Scheme 3. Formal synthesis of 1a and 1b via alkene 13. a) H2, Lindlar
catalyst, quinoline, benzene, RT, 100%; b) BnBr, Ag2O, toluene, RT!
408C, 62% (98% based on recovered starting material (borsm)).
Scheme 2. Conversion of the heterobicyclic building block 4 to alkyne 11.
a) H2, 10% Pd/C, HOAc (1 equiv), EtOAc, RT, 98%; b) DMSO,
semi-hydrogenation of 11 proceeded smoothly, and after
chemoselective benzylation of the secondary alcohol of the
resulting diol 12, the advanced intermediate 13 was isolated
which was identical to the reference compound in all re-
spects.[12]
ꢀ ꢂ ꢀ
(COCl)2, Et3N, CH2Cl2, ꢀ788C!ꢀ108C; c) Cl2Ce C C TBS, THF,
ꢀ788C, 87% (2 steps); d) Cl(PhO)C=S, DMAP, CH2Cl2, 08C!RT, 97 %;
G
e) Bu3SnH, AIBN, benzene, reflux, 95%; f) Bu4NF, HOAc, THF, 08C!
RT, 98 %; g) K2CO3, MeOH, 168C, 73% 10 (+17% monomethyl ester);
h) (Boc)2O, Et3N, 4-pyrrolidinopyridine, CH2Cl2, ꢀ38C, 89%. Bn=
benzyl, Bz=benzoyl, TBS=tert-butyldimethylsilyl, DMAP=4-(N,N-di-
methylamino)pyridine, AIBN=azobisisobutyronitrile, Boc=tert-butoxy-
carbonyl.
For the synthesis of 1c, the secondary alcohol of 11 was
esterified with octanoyl chloride to give intermediate 3
(Scheme 4). Addition of this polyfunctional alkyne 3 to the
known aldehyde 14,[13] without partial racemization of the
latter, was accomplished via the zinc derivative of 3, which
was generated under mild conditions with diethylzinc in the
presence of (ꢀ)-N-methylephedrine.[14] The diastereomeric
mixture of 2 and 4’-epi-2 (1:2) obtained in this way was uni-
fied by Dess–Martin periodinane oxidation followed by an
asymmetric transfer hydrogenation of the resultant alkynone
with the ruthenium catalyst 15 and isopropanol as the hy-
dride source[15] to afford 2 with excellent stereoselectivity
(diastereomeric ratio (d.r.)ꢁ20:1). The challenging chemo-
selective complete alkyne reduction of the propargyl alcohol
moiety in the presence of the styrene unit (as part of a bish-
omoallylic alcohol) was cleanly achieved by a hydroxyl-di-
rected hydrogenation of 2 with ruthenium catalyst 16.[16,17]
the stage for a smooth radical deoxygenation with tributyltin
hydride[11] to afford 8. Sequential removal of the tert-butyldi-
methylsilyl (TBS) unit to give 9 and cleavage of both benzo-
yl protecting groups by transesterification gave the desired
triol 10 and a small amount of a corresponding monomethyl
ester. As anticipated,[5b] a highly selective protection of the
C7 hydroxyl group of the tri-tert-butyl ester 10 gave the Boc
derivative 11.
At this stage we accomplished a formal synthesis of 1a
and 1b through transformation of alkyne diol 11 to alkene
13, which had already been converted to the two natural
products 1a and 1b by Hashimoto (Scheme 3).[4f] Lindlar
ꢀ
Scheme 4. Completion of the synthesis of 1c. a) C7H15 COCl, DMAP, CH2Cl2, 08C!RT, 97 %; b) i) Et2Zn, (ꢀ)-N-methylephedrine (15 mol%), toluene,
08C, ii) 14, 08C!RT, 51% (85% borsm); c) Dess–Martin periodinane, CH2Cl2, RT; d) 15 (5 mol%), iPrOH, RT, 86% (2 steps); e) 55 bar H2, [Ru{(S)-
binap}ACHTUNGTRENNUNG(OAc)2] (16, 2 mol%), MeOH, RT, 75% 17 (+24% diene); f) Ac2O, DMAP, CH2Cl2, 08C, 99%; g) TFA, CH2Cl2, reflux, 100%. binap=2,2’-bis(di-
phenylphosphino)-1,1’-binaphthyl, TFA=trifluoroacetic acid.
3336
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3335 – 3337