Communications
Initial attempts to perform the PKR with 5 gave, however,
compound 13 gave the desired compound 14 in 57% yield
under conventional PKR conditions.[11] NOE experiments
showed that C7 in 14 had the desired stereochemistry
(Scheme 3). Next, we optimized the reaction conditions to
develop the one-pot operation to transform 5 into 4. First, we
prepared the silyl-tethered compound 13, to which
[Co2(CO)8] was added, thus affording the alkyne cobalt
complex of 13. Then, we diluted the reaction mixture with
toluene and heated it under CO atmosphere to give the
bicyclic compound 14, which in turn was directly treated with
concentrated hydrochloric acid in MeOH to give the desily-
lated compound 4 in 92% yield from 5. To the best of our
knowledge, this is a first example of a stereoselective PKR
that utilizes a seven-membered silyl-tethered compound.
With the PKR product 4 in hand, we next focused on the
construction of the quaternary carbon center C12 (Scheme 4).
MOM groups were introduced to the two hydroxy groups in 4
and then the enone was reduced with the (R)-Me-CBS
reagent[12] to furnish allyl alcohol 15 with good stereoselec-
tivity. The stereochemistry at C5 was determined by NOE
experiments, and at this point, the enantiomeric excess of 15
was determined by HPLC analysis to be 99% ee.[13]
After conversion of 15 into sulfoxide 16,[14] 16 was heated
at 1708C in 1,2-dichlorobenzene to afford the desired
aldehyde 17 in excellent yield. Treatment of aldehyde 17
with the Wittig reagent gave the diene compound 18.
Our next task was the construction of an azonane ring
using the intramolecular Mitsunobu reaction (Scheme 5). We
prepared substrate 19 for the Mitsunobu reaction from diene
18 by using a sequential reaction that involved a simultaneous
hydroboration/oxidation[15] at two positions (C4–C5 and C9–
C10), the introduction of a nitrogen functional group to C9,
and the subsequent removal of a TBDPS group. With the Ns-
protected derivative 19 in hand, we
12, the undesired C7 epimer as the major product. Mecha-
nistic considerations indicated that a reaction intermediate
such as 5i would have a chairlike conformation with an
equatorial side chain at C15, and therefore control the
stereochemistry at C7. On this basis, we devised the silyl-
tethered compound 13, which would alter the conformation of
the reaction intermediate to yield a bicyclic product having
the desired C7 stereochemistry. Actually, the silyl-tethered
Scheme 2. Synthesis of the chiral diol 5. Reagents and conditions:
a) nBuLi, ZnCl2, THF, À788C, 91%; b) [Ru{(R,R)-Tsdpen}(p-cymene)],
iPrOH, 288C and then PPTS, toluene, 808C, 68%; c) Allylbromide,
LHMDS, HMPA, THF, À788C, quant, 10/11=2.3:1; d) LHMDS, THF,
À788C and then BHT, 86%, 10/11=1:16.5; e) LiBH4, THF, RT, 95%.
BHT=2,6-di-tbutylated-hydroxytoluene, dpen=1,2-diphenylethylenedi-
amine, HMPA=hexamethylphosphoramide, LHMDS=lithium bis(tri-
methylsilyl)amide, PPTS=pyridinium p-toluenesulfonate, THF=tetra-
hydrofuran.
tried to construct the azonane ring.
After several screening steps, we
found that the treatment of 19 with
diethyl azodicarboxylate (DEAD) in
the presence of PPh3 in toluene at
708C afforded 20 in excellent
yield.[4e,16] At this stage, the X-ray
crystallographic analysis of 20 was
performed, and enabled us to confirm
the absolute configuration of all the
chiral centers.[17]
For the completion of the total
synthesis of 1, we converted 20 into
the fawcettimine derivative 2 as fol-
lows (Scheme 6). The removal of the
two MOM groups with trimethylsilyl
bromide gave the corresponding diol
21 in quantitative yield.[18] Then, the
selective acetylation of the primary
alcohol[19] at C16 and the subsequent
Dess–Martin oxidation of the secon-
Scheme 3. Stereoselective synthesis of bicyclic compounds 12 or 14 and one-pot operation to give
4. Reagents and conditions: a) [Co2(CO)8] toluene, RT to 1008C under CO atmosphere, 44% of 12
and 3% of 4; b) SiMe2Cl2, Et3N, DMAP, CH2Cl2, RT, 85%; c) [Co2(CO)8], toluene, RT to 1008C
under CO atmosphere, 57%; d) 1. SiMe2Cl2, Et3N, DMAP, (CH2Cl)2, RT, 2. [Co2(CO)8], toluene, RT
dary alcohol at C13 were carried out
in a one-pot operation to afford 22.
The successive removal of the Ns
to 1008C under CO atmosphere, 3. HCl, MeOH, 08C, 92%. DMAP=N,N-4-dimethylaminopyridine. group and diacetyl groups was also
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8025 –8028