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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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The biological activity and the interesting structure stimulated efforts towards its total synthesis. Evans and Calter reported the first synthesis by an efficient aldol method.4 Toshima and co-workers also succeeded in the total synthesis of bafilomycin Aj.5 This chapter is based on the enantioselective total synthesis by William R. Roush and co-workers, which was published in 1999.6
16
2 (-)-Bafilomycin At
2.2 Overview
1. OTBS
ohcx ^OPMB -> H0\^ y "r" "opmb
1. (COCI)2, DMSO, Et3N, CH2CI2, -78 C, 30 min, 99 %
2. CBr4, PPh3, CH2CI2, 30 min, 89 %
3. nBuLi, THF, -78 C -> 0C, 15 min, 99 %
4. DDQ, CH2CI2, pH 7-buffer, 0 C, 20 min, 96 %
OTBS
OH
1. (COCI)2, DMSO, Et3N, CH2CI2, -78 C, 30 min
2. Ph3PCH(Me)C02Et, toluene, 60 C, 15 h,
90% (over two steps)
3. DIBAH, THF, -78 C, 3.5 h, 99%
OH
C02Me OMe
DMPMO OTBS
1. cat. 0s04, NMO, THF/acetone/H20
2. Nal04, THF-H20
3. H2C=CHCH(OMe)2 CrCI2, TMSI, -42 C
56 % (over three steps)
2 () -Bafilomycin A /
17
TBS^
DMPMO OTES
OMe
1.DDQ, CH2Cl2, pH 7,
0 C, 25 min, 94 %
2.TFA, THF, H 20, 0C, 2.5 h, 88%
3.TESCI, CH2CI2, pyridine,
-40 C-r.t., 10 h, 92%
4. Catecholborane, 8 mol % 9-BBN, THF, 60 C, 4 h, 71 %
10
1.
6 + 10
1.1N KOH, dioxane, 80 C, 1.5 h
2.2,4,6-TrichIorobenzoylchloride, /Pr2EtN, THF; DMAP, toluene, reflux, 24 h 52 % (over two steps)
1.TMSCI, Et3N, ?HMDS, CH2CI2, -78 C, 30 min
2. 14, ?, 85 %
3.
TBS,

14
18
2 (-)-Bafilomycin ]
2.3 Synthesis
Problem.
OHC
OPMB
OTBS
HO
OPMB
Hints
A crotyl group is added to the aldehyde in an asymmetric reaction.
The resulting secondary alcohol is protected with a standard procedure.
Olefins can be transformed into alcohols using boron reagents.
Solution
COp/Pr
/
Me^^B-cT/COg/Pr
1. 16 , toluene, -78 C, 8 h, 78 %
2. TBSOTf, 2,6-lutidine, CH2C12, -50 C, 30 min, 99 %
3. Catecholborane, [(PPh3)3RhCl], THF, -5 C, 30 min, then MeOH, IN NaOH, H202, r. t 2 h, 87 %
Discussion
OH
OPMB
17
C02Pr
/
/ "02/
Enantioselective allyl additions to ketones and aldehydes have become synthetically very important reactions since they allow access to aldol-like compounds and have thus been used in various syntheses of natural products (for an introduction to allylation reagents see Chapter 3). In the crotylation reaction compared to allylations an additional stereocenter is formed which is not only influenced by the chiral reagent but also by the stereocenters at the aldehyde substrate. It is especially difficult to synthesize the anf/-anrf-stereotriad which is required by bafilomycin. Roush and co-workers succeeded in setting the three stereocenters in high selectivity by applying the method developed in their laboratories. Thus reaction of the aldehyde 1 with (7?,,ft)-diisopropyltartrate-(?)-crotylboronate (16) gave the required alcohol 17 in 78 % isolated yield with a selectivity of 85:15 and the undesired 3,4-ari-4,5-^y-diastereomer. This reaction proceeds through a mismatched reaction, i. e. the chiral methyl substituent would favor the anti-syn diastereomer (by Felkin selectivity) but the enantioselectivity of the chiral auxiliary can override this intrinsic preference. This is shown in the proposed transition structure 18: The chiral auxiliary places the aldehyde onto the Si side of the double bond. Therefore either the R group or the methyl substituent of the aldehyde is forced to interact with the methyl on the crotylate. Experiments with sterically more hindered substituents instead of methyl at the aldehyde show that the selectivity decreases with higher
2 (-)-Bafilomycin A/
19
steric requirements, making the Felkin selectivity the prominent factor (i. e. the aldehyde will then be on the Re side of the alkene).
Generally the reactivity of alcohols towards protection or deprotection decreases with higher substitution. In order to protect secondary alcohols as TBS ethers it is usually necessary to use the highly reactive silyl trifluoromethanesulfonate (triflate) instead of TBSC1, which is often used to protect primary alcohols selectively in the presence of secondary and tertiary alcohols. 2,6-Lutidine is used as the base and the TBS protection succeeds in almost quantitative yield. Hydroborations are standard procedures to transform double bonds regioselectively into the less substituted alcohols. Catecholborane (19) is a much more stable reagent for hydroboration than diborane and has the advantage that the boronic acid byproducts are more easily hydrolyzed than the corresponding dialkylboranes. Catecholborane reacts with alkenes to form an alkoxyborinate but usually requires elevated temperatures.7 Hydroborations using catecholborane can be catalyzed by Rhodium(I) complexes:8 By using 3 % (PPh3)3RhCl and one equivalent of 19 the reaction proceeds smoothly at -5 C over 30 min. Oxidative work-up with hydrogen peroxide in the presence of base gives 2 in 87 % yield.
1. (COCI)2, DMSO, Et3N, CH2CI2, -78 C - 0 C, 30 min, 99 %
OTBS 2- CBr4, PPh3, CH2CI2,
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