An ascending synthesis of adrenalcorticosteroids. The total synthesis of (+)-adrenosterone

Full text of DOI:10.1021/ja9602509

J. Am. Chem. Soc. 1996, 118, 4711-4712
4711
Scheme 1
An Ascending Synthesis of Adrenalcorticosteroids.
The Total Synthesis of (+)-Adrenosterone
Carolyn D. Dzierba, Kathleen S. Zandi,
Thomas Mo¨llers, and K. J. Shea*
Department of Chemistry, UniVersity of California
IrVine, California 92717-2025
ReceiVed January 24, 1996
Pharmaceutically useful steroids may be obtained by total
synthesis or by modification of readily available natural
steroids.1 The total synthesis route allows for enantiomer
selection2 as well as access to derivatives that may not be readily
available by degradation or functional group conversions. We
report a general strategy for the enantiospecific synthesis of the
steroid skeleton. The approach is demonstrated by the synthesis
of (+)-adrenosterone, an adrenalcorticosteroid.3
Scheme 2a
a (a) Br2, hν, CHCl3, 1 h; (b) aq NaOH, room temperature, 12 h,
87% (two steps); (c) methyl acrylate, cat. Pd(OAc)2, PPh3, NEt3,
CH3CN, reflux, 24 h, 60%; (d) oxalyl chloride, DMF, CH2Cl2, reflux,
1 h; (e) ethylene glycol, NEt3, CH2Cl2, 0 °C, 1 h, 97% (two steps); (f)
(-)-hydrobenzoin, NEt3, THF, room temperature, overnight, 70% (two
steps).
From a retrosynthetic perspective, an ascending strategy that
appends the C-ring to an A, B fragment (AB f ABC f ABCD)
utilizing a Diels-Alder construction represents a particularly
efficient approach to this important class of natural products.
The challenge entails control of regio-, stereo-, and π-facial
selectivity in the C-ring-forming step. Often, the requirements
for formation of the natural product countermand the intrinsic
bias of the cycloaddition reaction. Despite earlier efforts, this
strategy has not as yet been exploited in adrenalcorticoid
synthesis.4 Recent developments in controlling the stereo-
selectivity of the Diels-Alder reaction utilizing type 2 intra-
molecularity offered possible solutions to these problems.5
The strategy for the synthesis of (+)-adrenosterone is outlined
in Scheme 1. A key step in the synthesis utilizes a temporarily
union of diene and dienophile in a type 2 intramolecular Diels-
Alder (T2IMDA) reaction to form the C-ring of the steroid.5
The cycloaddition was designed to establish the four stereo-
centers in the BCD ring junctures (C8, C9, C13, and C14). In
addition, the strategy has the potential for exploiting the C19
methyl group to establish the correct absolute configuration at
the new centers.
entropically more favorable R,â-cycloaddition mode to deliver
the steroidal skeleton. Following removal of the temporary
tether and reduction of the R,â-unsaturated ester, completion
of the steroid relies upon Dieckmann cyclization/decarboxylation
to form the D-ring.
The diene precursor 4 for the Diels-Alder reaction was
prepared from (+)-Wieland-Miescher ketone by the procedure
of Swaminathan et al.6 Dienophile 6 was synthesized using a
Heck coupling protocol, Scheme 2. Methacrylic acid was
brominated in the presence of light followed by dehydrohalo-
genation with NaOH to give bromoacid 5 in 87% yield.
Palladium-mediated coupling of 5 with methyl acrylate afforded
diene acid 3 in 60% yield.7 Conversion to the acid chloride
with oxalyl chloride followed by quenching with excess ethylene
glycol afforded glycol ester 6 in 97% yield.8
The diene and dienophile fragments were then joined by a
temporary silyl acetal union, Scheme 3.9,10 Enone 4 was
kinetically deprotonated with KHMDS, trapped as the diphen-
ylchlorosilyl dienol ether, and quenched with glycol ester 6 to
give silyl acetal 2. The silyl acetal was taken directly into the
T2IMDA step without purification. The Diels-Alder reaction
was carried out in toluene at 200 °C for 35 h to afford a 1:10
mixture of diastereomers (8:9 respectively) in 90% yield from
4. The tether was removed with K2CO3 in MeOH to give the
corresponding ketones in a 1:10 ratio (10:11 respectively) in
84% yield. The diastereomers were separated, and their absolute
configurations were determined by X-ray crystallography.11 The
cycloadducts arose from exclusive tether endo attack of the
dienophile with complete regiochemical control (1,3 Vs 1,4 tether
Dienophile 3 installs the C18 methyl and the D-ring carbons.
To circumvent the low reactivity of the R,R,â-trisubstituted
dienophile, conjugation was extended through the carbomethoxy
group (3, Scheme 1). Although this ploy introduced ambiguity
in the chemoselectivity of the cycloaddition step (addition of
the diene to the R,â- Vs γ,δ-double bond), we relied upon the
(1) (a) Fieser, L. F.; Fieser, M. Steroids; Reinhold Publishing Corp.: New
York, 1959. (b) Akhrem, A. A.; Titov, Y. A. Total Steroid Synthesis;
Plenum: New York, 1970.
(2) (a) Rychnovsky, S. D.; Mickus, D. E. J. Org. Chem. 1992, 57, 2732.
(b) Mickus, D. E.; Levitt, D. G.; Rychnovsky, S. D. J. Am. Chem. Soc.
1992, 114, 359.
(3) For previous syntheses, see: (a) Velluz, L.; Nomine´, G.; Mathieu,
J.; Toromanoff, E.; Bertin, D.; Bucourt, R.; Tessier, J. Compt. Rendu 1960,
250, 1293. (b) Stork, G.; Winkler, J. D.; Shiner, C. S. J. Am. Chem. Soc.
1982, 104, 3767. (c) Stork, G.; Saccomano, N. A. Tetrahedron Lett. 1987,
28, 2087. (d) Van Royen, L. A.; Mijngheer, R.; De Clercq, P. J. Tetrahedron
1985, 41, 4667. (e) Kametani, T.; Matsumoto, H.; Honda, T.; Nagai, M.;
Fukumoto, K. Tetrahedron 1981, 37, 2555. (f) Horiguchi, Y.; Nakamura,
E.; Kuwajima, I. J. Am. Chem. Soc. 1989, 111, 6257.
(6) (a) Swaminathan, S.; Newman, M. S. Tetrahedron 1958, 2, 88. (b)
Ramakrishnan, V. T.; Ramachandran, S.; Venkataramani, P. S.; Swami-
nathan, S. Tetrahedron 1967, 23, 2453. (c) Darvesh, S.; Grant, A. S.; MaGee,
D. I.; Valenta, Z. Can. J. Chem. 1989, 67, 2237. (d) Swaminathan, S.;
Narayanan, K. V. Chem. ReV. 1971, 71, 429.
(4) (a) Nazarov, I. N.; Gurvich, I. A. IzV. Akad. Nauk. SSSR, Otd. Khim.
Nauk. 1959, 293. (b) Anner, G.; Miescher, K. HelV. Chim. Acta 1950, 33,
1379.
(7) Heck, R. F. Org. React. 1982, 27, 345.
(5) For examples of the type 2 intramolecular Diels-Alder reaction,
see: (a) Shea, K. J.; Wise, S J. Am. Chem. Soc. 1978, 100, 6519. (b) Shea,
K. J.; Beauchamp, P. S.; Lind, R. J. Am. Chem. Soc. 1980, 102, 4544. (c)
Shea, K. J.; Wise, S.; Burke, L. D.; Davis, P. D.; Gilman, J. W.; Greeley,
A. C. J. Am. Chem. Soc. 1982, 104, 5708. (d) Shea, K. J.; Wada, E. J. Am.
Chem. Soc. 1982, 104, 5715. (e) Shea, K. J.; Davis, P. D. Angew. Chem.,
Int. Ed. Engl. 1983, 22, 419; Angew. Chem. Suppl. 1983, 564-570. (f)
Shea, K. J.; Burke, L. D.; England, W. P. J. Am. Chem. Soc. 1988, 110,
860. (g) Shea, K. J.; Lease, T. G.; Ziller, J. W. J. Am. Chem. Soc. 1990,
112, 8627. (h) Lease, T. G.; Shea, K. J. J. Am. Chem. Soc., 1993, 115,
2248.
(8) This compound gave spectral (1H, 13C, IR) and analytical (HRMS)
data consistent with the assigned structure.
(9) (a) Shea, K. J.; Zandi, K. S.; Staab, A. J.; Carr, R. Tetrahedron Lett.
1990, 31, 5885. (b) Shea, K. J.; Staab, A. J.; Zandi, K. S. Tetrahedron
Lett. 1991, 32, 2715.
(10) (a) Craig, D.; Reader, J. C. Tetrahedron Lett. 1990, 31, 6585. (b)
Craig, D.; Reader, J. C. Tetrahedron Lett. 1992, 33, 4073. (c) Gillard, J.
W.; Fortin, R.; Grimm, E. L.; Maillard, M.; Tjepkema, M.; Bernstein, M.
A.; Glaser, R. Tetrahedron Lett. 1991, 32, 1145. (d) Posner, G. H.; Cho,
C.-G.; Anjeh, T. E. N.; Johnson, N.; Horst, R. L.; Kobayashi, T.; Okano,
T.; Tsugawa, N. J. Org. Chem. 1995, 60, 4617.
S0002-7863(96)00250-8 CCC: $12.00 © 1996 American Chemical Society

4712 J. Am. Chem. Soc., Vol. 118, No. 19, 1996
Communications to the Editor
Scheme 3a
Scheme 4a
a (a) (i) KHMDS, THF, -78 °C, 2 h; (ii) Ph2SiCl2, NEt3, 0 °C, 30
min; (iii) 6, 0 °C f room temperature, overnight; (b) toluene, 200 °C,
35 h, 90% based on 50% conversion (two steps; 1:10 ratio of 8:9); (c)
K2CO3, MeOH, room temperature, 14 h, 87% (1:10 ratio of 10:11).
a (a) (i) KHMDS, THF, -78 °C, 2 h; (ii) Ph2SiCl2, NEt3, 0 °C, 30
min; (iii) 7, DMAP, 0 °C f room temperature, overnight; (b) toluene,
200 °C, 18 h, 90% based on 45% conversion (two steps; 3:2 ratio of
13:14); (c) K2CO3, MeOH, room temperature, 14 h, 84% (3:2 ratio of
10:11).
linkage). This regio- and stereochemical outcome is charac-
teristic of the T2IMDA cycloaddition mode.5,8 The reaction
established the correct relative configuration at C8, C13, and C14.
However, the anticipated R-directing effect of the C19 methyl
group was not realized.4 The major product 9 was derived from
â-attack of the dienophile, a result that gives the nonnatural
stereochemical relationship between C10 and the C8, C9, C13,
and C14 stereocenters.
Scheme 5a
Control of the π-facial selectivity in the cycloaddition step
was the remaining hurdle in the synthesis.12 Following inspec-
tion of molecular models, it was found that interactions between
the phenyl groups on the silicon and an asymmetric center on
the ethylene glycol fragment could possibly differentiate the
π-faces of the T2IMDA cycloaddition step. To exploit this
opportunity, (-)-hydrobenzoin was chosen as the source of
asymmetry on the C2 chain. Chiral hydrobenzoin dienophile 7
was prepared by quenching the acid chloride of 3 with (-)-
hydrobenzoin13 in 70% yield, Scheme 2.
Diels-Alder precursor 12 was prepared analogously to 2,
using dienophile 7, Scheme 4. The triene, upon heating to 200
°C in toluene for 18 h, gave a 3:2 mixture of 13:14 in 90%
yield (based on 45% conversion) from 4. Subsequent treatment
with K2CO3 in MeOH gave a 3:2 ratio of 10:11 in 80% yield.
Gratifyingly, the (-)-hydrobenzoin auxiliary was found to
reverse the π-facial selectivity of the ring closure. The major
cycloadduct 8 arose from R-approach of the dienophile to give
the correct stereochemical relationship between C10 and the
stereocenters at the BCD ring junctures.14
a (a) (i) Mg°, MeOH, reflux, 2.5 h, 76% yield based on 70%
conversion; (b) tBuOK, benzene, reflux, 5 h; (c) (i) AcOH, HCl, H2O,
reflux, 1 h; (ii) 5% NaOH, MeOH, reflux, 1 h; (d) Hg(ClO4)2, THF,
H2O room temperature, 1 h, 45% (three steps).
overreduction of the desired product. Dieckmann cyclization
t
was induced upon heating with BuOK in benzene.16 Saponi-
fication with acid and decarboxylation with NaOH provided the
17
protected steroid. Deprotection of the dithiane with Hg(ClO4)2
yielded (+)-adrenosterone in 45% yield from 15.
(+)-Adrenosterone was prepared in seven steps from enone
4. A type 2 intramolecular Diels-Alder reaction was employed
to control the regio- and stereochemistry of the cycloaddition.
Temporary union of diene and dienophile by a chiral 1,2-diol
provided control of the π-facial selectivity.
This strategy provides a general method for the construction
of steroids. Since the stereocenters are set by the single
stereocenter in the starting material, either enantiomer of the
steroid can be prepared depending on the choice of enantiomer
of Wieland-Miescher ketone.
Acknowledgment. We are grateful to the National Institutes of
Health for financial support of this work. We thank Dr. Joseph Ziller
for the X-ray crystallographic data.
The remaining steps included reduction of the R,â-unsaturated
double bond with Mg°/MeOH,15 Scheme 5. It was desirable
to interrupt this reaction after 70% conversion to avoid
Supporting Information Available: Crystallographic data and
structures for compounds 10 and 11; detailed experimental procedures
as well as spectroscopic and analytical characterization of compounds
1-15 (63 pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the journal,
can be ordered from the ACS, and can be downloaded from the Internet;
see any current masthead page for ordering information and Internet
access instructions.
(11) (a) Compound 10 crystallizes from 8:2 hexanes/ethyl acetate in space
group P212121 with a ) 11.2595(4) Å, b ) 12.3209(6) Å, c ) 17.2587(14)
Å, V ) 2394.3(2) Å3, and Dcalc ) 1.289 mg/m3 for Z ) 4. Least-squares
refinement of the model based on 2232 reflections (F > 1.0σ(F)) converged
to a final Rf ) 3.6%. (b) Compound 11 crystallizes from 8:2 hexanes/ethyl
acetate in space group P21/c with a ) 6.8994(13) Å, b ) 19.501(2) Å, c )
18.162(2) Å, â ) 99.354(9)o, V ) 2411.1(6) Å3, and Dcalc ) 1.280 mg/m3
for Z ) 4. Least-squares refinement of the model based on 2682 reflections
(F > 2.0σ(F)) converged to a final Rf ) 5.7%.
(12) Shea, K. J.; Gauthier, D. R., Jr. Tetrahedron Lett. 1994, 35, 7311.
(13) Wang, Z-M.; Sharpless, B. K. J. Org. Chem. 1994, 59, 8302.
(14) Ongoing studies have revealed that the π-facial selectivity of the
cycloaddition step can be further improved by increasing the steric demands
of the chiral auxiliary. Details of this work will be included in the full
report of this work.
(15) (a)Youn, I. K.; Yon, G. H.; Pak, C. S. Tetrahedron Lett. 1986, 27,
2409. (b) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron Lett.
1987, 28, 5287.
JA9602509
(16) (a) Johnson, W. S.; Bannister, B.; Pappo, R. J. Am. Chem. Soc.
1956, 78, 6331. (b) Johnson, W. S.; Pappo, R.; Johns, W. F. J. Am. Chem.
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(17) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; p 203.