Total Synthesis of (-)-N-Methylwelwitindolinone C Isothiocyanate Based on a Pd-Catalyzed Tandem Enolate Coupling Strategy

Article abstract of DOI:10.1021/acs.orglett.5b01952

The highly stereocontrolled total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate is described, which features the expeditious construction of a bicyclo[4.3.1]decane ring system by a palladium-catalyzed tandem enolate allylation/arylation reaction.

Full text of DOI:10.1021/acs.orglett.5b01952

Letter
pubs.acs.org/OrgLett
Total Synthesis of (−)‑N‑Methylwelwitindolinone C Isothiocyanate
Based on a Pd-Catalyzed Tandem Enolate Coupling Strategy
Keita Komine, Yusuke Nomura, Jun Ishihara, and Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
*
S Supporting Information
ABSTRACT: The highly stereocontrolled total synthesis of
(
−)-N-methylwelwitindolinone C isothiocyanate is described,
which features the expeditious construction of a bicyclo[4.3.1]-
decane ring system by a palladium-catalyzed tandem enolate
allylation/arylation reaction.
oore and co-workers reported the isolation of a series
M
of fascinating welwitindolinone alkaloids from the blue-
Scheme 1. Retrosynthesis
green algae Hapalosiphon wetwitschii, Westiella intricata, Fischer-
1
ella muscicola, and Fischerella major (Figure 1). These alkaloids
Figure 1. Representative welwitindolinone alkaloids.
For the synthesis of the welwitindolinone alkaloids, we envi-
sioned diketo nitrile 7 as a common precursor (Scheme 1). We
expected that compound 7 would be derived from 8 by stereo-
selective methylation at the C12 center based on Martin’s pro-
tocol. To expeditiously access 8, we envisioned a palladium-
catalyzed tandem enolate allylation/arylation sequence from 9,
exhibit significant biological activities represented by the ability
to reverse P-glycoprotein-mediated multidrug resistance in human
2
cancer cells. Most of the welwitindolinones possess a densely
8
functionalized oxindole-fused bicyclo[4.3.1]decane ring system
containing two contiguous quaternary centers. The structural
challenges coupled with promising pharmacological properties
which had not previously been examined for the assembly of a
3c,5−8
3,4
[4.3.1] bicyclic core.
Considering steric repulsions during
have made these alkaloids attractive targets for synthesis. Thus, a
number of elegant methodologies to assemble a [4.3.1] bicyclic
the sequential cyclizations, we selected the relatively less bulky
9
10
3
c,5
cyanoketone functionality and 13S configuration for 9. To
stereoselectively synthesize 9, we considered an approach from
core have been developed from many research groups
but
6
7
only the Rawal group and the Garg group have succeeded
11 of S configuration via a Mannich-like reaction with 12
in the total syntheses of [4.3.1] bicyclic welwitindolinones
8
followed by epimerization at C15 under kinetic protonation
1
−6. Recently, the Martin group also reported the formal
syntheses of 2−6 though in racemic forms. We now report
the novel total synthesis of (−)-N-methylwelwitindolinone C
isothiocyanate (2).
Received: July 8, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01952
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conditions and nucleophilic opening of γ-lactone 10 with the
anion of acetonitrile.
Table 1. Pd-Catalyzed Tandem Cyclizations
Our synthesis thus began with the preparation of 11 with high
enantiopurity (Scheme 2). Commercially available carboxylic acid
Scheme 2. Synthesis of Cyclization Precursors
a
yield (%)
b
entry
conditions
(8a/8b)
c
1
Pd(PPh ) (0.3 equiv), i-Bu-PAP (1.2 equiv), t-BuOK
15 (3:1)
62 (2:1)
72 (2:1)
84 (2:1)
69 (2:1)
100 (2:1)
3
4
(
2 equiv), toluene, 90 °C, 3 h
c
2
Pd (dba) ·CHCl (0.3 equiv), i-Bu-PAP (1.2 equiv),
2 3 3
t-BuOK (2 equiv), toluene, 90 °C, 5 h
c
3
Pd (dba) (0.3 equiv), i-Bu-PAP (1.2 equiv), t-BuOK
2
3
(
2 equiv), toluene, 90 °C, 1 h
c
4
Pd (dba) (0.2 equiv), i-Bu-PAP (0.8 equiv), t-BuOK
2 3
(
2 equiv), toluene, 90 °C, 2 h
c
5
Pd (dba) (0.2 equiv), XPhos (0.8 equiv), t-BuOK
2
3
(
2 equiv), toluene, 90 °C, 2 h
d
6
Pd (dba) (0.2 equiv), XPhos (0.8 equiv), t-BuOK
2
3
(
2 equiv), toluene, 110 °C, 1 h
a
b
1
c
Total yield of 8a and 8b. Determined by H NMR. A mixture of 9
and all reagents in toluene (0.02 M) was heated at 90 °C. A solution
d
of 9 in toluene was added to a mixture of all reagents in boiling toluene
(
0.05 M) over 20 min and then heated at reflux. i-Bu-PAP = 2,8,9-
triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane, XPhos =
-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
2
this tandem cyclization less effectively (entries 1 and 2). It was
found that decreasing the amounts of Pd (dba) and i-Bu-PAP to
2
3
0
8
.2 equiv and 0.8 equiv improved the total yield of 8a and 8b to
4%, although the diastereoselectivity did not change. Further-
more, the combination of Pd (dba) and Xphos was also found
2
3
to effectively catalyze the tandem process (entry 5). Surprisingly,
slow addition of 9 to a mixture of Pd (dba) , Xphos, and t-BuOK
in boiling toluene provided a 2:1 mixture of 8a and 8b in quanti-
tative yield (entry 6). It is important to note that compound 16,
the 15-epimer of 9, did not produce any cyclization products under
1
1
1
3 was first converted to aldehyde 14 by a one-pot procedure
2
3
involving formation of the acid chloride, Rosenmund reduction,
and Wittig reaction. Without purification, 14 was then subjected
to NaBH reduction followed by silylation to give 11 with 98% ee
in 68% overall yield from 13. Compound 11 was coupled with
the known indole derivative 12, prepared from 4-bromo-3-acetyl-
-methyl-1H-indole, in the presence of TMSOTf under the
conditions reported by Martin et al. to deliver a 93:7 mixture
of 15 and 10 in 75% yield. Upon treatment of this mixture with
4
the Pd (dba) /i-Bu-PAP- or Pd (dba) /XPhos-catalyzed conditions
2
3
2
3
1
0
as we expected.
We also examined the tandem cyclization of 17 having a 12-
methyl group under the Pd (dba) /i-Bu-PAP-catalyzed condi-
8
1
1
7
8,12
2
3
tions (Scheme 3). However, the reaction afforded a complex
KHMDS followed by aqueous NH Cl at −78 °C, the kinetic
4
protonation of the resulting enolate took place to give a 10:90
Scheme 3. Cyclization of Compound 17
13
13
mixture of 15 and 10 which was chromatographically sepa-
rated. Lactone 10 thus obtained was then converted to 9 by a
four-step sequence involving reaction with lithiated acetonitrile,
silylation, selective removal of the TBDPS group under basic con-
14
ditions, and acetylation in good overall yield. Similarly, com-
pound 16 was also prepared from 15.
With the desired precursor 9 in hand, we then investigated
the crucial tandem cyclization (Table 1). Since the palladium-
6
catalyzed conditions reported by Rawal’s group and Martin’s
8
group did not promote the desired tandem cyclization, we
mixture from which bicyclic compound 18 was isolated as a 2:1
mixture in only 2% yield.
To understand the above-mentioned tandem process, we
15
focused on Verkade’s protocol developed for the arylation
of ethyl cyanoacetate with aryl bromides. We first examined the
reaction employing three palladium sources at 30 mol % loading
together with i-Bu-PAP (1.2 equiv) and t-BuOK (2 equiv) at 90 °C
in toluene. As a result, when Pd (dba) was used as a catalyst, the
performed the experiments shown in Scheme 4. The Pd (dba) /
2
3
i-Bu-PAP-catalyzed reaction of 9 at 70 °C for 30 min allowed us
to isolate intermediates 19, a 1.3:1 mixture, and 20. These inter-
mediates were then exposed to the conditions listed in entry 3
of Table 1. In the reaction of 19, the major isomer and minor
isomer produced 8a and 8b, respectively. On the other hand, the
2
3
tandem allylation/arylation took place within 1 h to produce the
16
desired cyclization products 8a and 8b in a ratio of 2:1 in 72%
yield (entry 3). Both Pd(Ph P) and Pd (dba) ·CHCl catalyzed
3
4
2
3
3
B
DOI: 10.1021/acs.orglett.5b01952
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Reaction Pathways
Scheme 5. Synthesis of (−)-N-Methylwelwitindolinone C
Isothiocyanate
reaction of 20 proceeded with high diastereoselectivity to pro-
duce a 10:1 mixture of 8a and 8b. These results suggest that the
tandem process would occur preferentially via an enolate allyla-
tion (path A) rather than an enolate arylation (path B).
Having successfully constructed the bicyclic framework, we then
pursued the synthesis of N-methylwelwitindolinone C isothiocya-
nate (2) from the diastereoisomeric mixture of 8a and 8b
(Scheme 5). This mixture 8ab was first converted to ketone 21 by
desilylation followed by Dess−Martin oxidation. The next
1
8
methylation step turned out to be problematic. Ater con-
siderable experimentation, we eventually found conditions where
the methyl group was introduced stereo- and regioselectively in
acceptable yield. Thus, after deprotonation of 21 with t-BuOLi
in DMF at −40 °C, the resulting dienolate was methylated
13
with methyl iodide to give our envisaged key intermediate 7 as
a single diastereoisomer. To assemble the vinyl chloride func-
7a
tionality in 7, we examined Garg’s protocol involving a trifla-
tion, stannylation, and chlorination. However, when triflate 22
was exposed to the stannylation conditions using (Me Sn) ,
3
2
Pd(Ph P) , and LiCl in 1,4-dioxane at 90 °C, none of the desired
3
4
product was obtained. It is worth noting that, upon heating 22
in the presence of [Cp*Ru(MeCN) ]OTf and LiCl in 1,3-
3
dimethyl-2-imidazolidinone at 75 °C according to Hayashi’s
1
9
20
procedure, pentacyclic compound 23 was obtained in 94%
yield. The production of 23 can be explained by the mechanism
In summary, we have completed the total synthesis of (−)-N-
methylwelwitindolinone C isothiocyanate (2) in 6% overall
yield (24 steps) from commercially available 13. The present
work illustrates the prowess of the palladium-catalyzed tandem
cyclization to enable expeditious access to a bicyclic skeleton
of welwitindolinone alkaloids. The methodology developed
is of general value in approaches to other [4.3.1] bicyclic
welwitindolinones.
21
proposed by Rawal et al., which proceeds through a Cope
rearrangement followed by C−C bond formation between the
resulting α-cyanoketone and dienylruthenium species. We
eventually found that triflate 24, prepared by NaBH reduction
of 22, cleanly underwent chlorination under Garg’s conditions
13
4
7a
to give chloride 25 in good yield. Upon DIBAL-H reduction and
Dess−Martin oxidation, 25 afforded keto aldehyde 26. Finally,
6c
following the procedure reported by Rawal et al., the total syn-
thesis of (−)-N-methylwelwitindolinone C isothiocyanate (2)
was achieved via selective oxidation of the indole ring with
magnesium monoperoxyphthalate (MMPP) giving oxindole
ASSOCIATED CONTENT
Supporting Information
■
*
S
1
13
Experimental procedures, spectroscopic data, H and C NMR
spectra, and X-ray crystallographic data (CIF). The Supporting
Information is available free of charge via the Internet at The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01952.
6
c,13
27
and installation of the isothiocyanate functionality by
an aldoxime rearrangement. The synthetic 2 exhibited spectral
1a,6c
properties identical in all respects to those reported.
Since
compound 2 has already been converted to N-methylwelwi-
6
c,7b
1
tindolinones 3−5,
the synthesis of 2 constitutes the formal
Experimental procedures, spectroscopic data, and H and
13
syntheses of these alkaloids.
C NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.5b01952
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
X-ray data of the alcohol derived from 8a (CIF)
Letter
(
16) The stereostructures were determined by X-ray crystallographic
analysis of the corresponding alcohols derived from 8a and 8b. The
crystallographic data (CCDC 1403797 and CCDC 1403798) can be
obtained free of charge from the Cambridge Crystallographic Data
centre via www.ccdc.cam.ac.uk/data_request/cif.
X-ray data of the alcohol derived from 8b (CIF)
X-ray data of compound 23 (CIF)
(
17) See the Supporting Information for the preparation of 17.
AUTHOR INFORMATION
Corresponding Author
E-mail: susumi@nagasaki-u.ac.jp.
■
*
(18) For example, methylation of 21 under Martin’s conditions
(
NaHDMS, MeI, DMF, −40 °C) produced 7 (22%) and the
corresponding α,α′-dimethylated compound (12%).
19) Imazaki, Y.; Shirakawa, E.; Ueno, R.; Hayashi, T. J. Am. Chem.
(
Notes
Soc. 2012, 134, 14760−14763.
The authors declare no competing financial interest.
(20) The stereostructure was determined by X-ray crystallographic
analysis. The crystallographic data (CCDC 1403796) can be obtained
free of charge from the Cambridge Crystallographic Data centre via
www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENTS
■
(
We acknowledge financial support from the Grant-in-Aid
25253002) from JSPS and the Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysis” (No. 2304) (24105526) from
MEXT.
(21) Bhat, V.; MacKay, J. A.; Rawal, V. H. Tetrahedron 2011, 67,
1
0097−10104.
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DOI: 10.1021/acs.orglett.5b01952
Org. Lett. XXXX, XXX, XXX−XXX