Synthesis of the polyketide moiety of the jamaicamides

Article abstract of DOI:10.1016/j.tetlet.2015.10.069

[Figure presented] Isolated from the Jamaican cyanobacterium Lyngbya majuscula, the jamaicamides are unique, mixed polyketide-peptides reported to be sodium channel blockers. The polyketide moiety contains an (E)-chloroolefin, an undetermined methyl stere

Full text of DOI:10.1016/j.tetlet.2015.10.069

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of the polyketide moiety of the jamaicamides
Ayano Tanaka-Yanuma, Satoshi Watanabe, Keita Ogawa, Sho Watanabe, Naoto Aoki, Tetsuhiro Ogura,
⇑
Toyonobu Usuki
Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 September 2015
Revised 15 October 2015
Accepted 20 October 2015
Available online xxxx
Keywords:
Marine natural products
Jamaicamides
Total synthesis
Polyketide
Julia–Kocienski coupling
Isolated from the Jamaican cyanobacterium Lyngbya majuscula, the jamaicamides are unique, mixed
polyketide-peptides reported to be sodium channel blockers. The polyketide moiety contains an
(E)-chloroolefin, an undetermined methyl stereocenter (C9), and an (E)-olefin (C10–C11). Herein we
report the stereo- and regioselective synthesis of the polyketide moiety of the jamaicamides via a
Julia–Kocienski coupling as the key step.
Ó 2015 Elsevier Ltd. All rights reserved.
The jamaicamides A, B, and C (Fig. 1) were isolated by Gerwick
and co-workers from a dark green strain of Lyngbya majuscula
found in Hector’s Bay, Jamaica.1 These marine natural products
have a rare and mixed polyketide-peptide structure that includes
a trisubstituted (E)-chloroolefin, an unconfirmed methyl stereo-
center (C9), an (E)-olefin (C10–C11), an unusual alkynyl bromide
(only in jamaicamide A), a pyrrolinone ring, and a b-methoxy
enone. The jamaicamide family exhibits sodium channel-blocking
activity and displays cytotoxicity against both H-460 human lung
and Neuro-2a mouse neuroblastoma cell lines. Intriguingly, jamai-
camide B also shows anti-malarial activity and cytotoxicity to Vero
cells.2
Despite their intriguing bioactivity and the unique biosynthesis
of these secondary metabolites,1,6 the total synthesis and struc-
ture–activity relationship (SAR) studies of the jamaicamides have
not yet been accomplished. Herein we report the stereo- and
regioselective synthesis of the polyketide moiety of the jamaica-
mides wherein the alkyne and carboxylic acid functionalities have
respectively been protected with triethylsilyl (TES) and benzyl (Bn)
groups.
As illustrated in Scheme 1, the polyketide moiety 1 of the jamai-
camides was retrosynthetically divided into two parts. The (E)-
Synthesis of (S)-jamaicamide C carboxylic acid employing a
Negishi cross-coupling and Johnson-Claisen rearrangement as the
key steps was reported by Paige and co-workers.3 Separately, the
synthesis of the N-di-t-butoxycarbonyl [(Boc)2]-protected peptide
moiety of the jamaicamides starting from natural amino acids
was accomplished in our laboratory.4 We also reported the con-
struction of the (E)-olefin moiety of the polyketide unit of the
jamaicamides employing a Julia–Kocienski coupling.5
⇑
Corresponding author. Tel.: +81 3 3238 3446; fax: +81 3 3238 3361.
E-mail address: t-usuki@sophia.ac.jp (T. Usuki).
Figure 1. Structures of the jamaicamides.
http://dx.doi.org/10.1016/j.tetlet.2015.10.069
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
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A. Tanaka-Yanuma et al. / Tetrahedron Letters xxx (2015) xxx–xxx
(MeI) from ꢀ78 to ꢀ40 °C in tetrahydrofuran (THF) gave 9 in 63%
yield.9,10 Removal of the chiral auxiliary via treatment with lithium
borohydride (LiBH4) in diethyl ether (Et2O) led to alcohol 10.11
Finally, 10 was oxidized using the Dess–Martin periodinane
(DMP) reagent to afford aldehyde 5 in 86% yield.
With the two segments 4 and 5 in hand, attention was focused
on the construction of the (E)-olefin via a Julia–Kocienski coupling
reaction (Scheme 3).12,13 Sulfone 4 in THF was treated with
NaHMDS at ꢀ78 °C for 30 min to produce the corresponding anion,
which was then reacted with aldehyde 5 at ꢀ78 °C for 3 h to give
the desired olefin 11 in 80% yield. The E/Z selectivity of 11 was
determined to be 16:1 by 1H NMR analysis.14 Next, the p-methoxy-
benzyl (PMB) protecting group was removed using 2,3-dichloro-
5,6-dicyano-p-benzoquinone (DDQ) to give alcohol 12.15 Finally,
12 was oxidized using DMP to afford aldehyde 2 in 88% yield.
To obtain compound 15, a Grignard reaction between aldehyde
2
and (5-bromo-pent-1-ynyl)-triethylsilane 3 was attempted
(Scheme 4).16,17 Formation of the dianion of pent-4-yn-1-ol 13
with n-BuLi followed by successive treatment with triethylsilyl
chloride (TESCl) and 2 M HCl produced 14 in 95% yield.18,19 The
Appel reaction was then performed to afford 3 in 97% yield. After
insertion of magnesium into 3, the reaction was then conducted
from ꢀ78 °C to room temperature in THF. However, because the
reaction did not proceed even after 18 h, likely due to the struc-
turally complexity of 2, this synthetic route was abandoned.
As an alternative strategy, the use of simplified aldehyde 17 was
considered for the Grignard reaction with alkyl bromide 3, as
shown in Scheme 5. The (E)-olefin (C10–C11) of 1 would be con-
structed via a Julia–Kocienski coupling reaction between phenyl
tetrazol sulfone 45 and the corresponding aldehyde 16.
Treatment of pentane-1,5-diol 18 with PMBCl and sodium
hydride (NaH) in the presence of tetra-n-butyl ammonium iodide
(TBAI) gave the monoprotected alcohol 19 in 64% yield
(Scheme 6).20 Swern oxidation of 19 furnished aldehyde 17 in
78% yield.21 Next, the reaction of 17 with the Grignard reagent
derived from 3 was performed to afford the desired product 20
in 53% yield.16,17
Scheme 1. Retrosynthesis of 1.
chloroolefin would be formed at the last stage via Grignard and
Wittig reactions of aldehyde 2 and bromoalkyne 3. The (E)-olefin
(C10–C11) of 2 would be established stereoselectively via a Julia–
Kocienski coupling reaction of phenyl tetrazol sulfone 4, which
was prepared previously,5 and aldehyde 5. In the previous study,
5 was protected using a Bn group.5 However, in the present inves-
tigation, a p-methoxybenzyl (PMB) group, which can be easily
removed under milder conditions, was employed. The fragment 5
would be obtained from commercially available d-valerolactone 6.7
The synthesis commenced with the preparation of aldehyde 5
from lactone 6 (Scheme 2). Treatment of 6 with potassium hydrox-
ide (KOH) and p-methoxybenzyl chloride (PMBCl) in toluene gave
carboxylic acid 7 in 58% yield.7 After acylation of 7 with pivaloyl
chloride (PivCl), the resultant ester was converted to imide 8 in
92% yield using (S)-4-benzyl-2-oxazolidinone and n-butyllithium
(n-BuLi).8 Utilizing the Evans reaction, stereoselective methylation
with sodium hexamethyldisilazide (NaHMDS) and iodomethane
Formation of the (E)-chloroolefin was then attempted via a
Wittig reaction (Scheme 7). First, Swern oxidation of 20 led to
Scheme 2. Synthesis of aldehyde 5. Reagents and conditions: (a) KOH, PMBCl, toluene, reflux, 16 h, 58%; (b) PivCl, Et3N, ꢀ78 to 0 °C, 2 h, then n-BuLi, (S)-oxazolidinone, THF,
ꢀ78 to 0 °C, 3 h, 92%; (c) NaHMDS, MeI, THF, ꢀ78 to ꢀ40 °C, 3.5 h, 63%; (d) LiBH4, MeOH, Et2O, 0 °C to rt, 3 h, 87%; (e) DMP, CH2Cl2, rt, 3 h, 86%.
Scheme 3. Synthesis of aldehyde 2. Reagents and conditions: (a) NaHMDS, THF, ꢀ78 °C, 3 h, 80%; (b) DDQ, pH 7 buffer, CH2Cl2, 0 °C to rt, 4 h, 94%; (c) DMP, CH2Cl2, rt, 4 h, 88%.
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Scheme 4. Attempted Grignard reaction of 2 and 3. Reagents and conditions: (a) n-BuLi, TESCl, THF, ꢀ78 °C to rt, 5.5 h, then 2 M HCl aq, 20 h, 95%; (b) CBr4, PPh3, CH2Cl2,
ꢀ78 °C to rt, 4 h, 97%; (c) Mg, 1,2-dibromoethane, THF, reflux, 2 h; (d) THF, ꢀ78 °C to rt, 18 h.
the desired ketone 21 in 89% yield. A Wittig reaction using CH2-
ClPPh3Cl then afforded chloroolefin 22 in 92% yield.22 Separation
of (E)-23 and (Z)-23 via silica gel column chromatography proved
successful after the PMB protecting group of 22 was removed using
DDQ. Elucidation of the stereochemistry of (E)-23 and (Z)-23 was
performed using two-dimensional nuclear magnetic resonance
(2D-NMR) spectroscopy, including nuclear Overhauser effect cor-
related spectroscopy (NOESY). NOEs were observed between H8
and H27 for (E)-23 and between H4 and H27 for (Z)-23.
Oxidation of (E)-23 using DMP provided aldehyde 24, which
was transformed into carboxylic acid 25 under Kraus–Pinnick con-
ditions23,24 (88% yield over two steps; Scheme 8). After acylation of
25 with PivCl, the resultant mixed anhydride was converted to
imide 26 in 65% yield using (S)-4-benzyl-2-oxazolidinone and n-
BuLi.8 Stereoselective methylation with NaHMDS and MeI at
ꢀ78 °C in THF then gave 27 in 45% yield.9,10 Removal of the chiral
auxiliary using LiBH4 in Et2O afforded alcohol 28 in 78% yield,11
which was oxidized with tetrapropylammonium perruthenate
Scheme 5. Revised retrosynthesis of 1.
Scheme 6. Grignard reaction of 17 and 3. Reagents and conditions: (a) PMBCl, NaH, TBAI, THF, reflux, 15 h, 64%; (b) DMSO, (COCl)2, Et3N, CH2Cl2, ꢀ78 °C, 1.5 h, 78%; (c) Mg,
1,2-dibromoethane, THF, reflux, 2 h; (d) THF, ꢀ78 °C to rt, 18 h, 53%.
Scheme 7. Synthesis of (E)-chloroolefin 23. Reagents and conditions: (a) DMP, CH2Cl2, rt, 6 h, 88%; (b) CH2ClPPh3Cl, n-BuLi, THF, CH2Cl2, ꢀ78 °C to rt, 3 h, 92%; and (c) DDQ,
pH 7 buffer, CH2Cl2, 0 °C, 5 h, (E)-23 49%, (Z)-23 43%.
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Scheme 8. Synthesis of polyketide moiety (1). Reagents and conditions: (a) DMP, CH2Cl2, rt, 2.5 h; (b) 2-methyl-2-butene, NaH2PO4ꢁ2H2O, NaClO2, t-BuOH, H2O, rt, 1 h, 88%
(2 steps); (c) PivCl, Et3N, ꢀ78 to 0 °C, 3.5 h, then n-BuLi, (S)-oxazolidinone, THF, ꢀ78 to ꢀ40 °C, 2 h, 65%; (d) NaHMDS, MeI, THF, ꢀ78 °C, 4 h, 45%; (e) LiBH4, MeOH, Et2O, rt, 3 h,
78%; (f) TPAP, NMO, MS4A, CH2Cl2, rt, 0.5 h, 74%; (g) NaHMDS, THF, ꢀ78 °C, 4 h, 46%.
(TPAP) to give aldehyde 16 in 74% yield.25 Finally, five equivalents
References and notes
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