Synthesis of the Tetracyclic Structure of Batrachotoxin Enabled by Bridgehead Radical Coupling and Pd/Ni-Promoted Ullmann Reaction

Article abstract of DOI:10.1021/acs.orglett.7b03482

The steroidal ABCD-ring system of the potent neurotoxin batrachotoxin was efficiently assembled in a convergent fashion. Bridgehead radical coupling between the simple AB-ring and D-ring fragments (3 and 4) formed the sterically congested linkage at the C9-oxygen-attached tetrasubstituted carbon. The C-ring was then cyclized by the Pd/Ni-promoted Ullmann reaction of the vinyl triflate and vinyl bromide of 19, giving rise to tetracyclic structure 1.

Full text of DOI:10.1021/acs.orglett.7b03482

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of the Tetracyclic Structure of Batrachotoxin Enabled by
Bridgehead Radical Coupling and Pd/Ni-Promoted Ullmann Reaction
†
Komei Sakata, Yinghua Wang, Daisuke Urabe, and Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
*
S Supporting Information
ABSTRACT: The steroidal ABCD-ring system of the potent
neurotoxin batrachotoxin was efficiently assembled in a
convergent fashion. Bridgehead radical coupling between the
simple AB-ring and D-ring fragments (3 and 4) formed the
sterically congested linkage at the C9-oxygen-attached tetrasub-
stituted carbon. The C-ring was then cyclized by the Pd/Ni-
promoted Ullmann reaction of the vinyl triflate and vinyl bromide
of 19, giving rise to tetracyclic structure 1.
aturally occurring steroids have a wide variety of
important biological activities. Therefore, many natural
Scheme 1. Retrosynthesis of Batrachotoxin
1
N
steroids and their synthetic derivatives are utilized as
pharmaceuticals. Steroidal compounds share a 6/6/6/5
2
ABCD-ring scaffold whose overall three-dimensional structure
is controlled by the ring fusion pattern. These skeletons with
distinct shapes are further varied by polar substituents and
unsaturated bonds, endowing them with diverse biological
functions.
Although numerous synthetic approaches to steroids have
3
been developed, highly oxygenated and unsaturated steroidal
natural products continue to be a formidable synthetic
challenge. This is the case because the high number of
potentially reactive polar functionalities and olefins amplifies
the complexity of synthetic problems. To address this issue, we
have focused our efforts on designing new convergent
approaches to these steroids, as such strategies are more
advantageous for realizing shorter synthetic routes. We recently
achieved the total syntheses of 19-hydroxysarmentogenin and
ouabagenin with unusual steroidal structures by the assembly of
4
the AB- and D-ring substructures. Here we report an
alternative convergent strategy for constructing the core
steroidal structure of batrachotoxin (1, Scheme 1).
group disclosed an efficient assembly of both enantiomers of
batrachotoxin and demonstrated their agonistic activities
10
against the channels.
Batrachotoxin was isolated from the skins of Columbian
poison-arrow frogs as a neurotoxic constituent and was
Our plan for a convergent synthesis of batrachotoxin is
illustrated in Scheme 1. Batrachotoxin was retrosynthetically
modified to the core tetracycle 1 by removing the C14- and
C17-substituents and interconverting the C11-hydroxy and
C18-amino groups to the C11-ethoxycarbonyl and C18-acetoxy
groups, respectively. The ABCD-ring system 1 was further
disassembled into AB-ring 3 and D-ring 4. In a synthetic
direction, 3 and 4 were planned to be assembled back into 1
5
structurally characterized in 1968 by Daly and Witkop. Its
neurotoxicity is attributed to its action to depolarize nerve and
muscle membranes by selectively activating voltage-gated
6
sodium channels. Batrachotoxin belongs to the class of
steroids yet possesses unique structural features such as C7-
and C16-double bonds, a C9α-oxygen atom that forms the six-
membered C3-hemiacetal across the AB-ring, and a C18-
nitrogen atom that forms the seven-membered oxazepane ring
on the CD-ring. Various creative routes to this complex
11
using two orthogonal transformations, radical coupling and a
12
transition-metal-promoted Ullmann reaction. First, a C9-
7
architecture have been pursued, culminating in the successful
total syntheses of batrachotoxinin A, a C20-OH analogue, by
the groups of Wehrli and Kishi. Most recently, the Du Bois
Received: November 9, 2017
8
9
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
13,14
bridgehead radical,
formed from the α-alkoxy acyltelluride
ether with the methyl vinyl ether, leading to 8a and 8b (4.9:1).
moiety of 3, would be added to the electron-deficient C11-
olefin of 4 to yield 2 by linking the two fragments in a C9-
stereospecific manner. Second, reductive cross-coupling of the
two electrophiles at the C8 and C14 positions would cyclize the
C-ring to generate the steroidal skeleton of 1. Although we
recently demonstrated facile decarbonylative α-alkoxy radical
formation from α-alkoxy acyltellurides, radical coupling
between 3 and 4 would be particularly challenging because of
the presence of the highly reactive C8-vinyl bromide and C14-
vinyl triflate. Nonetheless, this convergent route was expected
to rapidly build up the highly oxygenated and unsaturated
structure of 1 because 3 and 4 are fully equipped with all of the
functional groups required for C-ring annulation.
The 8a/8b mixture was subjected to catalytic RuCl in the
3
1
7
presence of NaIO to provide the ester mixture 9a/9b, which
4
was treated with LiI in refluxing pyridine to generate carboxylic
18
acid 10. Compound 10 was in turn derivatized into acyl
telluride 3 in two steps: formation of the mesyl ester with MsCl
19
and Et N and replacement of the OMs group with the TePh
3
15
group by the action of NaBH and (TePh) .
4
2
D-ring 4 was synthesized from readily available achiral
2
0
diketone 12.
Treatment of 12 with p-TsOH and
paraformaldehyde in AcOH installed the acetyl-protected
hydroxy methyl group at the C13-quaternary center, leading
21
to 13. The cyclopentadione structure of 13 was then
desymmetrized by asymmetric monoreduction of diketone
13. Namely, Ru-catalyzed asymmetric transfer hydrogenation
using Noyori catalyst A in i-PrOH converted 13 to 14 with high
diastereoselectivity (dr at C13 = 4:1) and excellent
AB-ring 3 was prepared from enantiopure Wieland−
Miescher ketone 5 (Scheme 2). The five-step sequence
22,23
Scheme 2. Synthesis of the AB- and D-Ring Fragments
enantioselectivity (96% ee).
TBS protection of secondary
alcohol 14 and its C13-epimer, followed by SiO purification,
2
provided enantio- and diastereopure 15. The remaining ketone
of 15 was in turn enolized with KN(TMS) and subsequently
2
24
reacted with Comins’ reagent B to furnish vinyl triflate 16.
After chemoselective oxidative cleavage of the terminal olefin of
diene 16 by stepwise use of OsO /N-methylmorpholine N-
4
oxide (NMO) and NaIO , the resulting aldehyde 17 was
4
treated with malononitrile and NH OAc to produce the
4
requisite D-ring 4.
The thus-obtained AB-ring 3 and D-ring 4 were subjected to
a radical coupling reaction (Scheme 3). Specifically, treatment
25
of 3 and 4 (2 equiv) with Et B (3 equiv) and O at 55 °C
3
2
resulted in the C9-stereospecific generation of a mixture of
C11-diastereomers 2a (α-C11−H, 41% yield) and 2b (β-C11−
H, 27% yield). Intermolecular formation of the sterically
Scheme 3. Bridgehead Radical Coupling of the AB- and D-
Ring Fragments and Its Proposed Mechanism
1
6
7g
converted 5 into the known C8-vinyl bromide 6.
Nucleophilic attack of lithium ethyl vinyl ether on the C9-
ketone of 6 proceeded from the convex face of the cis-decalin
system to afford 7 as the single isomer. Treatment of 7 with
camphorsulfonic acid (CSA) in CH(OMe)3 and MeOH
induced exchange of the 1,3-dioxolane with the six-membered
C3-methyl acetal and concomitantly substituted the ethyl vinyl
B
DOI: 10.1021/acs.orglett.7b03482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
encumbered bond between tetrasubstituted C9 and trisub-
stituted C11 and tolerance of the C8-vinyl bromide and C14-
vinyl triflate attested to the potent reactivity and high generality
of the present reaction.
activation of the vinyl triflate of our substrate 19b. Although
direct application of the Weix catalytic conditions was low-
yielding, the stoichiometric version of the reagent system
tripled the cyclization yield. When 19b was heated to 50 °C in
DMF with PdCl (3 equiv), NiBr ·1,2-dimethoxyethane (dme)
(3 equiv), 2,2′-bipyridine, and 1,3-bis(diphenylphosphino)-
propane (dppp) in the presence of Zn (10 equiv) and KF, the
cyclized product 1b was obtained in 68% yield. The same
reaction conditions successfully transformed C11-epimeric 19a
to 1a in 60% yield. Significantly, the acid-sensitive (C3-acetal
and C17-OTBS) and base-sensitive (C18-OAc and C11-
COOEt) functionalities remained intact, demonstrating the
high applicability of the Pd/Ni-promoted reaction.
In this coupling, the ethyl radical generated from Et B and
3
2
2
O chemoselectively cleaves the weak C−Te bond of AB-ring 3
2
15
in the presence of the C8−Br bond to generate acyl radical C.
Rapid decarbonylation from C affords the stereochemically
fixed α-alkoxy bridgehead radical D. Because of its electron-
rich and nucleophilic nature, D adds to the most electron-
deficient alkylidenemalononitrile of 4 selectively over the C8-
and C14-olefins, leading to E. Finally, the radical reaction is
26
terminated by the capture of E by Et B with the expulsion of an
3
2
7
ethyl radical, and hydrolysis of the resultant F affords the
adduct 2a/2b.
In summary, we have devised a new convergent strategy for
constructing the steroidal framework 1a/1b of batrachotoxin
(15 total steps from 5). The AB-ring 3 and D-ring 4 were
designed to possess both radical and transition-metal reacting
functionalities and were transformed into 1a/1b in only four
steps. First, a Et B/O -mediated intermolecular radical reaction
After the two fragments were linked, the preinstalled C8-
bromide and C14-triflate were utilized as handles for the
subsequent transition-metal-promoted C-ring closure (Scheme
4). Prior to the key cyclization, a two-step sequence permitted a
3
2
between 3 and 4 was performed to form the adduct 2a/2b via
C9-α-alkoxy bridgehead radical D in a C9-stereospecific
manner. Second, an intramolecular Pd/Ni-promoted reaction
cyclized the six-membered C-ring by linking the congested
C8−C14 bond. Noteworthily, the synthesis strategically
exploited the orthogonal nature of the radical and transition-
metal reactions for assembly of the highly oxygenated and
unsaturated structure. Further exploration of this newly
developed strategy for the total synthesis of batrachotoxin
and other related steroidal natural products is underway in our
laboratory.
Scheme 4. Pd/Ni-Promoted Ullmann Reaction for
Cyclization of the C Ring
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03482.
Experimental procedures, characterization data, and
NMR spectra of all newly synthesized compounds
(PDF)
AUTHOR INFORMATION
■
change of the malononitrile moiety of 2a/2b into the ethyl
ester of 19a/19b. Thus, oxidation of 2a/2b with magnesium
monoperoxyphthalate (MMPP) gave rise to acyl cyanides 18a
and 18b, which were submitted to mild basic ethanolysis with
Corresponding Author
*E-mail: inoue@mol.f.u-tokyo.ac.jp.
ORCID
28
NH to yield 19a and 19b, respectively, without affecting the
3
Masayuki Inoue: 0000-0003-3274-551X
Present Address
†D.U.: Faculty of Engineering, Toyama Prefectural University,
C18-OAc group.
The C-ring cyclization necessitated a powerful C−C bond
formation because the reacting C8 and C14 positions were
hindered by the adjacent fully substituted carbons C9 and C13.
To achieve this, the Ni-promoted Ullmann reaction was first
explored using one C11-isomer, 19b. Treatment of 19b with
5
180 Kurokawa, Imizu-shi, Toyama 939-0398, Japan.
Notes
NiCl (5 equiv), 2,2′-bipyridine (6 equiv), and Zn (7.5 equiv)
2
The authors declare no competing financial interest.
in CH CN and pyridine permitted the formation of cyclized
3
29
diene 1b, albeit in only 23% yield. Isolation of the C8-
debrominated derivative of 19b as a byproduct indicated the
slow oxidative addition of Ni(0) to the C14−OTf bond. During
this time, we noticed that the Weix group realized Ullmann
cross-coupling reactions between aryl bromides and triflates by
ACKNOWLEDGMENTS
■
This research was financially supported by Grants-in-Aid for
Scientific Research (S) (17H06110) and Scientific Research on
Innovative Areas (17H06452) to M.I. and a Grant-in-Aid for
Young Scientists (A) (16H06213) to D.U. from JSPS. A JSPS
Fellowship to K.S. is gratefully acknowledged.
30
employing multimetallic Pd/Ni catalysts, and we therefore
expected that use of a Pd reagent would accelerate the
C
DOI: 10.1021/acs.orglett.7b03482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
3
(
16) Buchschacher, P.; Fu
7.
17) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
18) Elsinger, F.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta
960, 43, 113. Treatment of hindered ester mixture 9a/9b with
aqueous LiOH or KOH solution resulted in no reaction.
19) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H.-S.; Fong, K.
C.; He, Y.; Yoon, W. H. Org. Lett. 1999, 1, 883.
20) (a) Novak, L.; Baan, G.; Marosfalvi, J.; Szan
980, 113, 2939. (b) Ruprah, P. K.; Cros, J.-P.; Pease, J. E.;
Whittingham, W. G.; Williams, J. M. J. Eur. J. Org. Chem. 2002, 2002,
145.
̈
rst, A.; Gutzwiller, J. Org. Synth. 1985, 63,
REFERENCES
■
(
1) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach, 3rd ed.; Wiley: Chichester, U.K., 2009.
2) For recent reviews of the roles of natural product structures in
drug discovery, see: (a) Harvey, A. L.; Edrada-Ebel, R.; Quinn, R. J.
Nat. Rev. Drug Discovery 2015, 14, 111. (b) Newman, D. J.; Cragg, G.
M. J. Nat. Prod. 2016, 79, 629.
(
(
1
̧
(
(
3) For recent reviews of total syntheses of steroids, see: (a) Saraber
F. C. E.; de Groot, A. Tetrahedron 2006, 62, 5363. (b) Chapelon, A.-S.;
Moraleda, D.; Rodriguez, R.; Ollivier, C.; Santelli, M. Tetrahedron
007, 63, 11511. (c) Heasley, B. Chem. - Eur. J. 2012, 18, 3092.
̀
,
(
1
́
́
́
tay, C. Chem. Ber.
́
2
(
(
d) Urabe, D.; Asaba, T.; Inoue, M. Chem. Rev. 2015, 115, 9207.
e) Michalak, M.; Michalak, K.; Wicha, J. Nat. Prod. Rep. 2017, 34,
3
(21) Manna, M. S.; Mukherjee, S. J. Am. Chem. Soc. 2015, 137, 130.
361.
(22) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R.
(
4) (a) Mukai, K.; Urabe, D.; Kasuya, S.; Aoki, N.; Inoue, M. Angew.
Chem., Int. Ed. 2013, 52, 5300. (b) Mukai, K.; Kasuya, S.; Nakagawa,
Y.; Urabe, D.; Inoue, M. Chem. Sci. 2015, 6, 3383.
5) (a) Tokuyama, T.; Daly, J.; Witkop, B.; Karle, I. L.; Karle, J. J. Am.
Chem. Soc. 1968, 90, 1917. (b) Tokuyama, T.; Daly, J.; Witkop, B. J.
Am. Chem. Soc. 1969, 91, 3931.
6) For recent reviews of voltage-gated sodium channels, see:
a) Wang, S.-Y.; Wang, G. K. Cell. Signalling 2003, 15, 151. (b) de Lera
Ruiz, M.; Kraus, R. L. J. Med. Chem. 2015, 58, 7093.
7) (a) Schumaker, R. R.; Keana, J. F. W. J. Chem. Soc., Chem.
Commun. 1972, 622. (b) Magnus, P.; Leapheart, T.; Walker, C. J.
Chem. Soc., Chem. Commun. 1985, 1185. (c) Hudson, P.; Pairaudeau,
G.; Parsons, P. J.; Jahans, A. W.; Drew, M. G. B. Tetrahedron Lett.
J. Am. Chem. Soc. 1995, 117, 7562. (b) Shi, B.; Merten, S.; Wong, D. K.
Y.; Chu, J. C. K.; Liu, L. L.; Lam, S. K.; Jager, A.; Wong, W.-T.; Chiu,
P.; Metz, P. Adv. Synth. Catal. 2009, 351, 3128.
23) See the Supporting Information for determination of the
̈
(
(
structure and enantiomeric excess of 14.
(24) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(25) Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415.
(26) For reviews of acyl radical reactions and decarbonylation rates,
see: (a) Boger, D. L. Isr. J. Chem. 1997, 37, 119. (b) Chatgilialoglu, C.;
Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.
(27) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991,
64, 403.
(
(
(
(28) Fo
2803.
̈
rster, S.; Tverskoy, O.; Helmchen, G. Synlett 2008, 2008,
1
993, 34, 7295. (d) Schow, S. R.; Rossignol, D. P.; Lund, A. E.;
Schnee, M. E. Bioorg. Med. Chem. Lett. 1997, 7, 181. (e) Trudeau, S.;
Deslongchamps, P. J. Org. Chem. 2004, 69, 832. (f) Lacrouts, P.;
Parsons, P. J.; Penkett, C. S.; Raza, A. R. Synlett 2005, 2767. (g) Sultan,
A.; Raza, A. R.; Khan, K. M. J. Chem. Soc. Pak. 2013, 35, 1369.
(29) Takagi, K.; Hayama, N. Chem. Lett. 1983, 12, 637.
(30) Weix proposed that the Ullmann reaction involves chemo-
selective oxidative addition of Ni(0) and Pd(0) to the C−Br and C−
OTf bonds, respectively. See: Ackerman, L. K. G.; Lovell, M. M.; Weix,
D. J. Nature 2015, 524, 454.
(
h) Devlin, A. S.; Du Bois, J. Chem. Sci. 2013, 4, 1059.
8) (a) Imhof, R.; Gossinger, E.; Graf, W.; Berner, H.; Berner-Fenz,
L.; Wehrli, H. Helv. Chim. Acta 1972, 55, 1151. (b) Imhof, R.;
Gossinger, E.; Graf, W.; Berner-Fenz, L.; Berner, H.; Schaufelberger,
R.; Wehrli, H. Helv. Chim. Acta 1973, 56, 139.
9) Kurosu, M.; Marcin, L. R.; Grinsteiner, T. J.; Kishi, Y. J. Am.
(
̈
̈
(
Chem. Soc. 1998, 120, 6627. As batrachotoxinin A was converted to
batrachotoxin (ref 5), Wehrli and Kishi completed the formal total
synthesis of batrachotoxin.
(
10) Logan, M. M.; Toma, T.; Thomas-Tran, R.; Du Bois, J. Science
016, 354, 865.
11) For recent reviews of radical reactions, see: (a) Rowlands, G. J.
Tetrahedron 2009, 65, 8603. (b) Rowlands, G. J. Tetrahedron 2010, 66,
2
(
1
1
593. (c) Jamison, C. R.; Overman, L. E. Acc. Chem. Res. 2016, 49,
578. (d) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. J. Am. Chem.
Soc. 2016, 138, 12692. (e) Inoue, M. Acc. Chem. Res. 2017, 50, 460.
12) For recent reviews of reductive cross-coupling between two
electrophiles, see: (a) Nelson, T. D.; Crouch, D. R. Org. React. 2004,
3, 265. (b) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346.
(
6
(
(
c) Everson, D. A.; Weix, D. J. J. Org. Chem. 2014, 79, 4793.
d) Knappke, C. E. I.; Grupe, S.; Gartner, D.; Corpet, M.; Gosmini, C.;
̈
von Wangelin, A. J. Chem. - Eur. J. 2014, 20, 6828.
(
(
13) Walton, J. C. Chem. Soc. Rev. 1992, 21, 105.
14) For our convergent total synthesis of natural products using
bridgehead radicals generated from α-alkoxy selenides, see: (a) Asaba,
T.; Katoh, Y.; Urabe, D.; Inoue, M. Angew. Chem., Int. Ed. 2015, 54,
1
4457. (b) Hashimoto, S.; Katoh, S.; Kato, T.; Urabe, D.; Inoue, M. J.
Am. Chem. Soc. 2017, 139, 16420.
15) (a) Nagatomo, M.; Kamimura, D.; Matsui, Y.; Masuda, K.;
(
Inoue, M. Chem. Sci. 2015, 6, 2765. (b) Nagatomo, M.; Nishiyama, H.;
Fujino, H.; Inoue, M. Angew. Chem., Int. Ed. 2015, 54, 1537.
(
2
c) Matsumura, S.; Matsui, Y.; Nagatomo, M.; Inoue, M. Tetrahedron
016, 72, 4859. (d) Fujino, H.; Nagatomo, M.; Paudel, A.; Panthee, S.;
Hamamoto, H.; Sekimizu, K.; Inoue, M. Angew. Chem., Int. Ed. 2017,
6, 11865.
5
D
DOI: 10.1021/acs.orglett.7b03482
Org. Lett. XXXX, XXX, XXX−XXX