Lasubines

During recent years, cross metathesis has found a wide range of applications in total synthesis. CM has been the key step in the syntheses of (-)-lasubine 11 [134], (+)-7a-ept-7-deoxycasuarine [135], and melithiazole C [136] to name just a few examples. It has been used for the modification of tetrapyrrolic macrocycles [137] as well as erythromycin derivatives [138], the dimerisation of steroids [139] and the synthesis of prostaglandin analogues [140]. 

Another example of this useful domino process is the enantioselective synthesis of the quinozilidine alkaloid (-)-lasubine II [234]. Condensed tricyclic compounds as 6/3-28 can also be prepared from norbomene derivatives 6/3-27 in excellent yield, as shown by Funel and coworkers (Scheme 6/3.6) [235]. 

Lasubines I and II are alkaloids containing a 4-arylquinolizidine substructure that have been isolated from plants of the Lythraceae family and have attracted the attention of synthetic chemists for some time. While numerous racemic syntheses of these and related compounds have been reported, only a few enantioselective syntheses are known. Some examples of these syntheses are given below, and the strategies involved in these examples are summarized in Scheme 92. Three of these syntheses involve the creation of the quinolizidine system by formation of one bond at the a- or 7-positions, while the fourth approach is based on a ring transformation associated with a photochemical Beckmann rearrangement. 

Enantiopure quinolizidinones and indolizidinones were obtained by Ma and Zhu in an intramolecular conjugate addition of the secondary amine of 293 to the alkynoate ester to provide the intermediate allenoate 294, which was subsequently trapped in a condensation reaction to afford 295 (Scheme 19.53) [62], In some instances, intermediate 296 was isolated, which could also be converted to 295. This quinolizidinone intermediate was then converted in a concise manner to lasubine II (297). 

The rare reports of quinolizidine formation by a nitrone cycloaddition strategy include the racemic total synthesis of lasubine II (58), one of a series of related alkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme 1.14) (104). While these alkaloids were previously accessed by infennolecular nitrone cycloaddition reactions, this more recent report uses an intramolecular approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59 affords predominantly the desired bridged adduct 60 along with two related... 

Natural Product Synthesis Using Grubb Metathesis Lasubine II, Ingenol, and Ophirin ... 

Practitioners of total synthesis have been pushing the limits of Grubbs metathesis. Siegfried Blechert of the Technisches Universitat, Berlin, envisioned (Tetrahedron 2004,60,9629) that Grubbs metathesis of 1 could open the cyclopentene, to give a new Ru alkylidenc that could condense with a styrene such as 2. In practice, this transformation worked well, yielding 3. Deprotection, intramolecular Michael addition and reduction then gave (-)-lasubine II4. 

Lactacystin synthesis 196 Lasubine synthesis 134 Lepadin synthesis 142... 

Natural Product Synthesis using Grubbs Metathesis Lasubine II, 134... 

Reduction of (28) with zinc-acetic acid provided the all-cu-piperidinol which was converted in several steps to ( )-lasubine 11. 

Fuji et al. (16) have recently isolated lasubine-I (64b) and lasubine-II (63b) from Lagerstroemia subcostata Koehne. The structures of these alkaloids have been established by correlation with synthetic compounds (63a and 64a) as well as by analysis of IR, PMR, 13C-NMR, and mass spectra. These alkaloids are listed in Table IV (16, 47, 48, 50, 51). 

The structure of these bases has been elucidated by spectroscopic and chemical methods. A basic hydrolysis of both subcosine-I and subcosine-II resulted in 3,4-dimethoxycinnamic acid as well as lasubine-I for 69 and lasubine-II for alkaloid 67. 

Cross metathesis (CM) reactions can also be used as the key step in a piperidine synthesis (Scheme 40) <2004TL1167> or in sequence with ring-rearrangement metathesis, for example, in the synthesis of (—)-lasubine (Scheme 41) <2004T9629>. 

Conjugate addition.s The key step in a stereocontrolled synthesis of the Lyth-raceae alkaloid lasubine II (4) is the conjugate addition of an alkylcopper complexed with BF3 to the N-acyl-2,3-dihydro-4-pyridone 1 to give the d.v-product 2 in 56% yield and >96% stereoselectivity. Hydrogenation in the presence of Li2C03 effects cyclization and deprotection of nitrogen to give the ketone 3, which is reduced stereoselectively by lithium trisiamylborohydride to the desired alcohol 4. 

Naturally occurring arylquinolizidine alkaloids synthesized within the period 1979-1987 include demethyllasubine (1), lasubine I (2), 10-epidemethoxyabres-oline (3), subcosine 1 (4), demethyllasubine II (5), lasubine II (6), and abresoline (7). Arylquinolizidine alkaloids are divided into two general classes. One class possesses a cw-quinolizidine skeleton, and the other has a frans-quinolizidine... 

The disadvantage of the intermolecular dipolar cycloaddition strategy is nonstereoselectivity. A recent stereoselective synthesis of lasubine 1 (2) utilizes the intramolecular tt cyclization of an /V-acyliminium ion as a key step (Scheme 4) (16). The reaction of carbinol 38, prepared from 3,4-dimethoxybenzaldehyde (33) and allylmagnesium bromide, with glutarimide under Mitsunobu conditions... 

Lasubine I (2) was also synthesized with the pelletierine condensation as a key step (15). Condensation of pelletierine (8) with 3,4-dimethoxybenzaldehyde (33) under standard conditions gave the cis- and rrans-quinolizidines 42 and 43 in 46 and 22% yield, respectively. Reduction of ris-quinolizidine 42 with sodium borohydride afforded lasubine I (2) in 83% yield. 

Lasubine II (6) was synthesized by three different routes. The first involves the traditional pelletierine condensation (75), in which frans-quinolizidine 43 was... 

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