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Kang Hyun JungKang Hyun Jung
O
O
O
O
O O
NO
NH
OMe
O
O
Me
1
57
9
12
17
1 : leucascandrolide A
IntroductionIntroduction
Leucascandrolide A (1, Scheme 1) was isolated in 1996 from the calcareous sponge Leucascandra caveolata,
collected off the east coast of New Caledonia, by Pietra and co-workers.
- This polyoxygenated 18-membered macrolide features two trisubstituted tetrahydropyran rings, one of
which has an unusual oxazole-bearing unsaturated side chain.
- Biological studies revealed potent cytotoxic activity against a range of cancer cell lines (IC50¼0.05 and
0.25 mgmL1 against KB oral epidermoid carcinoma and P388 leukemia cell lines, respectively), as well
as pronounced antifungal activity.
Retro-Synthetic AnalysisRetro-Synthetic Analysis
O
O
O
O
Me
O
O
NO
NO
OMeH
OTBS
CHO
5 C11-C15 subunit
O
OTIPS
O
O
Me
OH
OH
2
O
NO
NHCO2Me
OHO
3
O
OTIPS
OPMB
O
4 C1-C10 subunit
OTMS
6 C16-C23 subunit
1 : Leucascandrolide A
Mitsunobumacrolactonization
Mitsunobuesterification
double Lindlar hydrogenation
1,5-anti aldol reaction
enol silanealkylation
1
17
12
9
7
5
11
15 1
5
11
1'
11
15
5
1
16
23
Preparation of Advanced Intermediate 18Preparation of Advanced Intermediate 18
TBSO
O
H
OTES
OPMB
7
8
9 (10mol%)
4A MS, 20oC, 20h ;
acidified CHCl3, 20oC, 4h
80 %> 20:1 d.r. > 98% ee
TBSO
O
O
OPMB
10
NaBH4, MeOH
20oC, 2h, 99%
13 : 1 d.r.
R2O
O
OR1
OPMB
11 R1=H, R2=TBS
12 R1=TIPS, R2=H
1) TIPSOTf, 2,6-lutidine
CH2Cl2, -78oC, 2h
2) CSA, 2:1 MeOH/CH2Cl2
20oC, 1h, 82%
1) Tf2O, pyr, CH2Cl2, -10oC, 1h
2) LDA, TMSC CH, HMPA, -78-->20oC,
1h,K2CO3, MeOH, 20oC, 12h, 84%
R
O
OTIPS
OPMB
13 R= C CH
4 R= COMe
cat. Hg(OAc)2, PPTS
wet THF, 40oC, 1h, 86%
OTBS
CHO
5
cHex2BCl, Et3N, Et2O, 0oC, 30min
5, -78oC, 2h; -78->-30oC, 24h, 99%
O
OTIPS
OPMB
OTBS
OH O
1,5-anti
14
17 : 1 d.r.
Jacobsen Asymmetric Hetero Diels-Alder rxn [1]
[2]HgII- madeated hydration
Asymmetric Aldol Reaction [3]
Jacobson Asymmetric Hetero Diels-Alder Reaction Jacobson Asymmetric Hetero Diels-Alder Reaction [1][1]
O
N OCr
O
HTBSO
OPMB
TESO
TBSOH
O
OPMB
OTES
+
7
8
9
4A MS, 20oC, 20h;
acidified CHCl3, 20oC, 4h
(10mol%)
(80%)
> 20:1 d.r.> 98% ee.
TBSO
O
OPMB
O
10
O
N
O
Cr Cl
Angew. Chem. Int. Ed., 38, 2398-2400, 1999
Angew. Chem. Int. Ed., 41, 1668-1698, 2002
HgHgIIII-Mediated Hydration of Alkyne -Mediated Hydration of Alkyne [2][2]
- Alkynes are less basic than alkenes, Hg(OAc)2 (Hg+2 is a Lewis acid) is added to ensure complete reaction
R C CHHg(OAc)2 , H+
THF/H2O
C CR
OH
H
H
an enol intermediate
C CH3
R
O
energetically favored keto form
Hg OAcAcO
R C C H
Hg
OAc
H2O
Markovnikov rule
C C H
Hg
OAc
R
OH
H-OAc-
-OAc
C CR
OH
-AcOH
HOH
H
C CR
OH
C C H
Hg
OAc
R
OH
H3O+
H
H
H
HC C
R
OH
HH
H
H2OC C
R
O
HH
H -H3O+
enol intermediateketo form
C C
1,5-Anti Stereoindution in the Boron-Mediated Aldol Reaction1,5-Anti Stereoindution in the Boron-Mediated Aldol Reaction [3][3]
Org. Lett.,4, 4325-4328, 2002
O
OPMB
OTIPSMe
O
O
PMBO
TIPSO
OB
L
L
O C
OB
L
LO
H R
OTIPSH
HH
R
H
H
H
aldehydere-face attack
OTBS
CHO
5
cHex2BCl, Et3N, Et2O, 0oC, 30min
5, -78oC, 2h; -78->-30oC, 24h, 99%
O
OTIPS
OPMB
OTBS
OH O
1,5-anti
14
17 : 1 d.r.
O
OTIPS
OPMB
OTBS
OH O
14
Me4NBH(OAc)3, 3:1 MeCN/AcOH
-40 -20oC, 24h, 99%O
OTIPS
OPMB
OR
OH OH
15 R=TBS
16 R=H
CSA, 2:1 MeOH/CH2Cl2
25oC, 1h,
> 49:1 d.r.
TEMPO, PhI(OAc)2
CH2Cl2, 20oC, 12h, 79%(2steps)
O
OTIPS
OPMB
O
O OR
Me3OBF4, proton sponge
CH2Cl2, 0 20oC, 1h, 84%
1,3-anti reduction [4]
1,3- anti
Selective oxidation of primary alcohol [5]
O
OTIPS
OPMB
O
O OMe
1817
1,3-Anti Reduction of 1,3-Anti Reduction of β-Hydroxy Ketoneβ-Hydroxy Ketone [4][4]
R1 R2
OH O Me4NHB(OAc)3
R1 R2
OH OH
R1 R2
OH OH
Anti diol Syn diol
Major Minor
J. Am. Chem. Soc., 110, 11, 3560-3578, 1988
H
BO
H
R1
O
R2
OAc
OAc
H
BO
H
R1
R2
O
OAc
OAc
H
H
R1 R2
OH O
Me4NHB(OAc)3
Me4NHB(OAc)3
Major
Minor
R1 R2
OH OH
R1 R2
OH OH
Anti diol
Syn diol
Selective Iodine(III)/TEMPO-Mediated Oxidation Selective Iodine(III)/TEMPO-Mediated Oxidation [5][5]
PhI(OAc)2
R
OH
R'[bis(acetoxy)iodo]benzene
(BAIB)
N
OTEMPO (cat.)
R
O
R'PhI 2AcOH
J. Org. Chem., 62, 6974-6977, 1997
N
O
TEMPO(2,2,6,6-tetramethyl-1-piperidinyloxyl)
+ R1
R2
OH
H
-H+ O
R1 R2 N+
OH
N
OH
N
O
BAIB
2
H+
Radical
Elaboration to the Macrocyclic Core 24Elaboration to the Macrocyclic Core 24
O
OTIPS
OAc
O
O
OPMB
Me
19
O
OTIPS
OPMB
O
O OMeDIBAL, CH2Cl2, then Ac2O, pyr
DMAP, -78 -20oC, 15h
18
LAH(OtBu)3, CH2Cl2
-78 -10oC, 1.5h, 76%
OTMS
6
ZnBr2, CH2Cl2, 20oC
4h, 81%(2steps)
O
OTIPS
O
O
OPMB
Me
20
O
50 : 1 d.r.
O
OTIPS
O
O
Me
OH
32 : 1 d.r.
17(S)1,3-syn
OPMB
21
DIBAL- reduction & in situ acetylation [6]
1,3-Asymmetric redution
( LAH(OtBu)3, ZnBr2, 5:1 d.r. )
[7]
DIBAL Reduction and DIBAL Reduction and in situin situ Acetylation Acetylation [6][6]
R OR
O DIBAL
CH2Cl2
-78oC
R OR
OAl(iBu)2
H
Ac2O, pyr.
DMAP
-78oC 0oC
R OR
OAc
H
J. Org. Chem., 61, 8317-8320, 1996
O O
R O
O O
R O
O O
R OH
O O
R SPh
Unstable
O O
R OAlR2
Stable
O O
R OAc
1,3-Asymmetric redution 1,3-Asymmetric redution [7][7]
OO LAH(OtBu)3 OHO
1,3-syn
H H
OR
O H
H-
Evans polar model
H H
O H
OHR
H
OH
R
O OH
R
O
1,3-syn
O
OTIPS
O
O
Me
OH17(S)
1) Ac2O, pyt, DMAP, CH2Cl2, 0 20oC, 15h
2) DDQ, 10:1 CH2Cl2/pH7 buffer, 20oC, 1h, 99%
1) TEMPO, PhI(OAc)2, CH2Cl2, 20oC;
NaClO2, NaHPO4, methyl-2-butene
aq. tBuOH, 0 20oC, 1h
OPMB
O
OTIPS
O
O
Me
OAc
OH
21 22
O
OTIPS
O
O
Me
OH
OH
2
O
2) K2CO3, MeOH, 20oC, 18h, 71%
O
OTIPS
O
O
Me
O
O
17(R)
DEAD, PPh3, PhH
20oC, 5min, 65%
HF pyr. THF,
0 20oC
5h, 95%
23
O
OH
O
O
Me
O
O
24
Mistunobu macrolactonization [8]
Mistunobu Macrolactonization (Esterification)Mistunobu Macrolactonization (Esterification)[8][8]
N NC CC2H5O
O O
OC2H5
PPh3
N NC CC2H5O
O O
OC2H5
PPh3
RC
O
OH
NHNC CC2H5O
O
OC2H5
PPh3
O
RC
O
O
HO
HN
HNC CC2H5O
O
OC2H5
ORC
O
O
R2
R1O
Ph3P
SN2 type
inversion
R2
R1
RC
O
O
R1
R2
R2
R1HO
DEAD, PPh3R2
R1O
O
R
O
R OH
Synthesis, 1, 1981
Preparation of the Oxazole-bearing Side Chain 3Preparation of the Oxazole-bearing Side Chain 3
NNMe2
OTBS
OPMB
Br
26
25
1) LDA, HMPA, THF, -78 20oC, 2h
2) TBAF, THF, 20oC, 1h, 65%OH
OPMB
O
27
1) Cl3CC(O)NCO, CH2CL2, 20oC, 1h;
K2CO3, MeOH, 20oC, 1h
2) 4A MS, Toluene, 90oC, 2h, 49%
O NH
O
OPMB28
Tf2O, lit, CH2Cl2, -78 -10oC, 1hO N
OTf
OPMB29
HN
CO2Me
30
[Pd(PPh3)4], 30, lut, 1,4-dioxane, 20oC , 6h
NO
NHCO2Me
HO1) DDQ, 10:1 CH2Cl2/pH 7 buffer, 20oC, 1h
2) TEMPO, PhI(OAc)2, CH2Cl2, 20oC, 1h;
then NaClO2, NaHPO4, methyl-2-butene, aq. tBuOH
0 20oC, 1h, 36%( 5 steps)
NO
NHCO2Me
OHO
3
alkylation of hydrazone [9]
o
Sonogashira Coupling [10]
α-α-Alkylation of Hydrazone and Alkyl halide Alkylation of Hydrazone and Alkyl halide [9][9]
Sonogashira Coupling of Functionalized Trifloyl Oxazole Sonogashira Coupling of Functionalized Trifloyl Oxazole [10][10]
Org. Lett.,4, 2485-2488, 2002
Completion of the Total Synthesis of Leucascandrolide ACompletion of the Total Synthesis of Leucascandrolide A
NO
NHCO2Me
OHO
3
O
OH
O
O
Me
O
O
24
DEAD, PPh3, 1.5:1 THF/Toluene
0 20oC, 18h, 81%
O
O
O
O
Me
O
O
ON
O
NO
OMeH
5
31
H2, 5% Pd/CaCO3, poisoned with lead(Lindlar catalyst)
quinoline, EtOAc, 20oC, 2h, 92%
O
O
O
O
Me
O
O
NO
NO
OMeH
5
1 : (+)-leucascandrolide A
Mistunibu esterification [8]
Lindlar hydrogenation [11]
Lindlar Hydrogenation Lindlar Hydrogenation [11][11]
ConclusionConclusion
In summary, we have completed a highly stereocontrolled synthesis
of the potent cytotoxic macrolide leucascandrolide A, proceeding in
23 steps from 8 (longest linear sequence) and 5.3% overall yield. Key
features include a Jacobsen asymmetric hetero Diels-Alder reaction
to configure the right-hand tetrahydropyran ring, a 1,5-anti aldol
coupling, control over the C17 hydroxy center, and two sequential
Mitsunobu reactions, to close the 18-membered macrolactone and
append the oxazole-bearing side chain, respectively.
