Total Syntheses of Crinipellins Enabled by Cobalt-Mediated and Palladium-Catalyzed Intramolecular Pauson–Khand Reactions

Article abstract of DOI:10.1002/anie.201805143

Efficient total syntheses of the naturally occurring, potent antibiotic compounds (?)-crinipellin A and (?)-crinipellin B are described. The key advanced intermediate, a fully functionalized tetraquinane core, was constructed by a novel thiourea/palladium-catalyzed Pauson–Khand reaction. This intermediate can serve as a common intermediate for the collective total synthesis of other members of the crinipellin family.

Full text of DOI:10.1002/anie.201805143

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Accepted Article
Title: Concise Total Syntheses of Crinipellins Enabled by Co-Mediated
and Pd-Catalyzed Intramolecular Pauson-Khand Reactions
Authors: Zhen Yang, Zhihui Huang, Jun Huang, Yongzheng Qu,
Weibin Zhang, and Jianxian Gong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805143
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10.1002/anie.201805143
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Natural Products
Concise Total Syntheses of Crinipellins Enabled by Co-Mediated and Pd-
Catalyzed Intramolecular Pauson–Khand Reactions
Zhihui Huang+, Jun Huang+, Yongzheng Qu, Weibin Zhang, Jianxian Gong,* and Zhen Yang*
has inspired the development of new synthetic methods and
strategies.[4] The first total synthesis of racemic 2, in 22 steps, was
reported in 1993 by Piers’ group; the key step was Barbier
annulation[5] (Fig. 2, eq. 1). The first asymmetric total synthesis of 1
was accomplished by Lee’s group in 2014, featuring a tandem [3+2]
cycloaddition reaction to construct its tetraquinane core bearing three
consecutive quaternary stereogenic centers[6] (Fig. 2, eq. 2).
In connection with our development of the Pauson–Khand (PK)
reaction[7] as a powerful tool in natural product total synthesis,[8] we
identified tetramethylthiourea (TMTU) as an effective ligand in the
Co- and Pd-catalyzed PK reactions.[9] Herein we report our recent
contribution using the thiourea/Pd-catalyzed PK reaction of enyne E
as a key step in construction of the crinipellin scaffold F bearing the
desired C2 stereogenic center. This strategy enabled the asymmetric
total syntheses of crinipellin A (1) and crinipellin B (2) in 17 steps
and 18 steps, respectively (Fig. 2, eq. 3).
Abstract: Efficient total syntheses of the naturally occurring potent
antibiotic compounds (−)-crinipellin A and (−)-crinipellin B are
described. The key advanced intermediate, a fully functionalized
tetraquinane core, was constructed via a novel thiourea/Pd-catalyzed
Pauson–Khand reaction. This intermediate can serve as a common
intermediate for the collective total synthesis of other members of the
crinipellin family.
Crinipellin A (1, Fig. 1) is one of several related diterpenoids[1]
isolated from the fungus Crinipellis stipitaria (Agaricales) by
Steglich and co-workers in 1979.[1a] It has an -methylene ketone
motif and a unique tetraquinane core, which bears eight stereogenic
centers, of which three are contiguous all-carbon quaternary carbons
(C7, C10, and C11).
Figure 1: Selected tetraquinane crinipellins
Figure 2. Key steps for the synthesis of the tetraquinane core of
crinipellins
In terms of biological activity, 1 and 2 were originally reported to
have antibiotic activities.[1,2] 1a could completely inhibit the
syntheses of DNA, RNA, and proteins in Ehrlich carcinoma cells at a
[1a]
concentration of 5 g/mL.
The -methylene ketone motif in
crinipellins A and B makes them as potential irreversible probes[3] in
the field of drug discovery and chemical biology.
Synthesis of the densely packed array of stereogenic centers in
these polyquinanes is a challenge to existing synthetic methods and
Our synthesis began to stereoselectively construct the key
intermediate F with the required C2 stereogenic center on its CD ring.
Initial efforts focused on preparation of enyne E; its synthesis is
shown in Scheme 1. Given the rigid, bicyclic nature of intermediate
10, we expected to achieve diastereoselective installation of the
quaternary stereogenic centers at C11 and C7 via an allylation and
methylation sequence. We speculated that the synthesis of 10 bearing
two cis-configured vicinal stereogenic centers at C10 and C14 could
be achieved via an intramolecular PK reaction.[10]
Implementation of this approach required the enyne ester 9, which
was prepared via the Trost protocol[11] from known compound (R)-4-
isopropyl-3-methylcyclohex-2-en-1-one 6, which was prepared in 4
steps from commercially available 4-isopropyl-3-methylphenol 5.[12]
In the event, 6 underwent a diastereoselective Weitz−Scheffer-type
epoxidation, [13] and the resultant ketone 7 was condensed with p-
NO2ArSO2NHNH2 and subsequently treated with NaHCO3 to initiate
[] Z. Huang+, Dr. J. Huang+, Y. Qu, W. Zhang, Prof. Dr. J. Gong,
Prof. Dr. Z. Yang
State Key Laboratory of Chemical Oncogenomics, Key
Laboratory of Chemical Genomics, Peking University
Shenzhen Graduate School, Shenzhen 518055, China
E-mail: gongjx@pku.edu.cn
zyang@pku.edu.cn
Prof. Dr. Z. Yang
Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, Beijing National
Laboratory for Molecular Science, College of Chemistry and
Molecular Engineering, and Peking-Tsinghua Center for Life
Sciences, Peking University, Beijing 100871, China.
[+] These authors contributed equally to this work.
[] Supporting information for this article can be found under:
http://www.angewandte.org
1
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10.1002/anie.201805143
Angewandte Chemie International Edition
Eschenmoser fragmentation[14] to afford the acetylene ketone 8 in
68% yield. In the preparation of enyne ester 9, ketone 8 was first
subjected to a Wittig reaction, and the resultant enyne, without
workup, was directly treated with BuLi and ethyl chloroformate
sequentially to afford 9 in 75% yield. This one-pot transformation is
essential to ensure a high yield because the intermediate enyne is
volatile.
Ketoester 10 was reacted with an organocopper reagent (derived
from allylmagnesium chloride and CuBr∙Me2S[19]) at −78 °C to give
a highly diastereoselective conjugate addition reaction, and the
resultant enolate was reacted with Me2SO4 in the presence of Cs2CO3
and tetrabutylammonium fluoride (TBAF) [20] to afford methyl vinyl
ether 11 as a single isomer in 81% yield. This established the two all-
carbon quaternary stereogenic centers at the ring junction.
The preparation of enone 10 from enyne ester 9 was attempted via
We next focused on synthesis of the key intermediate 13 via regio-
and stereoselective installation of its C7 quaternary center.
PK reactions in the presence of various metal complexes, namely
[16]
Co2(CO)8,[15] Co2(CO)8/TMTU,[9a]
Mo(CO)3(DMF)3
and
Initially, we used Miyashita’s procedure.[21] A THF solution of
LHMDS was added to HMPA at −15 °C, followed by addition of a
THF solution of 11. The resultant enolate was reacted with MeI at
room temperature, the expected product 13 was obtained in 55% yield,
together with 12 in 18% yield. However, when we performed the
reaction by treating the generated enolate with MeI at −78 °C, product
12 was obtained as the sole product in 67% yield. This
regioselectivity depended on temperature, presumably because the
enolate configuration was affected significantly by the reaction
temperature, and a Curtin-Hammett situation was observed. [22] The
enolate 11a would form as 6-membered Li-chelated complex at low
temperature, in which the -position was sterically more congested
than the -position. However, the enolate 11a would stay chelated and
unchelated at higher temperature, and the later would be more
reactive at -position. Reduction of ester 13 with DIBAL-H, followed
by oxidation with the Dess–Martin reagent and reaction with the
Bestmann reagent,[23] gave enyne 14 in 66% yield.
[Rh(CO)2Cl]2.[17] However, none of these gave the expected product
10. After considerable experimentation, we found that by treatment
of 9 with a stoichiometric amount of Co2(CO)8 at room temperature
for 1 h followed by gradual heating of the resultant enyne/Co complex
to 76 °C in the presence of 4-methylmorpholine N-oxide (NMO) for
36 h, product 10 could be obtained in 40% yield with 98% ee after
crystallizations. The erosion of ee value presumably occurred during
the Wittig reaction. It is worth noting that pre-complexation of 9 with
Co2(CO)8 at room temperature and gradual warming are essential for
the desired reaction to occur; formation of the enyne/Co2(CO)8
complex is difficult because the electron-deficient alkyne is not a
good ligand for Co2(CO)8.[18]
Scheme 1: Synthesis of enyne 14.a
Table 1: Screening of conditions for the intramolecular PK reactionsa
aReagents and conditions: a) H2O2 (2.0 equiv), NaOH (0.3 equiv), MeOH,
0 °C to rt, 18 h, 72%; (b) p-NO2-ArSO2NHNH2 (1.05 equiv), NaHCO3 (3.0
equiv), THF, 30 h, -20 °C, 68%; (c) Ph3PMeBr (2.2 equiv), t-BuOK (2.0
equiv), toluene, rt, 5h; then n-BuLi (3.5 equiv), ClCOOEt (4.0 equiv), -78 °C
to 0 °C, 4 h, 75%; (d) Co2(CO)8 (1.05 equiv), NMO (3.5 equiv), CO (balloon
pressure), DCE, rt to 76 °C, 66%, 69% ee (98% ee, 40% yield after
crystallizations); (e) AllylMgCl (1.5 equiv), TMSCl (1.1 equiv), CuBr·Me2S
(1.5 equiv), THF, -78 °C; Me2SO4 (4.0 equiv), Cs2CO3 (4.0 equiv), 0 °C to rt
overnight, then TBAF (0.75 equiv), Me2SO4 (4.0 equiv), 2 h, 81%; (f)
LiHMDS (4.0 equiv), HMPA, THF, −15 °C, 20 min, then 11 (1 equiv), 1 h;
MeI, -78 °C, 4 h, 67%; (g) LiHMDS (4.0 equiv), HMPA, THF, −15 °C, 20
min, then 11 (1.0 equiv), 1 h; MeI, rt, 8 h, 13 (55%), and 12 (18%) ; (h)
DIBAL-H (2.5 equiv), DCM, 0 °C, 5 h, then t-BuOH (10.0 equiv), then
NaHCO3 (10.0 equiv), DMP (3.5 equiv), 0 °C, 3h, 95%; (i) Bestmann
reagent (2.5 equiv), K2CO3 (5.0 equiv), MeOH, rt, 48 h, 66% (94% brsm).
Having successfully implemented the PK reaction for the
stereoselective synthesis of ketoester 10, we next installed the two
vicinal quaternary stereogenic centers at C7 and C11 in 13 (Scheme
1).
a [14] = 0.01 ~ 0.05 M. bIsolated yield after flash chromatography.
With enyne 14 in hand, we investigated the PK reaction for the
construction of tetraquinane 15 (Table 1). Initially, enyne 14 was
added to toluene solution of Co–TMTU catalyst, which was prepared
2
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10.1002/anie.201805143
Angewandte Chemie International Edition
in situ by mixing Co2(CO)8 and TMTU.[9a] The resultant mixture was
stirred at 60 °C under a balloon pressure of CO for 12 h. Product 15
was obtained in 21% yield, together with its undesired isomer 15a in
42% yield (entry 1). Treatment of enyne 14 with Rh catalysts[17] under
a balloon pressure of CO gave 15a as the major product (entries 2–3).
We then turned our attention to the Pd-catalyzed PK reaction.
When the reaction was performed with enyne 14 in the presence of
TMTU–PdCl2 catalyst,[9b] which was prepared in situ by mixing
PdCl2 and TMTU in THF (entry 5), only trace amounts of the
annulated products 15 and 15a were observed after reaction under a
balloon pressure of CO at 50 °C for 50 h.
Knowing the Pd-catalyzed PK reaction could be accelerated by
addition of LiCl,[24] we decided to run the reactions in the presence of
LiCl. In the event, the reaction was carried out the presence of PdCl2,
PdCl2(CH3CN)2 as the catalysts (entries 6-8). To out delight, when
the reaction was carried out in the presence of TMTU, the desired
product 15 was obtained in 30% yield, together with its C2
diastereoisomer 15a in 20% yield (entry 8).
Realizing the importance of the thiourea ligand in the annulation,
we then ran the reaction in the presence of thioureas bearing phenyl
and isopropyl substituents (entries 9–11). However, under these
reaction conditions, the yields of products 15 and 15a were
significantly lower, and significant amounts of products 15b and 14a
were formed in two cases because of hydrolysis of their enol ether
moieties. Notably, the application of TU-1 ligand[25] could
dramatically improve the diastereoselectivity (entries 9 and 10). We
then performed the reactions in the presence of bases, namely Na2CO3
and NaHCO3 (entries 12 and 13). The yield of the desired product 15
increased to 61%, and its C2 isomer 15a was obtained in 16% yield,
when NaHCO3 was used (entry 13). The relative stereochemistry of
compound 15 was unambiguously confirmed by X-ray
crystallographic analysis.
hydrolysis,[28] and a substrate stereoselective Weitz−Scheffer-type
epoxidation. It is worth noting that Weitz−Scheffer-type epoxidation
did not occur without the directed carbonyl group[29] at C8.
Compound 16a has all the essential functional groups of crinipellin
A (1) except the methylene group at C3, therefore we performed a
modified Eschenmoser methylenation by reaction of 16a with N-
methylanilinium trifluoroacetate and paraformaldehyde in THF at
70 °C to give crinipellin A (1) in 86% yield. 1H NMR, 13C NMR and
optical rotation data of synthetic 1 were in good agreement to those
reported in the literature.[2a]
We next explored the total synthesis of crinipellin B (2) from 16b.
We envisaged that the thermodynamic stable compound 17 could be
synthesized from 16b via isomerization[30] of its α-hydroxy ketone
moiety. Attempts to isomerize 16b to 17 by treatment with various
acidic and basic reagents, i.e., MgBr2, Al(Me)3, silica gel, HCl,
KOtBu, and KOH, were unsuccessful. None of them afforded the
desired isomerized product 17 and in most cases 16b decomposed.
We eventually achieved the proposed isomerization by treatment of
16b with Al(iPrO)3 in toluene at room temperature for 42 min (desired
product 17 would be decomposed dramatically when the reaction
time was prolonged); 17 bearing the desired C8 stereogenic center
was obtained as a single isomer in 56% yield (88%, brsm). Further
treatment of 17 with N-methylanilinium trifluoroacetate and
paraformaldehyde in THF at 70 °C, the natural product crinipellin B
(2) was afforded in 74% yield. The structure of 2 was confirmed by
comparison of its spectra (1H NMR and 13C NMR) and optical
rotation data with those reported in the literature.[2a, 5]
In summary, we achieved the asymmetric total syntheses of (−)-
crinipellin A (1) and (−)-crinipellin B (2) in 17 and 18 steps from the
commercially available phenol 5. The key features of our synthesis
include use of our developed thiourea/Pd-catalyzed intramolecular
PK reaction for diastereoselective construction of the tetraquinane
core of the naturally occurring crinipellins. Tactical adjustments of
substituents and functionalities will enable the protocol developed
here to be used to synthesize tetraquinane cores with various
substituents, therefore this strategy will be useful in the collective
synthesis[31] of analogs of crinipellins.
With compound 15 in hand, we then investigated its elaboration for
the syntheses of crinipellins A (1) and B (2) (Scheme 2).
Scheme 2: Total syntheses of crinipellins A (1) and B (2).
Acknowledgements:
This work was supported by National Science Foundation of China
(Grant Nos. 21632002, 21602008, 21772008, 21702011 and
U1606403), Guangdong Natural Science Foundation (Grant No.
2016A030306011), Shenzhen Basic Research Program (Grant Nos.
JCYJ20160330095629781 and JCYJ20170818090044432), and
Qingdao National Laboratory for Marine Science and Technology
(No. 2015ASKJ02).
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords Pauson-Khand reaction, asymmetric synthesis, crinipellin A,
crinipellin B, consecutive quaternary carbon centers
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3
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Angewandte Chemie International Edition
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This article is protected by copyright. All rights reserved.

10.1002/anie.201805143
Angewandte Chemie International Edition
Natural Products
Zhihui Huang+, Jun Huang+, Yongzheng
Qu, Weibin Zhang, Jianxian Gong,* and
Zhen Yang*
__________ Page – Page
Concise Total Syntheses of Crinipellins Enabled by
Co-Mediated and Pd-Catalyzed Intramolecular
Pauson–Khand Reactions
Efficient total syntheses of the naturally occurring potent
antibiotic compounds (−)-crinipellin A and (−)-crinipellin B are
described. The key advanced intermediate,
functionalized tetraquinane core, was constructed via a novel
thiourea/Pd-catalyzed Pauson–Khand reaction. This
a
fully
intermediate can serve as a common intermediate for the
collective total synthesis of other members of the crinipellin
family.
5
This article is protected by copyright. All rights reserved.