1. Robert D. Hubbard, Ph.D.
Stanford University, Post-doctoral assistant for Paul AWender

2. O
OO
O
H
HHO
H
OH
O
H
Laulimalide
O
OO
HO
H
O
O
H
Isolaulimalide
OH
AcO O
O
O
Ph
HO
NH
O
Ph
OH
OH
OBzHO
Paclitaxel
EC50 (nM)
Laulimalide Isolaulimalide Paclitaxel
Cell line
MDA-MB-435
(Breast)
5.74 1970 1.02
SK-OV-3
(Ovarian)
11.53 2570 1.71
SKVLB-1
(Ovarian)
1210 2650 >100000
Laulimalide initiates tubulin polymerization (Cancer Res. 1999, 53, 653)
Laulimalide initiates apoptosis in vitro by a mechanism analogous to Paclitaxel.

3. O
OO
O
H
HHO
H
OH
O
H
Laulimalide
Asymmetric Sakurai Reaction
O
H
SiMe3
C3-C14 Subunit
OHC
O
H
OTBS
OTBS
C15-C27 Subunit
CO2H
(R)-Citronellic Acid
(7 steps to the C3-C14 Subunit)
O O
MeO2C CO2Me
2,3-O-isopropylidene-tartrate
(16 steps to C15-C27 aldehyde)
Macrolactonization

4. CO2H
(R)-Citronellic Acid
1. MeOH, cat. p-TsOH, 60C (89%)
2. (a) Ph2Se2, H2O2, MgSO4, CH2Cl2
0C to RT
OH
CO2Me
SePh
b. tBuOOH, 0C to RT (75%)
OH
CO2Me 3. (a) O3, NaHCO3, 1:1 CH2Cl2:MeOH, -78C
(b) DMS, -78C to RT (90%) O
CO2Me

5. O
CO2Me
4. (a) 4 mol% (S,S)-Cr-salen Catalyst,
Danifshefsky's diene (eq)
4A ms, TBME (M), Temperature (C)
(b) TFA, CH2Cl2, -78C to RT
O
O OMe
O
H
A
MeO2C
O
CO2Me
H
B
Entry Temperature
(oC)
Diene (eq) Concentration
(M)
Yield (%, A:B) de (%) of A
1 0 1.3 5 59:20 71
2 -78 1.3 5 60:20 82
3 -78 1.3 3 86:5 82
4 -78 1.8 3 87:~2 82
(Jacobsen, E. N. J. Org Chem. 1998, 63, 403)

6. O
O OMe
O
H
5. (a) CuCN, MeLi, tributylvinyltin, THF, -78C
(b) Comins' Reagent -78C (74%, 82%de)
O
O OMe
OTf
H H
6. LiCl, Bu3SnH, Pd(PPh3)4,
THF, RT (88%)
O
O OMe
H H 7. (a) CeCl3, TMSCH2MgCl, THF, -78C to RT
(b) Silica gel, CH2Cl2, RT (85%)
O
H H
TMS
The C3-C14 portion of (-)-Laulimalide was synthesized in 7 steps, 29% overall yield.

7. HO2C
CO2H
OH
OH
1. BnOH, 200C
Dean-Stark (> 90%)
BnO2C
CO2Bn
OH
OH
OH
OH
CO2H
2. MeI, K2CO3, DMF, RT
3. 2-iodopropane, K2CO3, DMF
(42% overall yield)
4. KOH, 9:1 MeOH:H2O,
80C (86%)
O
O
CO2H
5. TFAA, Benzene, 0C to RT (71%)
6. Pd/C, 1 atm of H2, EtOAc (92%)
O
O
O
O
CO2H
OH
CO2H
B(OH)2
F3C CF3
7. Propionitrile, RT
(prepared in situ)
O
O
O
O
O
O
O
B
O OH
F3C
CF3
CAB: Chiral (Acyloxy)Borane
(J. Am. Chem. Soc. 1993, 115, 11490)

8. O
O
O
O
O
O
O
B
O OH
F3C
CF3
O
H
SiMe3
C3-C14 Subunit
OHC
O
H
OTBS
OTBS
C15-C27 Subunit
+
1 equiv CAB, -78C
propionitrile (86%, > 90% de)
O
H
HO
OTBS
OTBS
O
H
O
H
HO
OH
OH
O
H
CO2H
2,4,6-trichlorobenzoyl chloride, Et3N
DMAP, benzene, RT (32%, C19:C20 3:1, Z:E 3:1)
O
O
OH
O
H
OR O
H
R = PMB
O
H
HPMBO
H
OH O
O
O
H

9. O
N
O
O
H
H
OTIPS
OH
H
O
N
O
O
OR
H
OR
O
H
H
CO2H
Yamaguchi conditions
followed by alkyne reduction
(JACS 2000, 122, 10033)
O
N
O
O
H
H
O
H
O
O
OTIPS
H
H
O
N
O
O
OR
OR
H
H H
O O
N2
P
O
O
O
K2CO3, MeOH
n-BuLi, then ClCO2Me, THF
-78C (63% from the aldehyde)
CO2Me
Lindlar catalst, quinoline, H2,
1-hexene, acetone, RT
(70%. > 10:1 E:Z)
O
OMe
Model System

10. O
H
HO
OTBS
OTBS
O
H
1. MOMCl, DIEA, CH2Cl2, RT (99%)
2. (a) BH3-DMS, cyclohexene, THF
(b) H2O2, 3 M NaOH, EtOH (87%)
3. Dess-Martin, NaHCO3, CH2Cl2, H2O (85%) O
H
MOMO
OTBS
OTBS
O
H
O
4. MeC(=O)C(=N2)P(=O)(OMe)2
K2CO3, MeOH (76%)
5. n-BuLi, ClCO2Me, THF,
-78C (79%, 86% BORSM)
O
H
MOMO
OTBS
OTBS
O
H
CO2Me
6. HF-pyridine, THF, RT (98%)
7. LiOH, THF, water, RT (76%)
O
H
MOMO
OH
OH
O
H
CO2H
8. 2,4,6-trichlorobenzoyl chloride,
Et3N, DMAP, benzene, RT (55%)
O
O
OH
O
H
OMOM
H
O
H
Alkynoate-based lactonization is completely regioselective.

11. Total synthesis of (-)-Laulimalide was completed in 25 steps
(longest linear), 36 total steps, 2.6% overall yield.

12. CO2H
(R)-Citronellic Acid
1. MeOH, cat. p-TsOH, 60C (89%)
2. (a) Ph2Se2, H2O2, MgSO4, CH2Cl2
0C to RT
OH
CO2Me
SePh
b. tBuOOH, 0C to RT (75%)
OH
CO2Me
3. (a) O3, NaHCO3, 1:1
CH2Cl2:MeOH, -78C
(b) DMS, -78C to RT
(90%) O
CO2Me
4. (a) 4 mol% (S,S)-Cr-salen Catalyst,
Danifshefsky's diene (1.8 eq)
4A ms, TBME (3 M), -78C
(b) TFA, CH2Cl2, -78C to RT
(87%, 82% de)
O
O OMe
O
H
5. (a) CuCN, MeLi,
tributylvinyltin, THF, -78C
(b) Comins' Reagent
-78C (74%, 82% de)
O
O OMe
OTf
H H
6. LiCl, Bu3SnH, Pd(PPh3)4,
THF, RT (88%)
O
O OMe
H H
7. (a) CeCl3, TMSCH2MgCl,
THF, -78C to RT
(b) Silica gel, CH2Cl2, RT
(85%)
O
H H
TMS
The C3-C14 portion of (-)-Laulimalide was synthesized in 7 steps, 29% overall yield.