Tetrahedron Letters
Stereoselective synthesis of C3–C17 and C18–C34 subunits of
bullatanocin utilizing a-chloro sulfide intermediates
L. Raju Chowhan a,b,1, Sadagopan Raghavan a,
⇑
a
Department of Organic Synthesis and Process Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent synthesis of bullatanocin is envisaged by the union of C18–C34, C3–C17 and the butenolide
subunits. The synthesis of the C3–C17 and C18–C34 subunits is disclosed that takes advantage of the chi-
rality of tartaric acid for 1,2-asymmetric induction, chloro sulfides for carbon chain elongation and [2,3]
sigmatropic shift for the preparation of 1,4-diol moiety via efficient 1,3-chirality transfer. The THF ring is
elaborated by intramolecular displacement.
Received 3 August 2019
Revised 5 September 2019
Accepted 9 September 2019
Available online 10 September 2019
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Bullatanocin
a-Chloro sulfide
[
2,3] Sigmatropic rearrangement
Substrate-controlled induction
Introduction
THF subunits of bullatanocin were synthesised utilizing iodoether-
ification of 1,2-O-isopropylidene-5-alkene precursors as the key
Three main structural types of tetrahydrofuran (THF)-contain-
ing acetogenins known are: mono-THF’s, adjacently linked bis-
THF’s and nonadjacently linked bis-THF’sÁ THF containing aceto-
genins have received wide attention from the synthetic commu-
nity due to their potent anti-tumour activity [1]. Several
syntheses of the natural products belonging to the first two groups
have been reported [2]. The non-adjacently linked bis-THF’s in
comparison have not garnered as much attention. Bullatanocin
step. These allylic THF fragments were further subjected to olefin
cross-metathesis and Wittig olefination to secure the target.
A modular synthesis that would provide for the synthesis of not
only bullatanocin but other analogues possessing different
stereoisomeric THF subunits and hydrocarbon chain lengths was
appealing. With this objective, the synthesis of bullatanocin was
envisioned by coupling three subunits, the subunit 2, comprising
of the C18–C34 carbon chain, subunit 3 consisting of the C3–C17
carbons and lactone 4, Scheme 1Á THF ring containing subunits 2
and 3 were to be united by a cross-metathesis reaction and the
ensuing C3–C34 fragment was envisaged to be coupled to the
known lactone 4 by alkylation. Herein we disclose the synthesis
(1) Scheme 1, also known as squamostatin C is a typical member
of the nonadjacently linked bis-THF acetogenins isolated from
the bark of Annona bullata Rich by McLaughlin and co-workers
[
3] and by Fujimoto and co-workers from the seeds of Annona squa-
mosa [4].
Bullatanocin was shown to be active against colon cell line HT-
of the THF ring containing subunits by taking advantage of
a-
chloro sulfide intermediates for CAC bond formation and the Mis-
low-Evans’ rearrangement of an allylic sulfoxide for stereoselective
CAO bond formation beginning from chiral starting materials.
The synthesis of subunit 2 began with acetonide 7, prepared in
three steps, following a known sequence of reactions [6] from (D)-
tartaric acid 6, Scheme 2. The sulfide 8, obtained following Hata’s
protocol [7], on treatment with N-chlorosuccinimide (NCS)
afforded an epimeric mixture of chloro sulfides 9. Reaction of the
chloro sulfide with alkynylzinc bromide prepared from alkyne 10
yielded the propargylic sulfide 11 as the sole product [8]. Partial
reduction of the alkyne using dicyclohexyl borane furnished the
cis-alkene 12. Oxidation of the sulfide with mCPBA afforded an
equimolar mixture of epimeric sulfoxides which on warming in
À8
2
9 and lung cell line A-549 (ED50 < 10
lg/mL). Structurally, bul-
latanocin is characterized by the presence of two 2,5-trans-disub-
stituted THF rings connected by a 1,4-dihydroxybutyl linker.
While the relative stereochemistry of bullatanocin was assigned
using empirical rules put together by analysis of many reference
compounds, unambiguous proof was provided by total synthesis
disclosed by Mootoo and co-workers [5]. In their report, the allylic
⇑
Present address: Centre for Applied Chemistry, Central University of Gujarat,
1
Sector 30, Gandhinagar 382030, India.
0
040-4039/Ó 2019 Elsevier Ltd. All rights reserved.