et. al. J. Am. Chem. Soc.

Total Synthesis of Apoptolidin
HO
MeO
OH
O
Me
Me
O
Me
Me
Me OH Me
MeO HO
Me
O
December 9 th , 2003
O
OH
O
OH
H
O O
Me
HO
Won-jin Chung
OMe
O
Me
Me
O
Me
OH
OMe

HO
MeO
OH
O
Me
Me
O
Me
Me
Me OH Me
MeO HO
Me
O
O
OH
O
OH
H
Apoptolidin
O O
Me
HO
OMe
O
Me
Me
O
Me
• Formula : C 58 H 96 O 21
• Molecular Weight : 1129.37
• Induced apoptotic cell death in rat glia cells transformed with a oncogene
OH
OMe
(IC 50 = 11 ng/mL) but not in normal cells (IC 50 > 100 mg/mL)
• Isolated from Nocardiopsis sp.
• Stereochemistry was determined by
NMR and degradation studies.
• The top 0.1% most selective agents tested in the NCI's 60 human cancer cell
line panel out of the more than 37,000 compounds analyzed to date

HO
MeO
OH
O
Me
Me
O
Me
Me
Me OH Me
MeO HO
Me
O
O
OH
O
OH
H
Apoptolidin
O O
Me
HO
OMe
O
Me
Me
O
• 20 membered macrolide with a side chain containing a 6 membered cyclic hemiketal.
Me
OH
OMe
• A disaccharide and a novel 6-deoxy-glucose residue
• 25 stereocenters and 5 geometrical sites
• Formula : C 58 H 96 O 21
• Molecular Weight : 1129.37
• Isolated from Nocardiopsis sp.
• Stereochemistry was determined by
NMR and degradation studies.

Apoptosis
There are two ways in which cells die:
1. they are killed by injurious agents
2. they are induced to commit suicide
-Programmed Cell Death, Apoptosis
Why suicide?
- for proper development
- to destroy cells that represent a threat to the integrity of the organism

Key Disconnections
Koert, U. et. al. Angew. Chem. Int. Ed. 2001, 40, 2063.

BnO
MeO
O
O O
1. Li TMS
2. LiHMDS, MeI
3. TBAF
88 % over three steps
OMe
Synthesis of the Southern Half
Ru-(S)-BINAP, H 2
BnO
MeOH, DMF, 95 o C
86 % yield, 97 % ee
OMe
MeO
H
O OH
Cp 2ZrCl 2, LiEt 3BH, NIS
THF, 88 %
OMe
1. TBSCl,
imidazole, 95 %
2. DIBAL-H
hexane, 90 %
BnO
H
OMe
O OTBS
I
OMe
Koert, U. et. al. Angew. Chem. Int. Ed. 2001, 40, 2063.
Koert, U. et. al. Tetrahedron Lett. 2000, 41, 621.

H
O OTBS
Me 4NBH(OAc) 3
HOAc, MeCN
74 %, dr >95 : 5
OMe
O
O
O
Bn
N
O
Synthesis of the Southern Half
O
N
Bn
O
Me
O
Sn(OTf) 2, Et 3N
97 %, dr 96 : 4
Me
OH
Me
OH
Me
OTBS
OMe
O
O
Bn
N
O
Me
O
Me
OH
OTBS
1. AlMe 3, MeNH(OMe) HCl
HOAc, CH 2Cl 2, 81 %
2. TMSCl, imidazole, 86 %
OMe
Me
OMe
N
O
Me
O
Me
O
TMS TMS
OTBS
OMe
Koert, U. et. al. Tetrahedron Lett. 2000, 41, 621.

BnO
PPTS
OMe
MeOH, CH 2Cl 2
87 % two steps
1. Ac 2O, py,
DMAP, 69 %
2. H 2, Pd(OH) 2/C
EtOAc, 97 %
3. Dess-Martin
periodinane
py, CH 2Cl 2, 91 %
OMe
Me
Me
N
Me
OMe
t-BuLi
+
O O O OTBS Et2O, -78
TMS TMS
o I BnO
C
BnO
H
O
OMe
OMe
Synthesis of the Southern Half
Me
OMe H
O
OH
AcO
OMe H
O
OAc
Me
OTBS
Me OTBS
Me OTBS
OMe
OMe
1. TBSOTf
2,6-lutidine
CH 2Cl 2, 98 %
2. K 2OsO 2(OH) 4
NMO, 90 days
78 %, dr 6 : 1
BnO
OMe
OMe
O
Me
O
Me
O
TMS TMS
HO
OMe H
O
OH
Me
OTBS
OTBS
Me OTBS
OMe
OMe
Koert, U. et. al. Angew. Chem. Int. Ed. 2001, 40, 2063.

H
O
OMe
AcO
OMe H
O
OAc
Me
OTBS
Synthesis of the Southern Half
Me OTBS
OMe
n-Bu 3Sn
Me
58 %, dr 93 : 7
MgBr
n-Bu 3Sn
Me
OH
OMe
AcO
Me
OAc
OMe H
O
OTBS
Me OTBS
OMe
Koert, U. et. al. Angew. Chem. Int. Ed. 2001, 40, 2063.

HO
O
Me
O
1. DIBAL-H
2. MnO 2
3. Me CO2Et PPh 3
86 % three steps
1. DIBAL-H, 80 %
2. MnO 2
3. Me CO2Et PPh 3
60 % two steps
1. TBSOTf
2,6-lutidine
CH 2Cl 2, 90 %
2. DIBAL-H
CH 2Cl 2, 95 %
TBSO
TESO
TBSO
Synthesis of the Northern Half
I
Me
Me
TBSO
Me
Me
Me
Me
O
CO 2Et
Me
Me CO 2Et
OH
1.
Me CO 2Et
PPh 3
2. TESCl
imidazole
82 % two steps
1. camphorsulfonic acid
MeOH, CH 2Cl 2, 95 %
2. Dess-Martin periodinane
3. CrCl 2, CHI 3, hydroquinone
69 % two steps
TBSO
TESO
TBSO
I
Me
Me
Me
CO 2Et
Me
Me
CO 2Et
Koert, U. et. al. Angew. Chem. Int. Ed. 2001, 40, 2063.

n-Bu 3Sn
Me
TBSO
I
OH
Me
OMe
AcO
Me
Me
Me
+
Completion of the Synthesis
Me CO 2Et
OAc
OMe H
O
OTBS
Me OTBS
Cu I -thiophene-2-carboxylate
N-methylpyrrolidinone, 80 %
OMe
TBSO
Me
Me
OH
Me
Me
Me CO 2Et
OMe
AcO
Me
OAc
OMe H
O
OTBS
Me OTBS
OMe
Koert, U. et. al. Angew. Chem. Int. Ed. 2001, 40, 2063.

TBSO
Me
HF, py
Me
THF, 55 %
OH
Me
Me
Me CO 2Et
OMe
AcO
Me
Me
HO
OAc
OMe H
O
Completion of the Synthesis
OTBS
Me
Me OTBS
OH
Me
Me
Me
OMe
HO
Me
OMe
O
O
OMe H
O
OH
1. LiOH, 87 %
2. Cl
O
Cl Cl
Cl
Et 3N, DMAP, 74 %
Me OH
OMe
TBSO
Me
Me
Me
Me
OH Me
OMe
HO
Me
O
O
OMe H
O
OTBS
Me OTBS
19 steps (the longest linear)
2.8 % yield
OMe
Koert, U. et. al. Angew. Chem. Int. Ed. 2001, 40, 2063.

Key Disconnections
Toshima, K. et. al. Tetrahedron Lett. 2001, 42, 8873.

H
O
Me
1. TIPSOTf
py, 90%
OTr
2. CSA, 87 %
H
TIPSO
THF, 60 %
H
Me
Synthesis of the Northern Half
TMS, n-BuLi
Cram : anti-Cram = 2 : 1
OH
HO
Me
TMS
(COCl) 2, DMSO, Et 3N
CH 2Cl 2
OTr
TIPSO
H
K 2CO 3
MeOH, 99 %
Me
O
H
HO
H
Me CO 2Et
PPh 3
toluene, 96 %
E : Z = 100 : 0
Me
OTr
TIPSO
H
Me
Me
CO 2Et
Toshima, K. et. al. Tetrahedron Lett. 2001, 42, 8873.

TIPSO
H
Me
1. DIBAL-H, 97%
2. MnO 2, 98 %
3. Me CO 2Et
P(O)(OEt) 2
n-BuLi, 99 %
E : Z = 100 : 0
Me
CO 2Et
TIPSO
H
Synthesis of the Northern Half
Me
1. DIBAL-H, 98%
2. MnO 2, 98 %
3. Me CO 2Et
PPh 3
toluene, 99 %
E : Z = 97 : 3
Me
Me
Me CO 2Et
TIPSO
H
Me
Me
Me
1. n-Bu 3SnH, PdCl 2(PPh 3) 2
toluene, 0 o C, 92 %
2. aq. LiOH
1,4-dioxane, 80 o C, 79 %
CO 2Et
TIPSO
n-Bu 3Sn
Me Me
Me
Me CO 2H
Toshima, K. et. al. Tetrahedron Lett. 2001, 42, 8873.

HO
Me
O
Me
OMPM
O
Dess-Martin
periodinane
py, rt, 73 %
H
Me
O
O
Me
OMPM
(c-Hex) 2BH
HO OMPM Dess-Martin
periodinane
H OMPM
THF, rt, 88 % O
py, rt, 99 %
O
O
Me
O
Me
Me
O
Me
1. MeOTf
2,6-di-t-butylpyridine, 90 %
2. (c-Hex) 2BH, THF, 89 %
Synthesis of the Northern Half
OH
OTBS
OMe
O
Me
Me
O
OMPM
O
Ph 3P=CH 2
benzene, 81 %
Me
O
Me
OTBS
OMPM
n-Bu3Sn OH
MgBr2 Et2O, 83 % O
1. TsCl, Et 3N, TMEDA
MeCN, 95 %
2. Li H
DMSO, 86 %
H
O
OTBS
OMe
O
Me
OTBS
Me
Me
O
Me
OMPM
OMPM
Toshima, K. et. al. Tetrahedron Lett. 2001, 42, 8873.
O

H
OTBS
OMe
O
Me
Me
OMPM
O
Synthesis of the Northern Half
1. MeI, n-BuLi
THF, 96 %
2. Cp 2ZrHCl, NIS
THF, 80 %
Me
I
OTBS
OMe
O
Me
Me
OMPM
O
DDQ
CH 2Cl 2, 99 %
Me
I
OTBS
OMe
O
Me
Me
OH
Toshima, K. et. al. Tetrahedron Lett. 2001, 42, 8873.
O

TIPSO
n-Bu 3Sn
Me
I
Me Me
+
Me
OTBS
Me CO 2H
OMe
O
Me
Completion of the Synthesis
Me
OH
O
1.
Cl
Cl Cl
Et3N, DMAP, 89 %
2. TBAF, 67 %
O
Cl
HO
n-Bu 3Sn
I
Me
Me Me
OH
Me
Me
OMe
O
Toshima, K. et. al. Tetrahedron Lett. 2001, 42, 8873.
Me
Me
O
O
O

HO
n-Bu 3Sn
I
Me
Me Me
OH
Me
OMe
O
Me
Completion of the Synthesis
Me
Me
O
O
O
PdCl2(MeCN) 2
Ph2PO2NBu4, LiCl
DMF, 30 %
Me
HO
Me Me
OH
Me
Me
OMe
O
Me
Me
17 steps (the longest linear)
5.2 % yield
Toshima, K. et. al. Tetrahedron Lett. 2001, 42, 8873.
O
O
O

MeO
Stille coupling
HO
OH
O
O
Key Disconnections
Glycosidation
OH
MeO HO
O
O
OH H
O
OH
O O
HO
Yamaguchi macrolactonization
OMe
O
O
Glycosidation
OH
OMe

Retrosynthetic Analysis
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

TES
TBSOTf
2,6-lutidine
Synthesis of Vinylstannane Methyl Ester (C 1 ~ C 11)
O
H
(+) (Ipc) 2B
BF 3 OEt 2
CH 2Cl 2, 0 o C, 2 h, 97 % TES
Me CO 2Et
PPh 3
toluene, 100 o C, 12 h
E : Z > 9 : 1,
90 % over two steps
THF, -78 o C, 6 h
TES
TBSO
TBSO
Me
Me
Me Me
CO 2Et
NaBO 3 4H 2O
THF / H 2O (2 / 1), rt, 12 h, 82 %
1. O 3, CH 2Cl 2, -78 o C
2. PPh 3, -78 o C then, rt, 12 h
1. DIBAL-H
toluene, -78 o C, 2 h, 90 %
2. 0.05 eq. TPAP, NMO
4 MS, CH 2Cl 2, rt, 30 min
Å
TES
TES
TES
TBSO
TBSO
OH
Me
Me
O
H
Me Me
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP
O
H

TES
TBSO
TBAF
Synthesis of Vinylstannane Methyl Ester (C 1 ~ C 11)
Me Me
O
H
Me
CO 2Et
PO(OEt) 2
HO
H
, NaH
THF, 0 o C then rt, 1 h
E : Z > 10 : 1,
81 % over two steps
Me
TBSO
Me
TES
Me
Me
CO 2Et
THF, 0
Me
oC then rt, 1 h, 98 % THF, 0 oC, 30 min, 69 %
Me
Me
CO 2Me
n-Bu 3SnH
1. DIBAL-H, 89 %
2. TPAP, NMO
3.
Me
CO 2Me
PO(OEt) 2
0.05 eq. Pd(PPh 3) 2Cl 2
, NaH
E : Z > 10 : 1,
95 % over two steps
TBSO
HO
n-Bu 3Sn
Me
TES
Me
Me
Me
Me
Me
Me
Me
CO 2Me
CO 2Me
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

HO
OH
H
O
Synthesis of Acetylenic Aldehyde (C 12 ~ C 20)
O
OH
1. Me 2C(OMe) 2
0.02 eq. TsOH
CH 2Cl 2, rt, 3 h
2.
Me
1. Me 2SO 4, BnEt 3NCl
50 % aq. NaOH, CH 2Cl 2
0 o C then rt, 86 %
2. PPTS, MeOH, rt, 90 %
3. SEMCl, TBAI, DIPEA
CH 2Cl 2, 40 o C, 99 %
OMe
CH 2Cl 2, rt, 7 h
Me
O
Me
O
Me
OMe
O
Me
O
O
OSEM
H
N
O
O
O
OMIP
morpholine
Me
65 o C, 15 h,
97 % over three steps
1. LiBHEt 3, THF, 0 o C, 81 %
2. PMBCl, NaH, TBAI
DMF, rt, 83 %
3. 60 % aq. AcOH, rt, 88 %
O
HO
Me
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP
O
OH
OH
OMe
O
OMIP
OSEM
N
O
OPMB

HO
OH
OMe
Synthesis of Acetylenic Aldehyde (C 12 ~ C 20)
OSEM
OPMB
1. 1.5 % HCl in MeOH
MeOH, rt, 30 min, 95 %
2. 1.2 eq. DDQ
4 MS, CH2Cl2, 0 o Å
C
then rt, 2 h, 78 %
1. DIBAL-H
CH 2Cl 2, 72 %
2. SO 3 py, Et 3N
DMSO / CH 2Cl 2 (2 / 1)
95 %
CH 3C(OCH 3) 3
PPTS
CH 2Cl 2, rt, 45 min
then, AcCl
CH 2Cl 2, rt, 5 h
then, K 2CO 3
MeOH, rt, 12 h, 88 %
H
CH 3
OH
OMe
OTBS
OMe
O
O
O
O
PMB
H
OPMB
OMe
OSEM
OPMB
MgBr
Et 2O, - 78 o C
1 h, 94 %
1. TBSOTf, 2,6-lutidine
CH 2Cl 2, 98 %
2. n-BuLi, MeI
THF, 99 %
H
CH 3
OH
OTBS
OMe
OMe
OSEM
OPMB
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP
O
O
PMB

O
OH
Acetylenic Aldehyde – The Second Generation
1. DDQ
CH 2Cl 2 / H 2O (18 / 1)
97 %
2. SO 3 py, Et 3N
DMSO / CH 2Cl 2 (2 / 1)
96 %
H 3C
1. MeOTf
2,6-di-t-butyl-4-methylpyridine
CH 2Cl 2, 85 %
2. AD-Mix-a
dr 6 : 1, 85 %
1. PMBCl, NaH, TBAI
DMF, 71 %
2.
MgBr
Et 2O, 90 %
H
CH 3
OTBS
OTBS
OH
O
OMe
H
OH
OPMB
OH
1. TBSOTf, 2,6-lutidine
CH 2Cl 2, 97 %
2. n-BuLi, MeI
THF, 95 %
(+) (Ipc) 2B
Et 2O, -100 o C, 2 h
then 30 % aq. H 2O 2
3 M aq. NaOH, rt, 15 h
dr 10 : 1, 95 %
1. DMBA, CSA
toluene, 110 o C, 99 %
2. DIBAL-H
CH 2Cl 2, 70 %
3. SO 3 py, Et 3N
DMSO / CH 2Cl 2 (2 / 1)
90 %
H 3C
CH 3
CH 3
OTBS
OH
OTBS
OTBS
OMe
OPMB
ODMB
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP
O
H

O
(+) (Ipc) 2B
Synthesis of Dithiane (C 21 ~ C 28)
1,3-dithiane
n-BuLi
OMe
THF, -78
S
oC then rt
30 min, 91 %
Me
BF 3 OEt 2, THF, -78 o C
then, NaBO 3 4H 2O
THF / H 2O (1 / 1), rt, 98 %
Me
OH
S
OPMB
OMe
OH
OMe
1. PMBCl, NaH
DMF, 99 %
2. MeI, K 2CO 3
MeCN / H 2O (6 / 1)
92 %
1. TBSOTf, 2,6-lutidine
CH 2Cl 2, 97 %
H
O
H
Me
2. OsO4, NMO, rt, 12 h
O O
then NaIO4, rt, 2 h, 94 % TBS
OPMB
OMe
OPMB
OMe
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

H
O
Me
O
MeNHOMe HCl
AlMe 3
CH 2Cl 2, -20 o C
then rt, 12 h 90 %
1. HS SH
BF 3 OEt 2, 78 %
2. TBSOTf
TBS
OPMB
2,6-lutidine, 97 %
OMe
Synthesis of Dithiane (C 21 ~ C 28)
O
Me
N OH
MeO Me
S
S
O
Me
O O
O
N
Me
Me
O
Ph
O
Me
n-Bu 2BOTf, Et 3N
CH 2Cl 2, -78 o C
then 0 o C, 2 h
TBS
TBS
TBS
OPMB
OPMB
OMe
30 % aq. H 2O 2
0 o C, 2 h
dr 10 : 1, 83 %
OMe
O
O
O
N
Me
1. TMSOTf
2,6-lutidine
CH 2Cl 2, -30 o C, 1h
2. DIBAL-H
CH 2Cl 2, -78 o C, 2 h
89 % two steps
OH
Me
Ph
H
O
TBS
O
Me
OPMB
O
Me
TMS
OMe
O
TBS
OPMB
OMe
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

Me
HO
O
NaBH 4
O
Me
SPh
O
Me
Synthesis of Carbohydrate Unit A
1. MeI, NaH
DMF, rt, 1.5 h, 92 %
2.
HO
TsOH
MeOH, 0 o C, 5 min, 70 %
OH
MeOH, rt, 12 h, 91 %
Me
MeO
O
OTBS
Me
MeO
SPh
OH
O
OH
SPh
OH
1. TBSOTf
1. TBSOTf
2,6-lutidine, 100 %
2. mCPBA
CH 2Cl 2, -78 o C
5 h, 67 %
2,6-lutidine, 95 %
2. (COCl) 2, DMSO, Et 3N
100 %
Me
MeO
O
A
OTBS
O
SPh
Me
MeO
OTBS
O
OTBS
SPh
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP
O

Me
HO
O
O
Me
SPh
O
Me
PMBCl, TBAI, NaH
DMF, 83 %
1. TBSOTf
Synthesis of Carbohydrate Unit D
2,6-lutidine, 95 %
2. BCl 3 SMe 2
CH 2Cl 2, 0 o C
30 min, 92 %
Me
TBSO
O
O
SPh
Me
TBSO
OPMB
O
OH
SPh
OH
n-Bu2SnO
toluene
reflux, 6h
0.05 eq. RhCl(PPh 3) 3
1.5 eq. DABCO
MeOH / H 2O (10 / 1)
reflux, 2 h
Br , CeF
DMF, 70 o C, 12 h
regioisomers 3 : 1
90 %
0.05 eq. OsO 4
1.2 eq. NMO
acetone / H 2O (10 / 1)
rt, 12 h, 92 %
Me
TBSO
Me
TBSO
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP
O
O
O
OH
SPh
OH
SPh
OPMB

Me
TBSO
O
OH
1. TBSOTf
SPh
OPMB
2,6-lutidine, 95 %
2. 1.2 eq. DDQ
4 MS, CH2Cl2, 0 o Å
C
then rt, 2 h, 78 %
BnOH, SnCl 2
Et 2O, 0 o C
then rt, 5 h, 90 %
Synthesis of Carbohydrate Unit D
DMP, NaHCO 3
CH 2Cl 2, rt, 1 h, 96 %
Me
Me
TBSO
Me
O
O
TBSO SPh
Me OTBS
Me
TBSO
SPh
OH
OTBS
OBn TBAF
O
O
DAST
SPh
OPMB
MeMgBr
CH 2Cl 2, 0 o C, 20 min
a : b = 1 : 10, 100 %
THF, rt, 6 h, 98 %
Et 2O, -78 o C,10 min
dr 7.5 : 1, 91 %
Me
O
Me
TBSO
Me
OBn
HO SPh
Me OH
Me
TBSO
Me
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP
O
F
SPh
OTBS
O
SPh
OPMB
OH

Me
TBSO
Me
TBSO
O
OH
O
OMe
SPh
OH
F
1. TESOTf
2,6-lutidine
CH 2Cl 2, 84 %
2. Raney Ni
EtOH, 55 o C
5 h, 92 %
SPh
Synthesis of Carbohydrate Unit D-E
n-Bu 2SnO
toluene
reflux, 6 h
Me
O
MeI, CeF
DMF, 55 o C
1 h, 83 %
OBn
HO SPh
Me OH
SnCl 2
Me
TBSO
O
OMe
SPh
OH
DAST
D +
D
Et 2O, 0 o C
then rt, 12 h, 45 %
TBSO
Me
Me
O
O OH
DAST
MeO
O
Me
OTES
TBSO
MeO
CH 2Cl 2, 0 o C, 30 min
a : b = 1 : 7, 100 %
Me
Me
O
E E
CH 2Cl 2, 0 o C, 15 min
a : b = 15 : 1, 100 %
SPh
O
Me
TBSO
OBn
O SPh
Me OH
TBSO
Me
Me
O
O F
D E D E
MeO
O
Me
OTES
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP
O
D
OMe
F
SPh

S
S
1. TBAF
Me
O
Me
TBS
THF, rt, 90 %
Dithiane Coupling to Synthesize Vinyl Iodide
O
2. PhI(OCOCF 3) 2
0 o C, 10 min
TBS
OPMB
CH 3
OMe
OH
+
MeO
HO
Me
CH 3
OTBS
ODMB
OH H
O
OH
OMe
O
H
ODMB
Me OPMB
OMe
t-BuLi, HMPA
THF, 96 %
dr 1.5 : 1
1. TBSOTf
CH 3
2,6-lutidine, 95 %
2. (MeO) 3CMe, PPTS
CH 2Cl 2, rt, 95 %
OTBS
OMe
CH 3
O
DMB
OH
OTBS
MeO
Me
S S
O
Me Me
Me
O
Me
TBS
ODMB
O
O H
O
TBS
OTBS
OPMB
Me OPMB
OMe
OMe
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

(Cp) 2ZrHCl, I 2
THF, 90 %
regioisomer 6 : 1
Dithiane Coupling to Synthesize Vinyl Iodide
Me
I
OTBS
MeO
HO
1. DDQ, LiOH, 85 %
Me
2. triphosgene, py, 88 %
3. TESOTf, 95 %
Me
I
OTBS
MeO
O
O
Me
ODMB
OMe H
O
OTBS
O
OMe H
O
OTBS
Me OPMB
Me OTES
OMe
OMe
+
Me
Me
I
NaBH 4, 86 %
I
OTBS
MeO
HO
OTBS
MeO
O
Me
Me
ODMB
OMe H
O
OTBS
ODMB
OMe H
O
OTBS
Me OPMB
Me OPMB
OMe
DMP, NaHCO 3
CH 2Cl 2, 88 %
OMe
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

Me
I
HO
n-Bu 3Sn
OTBS
MeO
Me
+
O
Synthesis of Fully Protected Apoptolidin
O
Me
1. Tf 2O, DTBMP,
Me
Me
Me
O
OMe H
O
Me
MeO
Et 2O, -90 o C, 1.5 h
2. KOH, 24 h
OTBS
O
A
CO 2Me
Me OTES
OTBS
O
SPh
OTBS
OMe
0.1 eq. PdCl 2(MeCN) 2
DMF, rt, 15 h, 86 %
TBSO
MeO
OTBS
A
O
Me
O
Me
OTBS
Me
MeO
HO
HO
Me
Me
Me Me Me
OH
OMe H
O
OTBS
MeO
CO 2H
OTBS
Me Me Me
O
O
Me
Me OTES
O
OMe H
O
OMe
CO 2Me
OTBS
Me OTES
OMe
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

Cl
Synthesis of Fully Protected Apoptolidin
O
Cl Cl
Cl
THF, 0 o C then rt, 5 h
1. (Cl 2Ac) 2O, py
0 o C, 5 min, 90 %
2. PPTS
0 oC, 15 h, 80 %
, Et 3N DMAP
toluene, rt, 12h
27 % over 3 steps
TBSO
OTBS
A
O
TBSO
OTBS
O
Me
Me
MeO
O
Me
Me
Me
TBSO Me
Me
Me
A
MeO
O
Me
Me
Me
TBSO
Me
MeO
Cl2AcO Me
O
O
OMe H
O
OTBS
MeO
HO
Me OH
Me
OMe
O
O
OMe H
O
OTBS
Me OTES
OMe
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

TBSO
Synthesis of Fully Protected Apoptolidin
OTBS
A
O
Me
Me
MeO
O
Me
Me
Me
TBSO
Me
TBSO
MeO
Cl2AcO Me
OTBS
A
O
O
OMe H
O
O
OTBS
Me
Me OH
Me
MeO
O
Me
Me
Me
TBSO
Me
MeO
Cl2AcO Me
OMe
O
+
O
OMe H
O
OTBS
SnCl 2
Me O
F
TESO Me
O Me
O
OMe
TESO Me
O
O Me
O
O
Me
Me
D E
Et 2O, rt, 12 h, 70 %
D E
OTBS
OMe
OTBS
OMe
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

TBSO
OTBS
Synthesis of Fully Protected Apoptolidin
O
Me
Me
MeO
O
Me
Me
Me
TBSO
Me
HO
A
OH
A
O
MeO
Cl2AcO Me
Me
Me
MeO
O
Me
Me
Me OH Me
MeO
HO
Me
O
O
OMe H
O
OTBS
O
O
OH H
O
OH
Me O
OMe
TESO Me
Me O
O Me
O
OMe
O
O Me
O
HO Me
O
Me
D E
Me
D E
OTBS
OMe
OH
OMe
1. HF py
THF, 96 h
2. Et 3N
MeOH, rt, 3.5 h
40 % over two steps
3. TsOH
THF / H 2O (1 / 1)
0 o C, 2.5 h, 60 %
36 steps (the longest linear)
0.28 % yield
Nicolaou, K. C. et. al. J. Am. Chem. Soc. ASAP

Hydrozirconation/iodination
Lipshutz, B. H. et. al. Tetrahedron Lett. 1990, 31, 7257.

Stereocontrolled Sn(OTf) 2 Mediated Aldol Reaction
Bn
O
H
N
O
R
Me
H
O
Me
H
O
L
O
Sn
L
Evans, D. A. et. al. J. Am. Chem. Soc. 1990, 112, 866.

Anti-Selective Reduction
Evans, D. A. et. al. J. Am. Chem. Soc. 1990, 110, 3560.

O
O
Li
t-BuLi
95 %
Cuprate
O
Bu 2Cu(CN)Li 2
Li
Preparation of Bromide
(Bu 3Sn)(Bu)Cu(CN)Li 2
O
MeI, 75 %
Cu CN
R
+
2-
Bu 3SnH
O Cu R
CN
HO
LiO
Me
SnBu 3
Cu(CN)Li
R
1. MsCl, Et 3N
2. LiBr, acetone
E +
Br
HO
Me
SnBu 3
Pancrazi, A. et. al. Tetrahedron 1996, 52, 6613.
E
R

Takai Reaction
Takai, K. et. al. Synlett 1999, 8, 1268.

Cu-Mediated Cross Coupling
Liebeskind, L. S. et. al. J. Am. Chem. Soc. 1996, 118, 2748.

Cl
Cl
O
Cl
Yamaguchi Lactonization
Cl
R'OH, DMAP
Benzene
+
R'O
O
RCOOH
R
+
Cl
Cl
Et 3N
THF
O
Cl
O
Cl
Cl
Yamaguchi, M. et. al. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
O
Cl
O
O
R

TrCl
MeO
Preparation of the Starting Aldehyde
O
Me
OTr
MeO
O
Me
OH
Methyl (R)-(-)-3-hydroxy-2-methylpropionate
LAH
1 g $ 20.30 Aldrich
HO
Me
OTr
Swern
H
O
Me
OTr
Terashima, S. et. al. Tetrahedron Lett. 1986, 27, 6241.

Addition of Trimethylsilylacetylene – Cram’s rule
TrO
O
H
Me
H
TMS

EtO
O
OH
OH
O
diethyl L-tartrate
BH 3THF
THF, reflux, 94 %
OEt
Preparation of the Starting Alcohol
HO
MeO
MeO
TsOH, DMF, 99 %
HO
OMPM
OH
OMe
EtO
O
O
O
O
Ar
3-pentanone, TsOH
THF, 89 %
OEt
NaBH 4, LiCl
THF, 100 %
Et
O
O
Et
OMPM
HO
OH
O
O
Ar
OH
Somfai, P. et. al. Tetrahedron 1993, 49, 6645.

Addition of Allyl Stannane to Aldehyde – Chelation
OTBS
s-BuLi
n-Bu 2SnCl, 77 % n-Bu 3Sn
TBSO
H
n-Bu 3Sn
O
H
H
Mg ++
OMPM
R
OTBS
100 % cis
Keck, G. E. et. al. Tetrahedron Lett. 1987, 28, 139.

Preparation of the Propagyl Aldehyde Derivative
H
PTS
OH
MeOH, 92 %
DHP, PPTS
CH 2Cl 2, 80 %
TES
OH
H
OTHP
PCC, NaOAc
CH 2Cl 2, 76 %
n-BuLi, TESCl
THF, 71 %
TES
O
H
TES
OTHP
Chattopadhyay, S. et. al. J. Org. Chem. 1998, 63, 6128

Pd Catalyzed Hydrostannylation
Pd(PPh 3) 2Cl 2 + 2 n-Bu 3SnH
R Br
Pd(PPh3) 2 + H2 + 2 n-Bu3SnCl n-Bu 3SnH R Br
Pd(PPh 3) 2Cl 2
n-Bu 3SnH R H
Pd(PPh 3) 2Cl 2
H Snn-Bu 3
H Snn-Bu 3
Guibe, F. et. al. J. Org. Chem. 1990, 55, 1857

Transformation of 1,2-Diols into Epoxides
Sharpless, K. B. et. al. Tetrahedron 1992, 48, 10515

HO
OH
H
HO
O
Preparation of the Starting Lactone
O
OH
L-Ascorbic Acid
H 2, Pd/C
EtOAc, Et 3N, 95 %
AcO
H 2, Pd/C
H 2O, 99 %
OAc
H
O
O
OAc
HO
OH
H
HO
KOH
72 %
O
O
OH
HO
AcCl
90 %
OH
H
O
O
OH
AcO
OAc
H
AcO
O
O
OAc
Andrews, G. C. et. al. J. Org. Chem. 1981, 46, 2976.
Pedersen, C. et. al. Acta. Chem. Scand. B 1981, 35, 155.