(-)-laulimalide (080524-US.TKG) J.

Uenishi

OH
O H

OH O O O
H H
O

Activity antitumor
A) cross coupling reaction B) Pd-catalyzed cyclization C) proto- desilylation of
Key Reactions bis(trimethylsilylmethyl)alkene D) Hosomi-Sakurai reaction E) Yamaguchi
macrolactonization

OPMB
OPMB 1) TBDMSCl 1) ?
OPMB 1)?
CH2Cl2 imidazole THF:H2O (5 : 1)
-78 °C DMF, rt OTBDMS 2) cat. ?-? B-41
OH
2) (+)-Ipc2BAllyl 2) Cat. OsO4, NMO OBz
CN OH
THF:H2O
DMF, rt
(5 : 1) OH I

1) Dess-Martin ox.
CH2Cl2, rt
OPMB 2) H Ph OPMB
Ph OPMB
H OTBDMS O
N B PdCl2(MeCN)2
OBz H
Me OH (15 mol%) H H
OBz O OBz
? benzoquinone
THF, -30 °C (0.3 eq)
OH
3) ? OH THF, -5 °C

OPMB OPMB
1) ? B-49
2) ? BuLi
Br H H
CH2Cl2, rt H H THF, -78 ℃ O
O
3) ?, ? Br then (HCHO)n OH
CH2Cl2, 0 °C
OH Br Br
1) Ph2(tBuO)SiCl 1) Dess-Martin ox.
Et3N, CH2Cl2, rt H H CH2Cl2, rt
O H H
2) ? 2) CBr4, PPh3 O
CH2Cl2 : buffer (pH 7) CH2Cl2, 0 °C
(10 : 1) OSi(OtBu)Ph2
OSi(OtBu)Ph2
 Me3Si C-5
Me3SiCH2MgCl
Cat. Pd(OAc)2, PPh3 PPTS
? 1
THF, 50 °C THF: MeCN (9 : 1) H H
O
OSi(OtBu)Ph2

† † †

1) ? O O
NaH, THF, rt PMBO OEt
?
PMBO PMBO
CHO P(OMe)2
2) AD-mix α O O THF, -78 ℃
tBuOH-H O (1 : 1) O O O
2 B-99
3) ? CSA, rt 2

† † †

TMS
? TMS
Br Br Br ? (Sia)2BH, THF
? Me
Cat. PdCl2(dppf) -30~-5 ℃
benzene THF, 0 ℃~rt then H2O2
OTBDPS 0 ℃~rt OTBDPS 3 M NaOH aq.
OTBDPS

Me Me HO Me O Me
HOOC MeOOC
?, ? ? ?
H
benzene, rt THF, rt CH2Cl2, rt
OTBDPS OTBDPS OTBDPS 3 OTBDPS

† † †

1) ? (2 eq), rt O
O
O Me PMBO
PMBO THF:H2O (1:1)
P(OMe)2
H 2) NaBH4/? O OH
O O O
MeOH, -78 °C
OTBDPS OTBDPS
2 3
α : β = 1 : 10 <
 O O
PMBO PMBO
?
O OBz O BzO
?, ?
Benzene, rt OTBDPS OTBDPS
1:1

1) MeOH, K2CO3 1) TBAF, THF

2) Cat. Pd2(dba)3
2) TBAF, THF
neocuproine
THF, rt

O Cat. O
PdCl2(MeCN)2 H
PMBO PMBO
O THF, 0 ℃, 3 hr
OH O O

OH
OH
H OR
1) HCl aq. 1) TBDMSCl H
HO
MeOH imidazole, DMF
O O O
2) ?, ? OPMB O
2) ?
CH2Cl2, 0 ℃ PMP
CH2Cl2, -20 ℃ R = H and TBDMS

3 steps

1) Dess-Martin ox. OTBDMS 1) DIBAL-H OTBDMS

H CH2Cl2, -78 ℃ H
CH2Cl2
MeOOC OHC
2) ? b enz ene 2) Dess-Martin ox.
OPMB O OPMB O
CH2Cl2
4

† † †
OTBDMS
H
OHC OTBDMS
Me3Si H
OPMB O

4 SnCl4 OH OPMB O
+
H H
H H CH2Cl2, -78 °C O
O
OSi(OtBu)Ph2
OSi(OtBu)Ph2

1
dr = 1 : 1
 1) Dess-Martin ox. OTBDMS
H
CH2Cl2, 0 °C
2) ? 1) K2CO3, MeOH, rt
OTBDMS OPMB O
? H H 2) Dess-Martin ox.
THF, -40 °C O
CH2Cl2, 0 °C
3) TBSCl, imidazole OSi(OtBu)Ph2
DMF, rt

OTBDMS OTBDMS
H H
1) DDQ
CH2Cl2-pH 7 buffer OTBDMS OH O
OTBDMS OPMB O
(2 : 1)
H H H H
O 2) NaClO2, NaH2PO4 O
C-82 2-methyl-2-butene OH
CHO
t
BuOH-THF (2 : 1) O

OTBDMS
H
1) HF•Py, MeCN
?
OTBDMS O O
2) ?, ?
DIEA, DMAP H H
O quinoline
toluene, 0 °C O EtOAc : 1-hexene
(1 : 1)

OH OH
H O H
(+)-DIPT, Ti(OiPr)4
OH O O O OH O O O
TBHP
H H H H
O CH2Cl2, -20 °C O

(-)-Laulimalide

References:
1) J. Uenishi, M. Ohmi, Angew. Chem. Int. Ed., 44, 2756 (2005)