kashiwada, J. Kobayashi, Tetrahedron Lett. 56
(2015) 4502–4504.
[8] (a) S. Han, D.S. Siegel, K.C. Morrison, P.J. Hergenrother, M. Movassaghi, J. Org.
Chem. 78 (2013) 11970–11984;
(b) A.E. Gamal, V. Agarwal, S. Diethelm, I. Rahman, M.A. Schorn, J.M. Sneed, G.
V. Louie, K.E. Whalen, T.J. Mincer, J.P. Noel, V.J. Paul, B.S. Moore, PNAS 113
(2016) 3797–3802.
[14] (a) M.G. Banwell, A.M. Bray, A.C. Willis, D.J. Wong, New J. Chem. 23 (1999)
687–690;
(b) A.C.B. Sosa, K. Yakushijin, D.A. Horne, Tetrahedron Lett. 41 (2000) 4295–
4299;
(c) G. Papeo, M.A.G.-Z. Frau, D. Borghi, M. Varasi, Tetrahedron Lett. 46 (2005)
8635–8638.
(b) T. Yoshimitsu, T. Ino, T. Tanaka, Org. Lett. 10 (2008) 5457–5460;
(c) N. Hama, T. Matsuda, T. Sato, N. Chida, Org. Lett. 11 (2009) 2687–2690;
(d) M.M. Domosto, E. Irving, F. Scheinmann, K.J. Hale, Org. Lett. 6 (2004) 2615–
2618.
[15] A. Mitchinson, W.P. Blackaby, S. Bourrain, R.W. Carling, R.T. Lewis, Tetrahedron
Lett. 47 (2006) 2257–2260.
[16] (a) K.L. Baddeley, Q. Cao, M.J. Muldoon, M.J. Cook, Chem. Eur. J. 21 (2015) 1–6;
(b) W. Chazadaj, R. Kowalczyk, J. Jurczak, J. Org. Chem. 75 (2010) 1740–1743.
[17] CCDC contains the supplementary crystallographic data for this paper.
1815441 (10).
[9] C.L.P. Patino, C. Muniain, M.E. Knott, L. Puricelli, J.A. Palermo, J. Nat. Prod. 77
(2014) 1170–1178.
[10] (a) F.A. Khan, S. Ahmad, Tetrahedron Lett. 54 (2013) 2996–2998;
(b) S. Ahmad, S. Choudhury, F.A. Khan, Tetrahedron. 71 (2015) 4192–4202;
(c) F.A. Khan, S. Ahmad, J. Org. Chem. 77 (2012) 2389–2397.
[11] F.A. Khan, S. Ahmad, N. Kodipelli, G. Shivange, R. Anindya, Org. Biomol. Chem.
12 (2014) 3847–3865.
[18] (a) K.R. Rathikrishnan, V.K. Indirapriyadharshini, S. Ramakrishna, R. Murugan,
Tetrahedron 67 (2011) 4025–4030;
[12] (a) P. Li, Y. Ji, W. Chen, X. Zhang, L. Wang, RSC Adv. 3 (2013) 73–78;
(b) M. Wang, P. Li, W. Chen, L. Wang, RSC Adv. 4 (2014) 26918–26923.
[13] (a) M.-Z. Wang, H. Xu, T.-W. Liu, Q. Feng, S.-J. Yu, S.-H. Wang, Z.-M. Li, Eur. J.
Med. Chem. 46 (2011) 1463–1472;
(b) H.J. Lim, J.C. Gallucci, T.V. Rajanbabu, Org. Lett. 12 (2010) 2162–2165.
[19] (a) C. Pieri, D. Borselli, C.D. Giorgio, M.D. Meo, J.-M. Bolla, N. Vidal, S. Combes, J.
M. Brunel, J. Med. Chem. 57 (2014) 4263–4272;
(b) N. Ullah, S.A. Haladu, B.A. Mosa, Tetrahedron Lett. 52 (2011) 212–214.