Progress toward the total synthesis of (+)-aldosterone: synthesis of the A-D rings.

Article abstract of DOI:10.1021/ol034218c

[reaction: see text] Synthesis of the A-D rings of the cortical hormone (+)-aldosterone is described. The key step incorporates a chiral tether in a type 2 intramolecular Diels-Alder reaction that establishes the absolute configuration of four contiguous

Full text of DOI:10.1021/ol034218c

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1613-1616
Progress toward the Total Synthesis of
(+)-Aldosterone: Synthesis of the A−D
Rings
Brian R. Bear, Jason S. Parnes, and Kenneth J. Shea*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine,
IrVine, California 92697-2025
kjshea@uci.edu.
Received February 6, 2003
ABSTRACT
Synthesis of the A−D rings of the cortical hormone (+)-aldosterone is described. The key step incorporates a chiral tether in a type 2
intramolecular Diels−Alder reaction that establishes the absolute configuration of four contiguous asymmetric centers. This approach provides
an efficient route for either enantiomer of the steroid skeleton.
Synthesized in the adrenal cortex, the cortical hormones play
a vital role in the biochemistry of man.1 Aldosterone (1),
the most common mineralocorticoid, was isolated in 1953.2
It maintains proper blood pressure and blood volume by
regulating the reabsorption of water and sodium ions from
urine. This and other steroids have provided an arena for
testing synthetic strategy and methodology for over fifty
years. (()-Aldosterone was first synthesized by Wettstein3
in 1955, and later by Johnson.4 Barton’s three-step partial
synthesis of (+)-aldosterone from commercially available
corticosterone acetate provided a method for producing
quantities of aldosterone.5 Other total and partial syntheses
are given in ref 6.
application of these efforts to the synthesis of (+)-aldosterone
is illustrated in Scheme 1. The overall strategy is an
ascending synthesis of the tetracyclic steroid core starting
from the AB rings and building the C and D rings in
subsequent steps.
We envisioned the hormone to be derived from the steroid
core 2. This precursor could in turn arise from a D-ring
forming Dieckman-demethoxycarbonylation sequence of
bridged bicycle 3.
(5) (a) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J.
Am. Chem. Soc. 1960, 82, 2640-2641. (b) Barton, D. H. R.; Beaton, J. M.
J. Am. Chem. Soc. 1960, 82, 2640. (c) Barton, D. H. R.; Beaton, J. M. J.
Am. Chem. Soc. 1961, 83, 4083-4089. (d) Barton, D. H. R.; et al. J. Chem.
Soc., Perkin Trans. 1 1975, 2243-2251.
We have developed procedures for controlling stereo- and
regiochemistry in Diels-Alder cycloaddition reactions.7 An
(6) For additional studies of the synthesis of aldosterone, see: (a) von
Euw, J.; Neher, R.; Reichstein, T. HelV. Chim. Acta 1955, 38, 1423-1437.
(b) Lardon, A.; Schindler, O.; Reichstein, T. HelV. Chim. Acta 1957, 40,
666-704. (c) van der Burg, W. J.; et al. Recl. TraV. Chim. Pays-Bas 1958,
77, 171-176. (d) Szpilfogel, S. A.; van der Burg, W. J.; Siegmann, C. M.;
van Dorp, D. A. Recl. TraV. Chim. Pays-Bas 1956, 75, 1043-1052. (e)
Schmidlin, J.; et al. HelV. Chim. Acta 1957, 40, 1034-1051. (f) Vischer,
E.; Schmidlin, J.; Wettstein, A. Experientia 1956, 12, 50-52. (g) Schmidlin,
J.; Wettstein, A. HelV. Chim. Acta 1962, 45, 331-347. (h) Miyano, M. J.
Org. Chem. 1981, 46, 1845-1853.
(1) (a) Voet, D.; Voet, J. Biochemistry, 2nd ed.; John Wiley & Sons:
New York, 1995; p 1269. (b) Campbell, N. A.; Reece, J. B.; Mitchell, L.
G. Biology, 5th ed.; Benjamin/Cummings: Menlo Park, CA, 1999; pp 908-
909.
(2) Simpson, S. A.; Tait, J. F.; Wettstein, A.; Neher, R.; von Euw, J.;
Reichstein, T. Experientia 1953, 9, 333-335.
(3) Schmidlin, J.; Anner, G.; Billeter, J. R.; Wettstein, A. Experientia
1955, 11, 365-368.
(7) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001,
40, 821-849.
(4) Johnson, W. S.; et al. J. Am. Chem. Soc. 1963, 85, 1409-1430.
10.1021/ol034218c CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/11/2003

Scheme 1. Retrosynthetic Plan for the Synthesis of Advanced
Intermediate 2 and (+)-Aldosterone (1)
Scheme 3. Type 2 IMDA Reaction of Silyl Acetal 12 Leading
to the Diastereoselective Synthesis of Intermediate 14
Bridged pentacycle 3 arises from a type 2 intramolecular
Diels-Alder reaction (IMDA).7 The cycloaddition, which
can form up to eight diastereomeric products, requires control
of regiochemistryand stereochemistry, as well as π facial
selectivity, to provide the isomer required for the synthesis.
This key intramolecular cycloaddition can be staged by
temporarily uniting latent diene 48,9 and dienophile 5 through
Scheme 2. Synthesis of Dienophile 5
a chiral silyl acetal tether.10 A related synthesis of adreno-
sterone demonstrated that the (S, S)-hydrobenzoin auxiliary
in the bridging group induced formation of the cycloadducts,
favoring the R-approach of the dienophile to generate the
natural steroid stereochemistry at C8, C9, C11, C13, and C14,
respectively.10 This work culminated in the total synthesis
of (+)-adrenosterone.11
This same strategy was employed to bias the π facial
selectivity for the critical construction of the C-ring of (+)-
aldosterone. The aldosterone synthesis requires a dienophile
with the C18 carbon (steroid numbering) in an elevated
oxidation state. Having identified an approach to the target
steroid in Scheme 1, the synthesis of chiral dienophile 5 was
undertaken. A major challenge in the synthesis of 5 was
differentiating the two ester groups. The solution to this
(8) Bols, M.; Skrydstrup, T. Chem. ReV. 1995, 95, 1253-1277.
(9) (a) Gauthier, D. R., Jr.; Zandi, K. S.; Shea, K. J., Tetrahedron 1998,
54, 2289-2338. (b) Shea, K. J.; Zandi, K. S.; Staab, A. J.; Carr, R.
Tetrahedron Lett. 1990, 31, 5885-5888. (c) Shea, K. J.; Staab, A. J.; Zandi,
K. S. Tetrahedron Lett. 1991, 32, 2715-2718.
(10) Shea, K. J.; Gauthier, D. R., Jr. Tetrahedron Lett. 1994, 35, 7311-
7314.
(11) Dzierba, C. D.; Zandi, K. S.; Mollers, T.; Shea, K. J. J. Am. Chem.
Soc. 1996, 118, 4711-4712.
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Org. Lett., Vol. 5, No. 10, 2003

Scheme 4. Stereoselective Synthesis of Advanced Aldosterone
Intermediate 2 Containing A-D Rings
Figure 1. Molecular structure of advanced intermediate 2.
coupled with the silyl chloride intermediate to produce
hydrobenzoin tethered cycloaddition precursor 12. It was
found that upon addition of the dienophile to the chlorosiloxy
intermediate, the acid byproduct caused trans-silylation from
the hexamethyldisilazane to the dienophile 5, capping the
alcohol with a TMS group and rendering it inactive for
coupling. By simply concentrating the reaction mixture and
then subjecting the residue to high vacuum after coupling
the dichlorosilane to the diene derived from 4, excess
hexamethyldisilazane was removed. This modification en-
hanced the yield of the coupling step.
Heating a dilute solution of 12 in toluene produced a 2.7:
1.0 mixture of diastereomeric cycloadducts 3 and 13 in 78%
combined yield where the major product, 3, arose from an
R-approach of the dienophile. Cycloadduct 3 has the neces-
sary stereochemistry at C8, C10, C13, and C14 for comple-
tion of the enantioselective synthesis of aldosterone. Fol-
lowing removal of the chiral disposable tether, the diastereo-
meric products could be separated to provide intermediate
14 where the trans-stereochemistry of the B-C ring junction
is established during the cleavage process. The type 2 IMDA
reaction of 12 established the four contiguous stereocenters
(C8, C9, C13, and C14) within the C-ring of the steroid core
relative to C10.
problem can be found in Scheme 2. Acetate 612,13 was
saponified to allylic alcohol 7, which was protected to give
benzyl ether 8. Methyl ester 8 was transesterified14 with TBS-
protected (S,S)-hydrobenzoin 915 to furnish ester 10. Selective
γ,δ-olefin ozonolysis16 of 10 provided the aldehyde, which
was converted to conjugated diester 11 under modified
Horner-Wadsworth-Emmons conditions.17 Fluoride-
assisted desilylation of 11 completed the synthesis of
dienophile 5.
A three-component coupling procedure was used to set
the stage for the key type 2 IMDA cycloaddition (Scheme
3). Diene precursor 411,18 (derived from (+)-Wieland-
Miescher ketone) was kinetically deprotonated and O-
silylated with dichlorodiphenylsilane. Dienophile 5 was
Construction of the D-ring of the steroid skeleton is
outlined in Scheme 4. Selective reduction of the C11 ketone
of 14 with NaBH4 provided â-C11 alcohol 15.19 Reduction
of R,â-unsaturated ester 15 gave diester 16,20 which under-
(12) Compound 6 was prepared by coupling methyl acrylate and trans-
cinnamaldehyde under Baylis-Hillman conditions followed by acetylation
of the resulting alcohol and an acetate transposition procedure developed
by Foucaud and El Guemmout. See Supporting Information and ref 13.
(13) Foucaud, A.; El Guemmout, F. Bull. Soc. Chim. Fr. 1989, 3, 403-
408.
(14) Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1986, 695-607.
(15) Crosby, J.; Stoddart, J. F.; Sun, X.; Venner, M. R. W. Synthesis
1993, 141-145.
(16) Stotter, P. L.; Eppner, J. B. Tetrahedron Lett. 1973, 26, 2417-
2420.
(18) (a) Swaminathan, S.; Newman, M. S. Tetrahedron 1958, 2, 88-
99. (b) Ramakrishnan, V. T.; Ramachandra, S.; Venkataramani, P. S.;
Swaminathan, S. Tetrahedron 1967, 23, 2453-2459. (c) Darvesh, S.; Grant,
A. S.; MaGee, D. I.; Valenta, Z. Can J. Chem. 1989, 67, 2237-2240. (d)
Swaminathan, S.; Narayanan, K. V. Chem. ReV. 1971, 71, 429-438.
(19) (a) Bernstein, S.; Lenhard, R. H.; Williams, J. H. J. Org. Chem.
1953, 18, 1166-1176. (b) Zderic, J. A.; Iriarte, J. J. Org. Chem. 1962, 27,
1756-1760. (c) Oliveto, E. P.; Clayton, T.; Hershberg, E. B. J. Am. Chem.
Soc. 1953, 75, 486-488. (d) Oliveto, E. P.; et al. J. Am. Chem. Soc. 1956,
78, 1736-1738.
(17) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624-2626.
Org. Lett., Vol. 5, No. 10, 2003
1615

went Dieckman cyclization to furnish â-keto ester 17 as a
3:1 mixture of epimers. Demethoxycarbonylation of 17
resulted in the formation of intermediate 2.21 This advanced
intermediate incorporates the A-D rings of the steroid
aldosterone as well as an elevated oxidation state of the C18
carbon.
The absolute stereochemistry of intermediate 2 was
confirmed by X-ray analysis (Figure 1). The molecular
structure of 2 proves the stereochemistry of the six stereo-
centers including the â-orientation of the C11 hydroxyl
group.
intramolecular Diels-Alder reaction that sets the four
contiguous stereocenters of the C-ring. Further elaboration
of 2 should allow for the enantioselective total synthesis of
(+)-aldosterone.
Acknowledgment. The authors gratefully acknowledge
the financial support of the NIH and the assistance of Dr.
Joseph Ziller (X-ray analysis) and Dr. John Greaves and Dr.
John Mudd (mass spectral analysis). We also wish to thank
Neal N. Reed for preliminary studies and C. P. Chow for
assisting with the preparation of the manuscript.
In summary, we have developed a concise route into the
A-D rings of the cortical steroid aldosterone. The key step
in the synthesis of advanced intermediate 2 was a type 2
Supporting Information Available: X-ray crystal struc-
ture and crystallographic data for 2 and experimental
procedures and full characterization data for 2, 3, 5, 6-8,
10-11, and 14-17. This material is available free of charge
via the Internet at http://pubs.acs.org.
(20) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron Lett.
1987, 28, 5287-5290.
(21) Lin, R.; Castells, J.; Rapoport, H. J. Org. Chem. 1998, 63, 4069-
4078.
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