Recent Highlights from theRecent Highlights from the Nicolaou Laboratory

Me

Me

HMeH H MeO

HHNO

O OH

Me

O O

Me

MeH Ph O

O

O OH

OH

Truncated Haplophytine UncialamycinBiyouyanagin A

O OH

Ch i ti S St ffChristina S. StaufferFebruary 27, 2008

HaplophytineMe

NN

NO O

Me

HO

NO

OHMe

MeOOMe

Haplophytine

N

NO O

CO2Me

9'

N

O

p p y

NMeOOMe CO2Me

159

NO

OHMe

MeOOMe

AspidophytineTruncated haplophytine Syntheses: Corey, 1999

Fukuyama, 2003Padwa, 2006Marino, 2006

• Potent insecticidal alkaloid• Potent insecticidal alkaloid.• Isolated in 1952 by Snyder and co-workers from Mexican plant Haplophyton

cimicidum.• Consists of a central indole moiety with two tetracyclic heterocycles attachedConsists of a central indole moiety with two tetracyclic heterocycles attached.• Four reported syntheses of aspidophytine, while only one report of studies towards

the left-hand domain (Corey, 2006).

Retrosynthesis of the “Left Domain” of Haplophytin

NO O

CO2Me

N

NO O

M O

159'

NMeOOMe CO2Me

Truncated haplophytine

NN

CO MeNH

CO2Me

CO2MeN

OHHO

CO2Me

Nicolaou, K. C.; Majumder, U.; Roche, S. P.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2007, 46, 4715-4718.

Synthesis of indole fragment

NH

NH

NH

NCO2Me

NCCO2Me, CH2Cl2, 0 °C

51%

CO2MeCO2Me

Synthesis of the indoline fragment

CHO 1. Ac2O, Et3N, cat. DMAP CHO

OMeHO

2 32. fuming HNO3

3. aq. KOH, refluxOMe

HO NO2

69%

1. K2CO3, BnBr, DMF2. CH3NO2, NaOH, NO2 1. Fe, AcOH, tol, 110 °C3 2, ,

MeOH/H2O, 0 °C

3. Ac2O, NaOAc, 140 °C88% OMe

BnO NO2

2

2. KHMDS, NCCO2Me,THF, -78 °C

96%

1. Pd/C, H2, MeOHN

OHHO

CO2MeN

OMeBnO

CO2Me

, 2,

2. BBr3, CH2Cl2,-78 °C to 0 °C

86%

Coupling of indole and indoline fragments

O

N CO2Me

NH

NCO2Me N

OHHO

CO2Me

PIFA = PhI(CF3CO2)2CH2Cl2, CH3CN, -40 °C

25%

NN

CO M

OH

O

CO2Me NH

CO2Me

CO2Me

OM

N CO2MeN CO2Me

Cs2CO3, MeIDMF

60%N

NCO M

OMe

OMe NaH, THF

80% N

OMe

OMe

N

CO2Me

CO2Me NN

CO2Me

O

Completion of the construction of the “left domain” of haplophytin

Uncialamycin

HNO

O OH

Me

O OH

OH

Cladonia uncialis

O OH

• A recently discovered enediyne antibiotic isolated in 2005 by Anderson from the surface of the lichen, Cladonia uncialis.

• The scarcity of uncialamycin (300 μg) limited structural elucidation (C26 hydroxyl group was unassigned).

• Potent biological activity demonstrated against S. aureus, E. coli, and B. cepacia.

Nicolaou’s retrosynthesis of uncialamycin

Me

HNO

O

OH

OH

O OH

NO

CNMe

OH TMS

OODMB

OTES

Nicolaou, K. C.; Zhang, H.; Chen, J. S.; Crawford, J. J.; Pasunoori, L. Angew. Chem. Int. Ed. 2007, 46, 4704-4707.

Synthesis of the substituted quinoline systemO

HN

Me

O

CO2H

OMe

1. 48% aq. HBr,nBu4NBr, 110 °C

N

O

Me

CO2DMB

HCO2H, Et3N,CH2Cl2, 0 °C

NO

Me

2. DMBBr, K2CO3,nBu4NI, DMF

55%ODMB

2

MeMe

TsNPh

ODMB

O

MeRu

ClNH2Ph

95%, 98% ee

1. DIBAL-H, CH2Cl2N

O

Me

DMB =

OMe

O

2. TESCl, im, DMF86%

ODMB

OTES OMeOR

Ph

Introduction of the enediyne functionality

NO

Me

H TMSAllocN

O

MeTMS

1. AcOH, MeCN,H2O, 91%

2. NaBH4, MeOH AllocN

TMS

OOH

Me

ODMB

OTES EtMgBr, AllocCl

ODMB

OTES92%

4,

3. mCPBA, CH2Cl280% (2 steps)

4. AcCl, collidine, 82%ODMB

OAc

O

ODMB

TMS

1. Dess-Martin

2 NaBH4 MeOH

AllocN

TMS

OOH

Me1. TESCl, Im,

DMF

2 K2CO3 THFAllocN

H

OOTES

Me

2. NaBH4, MeOH

90%ODMB

OAc2. K2CO3, THF

MeOH78%

ODMB

OH

Intramolecular acetylide addition to form the enediyne ring system

AllocN

H

OOTES

Me 1. Dess-Martin, 87%

2 DDQ CH2Cl2/H2O AllocN

H

OOTES

Me CeCl3, KHMDS- 78 °C to - 40 °C

ODMB

OH

O 2. DDQ, CH2Cl2/H2O87%

OH

O

O 61%(30% C17 epimer)

Me1 PhI(OA ) M OH

Me

AllocNO

OH

OTES17

1. PhI(OAc)2, MeOH80%

2. [Pd(PPh3)2Cl2]nBu3SnH, H2O,CH2Cl2, 74%

NO

OH

OTES

O

CN

O

1.

Me

OH2 2

O OLiHMDS, 63%

2. 3HF•Et3N, THF92%

HNO

O

OH

OH

Me

O OH

Uncialamycin

Synthesis of Biyouyanagin A

(H. chinense L. var. salicifolium)

• Isolated from the leaves of a Hypericum species in 2005.• Traditionally used as folk remedy for female disorders.• Shows significant activity against HIV and lipopolysaccharide-induced cytokine

production.• Stereochemistry at C24, C17, C18 needs to be elucidated.

Structural assignment of biyouyanagin A

MeH

MeH H MeO

MeH

MeH H MeOH H

O O

MeH

H

H

Ph OO O

MeH

H

H

Ph O

H H

MeH Ph O Me

H Ph O

Originally proposed possible structures

MeH

MeH H MeO24

MeH

MeMeO

O O

MeH

H

H

Ph

O24

1718

O O

MeH H MeOH H

MeH Ph O

MeH Ph O

Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem. Int. Ed. 2007, 46, 4708-4711.

Biyouyanagin A retrosynthesis

HMe

Me

HMeH H MeO

[2 + 2]O

Me

Me

HMe MeO

HH

O O

MeH Ph O

O O

MeO

Ph

Synthesis of the terpene-derived diene

Cl

N NTf

TfComins reagent

Formation of the spirolactone

[2+2] Photocycloaddition

MeH

MeMeH

Me

O O

Me

Me

MeH

H

H

Ph

MeO

O O

Me

Me

Me Me

O

O

Ph

H Hh , 2'-acetonaphthoneCH2Cl2, rt, 5h

46%Me

H Ph OMeO

Me HMe

HMe

OO

H

Me

O O

Me(exo)