growth of those new blood vessels thus saving still-intact areas the retina.
The sequence for preparation of the agent begins with the conversion of the
ketone at 3 to its enol ether 88 , for example, with methyl orthoformate.
Addition of cyanide to the carbonyl at 17 initially leads to a mixture of epi-
meric cyanohydrins. Conditions were developed for converting this to the
desired isomer 89 , by crystallization under equilibrating conditions. The
17 bcyano isomer is apparently less soluble that its epimers. The hydroxyl
group at 17 is then protected as its trimethylsylyl ether ( 90 ). Reduction by
meansofdiisobutylaluminumhydridefollowedbyproticworkupconvertsthe
cyano group to an aldehyde. Condensation of this intermediate with the anion
from methylene bromide probably leads initially to adduct 92. Excess base,
lithium diisopropylamide (LDA), is thought to remove one of the bromine
atoms. The resulting intermediate then rearrangesto give the observed bromo-
ketone. Removal of the protecting groups leads to diketone 94 , which lacks
only oxygen at positon 21. Displacement of bromine atom at that position
with sodium acetate completes construction of the corticosteroid side chain
at position 17.^16 Thus 96 is obtained.
OOOCH 3 O(CH 3 ) 3 CH87 88KCN
AcOHCNCH 3 O
89OH(CH 3 ) 3 SiCl
CNCH 3 O
90CH=O OTMSCH 3 O
91OTMS
DIBAL-H
CH 3 O
92OTMS
CH 2 Br 2
LDACH 3 O
93OTMSLiO BrLiO BrBrO
94OHO BrNaOAcO
95OHO OCOCH
3Topically applied corticosteroids have proven very effective in treating
asthma. The amount of drug from the inhaled dose that reaches the
small airways has a critical effect on relieving asthmatic episodes. The
acetal at positions 16,17 of the diol ( 97 ) with acetone,^17 desonide, has
- POLYCYCLIC COMPOUNDS: STEROIDS 35