Stemoamide synthesis

The stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

A total synthesis of (—)-stemoamide is achieved from (—)-pyroglutamic acid using ruthenium-catalyzed enyne metathesis as a key step in 14 steps in 9% overall yield [Eq. (6.79)]... 

The total synthesis of polycyclic alkaloid (-)-stemoamide was achieved in the laboratory of M. Mori via a ruthenium carbene catalyzed enyne metathesis. The cyclization was effected by 5 mol% of catalyst in benzene at 50 °C. After 11h of stirring under these conditions, 87% of the 5,7-fused bicyclic system was formed. 

Kinoshita, A., Mori, M. Total Synthesis of (-)-Stemoamide Using Ruthenium-Catalyzed Enyne Metathesis Reaction. J. Org. Chem. 1996, 61, 8356-8357. 

Scheme 44. Ring-closing enyne metathesis using Grabbs catalyst for the synthesis of ( )-stemoamide.

An alternative method for preparing vinyl bromides can be incorporated into a synthesis of alkynes when combined with an E2 reaction. In Jacobi s synthesis of (-)-stemoamide,l aldehyde 196 was treated with... 

Ring closure metathesis (RCM) has been used in the cyclisation of 6 to give the pyrrolidinoazepine 7 <97SL1179>. This reaction has also been used to prepare the corresponding 5, and 6-membered systems. In an extension of this methodology, the ring closure of 8 to 9, has been used in the total synthesis of (-)-stemoamide 10 <97H(46)287>. 

Jacobi and Lee ° found P2O5 to be effective for preparing larger quantities (20 g) of an oxazole required for their synthesis of ( )-stemoamide. In this case, 2-(3-chIoropropyI)-5-methoxy-4-methyIoxazoIe 464 was prepared from 463 (Scheme 1.126). The authors found that 464 was sufficiently pure as isolated to prepare the acetylenic oxazole 465. 

Synthesis of Evodone Synthesis of Ligularone and Petasalbine Synthesis of Paniculide-A Synthesis of Gnididione Synthesis of Norsecurinine Synthetic Approach to Geigerin Synthesis of Stemoamide Thiofurans and Amidofurans... 

Jacobi and co-workers ° described the total synthesis of racemic stemoamide, a member of the stemona alkaloids isolated in 1992 from Stemona tuberosa, and an enantioselective route to (-)-stemoamide. The starting alkyne oxazoles 200 and 203 were prepared from y-chlorobutyryl chloride 199 in five steps (Fig. 3.60). 

The synthesis was completed by reduction of 206 with the nickel boride catalyst derived from nickel(ll) chloride and sodium borohydride directly producing ( )-stemoamide in 73% yield. In addition, a 15% yield of the cfr-lactone 207, derived from a-face reduction of 206 followed by epimerization at C-10, was also obtained. 

An enantioselective synthesis of natural (-)-stemoamide was carried out precisely as described for the synthesis of racemic stemoamide. In this case, enantiomerically pure 203 was prepared from L-pyroglutamic acid in eight steps. 

Allenols may be carbonylated under quite different conditions. Using Rus (CO)i 2 as the catalyst, unsaturated lactones can be synthesized efficiently." The reaction may also be extended to lactams." This cyclization, combined with an intramolecular propargylic Barbier reaction has been used in syntheses of mintlactone 4.111 from allenol 4.110 (Scheme 4.43)" " and its diastereoisomer, isomintlactone," as well as the stemona alkaloid, stemoamide 4.115 from allenol 4.113 (Scheme 4.44)," and in the skeleton of stenine." A different synthesis of stemoamide can be found in Chapter 8, Scheme 8.112. 

Ene-yne metathesis has been employed in an elegant synthesis of stemoamide 8.415 (Scheme 8.112). The starting lactam 8.407, available itself from glutamic acid, was iV-alkylated, then subjected to deprotection, Swern oxidation and application of the Corey-Fuchs method for installation of an alkyne by Wittig... 

The relative configuration of stemoamide (15) was originally proposed based on comparison of its NMR data with those available for stemoninine (27) (12,39). Eventually, the structure of stemoamide (15) was confirmed by total synthesis (Section III), which also contributed to validate the stereochemical assignment for stemoninine (27). 

Pyroglutamic acid (130) was employed in the total synthesis of (—)-stemoamide (15) by Sibi and Subramanian (Scheme 8) 68). After its conversion to the /cr/-butyldimethylsilyl ether 131, iV-alkylation with 4-bromo-l-butene and chain extension via a Wittig reaction set the stage for the key stereoselective addition of vinyl copper... 

By far the most concise and efficient approach to ( + /—)-stemoamide (15) was developed by Jacobi and Lee (71,72) and featured an intramolecular Diels-Alder/retro Diels Alder cyeloaddition between the 2-methoxyoxazole and acetylenic moieties in 151 followed by equilibration to set the correct relative configuration at C8 and C9a (151 147, Scheme 11). The stereochemistry at C9 and CIO was established after nickel boride reduction of the unsaturated butyrolactone ring and epimerization at CIO to afford a 73% yield of ( + /—)-stemoamide (15), together with its epimer at C9 and CIO. Overall, the total synthesis of (+ /—)-stemoamide (15) was achieved in seven steps from 4-chlorobut5Tyl chloride (148) and in 20% overall yield. 

The approach was extended to the synthesis of (—)-stemoamide (15) from enantiomerically pure alkyne oxazole 153, prepared from (S)-pyroglutamic acid... 

Ring-Closing Metathesis of Enyne Precursor The first example of target-directed synthesis using enyne metathesis is the total synthesis of (—)-stemoamide 179, an alkaloid isolated from the roots of Stemona... 

SCHEME 24.46. Total synthesis of (—)-stemoamide using enyne RCM. 

Kinoshita A, Mori M. Total synthesis of (—)-stemoamide using ruthenium-catalyzed enyne metathesis reaction. J. Org. Chem. 1996 61 8356-8357. 

The first application of ene-yne RCM was reported in the total synthesis of the natural product (—)-stemoamide [8]. (—)-Pyroglutamic acid was converted into ene-yne 16 having an ester group on the alkyne, and RCM of ene-yne 16 was carried out in the presence of ruthenium-carbene complex [Ru]-I (4 mol%) to afford bicyclic compound 17 in 87% yield. Conversion of 17 into 18 followed by... 

---