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its MPM ether, and desilylation afforded alcohol 22. Iodina-
tion under standard conditions then furnished iodide 8 in
76% yield.
Assembly of the advanced fragments (namely, 6 and 8)
and construction of the 2,4,6-trisubstituted tetrahydropyran
substructure are illustrated in Scheme 5. Lithiation of 8 with
Scheme 3. Reagents and conditions: a) (+)-Ipc2BOMe, allylMgBr,
Et2O, À788C; then aqueous NaOH, H2O2, RT, 98%; b) MPMOC-
(=NH)CCl3, La(OTf)3, toluene, RT; c) methyl acrylate, Grubbs II cata-
lyst (3 mol%), CH2Cl2, 408C, 58% (over 2 steps); d) DIBALH, CH2Cl2,
À788C, 80%; e) (À)-DET, Ti(OiPr)4, tBuOOH, 4 M.S., CH2Cl2,
À208C, 97%; f) I2, PPh3, imidazole, THF, RT; g) Zn, AcOH, EtOH, RT,
75% (over 2 steps); h) BOMCl, iPr2NEt, CH2Cl2, RT; i) DDQ, CH2Cl2/
pH 7 buffer, RT, 72% (over 2 steps); j) Ac2O, Et3N, DMAP, THF, RT,
99%; k) KHMDS, (PhO)2P(O)Cl, THF/HMPA (1:1), À788C.
DDQ=2,3-dichloro-5,6-dicyanobenzoquinone; DET=diethyl tartrate;
DIBALH=diisobutylaluminum hydride; DMAP=4-dimethylaminopyri-
dine; HMDS=hexamethyldisilazane; HMPA=hexamethylphosphor-
amide; Ipc=isopinocampheyl; M.S.=molecular sieves; Tf=trifluoro-
methanesulfonyl.
allylic alcohol 14 by an iodination/reductive ring-opening
sequence. Protection of 14 (BOMCl, iPr2NEt), oxidative
cleavage of the MPM ether, and subsequent acetylation gave
acetate 15 in good overall yield. Enolization of 15 with
KHMDS in the presence of (PhO)2P(O)Cl furnished enol
phosphate 6.
The synthesis of iodide 8 commenced with the known
nitrile 16[15] (Scheme 4). DIBALH reduction of 16 (94%),
followed by asymmetric allylation[13] of the derived aldehyde
17, afforded alcohol 18 in 87% yield as a single diastereomer.
Methylation of 18 gave methyl ether 19. Ozonolysis of the
double bond delivered aldehyde 20 (85%), which was
subsequently subjected to asymmetric allylation[13] to provide
alcohol 21 in 96% yield as a single diastereomer. Hydro-
genation of 21, protection of the remaining hydroxy group as
Scheme 5. Reagents and conditions: a) 8, B-MeO-9-BBN, tBuLi, Et2O/
THF (1:1), À788C to RT; then 3m aqueous Cs2CO3, [Pd(PPh3)4]
(10 mol%), 6 (1.5 equiv), DMF, RT; b) Grubbs II catalyst (10 mol%),
toluene (5 mm), 708C, 78% (over 2 steps); c) H2 (0.8 MPa), Pd/C,
EtOAc/MeOH (1:1), RT, 81%. B-MeO-9-BBN=B-methoxy-9-
borabicyclo[3.3.l]nonane; DMF=N,N-dimethylformamide. NOEs used
to establish the stereochemistry of the tetrahydropyran moiety are
indicated in the structure next to compound 5.
tBuLi in the presence of B-MeO-9-BBN generated the
alkylborate 7, which was reacted in situwith enol phosphate
6 using aqueous Cs2CO3 as a base and [Pd(PPh3)4]as a catalyst
in DMF at room temperature to give acyclic enol ether 23.
The intermolecular Suzuki–Miyaura coupling of 6 and 7
predominated over the possible intramolecular Heck cycliza-
tion of 6. Subsequent RCM of 23 using the second-generation
Grubbs catalyst in toluene (5 mm) furnished the endocyclic
enol ether 24 in 78% overall yield from 8. It was imperative to
carry out the cross-coupling process at room temperature,
since enol phosphate 6 was found to be rather labile under
alkaline conditions. Stereoselective hydrogenation of 24
cleanly afforded tetrahydropyran 5 in 81% yield as a single
stereoisomer. The stereochemistry of the tetrahydropyran
moiety was established by NOE experiments as shown in
Scheme 5. Since we could not prepare the lactone-derived
enol phosphate 26 nor its triflate counterpart 27 from lactone
25,[16] the present Suzuki–Miyaura coupling/RCM sequence
would represent an efficient strategy for the synthesis of 2,4,6-
trisubstituted tetrahydropyrans.
Scheme 4. Reagents and conditions: a) DIBALH, CH2Cl2, À788C, 94%;
b) (+)-Ipc2BOMe, allylMgBr, Et2O, À788C; then aqueous NaOH,
H2O2, RT, 87%; c) MeOTf, 2,6-di-tert-butylpyridine, CH2Cl2, RT, 88%;
d) O3, CH2Cl2, À788C; then PPh3, RT, 85%; e) (À)-Ipc2BOMe,
allylMgBr, Et2O, À788C; then aqueous NaOH, H2O2, RT, 96%; f) H2,
=
Pd/C, EtOAc, RT, 100%; g) MPMOC( NH)CCl3, La(OTf)3, toluene, RT,
Completion of the total synthesis of 2 is depicted in
Scheme 6. Removal of the TIPS group from 5 gave alcohol 28.
A two-stage oxidation of 28 and ensuing esterification
75%; h) TBAF, THF, 508C, 87%; i) I2, PPh3, imidazole, THF, RT, 76%.
PG=protecting group; TBAF=tetra-n-butylammonium fluoride;
TBDPS=tert-butyldiphenylsilyl.
4738
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 4737 –4739