Tetrahedron Letters
Diastereoselective synthesis of the C29–C41 fragment of karlotoxin 2
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D. Srinivas Reddy, Janardhan Gaddam, Nagaraju Devunuri, Debendra K. Mohapatra
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 5000 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly diastereoselective synthesis of the C29–C41 fragment of karlotoxin 2 (KmTx2) is described by
employing regio-selective epoxide opening, our own developed domino isomerization followed by C–O
and C–C bond formation reaction and chelation-controlled Grignard reaction as key steps. The synthesis
involves installation of seven stereocenters present in the C29–C41 fragment of karlotoxin 2.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 8 April 2015
Revised 14 May 2015
Accepted 15 May 2015
Available online 19 May 2015
Keywords:
Regioselective epoxide opening
Domino isomerization followed by C–O and
C–C bond
Formation reaction
Sharpless asymmetric dihydroxylation
Chelation-controlled Grignard reaction
Karlotoxins are fascinating group of metabolites, isolated from
Karlodinium venificum in Maryland.1 Karlotoxin 2 (KmTx2) was
obtained from cultured material of K. Venificum (ccmp 2064) actu-
ally collected from a fish-kill in Georgia.2 Two families of karlotox-
ins have been described as belonging to the karlotoxin 1 (KmTx1)
and karlotoxin 2 (KmTx2) groups. The main difference between
these two groups is in carbon chain structure which is localized
to the length of the lipophilic side chain. KmTx2 is two carbons
shorter, whereas KmTx1 has 18 carbon chain and lipophilic arm
length an important determinant for potency of both the karlotox-
ins. Karlotoxins shows similar activity to amphotericin B, and
amphidinol 3 (AM3) (Fig. 1).
According to our retrosynthetic analysis, compound 3 could be
prepared from 4, following a chelation controlled Grignard reaction
on aldehyde. Advance intermediate trans-2,6-disubstiuted dihy-
dropyran 6 could be achieved from d-hydroxy
a
,b-unsaturated
following our own developed methodology. d-
,b-unsaturated aldehyde 5 could be prepared from a
aldehyde
Hydroxy
5
a
known epoxide 7 which in turn could be synthesized starting from
commercially available 1,4-butyne diol (8) (Scheme 1).
The synthesis was started with a known epoxy alcohol 7, which
was accessed starting from butyne-1,4-diol, following a three-step
protocol6 (Scheme 2). Oxidation of alcohol 7 with Dess–Martine
periodinane7 in CH2Cl2 at room temperature afforded a corre-
sponding aldehyde that was immediately treated with
Ph3P@CHCO2Et in toluene at room temperature to obtain the
KmTx2 exhibits potent homolytic, cytotoxic, ichthyotoxic activ-
ity1a through the membrane and sterol binding.
KmTx2, which resembles the structural features of amphidinol
3, possesses 28 stereogenic centers, two immensely oxygenated
tetrahydropyrans, a long irregular polyol system and with a chlo-
rine atom.3 Recently, we have developed a novel protocol that is
tandem isomerization followed by C–O and C–C bond formation
reaction for the synthesis of a trans-2,6-disubstiuted dihydropyran
a
,b-unsaturated ester 9 in 76% yield over two steps as exclusive
E-isomer. Regioselective opening of epoxy ,b-unsaturated ester
under Lewis acid conditions with benzyl alcohol as a nucleophile
a
in CH2Cl2 afforded the d-hydroxy a,b-unsaturated ester 10 as a sin-
gle isomer in 82% yield.8
DIBAL-H reduction of the ester at À78 °C provided the corre-
sponding allyl alcohol 11 in 89% yield. Selective oxidation of allyl
alcohol was carried out under 2,2,6,6-tetramethyl-1-piperidiny-
loxyl (TEMPO) and [bis(acetoxy)iodo]benzene (BAIB) conditions9
from d-hydroxy
a,b-unsaturated aldehyde and applied for a syn-
thesis of a number of complex biologically active molecules.4 As
there is only one synthesis of C42–C63 fragment of karlotoxin 2 till
date,5 we intrigued to apply our own developed protocol for the
synthesis of C29–C41 fragment of karlotoxin 2.
at room temperature in CH2Cl2 to furnish the d-hydroxy a,b-unsat-
urated aldehyde 5 in 90% yield. Now, the stage is set to carry out
our own developed iodine-catalyzed tandem isomerization fol-
lowed by C–O and C–C bond formation reaction. Accordingly, com-
pound 5 was treated with 10 mol % of molecular iodine and
⇑
Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512.
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.