New synthesis of 18-norestradiol

Article abstract of DOI:10.1002/(SICI)1522-2675(19990113)82:1<30::AID-HLCA30>3.0.CO;2-T

The partial synthesis of 18-norestradiol (1) via Wittig-Schollkopf cyclization of an appropriately functionalized D-seco-steroid 9, obtained in nine steps from estrone, (2) is described. The crucial hydration of the C(13)=C(17) bond in an anti-Markovnikov

Full text of DOI:10.1002/(SICI)1522-2675(19990113)82:1<30::AID-HLCA30>3.0.CO;2-T

30
Helvetica Chimica Acta ± Vol. 82 (1999)
New Synthesis of 18-Norestradiol
by Alexander Kuhla), Heiko Karelsb), and Wolfgang Kreisera)*
a) Naturstoffchemie, Universität Dortmund, D-44221 Dortmund
b) Schering AG, Chemical Process Development, D-59179 Bergkamen
The partial synthesis of 18-norestradiol (1) via Wittig-Schöllkopf cyclization of an appropriately
functionalized D-seco-steroid 9, obtained in nine steps from estrone, (2) is described. The crucial hydration
of the C(13)ˆC(17) bond in an anti-Markovnikov sense was achieved via a diastereoselective hydroboration
procedure.
1. Introduction. ± The known literature procedures directed towards the synthesis
of 18-norsteroids [1] [2c] [4] generally suffer from lack of stereocontrol at the C(13)
atom1), leading to mixtures of both cis- and trans-fused D-rings at the perhydrophen-
anthrene moiety. In most cases, this problem may be attributed to the formation of 17-
oxo-18-nor intermediates which are prone to epimerization [2] at C(13) via the requisite
enol derivatives. Moreover, since there is some ambiguity2) about 18-norestradiol in the
literature, we now wish to introduce an alternative approach via Wittig-Schöllkopf
cyclization [3] for the partial synthesis of 18-norestradiol (1) [5].
During the course of our investigations [6] Beckmann fragmentation had proven to
be the best method for the functionalization of the angular methyl group Me(18).
Therefore, estrone (2) ± after protection as 3-methyl ether ± was transformed [7]
(Scheme 1) into the corresponding oxime in nearly quantitative yield. According to a
procedure published by Moffat and coworkers [8], subsequent treatment with
dicyclohexylcarbodiimide (DCC) and CF3COOH in a solution of DMSO and benzene
led to seco-nitrile 3. However, upscaling using the above procedure failed. Due to a
remarkable pH dependency of this cleavage reaction [8], we found, that CF3COOH
had to be added in aliquots to a cooled solution of the oxime in DMSO and CCl4 giving
± after column chromatography ± a 66% yield of 3 at best.
Early attempts to degrade the exocyclic CˆC bond of 3 by either ozonolysis [9],
RuO4-catalyzed oxidation [10], or cis-hydroxylation (OsO4) and subsequent glycol
cleavage [11] by NaIO4 resulted in only 39 ± 50% yield.
We, therefore, decided to take advantage of the exocyclic CˆC bond as a protecting
group for the requisite oxo function which could be liberated at a later stage during the
synthesis of 18-norestradiol (1). In fact this strategy payed off.
1
)
In the case of 18-norestrone, equilibrium values from 70:30 to 55:45 in favor of the cis-fused epimer have
been reported [2]; in general, cis-configuration of perhydroindenes is thermodynamically favored by far.
The 18-norestradiol (1) has been synthesized via a retro-pinacol rearrangement of estradiol 3-methyl ether
in 12 steps in ca. 0.01% total yield [4].
2
)

Helvetica Chimica Acta ± Vol. 82 (1999)
31
Scheme 1
i) Me2SO4, K2CO3, Me2CO, D; 99%. ii) NH2OH ´ HOAc, EtOH, D; 98%. iii) Dicyclohexylcarbodiimide
(DCC), CF3COOH, DMSO, CCl4, 08, 66%.
2. Results and Discussion. ± Thus, we continued the synthesis of 1 by transforming
the CN function of 3 (Scheme 2). Smooth hydrolysis3) of 3 proceeded under pressure
with NaOH in EtOH/H2O at 1358. Treatment of the crude acid with diazomethane
resulted in ester 4, which was reduced by LiAlH4 in quantitative yield. The preparation
of bromide 6 succeeded via mesylation of 5 and was followed by displacement with
LiBr [12]; we preferred the methanesulfonate of 5 to the corresponding less reactive
tosylate for this purpose, since the former could be conveniently purified by
crystallization from abs. MeOH4). In contrast to nitrile 3, the exocyclic CˆC bond of
bromide 6 could readily be oxidized with 1 equiv. of ozone at 788 in a solution of
abs. CH2Cl2 and MeOH [9], leaving the aromatic ring A unaffected5). Subsequent
reductive workup with dimethyl sulfide gave 80% of ketone 7 (after column
chromatography) apart from unchanged starting material, based on a 93% conversion.
No epimerization of the side chain at C(14) was observed under these conditions, since
1H- and 13C-NMR spectra of 7 displayed a single set of signals.
Scheme 2
i) NaOH, H2O, EtOH, 1358, then CH2N2 in Et2O, 08; 80%. ii) LiAlH4, THF, r.t. then D; 98%. iii) Et3N, MesCl,
CH2Cl2, 08; 83%. iv) LiBr, acetone; 100%. v) O3, CH2Cl2, MeOH, 788, then Me2S, r.t.; 80%.
3
)
)
)
Nitrile 3 was quantitatively reduced to the corresponding imine with DIBAH in benzene. However, hydrolysis
with dil. H2SO4 solution led mainly to polymerization and only in modest yield to the desired aldehyde.
The herein described secosteroids were isolated as oils, with the exception of the mesylate from 5 and the
phosphonium salt 8.
Introduction of O3 until complete consumption reduced the yield by the formation of by-products
resulting from attack at the steroidal ring A.
4
5

32
Helvetica Chimica Acta ± Vol. 82 (1999)
The preparation of the corresponding phosphonium salt from 7 turned out to be a
crucial step in this synthesis, since various commonly applied methods to substitute the
primary bromide by PPh3 failed. In solvents like benzene, toluene [13] or Et2O at
elevated temperature (general method for the synthesis of (oxoalkyl)triphenylphos-
phonium bromide [14]), only tarry materials were recovered. However, melting at 858
a neat mixture of bromide 7 and PPh3 (prepared by dissolving both components in abs.
CHCl3 and evaporating in vacuo) led to a quantitative yield of the glassy phosphonium
salt 8 which further on proved a suitable intermediate for the intramolecular Wittig
reaction [3] (Scheme 3). Best results were observed by single-batch addition of 8 in abs.
DMSO to a solution of dimsyl sodium (MeSOCH2Na) [15] prepared from 1.1 equiv. of
NaH and DMSO. The alkene 9 was obtained after column chromatography as a
colorless oil in 80% yield, along with minor amounts (10%) of its 14b-epimer6).
Scheme 3
i) PPh3, 858; 100%. ii) H3CSOCH2Na, DMSO, r.t., then 758; 80%.
To achieve a regioselective hydration of the C(13)ˆC(17) bond yielding the
anticipated trans-fused alcohol 11 (Scheme 4), we examined several hydroboration
procedures with regard to yield and diastereoselectivity. The use of in situ prepared [16]
B2H6 or BH3 ´ Me2S in THF [17] at 08 led, after oxidative workup, to a 2:1 mixture7) in
favor of the undesired cis-fused gonane 10 in 59 and 60% yield, respectively; in both
cases, concomitant hydrogenation of 9 to ca. 30% was observed. Application of
substituted boranes like catecholborane [18] or 9-borabicyclo[3.3.1]nonane (9-BBN)
[19] under standard conditions failed as well. Apart from the expected 10 and 11, the
formation of several different secondary alcohols was noticed, as by-products of
suspected borane rearrangements [20]. We noticed that this process did not occur when
powdered LiBH4 was added8). Best results were achieved when a solution of 9 in abs.
benzene was treated with 2.5 equiv. of freshly prepared [22] catecholborane and
10 mol-% of LiBH4 under reflux for 24 h. Oxidative workup and purification by column
chromatography gave a 1:2 mixture of 10 and 11 in 67% yield.
The undesired cis-fused 109) was easily separated by fractional crystallization from
MeOH and the 4-chlorobenzoate derivative of 10 was subjected to X-ray analysis [23].
The latter was taken as an independant proof of the relative and absolute configuration.
6
)
)
Ratio established by the chemical-shift difference of the olefinic H C(17) in the 1H-NMR spectrum
(400.13 MHz, CDCl3; 14a-isomer 9 at 5.29 (J ˆ 1.7 Hz) and 14b-isomer (minor) at 5.42 ppm (J ˆ 1.7 Hz)).
The diastereoselectivity was determined by integration of the 13C-NMR signals (CDCl3) of C(17) (17a-
isomer 10 at 73.9 and 17b-isomer 11 at 77.7 ppm) since the m of Ha C(17) in the 1H-NMR spectrum of 11
was partly overlapped by the s of MeO C(3).
A promoting effect of LiBH4 on hydroboration with catecholborane in THF at 08 was reported [21].
Data of 10: M.p. 144 ± 1458. [a]D20 ˆ ‡22 (c ˆ 1.03, CHCl3).
7
8
9
)
)

Helvetica Chimica Acta ± Vol. 82 (1999)
33
Scheme 4
i) Catecholborane (CB), LiBH4, C6H6, D; EtOH, NaOH, H2O2, 08, 67% ii) DIBAH, C6H6, D; 99%. iii) POCl3,
py, 08; 45%.
For the isolation of the configurational isomer 1110) in pure form, the alcohol mixture
10/11 was separated by prep. reversed-phase HPLC. Subsequent removal of the
3-methyl ether group of 11 proceeded readily with an excess of DIBAH [24] in abs.
benzene under reflux and led after one crystallization from AcOEt to 111) in 12 steps,
overall. Moreover, it was possible to transform the by-product of the hydroboration,
alcohol 10, back into the starting alkene 9 by dehydration with POCl3 in abs. pyridine
[25], thus increasing the total yield of this synthesis of 1 from 12 to 13%.
REFERENCES
[1] K. H. Loke, E. J. D. Watson, G. F. Marrian, J. Biochem. 1959, 71, 230; M. M. Coombs, C. W. Vose, J. Chem.
Soc., Chem. Commun. 1974, 602; J. C. Chapman, J. T. Pinhey, Aust. J. Chem. 1974, 27, 2421; M. Han, D. F.
Covey, J. Org. Chem. 1996, 61, 7614.
[2] a) W. F. Johns, J. Am. Chem. Soc. 1958, 80, 6456; b) N. A. Allinger, R. B. Hermann, C. Djerassi, J. Org.
Chem. 1958, 25, 922; c) W. L. Meyer, D. D. Cameron, W. S. Johnson, ibid. 1962, 27, 1130.
[3] K. B. Becker, A. F. Boschung, C. A. Grob, Helv. Chim. Acta 1973, 56, 2733.
[4] W. F. Johns, J. Org. Chem. 1961, 26, 4583; W. F. Johns, ibid. 1963, 28, 1856; W. F. Johns, ibid. 1968, 33, 109.
[5] A. Kuhl, H. Karels, W. Kreiser, presented at the ꢀ17th Conference on Isoprenoidsꢁ, Cracow, 1997.
[6] A. Kuhl, W. Kreiser, Helv. Chim. Acta 1998, 81, 2264.
[7] R. Anliker, M. Müller, J. Wohlfahrt, H. Heusser, Helv. Chim. Acta 1955, 38, 1404.
[8] A. H. Fenselau, E. H. Hamamura, J. G. Moffat, J. Org. Chem. 1970, 35, 3546.
[9] P. L. Stotter, J. B. Eppner, Tetrahedron Lett. 1973, 2417.
[10] P. H. J. Carlson, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem. 1981, 46, 3936.
[11] R. Pappo, D. S. Allen. Jr., R. U. Lemieux, W. S. Johnson, J. Org. Chem. 1956, 21, 478.
[12] J. W. Wilt, S. N. Massie, R. B. Dabek, J. Org. Chem. 1970, 35, 2803.
[13] K. Sasse, in ꢀHouben-Weyl, Methoden der org. Chemieꢁ, 4th edn., Thieme Verlag, Stuttgart, 1963, pp. 78.
[14] K. B. Becker, Helv. Chim. Acta 1977, 60, 68.
[15] R. Greenwald, M. Chaykovsky, E. J. Corey, J. Org. Chem. 1963, 28, 1128.
[16] M. Nussim, Y. Mazur, F. Sondheimer, J. Org. Chem. 1964, 29, 1120.
[17] C. F. Lane, J. Org. Chem. 1974, 39, 1437.
[18] H. C. Brown, S. K. Gupta, J. Am. Chem. Soc. 1975, 97, 5249.
10
)
)
Data of 11: M.p. 153 ± 1558 (Et2O). [a]D20 ˆ‡ 74 (c ˆ 0.99, CHCl3).
Data of 1: M.p. 222 ± 2258. [a]D20 ˆ‡ 69 (c ˆ 0.90, MeOH). IR (KBr; in cm 1): 3410 (OH, arom.), 3232
(OH); 1618, 1582, 1497 (CˆC(arom)). 1H-NMR (300.13 MHz, CD3OD; d in ppm, J in Hz): 2.89 ±
2.95 (m, 2 H C(6)); 3.87 ± 3.95 (m, H C(17)); 6.63 (d, 4J ˆ 2.6, H C(4)); 6.68 ± 6.72 (dd, 3J ˆ 8.3, 4J ˆ
2.6, H C(2)), 7.26 (d, 3J ˆ 8.3, H C(1)); 8.01 (s, OH(arom.)). 13C-NMR (CD3OD): 25.3 (t, C(15));
26.4 (t, C(11)); 27.8 (t, C(7)); 28.7 (t, C(6)); 29.8 (t, C(16)); 31.2 (t, C(12)); 42.1 (d, C(8)); 45.4 (d, C(9));
46.8 (d, C(14)); 52.2 (d, C(13)); 76.1 (d, C(17)); 111.6 (d, C(2)); 113.8 (d, C(4)); 125.4 (d, C(1));
11
.
‡
130.2 (s, C(10)); 136.7 (s, C(5)); 153.7 (s, C(3)). MS (m/z (%)): 258 (100, M ), 240(12), 225(2),
‡
211(17), 183(5), 159(9). HR-MS: 258.1619 (C17H22O2 ; calc. 258.16199).

34
Helvetica Chimica Acta ± Vol. 82 (1999)
[19] H. C. Brown, E. F. Knights, C. G. Scouten, J. Am. Chem. Soc. 1974, 96, 7765.
[20] H. C. Brown, in ꢀHydroborationꢁ, W. A. Benjamin, New York, 1962, pp. 136.
[21] A. Arase, Y. Nunokawa, Y. Masuda, M. Hoshi, J. Chem. Soc., Chem. Commun. 1991, 205.
[22] C. F. Lane, G. W. Kabalka, Tetrahedron 1976, 22, 981.
[23] A. Kuhl, D. Schollmeyer, M. Schürmann, H. Preut, W. Kreiser, Acta. Crystallogr., Sect. C 1998, 54, 521.
[24] E. Winterfeldt, Synthesis 1975, 617.
[25] S. Bernstein, R. Littell, J. Org. Chem. 1961, 26, 3610.
Received September 4, 1998