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

rainier@chem.utah.edu; coakoto@yahoo.ca

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

rainier@chem.utah.edu; coakoto@yahoo.ca

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