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Scheme 6. a) 1. 10, tBuLi, Et2O, À788C, then B-OMe-9-borabicyclo[3.3.1]nonane (B-OMe-9-BBN), THF, À788C to RT; ii: 9, K3PO4, 5 mol%
[PdCl2(dppf)]·CH2Cl2, DMF, RT, 79%; dppf=1,1’-bis(diphenylphosphanyl)ferrocene; b) p-NO2BzCl, CH2Cl2, pyridine, 08C, 97%; c) tetrabutylammo-
nium tribromide (TBABr3), MeOH, RT, 97%; d) 2 mol% 17, H2 (90 bar), CH2Cl2, RT, 98%; e) TBSCl, imidazole, 4-dimethylaminopyridine (DMAP),
CH2Cl2, RT, 99%; f) MeOH, K2CO3, 608C, 94%; g) TBDPSOTf, 2,6-lutidine, CH2Cl2, 08C, 98%; h) TBABr3, MeOH/THF, RT, 99%; i) PPh3,
imidazole, I2, Et2O/CH3CN, RT, 99%; j) 1. tBuLi, Et2O, À788C, then B-OMe-9-BBN, THF, À788C to RT; 2. 8, K3PO4, 5 mol% [PdCl2(dppf)]·CH2Cl2,
DMF, RT, 85%; k) TBAF, THF, RT, 94%; l) 2.5 mol% 21, H2 (60 bar), CH2Cl2, RT, 99%; m) NaHCO3, KBr, NaOCl, 2,2,6,6-tetramethylpiperidin-N-
oxyl (TEMPO) (5 mol%), CH2Cl2, 08C, 93%; n) tBuOH/H2O/isoprene, NaClO2, NaH2PO4, RT, 88%.
instantly succeeded with the Crabtree catalyst (as BArFÀ salt)
with a diastereoselectivity of 95:5 in favor of the syn isomer of
18. We then turned to the further optimized iridium catalyst
oxidation furnished hydroxyphthioceranic acid (3) in 82%
yield. Thus, the natural product was produced in 23 steps
along the longest linear route and 25% overall yield (starting
with the N-acylated Evans auxilary) and on a practical half-
gram-scale.
([Ir(cod)(SIMes)(Pyr)]+PF6 ) (17; cod = cyclooctadiene,
À
SIMes = 1,3-dimesitylimidazolin-2-ylidene)[18] carrying an N-
heterocyclic carbene (NHC) ligand instead of the PCy3 ligand.
With this catalyst the diastereoselectivity increased to 98:2
syn/anti and the catalyst loading required for full conversion
could be lowered to 2 mol%. The relative configuration of 18
was determined by two-dimensional NMR spectroscopy
according to the method of Breit et al. (see the Supporting
Information).[19]
In order to facilitate the second Suzuki–Miyaura cross-
coupling the base-sensitive p-nitrobenzoyl group was
exchanged for a TBDPS group in 19 which was further
converted into iodide 7. Under the same conditions, which
had been proven successfully above, the sp2–sp3 cross-
coupling of alkyl iodide 7 and vinyl iodide 8 delivered the
product in 85% yield. Once again, an excess of one of the
substrates was not necessary and after cleavage of the silyl
ether, alkene 20 was obtained in very good yield and as
a single stereoisomer.
In order to establish the last stereogenic center in the
carbon backbone of the natural product, the trisubstituted
alkene 20 needed to be hydrogenated with full stereochemical
control. For this purpose we intended to use our experience in
the enantioselective hydrogenations of unfunctionalized,
trisubstituted alkenes with chiral iridium pyridyl phosphinite
complexes.[20,21] In the event, alkene 20 was hydrogenated
with the assistance of the chiral iridium complex 21
(2.5 mol%) to afford the all-syn-configured alkane 22 with
complete diastereoselectivity and excellent yield in direct
analogy to g-tocotrienyl acetate.[21] Again, the relative con-
figuration of 22 was assigned with the method of Breit[19] and
was in agreement with the observed asymmetric induction in
hydrogenations of structurally similar, trisubstituted alke-
nes.[20b–d] Final oxidation of hydroxyphthioceranol (22) in
a two-step process consisting of TEMPO and Pinnick
For the synthesis of phthioceranic acid (4) we pursued
a slightly modified strategy because this natural product has
both one hydroxy group and one deoxypropionate unit less
than 3. At the same time we intended to demonstrate the
flexibility of our strategy. The key step for the assembly of the
polydeoxypropionate backbone of 4 should be the sp2–sp3
Suzuki–Miyaura cross-coupling of building blocks 23 and 24
with subsequent hydrogenation, reactions that had served so
well in the synthesis of hydroxyphthioceranic acid
(Scheme 7). The terminal vinyl iodide 24 is identical to
building block 8 used in the synthesis of 3 except for the
MOM group. Alkyl iodide 23 differs from the coupling
partner 10 employed in the previous synthesis in terms of the
exchanged functional groups at the termini. This was done
since it seemed easier now to first join building blocks 23 and
24 and complete the polydeoxypropionate fragment of the
natural product before attaching the long, lipophilic alkyl
chain in a copper-catalyzed Grignard reaction.
Owing to the bifunctional character of trideoxypropionate
6 as starting material this strategic change posed no problems
and the envisioned synthesis worked smoothly. Both building
blocks 23 and 24 were synthesized in very good overall yields
Scheme 7. Strategy for the convergent synthesis of phthioceranic acid
(4). MOM=methoxymethyl.
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 8968 –8972