Modern Organic Synthesis an Introduction

G. S. Zweifel M. H. Nantz W.H. Freeman and Company

Chapter 1 Synthetic Design

• What is an ideal or viable synthesis, and how does one approach a synthetic project? • The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps) and selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity). • This chapter outlines strategies for the synthesis of target molecules based on retrosynthetic analysis.

1 1.1 Retrosynthetic Analysis Basic Concept

The symbol signifies a reverse synthetic step and is called atransform. The main transforms are disconnections, or cleavage of C-C bonds, and functional group interconversions (FGI)

Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions(FGI).

Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM.

The actual substrates used for the forward synthesis are the synthetic equivalents (SE).

Synthetic design involves two distinct steps (1) Retrosynthetic analysis (2) Subsequent translation of the analysis into a “forward direction” synthesis.

Chemical bonds can be cleaved heterolytically, homolytically, or through concerted transform.

2 Donor and Acceptor Synthons

Acceptor synthon Æ carbocation (electrophilic) Donor synthon Æ carbanion (nucleophilic)

Table 1.1 Common Acceptor Synthon Synthetic equivalents

Common Acceptor Synthon Synthetic equivalents

3 Table 1.2 Common Donor Synthons

Common Donor Synthon Synthetic equivalents

Retrosynthetic Analysis A

Synthesis A

4 Retrosynthetic Analysis B

Synthesis B

Alternating Polarity Disconnections

The presence of a heteroatom in a molecule imparts a pattern of electrophilicity and nucleophilicity to the atom of the molecule.

The concept of alternating polarities or latent polarities (imaginary chargies) often enables one to identify the best positions to make a disconnection within a complex molecule.

Functional groups may be classified as follows.

E class: Groups conferring electrophilic character to the attached carbon (+):

-NH2, -OH, -OR, =O, =NR, -X (halogens) G class: Groups conferring nucleophilic character to the attached carbon (-):

-Li, -MgX, -AlR2, -SiR3 A class: Functional groups that exhibit ambivalent character (+ or -):

-BR2, C=CR2, CCR3, -NO2, N, -SR, -S(O)R, -SO2R

5 Consonant Pattern: Positive charge are placed at carbon atom bonded to the E class groups.

Dissonant Pattern: One E class is bonded to a carbon with a positive charge, whereas the other E class group resides on a carbon with a negative charge.

Alternating Polarity Disconnections

Consonant

Simple synthesis

Dissonant

One Functional Group

Analysis

6 Synthesis

Two Functional Groups In a 1,3-Relationship

Analysis

7 Synthesis (path a)

Synthesis (path b)

8 Two Functional Groups in 1,4-Relationship

The α-carbon in this synthon requires an inversion of polarity (umpolung in German) from the negative (-) polarity normally associated with a ketone α-carbon. Analysis

α-bromoketone

Enolate cannot be used because of the formation of an epoxy ketone (Darzens condensation). Instead, enamine is used.

Synthesis

9 Analysis Umpolung

Synthesis

10 Regioselective opening of epoxide by nucleophilic reagent provides For efficient two-carbon homologation reactions.

1.2 Reversal of the Carbonyl Group Polarity (Umpolung)

The carbonyl group is electrophile at the carbon atom and hence is susceptible to attack by nucleophile.

11 Reversal of polarity of a carbonyl group has been explored and systemized by Seebach.

Unnatural negatively negative charge charged c carboxylic synthon Since formyl and acyl anions are not accessible, one has to use synthetic equivalents of these anions.

Umpolung in a synthesis usually requires extra steps.

Formyl and Acyl anion derived from 1,3-dithianes

2-lithio-1,3dithian species; acyl anion equivalents

EtSH: pKa 11 (more acidic) EtOH: pKa 16

12 13 With HMPA (hexamethylphosphoramide), [(Me2N)3P=O], dithiane-derived carbaions may serve as Michael donors. But without HMPA, 1,2-addition to the carbonyl group prevails.

14 Acylanions derived from Nitroalkanes

CH3NO2, pKa 10.2; CH3CH2NO2, pKa 8.5

Nitronates of primary nitro compounds yield carboxylic acid.

Nef Reaction under acidic condition

R O + H O 1 H R1 OH H2O R1 OH R1 2 N N HO N H O + R O HNO 2 R2 OH R2 OH R2 hyponitrous acid work up

R O-TiCl R Tautomerization R TiCl3 1 2 -O=TiCl2 1 1 N N N -Cl- R2 O R2 O R2 OH nitroso compound oxime

15 16 Acyl anions derived from cyanohydrins

O-protected cyanohydrins contains a masked carbonyl group with inverted polarity.

(Stetter reaction)

17 Acyl anion synthon derived from cyanohydrins may be generated catalytically by cyanide ion via the Stetter reaction.

18 Acycl anions derived from Enol ethers

Acyl anions derived from lithium acetylide

19 1.3 steps in planning a synthesis

• Construction of the carbon skeleton • Control of relative stereochemistry • Functional Group interconversion • Control of enantioselectivity

Construction of the carbon skeleton

Important C-C bond forming reactions encountered in organic synthesis • Reactions of organolithium and Grignard reagents, such as RLi, RC≡Cli, RMgX, and RC≡CMgX, with aldehyde, ketones, esters, epoxides, acid halides, and nitriles

• Reactions of 1oalkyl halides with -C≡N to extend the carbon

• Alkylations of enolate ions to introduce alkyl groups to carbons adjacent to a carbonyl group (e.g., acetoacetic ester synthesis, malonic ester synthesis)

20 • Condensations such as aldol (intermolecular, intramolecular), Claisen, and Dieckmann

• Michael additions, organocuprate additions (1,4- additions)

• Friedel-Crafts alkylation and acylation reactions of aromatic substrates

• Wittig reactions, and Horner-Wadsworth-Emmons olefination

• Diels-Alder reactions giving access to cyclohexenes and 1,4-cyclohexadienes

• Ring-closing olefin metathesis

Table 1.3 Summary of Important Disconnections

21 • Disconnections of bonds should be carried out only if the resultant fragments can be reconnected by known and reliable reactions.

• fewest number of disconnections (see Section 1.4, convergent vs. linear synthesis)

• It is often advantageous to disconnect at a branching point since fragments can be easily accessible, either by synthesis or from a commercial source.

22 • A preferred disconnection of cyclic esters (lactones) or amides (lactams) produces hydroxy-carboxylic acid or amino- carboxylic acids as targets.

• Functional groups in the TM may be obtained by functional group interconversion.

23 • Symmetry in the TM simplifies the overall synthesis by decreasing the number of steps required for obtaining the TM.

• Introduction of an activating functional group may facilitate carbon-carbon bond formation. After accomplishing its role, the activating group is removed.

24 •The presence of a 1,6-dioxygenated compound suggests opening of a six-membered ring. A variety of cyclohexene precursors are readily available via condensation and Diels-Alder reaction or via Birch reductions of aromatic compounds.

• Disconnection of an internal (E)- or (Z)-double bond or a side chain of an alkene suggests a Wittig-type reaction or an alkylation of a vinylcuprate, respectively.

25 • The presence of a six-membered ring, especially a cyclohexene derivative, suggests a Diels-Alder reaction.

• The structural feature of an α,β-unsaturated ketone or a β-hydroxy ketone in a six-membered ring suggests double disconnection coupled with functional group interconversions. (Robinson annulation)

Functional Group Interconversion

a. Alkyl Chlorides

b. Alkyl Bromides

26 c. Allylic and Propargylic Bromides

d. Alkyl Iodies

e. Nitriles

27 f. 1o and 2o Alcohols

g. 1o, 2o and 3o Amines

28 h. Aldehydes and Ketones

29 i. Carboxylic Acids

30 j. Alkenes

k. Alkynes

31 Control of Relative Stereochemistry (stereoselctive and stereospecific)

• SN2 displacement reaction; E2 elimination reactions • Catalytic hydrogenation of alkyne (cis product) • Metal ammonia reduction of alkyne (trans product) • Oxidation of alkenes with osmium tetroxide

• Addition of halogens, interhalogens (e.g., BrI) or halogen-like species (e.g., PhSCl, BrOH) to double bond • Hydroboration reactions • Epoxidation of alkenes; ring-opening of epoxide • Cyclopropanation

Control of enantioselectivity

32 1.4 Choice of Synthetic Methods The choice of a method for synthesizing a compound derived from a retrosynthetic analysis should be based on the following criteria

• Regiochemistry, the preferential addition of the reagent in only one of two possible regions or directions. • Chemoselectivity, selective reaction of one functional group in the presence of other functional groups • Stereoselectivity, the exclusive or predominant formation of one of several possible stereoisomeric products.

• Efficiency, fewest number of steps • High yields in each step • Availability and costs of starting material • Most environmentally friendly route. Ideally the atoms of substrate and any additional reagents used for the reaction should appear in the final product, called “atom economy”

33 • Simplicity of selected procedure. • Isolation and purification of reaction products. Ability and utility to separate and recover the reaction product from other materials • Possibility of a convergent synthesis or a “one-pot process.

Linear and Convergent Syntheses

• In a linear synthetic scheme, the hypothetical TM is assembled in a stepwise manner. If 80% yield is obtained in each step, 21% (0.87 x 100) overall yield of product can be isolated after 7 steps. If 70%, only 8% overall yield.

34 • Convergent synthesis should be considered in which two or more fragments of the TM are prepared separately and then joined at the latest-possible stage of the synthesis. Only three stages are involved in the convergent strategy, with overall yield of 51% (0.83 x 100).

• Another important consideration in choosing a convergent protocol is that failure of a single step in a multistep synthesis does not nulify the chosen synthetic approach as whole, whereas failure of a single step in a linear scheme may require a revision of the whole plan.

35 • Convergent syntheses involve consecutive reactions, where the reagents or catalysts are added sequently into “one pot”.

36 1.5 Domino Reactions (also called cascade or Tandem reactions)

• Domino-type reactions involve careful design of a multistep reaction in a one-pot sequence in which the first step creates the functionality to trigger the second reaction and so on. Robinson annulation (a Michael reaction followed by aldol condensation and dehydration)

37