Steroid Synthesis
Steroids occur widely in nature and play key roles in the functioning of the human and animal
organisms. They are a group of cyclical organic compounds based on a characteristic
arrangement of seventeen carbon atoms in a four-ring structure linked together from three-6carbon rings followed by a 5-carbon ring with a side chain on carbon 17. The three cyclohexane
rings are designated as rings A, B and C in the figure to the right and the one cyclopentane ring
as ring D. Individual steroids vary, first and primarily, by the oxidation state of the carbon atoms
in the rings and by the chains and functional groups attached to this four-ring system; second,
steroids can vary more markedly via changes to the ring structure (e.g., via ring scissions that
produce secosteroids like vitamin D3). Sterols are a particularly important form of steroids, with
sterols having a cholestane-derived framework and a hydroxyl group at the C-3 ring position
being the most prominent (e.g., as in cholesterol). The most important steroid structure as
examples include testosterone (an anabolic steroid and the principal male sex hormone),
dexamethasone (a synthetic corticosteroid drug, prescribed steroid for pain), bile acid (or cholic
acid), progesterone (a steroid hormone involved in fermale menstrual cycle, pregnancy and
embryogenesis), medrogestone (a synthetic drug with similar effects as progesterone), βsitosterol (a plant or phytosterol), cholesterol (a prototypical animal steroid and key steroid
biosyntetic precusor) and estradiol (estrogen).
Because of the importance of the steroid compounds, the research on their synthesis and
application has been widely carried out. The series by Hanson in “Natural Product Reports”
regularly discuss the reactions and partial synthesis of diverse new steroids[1]. Stéphan has
reviewed the syntheses of modified steroids having a five carbon ring D in the androstane and
androstene series[2]. Schneider reviewed synthesis of the modified steroids[3]. Other reviews on
the synthesis of steroids include the Diels-Alder reaction in steroid synthesis[4], ring C closure
as key step in steroid synthesis[5], transition-metal-catalyzed reactions in steroid synthesis[6],
reactions and partial synthesis of steroids[7] and industrial steroid synthesis[8]. Some reviews
published in early days are Sykes’s steroid synthesis with 214 references[9], May’s steroid
synthesis with 594 references[10], design of steroid synthons[11] and biosynthesis of
steroids[12]. It is worthy to point out that the synthesis of 6-hydroxy derivatives of steroids has
been widely studied duo to the fact that mammalian as well as microbial organisms possess
enzyme system capable of hydroxylating 3-oxo-Δ4-unsaturated steroids at 6-carbon position,
which greatly stimulated the interest in 6-hydroxy derivatives of steroid hormones and their
synthetic methods. Generally speaking the used methods to introduce a hydroxyl group at the 6carbon position of steroids are as follows:
O
Cl
mCPBA
+
O
O
or O2
O
O
O
OH
OH
Ph
β
SeO2
O
α
+
O
O
OH
OH
Generally speaking 6β-hydroxy derivative is the major product and it can be separated from the
minor 6α-hydroxy derivative through a silica gel column.
In our lab, we focus mainly on the synthesis of modified steroids including 6-hydroxy
derivatives, new steroids and isotopically labeled steroids. During our experiment we found that
the steroids exhibit their unique properties in reactions due to their unique structure and
conformation. For example, it will become basic sensitive if the steroids have both hydroxyl
group at the 16 and 21 position in their molecules. On the other hand the hydroxyl at position 11
is hard to react with most active reagents such as anhydride or carbonyl chloride unless the
reagent molecules are small enough. Furthermore it has also been found that the halogen group at
the 9th position in some steroids have much to do with the their reactivity.
References
1.
2.
3.
4.
Hanson, J. R., Natural Product Reports, 27(6), 887-899 (2010)
Stéphan, E., Org. Prep. Proced. Int., 38, 217 (2006)
Schneider, G., Magyar Kemikusok Lapja, 56(3), 109-111 (2001)
Mackay, E. G.; Sherburn, M. S., Synthesis, 47(1), 1-21 (2015)
5.
6.
7.
8.
Saraber, F. C. E. et al, Tetrahedron, 62(23), 5363-5383 (2006)
Skoda-Foeldes, R.; Kollar, L., Chemical Reviews, 103(10), 4095-4129 (2003)
Turner, A. B., Natural Product Reports, 6(6), 539-575 (1989)
Schwarz, S., Wissenschafliche Zeitschrift der Technischen Hochschule
Schorlemmer Leuna-Merseburg, 29(4), 444-454 (1987)
9. Sykes, P. J et al, Terpenoids and Steroids, 6, 276-343 (1976)
10. May, P. J., Terpenoids and Steroids, 1, 404-538 (1971)
11. Bull, J. R., South African Journal of Science, 70(6), 174-178 (1974)
12. Mulheirn, L. J.; Ramm, P. J., Chemical Society Reviews, 1(2), 259-291 (1972)
Carl