Macrocycles Mitsunobu reaction

It was converted to the phthalimide via a Mitsunobu reaction, reduced to the amine, and the amine was coupled with />-nitrophenylacetic acid to give the precursor to the macrocycle. Macrocylization was done via Troger s base formation using Johnson s method, which resulted in two isomers of the amide macrocycle. These were separated and reduced to give the cyclophane host. This was the first time two diastereomers were observed in these syntheses and the separation of these diastereomers was very difficult. 

In a process resembling the Mitsunobu reaction (Chapter 17), alcohols and acids can be coupled to give esters, even macrocyclic lactones as shown below. In contrast to the Mitsunobu reaction, the reaction leads to retention of stereochemistry at the alcohol. Propose a mechanism that explains the stereochemistry. Why is sulfur necessary here ... 

The 14-membered ring phosphonate 208 was synthesized via cyclization of the acyclic precursor 207 using the Mitsunobu reaction. Macrocycle 208 was obtained in 82% yield as a mixture of two diastereomers (5 1). The phenyl moiety in 208 was substituted with iV-Cbz-protected aminopentanol, followed by hydrogenolysis in EtOH with hydrogen and 10% Pd/C to afford amine 209 in 50% yield <20010L643, 2002CJC1643>. 

A further reaction mechanistically similar to the Mitsunobu reaction as shown in Scheme 26, with the use of AT,iV-dimethylformamide dineopentylacetal (80), can also be employed for macrolactonization [47]. Takei and coworkers [48] applied it to the synthesis of the macrocyclic antibiotic A26771B (55). As shown in Scheme 27, treatment of the linear precursor 82 with 80 in refluxing dichloromethane for 7 h afforded the lactone 83 (39% yield). 

For the total synthesis of baccharin B5 (379) six more steps were necessary. First, the alcohol group was protected and then the unconjugated double bonds could be epoxidized selectively to provide 477 as a single product. Subsequently, the epoxide of the macrocycle 477 was eliminated to an allylic double bond, which could be epoxidized again and gave the epimer of baccharin B5. Last, the epimer was converted into baccharin B5 (379) via a Mitsunobu reaction (Scheme 8.21). 

Finally, Mitsunobu reaction of macrocycle 282 with the acid 299 afforded the axial ester, which was hydrogenated using Lindlar catalyst to yield (+)-leucascandrolide A (199) (Scheme 64). 

Other applications of the Mitsunobu/RCM approach are shown in the figure below. The respective arrows indicate the use of the Mitsunobu reaction to prepare the acyclic precixrsor and the olefin formed in the ringclosing metathesis reaction. The first example shows an advanced intermediate (58) in the preparation of octalactin ketone. McLeod and coworkers employed a Mitsunobu reaction to set up an ROM precursor for the preparation of a key intermediate (59) for the synthesis of (-)-dactylolide. An alternative approach towards (+)-zampanolide and (+)-dactylolide was taken by Smith et al., their approach, which is not shown, attached a diethylphosphonacetic acid moiety to an alcohol via a Mitsunobu reaction and yielded the desired macrocycle after deprotonation and reaction with a pendant aldehyde via an intramolecular olefination reaction. ... 

Other approaches to make macrocyclic ring systems exist as well. Smith and Ott prepared the central framework of (-)-macrolactin A by using a Mitsunobu reaction to prepare a linear precursor for the final ring closure reaction with a Stille reaction. The Mitsunobu reaction proceeded in 74% yield the Stille reaction, in contrast, took seven days and provided the desired macrocyclic intermediate 60 in 42% yield. In an inverse approach, Williams and Meyer prepared (+)-amphidinolide K by preparing a seco-acid macrolactonisation precursor via Stille reaction and then using the Mitsunobu reaction to close the ring to form 61. ... 

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

Intramolecular coupling of 120 having an aryl iodide group and a vinylstannane group accomplished the total synthesis of (-)-zealarenone (99) (Scheme 19) [77]. The first total synthesis of macrolactin A (124) was efficiently accomplished based on the Stille reaction of 122 for both stereospecific construction of the diene moieties and closure of the 24-membered macrocyclic ring [78]. The key precursor 122 was synthesized via two Stille couplings and Mitsunobu esterification. An alternative route to the dimethyl ether 125 was reported by cyclization of 123, which was prepared by the Stille and Suzuki couplings followed by DCC-DMAP esterification... 

HCV protease inhibitor intermediate) 86 (azamacrocycles) Figure 11.11 Macrocycles produced using Mitsunobu-type reactions. 

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