A Multifaceted Phosphate Tether Application to the C15-C30 ...ccc.chem.pitt.edu/wipf/Current Literature/Karla_1.pdf · 5/11 Karla Bravo @ Wipf Group Page 5 of 11 3/30/2008 - Bicyclic

A Multifaceted Phosphate Tether :Application to the C15-C30 Subunit of

Dolabelides A-D

Karla BravoCurrent Literature

03/29/2008

Karla Bravo @ Wipf Group 03/29/2008

OAc OR1 OR2

Me

OR2 OR2 O

O

Me

OR1

Me

MeMe OAc

19 21 23 25 273015

Dolabelide C R1 = Ac, R2 - H

Dolabelide D R1 = R2 = H

O

POO

O

Hydroboration or CM

CuprateAddition

19

21

OH OH

19 21

Whitehead, A.; Waetzig, J. D.; Thomas, C. D.; Hanson, P. R. Org. Lett. 2008 ASAP

1/11

Karla Bravo @ Wipf Group Page 1 of 11 3/30/2008

Dolabelides A-D- Isolated from the Japanese sea hare Dolabella auricularia Solander (family Aplysiidae).

Ojika, M.; Nagoya, T.; Yamada, K. Tetrahedron Lett. 1995, 36, 7491-7494.Suenaga, K.; Nagoya, T.; Shibata, T.; Kigoshi, H.; Yamada, K. J. Nat. Prod. 1997, 60, 155-157.

- Dolabelides A-D show cytotoxicity against human cervical cancer HeLa-S3 cells with IC50 values of 6.3, 1.3, 1.9, and 1.5 µg/mL, respectively.

- Unknown mechanism of action.

- Attributes: 11 stereogenic centers (8 C-O), two E- trisubstituted olefins,1,3 anti-diol at C7/C9 and C19/C21, 1,3-syn-diol at C9/C11

OAc OAc OH

Me

OH O OH

Me

OR

Me

MeMe OAc

19 21 23 25 273015

O

dolabelide A R = Ac

dolabelide B R = H

22-member macrolides

OAc OR1 OR2

Me

OR2 OR2 O

O

Me

OR1

Me

MeMe OAc

19 21 23 25 273015

dolabelide C R1 = Ac, R2 = H

dolabelide D R1 = R2 = H

24-member macrolides

79 79

11 11

33

1414

11

2/11


Only total synthesis in the dolabelide family: Dolabelide D

Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am. Chem. Soc. 2006, 128, 2796-2797.

Leighton strategyFragment C15-C30: 10 steps, 11% overall yield

C15-C30

3/11

n-Pr

OH

Me

SiH2

t-Bu4 mol% CuCl, 4 mol% NaOt-Bu,

4 mol% (R,R)-BDPP, PhH

Me

Sit-Bu

O

n-Pr

H

Me

n-Pr

OTESSiMe Me

t-Bu

OH

i. 2 mol% [Rh(acetone)2(P(OPh)3)2]BF4,

CO, PhH, 60oC

ii. MeLi, Et2O, -78 to 23oC, 56%, 4:1 dr

iii. TESCl, Et3N, CH2Cl2, -20oC, 74%

95%, 4:1 dr

n-BuLi, THF, -78oC;

CuBr.Me2S, DMPU, 23oC;

MeI, -78 to 23oCMe

n-Pr

OTESMeOTBS

92%

i. 25 mol% PdCl2, CuCl, DMF, THF, H2O, O2

ii. Ac2O, pyr, DMAP, CH2Cl2

Me

Me

n-Pr

OAcO Me

TBS

O

78%

(+)-(ipc)2BCl, Et3N, 5-hexenal,

Et2O, -78 to 23oC

Me

n-Pr

OAcO Me

TBS

O

3

OH

85%; >10:1 dr

Me4NBH(OAc)3, AcOH, CH3CN, THF,

-40 to -20oC91%, >10:1 dr

Me

n-Pr

OAcO Me

TBS

OH

3

OH

Me

n-Pr

OAcOH MeO

3

O

i. 1,1-Dimethoxycyclopentane, PPTS, CH2Cl2

ii. n-Bu4NF, THF

50%

OAc OTES OPMB

Me

OHO

Me

OPMBMe+

i. 2,4,6-trichlorobenzoyl chlorideEt3N, DMAP, tol, -78 to 0oC

ii. PPTS, MeOH

iii. DDQ, CH2Cl2, pH 7 buffer

OAc OH OH

OH OH O

O

Me

OH

Me

MeMe OAc

Me3

25 mol% 2nd. Gen. Grubbs catalyst,CH2Cl2, reflux

52%

31%

Dolabelide D

OAc OR OR

Me

OHO

Me

ORMe

1

14

O

Me

Me OAc

3015

O OH

Esterification

RCM

Fragment C1-C14

Fragment C15-C30


Hanson Strategy : Retrosynthetic analysis of dolabelide by means of phosphate tethers

Waetzig, J. D.; Hanson, P. R. Org. Lett. 2008, 10, 109-112.

4/11

OAc OAc OH

Me

OH O OH

Me

OAc

Me

Me

Me OAc

19 21 23 25 2730

15

O

79

11

3

14

1

Lactonization

RCM

dolabelide AOR OR OPMB

Me

OH

Me

OR

MeO

79

11

3

14

1

2

1 C1-C14O

P

O

OO

Me

OPMB

Me

OP3

Pd(0)-Reductive Ring OpeningCM

n-Pr

OP1 OP2 OP2

Me

Me OP2

19 21 23 25 27

3

C15-C30

15

4

OP1 OP2

Me

19 21 23

O

H

n-Pr

Me OP2

27I

24

+

O

POO

O

Hydroboration or CM

CuprateAddition

19

21

OH OH

O

P

O

OO

RCM

(S,S) -8

5

6

Me

OPMB

Me

OP3

+

7(R,R) -8

7

9

14

7

9

56

OH OH

(S,S) -9 (R,R) -9

P

O

Cl Cl

Cl

O O


Phosphorus based tethersPhosphorus based tethers

The concept: temporary union of two reacting centers with a "disposable" bridging or tether group unimolecularity implies reduction of entropic demands and degrees of freedom

Representative examples:Representative examples:

O

BnO

BnOOBn

SePhHN

POPh

OO

OBn

OMe

OBn

O H2CO

OHHO

HONHAc

OH

OH

OMeHO

i. Bu3SnH, AIBN, tol; ii. LiAlH4, THF, 0oC;

iii. Ac2O, Pyr; iv. MeONa, MeOH;

v. H2, Pd/C, MeOH

47%

Rubinstenn, G.; Esnault, J.; Mallet, J.-M.; Sinay, P. Tetrahedron: Asymmetry 1997, 8, 1327-1336.

RP(O)Cl2

Et3N, DMAP, CH2Cl2, reflux

R = Ph, 84%R = OPh, >95%

H2NHCl.

HN NHP

O R

i. 2nd. Gen. GC, benzene, reflux

ii. HCl/H2O/THF 50oC

R = Ph, 70%

R = OPh, 91%

N N

iPr iPr

H2H2

Sprott, K. T.; McReynolds, M. D.; Hanson, P. R. Org. Lett. 2001, 3, 3939-3942.

5/11


- Bicyclic 8 possess electrophilic character at seven non-O atoms, allowing nucleophilic attack at P or at any of six carbinol and allylic phosphate carbons.

- Stereoelectronic effects within 8 lend orthogonal PG stability.

i.e. lack of lone pairs on the adjacent O-atoms antiperiplanar (app) to the P(O) provide acid stability.

“ t1/2(MeO)3PO in 1 M aq. NaOH at 35°C is 30 min; t1/2(MeO)2PO2Na is 11 years”…. Westheimer, F. H. Science1987, 235, 1173-1178.

i.e. Use of the leaving group ability of a phosphate monoanion in basic hydrolysis.

- Allow di- and tripodal coupling and multivalent activation for further transformations.

- Play a role as latent leaving groups in a number of unprecedented selective cleavage reactions.

8

8

Phosphates Phosphates triesters triesters as tethersas tethers

Whitehead, A.; McReynolds, M. D.; Moore, J. D.; Hanson, P. R. Org. Lett. 2005, 7, 3375-3378.

6/11


Synthesis of Synthesis of PP-based tether-based tether 8 8 and application in and application in polyol polyol synthesissynthesis

ClCl

OH OH Me3SiI, BuLi,

THF

-30oC to rt

OH OH

80%

POCl3,

Et3N, DMAP

CH2Cl2, 90%Cl

POO

O OLi

THF, -40oC

80-90%O

POO

O2nd. Gen. GC

(3 mol%)

CH2Cl281%

O

POO

O

(S,S) -8(S,S) -9

Waetzig, J. D.; Hanson, P. R. Org. Lett. 2008, 10, 109-112.

Whitehead, A.; McReynolds, M. D.; Moore, J. D.; Hanson, P. R. Org. Lett. 2005, 7, 3375-3378.

7/11

O

P

O

OO

(R,R) -8

6 mol% H.-G. cat.

DCE, 90oC, 72%

Me

OPMB

Me

OTBS

O

P

O

OO

Me

OPMB

Me

OTBS o-nitrobenzen-sulfonylhydrazine

Et3N, DCM, rt, 24 h

72% O

P

O

OO

Me

OPMB

Me

OTBS

5 mol% Pd(OAc)2, formic acid

Et3N, DCE, 40oCO

P

O

OO

Me

OPMB

Me

OTBS

PdLnthen MeOH, TMSCHN2

87%

OTBS

Me

O

Me

PMBOOP

O OMe

LAH,

Et2O

75%

OTBS

Me

O

Me

PMBOHOHOH OH OPMB

Me

OTBS

Me

OHMe

79

11

3

14

1

C1-C14 subunit of dolabelide


Current paperCurrent paper: P-tether: P-tether (S,S)(S,S)--88 in the construction of the C15-C30 subunit of in the construction of the C15-C30 subunit of dolabelidesdolabelides

Route A

Whitehead, A.; Waetzig, J. D.; Thomas, C. D.; Hanson, P. R. Org. Lett. 2008 ASAP.

O

POO

O

(S,S) -8

i. 9-BBN, then H2O

10 equiv. NaBO3.4H2O, 80%

ii. PPTS, DCM, p-OMeC6H4OCH2OC=NH(CCl3)

89%O

POO

O

OPMB i. CuCN.2LiCl

Me2Zn, THF

single diastereoisomer

ii. TMSCHN2

MeOH, 87% Me

OOP

O OMe

OPMB

22

C22 selective cuprate addition

LiAlH4, Et2O

0oC, 96%

Me

OHOHOPMBTIPSCl, Im., DMAP

DCM, 86%Me

OHOTIPS

PMBO

19 21

i. MOMCl, iPr2NEt, 91%

ii. O3, pyr, -78oC;

Me2S, 75%

Me

OP2OP1

PMBO

19 21

O

H

P1=TIPS, P2=MOM

Cuprate Addition

5

n-Pr

Me OMOM

27I

24

6

n-Pr

OHH

i. Cp2ZrHCl, AlMe3

H2O; then I2, 61%

ii. MOMCl, iPr2NEt,

DCE, 50oC, >95%

chemoselective hydroboration-oxidation

8/11


Route ARoute A cont. cont.

Me

OP2OP1

PMBO

O

H

P1=TIPS, P2=MOM

5

n-Pr

Me OP2

I

6

+ t-BuLi, -78oCn-Pr

OP1 OP2

Me

Me OP2

23

OH

PMBO2470%, dr = 1:1

i. DMP, 98%

ii. LAH, LiI4.3:1 dr, 90%

n-Pr

O OP2 OH

Me

Me OP2

19 21 23

21,23-synOPMB

17

TIPS

P2=MOM

iPr2NEt, DCE, 82%

MOMCln-Pr

O OP2 OP2

Me

Me OP2

OPMB17

TIPS

DDQ, pH 7 buffer

92%n-Pr

O OP2 OP2

Me

Me OP2

OH17

TIPS

TsCl, DABCO

90% n-Pr

O OP2 OP2

Me

Me OP2

OTs17

TIPS

19 21

allylMgBr, CuI

-20oC to 0oC

89%

n-Pr

O OP2 OP2

Me

Me OP2TIPS

19 21

15 17

23 27

P2=MOM


Construction of the C15-C30 subunit of Construction of the C15-C30 subunit of dolabelidesdolabelides


**asymmetric vinylate addition

No reproducibilityOppolzer’s - Marshall protocol: t-BuLi, ZnBr2; n-BuLi, (R,S)-NME; yield= 55%; dr 11:1 (21,23-syn : 21,23-anti)

**asymmetric vinylate addition

9/11

12 steps,13% overall yield


Construction of the C15-C30 subunit of Construction of the C15-C30 subunit of dolabelidesdolabelides

RouteRoute BB

O

POO

O

(S,S) -8

6 mol% H-G

DCE, 90oC, 82%

O

POO

O

Ar= o-NO2C6H5

i. TIPSCl, Im., 80%

ii. MOMCl, iPr2NEt, 95%

O3, DCM, -78oC;

Me2S, 85%

n-Pr

Me OMOM

I 6

CM

OPMB

OPMB

3

ArSO2NHNH2, Et3N, DCM, 75%

O

POO

O

OPMB

3

i. CuCN.2LiCl, Me2Zn;

TMSCHN2, MeOH, 91%

ii. LAH, Et2O, 92%

PMBO

Me

OHOH

5

PMBO

Me

OP1O

5

TIPS

P1= MOM

PMBO

O

Me

OP1O

5

TIPS

H t-BuLi, Et2O, -78oC to 0oC

70%

PMBOn-Pr

O OP1

Me

Me OP1

23

OH

i. DMP, pyr, 98%

ii. LAH, LiI, -78 oC

5.0:1 dr, 92%n-Pr

O OP1 OP1

Me

Me OP1TIPS

n-Pr

O OP1 OP1

Me

Me OP1TIPS

19 21

15 17

23 27

P1=MOM


TIPS

5 iii. MOMCl, iPr2NEt, 96%iv. DDQ, 92%

23HO

i. PPh3, I2, Im., 83%

ii. tBuOK, 92%


10/11

13 steps,14% overall yield


Summary and ConclusionsSummary and Conclusions

- Phosphate tether methodology has been applied in the synthesis of the C15-C30 subunit of dolabelides A-D.

- Key steps: Regio- and diastereoselective cuprate addition & selective terminal oxidation or CM/selective hydrogenation sequence.

-To note: Orthogonal protecting- and leaving-group properties of phosphate esters are exploited.

CM/selective hydrogenation

selective terminal oxidation regio and

diastereoselectivecuprate addition

OAc OR1 OR2

Me

OR2 OR2 O

O

Me

OR1

Me

Me

Me OAc

19 21 23 25 273015

- There is room for improvement in the selectivity of the asymmetric vinylate addition.

- Completion of the total synthesis of dolabelides using the present strategy is still pending.

O

POO

O

Hydroboration or CM

CuprateAddition

11/11


Documents

A Multifaceted Phosphate Tether Application to the C15-C30 ...ccc.chem.pitt.edu/wipf/Current Literature/Karla_1.pdf · 5/11 Karla Bravo @ Wipf Group Page 5 of 11 3/30/2008 - Bicyclic