Page 1274 - Advanced Organic Chemistry Part B - Reactions & Synthesis

1250 Scheme 13.78. Synthesis of a Cyclosporin Analog by Solid Phase Peptide Synthesis a

CHAPTER 13
Multistep Syntheses
OH
10
CH 3 11 1 2 CH 3
N N N N
O N 3
O O H O
CH 3 O CH 3
O
9
N
N O H O H
CH 3 4 CH 3
N N N N
O 8 7 O 6 5 O
H CH 3
Cyclosporin A
8 9 10 11 1 2 3 4 5 6 7
D-Ala-MeLeu-MeLeu-MeVal-MeLeu-Abu-Sar-MeLeu-Val-MeLeu-DAla link

coupling
reagent
and yield
HOAt 70 84 73 78
HATU 95 75 50 62 98

a. Y. M. Angell, C. Garcia-Echeverria, and D. H. Rich, Tetrahedron Lett., 35, 5981 (1994); Y. M. Angell, T. L. Thomas,
G. R. Flentke, and D. H. Rich, J. Am. Chem. Soc., 117, 7279 (1995). The analog contains N-methylleucine at position 1.

13.3.2. Solid Phase Synthesis of Oligonucleotides
Synthetic oligonucleotides are very important tools in the study and manipulation
of DNA, including such techniques as site-directed mutagenesis and DNA amplifi-
cation by the polymerase chain reaction. The techniques for chemical synthesis of
oligonucleotides are highly developed. Very efficient automated methodologies based
on solid phase synthesis are used extensively in fields that depend on the availability
of defined DNA sequences. 52
The construction of oligonucleotides proceeds from the four nucleotides by
formation of a new phosphorus oxygen bond. The potentially interfering nucleophilic
sites on the nucleotide bases are protected. The benzoyl group is usually used for
the 6-amino group of adenosine and the 4-amino group of cytidine, whereas the
i-butyroyl group is used for the 2-amino group of guanosine. These amides are cleaved
by ammonia after the synthesis is completed. The nucleotides are protected at the

5 -hydroxy group as ethers, usually with the 4,4 -dimethoxytrityl (DMT) group.
In the early solution phase syntheses of oligonucleotides, coupling of phosphate

diesters was used. A mixed 3 -ester with one aryl substituent, usually o-chlorophenyl,

was coupled with a deprotected 5 -OH nucleotide. The coupling reagents were
sulfonyl halides, particularly 2,4,6-tri-i-propylbenzenesulfonyl chloride, 53 and the
reactions proceeded by formation of reactive sulfonate esters. Coupling conditions
52 S. L. Beaucage and M. H. Caruthers, in Bioorganic Chemistry: Nucleic Acids, S. M. Hecht, ed., Oxford
University Press, Oxford, 1996, pp. 36–74.
53
C. B. Reese, Tetrahedron, 34, 3143 (1978).