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estrogen_synthesis

(±)-Estrone, a natural hormone and estrogen receptor agonist, was synthesized by Funk and Vollhardt in 1979 using a cobalt-mediated total synthesis. The method involves a thermally induced electrocyclic ring opening followed by a Diels–Alder cycloaddition, allowing for the stereoselective construction of steroidal rings in a single step. The synthesis is efficient, requiring only six steps and achieving a 24% overall yield, making it relevant for the development of oral contraceptives.

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13 views1 page

estrogen_synthesis

(±)-Estrone, a natural hormone and estrogen receptor agonist, was synthesized by Funk and Vollhardt in 1979 using a cobalt-mediated total synthesis. The method involves a thermally induced electrocyclic ring opening followed by a Diels–Alder cycloaddition, allowing for the stereoselective construction of steroidal rings in a single step. The synthesis is efficient, requiring only six steps and achieving a 24% overall yield, making it relevant for the development of oral contraceptives.

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abhinavonlinecoding
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Category R. L. FUNK, K. P. C.

VOLLHARDT* (UNIVERSITY OF CALIFORNIA, BERKELEY, USA)


Transition-Metal-Catalyzed Alkyne Cyclizations. A Cobalt-Mediated Total Synthesis of dl-Estrone
Synthesis of Natural
J. Am. Chem. Soc. 1980, 102, 5253–5261.
Products and
Potential Drugs

Synthesis of (±)-Estrone
Key words

(±)-estrone
O
B, CuI, THF, –40 °C OTMS
steroid Li, NH3(l), THF, Δ
O then TMSCl, HMPA, Et3N
alkyne trimerization –60 °C to r.t. then D, –45 to –35 °C
89% 64%, dr = 2:1
electrocyclic ring
opening

Diels–Alder A C E
cycloaddition
I
CpCo(CO)2 (25 mol%)
MgBr

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F (solvent), Δ
B
alkyne
D cyclotrimerization
O
O O

H decane, Δ
TMS TMS
71%
H H (two steps)
TMS
TMS TMS
Diels–Alder 4π-electrocyclic
cycloaddition ring opening TMS
H G

TFA
100%
CDCl3–CCl4 (7:1)
rr = 9:1
–60 to –10 °C
O O
Pb(OAc)4, TFA TMS
H –30 to –5 °C H
TMS
88%
H H H H F

TMS HO
I (±)-Estrone

Significance: (±)-Estrone, a naturally occurring Comment: Vinyl cuprate addition to cyclopente-


hormone and agonist of estrogen receptors ER none A and subsequent trapping of the resulting
and ER, was synthesized in 1979 by Funk and Voll- enolate gave silyl enol ether C in 89% yield. Forma-
hardt. The presented synthesis allows the stereose- tion of the lithium enolate and alkylation with D af-
lective construction of the B and C steroidal rings in forded diyne E. Importantly, the trans-substituted
a single step through a thermally induced 4 elec- cyclopentanone was formed as the major product.
trocyclic ring opening of a benzocyclobutene, fol- Cobalt-catalyzed cyclotrimerization of E with F gave
lowed by an exo-Diels–Alder cycloaddition. Benzo- benzocyclobutene G along with small quantities of
cyclobutene G was synthesized by cobalt-catalyzed tetracycle H. Heating G in decane afforded H in 71%
cyclotrimerization of E and F. The application of this combined yield over two steps. Subsequent proto-
methodology combined with the evolved synthetic and oxidative-desilylation steps culminated in for-
strategy allowed rapid access to intermediates en- mation of (±)-estrone. Notably the synthesis pro-
route to oral contraceptives. ceeds in only six steps and 24% overall yield.

SYNFACTS Contributors: Erick M. Carreira, Robert J. Gillespie


Synfacts 0
20
42019, 15(04), 0346 Published online: 19.03.20191861-19581861-194X
DOI: 10.1055/s-0037-1612277; Reg-No.: C01419SF ©GeorgThiemeVerlagStutgart· NewYork

346 2019 © Georg Thieme Verlag Stuttgart · New York

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