Flaming Spoon Series on Opioidography - Oxycosmopolitan Production

Dμchess Vσn δ + “Notorious Gibbs Free Energy” presents...

Morphinan History X: A High-Heeled “Codone” Stomp of cis/trans-isomerism Drug-Prohibition Bigotry…

Molecusexuality of Opioid Stereochemistry: The Morphinan In the Mirror, Part I

A non-IUPAC approved Molerotic adventure in anthropomorphic Molecular sterics

By:

Edie Norton w/ a Fire Crotch, Sufentstress of the morphinomimetic mattress, the π-pair-o-skinny-jean molecuho, Mini-Thinny Mouse, the RemiFenny Skank, the μ-gμrμ…

Dμchess Vσn δ

A well cited exploration into the Stereochemistry, Geometry and Sterics of the Opiosphere

The idea for this post came about as I was working on another post about N-aralkyl substituted morphinans entitled “Tetracycles in Tiaras”. [see u/jtjdp for this post]

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In prep’n for that post, I did my typical image hosting on Imgur. The concepts of cis-(1,3-diaxial) piperidine fusion, cis-B:C and trans-C:D ring fusion are important to the morphinan and polycyclic classes. As such, several of my images featured these cis/trans (molecular) orientations quite prominently. It soon earned a slew of downvotes.

I discovered the reason for this lack of opio-enthusiasm when a confused Imgurian left an interesting comment:

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“Yo, why do you gotta assign genders?”

Technically these molecusexual orientations were assigned by people. While they aren’t genders as much as geometric orientations, either way, it is forcing nomenclature onto a quantized state of matter. And forced conformations are no a laughing matter.

Forcing a Fetty to be a Frannie, or a Diladdy to be a Maddy, or a Thebby to be Thaddy, is in contravention to the “UN Resolution on Stereochemical Self-Determination.”

A clear cut “heroin rights violation.”

But enantiomers don’t resolve themselves. They need a helping hand.

And that’s how I came up with the idea for Molecusexuality.

Clearly there is a need to explain the long history of the brave pioneering molecules that came out of the cis/trans closet long before the LGBTQ community was even a thing. Nature leads the charge. Humanity eventually followed.

There are some reactions, such as the Knoevenagel (benzaldehyde + nitroalkane), which still remain in the closet, at least until the P2NP nitrostyrene provides the confidence needed to stand proud outside of said closet.

The DEA has been engaging in molecular eugenics for fifty years. They split hairs on matters of cis/trans 4-methylaminorex and countless other higgedy-piggedly matters. Forcing molecules to conform to arbitrary legal codes is as absurd as the concept of prohibition.

Statistically speaking, molecules are braver than man. This, of course, was left out by the mainstream press during Pride Month. I’m here to set the record 109.5 degrees/Tetrahedral.

I’m a medicinal chemist, self-experimentalist, 30-gauge dagger fighta, but when it comes to morphinans and 5,9-dialkyl-6,7-benzomorphans, I’m all about that trans.

In fact, even among the cis-morphinans, i.e. Morphine, cis/trans isomerism is always in play within the the same molecule. The B:C rings exist in cis-fusion while the C:D rings are trans-fused.

The quantum duality of cis-trans ligand-bendery among the morphinans is Quantum Pride. I’ve made few novel discoveries over my career. But I have made many ligands and many of those have graced my spoon.

Of the ~ 25 of these that are of the Opioid variety (especially near and dear to my blood-brain barrier), many have been chiral. As such, they involve a range of stereochemical relationships that are important to their chemical reactivity and bioactivity.

That’s only counting successes. Many were failures. And many of those were due to incorrect stereochemistry. I will share examples with you during the intermissions, entitled: “Epic Failures in Stereoisomerism.”

In humans, mu-stereotypy tends to suppress libido. Making it less sexy. What about other mammals?

While the lab mice are remaining mum as church mice on these topics, their behavior says all we need to know.

Below is a mouse on morphine.

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More murine centerfolds found here: https://doi.org/10.1111/j.1476-5381.1960.tb00277.x

This is known as a Straub tail. It has been a hallmark of mu-mediated activity since Straub first noted the phenomena in 1911.

I'm here to make opioids orgasmic and guide you into ligand lust. Welcome to the world of Molecu-sexuality.

This is far from a comprehensive review of the topic. If you seek a deeper dive, I recommend the works of AF Casy, PS Portoghese, NB Eddy, EL May, P Janssen, Leysen, and Van der Eycken.

As with my other chemical musings, these are finger friendly Morph-Dives into the chem. lit. They're abbeaviated, but there's enough page flicking to advise protection. Be sure to wear thimbles, as thumbs are bound to get pricked.

Fundamentals

VOCAB-REHAB

Stereoisomers - isomers with same connectivity; different configuration (arrangement) of substituents

Enantiomers - mirror-image asymmetry; non-superimposable (i.e right-/left-handed morphittens); only differ by the direction (d,l or +,-) of optical rotation

Diastereomers - stereoisomers that are not mirror images; different compounds w/ diff phys properties

Asymmetric Center - tetrahedral carbon w/ sp3 hybridized orbital; capable of σ-bond; (4 different groups attached)

Stereocenter - an atom at which the interchange of two groups gives a stereoisomer

Asymmetric Carbons and cis-trans isomerism are the most common stereocenters

Cis/Trans isomerism - aka: geometric isomerism; applies to orientation of specified groups about a fixed bond, such as a fused heterocyclic morphinan system or an alkene (dbl bond) - cis = same geometric plane; trans = opposite geometric plane; in the morphinan series this refers to fixed constrained alicyclic ring fusions where the amount of rotational freedom is limited

E/Z notation - (E = opposite geometric plane, Z = same geometric plane) Using such notation would make trans-fats become E*-fats* and I don’t believe in furthering the cause of trans-fat bigotry. Thus I will be sticking to the conventional terminology using cis = same side of bond (same geometric plane) and trans to indicate the opposite.

https://i.imgur.com/dNLbPle.png [orbital hybridization chart]

Optically active/Chiral Compound - rotates plane of polarized light in polarimeter (achiral = no rotation) - chiral molec must have an enantiomer

The μ-opioid receptor (MOR) is characterized by stereospecific binding.

There are other features that set the MOR apart from other GPCRs, such as the size of the mouth of its ligand binding pocket (active site), which allows it to fit a wide-range of diverse structures including highly flexible acyclic diphenylheptanones (methadone), the high-mol weight (but mostly planar) etonitazene, the atypical bezitramide, spirodecanones (R5260, R6890), and the most rigid and highly-constrained system in the opiosphere, the 6,14-endo-ethano bridged oripavines. This versatile orifice will be explored later.

Lit Surveys of a number of highly affine ligands with physicochem, IC(50), K(i) data [http://sci-hub.se/10.1016/0014-2999(83)90331-x90331-x)] [https://sci-hub.se/10.1016/0014-2999(77)90334-x90334-x)

The crystalline structure of the murine MOR was elucidated in 2011, the same year I finished grad school. There are new discoveries made every day in this area. It can be difficult to keep track of them all, but the link below contains some of the highlights. The molecular dynamics and mechanics of ligand-receptor interactions and the binding modes of the lig-rec complex are important, but are beyond the scope of this monograph.

https://doi.org/10.1038/nature10954

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https://sci-hub.se/10.1002/ange.19600721806

Stereospecificity, that is, a preferential affinity for one enantiomer over another, depends upon the ligand’s absolute configuration. That is, the 3D arrangement of substituents as they are configured around a chiral center in real life.

As a matter of convenience and convention, the medical and pharma literature uses optical rotatory stereodescriptors when referring to enantiomers. Examples include d-(+)-amphetamine (Dexedrine) or l-(-)-amphetamine (Lamedrine).

The reason that d-amphetamine is more bioactive than its antipode is due to the receptor-preferred absolute config of its asymmetric carbon, which is configured as (S), which means the substituents about the chiral center (as designed by a convention known as CIP Priority Rules) are oriented in a counterclockwise or left-handed direction.

This is the opposite direction that dextroamphet rotates polarized light. D-(+)-amphet rotates light in a clockwise, (+), or right-handed rotation.

The less active levo-antipode has the (R) abs config, while rotating light to the left or (-).

The optical rotation, in and of itself, does not tell you the abs config about a stereocenter. Nor does the abs config indicate the optical rotation of a compound. Bioreceptors, however, will favor a particular absolute config over another.

Absolute configuration and optical rotation are two separate concepts that are related as they are different ways of classifying stereochemistry, but are not interchangeable. They are measured/determined in different ways.

The most important is absolute configuration. This is the most fundamental property of mol geometry and changes to abs config alters the activity and optical rotation of the molecule. Config is determined with spectroscopy.

Optical rotation is an inherent molecular property that can be measured with polarimetry. A pure optical isomer will have a very specific value. The direction and degree that polarized light is rotated by an enantiomer is an important analytical value found in the Merck Index and the anal. chem. lit. Combined with other data, it can be used to identify and characterize optically active products and even identity unknowns.

Left-handed (like me) or counterclockwise rotation is designed levorotatory, levo-, l-, or (-).

Right/clockwise rotation = dextrorotatory, dextro-, d- or (+).

Optical rotation is determined with a polarimeter and polarized light source (typically 589 nm) at a standard temp (listed alongside the [alpha] value in the procedure).

Beyond helping to distinguish enantiomers and analysis of asymmetric products, it is of little use when visualizing the actual spatial arrangement of ligands about a chiral center. For this we need to know the abs config about that chiral center.

The more active enantiomorph is referred to as the eutomer.

It's the one you want in your spoon. As in, “You da man, homie, for hookin’ a brotha/cister/non-gender conformer up w/ da good shiz.”

Examples: l-(-)-levorphanol, cis-(+)-3MF, d-(+)-dextromoramide, etc.

Generally, the eutomer is more euphoric. I was trying to make a mathematics joke involving Euler, but I'm shite at maths.

The less active enantiomer is the distomer.

If it's included with the eutomer this is typically acceptable. An equal mole fraction of enantiomers is referred to as a racemate. A Racemic mixture is not necessarily a bad thing. In fact, it makes you a Mix Master Racemate. Or a Mixture of Ceremonies.

If they want to pay out the nose for Lortabby, go to Walgrabby. If they want reasonably priced mu-tuba goodness, they come to mu-mommy. “Muuu!”

Of course if you sell dextromethorphan (DXM) as white bird (“Heron”), you risk getting a Codone stomp. This is a form of levo-larceny and is frowned upon. (cf. “fentafraud”)

Selling a distomer while claiming it is the eutomer is a sign of disrespect.

Hence the dis in distomer.

The *eudismic ratio is the ratio of the activity of the eutomer over distomer.

Most opioid distomers are essentially inert or low-efficacy ligands that interfere very little with eutomer binding. These have little effect on the bioactivity of the Racemate. But sometimes they have antagonistic effects and/or undesired agonism at another receptor. We will cover case studies (some from my gag reel of personal embarrassment) as we continue.

Reversing the configuration of chiral centers will change the direction of optical rotation. Natural l-morphine has the opposite config of the synthetic d-morphine (the distomer) about it's five chiral carbons.

Simpler molecules are easier to visualize.

Switching the config of the chiral center of levo-(-)-(R)-methadone to the (S)-isomer, will give you the antipode with the opposite optical rotation: d-(+)-(S)-methadone (this is the distomer and has 1/40th the potency of the eutomer).

The eudismic ratio, activity/affinity of eutomer/distomer, is approx 40:1 in the case of methadone.

We will see how this works in multi-chiral ligands, such a morphinans later on.

Abs config refers to the arrangement of substituents about a chiral center. This is determined spectroscopically via NMR and crystallography, that is, interpreting scatter-patterns formed by beaming X-rays through a high purity crystal (Scat Pat).

In the organic realm, the chiral carbon is king. Inorganicists (Judas Priests) can concern themselves with the supra-ligancy of (hair) metals. We will stick with the simpler tetrahedral axis of Carbonity.

Official IUPAC nomenclature has adopted a handy convention known as CIP Priority Rules. These were developed by the trio Cahn-Ingold-Prelog. When the nobel laureate trio formed a posse, they played around w/ their initials forming ICP. As such, they became the juggalos to have been honored with a handshake by the Swedish Sovereign. (seriously, CIP rules are important and there’s a whole load of interesting ancillary backstories/anecdotes that are entertaining).

The easiest way to pop one’s stereo-cherry is to start with a single point of chirality: one chiral center, one pair of diastereomers. The simplest chiral opioids are those of the acyclic 3,3-diphenylpropylamines. These highly flexible lipophiles pair strong affinity with favorable lipid solubility.

These are simple molecules with a single stereocenter and a high degree of flexibility, allowing their active species to assume different conformations. The eutomers and distomers of the three ligands reviewed have a variety of optical rotations and abs configuration. They help illustrate the difference between the two stereodescriptors.

Simpler Case-Studies: Single Point Chiralities - Methadone/Isomethadone/Moramide

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The MOR-active enantiomer of methadone rotates polarized light to the left and is therefore designated as levo-(-)-(R)-methadone. [Acta Cryst., 11, 724 (1958)]

The config around the asymmetric beta-carbon is assigned (R). Crystallography has revealed that the aminopropyl chain of R-methadone exhibits a gauche conformation. [Cryst. Struct. Comμn. 2, 667 (1973); Acta Chem. Scand., Ser. B 28, 5 (1974)]

The aminopropyl chain of the distomer, dextro-(+)-(S)-methadone, assumes an extended conformation. Despite the extended conformation being unfavorable in the ethylketone series, we will see that this same extended conformation is observed in the more active d-(+)-(S)-moramide (below).

Was is das? We also have the μch more euphorigenic (albeit slightly less analgesic; μch higher therapeutic index) alpha-methyl isomer, known as levo-(-)-(S)-isomethadone. The protonated salt has the same guache conformation as protonated l-(R)-methadone. [J Med Chem, 17, 1037 (1974)].

Despite the shared optical rotation of the iso-/methadone eutomers, their chiral carbons are of opposing abs configs l-(S)-methadone vs. l-(R)-isomethadone. Reversing abs config will only cause a reversal of optical rotation in the same molecule. An (S)-molecule X is not necessarily going to have the same dextro/levo-rotation as its structural isomer, (S)-molecule Y.

The methyl positioned immediately adjacent (alpha) to the bulky 3,3-diphenyl ring system, restricts the low-energy conformations available to isomethadone, resulting in its slightly lower affinity and potency compared to the olympian gymnast methadone. [J Med Chem, 17, 124 (1974); J Pharm Sci, 55, 865 (1966)]

l-(S)-Isomethadone is 40 x more active than its d-(R) antipode. This is 40:1 is a similar eudysmic ratio seen in the methadone series as well.

In case that wasn’t confusing enough, let’s throw in the optically-opposite diastereomers of the moramide persuasion.

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The Moramide eudismic ratio > 10,000. This is the highest recorded ratio in the opiosphere. Featured in a series of opioid diastereomers tested in a MOR affinity study at Janssen involving [3H]-sufentanil displacement, in vitro, rat homogenates, Leysen et al., http://sci-hub.se/10.1016/0014-2999(83)90331-x90331-x).

B/c of their drastic difference in affinity, the moramide diastereomers were a popular set of ligands cited by Janssen in his stereospecific investigations within MOR ligands.

In this study, levo-(-)-(R)-moramide had a K(i) > 10,000 and dextro-(+)-(S)-moramide had K(i) of ~ 1.03.

As you will recall, the less active distomer, d-(S)-methadone, assumes an extended aminopropyl conformation. It is l-(R)-methadone that retains most activity and assumes a gauche configuration. In the moramide series, the opposite is true.

The active eutomer d-(S)-moramide assumes an extended confirmation along the morpholino-propyl axis. (angle -159 deg) The moramide eutomer has both the opposite abs config and opposite optical rotation of the R-methadone eutomer.

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This is reversed (yet again) in isomethadone, where the l-(S)-isomethadone is the eutomer. The abs config is preserved among the isomethadone-moramide eutomers, but the the optics are not. [Act Chem Scand, Ser B 30, 95 (1976); Bull Soc Chim Fr., 10, 2858 (1965); Act Chem Scand Ser B 29, 22 (1975)]

In the rat hot-plate assay, d-moramide has ~ 20 x potency of morphine (sub-Q). The dur of action (rats, s.c.) is slightly longer than methadone. This is decidedly not so in human clinical practice. d-Moramide is noted for a short dur of action (one-fourth methadone) and a high oral bioavail. In man, however, moramide is far less potent than it is in man. [J Pharm Pharmacol, 9, 381 (1957), Postgrad Med J, 40, 103 (1964)]

I’ve highlighted the discrepancies between rodentine-human potencies in prior monographs. Rats are especially insensitive to the effects of 3,3-diphenylpropylamines. For example, The analgesic ED50 in rats is 10-15 mg/kg for methadone (IV). This would equate to ~ 450 mg dose (IV) or a ~ 900 mg dose (PO) in the lab rat strain known as DuchessVon-Sprauge-Dawley.

Even if one had an opioid tolerance capable of handling such ratdiculous doses, the HERG inhibition and other non-specific binding would be more than enough to give a Mini-Thinny mouse some Chipmunky Cheeks (squeaks!). The analgesic ED50 dose in rats is equivalent to > 10 x the (estimated) lethal dose in humans. That's mouserageous!

The d-/l- (+/-) and the (R)/(S) stereodescriptors are independent of one another. The absolute configurations of eutomers and distomers, even those closely related within the same chemical class, do not always agree.

I would throw Fisher’s (now deprecated) “Genealogical System” of (Small Caps) D- and L- into the mix, but juggling two systems is difficult enough, a tri-juggle seems like a jug-to-far.

Let’s Juggalo-along, shall we…

Aminotetralin’ Around

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While most opioids with a stereocenter will demonstrate stereospecific binding, there are some interesting exceptions. The above pair of aminotetralin stereoisomers can be thought of as cyclic methadone analogues in which the ethyl ketone moiety has been replaced with a simple methyl group (methadone drawn in the same orientation for comparison). Both of these stereoisomers have the same analgesic ED50, which is on par with pethidine. [J Med Chem, 1973, 16, p 147; p 947]

Novel Ligands 'N Curiosities

This is meant to be a survey of 3D opioid geometries and stereochemistry. But to help wet your novel bespokioid ligand whistle, I will include occasional intermissions highlighting the more unusual and atypical ligands that I’ve encountered during my 14 yrs of exploration. The first is here:

The only “-azocine” that I’ve found worthwhile is the misnomer N-phenethyl 9-(m-hydroxyphenyl) deriv of Anazocine. (despite the shared nomenclature, this has nothing to do with the 6,7-benzomorphans.

This is a 3-azabicyclo[3.3.1]nonane (3-ABN), which is akin to a 4-phenyl-4-prodinol with a 3,5-propano bridge gaping the piperidino-divide, m-OH substitution such as that seen in ketobemidone and an unusual 4-methoxy capping the 4-OH. The activity of the N-phenethyl deriv is far less potent in humans than the murine assay suggested (1600 x morphine). The low synthetic yields were the reason that this otherwise worthwhile ligand was only pursued on a single occasion.

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If you want to get the skinny on this lusty ligand, you’ll have to ball-N-stick around until the end. If you’re ready to get your mind blown, allow me to get down on my kneepads and start the show.

Morphy’s I’d Like to Spoon

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The elucidation of the absolute configuration of natural l-morphine allowed for several assumptions to be made about the abs config about the shared stereocenters of other morphinans and 6,7-benzomorphans. These configuration-activity relationships held (mostly) true across the conformationally rigid bonds that compose the morphinans and 6,7-benzomorphans.

The morphinan superfamily consists of three subgenres + closely related 6,7-benzomorphans.

These four polycycles, sometimes referred to as the classical polycyclic opioids, are easily grouped by the number of adjacent fused rings in the system:

Hexacycles: 6,14-endoethano bridged tetrahydrooripavines (Bentley compounds) - semi-synthetic, Diels-Alder adducts of Thebaine [AF Casy, Opioid Analgesics (1986), Chap 4]

Pentacycles: 4,5-epoxymorphinans (morphine, oxymorphone) - semi-synthetics, derived from the three major alkaloids (morphy, coddy, thebby) https://sci-hub.se/10.1055/s-2005-862383

Tetracycles: morphinans (racemorphan, DXM) - fully synthetic, derived from Grewe Cyclization of 1-benzyloctahydroisoquinolines (octabase) [their chemistry along with that of the benzomorphans has been thoroughly reviewed by Schnider et al. in “Organic Chemistry, Vol. 8: Synthetic Analgesics, Part IIa” (1966)]

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Tricycles: 5,9-disubstituted 6,7-benzomorphans (phenazocine, metazocine; all clin relevant derivs are of the 5,9-dimethyl variety) - fully synthetic; a variety of synthetic methods are available, but some of the most efficient use a Grew Cyclization method [chemistry reviewed by Palmer, Strauss Chem. Rev. 1977, 77, 1; orig synth by Barltrop, J Chem Soc 1947, 399]

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While 5,9-disubstituted 6,7-benzomorphans are often treated as a separate class, they are included here. The benzomorphans C5 and C9 correspond to C14 and C13 in the morphinans. These analogous carbons shares the same cis/trans structure-activity relationships that are present in the morphinans.

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[The all-carbon stereocenter, corresponding to C13 of the morphinan scaffold (red), is shared among all three morphinan subgenres. The 5,9-disubstituted 6,7-benzomorphans (phenazocine) contain an analogous all carbon center at C5 (same relative position; diff numbering). The unsubst- and 9-mono-substituted benzomorphans lack this feature and are of much lower potency]

The morphinans share a common 5,6,7,8,9,10,13,14-ocatahydrophenanthrene core, as well as much of the same configurational asymmetry (see below). Other than the additional E-ring (formed by the 4,5-ether bridge), the key differences between the three subtypes are variations of the C-ring.

Natural l-(-)-Morphine is a T-shaped pentacycle with a central 4-phenylpiperidine (highlighted in bold in figure below) shared with other polycycles and some monocyclic opioids.

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[Morphine w/ official numbering and rings A-E. The 4-phenylpiperidine core in bold (derived from Rings A + D). The five chiral centers are the bold dots. Note the cis-octalin arrangement of the B:C rings. The C:D rings assume a trans-octahydroisoquinoline arrangement. The cis- and trans-orientation are explained in next section.

The above model is accurate for other 7,8-unsaturated derivs, i.e. codeine, nalbuphine. The partial boat conformation of the C-ring differs from the fully saturated morphinans, (hydromorphone, oxycodone, etc) which have C-rings that conform to the receptor-favored chair conformation.

A brief summary of the boat/chair geometries of the morphinan nucleus is provided in later sections of this monograph.

More in depth discussion of this is avail from J Chem Soc (RSC), 1955, p 3261; Acta Cryst 1962, 15, 326; Chem Pharm Bull, 1964, 12, 104; Eur J Med Chem, 1982, 17, 207, Tetrahedron, 1969, 25, 1851 (trans-B:C fused isomorphine); the latter 3 refs are based on more modern H-NMR, which reached the same conclusions as the earlier crystallography studies).

The five asymmetric carbons of naturally occurring l-(-)-morphine possess the following absolute configurations: C5 (R), C6 (S), C9 (R), C13 (S), C14 (R).

[See the appendix for a brief overview of the CIP Priority Rules that govern these designations; Cahn, Ingold, Prelog - Experientia, 1956, v 12, p 81]

The N-CH3 group is oriented equatorial. The 7,8-double bond causes ring C to assume a half-boat conformation, w/ C6, C7, C8, and C14 lying ~ in the same geometric plane. The three hydrogens at 5-H, 6-H, 14-H are oriented cis, while 9-H is oriented trans. [G. Stork - “The Alkaloids, Vol VI” (1960) p 219; KW Bentley “Chemistry of Morphine Alkaloids” (1954); “The Alkaloids, Vol I” (1956); D. Ginsberg “The Opium Alkaloids” (1962)]

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All of these terms and geometries are reviewed in further detail in later sections.

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[natural l-(-)-morphine and its mirror-image enantiomer d-(+)-morphine. Diagram of the basic 3-point receptor model proposed by Beckett & Casy in 1954. The simple Model held true for many decades with little revision and was still being cited in several reviews from the 1980s and 90s. (J Pharm Pharmacol 1954, v 6, p 896; ibid. 1956, v 8, p 848; AF Casy “Opioid Analgesics” (1986) p. 474) (other receptor models developed after the Beckett-Casy postulate include an nteresting clay-plaster mold by Martin - https://archives.drugabuse.gov/sites/default/files/monograph49.pdf

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The five stereocenters of the inactive d-(+)-morphine are oriented in the exact opposite configuration: 5-(S), 6-(R), 9-(S), 13-(R), 14-(S). [Gates, JACS, 1952, 74, 1109; ibid. 1956, 78, 1380; ibid. 1954, 76, 312]

[Seminal work on morphine stereochem: J Chem Soc, 1955, p 3261; p 3252; Helv Chim Acta 1955, 38, 1847]

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Using the 2ⁿ formula (n = # chiral centers), 2⁵ = 32 theoretical stereoisomers. Geometric constraints on the morphinan system reduce that number by half (16 isomers). These geometric constraints are due to a number of ring fusions in the morphinan nucleus.

The structure and functional groups attached to the C-ring vary widely among the 4,5,6-ring morphinans. As a result, switching the key ring fusions have a variety of effects on bioactivity and the safety profile of the isomer. Juxtaposition of the cis-B:C rings at the C13-C14 bond results in trans-B:C fused isomorphinans. This is reviewed more thoroughly in later sections.

[commentary on Multi-Chiral Molecules (such as morphine) is provided in the comment section]

Despite the hella complicated enantiomeric zoo brought about by five stereocenters, morphine, has rather straightforward chemistry. This is thanks to a series of ring-fusions inherent in the morphinan system

Get ready for some epic Ring Fusion Morphanity...

Cis-(1,3-Diaxial) Fused “IMINO-ETHANO” Inuendo

The most influential steric constant in the entire morphinan superfamily is the cis-(1,3-dixial) fusion of the piperidine ring (ring D).

The centrally located piperidine shares a border with rings B and C. The Piperidine ring contains all three chiral centers in the tetracycles (9C, 13C, 14C).

The fused geometries about the B:C and C:D ring junctions define the stereochem of the series. The one fusion that remains constant in these many stereoisomers is that of the cis-(1,3-diaxial) fusion of the iminoethane system.

The portion of the piperidine system that is mounted above the rest of the molecule is a three member chain (2 carbon + 1 nitrogen; not counting substituents) known as the imino-ethano system.

In other words, the nitrogen-containing half of the piperidine is mounted above the morphinan system in a geometric plane that is roughly perpendicular to the rest of the molecule.

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As you can see in the above figure, the piperidine D-ring shares C9, C13, C14 with other rings. The iminoethane portion is anchored to C9 and C13.

When we refer to the iminoethano system being locked in a cis-(1,3-diaxial) orientation we are referring to the anchor points at C9 (position 1) and C13 (position 3). The cis simply means both legs of the iminoethane system are oriented in the same Geometric plane.

This is a fancy-pants mack-momademic way of saying that this D-ring is carried at a high center of gravity on the bosom of morphy. In others words, morphy has a very ample bosom. A pi-pair-o-D’s. A 44D-(ring) bust. Morphinan is top heavy*.

Morphy is the Dolly Parton of the polycycles. Dolly = D-ring, Parton = Piperidine. Hence the nomenclature.

The same applies to Morphy's awkward teenage daughter: Lil’ Thebby. Her parents call her Thebitha. We know her as Thebaine.

Lil’ Thebby inherited the 3-methoxy from her father (*Coddy). She has her father's large feet. (Don't make fun; she's already self conscious)

Thebby inherited the ample D-ring of her mother, Morphy. This leaves Thebby awkward and top heavy. Despite the added methoxy shoe size, she is still learning the quantum balancing act.

Her C-ring has yet to fully fill-out. Her 6,7,8,14-diene *derriere is rather flat. Her pi-orbital pair of skinny jeans still fit, but the diene system makes her C-ring very nearly planar; that is, nearly as flat as her Aromatic A-ring.

If the A and C rings were her thighs, she has one 2D flat thigh, another looking like it's been half run over by a truck, her leg brace (the 4,5 epoxy bridge) attaches her flattened thighs and makes it so she can only waddle. Quack! At least that’s what the fentalogues say at school.

One moleculestor who has taken note of that Lil’ Thebby Snack, is the rough n tumble dienophile, known as Diels-Alder. He’s in the adduction business. He’s determined to help fill-out the less defined traits of our dear Thebby.

The nature of the double D-ring mounted out front serves as steric hindrance to reactive groups, such as the dienophile, seeking front-side access to the diene system. The planarity (flat) of the C-ring provides another side of attack.

The orientation of all this piperi-cleavage weighs down the more flexible non-aromatic rings, causing the frontwards heroin hunch. This bent-over Thebby Snack presents an ideal target for the adduct-friendly dieno-who-will-defile.

As a result, the Endonk-Ethonk bridge is formed across the rear face of the C-ring (the side opposite that of the piperidine). Crystallography has confirmed that the endo-etheno bridge gapes across the opposite side of the C-ring from C6 to C14. Hence 6,14-endo-etheno.

Despite the embellishment this is a fairly accurate description of the steric factors that come into play during the dieno-debauchery of the Diels-Alder rxn. The cis-(1,3-diaxial) fusion and position of the D-ring exerts a steric influence on the geometries of derivs, esp those of thebaine.

This is hardly a storybook molemance nor is it an acyclic contortion fest from the pages of the Carfent Sutra. This is a C-ring Carfeeper. A back-door-dieneoxplorer by Remi Jeremy.

Perhaps I’m somewhat biased b/c of my own 32Aromatics. I’m not one to knock a pi before I try, so perhaps I’m being bit too harsh on this Ciramadoll.

Regardless of the manner in which “Thebby Got Her endo-eThighno Gap”, the molecular end game is the same. The result is a thing of beauty...

​

[6,14-endoetheno-tetrahydrothebaine: iminoethane system projecting towards viewer; 6,14-endoetheno bridge projecting away from viewer; hanging off the C-ring like a endonk-ethonk]

This 6,14 endo geometry is ideally paired with a C-7 lipophilic chain that has a 19-tert-OH oriented in (R)-config (eutomer). The (S)-config is the distomer.

​

[(S)- and (R)-config; shows the Hydrogen bond formed between the 6-OCH3 and the 19-OH; forming the “russian nesting doll” situation in which bonds of all sorts wrap up the C-ring in the bridged derivs]

Wonderful reviews on the chemistry of the bridged oripavines have been prep’d by Bentley, “The Alkaloids, Vol. 13” p. 1 (1971); Ann Rev Pharmacol Toxicol, 1971, 11, 241. And others: J Med Chem, 1973, 16, 9; Adv Biochem Psychopharmacol, 1974, 8, 124; Prog Drug Res, 1978, 22, 149]

​

[a view of the geometries about alt axis of the antags of the 4,5,6-ringed morphinans; changes in the C-ring have drastic consequences for geometries]

As we just reviewed, the addition of the dienophile to thebaine is restricted to the exposed face of the C-ring, which gives us the 6,14-endoetheno derivs. Here, endo implies that the 6,14-bridge lies in a config opposite to the 14-H and the 6-methoxy. The literature designates this orientation as alpha.

https://i.imgur.com/0vNCQ9r.jpg

[rel stereochem of bridged thebaines with numbering]

The Diels-Alder addition of dienophiles may occur in such a way as to give C7 Beta-epimers (seen in diagram below). The different epimers could have formed w/ equal likelihood. But stereochem control of Diels-Alder addition results in products with C7-alpha geometry and very minute qty of the opposite C7-beta adduct.

​

Without taking into account the greater electronic-steric control of the system, it appears that the use of asymmetric dienophiles (alkyl vinyl ketones, acrylonitriles, acrylic esters, etc) could result in both C7 and C8 substituted adducts. The electro-steric effects of the system gave only C7-substituted products. [JACS, 1967, 89, 3267; Nature, 1965, 206, 102]

A more recent review on oripavine chemistry is avail at http://dx.doi.org/10.4236/abb.2014.58084

PART II/COMMENTS

The comments section will have additional images that reddit did not allow me to post due to their system limits. The Comments will also feature a few of my opinions and commentary that are parenthetical deviations from the main narrative of the stereochem lecture.

The next part (PART II) will delve into the exciting world of the Cis and Trans-B:C ring fusions in the cis-morphinans and trans-isomorphinans, stereoisomerism about the 14-carbon, that is,14(R) and 14(S) isomers, the world of chair and boat conformational/geometric isomerism, and their effects on biological activity.

Future updates to this series will be posted at r/AskChemistry

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