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3 Curacin Ë
Dialkylalkoxyborane 29 is treated with ethanolamine to liberate homoallylic alcohol 7 - this work-up allows the recycling of the chiral auxiliary.13 After precipitation of the (IPC)2B-ethanolamine adduct 30 it can be transformed into the allylating agent 27 via compound 31.
Advantages of Brown’s chiral allylboranes (isopinocampheyl and later caranyl borane) are the easy access to the ligands (a-pinene is a natural product, chiral pool), the availability of both enantiomers and their low price. Excellent selectivities (96-99% åå) can be obtained at reaction temperatures of -100 °C. Other important mediators for enantioselective allylation of aldehydes are shown below.14
H. C. Brown
E. J. Corey
W. R. Roush
R. W. Hoffmann S. Masamune
Ì. T. Reetz
3 Curacin A
L. F. Tietze
R. O. Duthaler
In recent years methods for the catalytic asymmetric allylation have also been developed.14
Me3Si E. M. Carreira
X = OPr: G. E. Keck X = Cl : E. Tagliavini/A. Umani-Ronchi
1. NaH, Mel, THF, r. t., 6 h, 90 %
3 h, 89 %
3. MsCI, NEt3, r. t„ overnight, 95 %
4. Nal, acetone, reflux, 2 h, 99 %
5. PPh3, MeCN,
90 °C, 24 h, quant.
• An ether is cleaved with TBAF.
• Steps 3 and 4 are an alternative to the Appel-reaction.
• Product 8 is a salt.
3 Curacin A
Before the TPS ether is cleaved with TBAF7, secondary alcohol 7 has to be protected as methyl ether. TBAF is a reagent to cleave every silyl ether. Most other functional groups are not affected (see Chapter
2). In the next two steps the conversion of alcohol 33 into mesylate 34, which is a good leaving group, and then into iodide 35 in a Finkelstein type reaction occurs.15 Acetone is the solvent of choice, because Nal is better soluble in it than NaOMs and consequently reaction equilibrium is forced to the product side. Direct transformation from an alcohol to an iodide is possible with PPh3 and
I2 in an Appel-like reaction, but in some cases this reaction fails. Final procedure is the generation of phosphonium salt 8.
• First an enantioselective cyclopropanation occurs.
• For the enantioselective cyclopropanation, the presence of an allylic hydroxy group, the use of an organozinc reagent and a chiral ligand are needed.
• How is a primary alcohol converted in one step into a carboxylic acid?
1. 36, Zn(CH2I)2DME, CH2C12, -10 °C, 2 h, 75 %, 95 % åå
2. cat. RuC13 H20, NaI04, MeCN, HzO, r. t„ 6 h, 71 %
3 Curacin A
Discussion Cyclopropanes are commonly synthesized with Zn(CH2I)2 (37) using
the Simmons-Smith-reaction,16 This reaction proceeds via one-step Me2NOC4 ,coNMe2 addition of one of the methylene groups of the zinc reagent to olefins.
As an advantage of the Simmons-SVwf/z-reaction no free carbene is
a P , ,
In the presence of the chiral dioxaborolane 36 the attack of the methylene group proceeds selectively from the w-face.17 This is the Zn-CH2i asymmetric Charette cyclopropanation:18 The presence of
0^ììå2 coordinating groups on the dioxaborolane ring in 36 is crucial for obtaining high enantioselectivities. For steric and stereoelectronic ÑÃ^ÌÌå2 reasons it is postulated that the allylic alkoxide in 41 adopts the more
î stable pseudoaxial configuration and the cyclopropanation occurs via
the formation of a bidentate chelate 41 between reagent and substrate. The complex 41 is believed to involve the carbonyl oxygen of one of
î î the amide groups and the allylic oxygen.
°-ru"oh °-ru'oh Catalytic amounts of RuCl3 with NaI04 as the co-oxidant provides one-pot oxidation of 39.10'19 The active agent Ru04 is formed in situ -ñ— í R-c— H and oxidizes alcohol 39 first to the aldehyde via intermediate 42 and
H 0H then to the carboxylic acid 10 via the aldehyde hydrate intermediate
42 43 43.
The use of chrome reagents (Jones conditions) is also possible.
1. L-Serine-OMe 44, DCC, DMAP, CH2CI2, r. t,, overnight, 71 %
2.TBSCI, imidazole, DMAP, CH2CI2, r. t., overnight, 89 %
3. LiCI, NaBH4, THF, EtOH, r. t„ overnight, 88%
4. (COCI)2, DMSO, NEt3, CH2CI2, -60 °C,
20 min, quant.
• In the first step an amide bond is formed.
• The second step introduces a protecting group.
• NaBH4 is a reagent to reduce esters.
3 Curacin A
First the carboxylic acid 10 reacts with the amino group of the amino Discussion
acid L-serine methyl ester 44. This reaction is carried out with DCC C02Me
45 and DMAP 46 as activators of the carboxyl group.20,21 íî
With the basic DMAP 46 as the catalyst, a proton transfer between the 44 NH2
carboxylic acid 10 and the diimide 45 yields the carboxylate anion 47 which undergoes nucleophilic addition to the protonated diimide 48. / \_N=C=N
This activated ester 49 is readily attacked by the amino group of L- \—/