Organic Letters
Letter
a
a
Scheme 3. Synthesis of the Oxazole Fragment
Scheme 4. Construction of the Macrocycle
a
a
Reagents and conditions: (a) amano lipase PS, vinylacetate, MS 4 Å,
Reagents and conditions: (a) Pd(PPh ) Cl , CuI, TEA, ACN, −10
3
2
2
pentane, 30 °C, 47% (R)-15 and 48% OAc-(S)-15; (b) proton
sponge, Me OBF , DCM, rt, 77%; (c) O , DCM/MeOH 5:1, PPh ,
°
C to rt, 85%; (b) CSA, DCM/MeOH 1:1, 0 °C, 95%; (c) 1 M
3
4
3
3
LiOH, THF, rt, 99%; (d) 1. TCBC, TEA; 2. DMAP, THF/toluene, rt,
−
78 °C, 89%; (d) 18, n-BuLi, THF, −78 °C to 0 °C, 60%; (e)
7
1
5%; (e) CSA, DCM/MeOH 1:1, 0 °C; (f) 1 M LiOH, THF, rt; (g)
. TCBC, TEA; 2. DMAP, THF/toluene, rt, 70% from 28.
HCOOH, rt, 99%; (f) serine methylester hydrochloride, TFFH,
DIPEA, THF, rt, 90%; (g) DAST, K CO , DCM, −78 °C; (h) DBU,
2
3
BrCCl , DCM, 0 °C to rt, 62% from 21; (i) TBAF, THF, 0 °C to rt,
3
8
1%.
14 and 24 to obtain major building block 25 in high chemical
yield. With compound 25 we could make use of the C2-
symmetry of the target structure synthesizing compounds 26
utilizing a selective CSA-promoted desilylation and also
compound 27 via saponification with LiOH all from the
same starting material. Yamaguchi esterification between acid
27 and alcohol 26 gave compound 28 in 75% yield. An
additional CSA-promoted desilylation, followed by another
smooth hydrolysis of the methyl ester in the presence of
lithium hydroxide and final macrolactonization using Yama-
guchi’s conditions, resulted in the formation of the symmetric
macrocycle 29 in 70% yield over three steps, as depicted in
Scheme 4.
(
15%) and 12 (80%), which were directly oxidized using a
Swern protocol to yield aldehyde 13 in 77% over two steps. A
modified Wittig reaction using iodomethyl triphenyl-
phosphonium iodide
at −78 °C gave selectively the Z iodide 14 in 67% as shown in
Scheme 2.
The oxazole fragment was synthesized using known methods
starting with a lipase resolution, yielding the (R)-enantiomer of
13,15a
in the presence of sodium disilazane
1
7
11
1
5 in 47%. Methylation was achieved with Meerwein salt,
followed by ozonolysis and subsequent Wittig reaction with
TIPS-protected propargyl triphenylphosphonium bromide 18
to obtain the desired E ene-yne-fragment 19 in 60% yield,
along with 22% of the Z isomer; the two isomers could be
easily separated by flash chromatography. Quantitative
hydrolysis of the t-butyl ester with formic acid and later
condensation with serine methyl ester provided amide 21 in
At this point, the critical phase of the synthesis started
because the polyunsaturated macrocycle 29 had to be treated
with precaution and the final sequence of events had to be
decided carefully. Many attempts to cleave the MOM group
completely failed and resulted only in decomposition
25
9
0% yield.
products. In addition, partial hydrogenation of compound
Cyclization in the presence of diethylaminosulfur trifluoride
29 also did not work in a satisfactory way using classical
2
3
10,12,26
(
DAST) followed by elimination with BrCCl and 1,8-
Lindlar conditions.
Finally, we found that reduction
3
24
27
diazabicyclo[5.4.0]undec-7-ene (DBU) gave the required
oxazole 23 in 62% yield over two steps. Consequent
desilylation with tetra-n-butylammonium fluoride (TBAF)
offered compound 24 in 81% yield as depicted in Scheme 3.
With all fragments in hand the final connections could be
envisioned using a Sonogashira reaction to couple fragments
under Boland conditions in the presence of Zn(Ag/Cu)
yielded the MOM-protected natural product 30 in 65% yield.
As we expected, considering the documented problems in
deprotecting these sensitive compounds, the last step proved
to be one of the most difficult of the overall synthesis. After
having carefully tested more than 20 published reagents for the
4
545
Org. Lett. 2021, 23, 4543−4547