Total synthesis of kottamide e

Article abstract of DOI:10.1039/c3cc39062d

The first synthesis of kottamide E, a marine natural product containing a 5,6-dibromoindole linked via a (Z)-enamide to an unusual 1,2-dithiolane- containing amino acid, is reported. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc39062d

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Total synthesis of kottamide E†
Thomas B. Parsons, Neil Spencer, Chi W. Tsang and Richard S. Grainger*
Cite this: Chem. Commun., 2013,
49, 2296
Received 19th December 2012,
Accepted 1st February 2013
DOI: 10.1039/c3cc39062d
www.rsc.org/chemcomm
The first synthesis of kottamide E, a marine natural product con-
taining a 5,6-dibromoindole linked via a (Z)-enamide to an unusual
1,2-dithiolane-containing amino acid, is reported.
Kottamide E (1), isolated as a minor component from the
New Zealand ascidian Pycnoclavella kottae in 2003 by Appleton
and Copp, is the only natural product reported to date containing
the unusual 4-amino-1,2-dithiolane-4-carboxylic acid residue.1
Related mono- and dibrominated Z-enamide-containing indole
alkaloids, kottamides A–D, isolated from the same source, have
been shown to exhibit anti-inflammatory, antitumour and anti-
metabolic activities.2 Given the paucity of the natural product
and absence of biological data, we have investigated a total
synthesis of kottamide E, which we report herein.
Retrosynthetically we envisaged that union of a protected
(Z)-enamide 2 with an appropriate oxalic acid derivative and the
amide 3 offered a viable approach to kottamide A (Scheme 1).
The synthetically challenging, thermodynamically less stable
(Z)-enamide 2 was planned to arise from reaction of a vinyl
isocyanate with 2-trimethylsilylethanol, the isocyanate in turn
produced from Curtius rearrangement of an acyl azide derived
from a,b-unsaturated ester 4. We were particularly attracted to
Scheme 1 Retrosynthetic analysis of kottamide E.
this general approach3,4 to stereodefined enamides given its stereocontrol in favour of the expected (Z)-isomer 7, which
successful utilization in complex natural product synthesis,5,6 could be readily separated from the corresponding (E)-isomer
including indolic enamides.7 The (Z)-double bond geometry by column chromatography. Attempted ester hydrolysis of 7a–c
within 4 would be set through an appropriate Horner– was complicated by the faster removal of the indole protecting
Wadsworth–Emmons reaction of 5,6-dibromoindole 5, which group and loss of integrity of the alkene double bond geometry.
we have previously shown can be readily accessed in 3 steps For example, in the case of the Boc-protected indole 7a, sodium
from commercially available methyl indole-3-carboxylate via hydroxide caused complete removal of the Boc group after
regioselective dibromination.8–10
16 hours at room temperature, with no ester hydrolysis and a
Although the Ando-modified Horner–Wadsworth–Emmons small amount of alkene isomerisation. Upon warming to 65 1C
reaction11 of 5 proceeded with no selectivity, protection of saponification was complete within 3 hours but the (Z)-alkene
the indole nitrogen gave rise to good to excellent levels of was completely converted to its (E)-isomer. Similarly the Teoc
group of 7b and the tosyl group of 7c were removed within 30
and 5 minutes respectively at 0 1C. However, the SEM-protected
indole 7d could be progressed via the carboxylic acid to the acyl
azide 8 with complete retention of double bond geometry.
School of Chemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT,
UK. E-mail: r.s.grainger@bham.ac.uk; Fax: +44 (0)121 4144403;
Tel: +44 (0)121 4144465
Heating 8 in the presence of 2-(trimethylsilyl)ethanol gave
the unstable Teoc-protected enecarbamate 9. This was found to
† Electronic supplementary information (ESI) available: Experimental procedures
and analytical data for all new compounds. See DOI: 10.1039/c3cc39062d
c
2296 Chem. Commun., 2013, 49, 2296--2298
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decompose rapidly, even when stored in the freezer under an
atmosphere of argon. N-Acylation of 9 via deprotonation with
NaHMDS and quenching with methyl chlorooxoacetate gave
methyl oxoacetate 10, which was not amenable to purification.
Instead, treatment of the crude reaction mixture with TBAF
afforded 11 in acceptable yield. Unfortunately the acylation step
proved somewhat capricious and was not amenable to scale-up,
which required recourse to multiple smaller scale reactions.
The combined crude reaction mixtures were subjected to Teoc
deprotection to afford 11, which is stable for several weeks at
low temperature. Saponification of 11 gave acid 12 in quanti-
tative yield.
The instability of 10 is consistent with the observations of
Kitahara on Teoc-protected enamines appended to indoles,
where N-acylated products could not be purified until the
Teoc-group had been removed.7 We observed that 10 was highly
sensitive to base and that acylation was somewhat reversible:
if crude 10 was treated with triethylamine it rapidly reverted to
Teoc-protected enamide 9. It is thought that this is the reason
for the modest yield of the acylation-deprotection sequence:
the basic nature of TBAF can cause competitive deacylation of
intermediate 10 to return 9.‡
The novel amide 3 was prepared as its hydrochloride salt in
3 steps from the known12 protected amino acid 13 in 88%
overall yield (Scheme 2). Coupling of 13 with carboxylic acid 3
proceeded smoothly using HBTU in DMF at 50 1C over 3 days to
afford SEM-protected kottamide E 14 in 66% yield. Unfortunately,
clean removal of the SEM group proved to be highly problematic.
A wide variety of methods were tested without success.13 In each
case reaction progress was followed by tlc, mass spectrometry
and HPLC but we were unable to find conditions to deprotect
kottamide E without concomitant fragmentation of the target.
In most cases HPLC analysis of the reaction mixture indicated the
presence of numerous by-products; mass spectrometric analysis
suggested that various mono- and dibrominated fragmentation
products were being formed, but sufficient material could not be
isolated to confirm the identity of any such by-products.§
Given the difficulties encountered in removing the SEM
protecting group from 14 to unveil kottamide E, an alternative
approach was devised whereby the potentially sensitive natural
product would be accessed directly upon formation of the
amide bond. Considering the previously observed labile nature
of the tosyl protecting group in 7c under saponification condi-
Scheme 2 Synthesis of SEM-protected kottamide E. Reagents and conditions:
(i) for 6a: NaH, di-tert-butyl dicarbonate, THF, 95%; for 6b: NaH, 4-nitrophenyl
2-(trimethylsilyl)ethyl carbonate, THF, 95%; for 6c: NaH, TsCl, THF, 81%; for 6d:
NaH, SEMCl, THF, 95%; (ii) EtO2CCH2P(O)(OPh)2, NaH, THF, À40 1C. For 7a: 81% +
13% (E)-isomer; for 7b: 81% + 13% (E)-isomer; for 7c: 80%; for 7d: 68% + 31%
(E)-isomer 15; (iii) aq. NaOH, MeOH, THF, 65 1C then NaH, DPPA, THF, 91%;
(iv) TMSCH2CH2OH, toluene, reflux, 77%; (v) NaHMDS, MeO2CC(O)Cl, THF, 0 1C;
(vi) TBAF, THF, 0 1C, 66% over 2 steps; (vii) aq. NaOH, MeOH, THF, 100%; (viii) aq.
NaOH, THF, MeOH, 99%; (ix) i-BuOC(O)Cl, Et3N, THF, 0 1C then NH3, MeOH,
À20 1C, 89%; (x) SOCl2, MeOH, 50 1C, 100%; (xi) HBTU, DMF, Et3N, 50 1C, 66%.
tions, this new approach sought to exploit the expected removal of saponification of the ester moiety of 20 gave carboxylic acid 21.
this group alongside methyl ester hydrolysis in the penultimate This was subjected to the previously optimised conditions for
step (Scheme 3).
amide bond formation with amine 3. Purification of the reac-
Towards this goal, tosyl-protected indole-3-carbaldehyde tion mixture required semi-preparative and analytical HPLC to
6c underwent Ando-modified Horner–Wadsworth–Emmons give kottamide E in modest yield and in approximately 85%
reaction11 to afford (Z)-tert-butyl ester 17 as the major product, purity, whose spectroscopic data were in agreement with those
along with the separable (E)-isomer (Scheme 3). Hydrolysis of reported by Appleton and Cobb.1,14
the ester under acidic conditions followed by reaction with
In conclusion, the first total synthesis of kottamide E has
DPPA gave acyl azide 18 as a 3.2 : 1 mixture of double bond been achieved in 8 steps starting from the known dibromoindole
isomers. Curtius rearrangement and trapping gave protected 5, itself prepared in three steps from commercially available
enamine 19 which was subjected to acylation and immediate methyl indole-3-carboxylate. The successful approach necessi-
deprotection to afford enamide 20. At this point the unwanted tated a change in protecting group strategy, but still suffered
(E)-isomer could be removed by flash column chromatography. from a modest-yielding final step and recourse to purification
As expected, removal of the tosyl protecting group and concomitant by HPLC. This, along with the lack of tolerance towards a wide
c
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reaction was subjected to the same reaction sequence to give (E)-enamide
16 (see ESI† for details). Notably the acylation and Teoc-deprotection
steps proceeded smoothly and could be conducted on larger scale than
in the (Z)-series with no decrease in reaction yield. Presumably this is a
reflection of the substantially lower steric crowding around the enamide
in the (E)-series compared to the (Z)-series, where, particularly in the
case of 10, a planar, conjugated arrangement is difficult to achieve.
Similarly, reaction of (Z)-enamide 9 with TBAF was significantly faster
than the corresponding (E)-isomer (1 hour at room temperature vs.
ca. 50% consumption after 2 days), indicating orders of magnitude
difference in reactivity between the two double bond isomers.
§ The (E)-enamide 16 was also progressed to the same stage but the
SEM group again could not be cleanly removed to afford the (E)-isomer
of kottamide E. See ESI† for details.
1 D. R. Appleton and B. R. Copp, Tetrahedron Lett., 2003, 44, 8963.
2 D. R. Appleton, M. J. Page, G. Lambert, M. V. Berridge and
B. R. Copp, J. Org. Chem., 2002, 67, 5402.
3 R. Brettle and A. J. Mosedale, J. Chem. Soc., Perkin Trans. 1, 1988,
2185.
4 K. Kuramochi, H. Watanabe and T. Kitahara, Synlett, 2000, 397.
5 A. B. Smith III and J. Zheng, Synlett, 2001, 1019; A. B. Smith III and
J. Zheng, Tetrahedron, 2002, 58, 6455.
6 J. T. Feutrill, M. J. Lilly and M. A. Rizzacasa, Org. Lett., 2002, 4,
525; J. T. Feutrill, M. J. Lilly, J. M. White and M. A. Rizzacasa,
Tetrahedron, 2008, 64, 4880.
Scheme 3 Total synthesis of kottamide E. Reagents and conditions: (i) t-BuO2-
CCH2P(O)(OPh)2, NaH, THF, À78 1C, 78% + 5% (E)-isomer; (ii) TFA, CH2Cl2 then
NaH, DPPA, THF; (iii) TMSCH2CH2OH, toluene, reflux; (iv) NaHMDS, MeO2CC(O)Cl,
THF then TBAF, THF, 32% over 5 steps; (v) aq. NaOH, MeOH, THF, 97%; (vi) 3ÁHCl,
HBTU, DMF, Et3N, 38%.
7 K. Kuramochi, Y. Osada and T. Kitahara, Tetrahedron, 2003,
59, 9447.
8 T. B. Parsons, C. Ghellamallah, L. Male, N. Spencer and R. S.
Grainger, Org. Biomol. Chem., 2011, 9, 5021.
9 For a similar approach to 3 see: E. M. Boyd and J. Sperry, Synlett,
2011, 826.
10 For recent syntheses of 5,6-dibromoindole containing natural pro-
ducts, in addition to ref. 8 and 9, see: A. Mollica, A. Stefanucci,
F. Feliciani, G. Lucente and F. Pinnen, Tetrahedron Lett., 2011,
52, 2583; J. Sperry, Tetrahedron Lett., 2011, 52, 4042; J. Sperry,
Tetrahedron Lett., 2011, 52, 4537.
11 K. Ando, J. Org. Chem., 1997, 62, 1934; K. Ando, J. Org. Chem., 1999,
64, 8406.
12 E. Morera, M. Nalli, F. Pinnen, D. Rossi and G. Lucente, Bioorg. Med.
Chem. Lett., 2000, 10, 1585; E. Morera, G. Lucente, G. Ortar, M. Nalli,
F. Mazza, E. Gavuzzo and S. Spisani, Bioorg. Med. Chem., 2002,
10, 147.
range of SEM deprotection conditions, suggests an inherent
sensitivity of the natural product that means the choice of final
steps in future syntheses of kottamide E should be of particular
concern.
We thank EPSRC for funding. The NMR spectrometers used
in this research were obtained through Birmingham Science
City: Innovative Uses for Advanced Materials in the Modern
World (West Midlands Centre for Advanced Materials Project 2),
with support from Advantage West Midlands (AWM) and part
funded by the European Regional Development Fund (ERDF).
Notes and references
13 See ESI† for a complete list of conditions with references.
‡ In order to gain further insight into the stability issues, the minor 14 We have been unable to identify the impurities present in the
(E)-enoate 15 from the Ando-modified Horner–Wadsworth–Emmons
aliphatic region of the NMR spectra of synthetic 1.
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2298 Chem. Commun., 2013, 49, 2296--2298
This journal is The Royal Society of Chemistry 2013