Collective Synthesis of cladiellins based on the gold-catalyzed cascade reaction of 1,7-diynes

Article abstract of DOI:10.1002/anie.201309449

The cladiellin family of natural products, which includes molecules with various biological activities, continues to invite new synthetic studies. A gold-catalyzed tandem reaction of 1,7-diynes to construct the 6-5-bicyclic ring systems that are present in a number of natural products was developed. This reaction was applied as the key step to realize the formal and total syntheses of nine members of the cladiellin family in an enantio- and diastereoselective manner. This modular and efficient approach could also be used for the construction of other cladiellins, as well as their analogues, for follow-up studies. Clad(iellins) in gold: A gold-catalyzed tandem reaction of 1,7-diynes was previously developed to construct the 6-5-bicyclic ring systems that are present in a number of natural products. This reaction was applied to realize the total synthesis of nine members of the cladiellin family. This modular and efficient approach, which is enantio- and stereoselective, could also be used for the construction of other cladiellins and their analogues. Copyright

Full text of DOI:10.1002/anie.201309449

Angewandte
Chemie
DOI: 10.1002/anie.201309449
Natural Product Synthesis
Collective Synthesis of Cladiellins Based on the Gold-Catalyzed
Cascade Reaction of 1,7-Diynes**
Guozong Yue, Yun Zhang, Lichao Fang, Chuang-chuang Li, Tuoping Luo,* and Zhen Yang*
Abstract: The cladiellin family of natural products, which
includes molecules with various biological activities, continues
to invite new synthetic studies. A gold-catalyzed tandem
reaction of 1,7-diynes to construct the 6-5-bicyclic ring systems
that are present in a number of natural products was
developed. This reaction was applied as the key step to realize
the formal and total syntheses of nine members of the cladiellin
family in an enantio- and diastereoselective manner. This
modular and efficient approach could also be used for the
construction of other cladiellins, as well as their analogues, for
follow-up studies.
development of small-molecule probes and drugs.[6] Several
members of the cladiellin family have been successfully
synthesized by a number of research groups.[7–15] In fact,
research into the total synthesis of cladiellins has played an
important role in determining their structures.[7,8,9e] The
tricyclic compound 10 has been used as a common late-
stage intermediate in a number synthetic strategies for
accessing various cladiellins, including 1, 2, 5, and 6.[9f,12a,c,15]
Given that compounds 1–9 differ only in terms of their
substituents at C6, C7, and C11 (sclerophytin A numbering
used throughout), the development of a method for the
conversion of 10 into 3, 4, 7, 8, and 9 would represent
a significant addition to the techniques currently available for
the synthesis of cladiellins (Figure 1).[12c]
The cladiellins (compounds 1–9) are a group of structurally
complex natural products that have attracted considerable
attention from the organic synthesis community.[1] Among
them, (À)-sclerophytin A (1) is of particular interest because
it has been reported to be toxic to mouse lymphocytic
leukemia L1210 cells at concentrations as low as 3 nm.[2]
Several other cladiellins have also been reported to possess
potential antitumor activities, including (+)-vigulariol (6),
which exhibited in vitro cytotoxicity towards human lung
adenocarcinoma A-549 cells, and (À)-pachycladin D (9),
which showed anti-invasive activity.[3,4] Another cladiellin,
(+)-polyanthellin A (4), has been reported to be an antima-
larial reagent based on its inhibitory activity towards Plasmo-
dium falciparum.[5] Despite these reports, the antitumor and
antimicrobial activities of the many other compounds belong-
ing to the cladiellin family have not been extensively
evaluated. Comparison studies with cladiellins and their
unnatural structural analogues through the use of biological
assays could provide a detailed understanding of their
structure–activity relationships and could effectively highlight
the potential of cladiellins as lead compounds for the
Among the different strategies that have been developed
for the construction of enantiopure 10,[9f,12c,15] the preferential
ring-closing olefin metathesis of bicyclic compound 11 is
relatively straightforward but only provides the desired
product in 40–50% yield under the reported conditions.[15]
Operating under the assumption that the yield for this ring-
closing olefin metathesis step could be improved, it was
envisaged that the 6-5-bicyclic ring system of 11 could be
accessed through the gold-catalyzed cascade reaction of 1,7-
diynes that we recently developed during our synthesis of
compounds belonging to the drimane family of natural
products.[16] The precursor for 11, compound 12, could be
produced from 1,7-diyne 14 in one step via intermediate 13.
Enantiopure 1,7-diyne 14, which has three contiguous stereo-
genic centers, could itself be prepared by a Marshall coupling
reaction between propargyl mesylate 15 and ethyl glyoxalate
(16).[17] Herein, we disclose our contribution towards the
development of an efficient and modular strategy for the
synthesis of cladiellins that complements other approaches in
terms of providing a platform for the synthesis of related
analogues.
[*] Prof. Dr. T. Luo, Prof. Dr. Z. Yang
Our modular and scalable synthesis of chiral 1,7-diyne 14
is shown in Scheme 1. The diastereoselective a-alkylation of
amide 18, which was prepared from commercially available
hex-5-ynoic acid (17), afforded the tertiary stereogenic center
at C14 of the cladiellins.[18] The superiority of pseudoephen-
amine as an auxiliary in asymmetric alkylation reactions
involving isopropyl iodide as the electrophile allowed 19 to be
prepared on a multigram scale.[19] Successive hydrolysis and
amide coupling reactions yielded a Weinreb amide, which was
subsequently allowed to react with an acetylenyl Grignard
reagent to give ketone 21. The asymmetric reduction of
ketone 21 with (S)-alpine-borane[20] followed by mesylation of
the resulting alcohol afforded mesylate 15 as a single
diastereomer in 56% yield. Marshall coupling of 15 and
aldehyde 16 under optimized conditions afforded a separable
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education and
Beijing National Laboratory for Molecular Science (BNLMS)
Peking-Tsinghua Center for Life Sciences, Peking University
Beijing 100871 (China)
E-mail: tuopingluo@pku.edu.cn
zyang@pku.edu.cn
G. Yue, Y. Zhang, L. Fang, Prof. Dr. C.-c. Li, Prof. Dr. Z. Yang
Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University Shenzhen Graduate School
Shenzhen 518055 (China)
[**] We thank the National Basic Research Program of China (973
Program, Grant No. 2009CB940904) and the National 863 Program
(Grant No. 2013AA092903) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309449.
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Scheme 1. Scalable enantioselective synthesis of 1,7-diyne 14. Yields of
isolated products (%) are indicated. Reagents and conditions: a) EDCI
(1.1 equiv), HOBt (1.1 equiv), (À)-(1S,2S)-pseudoephenamine
(1.1 equiv), DIPEA (3.0 equiv), DMF, RT. b) LiCl (6.0 equiv), LDA
(4.0 equiv), isopropyl iodide (6.0 equiv), THF. c) nBu4NOH (5.0 equiv),
tert-butyl alcohol/water=1:1, reflux. d) EDCI (3.0 equiv), HOBt
(3.0 equiv), DIPEA (6.0 equiv), N,O-dimethylhydroxylamine hydrochlo-
ride (3.0 equiv), DMF. e) ethynylmagnesium chloride (2.0 equiv), THF.
f) (S)-alpine borane (2.0 equiv). g) MsCl (2.0 equiv), Et3N (4.0 equiv),
CH2Cl2. h) 5% [Pd(dppf)Cl2]·CH2Cl2, InI (1.1 equiv), 16 (2.0 equiv),
THF/HMPA=3:1. i) PPh3 (2.5 equiv), DIAD (3.0 equiv), p-NO2PhCO2H
(2.5 equiv), THF. j) K2CO3 (2.0 equiv), EtOH. EDCI=1-ethyl-3-(3-di-
methylaminopropyl)carbodiimide, HOBt=1-hydroxybenzotriazole,
LDA=lithium diisopropylamide, DIPEA=diisopropylethylamine,
Ms=methanesulfonyl, TEA=triethylamine, dppf=1,1’-bis(diphenyl-
phosphanyl)ferrocene, HMPA=(hexamethylphosphoramide,
DIAD=diisopropyl azodicarboxylate.
Figure 1. Retrosynthetic analysis of cladiellins via key intermediate 10:
a strategy enabled by the gold-catalyzed cascade reaction of 1,7-diyne
14.
mixture of diynes 14 and 22 in 90% overall yield with
a moderate level of stereoselectivity (d.r. = 2.5:1; Table S1,
see the Supporting Information for details). Pleasingly, the
undesired diastereomer 22 could be readily converted into 14
in two steps through the inversion of one stereogenic center.
With abundant 1,7-diyne 14 in hand, we proceeded to
investigate the feasibility of our key cascade transformation
for the construction of the 6-5-bicyclic skeleton. Subjecting 14
to the gold-catalyzed cascade reaction in the presence of
excess methylallyl trimethylsilane, however, led only to the
O-TMS protection product 23,[21] and decomposition was
observed when phenol was added to scavenge the TMS
group.[22] By contrast, the use of p-nitrobenzylic alcohol as
a nucleophile allowed the desired 6-5-bicyclic skeleton to be
formed successfully, albeit as a pair of diastereomers 24a and
24b. Following a period of optimization (Table S2 in the
Supporting Information), 14 could be converted into 24a
(98% ee) and 24b in 65% yield with 3:1 diastereoselectivity
on a gram scale (Scheme 2). Given that both 24a and 24b
could be used in the next step, the mixture of 24a and 24b was
treated with excess (methylallyl)trimethylsilane and
TMSOTf[23] to give 12 and its C9 diastereomer 25 in yields
of 60 and 20%, respectively. Ester 12 was then converted into
11 through sequential Weinreb amide formation and
Grignard reactions. Morken and co-workers. reported the
ring-closing metathesis of 11 to afford 10 in 55% yield after
resubjection of the recovered starting material and side
product to the reaction conditions,[15] and this result was
successfully reproduced in our hands. Pleasingly, however, the
use of the Zhan 1B catalyst 26 led to a significant increase in
the efficiency of the desired transformation, presumably
because of the enhanced stability of the catalyst.[24] This
modification afforded the key intermediate 10 in 70% yield in
a single operation. The analytical data for 10 were identical to
those reported[9f,12a,c,15] and confirmed that we had produced
the material required to explore the synthesis of compounds
1–9. Our initial efforts focused on the synthesis of compounds
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Scheme 3. Synthesis of (+)-deacetylpolyanthellin A (3) and (+)-polyan-
thellin (4). Yields of isolated products (%) are indicated. Reagents and
conditions: a) Hg(OAc)2 (2.0 equiv), THF, RT, 2 h; then H2O, Hg-
(OAc)2 (2.0 equiv), 2 h; then Et3B (10.0 equiv), NaBH4 (10.0 equiv),
À208C to RT, overnight. b) Ac2O (5.0 equiv), Et3N (5.0 equiv), DMAP
(5.0 equiv), CH2Cl2, RT, 24 h.
aimed to prepare 3 from 5 by installing additional cyclic
ether and tertiary alcohol moieties (Scheme 3). A regio- and
stereoselective double oxymercuration followed by a reduc-
tion, the combination of which is an efficient one-pot protocol
that has successfully been used for the synthesis of 3 from the
other two advanced intermediates,[11,14] accomplished this task
in moderate yield. Thus, the total synthesis of the natural
product (+)-polyanthellin A (4) was achieved in 62% yield
by the reaction of 3 with acetic anhydride in the presence of
Et3N and DMAP.[11,12c,14]
To access (À)-cladiellinsin (7), (À)-pachycladin C (8), and
(À)-pachycladin D (9), we first converted 10 into hemiketal
27 by following known procedures (Scheme 4).[9f,15] Selective
protection of the hemiketal hydroxy group in 27 afforded
tertiary alcohol 28, which underwent regioselective dehydra-
tion followed by deprotection to furnish hemiketal 29 in 72%
yield over three steps.[25,26] The addition of methylmagnesium
chloride at an elevated temperature afforded 7 in 93% yield
as a single diastereoisomer. Finally, 7 was converted into 8 and
9 by acetylation and oxidation of the secondary alcohol,
respectively. The analytical data for 7, 8, and 9 corresponded
well with those reported from the isolated natural materials.[4]
In summary, we have developed a concise and general
strategy to access a number of cladiellins through the gold-
catalyzed cascade reaction of 1,7-diynes. The modularity of
our approach will enable the efficient preparation of a variety
of natural product analogues. The biological activities of our
synthesized cladiellins, especially their cytotoxicities against
various cancer cells, are under evaluation.
Scheme 2. Synthesis of (À)-sclerophytin A (1), (À)-sclerophytin B (2),
(+)-cladiella-6Z,11(17)-dien-3-ol (5), and (+)-vigulariol (6). Yields of
isolated products (%) are indicated. Reagent and conditions:
a) [(IPr)AuCl] (5 mol%), AgSbF6 (5 mol%), p-NO2PhCH2OH
(1.5 equiv). b) TMSOTf (1.6 equiv), methylallyl-trimethylsilane
(3.2 equiv), CH3CN. c) N,O-Dimethylhydroxylamine hydrochloride
(3.0 equiv), isopropylmagnesium chloride (6.0 equiv), THF. d) 3-Bute-
nyl magnesium bromide (2.0 equiv), THF. e) Grubbs 2nd generation
catalyst (10 mol%), PhH, reflux. f) Zhan 1B catalyst (10 mol%),
toluene, reflux. g) mCPBA (1.4 equiv), CHCl3, À128C. h) LiOH
(18.0 equiv), dioxane, H2O; then KHSO4 (18.0 equiv), Sc(OTf)3
(1.5 equiv), CH3CN, H2O, RT. i) MeMgCl (120.0 equiv), THF, 528C,
24 h. j) Ac2O (3.0 equiv), Et3N (7.5 equiv), DMAP (1.0 equiv), CH2Cl2,
08C. k) MeMgCl (20.0 equiv), THF, 08C. l) mCPBA (2.0 equiv), CH2Cl2,
08C. TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl, mCPBA=m-
chloroperbenzoic acid, DMAP=4-dimethylaminopyridine.
1, 2, 5, and 6 by using the published procedures.[8c,9f,12,15] The
spectroscopic data (1H and 13C NMR spectra, HRMS analy-
ses, and optical rotation) of the synthesized samples of 1, 2, 5,
and 6 were in good agreement with those reported for the
corresponding natural materials.[9f,12,13,15]
Given that (+)-polyanthellin A (4) can be prepared by the
acetylation of (+)-deacetylpolyanthellin A (3),[11,12c,14] we
Received: October 30, 2013
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Scheme 4. Total synthesis of (À)-cladiellinsin (7), (À)-pachycladin C
(8) and (À)-pachycladin D (9). Yields of isolated products (%) are
indicated. Reagents and conditions: a) mCPBA (1.4 equiv), CHCl3,
À128C. b) LiOH (18.0 equiv), dioxane, H2O; then KHSO4 (18.0 equiv),
Sc(OTf)3 (1.5 equiv), CH3CN, H2O, RT. c) N-(Trimethylsilyl)imidazole
(10.0 equiv), CH2Cl2. d) Burgess reagent (4.0 equiv), toluene, 708C.
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Keywords: cascade reaction · cyclization · gold ·
.
natural products · total synthesis
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