Communications
glycol cleavage using sodium periodate.[11] In contrast, trans-
subsequent TPAP oxidation[27] (Scheme 4). An a hydroxy-
lation with MoOPH,[28] basic hydrolysis of the functionalized
lactone, and subsequent reduction[29] gave a triol; the
tetracyclic compound 16 was revealed after oxidative cleav-
forming 6 into 8 required an additional 1,2-carbonyl shift,[12]
which was achieved in six steps with a good overall yield of
57%. An initial aldol condensation of 6 with benzaldehyde
(tBuOK, tBuOH, reflux)[13] caused a partial epimerization a
to the carbonyl group, which was avoided by using a sequence
consisting of a kinetically controlled deprotonation,[14] an
aldol reaction with benzaldehyde, and subsequent elimina-
tion.[15] Removal of the keto functionality from the molecule
was accomplished by reduction[16] to give the allyl alcohol 9,
esterification to provide the corresponding carbonate 10,[17]
and palladium-catalyzed reduction of 10 using triethylamine
and formic acid to yield 11.[18] A double osmium tetroxide
catalyzed dihydroxylation and subsequent glycol cleavage
delivered diketone 8.[19]
An intramolecular aldol condensation of 8 under basic
reaction conditions effected ring closure to give the bicyclic
product (Scheme 3).[20] Annelation of the five-membered ring
was accomplished by a short sequence including a diastereo-
selective allylation[21] to provide 12, a Wacker oxidation under
Scheme 4. Completion of the synthesis of 2. a) TsOH, THF, H2O, RT,
80%; b) 3 mol% TPAP, NMO, MS 4 ꢁ, CH2Cl2, RT, 100%;
c) 1. LiHMDS, THF, ꢀ788C, 2. MoOPH, ꢀ788C, 85%; d) 1. 50% aq.
KOH, THF, RT, 2. LiAlH4, THF, reflux, 89%; e) NaIO4, THF, H2O, RT,
98%; f) Me4NBH(OAc)3, HOAc, MeCN, THF, ꢀ208C, 68%;
g) MOMCl, iPr2NEt, TBAI, CH2Cl2, 08C!RT, 57% 18, 27% 19; h) 6n
HCl, THF, 508C, 81%; i) 1. BuLi, THF, 08C, 2. CS2, 08C, 3. MeI, 08C,
84%; j) Bu3SnH, AIBN, toluene, reflux, 80%; k) 6n HCl, THF, 508C,
91%. TsOH=p-toluenesulfonic acid, TPAP=tetrapropylammonium
perruthenate, NMO=N-methylmorpholine N-oxide, MS=molecular
sieves, MoOPH=MoO5·pyridine·HMPA, MOMCl=methoxymethyl
chloride, AIBN=2,2’-azobis(isobutyronitrile).
Scheme 3. Construction of enol ether 4. a) tBuOK, tBuOH, THF, 658C,
81%; b) 1. LiHMDS, THF, 08C, 2. allyl iodide, 08C, 84%; c) 5 mol%
PdCl2, p-benzoquinone, DMA, H2O, 358C, 85%, d) tBuOK, tBuOH,
THF, microwaves (150 W), 408C, 10 min, 64%; e) LiAlH4, Et2O, ꢀ78!
08C, 100%; f) propargyl bromide, 20 mol% TBAI, 50% aq. KOH,
toluene, RT, 91%; g) tBuOK, tBuOH, THF, microwave (300 W), 1508C,
15 min, 83%. DMA=N,N-dimethylacetamide, TBAI=tetrabutylammo-
nium iodide.
age of the 1,2-diol unit. A hydroxy-directed 1,3-anti reduc-
tion[30] afforded diol 17 with high diastereoselectivity; the
structure was proven unequivocally by X-ray diffraction
analysis.[24] Transformation of 17 into the desmethylripper-
tene 2 required removal of the hydroxy group at C5. To this
end, the 3a-OH group was first protected as the methoxy-
methyl ether[31] (18), but a significant quantity of the doubly
protected diol 19 was always obtained. However, the protect-
ing groups of 19 could be removed to give 17 in good yield.[32]
To remove the free 5b-OH group in 18, it was converted into
the corresponding xanthogenate, which was subsequently
reduced using tributylstannane and AIBN.[33] The final
deprotection step to yield the desmethylrippertene 2 pro-
ceeded without any problems by using acidic cleavage of the
MOM protecting group.[31]
modified conditions,[22] and an additional aldol cyclization
under microwave irradiation to generate 13.[23] Dienone 13
contained four of the seven stereogenic centers needed for 1
and 2; the configuration was unambiguously confirmed by
X-ray diffraction analysis.[24] Construction of the tetracyclic
rippertene core was achieved by an efficient intramolecular
Diels–Alder reaction from the cyclization precursor 14, which
was made by the diastereoselective reduction of 13 and
subsequent etherification using propargyl bromide.[6] Com-
pound 14 then underwent isomerization under basic con-
ditions to give the corresponding allenyl ether, which then
cyclized under microwave irradiation to yield the enol ether 4
with complete diastereoselectivity.[25]
The cycloaddition strategy described herein led to the
enantioselective synthesis of 4-desmethyl-3a-hydroxy-15-rip-
pertene (2) in only 19 steps from cyclohexanone 5. Installa-
tion of the methyl group at C4, which is still missing for the
natural product 1, is the subject of ongoing work.
For completion of the norditerpene 2, enol ether 4 was
Received: September 21, 2008
Published online: January 7, 2009
first converted into the lactone 15 by hydration[26] and
1158
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 1157 –1159