Angewandte
Chemie
dichloride (5 mol%) afforded the dienes 20 in almost
identical yield (91–93%) fromeither epimeric alcohol.
Evidently, the reaction proceeds with very high, and perhaps
complete, selectivity among the double bonds.[8,26] Oxidation
to 21 was straightforward, and pure 1 ([a]D = 19.7; c = 0.28,
CHCl3) was then reached by removal of the silyl protecting
group on the aromatic ring with Bu4NF in CH2Cl2 (08C,
10 min); the cis stereochemistry at the ring fusion was not
compromised when this step was carried out under the
indicated conditions.
Our route to ottelione B was also based on aldehyde 18.
Treatment of the aldehyde with DBU at room temperature
afforded a mixture of the C3a isomers that was mainly the
desired trans compound 22 (> 10:1 trans/cis; Scheme 5).
Reaction of this mixture with vinylmagnesium bromide gave
the alcohols 23 (88%), epimeric only at C4. These tetraenes
underwent efficient and regioselective ring-closing metathesis
to give the desired alcohols 24. Once again, the synthesis was
completed by Dess–Martin oxidation and desilylation with
Bu4NF; the product 2 had an [a]D of ꢀ331.4 (c = 0.18, CHCl3).
We were unable to crystallize ottelione A, but did obtain
crystals of ottelione B that were suitable for X-ray analysis.
The X-ray data show that the six-membered ring is in a half-
chair conformation, and that the vinyl group is oriented in
such a way that the hydrogen atoms at the C1’ and C7a
Scheme 3. Reagents and conditions: a) LDA, THF, ꢀ788C, 1 h, 4-
methoxy-3-(tert-butyldimethylsiloxy)benzaldehyde (9), 91%; b) Et3SiH,
BF3·Et2O, CH2Cl2, 08C, 1 h, 87%; c) LiAlH4, THF, 08C , to RT, 4 h;
d) tBuCOCl, pyridine, THF, 08C, 1 h, RT, 30 min; e) DMP, CH2Cl2, RT,
1 h, 77% from 11; f) SmI2, MeOH, THF, 08C, 5 h, 82%; g) KHMDS,
THF, ꢀ788C, 1 h, Comins reagent, 2 h, 92%; h) Pd(OAc)2, Ph3P, Et3N,
MeOH, CO, DMF, 24 h, 77%; i) DIBAL, CH2Cl2, ꢀ788C, 1 h; j) DMP,
CH2Cl2, 45 min, 93% overall. DIBAL=diisobutylaluminum hydride,
DMF=N,N-dimethylformamide, DMP=Dess–Martin periodinane,
KHMDS=potassium 1,1,1,3,3,3-hexamethyldisilazide, LDA=lithium
diisopropylamide, Piv=pivaloyl, Tf=trifluoromethanesulfonyl.
ꢀ
positions are syn to each other, with both of the C H bonds
parallel. The dihedral angle between the carbonyl group and
ꢀ
the C3a H bond is around 1148.
cally less stable than the corresponding
cis isomers,[20] the product formed by the
present route was exclusively trans; attempts
to introduce the vinyl group by conjugate
addition to a cyclopentenone gave poor
stereoselectivity.
Scheme 4. [a] 60% yield of a mixture, >7:1 in favor of the indicated 3a,7a-cis stereochem-
istry. [b] Epimeric only at C4. Reagents and conditions: a) 1. 2-chloro-1,3-butadiene, Mg,
ZnCl2, THF/toluene, reflux, 1 h; 2. ꢀ788C, CuBr·SMe2, HMPA, Me3SiCl, 3. CF3CO2H, 08C;
b) vinylmagnesium bromide, THF, 08C, 45 min, 69%; c) 5 mol% Grubbs I cat., CH2Cl2,
The next task was to introduce a buta-
dienyl group at the C7a position, and in
preparation, ketone 14 was converted into
enol triflate 15 by quenching the derived
RT, 24 h, 91–93%; d) DMP, mixure of C4 epimers of 20, C HCl2, 1 h, 91%; e) Bu4NF,
2
kinetic enolate with the Comins reagent.[21] CH2Cl2, 08C, 10 min, 84%. HMPA=hexamethyl phosphoramide.
Carbonylation in the presence of MeOH[22]
then afforded ester 16, which was converted
into aldehyde 17 by reduction with DIBAL
and Dess–Martin oxidation. Aldehyde 17 is
an advanced key intermediate as it allows the
introduction of the butadienyl group as well
as divergence of the route to either ottelione.
Conjugate addition of a butadien-2-yl
Scheme 5. [a] >7:1 in favor of 3a,7a-cis stereochemistry. [b] >10:1 in favor of indicated
stereochemistry. [c] Epimeric only at C4. Reagents and conditions: a) DBU, CH2Cl2, RT,
36 h, 91%; b) vinylmagnesium bromide, THF, 08C, 1 h, 88%; c) 10 mol% Grubbs I cat.,
cuprate[23–25] to 17 occurred exclusively trans
to the vinyl group at the C1 position
(Scheme 4), and protonation of the resulting
enolate occurred mainly (> 7:1) fromthe face
opposite the C3 substituent to give aldehyde
18. This compound was used directly for
CH2Cl2, RT, 20 h, 86%; d) DMP, mixture of C4 epimers of 24, C HCl2, 1 h, 93%; e) Bu4NF,
2
CH2Cl2, 08C, 10 min, 87%.
reaction with vinylmagnesium bromide to form 19 (69%) as a
mixture of two alcohols, which were epimeric only at the C4
position. Ring-closing metathesis with the Grubbs I catalyst
Our synthetic route demonstrates a high degree of
selectivity between several double bonds in the ring-closing
metathesis and the ability of a cyclopropane ring to first exert
a steric effect and then to provide a vinyl substituent. The
bis(tricyclohexylphosphine)benzylidene
ruthenium(IV)
Angew. Chem. Int. Ed. 2007, 46, 3738 –3740
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3739