Editing Progesterone (section)

==Chemistry==
[[File:Sample of Progesterone.jpg|thumb|upright|right|A sample of progesterone]]
{{See also|List of neurosteroids}}

Progesterone is a [[natural product|naturally occurring]] [[pregnane]] [[steroid]] and is also known as pregn-4-ene-3,20-dione.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1024 |date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=1024–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory |url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA880 |date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=880–}}</ref> It has a [[double bond]] ([[-ene|4-ene]]) between the C4 and C5 positions and two [[ketone]] [[functional group|group]]s (3,20-[[diketone|dione]]), one at the C3 position and the other at the C20 position.<ref name="Elks2014" /><ref name="IndexNominum2000" />

===Synthesis===
Progesterone is commercially produced by semisynthesis. Two main routes are used: one from yam [[diosgenin]] first pioneered by Marker in 1940, and one based on soy [[phytosterol]]s scaled up in the 1970s.  Additional (not necessarily economical) semisyntheses of progesterone have also been reported starting from a variety of steroids. For the example, [[cortisone]] can be simultaneously deoxygenated at the C-17 and C-21 position by treatment with iodotrimethylsilane in [[chloroform]] to produce 11-keto-progesterone (ketogestin), which in turn can be reduced at position-11 to yield progesterone.<ref name="pmid3815593">{{cite journal | vauthors = Numazawa M, Nagaoka M, Kunitama Y | title = Regiospecific deoxygenation of the dihydroxyacetone moiety at C-17 of corticoid steroids with iodotrimethylsilane | journal = Chemical & Pharmaceutical Bulletin | volume = 34 | issue = 9 | pages = 3722–3726 | date = September 1986 | pmid = 3815593 | doi = 10.1248/cpb.34.3722 | doi-access = free }}</ref>

====Marker semisynthesis====
{{main|Marker degradation}}
An economical [[semisynthesis]] of progesterone from the plant steroid [[diosgenin]] isolated from yams was developed by [[Russell Earl Marker|Russell Marker]] in 1940 for the [[Parke-Davis]] pharmaceutical company.<ref name="Marker1940">{{cite journal |vauthors=Marker RE, Krueger J | title = Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone | journal = J. Am. Chem. Soc. | volume = 62 | issue = 12 | pages = 3349–3350 | year = 1940| doi = 10.1021/ja01869a023 | bibcode = 1940JAChS..62.3349M }}</ref> This synthesis is known as the [[Marker degradation]].
[[File:Marker snythesis.png|class=skin-invert-image|thumb|center|upright=3.65|The Marker [[semisynthesis]] of progesterone from [[diosgenin]].<ref name="Marker1940"/>]]

The [[16-DPA]] intermediate is important to the synthesis of many other medically important steroids. A very similar approach can produce 16-DPA from [[solanine]].<ref name="Goswami-2003">{{cite journal | vauthors = Goswami A, Kotoky R, Rastogi RC, Ghosh AC |title=A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate |journal=Organic Process Research & Development |date=1 May 2003 |volume=7 |issue=3 |pages=306–308 |doi=10.1021/op0200625}}</ref>

====Soy semisynthesis====
Progesterone can also be made from the [[stigmasterol]] found in [[soybean oil]] also. c.f. [[Percy Julian]].

[[File:Stigmasterol to progesterone synthesis.png|class=skin-invert-image|thumb| center |upright=3.65|[[Stigmasterol]] to progesterone synthesis.<ref name=Heyl>{{cite journal | vauthors = Heyl FW | title = Progesterone from 3-Acetoxybisnor-5-cholenaldehyde and 3-Ketobisnor-4-cholenaldehyde | journal = Journal of the American Chemical Society | volume = 72 | issue = 6 | pages = 2617–2619 | date = 1950 | doi = 10.1021/ja01162a076 | bibcode = 1950JAChS..72.2617H }}</ref><ref name="Slomp-1958">{{cite journal | vauthors = Slomp G | title = Ozonolysis. II. 1 The Effect of Pyridine on the Ozonolysis of 4,22-Stigmastadien-3-one 2 | journal = Journal of the American Chemical Society | volume = 80 | issue = 4 | pages = 915–921 | date = 1958 | doi = 10.1021/ja01537a041 | bibcode = 1958JAChS..80..915S }}</ref><ref name="pmid915584">{{cite journal | vauthors = Sundararaman P, Djerassi C | title = A convenient synthesis of progesterone from stigmasterol | journal = The Journal of Organic Chemistry | volume = 42 | issue = 22 | pages = 3633–3634 | date = October 1977 | pmid = 915584 | doi = 10.1021/jo00442a044 }}</ref><ref name="PBS.org-2007">{{cite web | url = https://www.pbs.org/wgbh/nova/transcripts/3402_julian.html | date = 6 February 2007 | title = Nova Transcripts: Forgotten Genius | publisher = PBS.org | access-date = 8 September 2017 | archive-date = 11 October 2018 | archive-url = https://web.archive.org/web/20181011224654/http://www.pbs.org/wgbh/nova/transcripts/3402_julian.html | url-status = live }}</ref><ref name="lipidlibrary.aocs.org">{{cite web | url = http://lipidlibrary.aocs.org/history/Julian/index.htm | title = Giants of the Past | publisher = lipidlibrary.aocs.org | url-status = dead | archive-url = https://web.archive.org/web/20120415001340/http://lipidlibrary.aocs.org/history/Julian/index.htm | archive-date = 15 April 2012 }}</ref>]]

====Total synthesis====
[[File:Progesterone Synthesis.png|class=skin-invert-image|thumb|right|upright=2|The Johnson total synthesis of progesterone.<ref name="pmid5131151"/>]]

A [[total synthesis]] of progesterone was reported in 1971 by [[William Summer Johnson|W.S. Johnson]].<ref name="pmid5131151">{{cite journal | vauthors = Johnson WS, Gravestock MB, McCarry BE | title = Acetylenic bond participation in biogenetic-like olefinic cyclizations. II. Synthesis of dl-progesterone | journal = Journal of the American Chemical Society | volume = 93 | issue = 17 | pages = 4332–4334 | date = August 1971 | pmid = 5131151 | doi = 10.1021/ja00746a062 | bibcode = 1971JAChS..93.4332J }}</ref> The synthesis begins with reacting the [[phosphonium salt]] '''<u>7</u>''' with [[organolithium reagent|phenyl lithium]] to produce the [[phosphonium ylide]] '''<u>8</u>'''. The ylide '''<u>8</u>''' is reacted with an [[aldehyde]] to produce the [[alkene]] '''<u>9</u>'''. The [[ketal]] [[protecting group]]s of '''<u>9</u>''' are hydrolyzed to produce the diketone '''<u>10</u>''', which in turn is cyclized to form the cyclopentenone '''<u>11</u>'''. The ketone of '''<u>11</u>''' is reacted with methyl lithium to yield the tertiary alcohol '''<u>12</u>''', which in turn is treated with acid to produce the tertiary cation '''<u>13</u>'''. The key step of the synthesis is the π-cation cyclization of '''<u>13</u>''' in which the B-, C-, and D-rings of the steroid are simultaneously formed to produce '''<u>14</u>'''. This step resembles the cationic cyclization reaction used in the biosynthesis of steroids and hence is referred to as ''biomimetic''. In the next step the [[enol]] [[orthoester]] is hydrolyzed to produce the ketone '''<u>15</u>'''. The cyclopentene A-ring is then opened by oxidizing with ozone to produce '''<u>16</u>'''. Finally, the diketone '''<u>17</u>''' undergoes an intramolecular [[aldol condensation]] by treating with aqueous potassium hydroxide to produce progesterone.<ref name="pmid5131151"/>