Total Syntheses of Ningalins D and G

Article abstract of DOI:10.1021/acs.orglett.7b02372

A flexible synthetic strategy for the total syntheses of ningalins D and G is described. The highly effective TMS-OTf/2,6-lutidine-mediated [3,3]-sigmatropic rearrangement of densely loaded dinaphthyl hydrazides and cyclization of the resulting 2,2′-diami

Full text of DOI:10.1021/acs.orglett.7b02372

Letter
pubs.acs.org/OrgLett
Total Syntheses of Ningalins D and G
Jang-Yeop Kim, Dong-Hyun Kim, Tae-Hong Jeon, Woo-Hyung Kim, and Cheon-Gyu Cho*
Center for New Directions in Organic Synthesis, Department of Chemistry, Hanyang University, 222 Wangshimni-ro,
Seongdong-gu, Seoul 04763, Korea
*
S Supporting Information
ABSTRACT: A flexible synthetic strategy for the total syntheses of ningalins D and G is described. The highly effective
TMS-OTf/2,6-lutidine-mediated [3,3]-sigmatropic rearrangement of densely loaded dinaphthyl hydrazides and cyclization of the
resulting 2,2′-diamino-1,1′-dinaphthyls afforded the key 7H-dibenzo[c,g]carbazole intermediates. Successful conversions to
biphenylene quinone methides followed by regioselective brominations completed the total syntheses of the titled marine alkaloids.
ingalin D is a benzocarbazole marine alkaloid isolated from
Construction of the C and D rings via Dieckmann conden-
sation delivered the key dibenzocarbazole intermediate 5.
Subsequent transformations including Suzuki−Miyaura coupling
and Curtius rearrangements completed the total synthesis of
ningalin D. Before this work, Steglich and co-workers reported a
N
a western Australian unidentified ascidian belonging to the
1
genus Didemnum. Ningalin D contains a biphenylene quinone
methide framework with a multiply hydroxylated dibenzocarba-
zole core containing one dihydroxyphenethyl and two dihydrox-
2
yphenyl groups (1, Figure 1). Recently, Capon et al. isolated
a closely related marine natural product, ningalin G, from an
Scheme 1. Approaches to Ningalin D and Purpurone
Figure 1. Structures of ningalin D, G, and purpurone.
extract of a Southern Australian marine ascidian, Didemnum
3
(
3, Figure 1). Unlike ningalin D, its hydroxyl groups present in
an unsymmetrical pattern (C7′ vs C9′ in ningalin D). Together
with other ningalin natural products, ningalins D and G exhibit
various intriguing bioactivities ranging from antidiabetic effects
to kinase inhibitory activities, as well as multidrug resistance
4
reversal properties. Despite the growing interest in their func-
tions, there are very few synthetic studies regarding these
compounds (vide infra).
Specifically, Boger and co-workers reported the only synthetic
5
method for ningalin D. They prepared pyrrole 4 from the
cycloaddition product between 1,2-diaryl ethyne with tetrazine
dicarboxylate (eq 1, Scheme 1).
Received: July 31, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02372
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Letter
strategy employing pyrrole 6 en route to the total synthesis of
purpurone (2). In this report, tetra-substituted pyrrole dicarbo-
Scheme 3. Preparation of Naphthalene Bromides
xylic acid 6 was subjected to Ac O/KOAc mediated Friedel−
2
Craft cyclization reactions to construct the C and D rings of
6
dibenzocarbazole intermediate 7 (eq 2). However, there are no
reports regarding the synthesis of ningalin G. The unsymmetrical
substitution pattern of the hydroxyl groups likely levies an
additional synthetic challenge. In accord with our ongoing7
research program exploring synthetic utilities of aryl hydrazide,
we elaborated a flexible synthetic route that provides access
to both ningalin D and G by way of highly substituted
7H-dibenzo[c,g]carbazoles 12/13. Herein, we report a TMS-
OTf/2,6-lutidine catalyzed [3,3]-sigmatropic rearrangement
and cyclization of dinaphthyl hydrazides 8/9 to key intermediates
12/13 and successful transformations for the total syntheses of
ningalins D and G (eq 3).
Previously we reported that diaryl hydrazides may undergo
acid-catalyzed [3,3]-sigmatropic rearrangements to afford
7
f,h
1
,1′-biaryl-2,2′-diamines. Furthermore, theresultingdiamines,
on isolation or in situ, can cyclize into the corresponding carba-
indeed proceeded to give 15a along with regioisomer 24a as a 4:1
inseparable mixture in 71% combined yield. In this process, the
more electron-rich 2-pyrone C6 carbon appeared to attack the
7e
zoles, upon heating in acidic media. Based on these observations,
we devised a new synthetic strategy toward ningalins D and G,
given the easy access to the key intermediates, 7H-dibenzo[c,g]-
carbazole 12/13, from the acid catalyzed [3,3]-sigmatropic
rearrangement and cyclization cascade of dinaphthyl hydrazides
13
more electrophilic C1 carbon of benzyne 21.
Toward the preparation of diaryl hydrazides 8a−8d with
various Zgroup, naphthylbromide14awasconvertedintoamore
reactive iodide via a Finkelstein-type halogen exchange reaction
1
0 with proper latent hydroxyl surrogates Z, as illustrated
14
under the protocol developed by Buchwald and co-worker.
in the retrosynthesis (Scheme 2). It is anticipated that the
Subsequent one-pot Cu(I)-catalyzed C−N coupling with di-tert-
butyl hydrazine-1,2-dicarboxylate (16) delivered diaryl hydra-
zides 8a − 8d with various Z groups in good to reasonable yields
Scheme 2. Retrosyntheses of Ningalins D and G
(
Scheme 4). Dinaphthyl hydrazide 9a with an unsymmetrical
Scheme 4. Synthesis of Diaryl Hydrazides 8a−8d and 9a
groups Z para to the reaction sites are likely to affect the pivotal
[
3,3]-sigmatropic rearrangements of 10/11. Further retrosyn-
thetic analysis calls for naphthyl bromides 14/15 with electroni-
cally different Z groups and di-tert-butyl hydrazine-1,2-dicarbox-
ylate (16).
substitution pattern around the naphthalene rings was prepared
via two successive C−N coupling reactions. Naphthyl hydrazide
25 prepared from 14a and 16 was then coupled with a 4:1 mixture
ofnaphthylbromides15aand24atogivedinaphthylhydrazide9a
in 72% yield after isolation.
With dinaphthyl hydrazides 8a−8d and 9a in hand,
we investigated the optimal conditions for the acid-catalyzed
[3,3]-sigmatropic rearrangement and cyclization reaction using
8a as the model substrate under various solvents, acids, and
temperatures. The best results were obtained when the reaction
was conducted in n-PrOH with aqueous HCl under reflux,
affording 12a in 54% yield (entry 1, Table 1). Notably, 8b with an
electron-withdrawing ester group did not give the corresponding
carbazole product even after prolonged heating (entry 2).
To begin, naphthalene 14a (Z = Me) was prepared as a starting
point for derivatization (Scheme 3). A Diels−Alder reaction of
8
3
4
-methyl-5-bromo-2-pyrone 19 was implemented with
9
,5-dimethoxy-benzyne generated from diazonium salt 18 to
give naphthalene 14a in 89% yield. In this tandem process, the
initially formed cycloadduct 20 underwent a retro-Diels−Alder
reaction, extruding CO . The methyl group was then oxidized to a
2
1
0
nitrile (14e), before conversion to ester 14b (Z = CO Et),
2
amine 14c (Z = NH ), and pivalamide 14d (Z = NHPiv).
2
Similarly, the synthesis of ningalin G required naphthalene 15a
with two uniquely positioned methoxy groups. Toward this end, a
Diels−Alder reaction between 2-pyrone 19 and 3,4-dimethoxy
1
1
benzyne 23 was carried out, anticipating that cycloadduct 21
12
would form based on the aryne distortion model. The reaction
Hydrazides 8c and 8d with electron-donating NH and NHPiv
2
B
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Letter
a
Table 1. IMFIS of 6b under Various Conditions
Scheme 5. Synthesis and Oxidation of Dibenzocarbazole 33
entry
8/9
conditions
results (%)
1
2
3
4
5
6
7
8
9
8a (R = OMe, R′ = H, Z = Me)
A
A
A
A
A
B
12a (54)
8b (R = OMe, R′ = H, Z = CO Et)
12b (trace)
2
8c (R = OMe, R′ = H, Z = NH2)
8d (R = OMe, R′ = H, Z = NHPiv)
9a (R = H, R′ = OMe, Z = Me)
9a (R = H, R′ = OMe, Z = Me)
9a (R = H, R′ = OMe, Z = Me)
9a (R = H, R′ = OMe, Z = Me)
8a (R = OMe, R′ = H, Z = Me)
12c (36)
12d (38)
13a (24), 26a (30)
13a (36), 26a (18)
13a (44), 26a (21)
13a (85), 26a (0)
12a (65)
C
D
D
With no other options remaining, we returned to 7H-dibenzo-
a
Reaction conditions: (A) HCl (aq) in n-PrOH (0.4 M), 120 °C, 12 h;
B) HCl in 1,4-dioxane (0.4 M), rt, 4 h, then n-PrOH, 120 °C, 24 h;
C) 0.4 M HCl in dioxane, rt, 4 h, then microwave irradiation,
n-PrOH, 5 min; (D) TMS-OTf, 2,6-lutidine, 0 °C, 2 h, then micro-
wave irradiation, 5 min.
[
c,g]-carbazole 12a and attempted the methyl group oxidation
before installation of the sterically demanding aryl groups
Scheme 6). Accordingly, 12a was converted into 34 and
(
(
(
Scheme 6. Total Syntheses of Ningalins D and G
groups afforded carbazoles 12c and 12d in moderate yields of
3
6% and 38%, respectively (entries 3 and 4). Under the optimized
conditions, hydrazide 9a gave carbazole 13a in 24% yield in
addition to diamine 26a in 35% yield owing to the unexpected
[
5,5]-sigmatropic rearrangement (entry 5). Meaningful improve-
ments were observed when the rearrangement was carried out at
room temperature before thermal heat or microwave irradiation
was applied for the cyclization (entries 6 and 7). Therefore, we
opted tounmask theN-Boc groups tofacilitate the rearrangement
at lower temperatures. Surprisingly, treatment with excess
TMS-OTf/2,6-lutidine15 at 0 °C gave the corresponding
[
3,3]-sigmatropic rearrangement product 27a along with a
small amount of carbazole 13a. Subsequent heating in n-PrOH
under microwave irradiation afforded carbazole 13a in 85%
overall yield (entry 8). When this procedure was applied with
dinaphthyl hydrazide 8a, an increased yield of 12a was observed
(
65%, entry 9).
With the efficient synthesis of carbazole 12a established, we
surveyed various literature methods to regioselectively halo-
genate the C6 and C8 carbons as a prelude for the installation of
16
the F and G rings. After extensive optimization, bromination
withHBrinDMSOundermodifiedconditionsofthosereported
1
7
by Jiao and co-workers turned out to be the most effective,
delivering desired dibromide 29 in a remarkably high yield of
7
8%, considering the presence of other potentially competing
sites (Scheme 5). Suzuki−Miyaura reactions of 29 with
3,4-dimethoxyphenyl)boronic acid (30) afforded carbazole
(
31 with rings G and H in quantitative yield. N-Alkylation with
3
,4-dimethoxyphenethyl iodide (32) gave N-3,4-dimethoxy-
phenethyl dibenzo-carbazole 33, which contained all necessary
groups for the final synthesis. Unfortunately, the oxidation
of the methyl groups was problematic. All attempts to convert
subjected to various oxidation conditions. Gratifyingly, the methyl
groups were cleanly oxidized to formyl groups when heated with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in an aque-
1
0,18
19
them into either nitriles
or aldehydes were unsuccessful,
presumably due to the steric impediment of the flanking aryl
groups.
20
ous acidic solution under reflux. Subsequent Dakin oxidation
C
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Letter
and hydrolysis of the resulting formate under air gave rise to
biphenylene quinone methide 38 in 51% total yield from 34.
Soenen, D. R.; Danishefsky, S. J.; Boger, D. L. Cancer Chemother.
Pharmacol. 2005, 56, 379.
21
(5) Hamasaki, A.; Zimpleman, J. M.; Hwang, I.; Boger, D. L. J. Am.
Although not anticipated, treatment with 2.0 equiv of NBS under
the standard conditions facilitated the remarkably selective
dibromination affording dibromide 40 in 78% yield. Subsequent
Suzuki−Miyaura coupling with arylboronic acid 30 gave fully
decorated biphenylene quinone methide 42 in quantitative
Chem. Soc. 2005, 127, 10767.
(
(
6) Peschko, C.; Steglich, W. Tetrahedron Lett. 2000, 41, 9477.
7) (a) Park, J.; Kim, D.-H.; Das, T.; Cho, C.-G. Org. Lett. 2016, 18,
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098. (b) Lim, B.-Y.; Jung, B.-E.; Cho, C.-G. Org. Lett. 2014, 16, 4492.
(c) Park, J.; Kim, S.-Y.; Kim, J.-E.; Cho, C.-G. Org. Lett. 2014, 16, 178.
2
2
yield. Removal of the methyl protecting groups with BBr gave
3
(d) Park, I.-K.; Park, J.; Cho, C.-G. Angew. Chem., Int. Ed. 2012, 51, 2496.
(e) Lim, B.-Y.; Choi, M.-K.; Cho, C.-G. Tetrahedron Lett. 2011, 52, 6015.
(f) Suh, S.-E.; Park, I.-K.; Lim, B.-Y.; Cho, C.-G. Eur. J. Org. Chem. 2011,
2011, 455. (g) Kim, H.-Y.; Lee, W.-J.; Kang, H.-M.; Cho, C.-G. Org. Lett.
ningalin D in 13% total yield over 10 steps from 3-methyl-5-
bromo-2-pyrone 19. Notably, a simple aqueous workup afforded
analytically pure ningalin D in 99% yield, in contrast to the
previous approach, which required reversed phase HPLC
2
007, 9, 3185. (h) Lim, Y.-K.; Jung, J.-W.; Lee, H.; Cho, C.-G. J. Org.
Chem. 2004, 69, 5778.
8) (a) Cho, H.-K.; Tam, N. T.; Cho, C.-G. Bull. Korean Chem. Soc.
2
3
purification. Following the successful synthesis of ningalin D,
we attempted the synthesis of ningalin G by subjecting
dibenzocarbazole 13a to the same reaction sequence used for
ningalin D. N-Phenethylation and a series of oxidations including
DDQ-mediated methyl oxidations and phenylseleninic acid and
air oxidations gave 39 in 41% overall yield. Highly regioselective
brominations with 2.0 equiv of NBS gave 41 in 78% yield.
Subsequent installation of the F and G rings via Suzuki−Miyaura
coupling with arylboronic acid 30 afforded fully decorated
biphenylene quinone methide 43 in 85% yield. Demethylation of
the phenolic alcohol protecting groups gave ningalin G (3) in 7%
total yield over 10 linear steps from 2-pyrone 19. Again, a simple
(
2
010, 31, 3382. (b) Ryu, K.; Cho, Y.-S.; Jung, S.-I.; Cho, C.-G. Org. Lett.
2
006, 8, 3343.
(
9) (a) Dockendorff, C.; Sahli, S.; Olsen, M.; Milhau, L.; Lautens, M. J.
Am. Chem. Soc. 2005, 127, 15028. (b) Perez, D.; Guitian, E.; Castedo, L. J.
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(10) Shu, Z.; Ye, Y.; Deng, Y.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed.
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Tetrahedron 1993, 49, 1251.
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́ ́ ́
ez, B.; Martín, G.; Guitian, E.; Castedo, L.; Saa, J. M.
(
Soc. 2014, 136, 15798 and references cited therein.
24
(13) 3-Methyl-5-bromo-2-pyrone (19) undergoes a highly regiose-
lective Diels−Alder reaction with acrolein to afford the corresponding
cycloadduct as a result of the preferred interaction between the
electronically rich C6 of 2-pyrone and deficient (more electrophilic) β-
carbon of dienophile (see ref 8b for details).
aqueous workup afforded analytically pure ningalin G.
In summary, we devised a flexible synthetic strategy that
allows for the syntheses of ningalins D and G. The TMS-OTf/
2
,6-lutidine-mediated [3,3]-sigmatropic rearrangement and cycliza-
tion cascades of highly substituted dinaphthyl hydrazides provided
rapid access to the key intermediates, 7H-dibenzo[c,g]carbazoles
ASSOCIATED CONTENT
■
(
14) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844.
*
S
Supporting Information
(15) Chen, L.-A.; Wang, C.-F.; Gin, M.-G.; Zhang, J.-L.; Huang, P.-Q.;
Wang, A.-E. Asian J. Org. Chem. 2013, 2, 294.
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b02372.
(
16) (a) Majetich, G.; Hicks, R.; Reister, S. J. Org. Chem. 1997, 62, 4321.
b) Racys, D. T.; Sharif, S. A. I.; Pimlott, S. L.; Sutherland, A. J. Org. Chem.
2016, 81, 772.
(
Experimental procedures and spectral data (PDF)
(
(
17) Song, S.; Sun, X.; Li, X.; Yuan, Y.; Jiao, N. Org. Lett. 2015, 17, 2886.
18) (a) Liu, J.; Zheng, H.-X.; Yao, C.-Z.; Sun, B.-F.; Kang, Y.-B. J. Am.
AUTHOR INFORMATION
■
*
Chem. Soc. 2016, 138, 3294. (b)Guo, S.;Wan, G.;Sun, S.;Jiang, Y.; Yu, J.-
T.; Cheng, J. Chem. Commun. 2015, 51, 5085.
Corresponding Author
(
19) (a) Mal, D.; Roy, J. Tetrahedron 2015, 71, 1247. (b) Thomas, C.;
Knolker, H. J. Tetrahedron Lett. 2013, 54, 591. (c) Nicolaou, K. C.; Baran,
P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2001, 123, 3183.
E-mail: ccho@hanyang.ac.kr.
̈
ORCID
(
(
20) Lee, H.; Harvey, R. G. J. Org. Chem. 1988, 53, 4587.
21) (a) Dakin, H. D. Am. Chem. J. 1909, 42, 477. (b) Friedmann, C. J.;
Cheon-Gyu Cho: 0000-0003-4851-5671
Notes
Ay, S.; Brase, S. J. Org. Chem. 2010, 75, 4612. (c) Abe, T.; Ikeda, T.;
Choshi, T.;Hibino,S.;Hatae, N.;Toyata, E.;Yanada, R.;Ishikura, M. Eur.
J. Org. Chem. 2012, 2012, 5018.
̈
The authors declare no competing financial interest.
(
22) The reported 13C NMR spectrum of permethyl ningalin D (42)
ACKNOWLEDGMENTS
■
has 12 methyl peaks (ref 5). On the other hand, our sample shows 6 well-
resolved methyl peaks under an identical 13C NMR setup.
This work was supported by the grants from the National
Research Foundation of Korea (2014R1A5A1011165).
(23) In the synthesis reported by Boger and co-workers, reversed phase
HPLC purification might have been necessary due to the possible
presence of inseparable impurities with permethylated ningalin D 42.
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24) All spectral data are consistent with the structure. However, a
(
(
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1
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Org. Lett. XXXX, XXX, XXX−XXX