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Organic Synthesis workbook li - Bittner C.

Bittner C. Organic Synthesis workbook li - John Wiley & Sons, 2001. - 292 p.
ISBN: 3-527-30415-0
Download (direct link): bittnerorganicsynthesisworkbook2001.pdf
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13 (-)-Scopadulcic Acid A
221
44 43
Step 2 cleaves the silyl protecting group using a standard protocol with tetrabutylammonium fluoride (TBAF) in THF.
Problem
222
13 (-)-Scopadulcic Acid
Hints
Which oxidation methods for alcohols do you know?
Overman used TPAP for oxidation; which co-reagent is necessary?
The angular methyl group is introduced by a Ni-catalyzed reaction.
Solution
1. TPAP, NMO, CH2Cl2/MeCN, r. t.,1 h, 95 %
2. Ni(acac)2, Me2Zn, Et20, 0 C r. t., 17 h, 88 %
Discussion
o
ii nPr4N 0-Ru=0
46
Me4 pc
CJ

47
The oxidation to the enone was realized with catalytic amounts of tetra-n-propylammonium perruthenate (TPAP)21 (46), which is a mild oxidant for conversion of multifunctionalized alcohols to aldehydes or ketones. Catalytic TPAP oxidations are carried out in the presence of stoichiometric or excess /V-meth 1 mrpho 1 i ne-/V-xidc (NMO)22 (47) as cooxidant. Other common reagents for oxidation of alcohols are e.g. DMS0/C202C1223, Dess-Martin periodinane24, PCC25, PDC26 or the Jones reagent27.
The second step is a Michael addition, that was not easy to perform because of the steric demand of the quaternary center nearby. Organocopper compounds have been the most extensively studied reagents for conjugate 1,4-additions to tt-enones.28 In this case, however, the addition of a cuprate failed to give the desired product. Especially with /?-disubstituted enones allylic alcohols are often produced rather than the normally desired conjugate-addition adducts. In contrast, the Ni-catalyzed reaction of ZnMe229 is highly regio- and stereoselective and occurs from the /?-side opposite to the ethano-bridge in 88 % yield.
Problem
1.(CH2OH)2, (0CH2CH20)CH0Me, Amberlyst 15, MeCN,
12 h, 92%
2. MCPBA, NaHC03, CH2CI2,
0 C r. t 3 h, 99 %
3. LiAIH4, Et20, r. t 14 h, 90 %
11
13 (-)-Scopadulcic Acid
Amberlyst 15 is an acidic ion exchange resin.
The first step introduces a protecting group.
The second step is a substrate controlled epoxidation. What stereochemistry do you expect?
LiAlH4 is able to open epoxides.
First, the carbonyl group is protected as an acetal under acidic conditions. The most common acid-catalysts are PTSA, CSA, PPTS or, as used in this case, acid exchange resins like Amberlyst 15. An advantage of ion exchange resins is that aqueous work-up is not necessary since the insoluble catalyst can be easily removed by filtration and then recycled.
In the second step mefa-chloroperbenzoic acid (MCPBA) epoxidizes the resulting bis-acetal from the y9-face. The weak 0-0 bond of MCPBA undergoes attack by electron rich substrates like alkenes. This reaction is syn stereospecific and believed to take place via transition state 48.30
Reduction of 49 with LiAlH4 provides 11 by an axial hydride transfer to the sterically less hindered carbon atom. Generally, LiAlH4 attacks at the less substituted carbon and in addition 1,2-epoxycyclohexanes exhibit a strong preference for axial directed reactions.31
224
13 (-)-Scopadulcic Acid A
Problem
Hints
Solution
Discussion
12
Deprotection of 11 is followed by a cyclization.
The second step introduces a MOM protecting group.
1. 20 % HCI, THF, r. t. -> 50 C, 24 h, 74 %
2. MOMC1, /Pr2EtN, CH2C12, 0 C, 7 h, 92 %
Acetals can be removed under acidic conditions. In this case the two dioxolane groups are cleaved, followed by acid-catalyzed cyclization of the keto-aldehyde to form the -ring. It is the enol tautomer of the ketone that functions as nucleophile while the aldehyde is activated towards nucleophilic attack by oxygen protonation (51). Cyclization is completed by water elimination to furnish the enone system in 53 (acid-catalyzed aldol-condensation).
13 (-)-Scopadulcic Acid A
,
50
+ H

H20
52
The MOM ether is produced under standard conditions with MOMCl and HUnigs base in CH2C12.
1. Et2AICN, TMSCI, THF, 0 C, 10 h, aq. HCI-THF, r. t., 15 min, 88 %
2. UAIH4, TMSCI,
DMAP, -78 C, 30 min, 97 %
3. LDA, BnOCH2Br, THF,
-78 C * 0 C, 2 h, 82%
225
Problem
13
226
Hints
Solution
Discussion
13 (-)-Scopadulcic Acid A
First a conjugate addition to the enone takes place.
The keto-function is reduced and subsequently protected as TMS ether.
A benzyloxy-methyl substituent is introduced in the last step.
1,4-addition of Et2Al+CN takes place selectively from the /Mace. Flowever, quenching of the resulting aluminum enolate 54 with acid provides some cis product 56. To overcome this problem the enolate was quenched with TMSCI. The resulting enoxysilane 57 was hydrolyzed with diluted HCI to provide only the fraws-fused ketone 55 in 88 % yield.
57 55
13 (-)-Scopadulcic Acid A
221
Reaction with LiAlH4 at -78 C selectively reduces the keto-function from the face opposite to the angular methyl group. Subsequently, the resulting alcohol is protected as TMS ether 58.
The carbinyl nitrile acidifies the -proton, which is deprotonated with LDA. The nucleophilic lithium salt is quenched with benzyloxymethyl bromide as electrophile to give 13 in 82 % yield. Again, the angular methyl group controls the facial selectivity: the benzyloxymethyl group is introduced from the or-face.
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