[4+3] cycloaddition towards natural product synthesis · [4+3] cycloaddition towards natural...

[4+3] [4+3] Cycloaddition Cycloaddition Towards Natural Product SynthesisTowards Natural Product Synthesis

SULAGNA PAULMarch 15th, 2005

Michigan State University

O

CH2OHH

OH

iPrOH

Me

Me Me

HO

HMe

OOMe

MeOMeO

MeONHAc

O

O HH

HO

O

O

O

H

OAcCO2Me

OAc

[4+3]

Direct Formation of Seven-Member Ring System

Dieckmann condensation:

Jacob, T. M.; Vatakencherry, P. A.; Dev, S. Tetrahedron 1964, 20, 2815.

CO2EtCO2Et

o

CO2EtNaH

Ether, 15h(85–90%)

Ruzicka cyclization:

Krapcho, A. P.; Mundy, B. P. J. Org. Chem. 1967, 32, 2041.

CO2HCO2HO

H

H

O

H

H

OFe

Ba(OH)2

(24%)

Thorpe–Ziegler reaction:


Allinger, N. L.; Zalkow, V. B. J. Am. Chem. Soc. 1961, 83, 1144.

Acid–mediated olefin cyclization:

Marshall, J. A.; Anderson, N. H.; Johnson, P. C. J. Org. Chem. 1970, 35, 186.

CHOOH

Silica gel

2–5% ether–C6H6

(80%)

CNCN

H

H

H

H

O

1. Ph(Me)N–Li+ PhBr, Ether

RT, 48h

(58%)

2. HCl 25 ºC, 0.5h


Ring expansion:

Heathcock, C. H.; Delmar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907.

Radical–induced cyclisation:

Duffault, J. M.; Tellier, F. Synthetic Communication. 1998, 28, 2467.

I

O O

O7–endoBu3SnH,cat. AIBN

C6H6, RT–0 ºC4hO O O

O6–exo

O

O

O

O

OOH

OAc

TsO

AcO

HO

1. KOH, tBuOH RT, 6h

(61%)

2. Ac2O, Py RT, 2d


Olefin metathesis:

Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, D. W.; Schulz, G. R.; Wagener,K. B. J. Am. Chem. Soc. 1992, 114, 10978.

O O

[CH3(CF3)2CO]2

NMo

1h, 95%

[5+2] Cycloaddition:

Taninu, K.; Kondo, F.; Shimizu, T.; Miyashita, M. Org. Lett. 2002, 4, 2217.

OTIPS

BzOCo(CO)3Co(CO)3

OTIPSTIPSO

H

O

Co(CO)3Co(CO)3

EtAlCl2

CH2Cl298%

Features

[4+3] Cycloaddition:

Involves an electron rich (4π electron, 4 Carbon) diene reacting with allylic cation(2π electron, 3 Carbon).

[4+3]

Fort, A. W. J. Am. Chem. Soc. 1962, 84, 4979.

First example of [4+3] Cycloaddition:

Ph Ph

Cl

OPh Ph

O–O

O

Ph

Ph

O2,6–lutidine

DMF, RT 96h, 18%

Class A: Concerted bond–formation

Mechanistic Categories

Z Y Z Y Z Y

transition state

Class B: Stepwise bond–formation

Z Y Z Y Z Y

intermediate

Hoffman, H. M. R. Angew. Chem. Int. Ed. Engl. 1984, 23, 1.

OH

OH

Entended (Chair like) Compact (Boat like) endoexo

Nucleophilicity of the diene electrophilicity of the allyl cation

Z Y—H+

The Nucleophilicity of the Diene

s–cis–1, 3–Butadiene:

Stepwise process is lower in energy Preference for [3+2] over [4+3] Two competitive [3+2] pathway Lowest energy pathway— [3+2]/ Claisen rearrangement

Cramer, C. J.; Barrows, S. E. J. Org. Chem. 1998, 63, 5523.

ΔG≠ [4+3] C—C 8.2 kcal/mol[3+2] C—O 1.2 kcal/mol[3+2] C—C 2.0 kcal/mol

OH

OH

[4+3]

OH

HO[3+2]

Claisenrearrangement

[4+3]

OH[3+2]

The Nucleophilicity of the Diene

1, 3–Cyclopentadiene:

Furan:

Stepwise. The intermediate is very stable for its substantial oxonium ion character— favors direct [4+3].

Pyrrol:

1–Azabutadienyl cation is so stable – no bond closure steps are energetically favorable. Generates electrophilic substitution product.

Cramer, C. J.; Barrows, S. E. J. Org. Chem. 1998, 63, 5523.

Completely Stepwise— more nucleophilic. Small preference for [3+2] over [4+3]— allyl cation is monosubstituted at either end.[3+2]

[4+3]

OH

O

OH

O

OH

OH

HNHN

OH

HN

OH

OH

OH

O

The Electrophilicity of the Allyl Cation

Lithium oxyallyl cation:

Order of free energy, TS 1>TS 2> TS 3 —favoring concerted pathway. Activation energy for Claisen rearrangement is higher than hydroxy analog. Order of free energy of the product, compact > extended.

Cramer, C. J.; Barrow, S. E. J. Phys. Org. Chem. 2000, 13, 176.

Sodium oxyallyl cation:

Concerted pathway is favorable over stepwise. Free energy for TS 1> TS 2> TS 3— the difference in energy is smaller than before. Free energy for extended is slightly less than compact product.

ONa

Oxyallyl:

O Uncharged species— TS1 for stepwise is too unfavorable. Free energy of activation for TS 3> TS 2. Free energy for products compact> extended cycloadduct.

OLi

OLi OLi

[4+3]

TS 2LiO Li

O

TS 3

[3+2]

OLi

extended

compact

OLiTS 1

IN

Claisen

rearrangement

Allyl Cation in [4+3] Cycloaddition

Oxyallyl

NR

OOSiMe3

RO

OR

TMS

2–Aminoallyl Allyl acetal

α, β– Unsaturated carbonyl

O

Configuration of the transient allyl cation:

RR

OM

R

OMR R

OMR

The ‘U’ form The ‘Sickle’ form The ‘W’ form

Allyl cation precursors:

Oxyallyl Cation Reductive condition:

Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1984, 23, 1.

Br

O

Br

O O O

O O O

O

ConditionsCu, NaI 48% 5% —

Zn, Cu 69% 8% 7%

Fe2(CO)9 40% — 50%

Shimizu, N.; Tanaka, M.; Tsuno, Y. J. Am. Chem. Soc. 1982, 104, 1330.

Solvolysis Condition:

O O O

O O O

t–Bu t–But–But–Bu

Cl

OTMSAgClO4

O

SolventTHF–Et2O 16% 22% 10% 40% 12%MeNO2 63% 37% — — —

OH

OTMS

OH

OTMS

(Z:E= 67:33)

Oxyallyl Cation Lewis acid catalyzed cycloaddition:

Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50.

ON

O

[O]— 45ºC N

OO

RR

Ochiral allenamide

NO

O

OR

H

nitrogen-stabilized oxyallyl cation

NO

O

R

X

— 45 ºC[4 + 3]

92% de

X

O

H

X = O or CH2

NO

R

O

OZn

Cl

ClH

X

blocking endo-2

endo-1

NO

O

OLA

LL

H

X

R

R

chiral Lewis acid-achiral allenamide

catalytic asymmetric[4 + 3] cycloadditions

NO

O

X

O

HR

X

O

H

N

O O

S

endo

Chiral Lewis Acid Catalyzed Enantioselective[4+3] Cycloaddition

Cu(OTf)2 (equiv) Ligand Equiv Temp ºC %Yield % ee 0.85 A 1.1 —55 62 78[S]

0.25 B 0.32 —78 46 82[S] 0.10 C 0.12 —78 76 59[S]

N

O

N

O

Ph PhN

O

N

O

Ph Ph

Ph PhN

O

N

OHH

Ph Ph

Ph Ph

A B C


ON

O

allenamide

Pre-mixed Cu(OTf)2 and ligand9.0 equiv of furan

3-5 equiv DMDO/syringe pump add.CH2Cl2 [0.05M], 8-10 h

NO

O

O

O

HR

O

O

H

N

O O

S



OHH

endo–1N

OO

X

O

HR

endo-1

SIDE VIEW

NO

O

OCu

N

NO

O

OHHendo–2

X

O

H

N

O O

S

endo-2

favoured due to less steric



Entry Dienes R additive product % Yield %ee

1 — — [S] 90 92

2 — AgSbF6 [S] 91 99

3 Me AgSbF6 [S] (20:1) 88 71

4 CO2Me AgSbF6 [S] (syn only) 61 67

5 — — [S] 81 36

6 Me AgSbF6 [S] (anti only) 91 99

O

O R

O MeMe

O

R

O

O

H

N

O O

SON

OO

O

H

N

O O

SR

R25mol% Cu(OTf)2, 32mol% C9.0 equiv diene, —78 ºC

2–5 equiv DMDO, syringe pump addAcetone/CH2Cl2 [0.05M], 8–10 h

4Aº Mol. Sieves and additivesyn anti



TOP VIEWS

N

O

N

O

Ph Ph

Ph Ph

Cu

NO

OO

A

3R

O

R

O

O

H

N

O O

SR

syn

3L

O

R

O

O

H

N

O O

SR

anti

N

O

N

O

Ph Ph

Ph Ph

Cu

NO

OO

B OR

HH

R2R

2L

sliding over

Oxyallyl Cation

Intramolecular [4+3] cycloaddition:

The initial geometry of the allyl cation is irrelevant with respect to the yield and stereochemistry.

EtTolSO2

CH3

CH3

OO

CH3CH3

OEtTiCl4

CH2Cl2, —78 ºC74%

OCH3CH3

OEt

not formed

OEtp

OEtCH3

CH3O2SpTol

O

Et

(E)/(Z)

OCH3CH3

OEtTiCl4

CH2Cl2, —78 ºC58%

Harmata, M.; Gamlath, C. B. J. Org. Chem. 1988, 53, 6156.

Nature of Mechanism

Harmata, M.; Schreiner, P. R. Org. Lett. 2001, 3, 3663.

OCH3CH3

OEt

OCH3CH3

OEtEt

B'

OCH3

CH3

OEtEt

A'

TS1

A' –0.4

TS18.4

B' 4.0

OCH3CH3

OEt

OCH3CH3

OEtEt

B

OCH3

CH3

OEtEt

A

TS2

A –3.5

TS22.2

B –3.4

Allylic Acetals

Stark, C. B. W.; Eggert, U.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. 1998, 37, 1266.

Diastereoselectivity attained by using chiral auxiliary in the form of mixed acetal.

Si OO

O

HHH

H

disfavored

O SiO

H

O

HHH

favored

OTESOCH3

O

Ph

O

O

O

OO O

Ph Ph

TMSOTf—95 ºC, 10min

Conditions Total Yield neat (—78 ºC, 30min) 2.9 : 1 54%MeNO2 4.1 : 1 36%DCM 7.5 : 1 67%DCM/pentane(—110 ºC) 8.2 : 1 37%

O

α,β—Unsaturated Carbonyl Compounds

Sasaki, T.; Ishibashi, Y.; Ohno, M. Tet. Lett. 1982, 23, 1693.

OSiMe3

OSiMe3

OSnCl4

COMeOSiMe3

COMeOH

OSiMe3OSnCl4

O

O

OSiMe3

OH

SnCl4

R = H

R = Me

O

R

H2O

H2O

(32 %)

(35 %)

Lewis Acid Catalyzed [4+3] Cycloaddition

Avenoza, A.; Busto, J. H.; Cativiela, C. Tet. Lett. 2002, 43, 4167.Arno, M.; Picher, M. T.; Domingo, L. R.; Andres, J. Chem. Eur. J. 2004, 10, 4742.

PhN O

Ph

O

PhN O

O

Ph

PhN O

O

Ph

ON

O

PhPh

–25 ºC

6h

ConditionAlCl3 (0.5 eq) 53 47 —AlCl3 (0.75 eq) 22 34 44AlCl2Et (0.75eq) 40 34 26AlCl2Et (1.5 eq, 0 ºC) — — 100

(3 eq)

PhN O

Ph

O

PhN O

O

Ph

PhN O

O

Ph

AlH3 AlH3 AlH3

Michael–typeaddition

PhN O

Ph

O

Friedel–Craft–typeaddition Ph N

O

OPh

AlH3

ON

O

PhPhAlH3

AlH3

Lewis Acid Catalyzed [4+3] Cycloaddition

PhN O

Ph

O

AlH3Ph

N

O

PhO AlH3

Ph N

O

OPh

AlH3

Ph N

O

OPh

AlH3

ON

O

PhPh

AlH3

TS 1

TS 2 TS 3

IN 1

IN 2

δ+

δ−

δ+

δ−

Arno, M.; Picher, M. T.; Domingo, L. R.; Andres, J. Chem. Eur. J. 2004, 10, 4742.

Mechanism for Friedel—Craft—type Addition:

2—Amino Allyl Cation

N

O

Bn NBnH

O

BF3 OEt2 (150 mol %)CH2Cl2, RT, 16h

67%

Prie, G.; Prevost, N.; Twin, H.; Fernandes, S. A.; Hayes, J. F.; Shipman, M. Angew. Chem. Int. Ed.2004, 43, 6517.

NR

X

NR

NRLA

NLA R N R

[4+3]

sBuLi then LA

2—Amino allyl cation

Prie, G.; Prevost, N.; Twin, H.; Fernandes, S. A.; Hayes, J. F.; Shipman, M. Angew. Chem. Int. Ed.2004, 43, 6517.

N

O

Bn NBnH

O

NBnH

O

1. BF3•OEt2 (150 mol %) CH2Cl2, 50 ºC, 16h

(Z) 56% (80:20)(E) 45% (32:68)

2. aq. H2SO4, MeOH 50 ºC,16h

NBn NBn

H

H

1. BF3•OEt2 (150 mol %) ClCH2CH2Cl,

reflux, 48h

53% (56:44)

2. aq. H2SO4, MeOH 16h

OH

NMe

H

F3B CH2Ph≠

OH

NH

Me

F3B CH2Ph≠

Straightforward and powerful approach for synthesizing seven member rings.

[4+3] Cycloaddition in Natural Product Synthesis

Sterpurene

H

OOMe

MeOMeO

MeONHAc

Me

MeMe

HO

HMe

O

O

H

OHOH

OH

iPrOHO

CH2OHH

Aphanamol I Lasidiol Dactylol

ColchicineSpatol Widdrol

O

O HH

HO

O

O

5–epi–10–epi–Vibsanin E

[4+3]

4–Substituted Butenolides

O OO OHnC8H17

Popillia japonica Eldana saccharina

Mori, K. Tetrahedron. 1989, 45, 3233.

O

O

O

OCO2R

OCO2R

OH

OH

OH

OH

OH

R

Synthetic building blocks

C1–C2 Cleavage: Preparation of 4–Substituted Butenolides

Montana, A. M.; Garcia, F.; Batalla, C. Tet. Lett. 2004, 45, 8549.

O OMeBr

O

BrO

O

OMe OO

O

O

O OMe

O

O O

1. Cu/NaI MeCN, RT 97% dr= 70:30

2. Chromatographic separation

HCl/MeOHRT, 10h

72%

HCl/MeOHRT, 25h

63%

H2/Pd—C100%

H2/Pd—C98%

O OR

OO

O

OO

O

OR

OCO2R

OCO2R

OH

OH

OH

OH

OH

R

Synthetic building blocks

Tricycloclavulone

Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563.

Isolated from soft coral Claularia viridis.

O

H

AcO CO2Me

OAc

Tricycloclavulone

O

H

AcO BrO

O

BrBr

Tricycloclavulone

Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563.

O

BrBr BrO O

BrTEA

TFE/ET2O, 1:1—78 ºC to RT

70% 6%

BrO O

O

H

HLiTHF

—78 to —30 ºC90%

CH2=CH2, CH2Cl2

5% G, RT,overnight,50%

O

H

AcORu

Ph

PCy3

PCy3

Cl

Cl= G

Aphanamol IThe first natural product synthesized using [4+3] cycloaddition.Isolated from the fruit peel of Indonesian timber tree Aphanamixis grandifolia.

Hansson, T.; Wickberg, B. J. Org. Chem. 1992, 57, 5370.

CHO

(PPh3)3RhClPhCN, 130 ºC, 1.5 h

90 %

(S)–A

O

BzO

(S)–Ahν

H H

OBz

O H OBz

H

O1:1

Me2S(O)=CH2

H OH

OBzO

H CH2OH

KOH/MeOHreflux, 2h

(+ )–Aphanamol I

Aphanamol IAdvantage of the direct formation of seven—membered rings by [4+3]cycloaddition.

Harmata, M.; Carter, K. W. Tet. Lett. 1997, 38, 7985.

P OEt

O

OEt

O

EtO

EtO 5

O

CH2OHH

8

OMOM

P

Li

O

Ph

Ph

2

CN

OMOM58%

3

OMOM

O

MeMgI

85%

1. LDA,

2. LAH 69%

4O

CH2OMOMH

7

Tf2O

CH2Cl2, 2,6–lutidine—78 ºC, 32%

H3O+

42%

OMOM

CH2OHEtO

6

(+ )–Aphanamol I

CN

CHO

1

Aphanamol ITransition metal catalyzed [5+2] cycloaddition

Wender, P. A.; Zhang, L. Org. Lett. 2000, 2, 2323.

OBn [5+2] cycloadditionH

OBn

0.5 mol% [Rh(CO)2Cl]2, 0.1M,Toluene, 110 ºC, 30 min, 93%

OxidativeAddition

RhLn

HOBn

Rotation and strain-drivenCyclopropane Cleavage

H

LnRh

OBn

ReductiveElimination

O

H

OH(+)–Aphanamol

OBn

•CHOOBn

CO2MeCO2Me

O

CO2Me

R–(+)–Limonene

Tropoloisoquiniline

OOR

OMeMeO

MeONHAc

OMeO

OMeMeO

MeONHAc N

ORO

MeO

MeO

MeO

N

OOMe

MeO

MeO

MeO

Colchicine (9): R = MeColchiceine (10): R = H

Isocolchicine Grandirubrine : R = HIsoimerubrine : R = Me Imerubrine

Lee, J. C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 3243.

Colchicine

Lee, J. C.; Jin, S. J.; Cha, J. K. J. Org. Chem. 1998, 63, 2804.

The principle alkaloid constituent of Colchicum autamnale Biological activity: arrests cell division during mitosis, potential antitumor agent

OHMeO

MeOOMe

1

OMeMeO

MeONHAc

6

O

MeO

MeOOMe

OH

O

N

N

OLi

H3B

Swern [O];

61%2

MeO

MeOOMe

O

NHN Me

O

5

MeO

MeOOMe

R2

O

N1. Swern [O]

2. Itsuno red.

3: R2 = β–OH

4: R2 = α–N3

PPh3, DEAD(PhO)2P(O)N3

60%

82%

1. PPh3, H2O2. Ac2O, Et3N 95–100%

o–Cl2C6H4

reflux(60—70%)

Colchicine


OMeMeO

MeONHAc

6

O

OTMS

OMe

OMe

OMeO

MeO

MeONHAc

OOMe

7

8

TMSOTfEtNO2–78 ~ 50 ºC (60%)

Undesired regioisomer

OMeMeO

MeONHAc

6

O OMeMeO

MeONHBOC

O

1. (BOC)2O2. LiOH

(98%)

OTMS

OMe

OMe

7TMSOTf (45%)

9

OMeO

MeO

MeONHBOC

O

OMe10

OOMe

MeOMeO

MeONHAc1. HCl

2. Ac2O (98%)

(—) Colchicine~ 90% ee

9

OOMe

MeOMeO

MeONHBOC

TMSOTfEt3N

CH2Cl2

0—10 ºC (62%)

11

Colchicine


O

NAcMeO

MeOOMe

OMe

OTMS

H

OMeO

MeO

MeONHAcOMe

8

Undesired regioisomer

O

6

OMeO

MeO

MeONHBOC

O

O

NBOCMeO

MeOOMe

H

MeO

TMSO

9

OMe10

Tropoloisoquiniline


Grandirubrine : R = HIsoimerubrine : R = MeImerubrine

O

ORN

MeO

MeO

MeO

O

N

MeO

MeO

MeO

N O

NP

MeO

MeO

MeO

N O

or

NHTsOMe

OMe

Imerubrine was isolated from the plant Abuta imeneGrandirubrine was isolated from Abuta grandifolia

Tropoloisoquiniline

N

OOMe

MeO

MeO

MeO

Imerubrine

N

MeO

MeO

MeO

O

OCl Cl

ClN

MeO

MeO

MeO

OO

1. Et3N, CF3CH2OH2. Zn NH4Cl, MeOH

73%

N

MeO

MeO

MeO

O

OH

PhI(OAc)2KOH–MeOH 83%

OMeOMe

N

MeO

MeO

MeO

OO

OMe

1. NaH, MeI2. 50% AcOH

92%

TMSOTfEt3NCH2Cl2

76%


Tropoloisoquiniline


N

MeO

MeO

MeO

O

OH

OMeOMe

N

MeO

MeO

MeO

OO

OH

N

OHO

MeO

MeO

MeO

Grandirubrine

N

OMeO

MeO

MeO

MeO

Isoimerubrine

50% AcOH

96%

TMSOTfEt3NCH2Cl2

62%

TMSCHN2MeOH–THF

N

OOMe

MeO

MeO

MeO

Imerubrine (34%) (32%)

(+)—Dactylol

Feldman, K. S.; Wu, M. J.; Rotella, D. P. J. Am. Chem. Soc. 1989, 111, 6457.

(+)–Dactylol was isolated from sea hare Aplysia dactylomela.

Tropone– alkene photocyclization

O

hν

ORH

CH3H H

O

Me

Me

HO

HMeOR

R = HR = CH3CO

Me

MeMe

HO

HMe

(+)–Dactylol

(+)—Dactylol

Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 8746.

O O1. methallyl bromide

Mg-graphite (4.3 equiv) THF, 65 ºC, 30 min

RO

RO

2. CeCl3, –78 ºC, 2h 80% combined yield

1a R = H

2a R = H

1a: 2a = 1: 1.2 1b R = SiMe3

2b R = SiMe3

a (93%)

a (95%)

a. (Me3Si)2NH (1.25 equiv), acetyl chloride (1.25 equiv)

DMAP

HO

HO

H

b

b

b. 1.molybdenum carbene X (3 mol%), hexane, 55 ºC, 3

2. aq. TBAF, THF, 50 ºC, 3h

92%

85%

NMo

O

O

F3C CF3

F3CF3C

X

Ph

(+)—Dactylol

Harmata, M.; Rashatasakhon, P. Org. Lett. 2000, 2, 2913.

Me

MeMe

HO

HMe

(+)–Dactylol

Me

HMe

CO

OCl

Me

Me

TMS

OCO2Me

Me I

Me TMSA

(+)—Dactylol


OCO2Me

Me1. NaH; nBuLi2. A O

CO2Me

Me

Me

TMS

70%

KCN, DMSOreflux, 94% O

Me

Me

TMS

1. LDA, TfCl2. TEA; TFE/Et2O3. TsOH

74%

Me

HMe

CO

25:1

CH2I2, Et2Zn95%

Me

HMe

CO

MMPPDMF, 84%

Me

HMe

CO

O

4:1

O R

Me Me

(+)—Dactylol


Me

HMe

CO

Me Me

O 1. KOH2.CH2N2

Me

HMeMe Me

OHMeO O

1. POCl3, HMPAPyridine

2. KOH84%, 4 steps

Me

HMeMe Me

HO O

1. COCl2, DMF2. mCPBA, Pyridine/DMAP3. LAH, Et2O

50%

Me

HMeMe Me

HO

(+)–Dactylol

Me

HMe

CO

O H2/PtO298%

Vibsanin E

O

O

O

O

O

H

HH

Vibsanin E

UV [4+2]

hetero [4+2][4+3]

Vibsanin E was isolated from the plant Viburnum odoratissimum in 1980 Its absolute configuration was established by Fukuyama & et al in the same year Vibsanin family has been extensively used in medicines of menstrual cramps

O

O

O

O

Vibsanin C

OH

BF3•OEt2CH2Cl2, -78 ºC, 18 min

50%

O

O

O

O

O

H

HH

Vibsanin E

Fukuyama, Y.; Minami, H.; Kagawa, M.; Kodama, M.; Kawazu, K. J. Nat. Prod. 1999, 62, 337.

Davies, H. M.; Loe, O.; Stafford, D. G. Org. Lett. 2005, 7, 5561.

Attemped Total Synthesis of Vibasanin E

Synthesis of A

Synthesis of B

N2EWG

O

R

N2EWG

OH

R

N2EWG

R

NaBH4 POCl3

NEt3


OH O(COCl)2DMSO

CH2Cl2—50~—60 ºC

Ph3P CH2

THF

(90–94%) (77–80%)

CO2MeN2 CO2Me 1. Rh(II), hexane,

Overnight, rt2. toluene, reflux, 5h

Rh2(OOct)4 62% yield

Rh2(S-DOSP)4 69% yield (64% ee)

A B



tandem conjugateaddition/alkylation

O

H

H

HO

A

O

O

O

O

O

H

HH

Vibsanin E

tandem conjugateaddition/alkylation

O

H

H

HO

A

O

H

H

HO

only product that could be achievedvia Me2CuLi induced reaction.

resistant to conjugate addition(probably due to steric)

X

1. DIBAL-H2. (COCl)2 DMSO

90%

OBF3•OEt2

hetereo [4+2]

86%

O

H

H

NaCNBH3/

84%

AcOH

O

H

H

H

1. SeO22. PCC

O

H

H

HO

CO2Me

Atricyclic core of

Vibsanin E


O

H

H

HOO

H

H

HO

ACis

BTrans

hν

O

H

H

HO

A

UV/pyrex

91%

O

H

H

HO

B

O

H

H

HO

CB:C = 2:1

O

O

O

O

O

H

HH

Vibsanin E

OsO4/NMO

O

H

H

HO

D 46%

O

H

H

HO

E 25%

HO

HOHO

HO


O

O 2Py, Catalyst

N

N

Catalyst

O

O

O

O

O

H

HH O

O

H

HH

O

OO

G 19%(±)-5-epi-10-epi-Vibsanin E

H 10%

NaIO4O

O

O

O

H

HH

F 81%

Summary

[4+3] Cycloaddition reaction is one of the most synthetically useful method for synthesizing seven–member rings.

A 1,3 diene and an allyl cation cyclizes either in a concerted or stepwise fashion.

The reaction depends on the nucleophilicity of the diene and electrophilicity of the allyl cation.

Different allyl cation– 2–oxyallyl, 2–amino allyl, allyl acetal etc. are known.

The reaction shows high levels of stereoselectivity.

Successfully employed in synthesizing important building blocks and several natural products.

Acknowledgments

Dr. Smith

Dr. Maleczka

Dr. Walker

Dr. Smith’s Group members

[4+3] cycloaddition towards natural product synthesis · [4+3] cycloaddition towards natural...

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