Note: 1) m-CPBA: meta-chloroperbenzoic acid 2) NBS: N-bromosuccinimide
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Stereochemical Control In Six-Membered Rings
1) In six-membered ring systems, there is generally a strong preference for substituents to occupy the equatorial positions; 2) Diastereomers may be equilibrated by processes such as enolization.
O Me LiAlH4 THF Me 77% Me 23% OH + OH
pseudoaxial attack O Me H pseudoequatorial attack peudoaxial and pseudoequatorial faces are quite similar
Note: When the size of the nucleophile is small, it can NOT discriminate these two similar faces.
O NaBH4 Me H Me H 50:50 form a ring NaBH4 O OH LiAlH(OB; Me H H OH
Note: 1) The reductions of cyclic ketone are stereoselective; 2) These stereoselective reactions give out two diastereomers, so it is diastereoselective; 3) The key to the difference is in the conformations (conformational effect).
Note: Diastereoselectivity remains the same whether the starting material is enantiomerically pure or racemic.
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Five-Membered Rings
1) It is NOT even necessary to have a stereogenic center in the α,βunsaturated five-membered ring for creating new stereochemistry; 2) A tandem conjugate addition and alkylation can create two stereocenters in one operation; 3) The product is usually trans.
CuLi
2
O O then Br O trans
O
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10
Five-Membered Rings
The stereochemical information can be transmitted across a ring even though the original source of that information may be lost during the reaction.
Br R OH cis -H Br Br H R
+
R
Br2 H2O
NaOH R O
H R H2O
Br
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14
Five-Membered Rings
1) If two substituents are present on the same side of the five-membered ring, their function can be combined to dictate the approach from the other side by any reagent; 2) In general, this type of the reaction stereoselectivity is excellent.
O OMe Me Ph O O Ph OMe Me Ph
O OMe
Ph Me
H CO2Me OCOPh
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anti-periplanar
4
Four-Membered Rings
1) The four-membered ring of β-lactones is flat, so is its lithium enolate ring; 2) Thus the lithium enolate ring can be attacked from two faces; 3) If a substituent is used to block one of two faces, then the electrophile simply adds to the face of the enolate NOT blocked by the substituent; 4) This is a very simple case of a diastereoselective reaction.
11
Five-Membered Rings
84% yield diastereoselectivity, >97:3 O O Ph O LDA O Ph O O Li Br O O O Ph H3O+ HO O Ph OH
X Ph O O Li
H But
O
almost planar
1) Making lithium enolate with LDA destroys the original stereocenter and that carbon becomes sp2-hybridized (trigonal); 2) The ring becomes planar; 3) The stereocenter of the acetal intermediate relays the stereochemical information through the reaction.
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8
Five-Membered Rings
1) When there are two or three trigonal carbons in the five-membered ring, the ring becomes flatter; 2) Reactions in such ring systems generally have execellent stereoselectivity.
1) Normal cyclopentane ring is very flexible with an envelop conformation; 2) All five C atoms are, on average, the same, because of rapid ring flipping; 3) Therefore, the stereoselectivity of normal cyclopentane rings is NOT great;
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5
Four-Membered Rings
1) The reduction of four-membered cyclic ketones is NOT highly stereoselective; 2) The stereoselectivity of the above reaction is ONLY noted when the ring substituent is in the 3-position and a small reducing reagent (e.g. NaBH4) is used.
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Five-Membered Rings
Five-membered rings can be highly diastereoselective in electrophilic reactions.
Me
RCO3H
Me trans 76%
O
+
Me cis 24%
O
Note: 1) The diastereoselectivity of the above reaction is affected by the bulkiness of the R group.; 2) The selectivity is 76:24 with a small methyl group; 3) Diastereoselectivity has nothing to do with chirality: none of the compounds in the above reaction is chiral.
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Five-Membered Rings
The opposite stereoselectivity can be obtained by bromination in water, followed by a stereospecific SN2 reaction in the presence of base.
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Five-Membered Rings
Using much more bulky reducing reagents (e.g. LiBHsBu3) can reverse and increase the stereoselectivity of the reaction.