Total Synthesis of Sandresolide B and

Amphilectolide

Ingrid T. Chen, Irina Baitinger, Lucas Schreyer, and Dirk Trauner*

University of Munich, Germany

Org Lett 2014, 16, 166–169. dx.doi.org/10.1021/ol403156r

2 •  Since the 1980’s more than 40 marine metabolites have been isolated from Pseudopterogorgia elisabethae, a caribbean octocoral

•  1 – 6 isolated from coral from deep-sea expedition

near Sand Andrés island, Columbia, by Rodríguez and coworker.

•  Biological activity against inflammation, tuberculosis, cancer, and antiplasmodial activity

Yang et al. JACS 2010, 132, 13608.

Asymmetric Total Synthesis of Caribenol A

3

Liu, L.-Z.; Han, J.-C.; Yue, G.-Z.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 13608–13609.

Retrosynthetic Analysis

4

OO

OHMe

HMe

HOMe

Sandresolide B, 3

O

MeH

MeHO

7

O

MeH

Me8

OHOO

MeH

Me

Amphilectolide, 1

OMe

HMe

OH

O

9

Preparation of Key Furan Building Block 7

5

1 Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972–6975. 2 Brancour, C.; Fukuyama, T.; Mukai, Y.; Skrydstrup, T.; Ryu, I. Org Lett 2013, 15, 2794–2797.

O

MeH

MeHO

7

O Me

(–)-β-citronellal

8 steps

O

H

MeTBSO

10

MeMeO

O

CNLDA, HMPA

–78 °C83%

O

H

MeTBSO

11

Me

O

OMe

1.) LDA, Tf2O– 78 °C (86%)2.) DIBAL–H

– 78 °C (83%)

H

MeTBSO

12

Me

OTf

OH

Pd(PPh3)4NBu3, LiCl, 85°C

with CO (3 atm) (98%)or with H2SO4, HCO2H

98%O

MeH

MeTBSO

13 O

DIBAL–H, – 78 °Cthen SIO2, CHCl3

88% O

MeH

MeTBSO

14

TBAF99%

[Ref 1]

[Ref 2]

Synthesis of Compound 102

6

O Me

(–)-β-citronellal

1.) ZnBr2 (70%)

2.) Ac2OH

Me

OAc[Ref 1]

O3, MeOHthen SMe2

89%H

Me

O OAc

(EtO)2P(=O)CH2CO2EtNaH, Δ

separation of E : Z (9:1)64% (mixture)

HMe

OAcEtO2C

semicorrin ANaBH4, CoCl2

H

Me

OAcCO2Et

90%DIBAL–H

75%

H

Me

OH

OH

1.) TBSCl, imid.2.) Swern ox.

H

Me

O

OTBS10

N N

CN

HOTBS OTBS

A

1 Nakatani, Y.; Kawashima, K. Synthesis 1978, 1978, 147–148. 2 Kocienski, P. J.; Pontiroli, A.; Qun, L.. J. Chem. Soc., Perkin Trans. 1 2001, 2356–2366. 3 Pfaltz, A. Acc. Chem. Res. 1993, 26, 339–345.

[Ref 3]

Preparation of Key Furan Building Block 7

7

1 Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972–6975. 2 Brancour, C.; Fukuyama, T.; Mukai, Y.; Skrydstrup, T.; Ryu, I. Org Lett 2013, 15, 2794–2797.

O

MeH

MeHO

7

O Me

(–)-β-citronellal

8 steps

O

H

MeTBSO

10

MeMeO

O

CNLDA, HMPA

–78 °C83%

O

H

MeTBSO

11

Me

O

OMe

1.) LDA, Tf2O– 78 °C (86%)2.) DIBAL–H

– 78 °C (83%)

H

MeTBSO

12

Me

OTf

OH

Pd(PPh3)4NBu3, LiCl, 85°C

with CO (3 atm) (98%)or with H2SO4, HCO2H

98%O

MeH

MeTBSO

13 O

DIBAL–H, – 78 °Cthen SIO2, CHCl3

88% O

MeH

MeTBSO

14

TBAF99%

[Ref 1]

[Ref 2]

Total Synthesis of Amphilectolide, 1

8

Rose bengal

1 Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68, 9340–9347. 2 Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53, 2773–2776.

O

MeH

MeHO

7

1.) MsCl, DMAPPyr (97%)2.) KCN, 90 °C(89%) O

MeH

Me15

NO

MeH

Me16

KOH, 130 °C90%

O

HO

O

MeH

Me17

O

1.) CDI,

2.) , 0 °C to rt

81% (over 2 steps)

NH

OMeMeHCl.

MgBr O

MeH

Me8

OH

NaBH4, CeCl3– 20 °C, (95%)

La(OTf)3

MeNO270%

MeH

MeO18

OO

MeH

Me

Amphilectolide, 1

1.) hυ, O2rose bengal, – 78 °C

Hünig's base[Ref. 2]

2.) NaBH411% (over 2 steps)

[Ref 1](1:1.5 ratio)

MgBr20%

Myers Alkylation to Access Ring-Closure Precursor 9

9

O

OH19

OH

Me

NMe

H

PivCl, TEA0 °C76%

OH

Me

NMe

O

20

1.) MsCl, DMAPPyr (97%)

O

MeH

MeHO

7

2.) NaI, 85 °C(84%) O

MeH

MeI

21

LDA, LiCl– 78 °C to rt

OMe

HMe

N

O

MeMe

OH22

n-Bu4NOH90 °C99%

OMe

HMe

OH

O

9

[Ref. 2]

[Ref. 1]

1 Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361–9362. 2 Myers, A. G. et al. J. Am. Chem. Soc. 1997, 119, 6496–6511.

Myers Alkylation

10

OLi(solvent)nH

NR1

H

MeH OLi(solvent)n

Primary Alkyl HalidesR2 – I

OHNMe

Me OR1

OHNMe

Me OR1

R2Me

1,4–syn

α−face

OHNMe

Me O LDA, LiCl-78 °C to rt

OLiNMe

Me OLi+ I

Me

OMeH

OHNMe

Me O

Me

O

Me

OMe

HMe

N

O

MeMe

OH22

1,3-syn

Myers, A. G. et al. J. Am. Chem. Soc. 1997, 119, 6496–6511.

Myers Alkylation to Access Ring-Closure Precursor 9

11

O

OH19

OH

Me

NMe

H

PivCl, TEA0 °C76%

OH

Me

NMe

O

20

1.) MsCl, DMAPPyr (97%)

O

MeH

MeHO

7

2.) NaI, 85 °C(84%) O

MeH

MeI

21

LDA, LiCl– 78 °C to rt

OMe

HMe

N

O

MeMe

OH22

n-Bu4NOH90 °C99%

OMe

HMe

OH

O

9

[Ref. 2]

[Ref. 1]

1 Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361–9362. 2 Myers, A. G. et al. J. Am. Chem. Soc. 1997, 119, 6496–6511.

Ring Closure and NOE Correlation to Characterize 24

12

OMe

HMe

OH

O

9

O

HMe

Me

O

HMe

Me

H

O

O

TFAA, ZnCl2 (2.5 equiv.)40 °C, 1 hour

71%

23 (1 diastereomer)

TFAA, ZnCl2 (0.2 equiv.)40 °C, 4.5 hours

46%

24 (23%)

+ 23 (23%)

DBU99%

observed NOE

à 24 thermodynamic product, 6.7 kcal/mol more stable than 23 (kinetic product) (10’000 step Monte Carlo search, solvent-free OPLS algorithm)

Completion of Sandresolide B, 3

13

Tetraphenyl- porphyrine

O

HMe

MeO

23

1.) MeMgBr, – 78 °C

2.) hυ, O2, TPP– 78 °C then DBU51% (over 2 steps) O

OOHMe

HMe

HOMe

Sandresolide B, 3

OHOMe

HMe

Me

OO H

B

via

O

HMe

MeO

BrMgMe"top" attack

"down" attackSandresolide B, 3

OO

MeHO

HMe

HOMe

Sandresolide C,4

Conclusion ¡ Scalable route to furan building block 7

¡ First total synthesis of amphilectolide, 1, and sandresolide B, 3

¡ Intramolecular Friedel-Craft alkylation for 1 and acylation for 3 to build third ring

¡ Use of two different sensitizer for photooxygenations (rose bengal and tetraphenylporphyrine)

¡ The use of building block 7 for the synthesis of other alkaloids of same source (Pseudopterogorgia elisabethae) is under active investigation

14