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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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3 Curacin A
39
15
H
+ ZrCpg Cl
16
TP
TPSO
H
ZrCp2
Cl
18
Hydrozirconation of terminal triple bonds is an essential method to obtain alkenes with defined stereochemistry. In the case of internal alkynes the zirconocene moiety adds to the sterically less hindered position of the triple bond. -selectivity is high, but the regioselectivity is sometimes moderate depending on the nature of the substrate.8
Before adding aldehyde 14 a transmetalation from zirconium to zinc is necessary because of low reactivity of the sterically hindered organozirconocene compounds like 18 toward most organic electrophiles.9 Resulting alkenylethylzinc 19 reacts in a 1,2-addition with the ',/^-unsaturated aldehyde 14 transferring exclusively the alkenyl moiety. The formation of Zs-allylic alcohol 20 reveals stereochemical retention of the double bond configuration in the transmetalation and addition steps.
Oxidation of sensitive divinyl alcohol 20 to dienone 4 is achieved by treatment with activated manganese dioxide. Commercially available active Mn02 21 is a synthetic nonstoichiometric hydrated material. This reagent provides mild conditions for oxidation of allylic, propargylic, and benzylic alcohols.10
o-h-q p-H-ov Mr/ 'Mn
/ \ U
O-H-O 0-H--0 21
Problem

19
14
20
1.
2.
3.
OTPS
OTPS
4
5
40
Hints
Solution
Discussion
22
Problem
3 Curacin A
Ketone 4 is converted to triene 5 via deoxygenation.
Initially a base deprotonates ketone 4.
Which hydrogen atom is abstracted and so which enolate arises?
Next step is the generation of a good leaving group.
Reductive elimination of this group yields triene 5.
1. KHMDS, THF, -78 C, 2 h, then
2. Tf2NPh, -78 - 0 C, overnight quant, (over two steps)
3. Bu3SnH, Pd2(dba)3 CHCl3, LiCl, PPh3, THF, reflux, 4 h, 71 %
At low temperature (-78 C) deprotonation with the bulky silyl amide KHMDS runs under kinetic control - enolization takes place regio-and stereoselectively at the terminal methyl group of ketone 4. The sterically less hindered enolate is transformed to enol triflate 22, which has all-trans configuration.
Vinyl- or aryl triflates have their application in C-C coupling reactions with organometallic reagents to form olefinic compounds. Another possibility is Pd-catalyzed reductive elimination: enol triflate 22 is treated with Bu3SnH in a Sfi/te-reaction to give triene 5 (see Chapter
1). Reduction of enol triflates with standard reducing agents such as LiAlH4 or DIBAH yields only the original enolate ion.
1. Cp2Zr(H)CI, CH2CI2, 40 C, overnight, then
2. nBuNC, 0 C r. t 4 h, then
6
5
3. HCI, -78 -> 0 C 54 % (from 5)
Hints
Schwartz reagent Cp2Zr(H)Cl behaves in a similar way to that described above.
//-Butyl isocyanide is an organic electrophile.
3 Curacin A
41
Besides hydrozirconation of terminal triple bonds Cp2Zr(H)Cl (16) also reacts with double bonds.8 The mechanism is similar to that described for alkynes. After coordination of alkene 5 to the Zr center giving ^-complex 23 the terminal double bond inserts into the Zr-H bond to form the stable -alkyl complex 24. The bulky zirconocene moiety again adds to the end-position of the terminal double bond.
The steric demand of the zirconocene moiety leads to rearrangements in the case of hydrozirconation of internal double bonds. Regardless of position or configuration of the double bond in the substrate, zirconium migrates to the terminal position of the alkyl chain via insertion and /Ml-elimination steps. Such isomerization does not occur upon hydrozirconization of internal alkynes.
/J-H-elimination
H
Although reaction of organozirconocene compounds fails with most organic electrophiles, treatment with sterically unhindered isocyanides, such as nBuNC, is possible.11 Organometallic species 24 attacks nBuNC 25 to give isocyanide-insertion product 26, which is finally hydrolyzed to the one-carbon homologated aldehyde 6.
Solution
Discussion
42
3 Curacin A
Problem
OTPS
Hints
A homoallylic alcohol is formed.
Which reagents for stereoselective allylation of aldehydes do you know?
Solution
1. [(-)IPC]2B-allyl 27,-78 C, 4 h, then
ethanolamine, -78 C > r. t., 2 h, 63 %, 93 %
Discussion
0
Au
R H H R
Sb face
Re-face
Investigations in the field of organoboron reagents for allylation of aldehydes resulted in a variety of powerful methods, e. g. the allylation by Brown.12 Allylation reaction with [(-)IPC]2B-allyl 27 (allyl diisopinocampheyl borane) proceeds via a six-membered chairlike transition state, the so called Zimmerman-Traxler transition state 28. Lewis acid boron coordinates to the oxygen of the carbonyl group and activates it for a nucleophilic attack by the allyl group. Chiral ligands at the boron atom are responsible for the facial differentiation of aldehyde 6, the 57-face is favored in this case. Because of the closed being transition structure and the relative short B-O bond (147 pm) asymmetric induction is normally very high. Thus, migration of the boron and creation of a terminal double bond furnishes compound 29.
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