Organic Synthesis Strateg ycook.chem.ndsu.nodak.edu/.../files/SyntheticStrategy.pdf · 2018-10-16 · Ideal Organic Synthesis 3 ‣ Highest chemical yields (and purity) - important

Organic SynthesisStrategy

Organic Synthesis

2

‣ The preparation of more complex molecules from commercially available starting materials via a multistep sequence of transformations.

Starting Materials

Target Product

OHO

AcO OH

AcO

H

PhOCO

O

O

PhCOHN

OH

O

Ideal Organic Synthesis

3

‣ Highest chemical yields (and purity) - important over many steps.

‣ As concise as possible.

‣ Convergent is more efficient.

‣ Introduce as many bonds and as much complexity as possible in a single operation.

Affect of Yield on Overall Efficiency

4

Number of Steps OVERALL Yieldaverage yield per step 80%90%

5 32%53%10 10%31%

20 1.1%11%

30 10-3%4%

60%

8%0.6%

0.004%

10-7%

Affect of Convergency on Overall Efficiency

5

Linear sequence of reactions

A B C D E F75% 90% 80% 85% 70%

Overall Yield: 32%

A B C

F

75% 90%

80%

G D E85% 70%

Overall Yield from A: 54%Overall Yield from G: 48%

Convergent Approach

Retrosynthetic Analysis

6

‣ a problem solving technique

‣ Start with the target structure and think about immediate precursor - how to make functional groups or new C-C bonds.

‣ Continue backwards until you get to the starting material.

HO OH

OO?

KMnO4Cl2

KOH

light

Cl

Retrosynthetic Analysis

7

‣ Need understanding of reactions, knowledge of feasible mechanism, repertoire of reactions.

‣ Need to understand selectivity

‣ Chemoselectivity - reaction one functional group

‣ Regioselectivity - where reaction takes place

‣ Stereoselectivity - control 3 dimensions

Thinking backwards

8

Br Br

Br Br

Br2(excess)

I

1) NaNH2

2)BrBr KOH

Br2

Thinking backwards

9

OH

BH3; thenH2O2, OH-

Br CuLi2

HBr

H2Lindlar catalyst

HC CNa

Multistep Synthesis

10

H2 / Lindlaror

Li / NH3

HBrBr

(CH2=CH)2CuLi

Multistep Synthesis

11

OHPBr3

NaCNHMPATos-Cl

base

D1)

2)

Mg

D2O

Br

OTos CNNaCNHMPA

CN

Best Strategy

12

OHPBr3

D1)

2)

Mg

D2O

Br

HBr

HBrBr

Br

+

no Regioselectivity and no Stereoselectivity

Best Strategy

13

OHgSO4H3O+

Which Alkyne ?

O

HgSO4H3O+

HgSO4H3O+

HgSO4H3O+

HgSO4H3O+

O

O

+

O

O

+

O

Multistep Synthesis

14

NBSor Br2light Na

BrH2Lindlarcat.

OH

Na

PBr3orSOCl2

XH2Pd/COH

Na

Multistep Synthesis

15

OH

TosClpyridine

NaCNDMSO

PBr3

NaOCH2CH3HOCH2CH3 HCl

a) BH3b) H2O2, -OH

BrCl

OTs CN

Multistep Synthesis

16

Cl

OH Br MgBr

OMg

1) Cl2, light2) KOH, EtOH3) BH3, then H2O2, NaOH4) PBr35) Mg, ether6)

7) H3O+

O

OH