PHƯƠNG PHÁP TỔNG HỢP HỢP CHẤT HỮU CƠ ĐA CHỨC

Retrosynthesis of B-Hydroxy Ketones/Aldehydes Aldol ketone TM Retrosynthesis of B-Hydroxy Ketones... Synthesis of a,B-Unsaturated Ketones/Aldehydes Aldol The B-hydroxy ketone or B-hydr

CHƯƠNG 4: PHƯƠNG PHÁP TỔNG HỢP HỢP CHẤT HỮU CƠ ĐA CHỨC

CHAPTER 4

SYNTHESIS OF TARGET MOLECULES WITH

TWO FUNCTIONAL GROUPS

A SYNTHESIS OF B-HYDROXY CARBONYLS AND a,f-

1 Synthesis of B-Hydroxy Carbonyls (Aldol)

Retrosynthesis of B-Hydroxy Ketones/Aldehydes (Aldol)

ketone TM

Retrosynthesis of B-Hydroxy Ketones

2 Synthesis of a,B-Unsaturated Ketones/Aldehydes (Aldol)

The B-hydroxy ketone or B-hydroxy aldehyde product of an aldol reaction can undergo

dehydration to give an a,B-unsaturated product

(not isolated)

Aldol Reactions Sometimes Give Only o,B-Unsaturated Ketones/Aldehydes

In intermolecular aldol reactions, the more stable alkene product is expected

Retrosynthesis of a,B-Unsaturated Ketones/Aldehydes (Aldol)

self (1+1) self(2+2) mixed (1+2) mixed (2+1)

Mixed Aldol Becomes “Messy” Aldol if Carbonyls Have Similar Reactivity

reversible reaction more stable pi bond

Choice of Base/Reaction Conditions Determines Regiochemistry

B SYNTHESIS OF a,B-UNSATURATED ESTERS USING THE WITTIG REACTION

1 Synthesis of a,B-Unsaturated Esters (Wittig)

While the Wittig reaction typically gives the (Z)-alkene as the major product, stabilized

ylides usually give the (E) stereoisomer

O ¬"^a

Retrosynthesis of a,B-Unsaturated Esters (Wittig)

this carbon was

Othe Nu: (Wittig)

was the E+ Wittig) a Is the better synthesis,

this carbon was the E+

PPh

was the + (poor SM) (Wittig)

Nu: (Wittig)

b has complex E+,

Retrosynthesis of o@,B-Unsaturated Esters via Wittig

EXAMPLE: a,B-UNSATURATED CARBONYL

OMe

TM

was the E+ Pho

Synthesis of TM via Wittig,

“ILLOGICAL” DISCONNECTIONS: UMPOLUNG (POLARITY REVERSAL)

An example of an “illogical” synthon is a negatively charged carbonyl nucleophile Since carbonyls are normally electrophilic, a reversal of polarity (called “umpolung”) must occur in order to accomplish the synthesis

HÀ

1,2-diol

Ù /® ®

Synthesis of 1,2-Diols from Alkenes

CH3CO3H }\ anti dihydroxylation

(racemic)

Synthesis of 1,2-Diols from Alkenes

a-Hydroxy Carboxylic Acid TMs: Umpolung

E* Nu: (workup) Cyanohydrin hydrolysis œ-hydroxy acid

Synthesis of a-Hydroxy Carboxylic Acids

a-Amino Acid TMs: The Strecker Synthesis

hydrolysis amino acid Strecker Synthesis of a-Amino Acids

a-Hydroxy Ketone TMs: The Dithiane Anion

Disconnection of an a-hydroxy ketone or aldehyde also results in an illogical synthon that requires a nucleophilic carbonyl carbon

The acyl anion ts unstable and cannot be prepared, the 1,3-dithiane anion is stable due

to the inductive withdrawal of electron density by the two sulfur atoms The 1,3-dithiane anion can be used as a nucleophile and then converted to a carbonyl by hydrolysis

eX

acyl anion dithiane anion

can be used instead

impossible to make (synthetic equivalent)

| 3-Dithiane Anion 1s the Synthetic Equivalent of an Acyl Anion

Preparation of a 1,3-Dithiane Anion

Reaction of a 1,3-dithiane anion nucleophile with a ketone or aldehyde electrophile, followed by a mercury-assisted hydrolysis, affords an a-hydroxy ketone

Synthesis of an o-Hydroxy Ketone

HO O Foi HO S$ » >> |}

was the E+ this carbon

XK H

Nu:

Retrosynthesis of o-Hydroxy Ketones

Synthesis and Uses of 1,3-Dithiane Anion

dithiane anion derived O O

from formaldehyde can

be used to synthesize aldehydes and ketones

aldehyde

AR

ketone

Example: a-Hydroxy Ketone TM

OH

O

>2 „„ ,OH this carbon o OH

GP & was theE+ "What SM ve

was the Nu:

<4

(dithiane anion)

Retrosynthesis of a-Hydroxy Ketone TM

The first step in the synthesis is an oxidation of the alcohol starting material (via

PCC or Swern conditions) to give the needed carbonyl Reaction of this ketone with

the 1,3-dithiane anion shown, followed by hydrolysis, affords the desired TM

ON TAP

1 Provide the corresponding synthetic equivalent for each of the following synthons

In other words, what starting material would have the desired reactivity?

2 Propose a possible disconnection/retrosynthesis for each of the following target

molecules Consider the pattern of functional groups when determining the best site for