Marker degradation

Synthetic route in steroid chemistry

The Marker degradation is a three-step synthetic route in steroid chemistry developed by American chemist Russell Earl Marker in 1938–1940. It is used for the production of cortisone and mammalian sex hormones (progesterone, estradiol, etc.) from plant steroids, and established Mexico as a world center for steroid production in the years immediately after World War II.[1] The discovery of the Marker degradation allowed the production of substantial quantities of steroid hormones for the first time, and was fundamental in the development of the contraceptive pill and corticosteroid anti-inflammatory drugs. In 1999, the American Chemical Society and the Sociedad Química de México named the route as an International Historic Chemical Landmark.[1]

The first large-scale application of the route took place in 1943, when Russell Earl Marker collected 10 tons of yam tubers to synthesize 3 kilograms (6.6 lb) of progesterone, which was the largest single amount of progesterone that had been produced by that time.[1] That single batch had a value of US$240,000 (approximately $3 million in 2009[2]) at the time it was synthesized.[1]

The discovery of the Marker degradation led to the development of a fine chemical industry in Mexico which, starting from scratch and in less than ten years, supplied more than half the human sex hormones sold in the United States. The booming industry caused a huge expansion in chemical education in Mexico.

## Early development

[edit]

Marker's research at Pennsylvania State College (now Pennsylvania State University) was directed towards finding synthetic routes to steroid hormones from "relatively inexpensive starting materials".[3] While working on a series of plant steroids called sapogenins, he realized that the structure of the side chain[note 1] of one of the compounds, sarsasapogenin, had been incorrectly described in the literature: rather than having an unreactive "double-tetrahydrofuran" side chain, it actually had a much more reactive "ketone spiro acetal" side chain.[3] While the ketone spiro acetal was unreactive in basic or neutral conditions, it could be degraded under acidic conditions: indeed, Marker described it as "unusually reactive".[3] In showing the true nature of the sarsasapogenin side chain, Marker had discovered the first of the steps in what would become known as the Marker degradation.

Sarsasapogenin was too expensive to be a commercial precursor to other steroids, so Marker set about looking for richer sources of sapogenins which were more closely related to progesterone. He identified one candidate in Trillium erectum ("Beth root" or "Wake-robin"), a sapogenin called diosgenin which had previously been found in Japanese yams (Dioscorea tokoro).[1][4] Marker showed that both sarsasapogenin and diosgenin could be converted into both progesterone[5] and other steroid hormones.[6][note 2] The quantities of diosgenin that could be extracted from T. erectum were still unsatisfactory, so Marker looked for richer sources. He eventually hit upon another species of Dioscorea, a Mexican yam known locally as cabeza de negro,[note 3] whose tubers were reported to grow up to 100 kg (220 lbs) in weight.[1]

## Route from diosgenin

[edit]

As with much steroid chemistry, the Marker degradation relies heavily on kinetic control to degrade the sapogenin side chain while leaving similar functional groups on the steroid nucleus (relatively) unaffected.

The first step is the reaction that led Marker to discover that the sapogenins had a ketone spiro acetal structure in their side chain.[7] Acetals are inert in basic conditions, but can be hydrolysed in acidic conditions. Marker uses acetic anhydride to block the hydroxyl group formed by opening the six-membered pyran ring.[8]

The five-membered furan ring is then oxidatively opened with chromic acid. This forms the acetyl side chain of progesterone and an esterified hydroxyl group on the steroid nucleus.

The ester is then hydrolyzed under strongly basic conditions. The use of ethanolic sodium hydroxide leads to the elimination of water to form a double bond.

The result in this 1939 version of Marker degradation is 16-dehydropregnenolone (3-hydroxypregna-5,16-dien-20-one, 16-DP).[5] In 1940, the final hydrolysis step was changed to use acetic acid, producing the more familiar 16-dehydropregnenolone acetate (16-DPA).[9]

### Downstream products

[edit]

Further information: 16-Dehydropregnenolone acetate § Downstream products

16-DP can be converted into progesterone in two steps. Firstly, the double bond in ring D is hydrogenated, followed by Oppenauer oxidation of the hydroxyl group and the concurrent migration of the remaining olefin from ring B to ring A so that it is in conjugation with the ketone carbonyl group at position 3.[5] Alternatively, a three-step procedure involving Br2, CrO3, and Zn/HOAc is used.[1]

The 16-DP can also be converted into testosterone and the downstream products estrone and estradiol.[1][6]

## Mexican steroid industry

[edit]

Further information: Mexican barbasco trade

Marker's early developmental work was supported by Parke-Davis, a leading American pharmaceutical company now part of Pfizer.[1] However, Marker realized that it made more sense commercially to produce steroids in Mexico, near to the raw material (Mexican Dioscorea sp.; D. composita would come to be the preferred species[1]), than to ship the tubers back to the United States. Parke-Davis did not believe that it was scientifically feasible to operate a fine chemicals production facility in Mexico, and the collaboration foundered.[1] Instead, Marker decided to look for Mexican partners himself, and resigned his academic post on December 1, 1943.[1] One consequence of this split was that the Marker degradation was never patented.[1]

Marker set up the Mexican company Syntex[note 4] in early 1944 in association with two Mexican investors, Emeric Somlo and Federico Lehmann. Marker is said to have partly paid for his 40% stake in Syntex with progesterone,[1] then valued at about $80/gram.[1] Within the year, Syntex was selling progesterone for $50/gram.[1] However Marker split with his partners in May 1945 in a row over profits, and set up a new company called Botanica-mex, which would later be sold to Gedeon Richter Ltd. and renamed Hormonosynth (later Diosynth).[1]

The difficulties in fine chemicals manufacture in Mexico were indeed considerable: there was a severe shortage of trained chemists and indeed no doctoral program in chemistry at any Mexican university. When Marker left Syntex, his associates found no instructions for the production process and reagent bottles labeled in code.[1] They hired George Rosenkranz, a Hungarian organic chemist trained at ETH Zurich (the Swiss Federal Institute of Technology) who had been stranded in Cuba by the entry of the United States into World War II, to replace Marker.[1] Rosenkranz would have to virtually reinvent the production process for progesterone from diosgenin: he also established an Institute of Chemistry at the National Autonomous University of Mexico,[1] where one of the first research students was Luis E. Miramontes, later to become a pivotal researcher at Syntex.

Rosenkranz also hired foreign talent for Syntex, including the Austrian Jewish refugee (and naturalized American) Carl Djerassi and the Uruguayan Alejandro Zaffaroni. In 1951, Djerassi, Miramontes and Rosencranz synthesized norethisterone at Syntex, the first orally active progesterone analog and a vital ingredient of the first oral contraceptive pills.[10] By this time, Syntex and its Mexican competitors (including Percy Lavon Julian, the first African-American chemist inducted into the U.S. National Academy of Sciences) were supplying more than half the human sex hormones sold in the United States,[note 5] and the price of progesterone had dropped to $2/gram.[1] Fortune ran a story that same year (1951) headlined "Syntex makes the biggest technological boom ever heard south of the border": by 1999, and with the benefit of hindsight, this was considered to be an understatement by the American Chemical Society, not least because of the truly global impact of the Syntex production and research.[1] The impact of the Syntex research can be seen from in the authoritative 1959 monograph Steroids by Louis and Mary Fieser:[11] Syntex accounted for 30% of all papers cited from industrial laboratories.[1] In 1959, Syntex redomesticated itself as a Panama corporation and relocated its headquarters to Palo Alto, California, United States.[12]

## Notes and references

[edit]

### Notes

[edit]

1. ^ Steroids are characterized by four fused rings of carbon atoms (three six-membered rings and one five-membered ring). Many steroids also have a "side chain" of carbon atoms, usually attached to the five-membered ring.
2. ^ Although it wasn't known at the time, the use of progesterone as a precursor for other steroid hormones closely mimics the biosynthetic pathway. Human males synthesize progesterone as a precursor to testosterone, and human females synthesize testosterone as a precursor to the various estrogens. Cortisone is also synthesized from progesterone in the human body, as in the industrial process developed after the discovery of the Marker degradation.
3. ^ Not to be confused with the fruit known as cabeza de negro or ilama (Annona purpurea).
4. ^ Now part of Hoffmann-La Roche.
5. ^ The availability of (relatively) cheap progesterone in (relatively) large quantities created a market, and had the effect of spurring other manufacturers to improve their production processes for steroid hormones: this is best seen in the case of cortisone, where Merck's original 36-step synthesis from ox bile was improved to remain competitive with cortisone prepared from Mexican yams.

### References

[edit]

1. ^ a b c d e f g h i j k l m n o p q r s t u v w "Russell Marker and the Mexican Steroid Hormone Industry". American Chemical Society. Retrieved June 5, 2012.
2. ^ "The Inflation Calculator". Archived from the original on 2011-07-18. Retrieved 2010-03-06.
3. ^ a b c Marker, Russell E.; Rohrmann, Ewald (1939), "Sterols. LIII. The Structure of the Side Chain of Sarsasapogenin", J. Am. Chem. Soc., 61 (4): 846–51, doi:10.1021/ja01873a020.
4. ^ Tsukamoto; Ueno; Ohta (1936), "Glycosides of Dioscorea tokoro I. Diocin, dioscoreasapooxin and diosgenin", Journal of Pharmaceutical Society Japan, 56: 135. Tsukamoto; Ueno; Ohta (1937), "Über die Konstitution des Diosgenins II", Yakugaku Zasshi, 57 (11): 985, doi:10.1248/yakushi1881.57.11_985.
5. ^ a b c Marker, Russell E.; Rohrmann, Ewald (1939), "Sterols. LXXXI. Conversion of Sarsasapogenin to Pregnanediol-3(α),20(α)", J. Am. Chem. Soc., 61 (12): 3592–93, doi:10.1021/ja01267a513. Marker, Russell E.; Rohrmann, Ewald (1940), "Sterols. LXXXVIII. Pregnanediols from Sarsasapogenin", J. Am. Chem. Soc., 62 (3): 518–20, doi:10.1021/ja01860a017. Marker, Russell E.; Tsukamoto, Takeo; Turner, D. L. (1940), "Sterols. C. Diosgenin", J. Am. Chem. Soc., 62 (9): 2525–32, doi:10.1021/ja01866a072.
6. ^ a b Marker, Russell E. (1940), "Sterols. CV. The Preparation of Testosterone and Related Compounds from Sarsasapogenin and Diosgenin", J. Am. Chem. Soc., 62 (9): 2543–47, doi:10.1021/ja01866a077.
7. ^ Myers, Rusty L.; Myers, Richard L. (2007), The 100 most important chemical compounds: a reference guide, Westport, Conn: Greenwood Press, pp. 205–8, ISBN 978-0-313-33758-1.
8. ^ Dewick, P. M. (2009), Medicinal natural products: a biosynthetic approach, New York: Wiley, pp. 281–83, ISBN 978-0-470-74167-2.
9. ^ Marker RE, Krueger J (1940). "Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone". J. Am. Chem. Soc. 62 (12): 3349–3350. doi:10.1021/ja01869a023.
10. ^ US 2744122, Djerassi, Carl; Miramontes, Luis & Rosenkranz, George, "Δ4-19-nor-17α-ethinylandrosten-17β-ol-3-one and process", published 1956-05-10, assigned to Syntex .
11. ^ Fieser, Louis F.; Fieser, Mary P. (1959), Steroids, New York: Van Nostrand Reinhold, ISBN 0-278-91709-7.
12. ^ Gereffi, Gary (1983). The Pharmaceutical Industry and Dependency in the Third World (2017 reprint ed.). Princeton University Press: Princeton. p. 110\. ISBN 9781400886227. Retrieved 11 January 2021.

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Topics in organic reactions

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List of organic reactions

Carbon-carbon
bond forming
reactions|

* Acetoacetic ester synthesis
* Acyloin condensation
* Aldol condensation
* Aldol reaction
* Alkane metathesis
* Alkyne metathesis
* Alkyne trimerisation
* Alkynylation
* Allan–Robinson reaction
* Arndt–Eistert reaction
* Auwers synthesis
* Aza-Baylis–Hillman reaction
* Barbier reaction
* Barton–Kellogg reaction
* Baylis–Hillman reaction
* Benary reaction
* Bergman cyclization
* Biginelli reaction
* Bingel reaction
* Blaise ketone synthesis
* Blaise reaction
* Blanc chloromethylation
* Bodroux–Chichibabin aldehyde synthesis
* Bouveault aldehyde synthesis
* Bucherer–Bergs reaction
* Buchner ring expansion
* Cadiot–Chodkiewicz coupling
* Carbonyl allylation
* Carbonyl olefin metathesis
* Castro–Stephens coupling
* Chan rearrangement
* Chan–Lam coupling
* Claisen condensation
* Claisen rearrangement
* Claisen-Schmidt condensation
* Combes quinoline synthesis
* Corey–Fuchs reaction
* Corey–House synthesis
* Coupling reaction
* Cross-coupling reaction
* Cross dehydrogenative coupling
* Cross-coupling partner
* Dakin–West reaction
* Darzens reaction
* Diels–Alder reaction
* Doebner reaction
* Wulff–Dötz reaction
* Ene reaction
* Enyne metathesis
* Ethenolysis
* Favorskii reaction
* Ferrier carbocyclization
* Friedel–Crafts reaction
* Fujimoto–Belleau reaction
* Fujiwara–Moritani reaction
* Fukuyama coupling
* Gabriel–Colman rearrangement
* Gattermann reaction
* Glaser coupling
* Grignard reaction
* Grignard reagent
* Hammick reaction
* Heck reaction
* Henry reaction
* Heterogeneous metal catalyzed cross-coupling
* High dilution principle
* Hiyama coupling
* Homologation reaction
* Horner–Wadsworth–Emmons reaction
* Hydrocyanation
* Hydrovinylation
* Hydroxymethylation
* Ivanov reaction
* Johnson–Corey–Chaykovsky reaction
* Julia olefination
* Julia–Kocienski olefination
* Kauffmann olefination
* Knoevenagel condensation
* Knorr pyrrole synthesis
* Kolbe–Schmitt reaction
* Kowalski ester homologation
* Kulinkovich reaction
* Kumada coupling
* Liebeskind–Srogl coupling
* Malonic ester synthesis
* Mannich reaction
* McMurry reaction
* Meerwein arylation
* Methylenation
* Michael reaction
* Minisci reaction
* Mizoroki-Heck vs. Reductive Heck
* Nef isocyanide reaction
* Nef synthesis
* Negishi coupling
* Nierenstein reaction
* Nitro-Mannich reaction
* Nozaki–Hiyama–Kishi reaction
* Olefin conversion technology
* Olefin metathesis
* Palladium–NHC complex
* Passerini reaction
* Peterson olefination
* Pfitzinger reaction
* Piancatelli rearrangement
* Pinacol coupling reaction
* Prins reaction
* Quelet reaction
* Ramberg–Bäcklund reaction
* Rauhut–Currier reaction
* Reformatsky reaction
* Reimer–Tiemann reaction
* Rieche formylation
* Ring-closing metathesis
* Robinson annulation
* Sakurai reaction
* Seyferth–Gilbert homologation
* Shapiro reaction
* Sonogashira coupling
* Stetter reaction
* Stille reaction
* Stollé synthesis
* Stork enamine alkylation
* Suzuki reaction
* Takai olefination
* Thermal rearrangement of aromatic hydrocarbons
* Thorpe reaction
* Ugi reaction
* Ullmann reaction
* Wagner-Jauregg reaction
* Weinreb ketone synthesis
* Wittig reaction
* Wurtz reaction
* Wurtz–Fittig reaction
* Zincke–Suhl reaction

| Homologation reactions|

* Arndt–Eistert reaction
* Hooker reaction
* Kiliani–Fischer synthesis
* Kowalski ester homologation
* Methoxymethylenetriphenylphosphorane
* Seyferth–Gilbert homologation
* Wittig reaction

|

Olefination reactions|

* Bamford–Stevens reaction
* Barton–Kellogg reaction
* Boord olefin synthesis
* Chugaev elimination
* Cope reaction
* Corey–Winter olefin synthesis
* Dehydrohalogenation
* Elimination reaction
* Grieco elimination
* Hofmann elimination
* Horner–Wadsworth–Emmons reaction
* Hydrazone iodination
* Julia olefination
* Julia–Kocienski olefination
* Kauffmann olefination
* McMurry reaction
* Peterson olefination
* Ramberg–Bäcklund reaction
* Shapiro reaction
* Takai olefination
* Wittig reaction

Carbon-heteroatom
bond forming
reactions|

* Azo coupling
* Bartoli indole synthesis
* Boudouard reaction
* Cadogan–Sundberg indole synthesis
* Diazonium compound
* Esterification
* Grignard reagent
* Haloform reaction
* Hegedus indole synthesis
* Hurd–Mori 1,2,3-thiadiazole synthesis
* Kharasch–Sosnovsky reaction
* Knorr pyrrole synthesis
* Leimgruber–Batcho indole synthesis
* Mukaiyama hydration
* Nenitzescu indole synthesis
* Oxymercuration reaction
* Reed reaction
* Schotten–Baumann reaction
* Ullmann condensation
* Williamson ether synthesis
* Yamaguchi esterification

Degradation
reactions|

* Barbier–Wieland degradation
* Bergmann degradation
* Edman degradation
* Emde degradation
* Gallagher–Hollander degradation
* Hofmann rearrangement
* Hooker reaction
* Isosaccharinic acid
* Marker degradation
* Ruff degradation
* Strecker degradation
* Von Braun amide degradation
* Weerman degradation
* Wohl degradation

Organic redox
reactions|

* Acyloin condensation
* Adkins–Peterson reaction
* Akabori amino-acid reaction
* Alcohol oxidation
* Algar–Flynn–Oyamada reaction
* Amide reduction
* Andrussow process
* Angeli–Rimini reaction
* Aromatization
* Autoxidation
* Baeyer–Villiger oxidation
* Barton–McCombie deoxygenation
* Bechamp reduction
* Benkeser reaction
* Bergmann degradation
* Birch reduction
* Bohn–Schmidt reaction
* Bosch reaction
* Bouveault–Blanc reduction
* Boyland–Sims oxidation
* Cannizzaro reaction
* Carbonyl reduction
* Clemmensen reduction
* Collins oxidation
* Corey–Itsuno reduction
* Corey–Kim oxidation
* Corey–Winter olefin synthesis
* Criegee oxidation
* Dakin oxidation
* Davis oxidation
* Deoxygenation
* Dess–Martin oxidation
* DNA oxidation
* Elbs persulfate oxidation
* Emde degradation
* Eschweiler–Clarke reaction
* Étard reaction
* Fischer–Tropsch process
* Fleming–Tamao oxidation
* Fukuyama reduction
* Ganem oxidation
* Glycol cleavage
* Griesbaum coozonolysis
* Grundmann aldehyde synthesis
* Haloform reaction
* Hydrogenation
* Hydrogenolysis
* Hydroxylation
* Jones oxidation
* Kiliani–Fischer synthesis
* Kolbe electrolysis
* Kornblum oxidation
* Kornblum–DeLaMare rearrangement
* Leuckart reaction
* Ley oxidation
* Lindgren oxidation
* Lipid peroxidation
* Lombardo methylenation
* Luche reduction
* Markó–Lam deoxygenation
* McFadyen–Stevens reaction
* Meerwein–Ponndorf–Verley reduction
* Methionine sulfoxide
* Miyaura borylation
* Mozingo reduction
* Noyori asymmetric hydrogenation
* Omega oxidation
* Oppenauer oxidation
* Oxygen rebound mechanism
* Ozonolysis
* Parikh–Doering oxidation
* Pinnick oxidation
* Prévost reaction
* Reduction of nitro compounds
* Reductive amination
* Riley oxidation
* Rosenmund reduction
* Rubottom oxidation
* Sabatier reaction
* Sarett oxidation
* Selenoxide elimination
* Shapiro reaction
* Sharpless asymmetric dihydroxylation
* Epoxidation of allylic alcohols
* Sharpless epoxidation
* Sharpless oxyamination
* Stahl oxidation
* Staudinger reaction
* Stephen aldehyde synthesis
* Swern oxidation
* Transfer hydrogenation
* Wacker process
* Wharton reaction
* Whiting reaction
* Wohl–Aue reaction
* Wolff–Kishner reduction
* Wolffenstein–Böters reaction
* Zinin reaction

Rearrangement
reactions|

* 1,2-rearrangement
* 1,2-Wittig rearrangement
* 2,3-sigmatropic rearrangement
* 2,3-Wittig rearrangement
* Achmatowicz reaction
* Alkyne zipper reaction
* Allen–Millar–Trippett rearrangement
* Allylic rearrangement
* Alpha-ketol rearrangement
* Amadori rearrangement
* Arndt–Eistert reaction
* Aza-Cope rearrangement
* Baker–Venkataraman rearrangement
* Bamberger rearrangement
* Banert cascade
* Beckmann rearrangement
* Benzilic acid rearrangement
* Bergman cyclization
* Bergmann degradation
* Boekelheide reaction
* Brook rearrangement
* Buchner ring expansion
* Carroll rearrangement
* Chan rearrangement
* Claisen rearrangement
* Cope rearrangement
* Corey–Fuchs reaction
* Cornforth rearrangement
* Criegee rearrangement
* Curtius rearrangement
* Demjanov rearrangement
* Di-π-methane rearrangement
* Dimroth rearrangement
* Divinylcyclopropane-cycloheptadiene rearrangement
* Dowd–Beckwith ring-expansion reaction
* Electrocyclic reaction
* Ene reaction
* Enyne metathesis
* Favorskii reaction
* Favorskii rearrangement
* Ferrier carbocyclization
* Ferrier rearrangement
* Fischer–Hepp rearrangement
* Fries rearrangement
* Fritsch–Buttenberg–Wiechell rearrangement
* Gabriel–Colman rearrangement
* Group transfer reaction
* Halogen dance rearrangement
* Hayashi rearrangement
* Hofmann rearrangement
* Hofmann–Martius rearrangement
* Ireland–Claisen rearrangement
* Jacobsen rearrangement
* Kornblum–DeLaMare rearrangement
* Kowalski ester homologation
* Lobry de Bruyn–Van Ekenstein transformation
* Lossen rearrangement
* McFadyen–Stevens reaction
* McLafferty rearrangement
* Meyer–Schuster rearrangement
* Mislow–Evans rearrangement
* Mumm rearrangement
* Myers allene synthesis
* Nazarov cyclization reaction
* Neber rearrangement
* Newman–Kwart rearrangement
* Overman rearrangement
* Oxy-Cope rearrangement
* Pericyclic reaction
* Piancatelli rearrangement
* Pinacol rearrangement
* Pummerer rearrangement
* Ramberg–Bäcklund reaction
* Ring expansion and contraction
* Ring-closing metathesis
* Rupe reaction
* Schmidt reaction
* Semipinacol rearrangement
* Seyferth–Gilbert homologation
* Sigmatropic reaction
* Skattebøl rearrangement
* Smiles rearrangement
* Sommelet–Hauser rearrangement
* Stevens rearrangement
* Stieglitz rearrangement
* Thermal rearrangement of aromatic hydrocarbons
* Tiffeneau–Demjanov rearrangement
* Vinylcyclopropane rearrangement
* Wagner–Meerwein rearrangement
* Wallach rearrangement
* Weerman degradation
* Westphalen–Lettré rearrangement
* Willgerodt rearrangement
* Wolff rearrangement

Ring forming
reactions|

* 1,3-Dipolar cycloaddition
* Annulation
* Azide-alkyne Huisgen cycloaddition
* Baeyer–Emmerling indole synthesis
* Bartoli indole synthesis
* Bergman cyclization
* Biginelli reaction
* Bischler–Möhlau indole synthesis
* Bischler–Napieralski reaction
* Blum–Ittah aziridine synthesis
* Bobbitt reaction
* Bohlmann–Rahtz pyridine synthesis
* Borsche–Drechsel cyclization
* Bucherer carbazole synthesis
* Bucherer–Bergs reaction
* Cadogan–Sundberg indole synthesis
* Camps quinoline synthesis
* Chichibabin pyridine synthesis
* Cook–Heilbron thiazole synthesis
* Cycloaddition
* Darzens reaction
* Davis–Beirut reaction
* De Kimpe aziridine synthesis
* Debus–Radziszewski imidazole synthesis
* Dieckmann condensation
* Diels–Alder reaction
* Feist–Benary synthesis
* Ferrario–Ackermann reaction
* Fiesselmann thiophene synthesis
* Fischer indole synthesis
* Fischer oxazole synthesis
* Friedländer synthesis
* Gewald reaction
* Graham reaction
* Hantzsch pyridine synthesis
* Hegedus indole synthesis
* Hemetsberger indole synthesis
* Hofmann–Löffler reaction
* Hurd–Mori 1,2,3-thiadiazole synthesis
* Iodolactonization
* Isay reaction
* Jacobsen epoxidation
* Johnson–Corey–Chaykovsky reaction
* Knorr pyrrole synthesis
* Knorr quinoline synthesis
* Kröhnke pyridine synthesis
* Kulinkovich reaction
* Larock indole synthesis
* Madelung synthesis
* Nazarov cyclization reaction
* Nenitzescu indole synthesis
* Niementowski quinazoline synthesis
* Niementowski quinoline synthesis
* Paal–Knorr synthesis
* Paternò–Büchi reaction
* Pechmann condensation
* Petrenko-Kritschenko piperidone synthesis
* Pictet–Spengler reaction
* Pomeranz–Fritsch reaction
* Prilezhaev reaction
* Pschorr cyclization
* Reissert indole synthesis
* Ring-closing metathesis
* Robinson annulation
* Sharpless epoxidation
* Simmons–Smith reaction
* Skraup reaction
* Urech hydantoin synthesis
* Van Leusen reaction
* Wenker synthesis

| Cycloaddition|

* 1,3-Dipolar cycloaddition
* 4+4 Photocycloaddition
* (4+3) cycloaddition
* 6+4 Cycloaddition
* Alkyne trimerisation
* Aza-Diels–Alder reaction
* Azide-alkyne Huisgen cycloaddition
* Bradsher cycloaddition
* Cheletropic reaction
* Conia-ene reaction
* Cyclopropanation
* Diazoalkane 1,3-dipolar cycloaddition
* Diels–Alder reaction
* Enone–alkene cycloadditions
* Hexadehydro Diels–Alder reaction
* Imine Diels–Alder reaction
* Intramolecular Diels–Alder cycloaddition
* Inverse electron-demand Diels–Alder reaction
* Ketene cycloaddition
* McCormack reaction
* Metal-centered cycloaddition reactions
* Nitrone-olefin (3+2) cycloaddition
* Oxo-Diels–Alder reaction
* Ozonolysis
* Pauson–Khand reaction
* Povarov reaction
* Prato reaction
* Retro-Diels–Alder reaction
* Staudinger synthesis
* Trimethylenemethane cycloaddition
* Vinylcyclopropane (5+2) cycloaddition
* Wagner-Jauregg reaction

|

Heterocycle forming reactions|

* Algar–Flynn–Oyamada reaction
* Allan–Robinson reaction
* Auwers synthesis
* Bamberger triazine synthesis
* Banert cascade
* Barton–Zard reaction
* Bernthsen acridine synthesis
* Bischler–Napieralski reaction
* Bobbitt reaction
* Boger pyridine synthesis
* Borsche–Drechsel cyclization
* Bucherer carbazole synthesis
* Bucherer–Bergs reaction
* Chichibabin pyridine synthesis
* Cook–Heilbron thiazole synthesis
* Diazoalkane 1,3-dipolar cycloaddition
* Einhorn–Brunner reaction
* Erlenmeyer–Plöchl azlactone and amino-acid synthesis
* Feist–Benary synthesis
* Fischer oxazole synthesis
* Gabriel–Colman rearrangement
* Gewald reaction
* Hantzsch ester
* Hantzsch pyridine synthesis
* Herz reaction
* Knorr pyrrole synthesis
* Kröhnke pyridine synthesis
* Lectka enantioselective beta-lactam synthesis
* Lehmstedt–Tanasescu reaction
* Niementowski quinazoline synthesis
* Nitrone-olefin (3+2) cycloaddition
* Paal–Knorr synthesis
* Pellizzari reaction
* Pictet–Spengler reaction
* Pomeranz–Fritsch reaction
* Prilezhaev reaction
* Robinson–Gabriel synthesis
* Stollé synthesis
* Urech hydantoin synthesis
* Wenker synthesis
* Wohl–Aue reaction

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