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In this case the Birc/i-reduction system (sodium in liquid ammonia) is used. Normally this system is employed to reduce aromatic rings to 1,4-dihydrobenzenes. Here it is advantageous because in contrast to catalytic hydrogenation it does not touch olefinic double bonds and the expected alcohol is generated in 95 % yield (see universal mechanism on the left).
Oxidation of the alcohol under Swern conditions (see Chapter 2) followed by addition of commercially available ethylmagnesium-bromide provided the secondary alcohol with nearly no stereocontrol (1:1.1 in favor of isomer 12b) in 90 % overall yield.
Generally additions of Grignard reagents to a-chiral-aldehydes proceed highly diastereoselectively. Of the three possible transition states (A) Cram-, (B) Felkin Anh-, the (C) Îøè-chelate-transition state 47 is favored here. The reason is the or-oxygen which should be chelated by the magnesium cation as well as the carbonyl group, leading to 12b as the main product. If R is small (e. g. Me or TMS) the medium group takes its place perpendicular to the carbonyl group. The attack of the nucleophile proceeds along the least hindered trajectory taking into account the Btirgi-Dunitz angle of about 107° measured from the C=0 bond.
9 (+ )-Laurallene
But this - and other examples16 - indicate, that chelation control is apparently limited in tt-alkoxyaldehydes where the chelating ether oxygen resides in a medium ring, probably because of reduced Lewis basicity of the ether oxygen.
Attempted use of diethylzinc in the presence of a chiral catalyst to control the stereochemistry at this carbon atom was not effective.
12a: X: 12b: X:
OH, Y = H : H, Y = OH
1. (COCI)2, DMSO, NEt3, CH2CI2, -78 °C, 40 min, r.t., 1 h
2. L-Selectride®, THF, -78 °C,
1 M NaOH, 30 % H202, r. t„ 1 h 83 % (over two steps)
3. CBr4, P(oct)3, C6H6, r. t., 30 min, 70 °C, 1 h, 88 %
• Crimmins took the mixture of secondary alcohols and first Hints reoxidized the stereogenic center.
• L-Selectride® is a selective reducing reagent.
• The last step is similar to an Ap/?e/-reaction.
In the first step Crimmins and co-workers used the Swern oxidation Discussion
protocol to provide a ketone as prochiral .v/r-center.
The formed ketone is selectively reduced to an alcohol with lithium-tris-sec-butylborohydride (L-Selectride®) at -78 °C in only 30 min..
Only one diastereomer is built. Because lithium belongs to the non-chelating cations, the reaction proceeds through transition state 48 proposed by Felkin and Anh}1 To remind: In the most stable conformation the largest group of the stereogenic center is perpendicular to the carbonyl group.
The reaction of the secondary alcohol with trioctylphosphine and carbon tetrabromide results in the formation of the 13. The conditions are similar to those established by Appel et al. for the conversion of alcohols to chlorides. The transformation proceeds through an SN2 mechanism resulting in inversion of the configuration.18
• Under which conditions is only the primary TBS-ether cleaved?
• Secondly the molecule is prepared for a chain extension.
• Finally a Wittig reaction takes place.
1. HF-pyridine, pyridine, THF, r. t„ 4 h, 90 %
2. (COCl)2, DMSO, CH2C12, -78 °C, 40 min, r. t., 1 h
3. Ph3P=CHOCH3, KOrBu, THF, 0 °C, 25 min 75% (over two steps)
The basic HF-pyridine/pyridine system represents a mild method to convert only the primary TBS-ether into the alcohol. The excess pyridine acts as buffer. Use of tetrabutylammoniumfluoride (TBAF) would result in cleavage of both TBS-ethers.10
In the second step the alcohol is transformed to an aldehyde by means of the Swern oxidation. Other reagents to oxidize alcohols to aldehydes are e. g. Dess-Martin-periodinane and chromium reagents like PCC or PDC.
At least the methoxymethylenation proceeds in good yield to give a Ph ci
mixture of vinylethers 14. The one-carbon extension follows the ^P-'
Wittig protocol. The ylide 51 is formed in situ from ph
(methoxymethyl)triphenylphosphonium chloride (49) and potassium 49
fert-butoxide at 0 °C in THF. 51 belongs to the semistable ylides, KOfBu
because the methoxy group is able to stabilize a carbanion only over an inductive effect. This results in a mixture of E- and Z-isomers. No further definition of the ratio of diastereomers is made, because the reaction serves the purpose of chain elongation and just in the next step configuration of the double bond is destroyed again. How to reach only the E- or Z-isomer is described later in this chapter.
Moreover the reaction runs the normal Wittig mechanism over the four-membered oxaphosphetane ring and collapses to the alkene mixture. (For mechanistic details see Chapter 10.)
1. Íä(ÎÀñ)ã, H20/THF (1:10), r. t., 1 h, 67%
THF, 0 °C, 15 min; r.t., 2 h, 90 % (E/Z 3:1)
• The vinylether system is forced to collapse to form an aldehyde.