Organic Synthesis Strategy

Organic Synthesis

The preparation of more complex molecules from

commercially available starting materials via a multistep sequence of transformations.
Target Product
AcO O

Starting Materials

OH

PhCOHN

O O OH HO PhOCO H AcO O

Ideal Organic Synthesis

Highest chemical yields (and purity) - important

over many steps.

As concise as possible. Convergent is more efcient. Introduce as many bonds and as much complexity
as possible in a single operation.

Affect of Yield on Overall Efciency

Number of Steps average yield per step 5 10 20 30 OVERALL Yield 90% 53% 31% 11% 4% 80% 32% 10% 1.1% 10-3% 60% 8% 0.6% 0.004% 10-7%

Affect of Convergency on Overall Efciency

Linear sequence of reactions 75% A B 90% C 80% D 85% E 70% F

Overall Yield: 32%

Convergent Approach 75% A B 90% C 80% 85% G D 70% E Overall Yield from A: 54% Overall Yield from G: 48% F

Retrosynthetic Analysis

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.
O ? HO Cl2 light Cl KOH
6

O OH KMnO4

Retrosynthetic Analysis

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

Br Br Br

Br

Br2
Br2 (excess)

1) NaNH2
Br Br
KOH

2)

Thinking backwards
OH

HBr

BH3; then H2O2, OH-

Br

CuLi 2

HC

CNa H2 Lindlar catalyst

Multistep Synthesis

H2 / Lindlar or Li / NH3

(CH2=CH)2CuLi

Br HBr

10

Multistep Synthesis

OH

PBr3

Br

1) Mg 2) D O 2 NaCN HMPA CN

Tos-Cl base

OTos

NaCN HMPA

CN

11

Best Strategy
OH PBr3 Br 1) Mg 2) D O 2 D

HBr
Br
HBr +

Br
no Regioselectivity and no Stereoselectivity

12

Best Strategy
Which Alkyne ? HgSO4 H3O+ O

HgSO4 H3O+ O

HgSO4 H3O+ O

HgSO4 H3O+ O

HgSO4 H3O+ O

O
13

Multistep Synthesis

NBS or Br2 light

Br
Na

H2 Lindlar cat.

OH

PBr3 or SOCl2

X
Na

H2 Pd/C

14

Multistep Synthesis

a) BH3 b) H2O2, -OH OH PBr3

TosCl pyridine OTs

NaCN DMSO CN

NaOCH2CH3 HOCH2CH3 Br

HCl Cl

15

Multistep Synthesis
OH

1) Cl2, light 2) KOH, EtOH 3) BH3, then H2O2, NaOH 4) PBr3 5) Mg, ether O 6)
OMg Cl

7) H3O+

OH

Br

MgBr

16