N. Guttenberger et al. / Tetrahedron Letters 58 (2017) 362–364
363
Fig. 1. Postulated structures for less-polar arsenolipids reported in the blue whiting fish11 and in Peruvian anchoveta.12
Scheme 1. Synthesis of the AsTAGs 1 and 2. Reagents and conditions: (a) cat. H
.9 eq Me , THF, 0 °C, 45 min then 2 eq 4 M NaOH, 3 h, rt then HCl then H
AsI, THF, À70 °C ? rt, overnight then 2.3 eq H
DIC, 5 mol% DMAP, CH Cl , 0 °C ? rt, 16 h; (e) ACN/TFA/H O (5+4+1 v/v/v), rt, 15 min; (f) 3.0 eq palmitoyl chloride, 40 eq pyridine, CH
0 min; (h) 1.1 eq TBDMSCl, 1.7 eq imidazole, THF, rt, 16 h, THF; (i) 1.0 eq palmitic acid, 1.3 eq DIC, 0.97 eq DMAP, CH Cl , 0 °C ? rt, 21 h; (j) 1.1 eq TBAF, THF, 0 °C ? rt, 24 h;
2
SO
4
, MeOH, reflux, overnight; (b) 1.1 eq CBr
S; (d) 1.2 eq 1,2-isopropylidene-rac-glycerol, 1.5 eq
Cl , rt, 24 h; (g) 12 eq H , 0 °C ? rt,
4 3 2 2
, 1.1 eq PPh , CH Cl , 0 °C ? rt, 2 h; (c) 5.7 eq Na,
2
2
2
O
2
2
2
2
2
2
2
2 2
O
3
2
2
(
k) 1.2 eq 11, 1.0 eq 3, 1.5 eq DIC, 0.6 eq DMAP, CH
Cl
2 2
, 0 °C ? rt, 19 h; (l) 12 eq H
2
O
2
, THF, rt, 30 min. TBDMS: tert-butyl-dimethylsilyl.
1
,2-isopropylidene-rac-glycerol using DIC/DMAP, conditions origi-
migration has been reported when standard protocols were used
19
23
nally developed by Neises and Steglich to give isopropylidene
protected 6. Acetonide deprotection using ACN/TFA/H O (5+4+1
v/v/v) afforded 7, which was converted to compound 8 via two
consecutive acylation reactions using palmitoyl chloride/pyridine
in 79% yield. The transformation 7 ? 8 was also performed using
for TBDMS removal in diacyl glycerols. In order to avoid migra-
2
4–
2
tion, alternative procedures have been applied that omit TBAF.
2
8
Notably, acylation across oxirane- and silyloxy systems has been
described as a strategy to the synthesis of enantiomerically pure
2
9,30
31
mono-, di- and triglycerides.
In a recent report, Fodran et al.
palmitic acid/DIC/DMAP and gave 8 in a yield of 57% (45
l
M scale).
achieved the synthesis of enantiopure triacylglycerols in a simple
two-step, one-pot procedure starting from glycidyl esters. We
exploited acyl migration for the synthesis of 11 by using TBAF for
silyl deprotection in 10, and could isolate 11 in a yield of 62%. Prata
A sulfur-oxygen exchange14 was successful when 8 was treated
2 2
with H O
to give desired AsTAG 1. Both 1H-NMR and C-NMR
show a clear upfield shift of the methyl groups of Me
13
2
As(O),
3
2
compared to Me As(S), which is in accordance with the
2
et al. synthesized the regioisomer 1,2-di-hexadecanoyl-rac-glyc-
erol via a TBAF-mediated desilylation when TBDPS was used as a
protecting group rather than TBDMS. The coupling of 11 with
arsenic-containing fatty acid 3 was successful and gave late inter-
mediate 12 in a yield of 65%. Theoretically, a transesterification
could occur in the transformations 7 ? 8 and 11 ? 12, which
would not be specifiable by MS or NMR. Transformation of As = S
2
0,21
literature.
nd
2
Strategy: AsTAG 2 was synthesized starting from 1,3-diacyl-
glycerol 11. Although 11 is commercially available, we decided to
synthesise this compound because the intermediate was
9
expected to be of use for the preparation of alternative AsTAGs,
and we could already demonstrate that an esterification of sec-
ondary alcohol in 9 using AsFA 3 is straightforward using DIC/
DMAP (see Supplementary Data, compound 13).
1
13
2 2
to As = O using H O gave 2 in 50% yield. H-NMR and C-NMR
spectra of 1 and 2 are nearly identical, which was expected because
of structural similarity.
We were able to synthesise the previously unknown AsTAGs
3-((15-(dimethylarsinoyl)pentadecanoyl)oxy)propane-1,2-diyl di-
palmitate 1 and 2-((15-(dimethylarsinoyl)pentadecanoyl)oxy)pro-
pane-1,3-diyl dipalmitate 2 via two different strategies, which
Thus, following a literature procedure22 we started with a selec-
tive protection of the primary alcohol in rac-1-palmitoylglycerol to
give the known silyl ether 9 in a yield of 82%. Introduction of the
second palmitoyl chain was achieved using palmitic acid/DIC/
DMAP and diacyl glycerol 10 could be obtained in 94% yield. Acyl