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serine methyl ester 44 as a nucleophile. 45
Î II *1*
È + Cy-N=C=N-Cy -^ VX3° + Cy-N=C=N~Cy
Y^oh 4 ^......___ ® >
9 i°^e ff 44 vLV °Ëí
+ Cy^X^Cy H H
51 50 49
+ N N --cy
H H H
The driving force of the terminal step is the formation of the very stable urea derivative 50, which is formed stoichiometrically. Further reagents employed in peptide bond forming reactions are diimide EDC 52 and triazole HOBT 53 which react similarly to DCC 45 but give water-soluble by-products.20
The hydroxy group of L-serine methyl ester does not undergo reaction with the activated ester 49 because of its smaller nucleophilicity.
The next step gives the TBS ether 54 at this position applying standard conditions to protect primary alcohols as silyl ethers.
NaBH4 provides a method to reduce the ester 54 to alcohol 55. The additive LiCl is used to enhance the reactivity of NaBH4 towards esters.10 Alcohol 55 is then oxidized to aldehyde 11 using Swern conditions with (ÑÎÑ1)ã and DMSO (see Chapter 2).
3 Curacin A
8 + 11
Hints • How will phosphonium salt 8 react with aldehyde 11 in the
presence of base?
• A double bond is formed.
Solution 1. NaHMDS, THF, -78 —» 0 °C, 62 %
Tetraene 12 is formed following the Wittig protocol: Deprotonation of the phosphonium salt 8 yields a phosphorus ylide which is subjected to condensation with aldehyde 11 (see Chapters 9 and 13).
3 Curacin A
• The TBS ether is cleaved in the first step.
• Step two is the conversion of an alcohol into a leaving group.
• Then a cyclodehydratization is carried out to form oxazoline 13.
1. HF-py 56, THF, 0 °C ^ r. t„ 3 h, 91 %
2. Et3NS02NC02Me 57, THF, r. t„ 9 h, 71
The HFpyridine complex 56 is a common reagent to cleave silyl ethers of primary alcohols. Thus, deprotection of TBS ether 12 gives primary alcohol 59.
To achieve formation of the oxazoline moiety in 13, Burgess reagent' 57 is employed as a mild reagent to provide a reactive alcohol derivative and as an intramolecular base to facilitate the cyclization process. Treatment of alcohol 59 with Burgess reagent results in nucleophilic attack of the hydroxy group on the sulfur atom and loss of NEt3. The resulting sulfonate 60 is converted to heterocycle 13 by intramolecular attack of the carbonyl group, liberating S03 and methyl carbamate 61.
Mitsunobu conditions with DIAD 58 and PPh3 have also been employed for oxazoline formation.23
N c0 H F
0 9 ©
3 Curacin A
Which nucleophile would you use to open the oxazoline ring? Another cyclodehydratization is carried out in the final step.
1. H2S, MeOH, NEt3, 35 °C, 20 h, 66 %
2. Et3NS02NC02CH2CH20PEG 62, THF, r. t„ 1 h, 63 %
3 Curacin A
Thiolysis with H2S as the nucleophile is employed to open the Discussion
oxazoline ring in 13.24 Attack on the sp2 carbon in the heterocycle leads to tetrahedral intermediate 63 which decomposes preferentially
under C-0 bond cleavage. î e 9 ©
The resulting thioamide 64 is subjected to cyclodehydratization with ^N-s-NEt;
the PEG supported Burgess reagent 6225 with the sulfur atom instead / oV"~ °
of the carbonyl group performing the intramolecular attack on the Jn
sulfonate group in a similar way to that described above. The Me° conversion of the oxazoline into a thiazoline ring as the final step yields curacin A (1).
-s Ó >
63 „ 64
The use of PEG supported Burgess reagent gave superior yields compared to the unsupported reagent because it provides milder reaction conditions for the substrate, which is especially sensitive toward acid or base treatments.
The structurally novel antimitotic agent curacin A (1) was prepared with an overall yield of 2.5 % for the longest linear synthesis. Three of the four stereogenic centers were built up using asymmetric transformations; one was derived from a chiral pool substrate. Key steps of the total synthesis are a hydrozirconation - transmetalation protocol, the stereoselective formation of the acyclic triene segment via enol triflate chemistry and another hydrozirconation followed by an isocyanide insertion. For the preparation of the heterocyclic moiety of curacin A (1) the oxazoline - thiazoline conversion provides efficient access to the sensitive marine natural product.
3 Curacin A
1 G. M. Konig, A. D. Wright, Planta Med. 1996, 62, 193-210.
2 W. H. Gerwick, P. J. Proteau, D. G. Nagle, E. Hamel, A. Blokhin, D. Slate, J. Org. Chem. 1994, 59, 1243-1245.
3 P. Verdier-Pinard, J. Y. Lai, H. D. Yoo, J. Yu, B. Marquez, D.
G. Nagle, M. Nambu, J. D. White, J. R. Falck, W. H. Gerwick,
B. W. Day, E. Hamel, Mol. Pharm. 1998, 53, 62-76.
4 a) P. Wipf, W. Xu, J. Org. Chem. 1996, 61, 6556-6562; b) D. J. Faulkner, Nat. Prod. Rep. 1996, 13, 75-125 and references therein.
5 a) M. Z. Hoemann, K. A. Agrios, J. Aube, Tetrahedron Lett. 1996, 37, 953-956; b) H. Ito, N. Imai, S. Tanikawa, S. Kobayashi, Tetrahedron Lett. 1996, 37, 1795-1798; ñ) H. Ito, N. Imai, K. Takao, S. Kobayashi, Tetrahedron Lett. 1996, 37, 1799-1800.