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This variation of the Wittig reaction uses ylides prepared from phosphonates.12 The Horner-Wadsworth-Emmons method has several advantages over the use of phosphoranes. These ylides are more reactive than the corresponding phosphoranes, especially when substituted with an electron withdrawing group. In addition the phosphorus product is a phosphate ester and soluble in water - unlike the Ph3PO product of the Wittig reaction - which makes it easy to separate from the olefin product. Phosphonates are also cheaper than phosphonium salts and can easily be prepared by the Arbuzov reaction from phosphanes and halides.
The silyl ether protecting groups are commonly removed by acidic conditions or a fluoride ion source.13 The high stability of the fluorine-silicon bond is exploited by many standard fluorine reagents such as HF, HF-pyridine complex as acidic and TBAF (tetra-è-butylammonium fluoride, as basic deprotecting agents. TBAF is commercially available as trihydrate which is highly hygroscopic, a fact that sometimes limits its use with water sensitive substrates. Compound 6 is later used in a coupling reaction. First we turn our attention to the synthesis of the other coupling partner.
Arbuzov reaction: (EtO)3P + RCH2X | -EtX
2 (-)-Bafilomycin Ai
1. cat. OsC>4, NMO, THF/acetone/H20
2. Nal04, THF-H20
3. H2C=CHCH(OMe)2, CrCI2, TMS-I, -42 °C
56 % (over three steps)
0s04 oxidizes the double bond.
A diol is formed by the OSO4 oxidation, NMO is cooxidant.
NaI04 cleaves the diol creating an aldehyde.
The acrolein dimethylacetal is reduced by the CrCl2 generating an active species that adds to the aldehyde.
An anti diol is formed.
i-VS> îýí h-c-o 3 i
TBSN DMPMO 0
The substrate 7 had been previously synthesized by Roush using the crotylation method described above.14
Osmium tetroxide is commonly used to add two OH groups to a double bond.15 The mechanism gives syn addition from the less hindered side of the alkene. Since OSO4 is expensive and highly toxic it is therefore mostly used in a catalytic fashion using stoichiometric cooxidants, like H2O2 or /V-methylmorpholine-,V-oxide (NMO).
1,2-Glycols are easily cleaved under mild conditions and in good yield by lead tetraacetate in organic solvents or periodic acid in water solutions. The yields are so good that olefins are often transformed into the diol and then cleaved to form two aldehydes - or ketones depending on the substrate - rather than cleaving the double bond directly with O3. The mechanism was proposed by Criegee to involve the intermediate 2416 and yields aldehyde 25.
Takai and co-workers introduced the use of the in situ generated j^methoxyallylchromium reagent to synthesize diol derivatives stereoselectively.17 Chromium(II) chloride has the ability to afford umpolung, transforming acrolein dialkyl acetate into the y-alkoxy substituted allylic chromium reagent. This mild nucleophilic species will then add to the aldehyde placing the methoxy group anti to the alcohol created from the aldehyde. The major diastereomer is formed with a 10:2:1 selectivity in 67 % yield.
2 (-)-Bafilomycin À/
TBS DMPMO Î
DMPMO Î OTES
• The reactive alcohol needs protection.
• The double bond is transformed into an aldehyde first.
• Bishydroxylation and oxidative cleavage creates the aldehyde.
• Aldehydes can be transformed into alkynes by a special phosphorane.
1. TESOTf, 2,6-lutidine, CH2C12, -50 °C, 1 h, 99 %
2. 0s04, NMO, THF, pH 7-buffer, 16 h
3. Pb(OAc)4, EtOAc, 0 °C, 10 min
4. (Me0)2P(0)CHN2, ÆèÎÊ, THF, -78 °C r. t„ 15 min 85 % (over three steps)
The free alcohol 8 needed to be protected temporarily since it interfered with following three steps.
Generally the stability of the silyl protecting groups increases with increasing steric hindrance of the alkyl substituents. Thus trimethylsilyl (TMS) ethers are only used as intermediates since they are labile to even weak acids. The triethylsilyl (TES) protecting group is more stable and survives column chromatography as well as oxidation, reduction and organometallic reagents, but is much more labile than the TBS group.
We have already seen the bishydroxylation using 0s04 and NMO; this time lead tetraacetate is used to cleave the diol and yield the aldehyde. The phosphorane (Me0)2P(0)CHN2 is named the Gilbert-Seyferth reagent.18 It basically behaves like the phosphoranes in the Horner-Wadsw î rth-Emmons reaction described above, except that the olefin subsequently loses nitrogen, creating the desired triple bond (also see Chapter 10).
2 (-)-Bafilomycin Aj
DMPMO Î OTES 9
1.DDQ, CH2CI2, pH 7,
0 °C, 25 min, 94 %
2.TFA, THF, H20, 0°C, 2.5 h,
3.TESCI, CH2CI2, pyridine,
-40 °C -> r. t., 10 h, 92 %
4. Catecholborane, 8 % 9-BBN,
THF, 60 °C, 4 h, followed by pH 7-buffer; 71 %