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Harnessing Glycal-Epoxide Rearrangements: The Generation of the AB, EF, and IJ Rings of AdriatoxinClement Osei Akoto and Prof. Jon D. Rainier*
Department of Chemistry, University of Utah315 South 1400 East Salt Lake City, UT 84112-085
[email protected]; [email protected]
O
O
O
O
O
O
O O
O O
NaO3SOH
HH
HH
Me Me
Me
H
H
Me
OSO3Na
OHH
H
A
EG
J
OH
H
H
HHHH
HH
HMe
Adriatoxin (ATX)
NaO3SO
BC
DF
H
I
Synthetic Studies of Adriatoxin:Synthetic Studies of Adriatoxin:
O
O
O
O
O
O
O O
O O
NaO3SOH
HH
HH
Me Me
Me
H
H
Me
OH
H
H
HHHH
HH
HMe
OH
HMe
OH
NaO3SO
AB
CD
E FG
H
I
J
K
5
8
11
14
17
21
24
29
32
3538
41
44
Yessotoxin (YTX)
Adriatoxin, an analog of yessotoxin (sulphated polyether toxin), was isolated from the digestive glands of mussels Mytilus galloprovincialis by Cimminiello and co-workers in 1997.1 It and its analogs exhibit potent neurotoxic action on cultured cerebellar neurons, they induce a two-fold increase in cytosolic calcium, they display potent cytotoxic activities against human tumor cell lines, and they induce caspase activation and cause apoptotic changes. 2
11st st Generation Retro-Synthetic Analysis of Adriatoxin:Generation Retro-Synthetic Analysis of Adriatoxin:
O
O
O
O
O
O
O O
O ONaO3SO
NaO3SOH
HH
HH
Me Me
Me
H
H
Me
OSO3Na
OHH
H
AB
CD
E FG
H
I
J
OH
H
H
HHHH
HH
HMe
O
O
PO
POH
HH
AB
HH
OH
HO
O
O
OH
H Me Me
E F
HHHPO
PO
O O
H
Me
OMe
OPH
H
I
J
OP
H
H+
+
O
OH
HO
OH
D-2-deoxyribose
HO
Homopropagyl alcoholO
OAc
OAc
OAc
D-glucaltriacetate
Our convergent 1st generation retro-synthetic strategy involves the coupling of the AB, EF and IJ ring subunits, which can be synthesized from D-2-deoxyribose, homopropagyl alcohol and D-glucal respectively.
Synthesis of the AB Ring Subunit of Adriatoxin:Synthesis of the AB Ring Subunit of Adriatoxin:
The A-ring was synthesized from D-2-deoxyribose in 6 steps having utilized our olefin metathesis, carbonyl olefination protocol. DMDO epoxidation followed by treatment with MgCl2 gave a ketone intermediate resulting from a stereoselective 1,2-hydride migration. Reduction, followed by cyclization and oxidation led to the AB ring core as a mixture of isomers. Oxidation, DBU equilibration and reduction of the resulting ketone gave the AB subunit as a single product. 3
Synthetic Studies of the IJ Ring Subunit of Adriatoxin:Synthetic Studies of the IJ Ring Subunit of Adriatoxin:
The synthesis of IJ ring subunit commenced from the functionalized I ring. Swern oxidation followed by MeLi addition provided the desired tertiary alcohol in 7 : 1 diastereomeric ratio. Subsequent vinylation followed by RCM led to the IJ ring framework. m-CPBA epoxidation in methanol followed by acetylation led to the IJ ring core. Inversion of the C32 stereocenter to that required for the synthesis of adriatoxin was achieved via hydrogenolysis and then oxidation of the resulting alcohol. Reduction of the resulting ketone with L-Selectride and acetylation gave the IJ-ring subunit. 3
11st st Generation Synthetic Studies of the EF Subunit of Adriatoxin:Generation Synthetic Studies of the EF Subunit of Adriatoxin:
BPSO OHL-DIPT, Ti(OiPr)4
t-BuOOH, 4A MS,CH2Cl2, -30oC, 30h, 85%, 88%ee
BPSO OHO
Ti(OiPr)4, PhMe,
OH, 70%
120oC, 6h1. TsCl, Py, DMAP,
2. K2CO3, MeOH, 50% (2 steps)
O
O
BPSO
CuCN, THF,CH2=CHMgBr, OBPSO
HO-78oC-(-40oC)-0oC, 2h, 80%
1.NaH, MeI, THF
2.''Ru'', PhMe, 60 oC, 60% (2 steps)
OBPSOH
MeOH
Rh(PPh3)3Cl,DABCO,
EtOH:H2O (9.5:0.5) 40%
OBPSOH
MeOH
1) DMDO, CH2Cl2
2) MgBr,
THF, 90%,
OBPSOH
MeOH
OHE
Ac2O, DMAP,Et3N, CH2Cl2
RT, 1 h, 90%
OBPSOH
MeOH
OAcE
J19,20 = 9.5 HzJ19,18 = 9.5 HzJ19,18` = 3.5 Hz
20
1918
d.r = ~10:1
OH
BPSO
OH
O
Starting from the allylic alcohol the acyclic diene was synthesized in 6 steps. Ring closing metathesis followed by isomerization with Wilkinsons catalyst resulted in the desired 7-membered ring formation. DMDO oxidation followed by allyl grignard addition gave the desired E ring framework in 10 : 1 diastereoselectivity.
22ndnd Generation Retro-Synthetic Analysis of Adriatoxin: Generation Retro-Synthetic Analysis of Adriatoxin:
The more convergent 2nd generation retro-synthetic analysis involves the formation of the EF subunit from D-mannitol, followed by the coupling of the 3 subunits (AB, EF and IJ rings) to generate Adriatoxin.
22ndndGeneration Synthesis of the EF Subunit of Adriatoxin:Generation Synthesis of the EF Subunit of Adriatoxin:
Starting from the acetonide protected D-glyceraldehyde, the E ring system can be synthesized in 5 steps using our olefin metathesis, carbonyl olefination protocol. Further 7 steps will lead to the EF ring core via our optimized glycal Claisen rearrangement protocol. 3 Further 9 steps will lead to complete functionalization of the EF subunit which will then be carried forward for coupling.
Coupling and End-Game of Adriatoxin:Coupling and End-Game of Adriatoxin:
Successful coupling of the AB and EF subunits gave the ABEF ring core in 82% yield. Followed by our olefin metathesis, carbonyl olefination reaction, and subsequent DMDO oxidation and reductive cyclization will give the fully functionalized ABCDEF ring. Coupling of the IJ-ring, followed by sulfonation and global deprotection will give the natural product adriatoxin.
ReferencesReferences
1.) Ciminiello, P.; Fattorusso, E.; Forino, M.; Magno, S.; Poletti, R.; Satake, M.; Viviani, R.; Yasumoto, T. Toxicon 1997, 35, 177–183.2.(a) Gomez, A. P.; Gutierrez, A. F.; Novelli, A.; Franco, J. M.; Paz, B.; Sanchez, M. T. F. Toxicological Sciences 2006, 90 (1), 168. (b) Konishi, M.; Yang, X.; Li, B.; Fairchild, C. R.; Shimizu Y. J. Nat Prod. 2004, 67, 1309. (c.) Malaguti, C.; Ciminiello, P.; Fattorusso, E.; Rossini, G. P. Toxicol. In Vitro 2002, 16, 357–363. (d) Leira, F.; Alvarez, C.; Vieites, J. M.; Vieytes, M. R.; Botana, L. M. Toxicol. In Vitro 2002, 16, 23-31.3.) Osei Akoto, C.; Rainier, J. D. Angew. Chem. Int. Ed. 2008, 47, 8055.
AcknowledgmentsAcknowledgments
Dr. Charles Mayne (NMR)Dr. Jim Miller (Mass Spec.)
University of UtahDepartment of Chemistry
Pfitzer Global Research and Development (PGRD)
1.H2, Pd(OH)2/C, EtOAc, 90%
2. SO3.Py, Et3N,
DMSO, DCM, 90%
O
(tBu)2SiO
OH
H
H
MeO
OAc
OMe
I J
O
Ac2O, DMAP,Et3N, CH2Cl2 O
(tBu)2SiO
OH
H
H
MeO
OAc
OMeI J
OAc
O
(tBu)2SiO
O
OBn
H
HOH
H 1.(COCl)2, DMSO, Et3N, CH2Cl2,
2.MeLi, PhMe,
-90 oC,
I O
(tBu)2SiO
O
OBn
H
HOH
H
Me(d.r = 7:1),
O
(tBu)2SiO
O
OBn
H
H
H
MeO
m-CPBA, MeOH,
2."Ru", RT, 1h, 60% (2 steps)
-63 oC-RT, 2h75% dr = 5.5:1
O
(tBu)2SiO
O
OBn
H
H
H
MeO
OH
OMe
I J 36
1,3J H36= 3.4, 3.6 Hz
Ac2O, DMAP,Et3N, CH2Cl2
RT, 1 h, 96%
O
(tBu)2SiO
O
OBn
H
H
H
MeO
OAc
OMeI J
353637
1,3J H36= 2.7, 3.3 Hz
80% (2 steps)
1.Hg(CF3O2C)2,
OEt
L-Selectride, 2 eqs.
THF, -78 oC, 90%
O
(tBu)2SiO
OH
H
H
MeO
OAc
OMeI J
OH(> 10:1)
J* = 3.4 Hz
96%32
32
O
OH
HH
AB
HH
Me
OH
TBSO
O
O
OH
H Me Me
E
HHHHO2C
TESO
O O
H
Me
OMe
OAcH
H
I
J
OBn
H
H++F
O
OPh
O
O
O
O
O
O
O O
O O
NaO3SOH
HH
HH
Me Me
Me
H
H
Me
OSO3Na
OHH
H
A
EG
J
OH
H
H
HHHH
HH
HMe
Adriatoxin (ATX)
NaO3SO
BC
DF
H
I1
4
8
14
1825
29
35 37
O
O
H
H
OH
MeO
Me
O
Ph
EF
OMe
22
23
19
HOOH
OH
OHOH
OH
D-Mannitol
O
O
H
H
O
Ph
O O
OH
H
Me
E 19
20
O
O
O
H
CH2CHCH2CH2Br, Mg, Et2O, rt-(-78 oC)
ZnCl2, -90 oC, Et2O, 87% (2 steps), d.r.= 6:1
O
O
OH1. PPTS, MeOH
reflux, 24h, 89% O
O
OHH
H
DCC, DMAP,CH2Cl2, RT, 24h
2. PhCH(OMe)2, CSA, RT, 82%
Ph
O
OH
O
O
OH
H
O
Ph
O
O
H
H
O
Ph
TiCl4, TMEDA,THF/DCM, Zn,
PbCl2, CH3CHBr2,
60 oC, 75 min., 65%
O O
O
OO O 1. DMDO, CH2Cl2;
DIBAL-H, CH2Cl2, -78 oC, 80%
2. SO3.Py, Et3N,
DMSO, DCM, 85%O
O
H
H
O
Ph
O O
O
H
E
1.MeMgBr, -78 oCPhMe (d.r.=5:1), 92%
2.PPTS, PhCl,Py, 135 oC, 75%
2. Allyl-Br, NaH, TBAI, DMF,0oC-65oC, 85%
1. m-CPBA, MeOH,-78 oC-RT, 2h, 88%
O
O
H
H
OH
MeO
Me
O
Ph
EFO
O
H
H
OH
MeO
Ph
EF
OMe
PPTS, PhMe,Py, 100-120 oC,
92%, d.r.= >10:1
O
O
H
H
OH
MeO
O
PhMe
1. NaBH4, MeOH 94%
2. PMBBr, KH, TBAI, DMF, 86%
EF O
O
H
H
OH
MeO
OPMB
PhMe
H
EF
2122
J21,22 = 4.4 HzJ21,22 = 12.2 Hz
3
2
1 1`
2`
3`O
O
H
H
OH
MeO
O
Ph
E
[3,3] Claisen Rearrangement
F[3,3]
2. TBSCl, DMF, imidazole, 50 oC, 85%3. CSA, MeOH, 93%
HO
TBSO
H
H
OH
MeO
OPMB
Me
H
EF
1. TsCl, Et3N, CH2Cl2, 94%2. NaCN, DMF, 60 oC, 96%
3. iBu2AlH, CH2Cl2, -78 oC,4. NaClO2, tBuOH, NaH2PO4, H2O, 2-Me-2-butene, THF, (65%, 2 steps)
1. CSA, MeOH, 93%HO2C
TBSO
H
H
OH
MeO
OPMB
Me
H
EF
O
O
O
OPh
Me H
H H
OHH
H
BA EHO2C
PMBO
H
H
O
Me
H
O Me
OPMBH
F
TESO
OH
H
H
MeO
OBn
OMe
OBn
I J
+
O
O
O
OPh
Me H
H H
OH
H
BAO
E
HO
H
H
O
Me
H
O Me
OPMBH
F
O
O
O
OPh
Me H
H H
OH
H
BA E
O
H
H
O
Me
H
O Me
OHH
F
C D
H
H
Yamaguchiesterification
1. RCM2. DMDO, DIBAL-H
coupling
Adriatoxin
3. Reductive cyclization
Cl3C6H2COCl, THF, Et3N;DMAP, PhMe, (82%)
O
OH
HO
OH
D-2-deoxyribose
1. Ph3PMeBr, t-BuOK, 2. PhCH(OMe)2,CSA, 60% (2 steps)
3. (COCl)2, DMSO, Et3N, -78 oC,4. MeMgBr, Et2O, -78 oC, 60% (2 steps)
O
OPh
MeOH
H
DCC, DMAP,DCM, RT, 24h
MeO
OMe
O
OH
80%
TiCl4, TMEDA,THF/DCM, Zn,
PbCl2, CH3CHBr2,
50 oC, 60 min., 60%
O
O
OMe
H
O
Ph
OMeMeO
O
OPh
Me
H
OOMe
OMe
A
DMDO, CH2Cl2, MeMgBr
1. NaBH4, MeOH 90%
orDMDO, CH2Cl2, MgBr2
.Et2O
O
OPh
Me
H
OOMe
OMe
O
H
DMDO, CH2Cl2,THF, MgCl2, 75%
O
OPh
Me
H
OOMe
OMe
O
H
J19,20 = 10.3 HzJ19,18 = 10.7 HzJ19,18`= 5.4 Hz
2019
18
O
OPh
Me
H
OOMe
OMe
OAc
H
H
O
OPh
Me
H
OH
HO
1) DMDO, CH2Cl2
2) MgBr,
THF,
O
OPh
Me
H
OH
HO
OH
A B
2. PPTS, PhCl, Py, 135 oC, 90%
2.3:1 mixture of isomers
1.(COCl)2, DMSO, Et3N, -78 oC
2. DBU, equilibration
O
OPh
Me
H
OH
HO
A B
H
A
AA B
O
OPh
Me
H
OH
HO
OH
A B
H
H
O NaBH4, MeOH
60% (3 steps)
EFFORTS TOWARDS THE SYNTHESIS OF PECTENOTOXINEFFORTS TOWARDS THE SYNTHESIS OF PECTENOTOXINClement Osei Akoto and Prof. Jon D. Rainier*
Department of Chemistry, University of Utah315 South 1400 East Salt Lake City, UT 84112-085
[email protected]; [email protected]
Synthetic Studies of Synthetic Studies of PectenotoxinPectenotoxin ::
Isolated from the scallop Patinopecten yessoensis in Japan in 1985 by Yasumoto et al.1 Toxin produced by dinoflagellates (toxic microorganisms) Dinophysis fortii and D. accuminata upon which the shellfish (scallop) feed.1 Displays very potent cytotoxic activities against human lung, colon and breast cancer cell lines with LC50 values in the nanomolar range.2 Lack of activity in DNA-cleavage and rat plasma membrane assays implying it does not block DNA synthesis or reduction-oxidation processes in cell membrane.2 Depolymerizes actin (F-actin) filaments and induces apoptosis in p53 deficient tumor cells.3
Retro-Synthetic Analysis of Retro-Synthetic Analysis of Pectenotoxin Pectenotoxin ::
Our retro-synthetic strategy involves the formation of pectenotoxin 1/6 from fragments A and B via sp2-sp2 (C-C) formation and macrolactonization. The coupling fragment B would come from fragments D, E and F through esterification and olefin metathesis, carbonyl olefination protocols4 to generate the imbedding furans. The fragment D would be generated from fragments G and H through esterification/olefin metathesis, carbonyl olefination, followed by lewis acid controlled or directed spirocyclization. The fragments G and H were formed from commercial available homopropagyl alcohol and D-gluconolactone respectively.
Synthesis of the Fully Functionalized Fragment H :Synthesis of the Fully Functionalized Fragment H :
The H-fragment was synthesized from D-gluconolactone in 6 steps having utilized acetonide protection, SN2 chloride displacement of the alcohol, base (NaOAc) induced β-elimination protocol, followed by hydrogenation/dehalogenation, then TBS-protection and hydrolysis. Efforts to cleave the TBS ether gave the lactone but was circumvented via switching to PMB ether.
Synthesis of the Fully Functionalized Fragment G :Synthesis of the Fully Functionalized Fragment G :
Starting from homopropagyl alcohol, the allylic alcohol was synthesized in 3 steps, which was subjected to Sharpless5epoxidation to give the epoxide in very good selectivity. From the epoxide, the requisite aldehyde was obtained in 5 steps which was then subjected to Evans6 oxazolidinone via Z-enolate to generate the desired syn product in good level of diastereocontrol. Removal of the chiral auxilliary, followed by selective primary benzyl ether protection gave the G-fragment.
Model Studies Towards Fragment D :Model Studies Towards Fragment D :
Swern oxidation followed by methyl Grignard addition provided the alcohol which was esterified to give the desired ester. Takai7 olefinition resulted in a highly unstable diene which easily hydrolysis on column to give back the alcohol and corresponding methyl ketone. Ring closing metathesis on the crude unstable diene either with Grubbs8 2nd generation catalyst or Schrock9 Mo catalyst leads to recovered starting material and decomposed products.
Towards the Synthesis of Fragments D and E : Towards the Synthesis of Fragments D and E :
TOP: Esterification of the fully functionalized fragments G and H gave D4, which would be subjected to olefin metathesis, carbonyl olefination to give the dihydropyran A-ring subunit. DMDO oxidation followed by Lewis acid spirocyclization and deoxygenation would give the D-fragment of pectenotoxin. BOTTOM: Starting from Roche ester, the methyl ketone E4 was synthesized in 5 steps, which would be subjected to Tietze’s allylation10, followed by hydroboration,/cyclization to give E2. Nitration and oxidation would give the E-fragment.
Coupling and End-Game of Coupling and End-Game of Pectenotoxin Pectenotoxin ::
We anticipated that esterification of fragments E and F, followed by our olefin metathesis, carbonyl olefination reaction, and cyclization would give fragment C. Further esterification of fragments C and D, followed by olefin metathesis, carbonyl olefination reaction and subsequent DMDO oxidation and 1,2-hydride migration would give the fully functionalized fragment B. Coupling of fragments A and B, followed by macrolactonization and global deprotection will give the natural product pectenotoxin.
ReferencesReferences
1.) Yasumoto, T.: Murata, M.: Oshima, Y.: Sano. M.: Matsumoto, G. K.: Clardy, J. Tetrahedron 1985, 41, 1019.2.) Jung, H. J. J. Nat Prod. 1994, 58, 1722.3.) Chae, H.: Choi, T.: Kim, B.; Jung, J. H.; Bang, Y.; Shin, D. Y. Oncogene (2005), 1-7.4.) Osei Akoto, C.; Rainier, J. D. Angew. Chem. Int. Ed. 2008, 47, 8055.5.) Gao, Y.; Klunder, M. J.; Hanson, M. R.; Masamune, H.; Soo Y. Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109; 5765-5780.6.) Evans, D. A. JACS 1981, 103, 2127. (b) Smith, A. B.; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011.7.) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994, 59, 2668.8.) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. (b) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783. (c) Rainier, J. D.; Cox, J. M.; Allwein, S. P. Tetrahedron Lett. 2001, 42, 179.9.) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. B. J. Am. Chem. Soc. 1990, 112, 3875.10.) Tietze, L.F.; Schiemann, K.; Wegner, C. J. Am. Chem. Soc. 1995, 117, 5851.
AcknowledgmentsAcknowledgments
Dr. Charles Mayne (NMR)Dr. Jim Miller (Mass Spec.)
University of UtahDepartment of Chemistry
Pfitzer Global Research and Development (PGRD)
O
Me
OHOH
O
O
H Me Me
O
H
OO
OP
H
HO
H
O
O
OO
MeH
H
Me
OHMe
Pectenotoxin 1/6, P = H
AB C
DEF
G
scallop Patinopecten yessoensis
O
Me
OHOH
O
O
H Me Me
O
H
OO
OP
H
HO
H
O
O
OO
MeH
H
Me
OHMe
Pectenotoxin 1/6
O
Me
OPOP
O
OP
H HX
OH
Me Me
OO
O
OP
H
HO
H
O
O
OO
MeH
H
Me
OHMe
Y
A
B
coupling
+
A
A
B
B
C
D
D
E
E
F
F
G
G
OROHO
OO
MeH
H
Me
OPD
Me Me
OOHHMe
Y O
HOPO
R
HPO
O
EF
+
+
esterification
OH
MeH
PO
OPOH
OO
HO
+
GH
BPSO
Ph
coupling
macrolactonization
C
cyclization
A
E
from fragment B
esterification,olefinic cyclization
spirocyclization
from fragment D
OHOH2C
OH
HO OH
O
D-gluconolactoneHomopropagyl alcohol
HO
CO2Me
O
OHO
Cl
H2, Pd/C, 12h,
CO2Me
O
OHO
OHOH2C
OH
HO OH
O O
,MeO OMe
H+, MeOH OH
CO2Me
O
O
OO CCl4, PPh3
imidazole
CO2Me
O
O
OO
Cl50h, rt, 75% 5h, 40 oC, 80%
Reflux, 24h 76% (2 steps)
D-gluconolactone
H1 H2
NaOAc, MeOH,
H3
CO2H
O
OTBSO
TBSCl, imidazole,
DMF, DMAP, RT, 3h, 95 %
CO2Me
O
OTBSO
LiOH, H2O, MeOH,
RT, 5h, quant.
H4
O
O
O
O
3) HF-Py, RT, 24h
1) TBAF, RT, 2h
2) TBAF, 0 oC, 30h
All 3 trials gave lactone
CO2Me
O
OHO
CO2Me
O
OPMBO
CO2Me
O
OHO
DDQ, CH2Cl2,H2O, RT, 20 min.
NH
OCl3CPMB
CSA (cat), DCM,0 oC-RT, 8h, 88%
H3 H3H6CO2H
O
OPO
H
H
86%
HOPMBO
PMB-Br, NaH
0 oC-RT, THF,PMBO OH
PMBO OH
24h, quantitative
BuLi, CH2O,
24h, 88%
Red-Al, THF
0 oC-RT, 85%
L-DIPT, Ti(OiPr)4
t-BuOOH, 4A MS,CH2Cl2, -30 oC2.5d, 90%, 98%ee
PMBO OHO
0 oC-RT, THF,
PMBO
OHH
OHC
OBPS
PPh3, I2, imidazole,CH3CN/THF (1:4),
Zn, HOAc, MeOH, 1h
DDQ, CH2Cl2,H2O, RT, 20 min.,
(COCl)2, DMSO,
RT, 30 min.,quantitative
PMBO IO
90%
BPSCl, DMF, imidazole, RT
20h, 90%
PMBO
OBPSH
90%
HO
OBPSH Et3N, CH2Cl2, -78 oC-RT, 93%
O N
O
Bn
OBu2BOTf, DIPEA
d.r.=8:1, 88%
+
OBPS
Xc
HO H
HMe
O
LiBH4, Et2O,
0 oC-RT, 86%
HO
OH OBPS
BnO
Me
OH OBPS
BnBr, Ag2O,CH2Cl2, RT
36 h, 60%G
OBPS
(COCl)2, DMSO,
HO
OBPSH
Et3N, CH2Cl2, -78 oC-RT, then,
MeMgBr, THF,0 oC, 70% (2 steps), (d.r. = 2:1)
Me
OH
DCC, DMAP,DCM, RT, 24h, 89%
CO2H
O
OPO
O
OPO
OO
Me OR
TiCl4, TMEDA,THF/DCM, Zn, PbCl2, CH2Br2,
40-50 oC, ~2h
O
OPO
O
Me OR
Highly unstable compound
on columnchromatography
O
OPO
O
+HO
Me OR
(acid hydrolysis)
P = PMB, TBSR = BPS, Me
Crude unstable compoundP = PMB, TBSR = BPS, Me
O
OPO
O
Me OR
SM + Decomposed products
"Ru" cat.2nd generation
CH2Cl2 or CHCl3, 1,4-benzoquinone,40-60 oC, 2-3 d
"Mo" cat.(Schrock)
Hexane, 55-60 oC1-2 d
O
OPO
O
Me OR
OROHO
OO
MeH
H
Me
OPD
AB
DCC, DMAP, DCM, RT, 24h, 78%
CO2H
O
OPMBO
BnO
Me
OH OBPS
G
O
O
MeH
HO
O
BnO
BPSO
OP
MB
OROHO
OO
MeH
H
Me
OP
DD4
H
HO
OMe
Cl3CCN, NaH(10%),Et2O, 0 oC-RT,
24h, 82%
NH
OCl3CPMB
HO O
Me
O
,
CSA (cat), DCM,0 oC-RT, 8h,quantitative
PMBO O
Me
O LiAlH4, THF,
0 oC-RT, 24h,quantitative
PMBO OH
Me
1)MsCl, Et3N, DCM,PMBO Ms
Me
2) NaCN, DMSO,60 oC, 24h,
80% (2steps)PMBO CN
Me
MeLi, Et2O,
PMBO
Me O
Me
E4
POMe
O HMe
O
EPO
Me
O OMe
E2
1) Tietze'sallylation
2) hydroboration,cyclization
1) nitration
2) oxidation
0 oC, 45 min. 0 oC, 1h, 80%
OH
E
AB
OROHO
OO
MeH
H
Me
OPD
Me Me
OOHHMe
Y O
HOPO
R
HPO
O
E
F
+
+
AE B
Me Me
OO
O
OP
H
HO
YD
E
OH
i. esterificationii. "Takai"
iii. cyclization
OH
Me Me
OO
O
OP
H
HO
H
O
O
OO
MeH
H
Me
OHMe
Y
B
AB
DE
C
i. esterificationii. "Takai"iii. oxidation
O
Me
OHOH
O
O
H Me Me
O
H
OO
OH
H
HO
H
O
O
OO
MeH
H
Me
OHMe
O
Me
OPOP
O
OP
H HX
A
AB C
DEF
FG
G
i. coupling
ii. macrolactonization+
C
Pectenotoxin 1/6