Chemistry Reference
In-Depth Information
the isolated yields were 56 and 60-65% respectively. Since higher dilution in
DCE did not have a substantial effect on the yield, it was decided to in-
vestigate alternative and greener solvents. Thus, at 2.4 mM in MTBE at re-
flux, slower reaction kinetics were observed, most likely due to the lower
boiling point of this solvent. However, in EtOAc at 5.0 mM, 114 was pro-
duced in 63% yield, and at 2.6-3.0 mM, the isolated yield increased to 69-
74%. In the plant, the RCM step was performed in 500 mL of EtOAc per gram
of diene (2.4 mM) with 3.3 mol% Zhan catalyst-1B (added in two portions) at
reflux with continuous nitrogen gas degassing to displace ethylene gas. After
3 h, charcoal was added to deactivate the catalyst and the mixture was stirred
at 65-68 1C for 30 min. The reaction mixture was cooled to 20-25 1C, filtered
and concentrated. The residue was chromatographed on silica and the
purified material was then subjected to two recrystallizations from IPA and
one from EtOH to afford 660 g of 114 in 45% yield with only 3.1 ppm Ru.
15.2.12 Nozaki-Hiyama-Kishi Coupling
The synthesis of homoallylic alcohols via addition of allylchromium(III) salts
to aldehydes and ketones was reported by Nozaki, Hiyama and co-workers in
1977.
127
The organochromium reagents were synthesized by treating allyl
halides with CrCl
2
and reacted with the carbonyl electrophile. An interesting
observation by both Nozaki's
128
and Kishi's
129
groups was that the addition of
Ni salts facilitated the reaction and led to a more reliable and reproducible
process that also expanded the nucleophile scope to the less reactive aryl and
alkenyl halides.
130
In addition to allyl, aryl and alkenyl halides, this trans-
formation can now be applied to alkynyl and propargyl halides and also tri-
flates, sulfonates and phosphates. This Barbier-type addition of organohalides
or pseudohalides to carbonyl compounds is nowadays called the Nozaki-
Hiyama-Kishi (NHK) reaction.
131
Some interesting features of this transfor-
mation include (a) chemoselectivity of the organochromium reagents for al-
dehydes even in the presence of ketones; (b) high functional group
compatibility on both nucleophile and electrophile; (c) g-monosubstituted
allylchromium reagents usually afford homoallyl alcohols with excellent anti
selectivity, regardless of the stereochemistry of the starting halide (E or Z
configuration); and (d) complete retention of double-bond geometry is ob-
served when alkenyl halides are employed as coupling partners.
131a
Despite the clear advantages of this transformation, especially for chiral
alcohol generation in its asymmetric version, the NHK coupling has received
little attention in process chemistry.
43,132
Notable exceptions are the Her-
culean syntheses of anti-cancer marine natural products discodermolide at
Novartis
132
and INN erubulin mesylate (Halaven), a synthetic analog of
halichondrin B, at Eisai.
43
A collaboration between the process groups at Novartis in Switzerland and
the United States and Paterson at the University of Cambridge in the UK
resulted in the publication of the multi-gram synthesis of discodermolide
(120).
132
The introduction of one of the 13 stereogenic centers and the
Search WWH ::
Custom Search