18 The Mitsunobu Reaction in the Synthesis
of Macrocyclic Lactones
18.1 Background
In 1976, Mitsunobu et al. described a macrolactonization protocol to obtain
medium- and large-ring macrolactones [115, 116]. This method is based on the
activation of the alcohol of the seco-acid using diethyl azodicarboxylate (DEAD) or
the more hindered diisopropyl azodicarboxylate (DIAD) and triphenylphosphine.
In this reaction mechanism, the key intermediate is an alkoxyphosphonium salt
produced in situ, and the macrolactonization proceeds via an intramolecular S N 2
reaction and with inversion of configuration (Scheme 67). To conclude, it is worth
noting that Mitsunobu reactions employing hindered alcohols can also proceed with
retention of configuration.
18.2 12-Membered Macrocyclic Lactones
18.2.1 Lonomycin A
Standard Mitsunobu conditions (i.e., PPh 3 /DEAD in benzene, toluene, or THF at
ambient temperature) may, however, suffer from some drawbacks such as the
formation of hydrazide by-products (e.g., 235, Scheme 68). Evans et al. encountered this problem in their total synthesis of the 12-membered lonomycin A
precursor, 234 (Scheme 68) and solved this issue by using the more hindered
DIAD in the nonpolar solvent toluene at low temperatures [149].
18.3 13-Membered Macrocyclic Lactones
18.3.1 (+)-Brefeldin C
Another classical adoption of Mitsunobu’s procedure was applied in the total
synthesis of (+)-brefeldin C 135 (Scheme 69). Macrolactonization of hydroxy
acid 237 yielded macrolactone 238 in excellent yield (85 %), along with a small
amount of unidentified polymeric lactones (<5 %) [150].
420
M. Cordes and M. Kalesse
of Macrocyclic Lactones
18.1 Background
In 1976, Mitsunobu et al. described a macrolactonization protocol to obtain
medium- and large-ring macrolactones [115, 116]. This method is based on the
activation of the alcohol of the seco-acid using diethyl azodicarboxylate (DEAD) or
the more hindered diisopropyl azodicarboxylate (DIAD) and triphenylphosphine.
In this reaction mechanism, the key intermediate is an alkoxyphosphonium salt
produced in situ, and the macrolactonization proceeds via an intramolecular S N 2
reaction and with inversion of configuration (Scheme 67). To conclude, it is worth
noting that Mitsunobu reactions employing hindered alcohols can also proceed with
retention of configuration.
18.2 12-Membered Macrocyclic Lactones
18.2.1 Lonomycin A
Standard Mitsunobu conditions (i.e., PPh 3 /DEAD in benzene, toluene, or THF at
ambient temperature) may, however, suffer from some drawbacks such as the
formation of hydrazide by-products (e.g., 235, Scheme 68). Evans et al. encountered this problem in their total synthesis of the 12-membered lonomycin A
precursor, 234 (Scheme 68) and solved this issue by using the more hindered
DIAD in the nonpolar solvent toluene at low temperatures [149].
18.3 13-Membered Macrocyclic Lactones
18.3.1 (+)-Brefeldin C
Another classical adoption of Mitsunobu’s procedure was applied in the total
synthesis of (+)-brefeldin C 135 (Scheme 69). Macrolactonization of hydroxy
acid 237 yielded macrolactone 238 in excellent yield (85 %), along with a small
amount of unidentified polymeric lactones (<5 %) [150].
420
M. Cordes and M. Kalesse