Angewandte
Communications
Chemie
[20]
liberated alcohol and aldoxime formation afforded fragment
corroborated by J-based configuration analysis (JBCA)
7
.
(see Supporting Information). Finally, sulfation afforded
(+)-bromodanicalipin A (3) in 99% yield.
The synthesis of fluorodanicalipin A (1) commenced with
the preparation of olefin 15 from (Z)-non-2-en-1-ol (13)
(Scheme 3). Allylic oxidation with MnO2 afforded the
Diastereoselective nitrile oxide cycloaddition involving
[9]
aldoxime 7 and olefin 8 furnished isoxazoline 9 in good yield
and d.r. = 79:21 (Scheme 2). The anti and syn diastereo-
mers were identified on the basis of their characteristic
[10]
Scheme 3. Reagents and conditions: a) MnO
2
(25 equiv), CH
0 min, 97%, Z/E=97:3; b) (vinyl)MgCl (1.3 equiv), THF, 08C, 2 h,
5%; c) mCPBA (1.2 equiv), Na HPO (2.0 equiv), CH Cl , 08C, 3 h,
2 2
Cl , RT,
3
9
8
2
4
2
2
4%, d.r.=96:4; d) BnBr (1.5 equiv), NaH (2.5 equiv), nBu NI
4
(
8
10 mol%), THF, À788C to RT, 90%; e) Et N·(HF) (4 equiv), 1508C,
3
3
h, 81%; f) F C SO F (4.0 equiv), Et N·(HF) (2.0 equiv), DBU
9 4 2 3 3
(3.0 equiv), THF, RT, 10 h, 38%. Bn=benzyl, mCPBA=meta-chloro-
perbenzoic acid, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
unstable (Z)-enal which was directly subjected to the action
of (vinyl)MgCl, providing the corresponding double-allylic
alcohol in 92% yield. Treatment with mCPBA then led to the
regioselective formation of an oxirane at C15/C16 and the
desired threo-epoxy-alcohol 14 could be isolated in 84% yield
and d.r. = 96:4, as identified by NMR analysis.
Protection of the secondary alcohol set the stage for the
introduction of the first fluorine. To this end, the benzyloxy
Scheme 2. Reagents and conditions: a) 8 (1.4 equiv), NaOCl (13% in
H O, 3.7 equiv), CH Cl , 08C to RT, 89%, d.r. =79:21;
2
2
2
b) H [P(W O ) ]·(H O) (3 mol%), MeCN/H O (10:1), RT; c) NaIO
3
3
10
4
2
24
2
4
(1.3 equiv), THF/pH 7 buffer (1:1), 08C to RT, 75% over 2 steps;
d) oct-1-yne (1.5 equiv), Cp Zr(H)Cl (1.2 equiv), Me Zn (1.2 equiv),
2
2
CH Cl , À788C to RT, 85%, d.r.=76:24, 95% ee; e) TBSOTf
[21]
2
2
(
1.3 equiv), Et N (1.5 equiv), CH Cl , 08C; f) Mo(CO) (1.2 equiv),
3 2 2 8
MeCN/H O (10:1), 908C; g) iPrCHO (11 equiv), SmI (0.09m in THF,
2
2
3
6
0 mol%), THF, À308C; h) (iBu)
2
AlH (3.0 equiv), CH
2
Cl
2
, À788C,
epoxide was mixed with Et N·(HF) and the solution heated
7% over 4 steps; i) CBr (4.9 equiv), PPh (5.4 equiv), pyridine
3
3
4
3
[22]
(
13 equiv), CH Cl , RT, 45%; j) HF·pyridine (33 equiv), THF, 08C to RT,
to 1508C, affording the (C16-F)-fluorohydrin in 81% as
a single regio- and diastereomer. The introduction of the
second fluoride at C15 was more challenging. After extensive
experimentation, it was found that treatment with a mixture
of F C SO F, Et N·(HF) and DBU in THF for 10 h provided
2
2
9
9%; k) PhNMe Br (1.4 equiv), CH Cl , 08C to RT, 99%, d.r.=90:10;
3 3 2 2
l) SO ·pyridine (4.1 equiv), THF, RT, 99%. Cp=cyclopentadienyl,
3
TBS=tert-butyldimethylsilyl, Tf =trifluoromethanesulfonyl.
9
4
2
3
3
[23]
difluoride 15 in 38% yield as a single diastereomer.
[11]
chemical shifts and coupling constants.
Chemoselective
The synthesis of the nitrile oxide precursor 19 was
addressed next. Undec-10-enal (16) was subjected to a-
hydrolysis of the 1,3-dioxolane without concomitant loss of
the TBS group was possible with phosphotungstic acid
[24]
difluorination (Scheme 4), and the difluoroaldehyde pro-
[12]
hydrate.
Subsequent glycol cleavage afforded a highly
duced was isolated and directly treated with NaBH to furnish
4
unstable formyl isoxazoline, which set the stage for nucleo-
difluoroalcohol 17 in 86% yield (2 steps). Following protec-
tion of difluoroalcohol 17 attention was turned towards the
elaboration of the terminal olefin into a suitable nitrile oxide
precursor. Consequently, hydroboration of the olefin and
subsequent in situ oxidation delivered primary alcohol 18 in
99% yield. Aldoxime 19 could be readily accessed in 70%
[
13]
philic addition. When this aldehyde was allowed to react
[
14]
with the vinyl zinc species obtained from 1-octyne (hydro-
zirconation followed by transmetallation with Me Zn), allylic
2
alcohol 10 was obtained in 85% yield and d.r. = 76:24.
[15]
[11]
Mosher ester analysis
and NMR spectroscopy studies
[25]
revealed anti-10 to be the major product. Additionally, the ee
could be unambiguously determined as 95% by HPLC
analysis.
yield and 2 steps by means of Dess–Martin oxidation
followed by condensation of the aldehyde produced with
HONH ·HCl. The 1,3-dipolar cycloaddition between olefin 15
2
Subsequent protection of the secondary alcohol and
and the nitrile oxide derived from aldoxime 19 was found to
proceed relatively slowly and therefore it became necessary
to add the latter component by syringe pump over 24 h in
[16]
opening of the isoxazoline afforded a b-hydroxy ketone,
[17]
which was subjected to an Evans–Tishchenko reduction to
furnish 1,3-anti-diol 11 (d.r. > 20:1) in 2 steps.
[10]
order to prevent extensive dimerization of the nitrile oxide.
Double Appel substitution of the 1,3-diol in 11 gave the
desired tetrabrominated compound as a single diastereo-
mer. Removal of both TBS ethers then afforded diol 12,
After an additional 16 h, isoxazoline 20 was isolated as a 84:16
mixture of diastereomers in favor of the desired C13/C14 anti-
[18]
3
[11]
product ( J = 3.4 Hz).
Separation of these by column
which was subjected to bromination with PhNMe Br3 to
chromatography proved simple, leading to 20 in 62% yield
3
deliver the desired product with d.r. = 9:1. The relative
as a single diastereomer. Reductive opening of the isoxazoline
[19]
[16]
configuration of the hexabromodiol
was unambiguously
with Mo(CO) at 908C followed by anti-selective reduc-
6
2556
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 2555 –2558