total syntheses of the marine illudalanes alcyopterosin i ...ccc.chem.pitt.edu/wipf/current...

Total Syntheses of the Marine IlludalanesAlcyopterosin I, L, M, N, and C

Welsch, T.; Tran, H.-A.; Witulski, B. Org. Lett. 2010, ASAP.DOI: 10.1021/ol102432q

Kara GeorgeWipf Group Current Literature

4 December 2010

O

H3C

O

H3C CH3

H OH

H

TsO

H

Rh-catalyst

[2+2+2]

H3C

CH3

CH3

OO

H

O2NO

OHH

alcyopterosin M

Kara George @ Wipf Group of 14 12/5/2010

Illudalane Sesquiterpenes: Alcyopterosin

The illundalane sesquiterpenes are a rare class of natural products typicallyisolated from fungi and ferns

The alcyopterosin subclass are the first illudalanes isolated from marine sources Alcyopterosins have an aromatized six-membered ring and almost all members

have either a Cl atom or a nitrate ester present on the ethylene side chain Alcyopterosins A-O were first isolated in 2000 by Palermo and co-workers from

the sub-Antarctic deep sea soft coral Alcyonium paessleri

Recently, nine additional alcyopterosins were isolated from the Antarctic softcoral Alcyonium grandis by Gavagnin and co-workers in 2009

Fraga, B. M.; Nat. Prod. Rep. 2008, 25, 1180.Palermo, J. A.; Rodriguez Brasco, M. F.; Spagnuolo, C.; Seldes, A. M. J. Org. Chem. 2000, 65, 4482.Carbone, M.; Nunez-Pons, L.; Castelluccio, F.; Avila, C.; Gavagnin, M. J. Nat. Prod. 2009, 72, 1357.

H3C

CH3

CH3

CH3

Alcyopterosin SkeletonR= Cl or ONO2

R

H3C

H3C

CH3

CH3

CH3

Illudalane Skeleton


Alcyopterosins: Structure and Biological Activity

Palermo, J. A.; Rodriguez Brasco, M. F.; Spagnuolo, C.; Seldes, A. M. J. Org. Chem. 2000, 65, 4482.Finkielstztein, L. M.; Bruno, A. M.; Renou, S. G.; Moltrasio Iglesias, G. Y. Bioorg. Med. Chem. 2006, 14, 1863.

H3C

CH3

CH3

R1

alcyopterosin Aalcyopterosin Balcyopterosin Dalcyopterosin Galcyopterosin O

R1

Cl

ONO2

Cl

ONO2

OH

R2

H

H

OH

OH

OH

R2

alcyopterosin Calcyopterosin Jalcyopterosin N

R1

H3C

CH3

CH3

O

R2

R1

ONO2

ONO2

OH

R2

H

OH

H

alcyopterosin Ealcyopterosin Lalcyopterosin M

H3C

CH3

CH3

OO

H

R1

R2H

R1

ONO2

Cl

ONO2

R2

H

OH

OH

alcyopterosin Halcyopterosin K

R1

ONO2

Cl

R2

H

OH

R3

OH

H

R4

H

OH

H3C

CH3

CH3

R1

R2

R4R3

H3C

CH3

CH3

CH3

O2NO

OH

alcyopterosin F

H3C

CH3

CH3

O

OHH

alcyopterosin I

Alcyopterosin E showed cytotoxicity toward Hep-2 (human larynx carinoma) cell lineand both alcyopterosin A and C were cytotoxic toward the HT-29 (human coloncarinoma) cell line

Alcyopterosin A and its analogs also exhibit DNA-binding properties


Alcyopterosins: Proposed Biosythesis

Cane, D. E.; Nachbar, R. B. Tetrahedron Lett. 1980, 21, 437.Hanssen, H.-P.; Abraham, W.-R. Tetrahedron. 1988, 44, 2175.Morisaki, N.; Furukawa, J.; Kobayashi, H.; Iwasaki, S.; Nozoe, S.; Okuda, S. Tetrahedron Lett. 1985, 26, 4755.

H3C

H3C

CH3

CH3

CH3

H3C

CH3

CH3

CH3

H3C

CH3

CH3

CH3

H

bond cleavageand

aromatization

Protoilludane Illudalane Aromatic Illudalane

Skeleton

O P

O

O

O P

O

O

O

H3C

CH3

CH3

CH3

H3C

CH3

CH3

CH3

OPP

Farnesyl Pyrophosphate

H+H


Synthetic Approaches to Alcyopterosins

Jones, D. M. Ph. D. disertation, The Florida State University, 2010.

Homo-coupling of acetylenes

Cross-coupling using at least onesymmetrical acetylene

Cross-coupling of tethered alkynes

Y

X

X

Y

X

Y

Metal Catalyst

X

Y

X

Y

X

Y

Y

X

X

X

X

X

Metal Catalyst

X

Y

Z

X

X

X

W

X

Y

Z

W

Y

Z

X

n n

Reppe’s cyclotrimeriation ofacetylenes

U

V

W

X

Y

Z

Metal Catalyst

V

U

V

U

V

U

V

U

W

X

V

U

X

W

V

U

X

W

38 homo- and cross-coupled products possible!



Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2002, 124, 9682.

One-Pot Metalative Reppe reaction developed by Sato and co-workers

First synthesis of alcyopterosin A

SiMe3

CO2t-BuC6H13

Ti(O-i-Pr)4/ 2 i-PrMgCl

-50 °CTi(O-i-Pr)2

SiMe3t-BuO2C

C6H13

-50 °C to rt

BrSiMe3

t-BuO2C

C6H13

Ti(O-i-Pr)2Br

SiMe3

t-BuO2C

C6H13

H

52%

H+

Cl

CH3

H3C

CH3

CH3

alcyopterosin ACH3

H3C

CH3

CH3

1. LiAlH4, 91%2. PCC, 96%3. Ph3P=CH2, 86%

1. BH3!THF; H2O2, NaOH, 67%2. SOCl2, pyr, 70%

O

CH3

H3C

H3C

CH3

CH3

Br

CO2Et

Me6 steps

isophorone

EtO2C

CH3

H3C

CH3

CH3

Ti(O-i-Pr)4/ 2 i-PrMgCl;

then H+

73%



Witulski, B.; Zimmermann, A.; Gowans, N. D. Chem. Comm. 2002, 2984.

The first total synthesis of alcyopterosin E by Witulski and co-workers catalytic intramolecular alkyne cyclotrimerization with electron deficient

alkynes

H3C

CH3

CH3

OO

H

O2NO

alcyopterosin E

H3C

CH3

CH3

OO

H

TsO

NaNO3, Bu4NNO3toluene, 110 °C

69%

10 mol% [Rh(PPh3)3Cl]

CH2Cl2, 40 °C, 72%

O

CH3

H3C

H3C

CO2HH3C

H3C

6 steps

isophorone

H3C

OH

OTs

L-ascorbic acid

O O

HO OH

OH

HOH 7 steps

H3C CH3

O

O

OTs

HH3C

DCC, DMAPCH2Cl2, -78 °C to rt

70%

H



Jones, A. L.; Snyder, J. K. J. Org. Chem. 2009, 74, 2907.

Microwave promoted Rh(I)-catalyzed [2+2+2] cyclization of diynes with α,β-unsaturated enones developed by Snyder and co-workers

First total synthesis of alcyopterosin I

X

R

OX

OR

1. [Rh(PPh3)3Cl], µW2. DDQ

H3C

CH3

CH3

O

OHH

alcyopterosin I

H3C

CH3

CH3

O

O

CH3

O

O

5 steps

EtO

O

CH3

CH3

ethyl isobutyrate

1. [Rh(PPh3)3Cl] PhCl, µW, 150 °C2. DDQ, rt

rac-alcyopterosin I(84%)

(-)-alcyopterosin I(99%, 57% ee)

NaBH4

BH3!THF10 mol% A

HO

PhH2N

A


Title Paper: Synthetic Strategy

Alcyopterosins L, M, and I

H OH

CH3

CH3

H3C

XO

FGs

O

TMS

CH3

CH3 TMS

CH3

CH3

H OMOM

CH3

CH3

H OMOM

X

OFGs

C-ring opening oxidation

A,B,C-ring formation

X= CO, CH2

Alcyopterosins C and N

enantioselective reduction

MOM-protection

carboxylationor

hydroxymethylation

ester or ether formation

B A

C

One step formation of the ABC-ring system via a transition metal catalyzed [2+2+2] cycloaddition reaction Variable tether lengths would provide access to angular fused [5-6-6] and [5-6-5] Take advantage of readily accessible chiral building blocks

Welsch, T.; Tran, H.-A.; Witulski, B. Org. Lett. 2010, DOI: 10.1021/ol102432q.


Preparation of Key Chiral Building Block

EtO

O

CH3

CH3Cl

O

H3C CH3

O

H3C CH3TMS

Br

H

1. LDA, THF, -78 °C, then

rt, 82%

2. KOH, EtOH, rt, 100%3. SOCl2, 85 °C, 99%

TMS TMS

AlCl3, CH2Cl20 °C, 94%

Ru

TsN

NH

Ph

Ph

H3C CH3TMS

H OMOM

1.

(1S, 2S)i-PrOH, 74% (99% ee)

2. CH2(OMe)2, LiBr p-TsCl, rt, 86%



Synthesis of Alcyopterosin I

H3C CH3TMS

H OMOM 1. n-BuLi, THF, (HCHO)n

-78 °C, 77%

2. CBr4, PPh3, CH2Cl2 0 °C, 99%

H3C CH3TMS

H OMOM

Br

OH

NaH, DMF, 96%

H3C CH3TMS

H OMOM

O

H3C


EtOH, rt, 66%

H3C

CH3

CH3

O

OMOMH


H3C

CH3

CH3

O

OHH

alcyopterosin I(11 steps, 29% overall)

HCl, dioxane70 °C, 74%

H3C CH3TMS

H OH

O

H3C


EtOH, rt, 89%

CBr4, i-PrOH80 °C, 91%


Synthesis of Alcyopterosins N and C

H3C

CH3

CH3

O

OHH

alcyopterosin I

H3C

CH3

CH3

O

O

H3C

CH3

CH3

O

BrHO

DIB, 10% TEMPOCH2Cl2, rt, 85%

BBr3, CH2Cl2reflux, 84%


O2NO

CH3

H3C

CH3

CH3

O

alcyopterosin C(16 steps, 13% overall)

HO

CH3

H3C

CH3

CH3

O

alcyopterosin N(14 steps, 19% overall)

n-Bu3SnH, AIBN

benzene, reflux, 93%

1. MsCl, NEt3, CH2Cl2 rt, 77%

2. NaNO3, n-Bu4NNO3

toluene, 110 °C, 88%


Synthesis of Alcyopterosins L and M

H3C CH3TMS

H OMOM

H3C CH3

H OMOM

CO2H

H3C CH3

H OMOM

O

O

OTs

HH3C

1. n-BuLi, THF, CO2(g)

-78 °C, 82%

2. TBAF, THF, 0 °C, 97%

OH

OTs

HH3C

DCC, DMAPCH2Cl2, 65%


H3C

CH3

CH3

OO

H

Cl

OHH

alcyopterosin L(12 steps, 10% overall)

H3C

CH3

CH3

OO

H

O2NO

OHH

alcyopterosin M(12 steps, 6% overall)

H3C

CH3

CH3

OO

H

TsO

OMOMH


CH2Cl2, 40 °C, 69%

1. LiCl, NH4Cl, DMF 100 °C, 78%

2. CBr4, i-PrOH 80 °C, 65%

1. NaNO3, n-Bu4NNO3 toluene, 110 °C

2. CBr4, i-PrOH, 80 °C 36% (over two steps)


Conclusions

The authors successfully synthesized a set of the rare marinealcyopterosins using a modular approach which features a Rh-catalyzed [2+2+2] alkyne cyclotrimerization

Application of this approach allowed for: The enantioselective total synthesis of alcyoptersin I The first total enantioselective syntheses of alcyopterosins L and M The total synthesis of alcyopterosin N and the first total synthesis of

alcyopterosin C

Further development of this approach could provide access to thealcyopterosins F, H, and K

alcyopterosin Halcyopterosin K

R1

ONO2

Cl

R2

H

OH

R3

OH

H

R4

H

OH

H3C

CH3

CH3

R1

R2

R4R3

H3C

CH3

CH3

CH3

O2NO

OH

alcyopterosin F


total syntheses of the marine illudalanes alcyopterosin i ...ccc.chem.pitt.edu/wipf/current...

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