Facile carbohydrate-based stereocontrolled divergent synthesis of (+)-pericosines A and B

Article abstract of DOI:10.1039/c1ob06383a

An isomer-divergent synthesis of naturally occurring pericosines A and B is described starting from a known d-ribose derived ene-diol in 35% and 41% overall yields respectively of which the latter is the best synthetic method reported for pericosine B. Th

Full text of DOI:10.1039/c1ob06383a

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Facile carbohydrate-based stereocontrolled divergent synthesis of
+)-pericosines A and B†
(
Subhankar Tripathi,‡ Ajam Chand Shaikh and Chinpiao Chen*
Received 13th August 2011, Accepted 31st August 2011
DOI: 10.1039/c1ob06383a
An isomer-divergent synthesis of naturally occurring peri-
cosines A and B is described starting from a known D-ribose
derived ene-diol in 35% and 41% overall yields respectively
of which the latter is the best synthetic method reported
for pericosine B. The key features of this synthesis include
the stereoselective NHK vinylation of the terminal aldehyde
to the versatile diolefinic chiral intermediate and elegant
conversions of the same to the corresponding final products
via RCM (Ring Closing Metathesis).
Introduction
Pericosines A–E (Fig. 1) have gained considerable interest in the
repertoire of synthetic organic chemistry since their isolation from
the cytotoxic shikimate related metabolites of the fungus Periconia
1
byssoides found in the gastrointestinal track of the sea hare
Aplysia kurodai. In the family of pericosines, the main focus of
Fig. 1 Structures of naturally occurring pericosines.
the cytotoxicity remained with pericosine A, due its significant
due to their two distinct advantages; one is undeniably their easy
availability with the other being their inherent chirality that can be
well-manoeuvred for establishment of important chiral centers in
the target compounds. With this backdrop of using a chirality-
rich carbohydrate based starting materials; we envisaged our
retrosynthetic plan based on a Ring-Closing Metathesis (RCM)
growth inhibitory activity against protein kinase EGFR, human
topoisomerase II and selective inhibition against human cancer
cell lines HBC-5 and SNB-75 along with anticancer activity
2
against P388 lymphocytic leukemia cells both in vitro and in vivo.
3–5
Understandably, several efficient synthetic efforts have been
initiated towards these compounds and their epimers in order to
find a robust synthetic route and to allow their correct structural
8
mediated strategy which is still not reported for pericosines to
4
the best of our knowledge. Accordingly, a suitably substituted di-
olefinic intermediate as a precursor for the cyclohexene core of
the majority of the pericosine related targets looked evident. A
close inspection revealed the resemblance of related stereocenters
of this intermediate to those of D-ribose and these are in the
desired orientation for the final products. We understood that the
success of our synthetic effort essentially lay upon two important
tasks ahead; how well we could retain all the three hydroxyl
containing chiral centers of ribose and secondly, the introduction
of the fourth one in a stereocontrolled manner. Thus, the known
reassignments of which contributions from the Usami group are
worth mentioning. A more recent report of a chemoenzymatic
5
synthesis of pericosines A–C by Stevenson and coworkers is also
a valid addition in this direction. The noticeable common feature
of these approaches is that different chiral starting materials have
been chosen for each different target in a scattered manner. Thus,
we felt the urgent need for devising a divergent synthetic route for
these highly potent targets which definitely fall under the category
6
of multifuntionalized cyclohexenoid carbasugars.
Carbohydrates are considered as important chiral starting
9
7
D-ribose derived ene-diol 6 was identified as the ideal starting
materials for stereocontrolled synthesis of many natural products
point for our approach. According to our plan selective oxidation
of the diol to the terminal aldehyde followed by introduction of
vinyl carbomethoxy group would lead to the versatile intermediate
8, in which the fourth chiral hydroxyl substituent is embedded
automatically. Now direct RCM cyclization or cyclization after
methylation of 8 with the residual synthetic manipulations en route
to both the pericosine A and B would be a be routine synthetic
exercise (Fig. 2).
Department of Chemistry, National Dong Hwa University, Hualien, 97401,
Taiwan, ROC. E-mail: chinpiao@mail.ndhu.edu.tw
†
Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data of all new compounds with copies of NMR,
mass and IR spectra. See DOI: 10.1039/c1ob06383a
‡
7
Current Address: Vivekananda Mahavidyalaya, Sripally, Burdwan,
13103, West Bengal, India
7
306 | Org. Biomol. Chem., 2011, 9, 7306–7308
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Scheme 1 Reagents and conditions: (a) (i) Me
3
SiCl, imidazole, CH
2
Cl
2
,
◦
0
8
C to rt, (ii) MOMBr, DIPEA, DMAP, CH
2
Cl
2
, reflux, (iii) TBAF, THF,
◦
6% (over three steps); (b) (COCl)
2
, DMSO, TEA, CH
2
Cl
2
, -78 C, 91%;
(
c) methyl 2-iodoacrylate, CrCl
2
/NiCl
2
(2 : 1), 12, THF, rt, 84%.
both 1 and 2, but also appends a non-terminal carbomethoxy
substituent and double bond with it. Obviously, at this point the
absolute stereochemistry of the generated hydroxyl at C-3 in the
major isomer may be doubted and accordingly we realized that a
decision could be made only after elaboration of this intermediate
to a particular target molecule. Then, confirmation could be made
by comparison of data with that of the corresponding reported
values. Thus, we felt pericosine B could be the ideal target to serve
this purpose as it could be accessible via a three step sequence viz
methylation, RCM and deprotection without affecting the chiral
center in question.
Much to our expectation the selection of suitable methylation
15
condition proved to be a tricky one as the substrate contained
both acid and base sensitive functional groups within. Almost
all methylation protocols, with MeI under strong to moderate
basic conditions, indeed proved futile as they ended up in
hydrolysis of the important carbomethoxy substituent instead,
Fig. 2 Retrosynthetic analysis of pericosine A and B.
16
in most cases. Even, mild neutral methylating reagents, e.g. MeI
with freshly prepared Ag O, were unreactive to this particular
Results and discussion
2
Our synthetic journey began with the selective protection of the
secondary alcohol functionality as its MOM ether of the known
D-ribose derived vinyl diol 6 following a smooth protection–
deprotection strategy. The primary TBS ether, isolated in high
substrate. This unusual passivity of the hydroxyl group towards
methylating reagents could be explained by possible involvement
of intramolecular hydrogen bonding of the hydroxyl proton with
the adjacent carbomethoxy carbonyl. Even the failed attempt of
methylation of the same hydroxyl after the RCM substantiated
our claim. Finally, carrying out the reaction in scrupulously dried
ether at reflux in the presence of excess MeI and powdered KOH
as base; till the disappearance of starting material followed by
a quick non-aqueous work up, afforded 76% of the product,
which helped to get over the impasse in the methylation step.
Subsequent RCM reaction in the penultimate step was smooth
with Hoveyda–Grubbs (II) (HG-II) catalyst in refluxing toluene;
produced the cyclohexene core in 86% yield, followed by a TFA
induced global deprotection lead to the final product 2. Thus, we
were able to synthesize pericosine B in 41% overall yield from 6
which happens to be the best reported in the literature for this
molecule. Furthermore, the spectroscopic data of pericosine B
synthesized by us were in excellent agreement with reported values,
and settled the absolute stereochemistry of the generated chiral
10
yield from 6 was treated with MOMBr–DIPEA conditions in
refluxing CH Cl to give fully protected 11, desilylation thereof
2
2
and subsequent Swern oxidation furnished the desired terminal
aldehyde 7 in 78% isolated overall yield over four steps (Scheme
1
). Now the stage is set for the stereoselective C–C bond formation
11
through Nozaki–Hiyama–Kishi (NHK) reaction Based on our
vast experience in the field asymmetric NHK reactions by using
bis-pinenopyridine ligands on various aromatic as well as
aliphatic aldehydes and ketones, we envisaged the application
of the same protocol to the task in hand. Gratifyingly, NHK
reaction of terminal aldehyde 11 with methyl 2-iodoacrylate
using simple bis-pinenopyridine ligand 12 worked well with a
very high degree of distereoselectivity. The reaction not only
established the very important hydroxyl functionality which could
be strategically utilizable for a diversified approach leading to
12
13
12
14
This journal is © The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7306–7308 | 7307

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center of 8 during NHK vinylation step as well as detailed in the
Scheme 2.
Conclusion
In essence, we have demonstrated the first RCM driven isomer-
divergent stereocontrolled synthesis of both isomers of pericosine
family pericosines A and B from an easily available carbohydrate
based acyclic precursor with 35% and 41% overall yields respec-
tively. Our method provides a simple means to these chirality-rich
targets without unnecessary dragging of synthetic steps. We feel
the well-knotted use of NHK vinylation and RCM in our effort
should find application in simplifying problems in many related
synthesis in future.
Acknowledgements
The authors thank the National Science Council of the Republic
of China (NSC 97-2811-B-320-004) for a post-doctoral fellowship
to ST and financial support of this work (NSC 97-2113-M-259-
002-MY3).
Notes and references
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Scheme 2 Reagents and conditions: (a) HG-II cat., toluene, reflux, 86%;
1
(
b) Cp
2
ZrCl
2
, isopropanol, 83%; (c) (i) 1-chlorocarbonyl-1-methylethyl
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Herczegh, Tetrahedron, 2009, 65, 8171.
◦
acetate, MeCN, 0 C, 15 min, rt, 2 h, (ii) MeOH, cat. MeCOCl, rt, 12 h; (d)
MeI, KOH, 76%; (e) HG-II cat., toluene, reflux, 86%; (f) TFA(aq), 96%.
5
6
7
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and references cited therein.
Our next target pericosine A, the most potent member of the
pericosine family, was synthesized by cyclization of the NHK
product under similar RCM conditions as mentioned before to
the corresponding cyclohexenoid intermediate 14 in 86% yield. As
expected, the selective deprotection of MOM ether in presence of
cyclohexylidene moiety to intermediate diol 10 would be crucial as
the remaining synthetic elaboration to the target is known. Indeed,
several attempts with a variety of conditions for attainment of
selectivity in the deprotection step were unsuccessful as they led to
either global deprotection or no reaction. Even the use of Lewis
8
9
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1
(
17
acids e.g. ZrCl
4
for MOM deprotections where acetonides are
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reported to survive, proved fatal to our case. Finally, the method
developed in our laboratory was as follows: deprotection under
mild condition using Cp
2
ZrCl , selectively cleaved MOM ether
2
1
3 J. A. McCauley, K. Nagasawa, P. A. Lander, S. G. Mischke, M. A.
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14 The exact ratio of diastereoisomers was not calculated as only one
isomer was isolable during chromatographic purification of the crude
product.
in 83% yield and the product diol was successfully converted to
5
the target pericosine A following Stevenson’s protocol recording
an overall yield of 35% from 6. Consequently, we succeeded
in synthesizing both the members of pericosine family from
easily available acyclic starting material following a well defined
divergent methodology in a reasonably good overall yield utilizing
RCM reaction as key step.
15 T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis,
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1
1
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7
308 | Org. Biomol. Chem., 2011, 9, 7306–7308
This journal is © The Royal Society of Chemistry 2011