Angewandte
Chemie
Scheme 4. A) Synthesis of fragment C (21) and B) completion of
preparation of 11. Reagents and conditions: a) Bu3SnH, AIBN, ben-
zene, reflux, 50%; b) MnO2, acetone, RT, 85%; c) EtO2CCH2P(O)-
(OEt)2, NaH, THF, 08C to RT, 74%; d) KHMDS, THF, ꢀ788C, 82%;
e) 21, [Pd2(dba)3], Ph3As, DMF, RT, 70%; f) PPTS, EtOH, 08C;
g) LiOH, THF, CH3OH, H2O, reflux, 2 steps 62%; h) 2,4,6-
Cl3C6H3COCl, Et3N, THF; DMAP, toluene, RT, 75%; o) HF·pyr, EtOH,
48C, 4 days, 64%. AIBN=azobisisobutyronitrile, KHMDS=potassium
bis(trimethylsilyl)amide, dba=dibenzylideneacetone, PPTS=pyridi-
nium p-toluenesulfonate, DMAP=4-dimethylaminopyridine.
Scheme 3. Synthesis of A) fragment A (19) and B) fragment B (20).
Reagents and conditions: a) (ꢀ)-DBNP, Et2Zn, hexanes, 08C, 66%,
92% ee; b) TESOTf, 2,6-lutidine, CH2Cl2, ꢀ788C; c) iBu2AlH, toluene,
ꢀ788C, 2 steps 78%; d) TiCl4, (ꢀ)-sparteine, CH2Cl2, 08C, 84%;
e) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C; f) LiBH4, Et2O, CH3OH, 08C, 2
steps 75%; g) TPAP, NMO, 4 ꢀ M.S., CH2Cl2, RT; h) (+)-Ipc2B(allyl),
Et2O, ꢀ788C, 2 steps 60%; i) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C,
87%; j) OsO4, NMO, THF, acetone, pH 7 buffer, RT; k) NaIO4, THF,
pH 7 buffer, RT; l) NaBH4, EtOH, RT, 3 steps 67%; m) PTSH, PPh3,
DIAD, THF, RT, 86%; n) (NH4)6Mo7O24, H2O2, EtOH, H2O, 48C;
o) TESOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 2 steps 91%; p) 1,3-dithiane,
nBuLi, THF, 08C, 94%; q) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 95%;
r) MeI, CaCO3, CH3CN, H2O, reflux, quantitative; s) (+)-Ipc2B(allyl),
THF, ꢀ788C; t) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 2 steps 67%;
u) OsO4, NaIO4, 2,6-lutidine, dioxane, H2O, RT, 83%; v) CrCl2, HCI3,
dioxane, THF, RT, 87%; w) DDQ, aq. CH2Cl2, RT; x) Dess–Martin
periodinane, CH2Cl2, RT, 2 steps 83%. OTf=trifluoromethane-
sulfonate, TPAP=tetrapropylammonium perruthenate, NMO=N-
methylmorpholine-N-oxide, Ipc=isopinocampheyl, PTSH=1-phenyl-
tetrazole-5-thiol, DIAD=diisopropyl azodicarboxylate, DDQ=2,3-
dichloro-5,6-dicyano-1,4-benzoquinone.
radical to propargyl alcohol (38) afforded (E)-vinylstannane
39. Oxidation of the hydroxyl group followed by Horner–
Wadsworth–Emmons olefination of the resulting aldehyde
furnished dienoate 21 in excellent overall yield. With all
fragments in hand, a Julia–Kocienski olefination connecting
19 and 20 was achieved using KHMDS at ꢀ788C to give the
desired product 40 with E selectivity in 82% yield (Scheme
4B). Then, a palladium-catalyzed Stille coupling between 40
and fragment C (21) effectively generated the linear ketide
18. The final steps to complete the synthesis of 11 involved
chemoselective deprotection of the TES group at C-21,
hydrolysis of the ethyl ester moiety to afford seco-acid 41,
and lactonization under Yamaguchi conditions to give macro-
lactone 42.[36] The finishing global deprotection of 42 proved
to be more challenging and partial deprotection or decom-
position was encountered under various conditions. We were
pleased to find that treatment of 42 with HF·pyridine in
ethanol at 48C for roughly 4 days eventually led to successful
production of 11 in satisfactory yield (64%).
In the second phase of our synthesis, we opted to take
advantage of our knowledge regarding spinosyn biosynthesis
and the availability of all post-PKS tailoring enzymes, and
apply a series of enzymatic transformations in one pot to
convert macrolactone 11 to 17-pseudoaglycone (17). As
shown in Figure 1A, the genes responsible for post-PKS
modifications in the spinosyn pathway are translationally
controlled by at least four operons (operons I–IV).[13] In our
poration of the terminal vinyl iodide group began with TBS
protection of 35 followed by oxidative cleavage of the
terminal olefin by Jinꢀs procedure.[34] The resulting aldehyde
36 was subjected to Takai iodoolefination[35] providing 37 with
> 9:1 E/Z stereoselectivity. Subsequent oxidative removal of
the PMB ether followed by Dess–Martin oxidation completed
the synthesis of fragment B (20).
Preparation of fragment C (21) was straightforward as
shown in Scheme 4A. Regioselective addition of tributytin
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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