Dearomatizing Conjugate Addition to Quinolinyl Amidines for !the Synthesis of Dehaloperophoramidine through !

Tandem Arylation and Allylation !

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Stephanie McCabe!Wipf Group Current Literature!

21st September 2013!

Takayuki Ishida, Hideo Ikota, Kei Kurahashi, ChihiroTsukano and Yoshiji Takemoto. Angew. Chem. Int. Ed., DOI: 10.1002/anie.20135581!

NH N

N N

HN NN

N

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•  Perophoramidine was isolated in 2002 by Ireland et al from the Philippine ascidian Perophora namei . Dehalogenation afforded dehaloperophoramidine. Structurally

related to the communesins.!!

•  Exhibits cytotoxicity toward HCT-116 colon carcinoma cells and is able to induce

apoptosis via poly(adenosine-5ʼ-diphosphateribose)polymerase (PARP) cleavage!!

•  The structure was determined by spectroscopic methods!!

•  Relative stereochemistry of the C4-C20 vicinal quaternary stereocentres was assigned a trans-relationship based on ROESY correlations. Computer modeling

showed the trans-isomer to be favoured by 44 kcal/mol!!

•  Absolute stereochemistry determined by Qin et al 2010!!

Verbitski, S. M., Mayne, C. L., Davis, R. A., Concepcion, G. P., Ireland, C. M., J. Org. Chem, 2002, 67, 7124!

Wu, H., Xue, F., Xue, X., Qin, Y., JACS, 2010, 132, 14052-12054!

Isolation and Activity!

Perophora namei !

NH N

N N

dehaloperophoramidine

1

20

42

NH N BrCl

Cl N N

perophoramidine

5 7

912

15

22

N NH

N N

O O

communesin A

H

4

20

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Previous Syntheses!Fuchs and Funk 2004 – (±)-Perophoramidine!

Fuchs, J. R., Funk, R. L., JACS, 2004, 126, 5068-5069!

NH

O

Br

N3Cs2CO3, CH2Cl2

rt, 48 h89%

Br

N

NH

O

Br

TIPSON3

dr > 20:1

NH

OTIPS

HNOTIPS

NBr

N3

O

NH

NO

TIPSO

N3

Br

NH

TIPSON

Br

N3

O

NH

TIPSON

Br

N3

O

Path A(DA)

Path B (Michael addition)3 steps from

commerciallyavailable

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Previous Syntheses!Fuchs and Funk 2004 – (±)-Perophoramidine!

Fuchs, J. R., Funk, R. L., JACS, 2004, 126, 5068-5069!

1) NaH, Boc2O THF, rt, 1 h, 92%

2) PPh3, THF, H2O 50 °C, 5 h, 89%

N

TIPSO

HNBoc

HNO

NH

NBoc

TIPSO Br

Br

HNO

H

1) NCS, AcOH rt, 24 h, 86%

NH N

BocBr

HNO

HCl

ClTIPSO

NH N

BocBrH

Cl

Cl N3NsNO 1) PMe3, THF

rt, 2 h, 86%

2) Cs2CO3, MeI, MeCN, rt, 6 h, 92%

NH N

BocBrH

Cl

Cl HN O NNs

Me3OBF4, DIPEACH2Cl2, rt, 48 h

68% NH N

HBrH

Cl

Cl N O NNs1) Cs2CO3, PhSH, DMF, 45 °C, 24 h,

70%2) MnO2, CH2Cl2, rt, 0.5 h, 65%

(±)-perophoramidine

N

NH

O

Br

TIPSON3

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Previous Syntheses!

Rainer, 2006 – (±)-Dehaloperophoramidine!!

Sabahi, A., Novikov, A., Rainier, J. D., ACIE, 2006, 45, 4317-4320!

protected tryptamine with N-tert-butyloxycarbonyl (N-Boc)-protected isatin followed by thioether incorporation andreduction with NaBH4 provided cyclization precursors 10 and11, respectively.[12]

With a facile route to their synthesis in hand, we wereprepared to examine the ability of 10 and 11 to undergo thekey cyclization reaction. As a further indication of thenucleophilicity of 2-thioindoles, the desired cyclization occur-red under the conditions used for the generation of themesylate from 11 to give spirocycle 13 as a 1:1 mixture of C4diastereomers. In contrast to the results with 11, unprotectedamide 10 did not undergo the desired cyclization but insteadunderwent competitive decomposition upon extended expo-sure to the reaction conditions. Presumably, this latter result isdue to the inability of 10 to overcome the propensity of theamide to exist as its s-trans rotamer.[13]

The fact that 13 existed as a mixture of C4 diastereomerswas inconsequential; treatment of the mixture with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) led to equilibration atC4, and only one of the two diastereomers underwent asubsequent cyclization to give the C12 amidine 15 in 79%overall yield from 9. Following optimization studies, we foundit best to carry out both transformations in a single flask byconcentrating the reaction mixture containing 13, dissolvingthe resulting residue in CH2Cl2, and subjecting the resultingsolution to DBU (Scheme 4).

With pentacycle 15 in hand, we examined the generationof the C4 quaternary center as a precursor to the A ring[Eq. (2)]. To achieve this goal, we ultimately settled upon anN,O-ketene acetal allylation reaction similar to that employedby Artman and Weinreb in their perophoramidine studies;[14]

although they had used NaH, we found it best to employ

KOtBu as the base. Quenching the resulting ketene acetalwith allyl iodide led to 16 as a single diastereomer in 89%yield.

Pentacycle 16 proved to be amenable to single-crystal X-ray analysis, thus firmly establishing that the reaction of 15had resulted in the desired C4 and C20 diastereomer neededfor the synthesis of perophoramidine (Figure 1).

With ready access to 16, all that remained to complete thesynthesis of dehaloperophoramidine was the generation ofthe A ring (Scheme 1). We anticipated accomplishing this aimby converting the olefin in 16 into the corresponding amine,activating the lactam, and carrying out the requisite cycliza-tion reaction to the C24 amidine. To accomplish these goals,we first needed to remove the benzyl group on the lactam.Although 16 decomposed when subjected to dissolving-metalconditions, we were able to affect the removal of the benzylgroup when the N11 Boc group was absent. Thus, removal ofthe Boc group from 16 and subjecting the resulting compoundto dissolving-metal conditions gave 17 after the selectiveformation of the o-nitrobenzensulfonyl (nosyl)-protectedamidine. Interestingly, as evidenced by the downfield shiftof the C15 proton in 17 relative to 16, this latter reactionresulted in the selective formation of the N13 nosyl derivative.Oxidative cleavage of the alkene and reductive aminationgave 19. Conversion of the secondary amine into the

Scheme 4. Cyclization to the perophoramidine pentacycle: a) MsCl,pyridine, 0 8C, 4 h; b) DBU, CH2Cl2, 0 8C!RT (R=Bn: 79%, 3 steps;R=H: 0%). Ms=methanesulfonyl chloride.

Figure 1. ORTEP drawing of 16 from X-ray crystallographic analysis.

Communications

4318 www.angewandte.org ! 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 4317 –4320

NH

SPh

BnNO

OBocHN

1) NaBH42) MsCl, pyridine

N

BnN O

SPh

NHBoc

NNBoc

BnNO

DBU

CH2Cl2

79% (3 steps)

1:1

KOtBu, THFallyl iodide, 0 °C

89% NNBoc

BnNO

NNs N

N O NNs

NH N

N N

dehaloperophoramidine

Cs2CO3

PhSH, MeCN

single diastereomer single diastereomer

3 steps from N-boc-tryptamine

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Previous Syntheses!

Rainer, 2006 – (±)-Dehaloperophoramidine!!!

NH N

HBrH

Cl

Cl N O NNs

N H2N BrCl

Cl N O NH

NH N

HBrH

Cl

Cl N N

N H2N BrCl

Cl N N

N NBoc

BnN O

NH N

CO2Me

N ONBoc

H

1) TFA, CH2Cl2, 95%2) KOH, MeOH H2O, 71%3) MnO2, CH2Cl2, 64%

dehalo-perophoramidine

9 steps

Fuchs and Funk

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Qin 2010 – (+)-Perophoramidine!

Previous Syntheses!

Wu, H., Xue, F., Xue, X., Qin, Y., JACS, 2010, 132, 14052-12054!

NH

O

TBSO O

Br

1. R*NH2, KHSO4, PhMe, 2. NaBH4, MeOH, 0 °C, 81-85% (over 2 steps)

1. Boc2O, NaOH, CH2Cl2, 87-93%

2.TBAF, THF, rt, 89-90%

SOCl2, pyridine, CH2Cl2, 0 °C

NMe

NO

O

+AgClO4, PhMe, -78 °C

88%

N

N Br

N O

NBr

Boc

NMe

S

OS

NMe

exo-transition state

Boc

O

SO

NH2

tBu

O

N O

N BrBoc

SO

tBu

NR

N NBoc

NR O

SO

Br

R* =

NH

O

TBSOHN S

O

tBu

NHBoc

HO

Br

N

O

StBu

O

NHBoc

Cl

Br

N

O

SO

t-Bu

tBu

orR R

tBu

dr 11: 1

Br

3 steps from isatin

X

yield expressed as a range due to parallel

synthesis of diene precursors

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Previous Syntheses!

Qin 2010 – (+)-Perophoramidine!

NH

N

N

Cl

Cl

HN

Br

NH

N

HNN

Br

Cl

Cl

PPTs, CHCl3,reflux, quant.

MeOTf, NaHMDS, THF, -78 °C, 73%

N NBoc

NR O

SO

Br

tBu

(+)-perophoramidine

steps

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Retrosynthesis/ Strategy!

•  Different disconnection strategy which features simultaneous assembly of the vicinal stereocentres in a single operation with amidine nitrogens in place!

!•  Compared to predecessors does not involve oxidation of an aminal intermediate to install the lower amidine unit!

12

11

NH N BrCl

Cl N N

Perophoramidine

N N

N NR1

R4

R2

R3

N N

N NR1R2

R3

previouswork

this workI

NH

NH

I

NH

S

O(HO)2B

BocHN

HN

Br

O

I

NCS

+

43 20

19

Qin123

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HN

Br

OPd2(PPh3)2, Na2CO3

H2O, dioxane, 100 °C, 88%

2. TFA, CH2Cl2, 0 °C, 99%

HN O

H2N

(HO)2B

BocHN1. I

NCSDMAP, PhMe, 60 °C, 85%

NH

NH

I

NH

S

O

1. I2, NEt3, AcOEt, 0 °C2. DCE, 80 °C

3. Boc2O, NEt3, DMAP, THF, rt, 69% (over 3 steps)

N·N

I

NHO NN

H

BocN O

I

NNPMB

BocN O

IPMBI, NaH, DMF, THF,

0 °C, 91%

NNPMB

HN S

I

1. TFA, CH2Cl2, 0 °C, 99%2. Lawesson's reagent, PhMe,

100 °C, 97%

NNPMB

N SMe

IMeI, Na2CO3, THF, rt, 89%

NNPMB

BocN NMe

I

1. MeNH2, MeOH, 80 °C2. Boc2O, NEt3, THF, rt,

87% (over 2 steps)

Synthesis of Key Dearomatization/ Alkylation Precursor!

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Key Step and Completion of the Synthesis!

Evans, M. A., Sacher, J. R., Weinreb, S. M., Tetrahedron, 65, 33, 6712-6719!!!Sabahi, A., Novikov, A., Rainier, J. D., ACIE, 2006, 45, 4317-4320!Lopez Ortiz, F., Iglesias, M., Fernandez, I, Andujar Sanchez, C. M., Ruiz Gomez, G., Chem. Rev., 2007, 107, 1580−1691!Lui, L., Wang, Z., Zhao, F., Xi, Z., JOC, 2007, 72, 3484!!

NPMB N

NMeN

OH

(3:2)NH N

NMeN1. OsO4, NMO, acetone, rt

2. NaIO4, NaHCO3, THF,H2O, rt, 75% (over 2 steps

1. NaCNBH3, AcOH, MeOH, 0 – 60 °C, 76%

2. H3PO4, anisole, 120 °C, 71%

NNPMB

BocN NMe

I

NPMB N

BocN NMe

1. nBuLi, THF, -78 °C2. allyl iodide, -78 °C – 0 °C, 67%

NNPMB

BocN NMe

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Summary and Conclusionss!

•  17 steps, 9.5 % overall yield (compared to Rainer 18 steps, 7.5 % yield)!!

•  Did not pass through an aminal intermediate !!

•  First example of a nucleophilic dearomatization of a 10 π –electron aromatic system! that enables the construction of two vicinal quaternary stereocentres. !

NNPMB

BocN NMe

I

NPMB N

BocN NMe

NNPMB

BocN NMe

nBuLi

I

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