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terminal diene on the molecule was accomplished following Paterson's one-
pot, two-step NHK-Peterson elimination strategy (Scheme 15.25).
133
The Ni-
free NHK reaction involved substrate-controlled, stereoselective coupling
between aldehyde 115 and allyl bromide 116. The protocol that was imple-
mented in the plant called for the sequential addition of solutions of alde-
hyde 115 and allyl bromide 116 (5.6 equiv.) in THF to a cold (0 1C)
suspension of CrCl
2
(4.3 equiv.) in the same solvent. After stirring at 0 1C for
15 min, the reaction mixture was warmed to 15 1C and further stirred at this
temperature for 1 h to afford a mixture of anti-adducts 117 (major) and 118
(minor; the actual diastereomeric ratio was not disclosed in the report).
MeOH and 6 M aqueous KOH were then added to effect Peterson syn-elim-
ination.
134
Originally, KH was employed as base, but for safety reasons KOH
was chosen on scale.
135
Even though both 117 and 118 provided the required
(Z)-olefin, they underwent syn-elimination at different rates. Following an
aqueous work-up and concentration, the residue was purified by chroma-
tography on silica to afford 1.27 kg of intermediate 119 as an oil with a
combined yield of 81%. No information was provided about the level of
residual Pd in intermediate 119.
Researchers at Eisai in the United States and Japan described the syn-
thesis of INN eribulin mesylate (Halaven, 126), a very complex molecular
structure that has recently been approved by the US Food and Drug Ad-
ministration (FDA) for the treatment of metastatic breast cancer.
43
One of
the 19 stereogenic centers on the molecule was generated via an asymmetric
NHK reaction
43a
between aldehyde 122 and alkenyl triflate 123 in the pres-
ence of chiral ligand (S)-121 (Scheme 15.26).
136
Prior to performing this
particular coupling, the researchers had investigated a similar transforma-
tion with different coupling partners employing ReactIR to monitor the
reaction. Thus, it was determined that (a) the complexation between ligand
(R)-121 (the R enantiomer was used in that case) and CrCl
2
required a
temperature 430 1C; (b) the oxygen level had to be closely monitored; and (c)
better results were obtained when the aldehyde and coupling partners were
added immediately after the addition of NiCl
2
while keeping the reaction
S
iMe
3
R
117
(major)
PMBO
Br
SiMe
3
116
(5.6 equiv)
CrCl
2
(4.3 equiv)
PMBO
OH
CHO
+
+
O
OPMB
THF, 0-15 ºC
75 min
SiMe
3
TB DMS
R
TBDMS
118
(minor)
115
PMBO
OH
Not isolated
PMBO
O
O
KOH (6 M, aq)
O
OPMB
OH
OH
O
NH
2
MeOH, rt, 16 h
TBDMS
119
(1.27 kg)
TBDMS
81%
(2 steps)
OH
OH
O
120
discodermolide
Scheme 15.25 NHK coupling during the synthesis of discodermolide (120).
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