Last Chem 125 Lecture 4/29/09 Projected material This material is for the exclusive use of Chem 125...

Last Chem 125 Lecture 4/29/09

Projected material

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Chapter 22

whateverR C

O

Hsubstitutionat -C

Ester Enolate (sec. 22.7B p. 1087)

C nucleophile

*

*

-Halogenation (sec. 22.3 p. 1057-1060)

Aldol (sec. 22.4 pp. 1063-1067)

,-unsaturated carbonyl

Hydrocinnamaldehyde Starting Material for “Clamshell” Synthesis

(Cf. p. 1068)

,-unsaturated carbonyl Aldol

H

acetaldehyde

H

Cinnamaldehyde(prepared by this

method in 1884)

Ph-CH2-CH2-CHO

H2 / cat (see frame 13)

“Claisen” or “Acetoacetic Ester” Condensation (pp. 1072-1075)

substitution at ester

Why not use OH-?

Equilibrium position?

Biological Claisen X = SR = coA(sec. 22.6, pp. 1081-1083)

Addn. to Conjugated Systems II-Unsaturated Carbonyl: C=O

p. 1100

Addn. to Conjugated Systems III-Unsaturated Carbonyl: C=C

Sec. 22.9pp. 1100-1101

O

via ?

1,4addn

enol ketone

Addn. to Conjugated Systems IV-Unsaturated Carbonyl: Conjugate

sec. 22.8 pp.1092-1095

“1,4” “Conjugate” Additionor “Michael”


sec. 22.10 pp. 1101-1103

sec. 22.10 pp. 1101-1103

PhMgBr 1,4 (96%)

PhLi 1,2 (75%)

CuI (cat) 1,4

RCuLi 1,4


LORE

Cortisone

from Fieser & Fieser, Advanced Organic Chemistry, Reinhold (1961)

1943100 mg from100 lbs. beef

adrenal glands

Woodward "Total" Synthesis (1951)

O

O

CH3

CH3

H

H H

OHCO

CH2OH

"Total" Synthesis Woodward (1951)

C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

LiAlH4

reduction

D?C

O

CH3O

CH3

OH

D?C

O

CH3O

CH3

OH

OH

OH

D?C

CH3O

CH3

HOH

D?C

O

CH3

H

H+/H2O

OH

D?C

CH3O

CH3

HOH

CH3

C

O

CH3O

O

H

H

OH-

H

H+

+

D?C

O

CH3

H

Ac2O

Zn

Why losethe top OH

not one of these?

H+

hemiacetal

Diels-Alder

via enolate

OH allylic rearrangement

known andreadily available

+ +

CH3CO

Zn:+2

CH3CO2-

D?C

O

CH3

H


C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

D?C

O

CH3

H

OO

D?C

CH3

H

H

B

OsO4

O

D?C

CH3

H

H

B

OH

OH

O

D?C

CH3

H

H

B

O

O

H+ O=C(CH3)2

(ketal)

O

D?C

CH3

H

H

B

O

OH2 / Pd

enolate-

-

-

“Michael” (1,4 or conjugate)

addition

aldol

p. 1098Robinson annulation

Robinson and Woodward after an MIT seminar on the Robinson annulation

(photo J.D. Roberts, 1951)

Protecting C=C

O

C

CH3

H

H

B

CH3


C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OHO

D?C

CH3

H

H

B

O

O

Abbreviate Ring D

Protectthe more

reactive position


C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

O

C

CH3

H

H

B

CH3

O

C

CH3

H

H

B

CH3

N(CH3)PhHO

C

CH3

H

H

B

N(CH3)PhHN

CH3

C

-

-OH-

(catalytic)

NC

C

B

O

CH3

CH3

H

H

OCH3

conjugate addition

H-N(CH3)Ph

OB

H

OCH3

O

B

H O

OB

H OHO

N(CH3)Ph

- -

:

like aldol -unsaturated ketone(also an enamine)

like Claisen

HH

HH

"vinylogous”

H

LORE!

H+

Protectthe more

reactive position


C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

O

C

CH3

H

H

B

CH3

O

C

CH3

H

H

B

CH3

N(CH3)PhHO

C

CH3

H

H

B

N(CH3)PhHN

CH3

C

- OH-

(catalytic)

NC

OH- (strong)

H2O

ON

C

CH3

H

H

B

CH3

C OO

CH3MgBr H+C

B

O

CH3

CH3

H

H

OCH3

C

CH3

H

H

B

CH3

OO

conjugate addition

A?-

O

N(CH3)PhHlose

HOH+

++

H +H

+

HCH3enolate


CH3

O

C

B

O

CH3

CH3

H

H

D?

O

OA

aldol C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH


CH3

H

D?

O

O

C D

BA

O

O

CH3

CH3

H

H H

OHCO

CH2OH

CH3

H

D?

OH

OH

H+

H2O

CH3

H

O

H

O H

CH3

H

D?

O

O

I

H

HO

O-

O

Formal (or "Relay")

This conversion was known from previous cortisone studies!

1) K2Cr2O7

OB

A

C-OHCH3

H

D

O

CH3 HC

BH4-

CCH3

H

D!

O

aldol(luck)

base

-H2O

I

OO-

O

O

H/ resolved(1909 method)

/ H2-cat

-IO3- pericyclic

H

2) CH2=N2

hydrolyze acetal

new “acetal”

reduces ketone

not ester

CH3

J. Am. Chem. Soc.

H2

Pd

1) NaBH4

2) Ac2O

4 5 6 7 8

O

OH

But What Was the Yield?

Intellectual Problem Solved.

Sequential (40 steps @ 80%) 0.01% yield

Convergent (4x9 steps + 2) 9% yield99

99

A

B

C

D

P

E

F

Cortisone Synthesis (Practical)

Choose an appropriate,readily availablestarting material.

properlymethylatedtetracyclic

carbonskeleton

with properstereochemistryat key positions

and functionalgroups at or near

some of the proper positions

but

from ox bile1946-49

Merck made 1 kg cortisonefrom 600 kg

of this bile acid

?

Br?Br

Br

?O

1949Merck

$200/gm

Cortisone Synthesis (Practical)

Pregnancyhormone

~1955$0.48/gm

Abundant ina Mexican yam

Russell Marker

Vitamin B12

(1973)

Albert Eschenmoser

ETH Zurich

Robert Burns Woodward

(1917-1979) Harvard

During this work RBW discovered control of stereochemistry by orbital symmetry

(pericyclic reactions, p. 1335)

with ~100 co-workersincluding…

postdoctoral Woodward collaborator

Yoshito Kishi(instructor Nagoya Univ.)

WOODWARD, PURE APPL CHEM 25: 283 (1971)

Kishi joined and then succeeded Woodward as professor at Harvard.

Palytoxin 62 Stereogenic Centers

42 Functional GroupsProtected 8 Different Ways

Convergent from 8 Pieces

Kishi et al. 1994

1020 stereoisomers7 E/Z Double Bonds

C123H213NO53

E7389 being developed commercially for breast cancer by Eisai Pharmaceutical

O

O

O

O O

O

O

O

O

HO

HO

MeO

O

H

H H

MeH

H

H

O O

OMe

OO

O

O

O

OO

Me

HH

H

H

H2N

OH

E7389halichondrin B C.1-C.38 macrolide

"In Vitro and In Vivo Anticancer Activities of Synthetic Macrocyclic Ketone Analogues of Halichondrin B"M.J. Towle, K.A. Salvato, J. Budrow, B.F. Wels, G. Kuznetsov, K.K. Aalfs, S. Welsh, W. Zheng, B.M.Seletsky, M.H. Palme, G.J. Habgood, L.A. Singer, L.V. DiPietro, Y.Wang, J.J. Chen, D.A. Quincy, A.DavisK. Yoshimatsu, Y. Kishi, M.J. Yu, and B.A. Littlefield, Cancer Res., February 1, 2001; 61(3): 1013-1021

SARActive Fragment

of Halichondrin B

"Simplified" Versionof Active Fragmentis Drug Candidate

E7389

~ 100,000 configurational isomers!

Friedrich Wöhler(1800-1882)

Organic Synthesis has comea long way from urea.

"Perhaps you still remember the experiment I carried out in that fortunate time when I was working with you, in which I found that whenever one tries to react cyanic acid with ammonia a crystalline substance appears which is inert, behaving neither like cyanate nor like ammonia."

To Berzelius (1828)

Good Luck on the Final Exam

Review at Class Time Friday

Last Chem 125 Lecture 4/29/09 Projected material This material is for the exclusive use of Chem 125...

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