Quick access to the core of mersicarpine through an SNAr strategy

Article abstract of DOI:10.1016/j.tetlet.2012.11.008

A quick access to the core of dihydroindole alkaloid mersicarpine was developed based on straightforward transformations from readily available and inexpensive starting materials. The synthetic route features an aldol reaction, a Beckmann rearrangement for the synthesis of the δ-lactam, an intramolecular S_NAr strategy for indoxyl heterocycle formation, and in situ autoxidation of indoxyl intermediate. The new strategy offered an alternative approach for the formation of an oxidized indoxyl moiety, which could potentially have a wider application in the total synthesis of indole alkaloids containing apparent or masked indoxyl moieties.

Full text of DOI:10.1016/j.tetlet.2012.11.008

Tetrahedron Letters 54 (2013) 242–244
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Quick access to the core of mersicarpine through an SNAr strategy
⇑
Zining Li, Guangxin Liang
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A quick access to the core of dihydroindole alkaloid mersicarpine was developed based on straightfor-
ward transformations from readily available and inexpensive starting materials. The synthetic route fea-
tures an aldol reaction, a Beckmann rearrangement for the synthesis of the d-lactam, an intramolecular
SNAr strategy for indoxyl heterocycle formation, and in situ autoxidation of indoxyl intermediate. The
new strategy offered an alternative approach for the formation of an oxidized indoxyl moiety, which
could potentially have a wider application in the total synthesis of indole alkaloids containing apparent
or masked indoxyl moieties.
Received 15 August 2012
Revised 22 October 2012
Accepted 2 November 2012
Available online 9 November 2012
Keywords:
Mersicarpine
Indole alkaloids
SNAr
Ó 2012 Elsevier Ltd. All rights reserved.
Beckmann rearrangement
Autoxidation
Introduction
The first asymmetric total synthesis of (À)-mersicarpine was
accomplished by Fukuyama and co-workers (Scheme 2).2c Taking
Mersicarpine (1; Fig. 1) is a structurally intriguing dihydroin-
dole alkaloid isolated from the Kopsia species of plants by Kam
and co-workers in 2004.1 This tetracyclic natural product possesses
an unusual 7-membered cyclic imine fused with both an indoline
and a d-lactam around a fully substituted hemiaminal stereogenic
center adjacent to a quaternary carbon center. Interestingly, the
Kopia species also contains a number of other challenging carbon
frameworks such as arboloscine (2; Fig. 1) and rhazinilam (3;
Fig. 1). The synthetically daunting structural features of this class
of molecules together with their biosynthetic relationship have
made them appealing synthetic targets and attracted a lot of atten-
tion among synthetic community.2
The first total synthesis of mersicarpine was reported by Kerr
and co-workers in 2008 (Scheme 1).2a They employed an elegant
malonic radical cyclization induced by Mn(III) to introduce the
quaternary carbon center in 5. The key intermediate 6 was oxi-
dized to form the required oxidation state for the indoline hetero-
cycle and subsequent deprotection and cyclization afforded the
natural product.
advantage of optically pure starting material 8 and Eschenmoser-
Tanabe fragmentation, they successfully prepared the chiral build-
ing block 9 for indole formation through a Sonogashira coupling
and a gold(III) catalyzed cyclization sequence. Hydrogenation of
11 followed by SN2 reaction afforded the unstable intermediate
12, which produced (À)-mersicarpine upon autoxidation.
Tokuyama and co-workers reported an alternative route for the
total synthesis of (À)-mersicarpine utilizing the same starting
material 8 (Scheme 3).2d Their synthesis featured a Fischer indole
synthesis and an elegant DIBAL-H mediated reductive ring-
expansion reaction for construction of the azepinoindole core in
the molecule. Going through the same intermediate 12 and
autoxidation as in Fukuyama’s synthesis, they completed a rather
concise synthesis of (À)-mersicarpine.
Noticing that the previous work all generated the indoline moi-
ety from indole itself, we decided to explore a new strategy. Here-
in, we report our different approach for forming the indoline
heterocycle and d-lactam in the target molecule. In our retrosyn-
thetic analysis (Scheme 4), we envisioned that autoxidation of
the intermediate 16 would provide the required tertiary hydroxyl
group because it has long been known that indoxyl could readily
be autoxidized.3 To prepare indoxyl 16, we proposed an intramo-
lecular nucleophilic aromatic substitution reaction (SNAr) from
substrate 17.4 The d-lactam required for the substitution in 17
could be produced through a Beckmann rearrangement on the
tosylated oxime 18.5 The carbonyl precursor 19 in principle could
be assembled through a domino Michael/aldol reaction sequence
from three readily available components 20, 21, and 22.
Based on Kerr’s synthetic intermediate 6, both Zard and Han
achieved the formal total synthesis of mersicarpine in 2009 and
2012, respectively. To construct 6, Zard and co-workers used an
efficient radical addition and cyclization cascade;2b while Han
and co-workers applied a cationic approach to build the quaternary
carbon center from silyl vinyl ether and tertiary alcohol.2e
⇑
Corresponding author.
E-mail address: lianggx@nankai.edu.cn (G. Liang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.008

Z. Li, G. Liang / Tetrahedron Letters 54 (2013) 242–244
243
Figure 1. Mersicarpine and biosynthetically related indole alkaloids from Kopsia
species.
Scheme 4. Retrosynthetic analysis of mersicarpine. PG = protecting group, Ts = 4-
toluenesulfonyl.
Scheme 1. First total synthesis of mersicarpine by Kerr and co-workers. Boc = tert-
butoxycarbonyl.
Scheme 2. First total synthesis of (À)-mersicarpine by Fukuyama and co-workers.
Scheme 5. A model study for the synthesis of the core of mersicarpine.
DCM = dichloromethane, DMA = N,N-dimethylacetamide, DMAP = 4-dimethylami-
nopyridine, DMF = N,N-dimethylformamide, LDA = lithium diisopropylamide,
RT = room temperature, TBAF = tetra-n-butylammonium fluoride, TBS = tert-butyl-
dimethylsilyl, THF = tetrahydrofuran.
produced 24a and 24b with a 10:3 diastereomeric ratio in 94%
yield, which is typical for a traditional aldol reaction.6 Given that
one of the stereogenic centers would be eventually lost in the oxi-
dation step; this pair of diastereomers was carried through the rest
of the synthesis without separation. The aldol adducts 24a and 24b
were then protected as tert-butyldimethylsilyl ether.7 Oxime
formation and subsequent activation of the oxime afforded the
substrates 27a and 27b for the subsequent Beckmann
Scheme 3. Total synthesis of (À)-mersicarpine by Tokuyama and co-workers.
A simplified model system was designed to quickly investigate
the SNAr strategy for the formation of the indoxyl moiety
(Scheme 5). The synthesis commenced with commercially avail-
able 2-fluoro-benzaldehyde 20 and cyclopentanone 23. Aldol
reaction mediated by LDA between these two compounds

244
Z. Li, G. Liang / Tetrahedron Letters 54 (2013) 242–244
Acknowledgments
We thank the State Key Laboratory of Elemento-organic Chem-
istry in China, the National Natural Science Foundation of China
(Grant Nos. 20902049, 21172117, 21032003, 21121002), Tianjin
Natural Science Foundation (Grant No. 12JCYBJC26400), and the
‘111’ project (B06005) of the Ministry of Education of China for
financial support.
Supplementary data
Supplementary data (detailed experimental analysis and spec-
tral analysis including 1H, 13C, and HRMS) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.11.008.
Scheme 6. Autoxidation of 32.
rearrangement.5e Due to the instability of the diastereomers, they
were treated with AcOH at room temperature directly without
purification. Under this condition, Beckmann rearrangement went
smoothly to produce
References and notes
1. Kam, T.-S.; Subramaniam, G.; Lim, K.-H.; Choo, Y.-M. Tetrahedron Lett. 2004, 45,
5995–5998.
d-lactams 28a and 28b in good yield. Deprotection of the second-
ary alcohol and Dess-Martin oxidation8 evenly gave the key
intermediate 30 in excellent yield. By treating 30 with NaH in
DMA and then heating the reaction mixture at 190 °C for 1 h, we
were able to isolate 31, the core of mersicarpine, in 65% yield. It
is worth pointing out that the solvent DMA played a key part in
this transformation. Substrate 30 refluxed in other solvents includ-
ing DMF, DMSO, and dioxane all decomposed without producing
identifiable products.
We assumed the overall transformation went through the SNAr
product 32, which was autoxidized to give 31 (Scheme 6). Initially,
we used 1.25 equiv of NaH in the reaction and assumed that the
autoxidation of 32 went through a radical process similar to the
autoxidation of intermediate 12 in Fukuyama’s synthesis.2c,9 But
later on, we observed the same results when 2–4 equiv of NaH
was applied in the reaction. Given that 32 would be deprotonated
in the presence of excess NaH, it is suggested that the autoxidation
could be an enolate oxidation process.10
In summary, starting from readily available and inexpensive
starting materials, we have developed a concise synthesis of the
core of mersicarpine based on straightforward transformations.
Our approach features an aldol reaction, a Beckmann rearrange-
ment for the synthesis of the d-lactam, an intramolecular SNAr
strategy for indoxyl heterocycle formation, and in situ autoxidation
of the indoxyl intermediate. The new strategy offered an alterna-
tive approach for the formation of an oxidized indoxyl moiety. Fur-
ther application of this strategy to the total synthesis of indole
alkaloids with apparent or masked indoxyl moieties is underway
in our laboratory.
2. For total synthesis of mersicarpine, see: (a) Magolan, J.; Carson, C. A.; Kerr, M. A.
Org. Lett. 2008, 10, 1437–1440; (b) Biechy, A.; Zard, S. Z. Org. Lett. 2009, 11,
2800–2803; (c) Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2010, 132, 1236–1237; (d) Iwama, Y.; Okano, K.; Sugimoto, K.;
Tokuyama, H. Org. Lett. 2012, 14, 2320–2322; (e) Zhong, X.; Li, Y.; Han, F.-S.
Chem. Eur. J. 2012, 18, 9784–9788; For a recent review on total synthesis of
rhazinilam, see: (f) Kholod, I.; Vallat, O.; Buciumas, A.; Neier, R. Heterocycles
2011, 82, 917–948.
3. (a) Oddo, B. Gazz. Chim. Ital. 1916, 46, 323–333; (b) Oddo, B. Gazz. Chim. Ital.
1920, 50, 268–275.
4. For selected applications of intramolecular SNAr strategy in total synthesis, see:
(a) Rocca, P.; Marsais, F.; Godard, A.; Quéguiner, G. Tetrahedron Lett. 1993, 34,
7917–7918; (b) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.;
Barrow, J. C.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2700–2704; (c) Tema-
Laieb, T.; Chastanet, J.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 583–590; (d) Wang,
Z.; Bois-Choussy, M.; Jia, Y.; Zhu, J. Angew. Chem., Int. Ed. 2010, 49, 2018–2022;
(e) Morales, J. C. C.; Torres, A. G.; Gonzalez-Zamora, E. Eur. J. Org. Chem. 2011,
3165–3170.
5. (a) Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988–993; (b) Donaruma, L. G.;
Heldt, W. Z. Org. React. 1960, 11, 1–156; (c) Tatsumi, T. Beckmann
Rearrangement In Sheldon, R. A., Bekkum, H., Eds.; Wiley-VCH: Weinheim,
New York, 2001; pp 185–204; For representative applications of Beckmann
rearrangement in total synthesis, see: (d) White, J. D.; Hrnciar, P.; Stappenbeck,
F. J. Org. Chem. 1999, 64, 7871–7884; (e) White, J. D.; Choi, Y. Org. Lett. 2000, 2,
2373–2376; (f) Smith, B. T.; Wendt, J. A.; Aube, J. Org. Lett. 2002, 4, 2577–2579.
6. Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press:
New York, 1984; Vol. 3, pp 111–212.
7. Tang, F.; Moeller, K. D. Tetrahedron 2009, 65, 10863–10875.
8. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
9. Ingold, K. U. Acc. Chem. Res. 1969, 2, 1–9.
10. For reports on autoxidation of enolate to generate a-hydroxyl product instead
of hydroperoxide, see: (a) Adam, W.; Metz, M.; Prechtl, F.; Renz, M. Synthesis
1994, 563–566; (b) Kasatkin, A.; Whitby, R. J. Tetrahedron 2003, 59, 9857–9864.