First total synthesis of cryptosporiopsin A

Article abstract of DOI:10.1039/c3ra47341d

The first total synthesis of polyketide natural product cryptosporiopsin A (1) was described. It has been accomplished in 12 longest linear steps with 15.4% overall yield starting from enantiomerically pure epoxide 12 prepared by hydrolytic kinetic resolu

Full text of DOI:10.1039/c3ra47341d

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First total synthesis of cryptosporiopsin A†
*
Barla Thirupathi and Debendra K. Mohapatra
Cite this: RSC Adv., 2014, 4, 8027
Received 5th December 2013
Accepted 10th January 2014
DOI: 10.1039/c3ra47341d
www.rsc.org/advances
The first total synthesis of polyketide natural product cryptosporiopsin against zoospores of the grapevine downy mildew pathogen
A (1) was described. It has been accomplished in 12 longest linear steps Plasmopara viticola as well as potent inhibitory activity against
with 15.4% overall yield starting from enantiomerically pure epoxide 12 mycelial growth of phytopathogens, Pythium ultimum, Aphano-
prepared by hydrolytic kinetic resolution. Other key steps were Stille myces cochlioides and a basidiomycetous fungus Rhizoctonia
coupling, Grignard reaction, De Brabander's esterification and ring solani. It also exhibited weak cytotoxic activity against brine
closing metathesis (RCM) reaction.
shrimp larvae.22 Because of its promising biological activities
and scarcity of the target natural product 1, we became inter-
ested in its total synthesis.
One of the most promising groups of natural products that have
recently emerged as new lead structures for kinase inhibition is
the resorcylic acid lactones (RALs), a unique class of fungal
polyketide metabolites, which are b-resorcylic acid derivatives
possessing a C11 side that is closed to form a 14-membered
macrolactone ring (Fig. 1).1 Since the rst isolation of radicicol
(monorden) in 1953,2 followed by zearalenone in 1962,3 LL-
Z1640-2 in 1978,4 and hypothemycin in 1980 (ref. 5) more than
30 naturally RALs have been reported. The RALs are endowed
with a breadth of biological activity such as transcription factor
modulations (zearalenone6 and zearalenol7), HSP90 inhibitors
(radicicol8 and pochonin D9), reversible (aigialomycin D10) as
well as irreversible kinase inhibitors (hypothemycin,11 IL-Z1640-
2,12 and L-783277 (ref. 13)), antifungal,14 antimalarial,15 anti-
parasitic,16 cytotoxic,17 oestrogenic,18 nematicidal,19 protein
tyrosine kinase and ATPase inhibition activities.20
Construction of macrolactone through the formation of C–C
bond and particularly by intramolecular ring closing metathesis
(RCM) reaction stands as a promising tool for the synthesis of
macrolides and heterocycles.23 As part of our ongoing program
in exploring ring-closing metathesis for macrolide syntheses,24
we demonstrated the use of RCM for the total synthesis of
It can thus be safe to be argued that the RAL framework is
privileged21 and that even analogues of these natural products
should be of interest. Recently, Laatsch et al.22 reported the
isolation of a new resorcyclic acid lactone, cryptosporiopsin A
(1) from Cryptosporiopsis sp. an endopyhtic fungus from leaves
and branches of Zanthoxylum leprieurii (Rutaceae). The relative
and absolute conguration of cryptosporiopsin A was assigned
on the basis of spectroscopic and spectrometric data. Crypto-
sporiopsin A (1) showed motility inhibitory and lytic activities
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, India. E-mail: mohapatra@iict.res.in; dkm0077@gmail.com
† Electronic supplementary information (ESI) available: Experimental details and
scanned copies of 1H and 13C NMR spectra for new compounds. See DOI:
10.1039/c3ra47341d
Fig. 1 Structures of some resorcyclic acid lactones (RALs).
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cryptosporiopsin A. According to our retrosynthetic analysis of
cryptosporiopsin A, shown in Scheme 1, could be achieved
through RCM reaction of 8 which in turn could be obtained by
coupling of lactone 9 and alcohol 10. Lactone 9 and alcohol 10
could be obtained from 2,4,6-trihydroxy benzoic acid 11 and
epoxide 12, respectively.
Results and discussion
The synthesis of compound 10 was started from enantio-
merically pure epoxide 12 in seven steps (Scheme 2). Epoxide
12 was prepared by Jacobsen's hydrolytic kinetic resolution
from racemic epoxide in 45% yield with 99% ee (by HPLC).25
Treatment of the epoxide with LiAlH4 in THF furnished the
corresponding secondary alcohol 13 in 85% yield.26 The
hydroxyl group present in 13 was protected as its PMB ether
to obtain 14 in 91% yield. Benzyl ether present in 14 was
selectively deprotected27 by Raney Ni in 88% yield and the
resulting primary alcohol was converted to its corresponding
aldehyde by using BAIB, TEMPO28 and subsequently used for
the Grignard reaction to get the desired product 16 in (with
z1 : 1 diastereomers by NMR and HPLC) 72% yield over two
steps. The hydroxyl group present in 16 was protected as its
TBS ether using TBDMSCl and imidazole in CH2Cl2 at room
temperature to afford 17 (z1 : 1 diastereomeric mixture) in
96% yield. PMB group present in 17 was selectively depro-
tected by careful treatment of DDQ29 in CH2Cl2–H2O (9 : 1) to
produce compound 10 (z1 : 1 diastereomeric mixture) in
89% yield.
Scheme 2 Reagents and conditions: (a) LiAlH4, THF, 0 ꢀC–rt, 3 h, 85%;
(b) PMBBr, NaH, 0 ꢀC–rt, 8 h, 91%; (c) Raney Ni, Ethanol, 4 h, rt, 88%; (d)
TEMPO, BAIB, CH2Cl2, 30 min, rt, 3-butenyl magnesium bromide, À78
ꢀC–rt, 72% over two steps; (e) imidazole, TBSCl, CH2Cl2, 0 ꢀC–rt, 4 h,
96%; (f) DDQ, CH2Cl2 : H2O (9 : 1), 0 ꢀC, 2 h, 89%.
conditions31 to afford 19 in 85% yield. Compound 19 was easily
converted to its triate with triic anhydride in pyridine.32 Then
it was subjected to allylation in presence of catalytic amount
Pd(PPh3)4 in anhydrous DMF to give 20 in 76% yield over two
steps.24c,33 By utilizing Jin's one-step dihydroxylation–oxidation
protocol34 terminal double bond present in compound 20 was
converted to corresponding aldehyde 21, which was subse-
quently subjected to Grignard reaction with vinyl magnesium
ꢀ
bromide at À78 C to furnish 22 in 87% yield. Allylic hydroxyl
group present in 22 was protected as its TBS ether with
TBDMSCl, imidazole to afford 9 in 92% yield.
The aromatic coupling fragment was prepared in six steps
starting from readily available 2,4,6-trihydroxy benzoic acid
monohydrate (11) which on treatment with triuoroacetic acid,
triuoroacetic anhydride and acetone to obtain compound 18
in 55% yield (Scheme 3).30 The hydroxyl group present in 18 was
selectively protected as its PMB ether by using Mitsunobu
Scheme 3 Reagents and conditions: (a) acetone, TFA, TFAA, 0 ꢀC–rt,
12 h, 55%; (b) PMBOH, DIAD, Ph3P, CH2Cl2, 0 ꢀC–rt, 4 h, 85%; (c) (1)
Tf2O, pyridine, 0 ꢀC–rt, 10 h; (2) Bu3Sn(allyl), LiCl, Pd(PPh3)4, DMF,
60 ꢀC, 4 h, 76% over two steps; (d) OsO4, NaIO4, 2,6-lutidine, dioxane,
H2O, rt, 3 h, 89%; (e) vinylmagnesium bromide, THF, À78 ꢀC, 4 h, 87%;
(f) imidazole, TBDMSCl, 0 ꢀC–rt, 3 h, 92%.
Scheme 1 Retrosynthetic analysis of cryptosporiopsin A.
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NOE experiment. The spectroscopic and analytical properties of
1 (1H and 13C NMR, and MS) were identical to those of reported
for the natural product 1. The optical rotation of synthetic 1
{[a]2D7 + 9.7 (c 1.05, MeOH)} was in good agreement with that of
natural 1 {ref. 22 [a]2D0 + 11.0 (c 0.1, MeOH)}, which conrmed
the absolute conguration.
Conclusions
In summary, the rst total synthesis of cryptosporiopsin A (1)
was accomplished in highly efficient way in 12 longest linear
steps with 15.4% overall yield, starting from a known enantio-
merically pure epoxide. The key steps of the synthesis were
Jacobsen's hydrolytic kinetic resolution, Stille coupling,
Grignard reaction, De Brabander's esterication and RCM
reaction. This total synthesis has veried the absolute cong-
uration of 1. The strategy is both concise and exible to produce
additional analogues of 1 in enantiomerically pure form. Efforts
to achieve this are currently underway in our laboratory.
Acknowledgements
We are thankful to the Director, CSIR-IICT and HoD, NPCD, for
their kind support and encouragement. The authors thank
CSIR, New Delhi for nancial support as part of XII Five Year
plan programme under title ORIGIN (CSC-0108). B.T. thanks
the University Grant Commission (UGC), New Delhi, India for
nancial assistance in the form of fellowships.
Scheme 4 Reagents and conditions: (a) (1) NaH, 10, THF, 0 ꢀC–rt, 5 h;
(2) MeI, 0 ꢀC–rt, 3 h, 85%; (b) NCS, chlorobenzene, 70 ꢀC, 10 h, 77%, (c)
Grubbs II, CH2Cl2, reflux, 18 h, 74%; (d) TBAF, THF, 0 ꢀC–rt, 4 h, 95%; (e)
DMP, CH2Cl2, 0 ꢀC–rt, 5 h, 92%; (f) TiCl4, 0 ꢀC, 10 min, 87%.
Aer synthesizing fragments 9 and 10, coupling of these two
fragments was carried out by subjecting them to De Brabanders
lactonization conditions led to the formation of compound 23
(z1 : 1 : 1 : 1 diastereomeric mixture) in 85% yield.35 Our next
task was to introduce the chlorine functionality which was
achieved by using N-chloro succinamide36 in chlorobenzene to
obtain compound 8 in 77% yield (Scheme 4). As it is a mixture of
four compounds, the regioselectivity of chlorination at this
stage was difficult to ascertain and we thought of conrming at
the later stage of the synthesis. With the required diene
compound in hand which sets the stage for crucial RCM reac-
tion and the 14-membered macrolactone formation proceeded
smoothly with Grubbs second generation catalyst under
reuxing conditions to afford 24 (1 : 1 : 1 : 1 diastereomeric
mixture) in 74% yield. At this stage the geometry of the double
could not be conrmed because of the presence of two racemic
centers. We proceeded further to remove the silyl groups which
was achieved with 1 M solution of TBAF in THF at room
temperature to give 7 (z1 : 1 : 1 : 1 diastereomeric mixture) in
95% yield. Oxidation of secondary alcohols to ketones was
achieved by Dess–Martin periodinane in CH2Cl2 to afford
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