Only the more stable epimers are shown as the energy differences
were calculated to be >16 kJ molꢀ1
.
It is known that the formation of zirconacyclopentanes is
reversible and heating is sometimes needed to form the
thermodynamically more stable product.13 Zirconium induced
co-cyclisation of triene 6 was monitored by quenching aliquots
to give the protonated compounds 14, which were assayed by
GC. After 1.25 h at room temperature we observed a
26 : 68 : 4 : 2 ratio, in order of GC retention times, of isomers
formed with around 34% of 6 uncyclised, whereas after
heating for 0.5 h at 65 1C the cyclisation was complete and
the corresponding isomer ratio was 63 : 24 : 11 : 2. Further
heating did not change the ratio significantly and additional
products started to form. In order to identify if the kinetic or
thermodynamic isomer was needed for mucosin we further
elaborated the zirconacycles formed under each condition
by insertion of 1-lithio-1-chloro-2-propene. The insertion
occurred exclusively into the unsubstituted C–Zr bond to
afford 15, followed by the BF3ꢁEt2O promoted addition of
benzaldehyde to give the alcohols 16.14 Chromatography gave
samples of 16 comprising 3.1 : 1 and 1 : 1.5 of major diastereo-
isomers (ignoring the hydroxyl stereochemistry) from the
thermodynamic and kinetic conditions, respectively. By
comparing the spectral data of the obtained alcohols 16 with
those of mucosin 1, we were able to establish that the major
product obtained under thermodynamic conditions was 16a
derived from zirconacycle 7a with the desired stereochemistry.
We speculate, but have not proven, that the major isomer
under kinetic conditions is the zirconacycle 7b.
Scheme 2 Synthesis of triene 6. Reagents and Conditions: (a) MeOH,
quinidine, PhMe, ꢀ55 1C, 8 h, then ꢀ18 1C, 3 days then 2.0 M HCl;
(b) Li(Et)3BH, THF, 0 1C, 1 h then rt, 15 h then 2.0 M HCl;
(c) DIBAL-H (fast addition), PhMe, ꢀ78 1C, 1 h, then 3.0 M HCl;
(d) MePh3P+Brꢀ, n-BuLi, THF, 0 1C - rt, 2 h, then 1.0 M HCl;
(e) MsCl, Et3N, DMAP, THF, 0 1C, 2 h; (f) KCN, NaI, 18-crown-6,
90 1C, 66 h; (g) DIBAL-H (dropwise addition), THF, ꢀ78 1C - rt,
2 h, then MeOH, aq NaHCO3; (h) BuPh3P+Brꢀ, n-BuLi, THF,
0 1C - rt, 2 h, then 1.0 M HCl.
With reasonable conditions for predominant formation of
the correct stereoisomer we examined introduction of the
carboxy containing side chain. We have previously shown that
allyl-zirconacycles similar to 15 react with the diethylacetal of
acrolein to afford around 20% of the 1,4-addition product.15
However, despite extensive investigation of different acrylate
equivalents and conditions on model systems we were unable
to achieve good yields of selective 1,4-addition.
An alternative stepwise approach was developed to complete the
total synthesis. Insertion of the silyl carbenoid 1716 into zircona-
cycle mixture 7 formed under thermodynamic conditions gave the
zirconacyclohexane 18. Subsequent protonation and the Woerpel
modification of the Fleming–Tamao oxidation17 yielded alcohol 19
as a 2.7 : 1 mixture of diastereoisomers in 75% overall yield
from triene 6. The pure desired diasteroisomer 19a could be
seperated by HPLC. Removal of the minor diastereoisomer was
also achieved by refluxing the mixture with iodine in benzene
then purification by normal chromatography. We assume that
the unwanted diastereoisomer was removed via iodoetherifica-
tion although such a product was not isolated. Unfortunately
the pure alcohol 19a was only recovered in 39% yield. Despite
the low recovery this method provided further evidence for the
relative stereochemistry of the major diastereoisomer given
that alcohol 19a cannot undergo iodoetherification, and some
evidence that the minor isomer is 19b which can.
Scheme 3 Zirconocene induced co-cyclisation of 6 and synthesis of
alcohols 16.
relative stereochemistry at centres b and c.4 The effect of the
stereocentre at a, and indeed of the fused 6-member ring was
harder to predict.10 Energies from Density Function Theory
calculations have been shown to be useful in predicting the
relative stability of zirconacycles.11 The four most stable
zirconacycle structures 7a–d, which should form from 6 are
shown in Scheme 3 with their calculated relative energies and
indicate that the desired isomer 7a is favoured. There are four
additional stereoisomers differing in the configuration of the propyl-
substituent, but we have shown in other systems that this centre is
independent of the stereochemistry of the starting alkene due to
rapid epimerisation via exocyclic b-hydride elimination/readdition.12
Oxidation of the alcohol 19a to aldehyde 20 followed by
Takai olefination18 with diiodide 21 and removal of the silicon
protecting group with TBAF gave the alcohol 23 in 81% overall
yield. Finally alcohol 23 was oxidised to mucosin 1 in 84% yield
using PDC in DMF (Scheme 4).19 Conversion of acid 1 to its
c
3410 Chem. Commun., 2012, 48, 3409–3411
This journal is The Royal Society of Chemistry 2012