2
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%.