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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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CQ2Et
1. LiOH, fiuOH, H20, 64 h
2. PivCI, NEt3, (S)-2-amino-
1-propanol, CH2CI2, 0 C, 2.5 h
17
Problem
Hints
Solution
Discussion
0=P(OEt)2
59
Problem
16
71 % (over two steps)
172
Hints
Solution
Discussion
60
Problem
10 Myxalamide A
Saponification of the ester occurs.
PivCl activates the resulting acid.
Which functionality of (5)-2-amino-l-propanol is more basic and reacts with the activated acid?
Hydrolysis of ester 16 proceeds smoothly. Activation of the resulting acid is achieved via conversion into the mixed anhydride 60. The amino group of LS')-2-amino-1 -propanol is more basic than the alcohol function; therefore there is no need for protection. It attacks the anhydride at the carbonyl carbon of the former acid because of the steric interaction with the pivaloyl group and gives amide 17 in 71 % yield.
1.
18
OH
13
2.17
OH
1
myxalamide A
Hints
13 is transformed into a compound that can undergo a metal-catalyzed cross-coupling reaction.
Which cross-coupling reaction is performed in the second step?
10 Myxalamide
173
1. Catecholborane, benzene, r. t., 90 min, A',,/V-diethylaniline, 23 h
2. Pd(OAc)2, TPPTS, ;Pr2NH, CH3CN, H20, r. t 3.25 h 44 % (over two steps)
The key step of this total synthesis is a Suzuki reaction25 forming myxalamide A. In organic synthesis, the Suzuki coupling is particularly useful as a method for the construction of conjugated dienes of high stereoisomeric purity. Using a palladium(O) catalyst and a base, the reaction accomplishes a cross-coupling of a
1 -alkenylboron compound with an organic electrophile such as vinyl iodide 17. First the 1-alkenylboron compound is generated in situ by reaction of 13 with catecholborane. The ?-vinylborane 18 is formed exclusively. In the first step of the catalytic cycle a coordinatively unsaturated palladium(O) species 61 - which is formed in situ from Pd(OAc)2 and TPPTS (triphenylphosphine-3,3',3"-trisulfonic acid Na03s. trisodium salt) 62 - inserts into the alkenyl iodine bond of 17 to give
63.
64
Solution
Discussion
S03Na
62
10 Myxalamide A
Next it is presumed that a metathetical displacement of the halide substituent in the palladium(II) complex 63 by hydroxide ion (the reaction is carried out in a mixture of water and acetonitrile) takes place to give the hydroxopalladium(II) complex 64. The latter complex then reacts with the alkenylborane 18, generating the diorganopalladium complex 65. Finally reductive elimination of 65 furnishes the cross-coupling product myxalamide A 1 and regenerates the palladium(0)catalyst 61.
10.4 Conclusion
The total synthesis of myxalamide A (1) was accomplished in 22 steps (longest linear sequence) and 4.9 % overall yield from bromide 5. The completion of the synthesis not only demonstrates the utility of the aldol-Claisen-Evans-Mislow strategy but also emphasizes the usefulness of the Suzuki coupling for the preparation of polyene-containing natural products. Furthermore the discussed synthetic strategy is also useful for the preparation of other members of the polyene natural product family as well as related diastereoisomers for biological evaluation.
10.5 References
1 a) R. Jansen, G. Reifenstahl, K. Gerth, H. Reichenbach, G. Hofle, Liebigs Ann. Chem. 1983, 1081-1095; b) R. Jansen, W.
S. Sheldrick, G. Hofle, Liebigs Ann. Chem. 1984, 78-84.
2 W. Trowitzsch-Kienast, E. Forche, V. Wray, H. Reichenbach,
G. Junsmann, G. Hofle, Liebigs Ann. Chem. 1992, 659-664.
3 . B. Andrus, S. D. Lepore, J. Am. Chem. Soc. 1997, 119, 12159-12169.
4 . M. Cox, D. A. Whiting, J. Chem. Soc., Perkin Trans. I, 1991, 1907-1911.
5 . . Mapp, . H. Heathcock, J. Org. Chem. 1999, 64, 23-27.
6 A. R. Daniewski, W. Wojceichowska, J. Org. Chem. 1982, 47, 2993-2995.
7 J.-L. Luche, J. Am. Chem. Soc. 1978,100, 2226-2227.
8 K. Krishnamurthy, H. C. Brown, J. Org. Chem. 1977, 42, 1197-1201.
9 R. E. Counsell, P. D. Klimstra, F. B. Cotton, J. Org. Chem. 1962, 27, 248-253.
10 D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277-7287.
11 M. Frigerio, M. Santagostino, S. Sputore, J. Org. Chem. 1999,
64, 4537-4538.
12 a) S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis 1994, 639-666; b) W. P. Griffith, S. V. Ley, G. P.
10 Myxalamide
175
Whitcombe, A. D. White, J. Chem. Soc., Chem. Comm. 1987, 1625-1627.
13 A. J. Mancuso, D. Swern, Synthesis 1981, 165-185.
14 D. A. Evans, Aldrichimica Acta 1982, 75, 23-32.
15 T. D. Penning, S. W. Djuric, R. A. Haack, V. J. Kalish, J. M. Miyashiro, B. W. Rowell, S. S. Yu, Synth. Commun. 1990, 20, 307-312.
16 R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am. Chem. Soc. 1976, 98, 2868-2877.
17 F. W. Schuler, G. W. Murphy, J. Am. Chem. Soc. 1950, 72, 3155-3159.
18 . H. Lipshutz, Synthesis 1987, 325-341.
19 a) R. Tang, K. Mislow, J. Am. Chem. Soc. 1970, 92, 2100-2104; b) D. A. Evans, G. C. Andrews, J. Am. Chem. Soc. 1972, 94, 3672-3674.
20 . E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863-927.
21 a) J. C. Gilbert, U. Weerasooriya, J. Org. Chem. 1979, 44, 4997-4998; b) D. Seyferth, R. S. Marmor, P. Hilbert, J. Org. Chem. 1971, 36, 1379-1386; c) D. G. Brown, E. J. Velthuisen, J. R. Commerford, R. G. Brisbois, T. R. Hoye, J. Org. Chem.
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