The Daphniphyllum Alkaloids

15 Pages·2015·2.1 MB·English

by  Peter Wipf

The
 Daphniphyllum
 Alkaloids:
 Total

Synthesis
 of
 (−)-­‐Calyciphylline
 N

Artem
 Shvartsbart
 and
 Amos
 B.
 Smith
 ,
 III

(cid:1)
J.
 Am.
 Chem.
 Soc.,
 2015,
 137
 (10),
 pp
 3510–3519
CO Me
2
N
H
HO
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(cid:1)
(−)-­‐Calyciphylline
 N
CO Me
2
N
H
HO
Isolated
 from
 the
 leaves
 and

stems
 of
 Daphniphyllum

calycinum(cid:1)
ReprensentaJve
 daphniphyllum
 alkaloids(cid:1)
J.Nat.
 Prod.
 2008,
 72,
 148(cid:1)
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(cid:1)
(−)-­‐Calyciphylline
 N
Dihydropyrole
A
N
HO
C B
Bicyclo [2.2.2]octane
CO Me
F
D 2
H
E
Decahydrocyclopentazulene
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Previous
 studies

Ø  Dixon’s
 synthesis
 of
 the
 DEF
 ring
 vis
 IPKR

(cid:1)
H
O
O Co (CO) , CH Cl , rt O K CO O
2 8 2 2 H 2 3 O
EtO NMO,CH2Cl2, rt EtO H EtOH, rt
58% 92% EtO
Ø  Carreira’s
 synthesis
 of
 Daphmanidin
 E
 via
 claisen

 rearrangement
 and
 Heck
 reacJon

Org.
 Le6.,
 2012,
 14
 (7),
 pp
 1684–1687

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OTs
(cid:1)
O O
O
OMOM
O O
O KHMDS, 18-crown-6 OMOM nonane, 155 °C H OMOM
OBz O O
O THF, -20°C, 89% 86%, d.r. 10:1
OBz OBz
OTBDPS
OTBDPS OTBDPS
AcO
KHMDS, 18-crown-6 O O
BocHN Cobaltoxime
allylbromide, THF, -20°C O
iPr NEt, blue LED
83% O 2
H OMOM
MeCN
o-xylene, 165 °C O OBz 93%
40% MOMO
OBz
I
OTBDPS
NHBoc OAc CO2Me
O N
O
MOMO HO
OBz OAc
Daphmanidin E

Angew.
 Chem.
 Int.
 Ed.
 2011,
 50,
 11501
 –11505

(cid:1)
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(cid:1)
Retrosynthesis
Condensation
PhthN
CHO
CO2Me O O O O
N
H aldol O
I
O
O Si
HO Si
HO
Tamao-Kumada allylation
oxidation epoxidation
O O O O O
O O
O O O O
Si Si Si Si
OH
I
cyclopentenone enolate alkylation
annulation
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(cid:1)
Retrosynthesis
Condensation
PhthN
CHO
CO2Me O O O O
N
H aldol O
I
O
O Si
HO Si
HO
Tamao-Kumada allylation
oxidation epoxidation
O O O O O
O O
O O O O
Si Si Si Si
OH
I
cyclopentenone enolate alkylation
annulation
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(cid:1)
Problem
 with
 the
 iniJal
 plan
1) LiAlH4, Et2O PhSMe
94% n-BuLi, DABCO
O O O
Si 2)I , PPh , imidazole Si THF, 0°C Si
2 3
85% 81%
CO Et SPh
2 I
LiDBB
THF, - 78 °C
O
HO
H TfO O
O
Si 70% Si O
H Si
Li
Problem solving:
1) PPh3, TBSOTf
1) NaCN, O
THF, 0°C
DMSO, 60 °C O
O 2) DIBAL-H O
Si Si 2) n-BuLi, 18 O
CH2Cl2, - 78°C Si
THF, -78 °C
91%
I CHO 3) 1M HCl
18 91%
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(cid:1)
Problem
 with
 the
 iniJal
 plan
m-CPBA, O O t-BuLi (2.2 equiv)
O NaHCO3 O I2, pyridine O THF, -78 °C complex
I
mixtures
O CH Cl , 0°C O CCl O or i-PrMgCl
Si 2 2 Si 4 Si
86% 86% THF, -78 °C
1) NaBH4,
OHTBSO
O CeCl3 •7H2O O
O MeOH, 0 °C OTBS
I I
O 2) TBSCl, Et3N O O
Si Si Si
DMAP, CH2Cl2
78 %, d.r. 1:1
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(cid:1)
Problem
 with
 the
 iniJal
 plan
1) NaBH4,
1) PPh3, TBSOTf CeCl3 •7H2O NaClO2, NaH2PO4
O
I THF, 0 °C O MeOH, 0 °C OHC O 2-methyl-2-butene
I I
2) LDA, -78 °C, 18 O 2) PhLi, Et2O t-BuOH/H2O
Si PhMe Si
3) 1M HCl 75% 2 80% (2 steps)
3) DMP, CH2Cl2
O
Palladium-mediated O O
HOOC I O cascade cyclization
PhMe Si
2
PhMe Si
2
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