Stereoselective synthesis of the C3-C12 subunit of laulimalide

Article abstract of DOI:10.1016/j.tetlet.2013.12.040

A stereoselective synthesis of the C3-C12 subunit of the tumor growth inhibitors laulimalide is disclosed. The key steps of the synthesis include asymmetric alkylation using Oppolzer's protocol and an asymmetric hetero-Diels-Alder reaction using Jacobsen'

Full text of DOI:10.1016/j.tetlet.2013.12.040

Tetrahedron Letters 55 (2014) 913–915
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Tetrahedron Letters
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Stereoselective synthesis of the C3–C12 subunit of laulimalide
⇑
Sadagopan Raghavan, Pradip Kumar Samanta
Division of Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the C3–C12 subunit of the tumor growth inhibitors laulimalide is disclosed.
The key steps of the synthesis include asymmetric alkylation using Oppolzer’s protocol and an asymmet-
ric hetero-Diels–Alder reaction using Jacobsen’s catalyst. Substrate controlled diastereoselective Luche
reduction followed by Ferrier type reactions are other key steps.
Received 4 October 2013
Revised 10 December 2013
Accepted 14 December 2013
Available online 18 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Laulimalide
Organocatalysis
Ferrier type rearrangement
Laulimalide (1), also known as figianolide B, a 20-membered
macrolide isolated from the Indonesian sponge Hyattella sp., has
shown remarkable antitumor activities.1 It promotes abnormal
tubulin polymerization and apoptosis in vitro and has a mode of
action similar to that of taxol 2. The structure of 1 was initially
established by NMR studies. Subsequently, its absolute configura-
tion was established by X-ray analysis by Higa et al.2 (Fig. 1).
Initially it was shown that laulimalide displayed potent cyto-
toxicity against the KB cell line with an IC50 value of 15 ng/mL
but it did not attract the attention of synthetic chemists until Moo-
berry et al.3 discovered that laulimalide displays microtubule sta-
bilizing activity similar to that of paclitaxel and the epothilones.
Furthermore, it has been shown to possess cytotoxicity against
P388, A549, HT29, and MEL28 cell lines with IC50 values in the
range of 10–50 ng/mL. The significant clinical potential of laulima-
lide 1, insufficient material for preclinical development and novel
structure has stimulated considerable interest in its synthesis
and several groups have disclosed the total synthesis of natural
laulimalide4 and its analogues.5 In a period of twelve years, five
syntheses of laulimalide have been reported in the literature. Ow-
ing to its potential as an anticancer lead, its restricted natural sup-
O
O
NH
O
O
OH
O
O
H
HO
O
O
HO
1
2
O
O
O
Figure 1. Tumor growth inhibitors laulimalide 1 and taxol 2.
reaction between fragments 3 and 4.4p Fragment 3 can be obtained
by diastereoselective hetero Diels–Alder reaction utilizing
Jacobsen’s protocol to form the enone followed by a Ferrier
reaction.
The synthesis of the pyran 3 commenced from the (R)-sultam 8
that on treatment with propionyl chloride yielded auxiliary 7.
Alkylation of the lithio anion of 7 generated using LDA as the base
and prenyl bromide as the alkylating agent furnished compound
10 via enolate intermediate 9.6 Alcohol 11 was obtained in 83%
yield along with the auxiliary by the reduction of 10 using LiAlH4,
Scheme 2.
a
ply and unique structure the total synthesis of
preparation of analogues are a hot topic.
1 and the
Herein, we describe the synthesis of the C3–C12 subunit 3 of
laulimalide utilizing organocatalytic asymmetric reactions and a
hetero Diels–Alder (HDA) as key intermediate for pyran ring for-
mation. The retrosynthetic analysis of laulimalide is depicted in
Scheme 1. Laulimalide 1 was envisaged to be synthesized via
addition of sulfone anion subunit to aldehyde fragment that is by
Sulfide 12 was prepared from 11 following Hata’s protocol7
using Bu3P and diphenyl disulfide. Sulfide 12 on ozonolysis in CH2-
Cl2 under standard reaction conditions furnished sulfone aldehyde
13 in 52% yield along with an epimeric mixture of sulfoxide alde-
hyde 14. Compounds 13 and 14 were confirmed by corresponding
alcohol. Thus, compounds 13 and 14 exposed to NaBH4 furnished
sulfone alcohol 15 in 50% yield along with an epimeric mixture
of sulfoxide alcohol 16, Scheme 3.
⇑
Corresponding author. Tel.: +91 124 4885456.
E-mail address: pch.sam@gmail.com (P.K. Samanta).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.040

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S. Raghavan, P. K. Samanta / Tetrahedron Letters 55 (2014) 913–915
Scheme 1. Retrosynthetic analysis of (À)-laulimalide 1.
sulfide 29, returning the starting material instead, (Scheme 6). The
alcohol in 28 and mesylate 30 do not exhibit nucleophilic substitu-
tion reaction because of pyran ring.
We were unsuccessful in synthesizing sulfide 29 by employing
aldehydes 13 and 14 using the hetero Diels–Alder reaction and also
from alcohol 11. We chose to prepare the same from allyl acetate
33 which was obtained taking advantage of the hetero-Diels–Alder
reaction as reported earlier by our group.11 The unsaturated ketone
31 was prepared by a straightforward sequence of reactions begin-
ning from a-chloro acetone, Scheme 7.
However, acetylation of 32 followed by Ferrier type reaction12
with silyl enol ether yielded the trans-dihydropyran derivative 34
(dr = >95%). To the best of our knowledge, this is the first example
of Ferrier type rearrangement using TiCl2(OiPr)2 in the presence of
sulfide. The trans-ring fusion of the pyran ring was confirmed by
previous literature precedent13 and for curiosity 2D-NOE NMR
spectral data recorded. Reduction of the aldehyde 34 using sodium
borohydride furnished alcohol 35 that was subsequently protected
as its TBS ether 36 under standard conditions. Oxidation of the sul-
fide using ammonium molybdate and H2O2 yielded sulfone 3,
Scheme 7.
Scheme 2. Synthesis of alcohol 11. Reagents and conditions: (a) NaH, CH3CH2COCl,
toluene, rt, 3 h, 95%; (b) prenyl bromide, nBuLi, DIPA, HMPA, THF, À78 °C, 1 h, 83%;
(c) LAH, THF, 0 °C, 1 h, 83%.
Attempted hetero Diels–Alder reaction8 of aldehydes 13/14,
with Danishefsky diene9 5 failed to afford any desired pyran prod-
uct 17/18, Scheme 4.
Hence, alcohol 11 was protected as its acetate 20 and further
subjected to ozonolysis to afford aldehyde 21. Attempted hetero
Diels–Alder reaction of aldehyde 21 with Danishefsky diene 5
afforded the desired pyran 22, (Scheme 5). Substrate controlled
chemoselective reduction of the carbonyl group using Luche’s
protocol10 afforded cis-2,4-disubstituted pyran derivative 23
exclusively. Acetylation under standard conditions yielded com-
pound 24 that on reaction with TBS-vinyl ether in the presence
of TiCl2(OiPr)2 as a Lewis acid afforded aldehyde 25. Thus the trans
configuration in the pyran ring was introduced stereoselectively,13
Scheme 5. Reduction of aldehyde 25 using NaBH4 in MeOH at 0 °C
yielded the primary alcohol 26 that was protected as its PMB ether
27 by reaction with the p-methoxybenzyl imidate in the presence
of Ln(OTf)3.
In conclusion, we have described a highly stereoselective con-
vergent route to the C3–C12 subunit 3, of laulimalide. The key
steps in the successful route to the C3–C12 fragment include the
The acetate group in 27 was hydrolyzed to 28 and then exposed
to diphenyldisulfide and tributyl phosphine in THF. Unfortunately,
at ambient or at reflux temperatures no change was observed.
Mesylation of 28 using methanesulfonic acid in the presence of
Et3N afforded the mesylate 30. Attempted displacement of the
mesylate using thiophenol in the presence of DBU failed to furnish
Scheme 4. Synthesis of pyran ring. Reagents and conditions: (a) 19 (4 mol %),
TBME, À30 °C, 24 h, then TFA, 2 h.
Scheme 3. Synthesis of sulfone aldehyde 13 and sulfoxide aldehyde 14. Reagents and conditions: (a) (PhS)2, Bu3P, THF, rt, 24 h, 95%; (b) O3, CH2Cl2, À78 °C, 20 min then Me2S,
rt, 2 h, (52% sulfone 13 and 36% sulfoxide 14); (c) NaBH4, MeOH, 0 °C, 30 min. (50% sulfone 15 and 35% sulfoxide 16).

S. Raghavan, P. K. Samanta / Tetrahedron Letters 55 (2014) 913–915
915
Scheme 5. Synthesis of sulfide 29. Reagents and conditions: (a) TEA, Ac2O, cat. DMAP, DCM, rt, 1 h, 95%; (b) O3, CH2Cl2, À78 °C, 30 min then Me2S, rt, 15 h, 88%; (c) 19
(4 mol %), TBME, À30 °C, 24 h, then TFA, 2 h, 75%; (d) NaBH4, CeCl3Á7H2O, MeOH, À10 °C, 5 min, 95%; (e) Ac2O, Et3N, cat. DMAP, CH2Cl2, 0 °C, 5 min, 92%; (f) Vinyl-TBS ether,
TiCl2(OiPr)2, toluene, À45 °C 2.5 h, 85%; (g) NaBH4, MeOH, À10 °C, 5 min, 85%; (h) PMB-imidate, Ln(OTf)3, toluene, 0 °C to rt, 5 min, 95%; (i) K2CO3, MeOH, rt, 30 min, 82%; (j)
(PhS)2, Bu3P, THF, 60 °C, 20 h.
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Acknowledgments
P.K.S. is thankful to the CSIR, New Delhi, for a fellowship. Finan-
cial assistance from the DST, New Delhi is gratefully acknowledged.
We thank Dr. B. Jagadeesh, Head, NMR center, for NMR spectra and
Dr. R. Srinivas, Head, NCMS division, for mass spectra.
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