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Organic Synthesis:
The Disconnection Approach
One Group C-C Disconnection of Alcohol and Alkene
1. Organic Synthesis:
The Disconnection Approach
One Group C-C Disconnection of
Alcohol and Alkene
Rabia Aziz
BS-IV Organic Chemistry
VIII Semester
Jinnah University For Women
2. One Functional Group
Analysis
Synthesis (path a)
Disconnection close to the functional
group (path a) leads to substrates (SE)
that are readily available. Moreover,
reconnecting these reagents leads
directly to the desired TM in high yield
using well-known methodologies.
Disconnection via path b also leads to
readily accessible substrates. However,
their reconnection to furnish the TM
requires more steps and involves two
critical reaction attributes: quantitative
formation of the enolate ion and control
of its monoalkylation by ethyl bromide.
3. Synthesis of Alcohol
Alcohols have wide applicability in our daily life. They are
useful as synthetic intermediates, cleansers, cosmetics,
fuels, alcoholic beverages, etc. The synthetic and
retrosynthetic analysis of alcoholic compounds are required
for their utility.
11. 1. Synthesis of Alkenes by Elimination
Reactions
• Alkenes can be made by the dehydration of
alcohols 2, usually under acidic conditions.
• This route is particularly good for cyclic alkenes 3
• The same alkene is formed from 2 regardless of
which side eliminates but 4 gives a 76% yield of
an 80:20 mixture of 5and 6.
12. • When Zimmermann and Keck wished to study
the photochemistry of a series of alkenes of
the general structure 7
• They used the Grignard method and
dehydrated 8 with POCI3 in pyridine.
13. • Eliminations on alkyl halides done by the E2
mechanism with a strong hindered base to
avoid SN2 reactions.
• This approach is good for terminal alkenes 10
as the elimination is successful on primary
halides.
14. 2. Alkene Synthesis by the Wittig
Reaction
Triphenyl phosphine, reacts with an alkyl halide in an SN2 reaction to
give a phos-phonium salt 18. Treatment with base, gives the
phosphoniumylid 19.
The carbanion end of the ylid adds to the aldehyde 22 and the
'betaine' then cyclises 23 to the four-membered ring which frag-
ments to give the products 24. So the Z-alkene 20 is formed from
the cis oxaphosphetane 24.
16. Application of Wittig Reaction
Synthesis of leukotriene antagonists
The 'optical brightener' Palanil 50—it makes your clothes look 'whiter than white' and
your T-shirts fluoresce in UV light
Hinweis der Redaktion
Alkenes can be made by the dehydration of alcohols 2, usually under acidic conditions.
This route is particularly good for cyclic alkenes 3 and those made from tertiary and/or benzylic alcohols as the E1 mechanism works well then.
The same alkene is formed from 2 regardless of which side eliminates but 4 gives a 76% yield of an 80:20 mixture of 5and 6.
When Zimmermann and Keck wished to study the photochemistry of a series of alkenes of the general structure 7 they could have put the OH group at either end of the double bond but they chose the branchpoint 8 because dehydration of the tertiary benzylic alcohol should be very easy and there is no ambiguity in the position of the alkene whatever R may be.
Eliminations on alkyl halides follow essentially the same strategy except that the reaction is now done by the E2 mechanism with a strong hindered base to avoid SN2 reactions.
This approach is good for terminal alkenes 10 as the elimination is successful on primary halides. The alcohol 12 can be made by any method.
So a typical synthesis might involve treating the alcohol 10 with PBr3 to make the bromide and eliminating with t-BuOK. There is again no ambiguity in the position of the alkene.
The most important method of alkene synthesis is now the Wittig reaction which gives full control over the position of the double bond and some control over its geometry.
A phosphine, usually triphenyl phosphine PI13P, reacts with an alkyl halide in an SN2 reaction to give a phos-phonium salt 18. Treatment with base, often BuLi, gives the phosphoniumylid 19.
An ylid is a species with positive and negative charges on adjacent atoms.
Reaction with an aldehyde gives the alkene, usually the Z-alkene 20 if R1 is an alkyl group, and triphenylphosphine oxide 21.
the carbanion end of the ylid adds to the aldehyde 22 and the 'betaine' then cyclises 23 to the four-membered ring which fragments to give the products 24. There is no doubt about intermediate 24 nor that its decomposition must be stereospecific. So the Z-alkene 20 is formed from the cis oxaphosphetane 24.
As the Wittig reaction forms both 7t and a-bonds, the disconnection is right across the middle of the alkene giving a choice of starting materials. So with the exo-cycY\c alkene 26, very difficult to make by elimination methods, we could use formaldehyde or cyclohexanone as the carbonyl component with either phosphonium salt 25 or 28. It is a matter of personal choice whether you draw the ylid, the phosphonium salt or the alkyl halide at this stage.
Wittig did this synthesis with the iodide 29, which he made himself, to give 26 in low yield (46%) but higher yields are routinely obtained nowadays: Vogel reports 64% from the commercially available bromide 30 using the sodium salt of DMSO as base.
Trisubstituted alkenes 32 are no trouble as either a secondary halide 35 or a ketone can be used. As both 33 and 35 are available we choose them.
The synthesis is straightforward but does produce a mixture of geometrical isomers.
This is another case where dehydration, even of the tertiary alcohol 36, would probably give a mixture of positional (and geometrical) isomers.
An excellent application of the distinction between stabilised and unstabilisedylids is in the synthesis of leukotriene antagonists. The intermediate 39 (R is a saturated alkyl group of 6, 11 or 16 carbon atoms) was needed and disconnection of the Z-alkene with a normal Wittig reaction in mind followed by removal of the epoxide exposed a second alkene with the E configuration that could be made from the aldehyde 43 and the stabilisedylid 42
This ylid is so stable that it is commercially available and reacts cleanly with 43 to give only £-41. Epoxidation under alkaline conditions gives the trans epoxide 40 and a normal Wittig on an unstabilisedylid gives 39: the yield depends on R.