Biomimetic synthesis of morphine

Studies on the synthesis of morphine. VI. Recent progress on the biomimetic synthesis of morphine... 

The very short and highly efficient biomimetic synthesis of morphine [16, 32] by Rice stands out in terms of overall yield and brevity no subsequent contribution to this area exceeds this milestone achievement. The route follows the biosynthetic pathway and delivers dihydrocodeinone in almost 30% overall yield. 

The First Biomimetic Synthesis of Morphine Isotope Dilution Method... 

The first biomimetic synthesis of morphine was described by Sir Derek Barton (Imperial College in London). Barton showed that oxidation of reticuline (31) with potassium ferricyanide gave salutaridine (32) in 0.015% yield. Since salutaridine had been converted to morphine, this constituted a synthesis of the target alkaloid. How does one isolate a product in 0.015% yield. Not easily. In this case, the isotope dilution method was used to establish yield. Reticuline was prepared in radioactive hot form (tritiation in the aromatic ring). The oxidation reaction was run and a known amount of cold salutaridine was added to the reaction mixture. The salutaridine was then isolated and purified to a constant level of radioactivity. The amount of hot salutaridine derived from reticuline was calculated based on the radioactivity that had been incorporated, and the percentage yield of salutaridine (from reticuline) was thus determined. The details are given on Morphine-6. The bottom line is that this demonstrated the feasability of this route to morphine, but it did not provide a practical route to the natural product. 

Snyder SH (1984) Drug and neurotransmitter receptors in the brain. Science 244 22-31 Szantay C, Blasko G, Barczai-Beke M, Ddrnyei G, Pechy P (1983) Studies on the synthesis of morphine VI. Recent progress on the biomimetic synthesis of morphine. Planta Med 48 207-211 and references cited therein... 

In the first place, the structure of the target molecule is submitted to a rational analysis in order to perceive the most significant structural features, and it may be useful to use different types of molecular models at this point. It should be remembered that a molecular structure has "thousand faces" and finding the most convenient perspective may greatly simplifly the synthetic problem. The synthesis of opium alkaloids, for instance, is much simplified if one realises that they are, in fact, derivatives of benzyltetrahydroisoquinoline (18) (see Scheme 3.8). This was indeed the inspired intuition of Sir Robert Robinson which led to the structural elucidation of morphine (19) and to a first sketch of the biogenetic pathway [22], and later on to the biomimetic synthesis of thebaine 20 [23] [24]. 

This is especially true in the analysis of the synthetic pathways to many natural compounds, where the most effective synthetic ideas can be often borrowed from the arsenal of the most skillful synthetic chemist of all times Mother Nature. A good illustration of the fruitfulness of this so-called biomimetic approach is provided by the synthesis of morphine group of alkaloids (Scheme 3.11). 

Sz ntay et al. [36) succeeded in a biomimetic synthesis of ( )-salutari-dine (52) in 2.7% overall yield from ( )-reticuline (51) with the aid of LTA oxidation conducted in CH2CI2 in the presence of trichloroacetic acid, with ( )-isoboldine (35) also being formed (Scheme 7). Since morphinan-dienone 52 (65) is an important precursor to morphine, the above synthesis is quite interesting in spite of the low yield. 

Eventual biosynthetic postulations and revelations have led several groups over the years to approach the synthesis of morphine as does Nature, choosing to adopt a biomimetic phenolic oxidative coupling as the key step. Unfortunately, the in vitro oxidation of reticuline derivatives to salutaridines tends to proceed with poor regiocontrol and in low yield, despite employment of a variety of novel reagents. This of course... 

A commercially profitable biomimetic synthesis of morphinane alkaloids will require the conversion of reticuline into salutaridine in sufficient yield (Scheme 14) (see Section III,D) and the conversion of salutaridine into thebaine, codeine, and morphine. 

Morphine Mulzer, 1996 Mulzer and Trauner published a conceptually completely different synthesis of morphine [145, 151]. The route does not follow the biomimetic synthesis of the natural product but was inspired by early degradation studies, which ultimately helped to... 

Mulzer s elegant synthesis of morphine is characterized by a stepwise elaboration of the ring motives in the natural product. While the biosynthetic pathway comprises an oxidative phenolic coupling, Mulzer employed a highly efficient Friedel-Crafts acylation to estabhsh the C12—C13 bond. Additionally, the implementation of observations from degradation studies represents an interesting alternative strategy to the exploitation of biomimetic pathways for natural product synthesis. 

More recent examples of biomimetic synthesis are the syntheses of thebaine [11] and usnic acid [12], as well as strychnine [13], morphine alkaloids [11] [14] and a great number of terpenic compounds [15]. On the other hand, hypothetic prebiotic considerations may also simplify tremendously the synthetic plans. Such is the case, for example, of the work of Eschenmoser on vitamin B12 who, after synthesising it in collaboration with Woodward by a linear sequence of almost fifty steps [16], investigated the prebiotic origen of this complex molecule. The experimental work undertaken in this direction demonstrates that the amount of "external instruction" required for "self-assembling" the different structural elements present in this molecule is surprisingly small. This fact could eventually lead to a very simple synthesis of vitamin Bj2 starting from a-amino nitriles which would involve only a few steps [17]. 

Initial investigations in opiate total synthesis at NIH focused on the biomimetic route, shown above and recently studied extensively by Szantay et al. (1983) and Schwartz and Zoda (1981) in which a reticuline derivative (11) is oxidatively cyclized to a salutaridine derivative (12) which would be convertible to thebaine and hence to codeine and morphine. Traditionally, this approach has been complicated by control of the product distribution ratio and the tendency of the desired morphinandienones to undergo secondary transformations. An effective synthesis of reticuline derivatives (Rice and Brossi 1980) was developed as a prerequisite to this approach at NIH, and a simple synthesis of racemic and chiral pavinans and isopavinans (Rice et al. 1980) resulted from these studies, but attempts at development of an oxidative cyclization which would be useful for large scale synthesis were unsuccessful. 

Schwartz MA, Zoda MF (1981) Biomimetic approaches to morphine alkaloids. Total synthesis of ( )-24iydroxycodeine and ( )-noroxycodone. J Org Chem 46 4623-4625 and references cited therein... 

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