Remarkable switch of regioselectivity in diels-alder reaction: Divergent total synthesis of borreverine, caulindoles, and flinderoles

Article abstract of DOI:10.1021/ol501078d

Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of

Full text of DOI:10.1021/ol501078d

Letter
pubs.acs.org/OrgLett
Remarkable Switch of Regioselectivity in Diels−Alder Reaction:
Divergent Total Synthesis of Borreverine, Caulindoles, and
Flinderoles
Dattatraya H. Dethe,* Rohan D. Erande, and Balu D. Dherange
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: Switchable reaction patterns of dimerization of indole
substituted butadienes via a Lewis acid and thermal activation are reported.
While under acidic conditions dimerization occurred around the internal
double bond of the dienophile, a complete switch of regioselectivity was
observed under thermal conditions, where dimerization occurred around the
terminal double bond of the dienophile. This switch of regioselectivity was
further exploited for the divergent total synthesis of structurally diverse indole
alkaloid natural products.
ono- and bis-prenylated isomers, as well as dimeric bis-
Mprenylated indoles, form the largest group of natural
products found in genus Isolona.1 In 2004, Nkunya et al.2 isolated
the four dimeric prenyl indoles that occurred as diastereomeric
pairs, namely caulindoles A−D (1−4), from I. cauliflora (Figure
1). Recently in 2010, Skaltsounis et al.3 reported the isolation of
another group of dimeric prenyl indole natural products, namely
raputindole A (5), and its regioisomers. Biosynthetically,
caulindoles might have been formed by the Diels−Alder reaction
of two monoprenyl indoles, one acting as the diene and the other
as a dienophile. Caulindoles and raputindoles showed optical
activity, thus implying an enzymatic cyclization of the isoprene
units. Caulindole A and D showed antifungal and mild
antimalarial activity. 1−4 and their natural isomers4 are yet to
succumb to total synthesis. Interestingly, in 2009 Avery et al.5
isolated another group of unprecedented natural products,
flinderoles A−C (6−8), along with previously known com-
pounds, borrerine (9), borreverine (10), isoborreverine (11),
and dimethylisoborreverine (12). 10−12 were isolated in 1977
by Riche et al.6 The structures of 10 and 11 were established by
single crystal X-ray diffraction analysis. Another natural product
possessing the borreverine skeleton, spermacoceine (13), was
isolated by the research group of Balde et al.7 in 1991 from
Borreria verticillata. Biosynthetically flinderoles and borreverines
could be derived by closure of isoprene units in the cyclopentyl
ring and cyclohexene ring by [3 + 2] and [4 + 2] cycloaddition
reactions respectively.
Encouraged by our recent synthesis of flinderoles8 and
isoborreverines,9 we became interested in the synthesis of
caulindoles A−D (1−4), raputindole A (5), and borreverine
(10). In 1979, Koch et al.10 reported the biomimetic synthesis of
10 and isoborreverine (11) by the acid mediated dimerization of
borrerine 9. Treatment of 9 with TFA in benzene at 65 °C
afforded 10 and 11 in a 1:1 ratio and 80% yield; when the
reaction was further continued for 12 h, they isolated only 11.
Recently during their synthesis of flinderoles, May et al.11
repeated the same reaction. In an effort to reproduce the original
report of formation of 10, a range of TFA equivalents, reaction
times, and reaction temperatures were screened, but contrary to
the previous report, they observed the formation of 11 only.
Figure 1. Structures of borreverine, caulindole, raputindole, and
flinderole natural products.
Received: April 14, 2014
Published: May 5, 2014
© 2014 American Chemical Society
2764
dx.doi.org/10.1021/ol501078d | Org. Lett. 2014, 16, 2764−2767

Organic Letters
Letter
Scheme 1. Biomimetically Inspired Retrosynthesis of
Caulindoles
Scheme 3. Total Synthesis of Caulindole C (3) and D (4)
Scheme 2. Total Synthesis of Caulindoles A (1) and B (2)
Scheme 4. Remarkable Switch of Regioselectivity in Diels−
Alder Reaction
During our efforts toward the synthesis of flinderoles and
isoborreverines,9 we also tried to reproduce the results obtained
by Koch et al., but in our hands, when we treated 9 with 5 equiv of
TFA at rt, 11 was isolated in 95% yield; we could not observe any
isolable amount of 10. Here, we report the divergent total
synthesis of structurally diverse indole alkaloid natural products:
caulindoles A−D (1−4), borreverine (10), flinderoles A−C (6−
8), and their analogues.
It was envisaged that, with fine-tuning of the reaction
conditions, it might be possible to dimerize indole diene 14 to
caulindoles by a [4 + 2] cycloaddition reaction (Scheme 1).
Diels−Alder dimerization can be carried out thermally or
catalyzed by a Lewis or Bronsted acid. But to our disappointment
under all such reaction conditions 14 (see Supporting
Information (SI) for preparation) decomposed, and we did not
observe even a trace amount of [4 + 2] or [3 + 2] cycloaddition
adduct. It was found that the phenyl sulfonyl protected indole
diene 15 was more stable and can be stored in a round-bottom
flask for many days at rt. Interestingly treatment of indole diene
15 with p-TSA afforded the Diels−Alder product 16, where
dimerization occurred around the internal double bond of the
dienophile. The structure and relative stereochemistry of 16 was
established by 2D NMR analysis (Scheme 2).
Surprisingly when diene 15 was heated in a sealed tube using
toluene as a solvent at 180 °C, it afforded 1:1 diastereomeric
mixture of [4 + 2] cycloaddition product 17, with a complete
switch of regioselectivity, as dimerization occurred around the
terminal double bond of the dienophile. The structure and
relative stereochemistry of 17 was determined by spectroscopic
analysis (1H, 13C NMR; IR; and HRMS) and by correlation with
the caulindole spectral data. Although the mechanism, reactivity,
and selectivity of the Diels−Alder reaction have been greatly
studied,12 this is one rare example where two different products
were obtained by changing reaction conditions in a highly
regioselective manner, and to the best of our knowledge, to date
no report exists in literature of the formation of different
products with such a switch of regioselectivity in the Diels−Alder
reaction as observed in this case. Deprotection of the phenyl
sulfonyl group followed by diastereomer separation by careful
silica gel column chromatography afforded the natural products 1
and 2, whose spectral data were in good agreement with the
literature report.2 After having synthesized 1 and 2, we next
turned our attention toward functionalization of C-3 and C-3′ of
the indole rings of caulindole A (1) and B (2), to generate
caulindole C (3) and D (4). In 2005, Tamaru et al. reported the
Pd-catalyzed C-3 selective allylation of indoles.13 We exploited
this reaction for diallylation of 1 and 2. Thus, independent
treatment of 1 and 2 with the prenyl alcohol in the presence of a
catalytic amount of Pd(Ph3P)4 generated 3 and 4 (Scheme 3),
whose spectral data were in complete agreement with the
literature report.2 After the biomimetic synthesis of 1−4 and
encouraged by the switch of regioselectivity in the Diels−Alder
dimerization of indole diene 15, we became interested in the
dimerization of another indole diene, 18. Based on our
experience in flinderole, isoborreverine, and caulindole synthesis,
it was contemplated that, unlike in the case of the Diels−Alder
reaction of the indole diene 15, there are three different Diels−
Alder products that would be possible in the Diels−Alder
dimerization of indole diene 18. As in the case of diene 15 we
expected diene 18 to generate a limonene derivative and
caulindole isomers upon dimerization under different conditions.
Based on our experience in the synthesis of flinderoles by the
formal [3 + 2] cycloaddition reaction of diene and tert-alcohol,
we also expected that the Diels−Alder reaction of diene 18 (see
SI for preparation) could generate the borreverine 10. As
expected, the Diels−Alder dimerization reaction of diene 18 with
catalytic Cu(OTf)2 in anhydrous CH2Cl2 afforded the limonene
derivative 19 in a highly regioselective manner (Scheme 4). The
structure and relative stereochemistry of 19 was established by
single crystal X-ray diffraction analysis.14 Yet, dimerization of
diene 18 in toluene at 150 °C in a sealed tube afforded the
isocaulindole derivative 20 in a 1:1 endo/exo ratio. More
2765
dx.doi.org/10.1021/ol501078d | Org. Lett. 2014, 16, 2764−2767

Organic Letters
Letter
Scheme 5. Proposed Mechanism for the Formation of Lactone
21
Scheme 7. Synthesis of Spermacoceine Analogue 29
Scheme 8. Retrosynthesis of Borreverine 10
Scheme 6. Diels−Alder Dimerization of Indole Diene 24
Scheme 9. Diels−Alder Dimerization of 32
tert-butylpyridine, to check the possibility that a different
concentration of the Bronsted acid is leading to the observed
change in reaction outcome, but unfortunately the reaction did
not occur in this case even after several attempts, with just the
starting material recovered. We next focused on the total
synthesis of borreverine 10. Based on the above-mentioned
reactions, it was contemplated that diene 30 on treatment with
Lewis acid would generate the borreverine derivative, which on
further functional group transformation would lead to 10.
Altough diene 30 failed to dimerize on treatment with Cu(OTf)2,
it smoothly underwent dimerization in the presence of BF3·OEt2,
affording the borreverine derivative 31. Although we were
delighted by these results, unfortunately we could not carry
forward the Diels−Alder adduct for the completion of the total
synthesis of 10, since in all these reactions only the endo isomer
resulted and for the synthesis of 10 the exo isomer was required.
It was contemplated that although diene 30 afforded endo isomer
31 exclusively, masked diene 32 on treatment with a Lewis acid
would generate both cisoid and transoid dienes 33a and 33b
respectively, which will lead to the formation of a mixture of exo/
endo isomers (Scheme 8). To our delight 32 resulted in two
steps from tryptamine, 3-methylbut-2-enal, and ClCO2Et
followed by protection of the indole nitrogen by the phenyl
sulfonyl group on treatment with BF3·OEt2 in CH2Cl2,
generating the Diels−Alder adducts 34 and 31 as a 3:5 mixture
of exo/endo isomers (Scheme 9). The structure and relative
stereochemistry of both isomers were established by single
crystal X-ray diffraction analysis of the major isomer 31.14 The
mixture of endo and exo isomers was separated by careful column
chromatography. Deprotection of the indole nitrogens by
reduction of the sulphonamides of 34 using Na/Hg followed
by LAH reduction of the resultant indole derivative 35 afforded
the natural product 10 in 85% yield, whose spectral data (1H, 13C
NMR; IR; and HRMS) were in complete agreement with the
literature report (Scheme 10).6 Similarly endo isomer 31
generated the epi-borreverine 37.
interestingly and surprisingly diene 18 on treatment with a
catalytic amount of Cu(OTf)2 in moist CH2Cl2 generated the
lactone 21 in 82% yield in a highly regio- and diastereoselective
manner. In this reaction five contiguous stereocenters were
generated in one pot. The structure and relative stereochemistry
of the lactone 21 was established by single crystal X-ray
diffraction analysis.14 In the presence of Cu(OTf)2, diene 18
generates diene intermediate 22, which, after an intermolecular
Diels−Alder reaction with diene 18, leads to intermediate 23.
Attack of H2O present in the solvent on the imine carbon
followed by the loss of a proton followed by subsequent
lactonization generates 21 (Scheme 5). To further check the
generality of this reaction and to prove the participation of H2O
in this reaction, we treated dienes 248 and 258 with Cu(OTf)2 in
moist CH2Cl2. Interestingly and as expected, diene 24 on
treatment with Cu(OTf)2 in moist CH2Cl2 generated the
compound 26, and by heating 24 in a sealed tube at 150 °C in
toluene, the caulindole derivative 27 resulted as a 3:1
diastereomeric mixture (Scheme 6). Similarly diene 25 gave
the Diels−Alder adduct 28 having a tetrahydrofuran ring, and
deprotection of the phenyl sulfonyl group generated the 3′-epi-
oxadesmethylspermacoceine 29 (Scheme 7). The structure and
relative stereochemistry of 26−28 were established by single
crystal X-ray diffraction analysis.14 It was thought that water
present in the reaction medium might be forming triflic acid from
Cu(OTf)2, and that it is a proton catalyzed process which is
responsible for the formation of 26. For this purpose we screened
different Bronsted acids, and indeed, the reaction on treatment
with triflic acid in moist CH2Cl2 afforded 26 in 80% yield. It was
observed that a small amount of water present in commercial
grade CH2Cl2 is optimum for this reaction and any external
addition of water hampers the reaction, probably due to catalyst
decomposition. Also, we attempted the reaction by adding di-
2766
dx.doi.org/10.1021/ol501078d | Org. Lett. 2014, 16, 2764−2767

Organic Letters
Letter
Scheme 10. Total Synthesis of Borreverine 10 and 3′-epi-
AUTHOR INFORMATION
Corresponding Author
■
Borreverine 37
*E-mail: ddethe@iitk.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is dedicated to Prof. Ganesh Pandey, on the occasion
of his 60th birthday. We thank Prof. Jiten Bera, Mr. Mithun
Sarkar, Dipankar Sahoo, and Subrata Kundu for crystal structure
analysis. R.D.E. and B.D.D. thank CSIR, New Delhi, for the
award of a research fellowship. Financial support from IIT
Kanpur is gratefully acknowledged.
Scheme 11. Total Synthesis of Flinderole A (6)
REFERENCES
■
(1) (a) Achenbach, H.; Lowell, M. Phytochemistry 1995, 40, 967.
(b) Hocquemiller, R.; Cabalion, P.; Bruneton, J.; Cave, A. Plant. Med.
Phytother. 1978, 12, 230. (c) Hocquemiller, R.; Cabalion, P.; Fournet,
A.; Cave, A. Planta Med. 1984, 50, 23.
(2) Makangara, J. J.; Henry, L.; Jonker, S. A.; Nkunya, M. H. H.
Phytochemistry 2004, 65, 227.
(3) Vougogiannopoulou, K.; Fokialakis, N.; Aligiannis, N.; Cantrell, C.;
Skaltsounis, A.-L. Org. Lett. 2010, 12, 1908.
(4) (a) Briggs, L. H.; Cambie, R. C. Tetrahedron 1958, 2, 256.
(b) Dreyer, D. L. Tetrahedron 1966, 22, 2923. (c) Kutney, J. P.; Inaba,
T.; Dreyer, D. L. J. Am. Chem. Soc. 1968, 90, 813. (d) Sharma, P. N.;
Shoeb, A.; Kapil, R. S.; Popli, S. P. Phytochemistry 1980, 19, 1258.
(5) (a) Fernandez, L. S.; Jobling, M. F.; Andrews, K. T.; Avery, V. M.
Phytother. Res. 2008, 22, 1409. (b) Fernandez, L. S.; Buchanan, M. S.;
Carroll, A. R.; Feng, Y. J.; Quinn, R. J.; Avery, V. M. Org. Lett. 2009, 11,
329.
(6) (a) Pousset, J.; Kerharo, J.; Maynart, G.; Monseur, X.; Cave, A.;
Goutarel, R. Phytochemistry 1973, 12, 2308. (b) Pousset, J. L.; Cave, A.;
Chiaroni, A.; Riche, C. J. Chem. Soc., Chem. Commun. 1977, 261.
(7) (a) Balde, A. M.; Pieters, L. A.; Gergely, A.; Wray, V.; Claeys, M.;
Vlietinck, A. J. Phytochemistry 1991, 30, 997. (b) Tillequin, F.; Koch, M.;
Rabaron, A. J. Nat. Prod. 1985, 48, 120.
(8) Dethe, D. H.; Erande, R. D.; Ranjan, A. J. Am. Chem. Soc. 2011, 133,
2864.
(9) Dethe, D. H.; Erande, R. D.; Ranjan, A. J. Org. Chem. 2013, 78,
We also completed the three-step total synthesis of flinderole
A (6) and desmethyl flinderole C (38) (Scheme 11). Known
compound 39 synthesized in a one-pot sequence11 from
tryptamine on treatment with TFA exclusively afforded
flinderole derivatives 40a,b in a 4:5 diastereomeric ratio and in
86% yield. The mixture of 40a and 40b was easily separated using
silica gel column chromatography. In this case not even a trace
amount of [4 + 2] cycloaddition product was observed. Results
were the same for other Lewis and Bronsted acids, except for a
minor change in the yield of the flinderole derivatives formed. So
the removal of the phenyl sulfonyl group from 32 completely
changed its reactivity and pattern of reaction from a [4 + 2] to a
formal [3 + 2] cycloaddition reaction. 40a and 40b on LAH
reduction afforded 6 and 38 in 83% and 86% yield, respectively.
This synthesis has an advantage over May’s synthesis11 since no
HPLC purification was required, as 40a and 40b were easily
separated in gram quantities by silica gel column chromatog-
raphy.
10106.
(10) (a) Tillequin, F.; Koch, M. J. Chem. Soc., Chem. Commun. 1978,
562, 826. (b) Tillequin, F.; Koch, M.; Bert, M.; Sevenet, T. J. Nat. Prod.
1979, 42, 92.
(11) (a) Vallakati, R.; May, J. A. J. Am. Chem. Soc. 2012, 134, 6936.
(b) Vallakati, R.; May, J. A. Synlett 2012, 23, 2577. (c) Vallakati, R.;
Lundy, B. J.; Popova, S. J.; May, J. A. Chirality 2013, DOI: 10.1002/
chir.22134. (d) Vallakati, R.; Smuts, J. P.; Armstrong, D. W.; May, J. A.
Tetrahedron Lett. 2013, 54, 5892.
(12) (a) Roush, W. R.; Gillis, H. R.; Ko, A. I. J. Am. Chem. Soc. 1982,
104, 2269. (b) Kurosu, M.; Marcin, L. R.; Grinsteiner, T. J.; Kishi, Y. J.
Am. Chem. Soc. 1998, 120, 6627. (c) Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41,
1668. (d) Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359.
(e) Paddon-Row, M. N.; Sherburn, M. S. Chem. Commun. 2012, 48, 832.
(13) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem.
Soc. 2005, 127, 4592.
(14) CCDC 957450 (19), CCDC 957454 (21), CCDC 957452 (26),
CCDC 957453 (27), CCDC 957451 (28), CCDC 957448 (31),
CCDC 957455 (35), and CCDC 957449 (36) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
In conclusion the biomimetic divergent total syntheses of
structurally diverse indole alkaloid natural products (caulindoles
A−D, borreverine, flinderole A−C, and their analogues) have
been achieved. We also discovered a switch of regioselectivity in
the Diels−Alder reaction by fine-tuning the reaction conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all the compounds
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
2767
dx.doi.org/10.1021/ol501078d | Org. Lett. 2014, 16, 2764−2767