[0001] This application claims priority from U.S. Provisional Application No. 61/786,969, filed March 15, 2013, the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to a synthetic process for preparing a tricyclic-bis- enone derivative (TBEs), viz., (±)-(4b5',8ai?,10a5 -10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo- 3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitril e ("TBE-31"), and to novel intermediates in the synthetic process.

BACKGROUND OF THE INVENTION

[0003] The TBEs (TBEs are the plural form of TBE) have been shown to be useful candidates for treating various types of diseases and disorders in mammals, including humans. One of these TBEs, TBE-31 , is the most potent amongst these synthetic tricycles. It has exhibited a wide range of biological activities, including, but not limited to, inhibiting proliferation of human myeloma cells, inhibiting the induction of iNOS in cells stimulated with interferon-γ, inducing heme oxygenase- 1 (HO-1), inducing CD l ib expression— a leukemia differentiation marker--, inhibiting proliferation of leukemia cells, inducing apoptosis in human lung cancer, and inducing apoptosis in other cancerous cells. It has been described as being useful agent for the treatment and prevention of many diseases, including cancer, neurological disorders, inflammation, and pathologies involving oxidative stress.

[0004] A synthetic method of preparing TBE-31 has already been reported. The synthetic route is shown in Scheme 1. Scheme 1.

Cyclohexanone A (91 %) B (100%) C (64%)

(a) e ₂ C0 ₃ , NaH, KH, THF; (b) 1-chloro-3-pentanone, Na, MeOH; (c) Cs ₂ C0 ₃ , Me ₂ S0 ₄ , DMF; (d) Li, NH ₃ , H ₂ 0, Mel; (e) CH ₂ N ₂ , Et ₂ 0, THF; (f) (CH ₂ OH) ₂ , PPTS, PhH; (g) LAH, Et ₂ 0; (h) (COCI) ₂ , DMSO, Et ₃ N, CH ₂ CI ₂ ;

(i) Ph ₃ PCH ₂ CI ₂ , n-BuLi, THF, HMPA; (j) eLi, THF; aq NH ₄ CI; (k) 10% aqueous HCI, MeOH; (I) Cr0 ₃ , f-BuOOH, CH ₂ CI ₂ ; (m) HC0 ₂ Et, NaOMe, PhH; (n) NH ₂ OH-HCI, aqueous EtOH; (o) NaOMe, MeOH, Et ₂ 0; (p) PhSeCI, pyridine, CH ₂ CI ₂ ; 30% H ₂ 0 ₂ , CH ₂ CI ₂

[0005] Although this method has been used to prepare TBE-31 on a laboratory scale, it is impractical to be used for the synthesis of TBE-31 on a commercial scale. More specifically, this method is not friendly to the large-scale synthesis of TBE-31 because the fourth step of the synthetic scheme, the reductive methylation of methyl ester C, gives two undesired compounds, identified as Da and Db, in addition to the desired compound, Dc. As shown in the scheme, the yield of the desired compound Dc (36%) is significantly less than the total yield of the undesired compounds Da and Db (51%). Consequently, the yield of TBE-31 is reduced as a result of the formation of the undesired compounds in this step. In addition, the presence of compounds Da and Db interfere with the synthetic yield of TBE-31 ; as a result, it is necessary to conduct an additional step of separating the desired compound Dc from compounds Da and Db.

[0006] Thus there is a need to improve the method of preparing TBE-31. More specifically, there is a need to prepare TBE-31 in a more efficient manner to obtain a higher overall yield for the process and to find a method of preparing TBE-31 so that every step either produces predominantly one product or if more than one product is prepared in any one step, the products could be used in a subsequent step in the synthetic process without the necessity of separation.

SUMMARY OF THE INVENTION

[0007] The present invention overcomes that problem. More specifically, a different synthetic route for preparing TBE-31 has been found. This synthetic route provides TBE-31 in good yield because all steps in the synthetic process produces either one product which could be used in the subsequent step or if it produces more than one product, they can be used in the synthetic process without the need for purification and separation by column chromatography.

[0008] An embodiment of the present application is the preparation of TBE-31 utilizing the synthetic process of the present application is depicted in Scheme 2: Scheme 2.

TBE-31 (59%)

(a) Me ₂ C0 ₃ , NaH, KH, THF; (b) 1-chloro-3-pentanone, Na, MeOH; (c) Red-AI ^® , toluene; (d) DDQ,

1 ,4-dioxane; (e) Li, NH ₃ , H ₂ 0, Mel; (f) (CH ₂ OH) ₂ , PPTS, PhH; (g) (COCI) ₂ , DMSO, Et ₃ N, CH ₂ CI ₂ ;

(h) Ph ₃ PCH ₂ CI ₂ , n-BuLi, THF, HMPA; (i) MeLi, THF; aq NH ₄ CI; (j) 10% aqueous HCI, MeOH;

(k) Cr0 ₃ , f-BuOOH, CH ₂ CI ₂ ; (I) HC0 ₂ Et, NaOMe, PhH; (m) NH ₂ OH-HCI, aqueous EtOH; (n) NaOMe,

MeOH, Et ₂ 0; PhSeCI, pyridine, CH ₂ CI ₂ ; 30% H ₂ 0 ₂ , CH ₂ CI ₂

[0009] More specifically an embodiment of the present process comprises:

(a) reacting 2-carbomethoxycyclohexanone (1) with l-chloro-3-pentanone under Robinson annulation condition in the presence of a base, such as an alkali metal, such as sodium or lithium, to form (±)-(4aS',8a5 -l ,4a-dimethyl-2-oxo- 2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthrene-8a-carboxylic acid (2);

(b) reducing the carbonyl group and the ester functionality in (±)-(4aS,8aS)-l ,4a- dimethyl-2-oxo-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthrene- 8a-carboxylic acid (2) to afford (±)-(2i?,4a ,8a5 -8a-(hydroxymethyl)-l ,4a-dimethyl- 2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol and (±)-(25,4a5,8a5)-8a- (hydroxymethyl)-l,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10- decahydrophenanthren-2-ol (3a and 3b);

(c) selectively oxidizing the hydroxyl group at the 2-position of (±)- (2i?,4a5,8a5 ^r )-8a-(hydroxymethyl)-l ,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10- decahydrophenanthren-2-ol and (±)-(25 ^, ,4aS,8a5)-8a-(hydroxymethyl)- 1 ,4a- dimethyl-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol (3a and 3b) to provide (±)-(4aS ^* ,8a ₁ S)-8a-(hydroxymethyl)-l ,4a-dimethyl-4,4a,6,7,8,8a,9, 10- octahydrophenanthren-2(3H)-one £4);

(d) reductively methylating (±)-(4aS',8a5)-8a-(hydroxymethyl)-l,4a-dimethyl- 4,4a,6,7,8,8a,9,10-octahydrophenanthren-2(3H)-one (4) to produce (±)- (4aS,8aS)-8a-(hydroxymethyl)- 1 , 1 ,4a-trimethyl-3 ,4,4a,6,7,8,8a,9, 10, 10a- decahydrophenanthren-2( 1 H)-one (5) ;

(e) ketalizing the carbonyl group at 2 position of (±)-(4a5 ^, ,8a5)-8a- (hydroxymethyl)- 1 , 1 ,4a-trimethyl-3 ,4,4a,6,7,8,8a,9, 10, 10a- decahydrophenanthren-2(lH)-one (5) to afford (±)-(4a ,8a ,10a'i?)-r,r,4a'- trimethyl-3 4 4a' ,& ,7 ,W 9 10', 1 Oa'-decahydro- 1 'H-spiro[[ 1 ,3]dioxolane- 2,2'-phenanthrene]-8a'-yl)methanol (6) and reacting 6 with an oxidizing agent under Swem oxidation conditions to afford (±)-(4a'5',8a'5',10a ^, i?)-l',r,4a'- trimethyl-3',4 ^, ,4a ^, ,6 ^, ,7',8',8a',9',10 ^* ,10a'-decahydro-rH-spiro[[l,3]dioxolane- 2,2'-phenanthrene]-8a'-carbaldehyde (7);

(f) reacting (±)-(4a ,8a'S, 1 Oa'R)- 1 ', 1 ',4a'-trimethyl-3',4 ^, ,4a',6',7',8',8a',9', 10', 1 Oa'- decahydro- 1 'H-spiro[[l ,3]dioxolane-2,2'-phenanthrene]-8a'-carbaldehyde (7) with (chloromethyl)triphenylphosphonium chloride under Wittig reaction conditions to produce (±)-(4a ,8a'i?,10a'i?)-8a'-(2-chlorovinyl)-l',l',4a'- trimethyl-S'^'^a'^'J'^'^a'^'aO'aOa'-decahydro-l'H-spirotfl^l dioxolane- 2,2'-phenanthrene] (8);

(g) dehydrochlorinating (±)-(4a'5',8a'i?, 10a'i?)-8a'-(2-chlorovinyl)- 1 ', 1 ',4a'- trimethyl-3',4',4a',6',7',8',8a',9 ^, ,10 ^, ,10a'-decahydiO-rH-spiro[[l,3]dioxolane- 2,2'-phenanthrene] (8) to afford (±)-(4a'S,8a'i?,10a'i?)-8a'-ethynyl-l ',l ',4a'- trimethyl-3',4',4a',6',7',8',8a',9',10 ^, ,10a'-decahydro-rH-spiro[[l,3]dioxolane- 2,2'-phenanthrene] (9);

(h) deketalizing (9) to form product 10 and then allylically oxidizing the

resulting product to produce (±)-(4a5 ^, ,8ai?,10ai?)-8a-ethynyl-l,l,4a-trimethyl- 4,4a,7,8,8a,9, 10, 10a-octahydrophenanthrene-2,6( 1 H, JH)-dione (11);

(i) formylating (11) under alpha-formylation conditions to produce (±)- (3Z,4aS Z,$aS, 10ai?)-8a-ethynyl-3 ,7-b w(hydroxymethylene)- 1 , 1 ,4a- trimethyl-4,4a,7,8,8a,9, 10,10a-octahydrophenanthrene-2,6( 1 H,3H)-dione (12);

(j) forming the 6/s-isoxazole, (±)-(4aS,$aS, 10a ?)-8a-ethynyl- 1 , 1 ,4a-trimethyl- 4,4a,7,8,8a,9, 10,10a-octahydrophenanthren[3,2-i :7,6-i/]diisoxazole (13);

(k) cleaving both isoxazole rings of bis-isoxazole 13 to form (±)-(4bS,8ai?, 10aS)- 10a-ethynyl-4b,8,8-trimethyl-3 ,7-dioxo- 1 ,2,3 ,4b,5,6,7,8,8a,9, 10, 10a- dodecahydrophenanthrene-2,6-dicarbonitrile (14); and

(1) reacting (14) with phenylselenium halide and then oxidizing the resulting product to produce TBE-31.

[0010] Another embodiment of the present invention is directed to the process of preparing (±)-(4aS,8aS)-8a-(hydroxymethyl)- 1 , 1 ,4a-trimethyl-3 ,4,4a,6,7,8,8a,9, 10, 10a- decahydrophenanthren-2(lH)-one (5), which comprises: reducing the carbonyl and carboxyl groups in (±)-(4aS,8aS)-l ,4a-dimethyl-2-oxo-2,3,4,4a,6,7,8,8a,9,l O-decahydrophenanthrene- 8a-carboxylic acid to afford a first product comprising (±)-(4a5',8a5)-8a-(hydroxymethyl)- l ,4a-dimethyl-2,3,4,4a,6,7,8,8a,9, 10-decahydrophenanthren-2-ol; selectively oxidizing the hydroxyl group at the 2-position of (±)-(4aS',8aiS -8a-(hydroxymethyl)-l ,4a-dimethyl- 2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol in the first product to form a second product comprising (±)-(4a5',8aS)-8a-(hydroxymethyl)-l ,4a-dimethyl-4,4a,6,7,8,8a,9,10- octahydrophenanthren-2(3H)-one and reductively methylating the second product to form a third product comprising (±)-(4aiS',8a _I S)-8a-(hydroxymethyl)-l ,l ,4a-trimethyl- 3,4,4a,6,7,8,8a,9,10, 10a-decahydrophenanthren-2(lH)-one. [0011] In another embodiment, the present invention is directed to the process of preparing (±)-(4a5,8a5)-8a-(hydroxymethyl)-l,l ,4a-trimethyl-3,4,4a,6,7,8,8a,9,10,10a- decahydrophenanthren-2(lH)-one (5), which comprises reacting (±)-(4aS,8a5)-l ,4a- dimethyl-2-oxo-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthrene- 8a-carboxylic acid with a reducing agent consisting of sodium 6w(2-methoxyethoxy)aluminum hydride and lithium aluminum hydride to form a first product comprising a mixture of (±)-(2i?,4a5 ^, ,8a.S)-8a- (hydroxymethyl)-l ,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-o l and (±)- (25,4a5,8a5)-8a-(hydroxymethyl)-l ,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10- decahydrophenanthren-2-ol and oxidizing the first product to form a second product comprising (±)-(4a5',8a5)-8a-(hydroxymethyl)-l,4a-dimethyl-4,4a,6,7,8, 8a,9,10- octahydrophenanthren-2(3H)-one and reductively methylating the second product to form a third product comprising (±)-(4a5',8aiS)-8a-(hydroxymethyl)-l,l,4a-trimethyl- 3,4,4a,6,7,8,8a,9,10,10a-decahydrophenanthren-2(lH)-one.

[0012] A further embodiment of the present invention is directed to the intermediate products (±)-(±)-(4a5',8a ₁ S)-8a-(hydroxymethyl)-l ,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10- decahydrophenanthren-2-ol, e.g., (±)-(2i?,4aS,8a5)-8a-(hydroxymethyl)- 1 ,4a-dimethyl-

2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol (3a) and (±)-(2S,4aS,8aS)-8a-

(hydroxymethyl)-l ,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-o l (3b).

Another embodiment is directed to the mixture comprising (±)-(2i?,4a5',8a5 -8a-

(hydroxymethyl)- 1 ,4a-dimethyl-2,3,4,4a,6,7,8,8a,9, 10-decahydrophenanthren-2-ol and (±)-

(2,S,4aS,8a5 -8a-(hydroxymethyl)-l ,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10- decahydrophenanthren-2-ol. A further product is directed to (±)-(435,83.¾-83-

(hydroxymethyl)-l ,4a-dimethyl-4,4a,6,7,8,8a,9,10-octahydrophenanthren-2(3H)-o ne. DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0013] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B is true (or present).

[0014] The use of "a" or "an" are employed to describe elements and components described herein. This is done merely for convenience and to give a general sense of the scope of the invention. This description should be read to include one or at least one and the singular also includes the plural unless it is obvious that it is meant otherwise.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. [0016] When an amount, concentration, or other value or parameter is given as either a range, preferred range or a list of upper preferable values and/or lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. Where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.

[0017] Before addressing details of embodiments described below, some terms are defined or clarified.

[0018] The term "alkyl", when used alone or in combination with other term refers to a saturated hydrocarbyl radical containing one to six carbon atoms. The alkyl radical may be straight-chained or branched. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like.

[0019] The term "aryl" refers to aromatic compounds comprised solely of carbon ring atoms. Examples of aryl include aromatic compounds having from 6 to 18 ring carbon atoms, such as phenyl, naphthyl, and the like.

[0020] The term "dehydrochlorination", "dehydrochlorinating", or "dehydrochlorinated", as used herein, means a process during which hydrogen and chlorine on adjacent carbons in a molecule are removed.

[0021] The term "an elevated temperature", as used herein, means a temperature higher than room temperature. [0022] The term, "cooling temperature" refers to a temperature less than room temperature. For example, a temperature of 0 °C is included in this definition; further a temperature of about -5 to -10 °C is also included in the definition of the term cooling temperature.

[0023] The term "solvent" refers to a substance in which the reactants and products dissolve and which is inert to the reactants and products of the reaction. Examples include liquid alkanes, such as pentanes, hexanes and ethers, such as diethyl ether, dimethy ether, THF and the like, as well as methylene chloride, tetrahydrofuran, dimethyl sulfoxide, pyridine and methanol.

[0024] The term "strong base" refers to a Lewis base or Bronsted-base that is capable of removing a proton from a carbon atom. Examples of strong bases include the conjugate base of acids whose pKa is greater than about 15, e.g. 16, 17, 18, 19, and so on. Examples of strong bases, as that term is used herein, include alkali hydroxides, alkali alkoxide, alkali amide, alkali hydrocarbide, alkali arylide, alkali alkyl amide, and the like. Examples include the bases listed in Table 8.1 on pages 331-332 in March, Advanced Organic Chemistry, published by John Wiley and Sons, 2001, wherein the pKa of the corresponding acid is greater than about 15.

[0025] The term "substantially pure" refers to a product which contains less than about 20% impurity.

[0026] The term "enantiomerically pure" refers to a product which has less than about 20% of an enantiomer.

[0027] As described hereinabove, an embodiment of the present invention is the process described in scheme 2 for preparing TBE. Each of the steps is described in more detail hereinbelow. In describing the present process, reference will be made to Scheme 2; the application will make reference to Scheme 2 either by the chemical name of the intermediate or the number designated in scheme 2 hereinabove.

[0028] An aspect of the present invention is directed to a novel process for preparing TBE- 31. Unlike the process of scheme 1, the present process provides greater amounts of TBE- 31. Further, the present process avoids the problem of the prior art synthesis, as it avoids the reductive methylation step, which produces 3 products, of which only one can be used in the synthetic scheme 1 to make TBE-31. In the present process, all steps either produce a single product or if more than one product is produced in the process in any one step, all of the products in that step of the process can be used without further purification. For example, although two products are produced in the third step in scheme 2 from the reduction of the carboxylic acid, both alcohols can be used without the necessity of separating the two products. However, if one wanted to separate the two alcohols and isolate them, this can be effected by one of ordinary skill in the art without undue amount of experimentation. This is unlike the previous synthesis, which could not give a single product from reductive methylation step separation. As a result, the previous method required the products from the reductive methylation step to be separated by column chromatography, and thus is not suitable for large scale synthesis. The present method overcomes this problem, as no separation by column chromatography is necessary in the present process for those steps replacing the alpha-methylation step.

[0029] This problem was solved by reducing the carboxylic acid 2 to form the diols 3 followed by selective oxidation of one of the hydroxyl functionality in the diol to form the

2-keto derivative. Unlike the synthetic route in scheme 1, where the alpha methylation step left intact the keto group at the 2-position of the ring, while the ester group at the 8a position is reduced, in the present process, the synthetic route of the present process involves reducing the keto group at the 2-position and the carboxylic derivative substituent at the 8a position in one step. This is followed by selective oxidation of the hydroxyl group at the 2- position back to the keto group and then reductively methylating the resulting product. Thus, it appears that the present process requires 2 additional steps to replace the alpha- methylation step in the prior art synthesis. However, that additional modification not only overcame the bottleneck of the reductive methylation of the methyl ester C, but also resulted in a synthetic process which is more efficient than the process in scheme 1 in forming TBE- 31. Moreover, even though two products are produced from reducing the keto group at the 2-position and the carboxylic derivative substituent at the 8a position in one step, the mixture of both products produced from this reaction can be used in the synthesis without the need of separating them, such as by using column chromatography.

[0030] Thus, a step in the present process comprises reducing the keto group and the ester group at the 2 and 8a position of the compound of formula 2. In an embodiment, this is effected by utilizing sodium Z>/s(2-methoxyethoxy)aluminum hydride (Red-Al®). This reaction is conducted in an inert solvent, such as toluene. The reaction is conducted at an elevated temperature. In another embodiment, the reaction is effected using lithium aluminum hydride, and the like. In an embodiment, compound 2 is reduced with Red-Al® in toluene at a temperature ranging from about 90 °C to about 130 °C. The product of the reduction is a mixture of 3a and 3b, where the difference is the stereochemistry of the hydroxyl group in position 2 of the molecule. In other words, the product is (±)-(±)-

(4a ₁ S',8a5)-8a-(hydroxymethyl)-l,4a-dimethyl-2,3,4,4a,6,7, 8,8a,9,10-decahydrophenanthren- 2-ol (3), and more specifically, a mixture of (±)-(2i?,4a5',8aS -8a-(hydroxymethyl)-l,4a- dimethyl-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol (3a) and (±)-(2S,4aS,8aS)-8a- (hydroxymethyl)-l,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10-decahyd rophenanthren-2-ol (3b).

[0031] In an embodiment, reduction of 2 with Red-Al ^® (Scheme 3 and Table 1, run 1) gave a mixture of 3a and 3b in 77% yield.

[0032] Compounds 3a and 3b can be recovered, isolated and purified using techniques known to one of ordinary skill in the art, such as by chromatography, such as column chromatography or gas chromatography, HPLC and the like.

Scheme 3.

(3a : 3 b = 1 :3)

Table 1. Reduction of carboxylic acid 2 with Red-Al . run 2 13 yield (%) ^a

1 13.6 g (49.6 mmol) 9.97 g (38.0 mmol) 77

2 10.3 g (37.5 mmol) 7.53 g (28.7 mmol) 77

3 10.3 g (37.5 mmol) 7.43 g (28.3 mmol) 76

Isolated yield. Allyl alcohol oxidation of 3 with DDQ

[0033] The next step is the allyl alcohol oxidation of the mixture of diols 3a and 3b. This is effected with an oxidizing agent that selectively oxidizes the allyl alcohol at the 2-position but does not oxidize the alcohol at the 8a position. An oxidizing agent used is 2,3-dichloro- 5,6-dicyanobenzoquinone (DDQ) and the like. In an embodiment, the oxidizing agent, e.g., DDQ, is utilized in an inert solvent, e.g., 1, 4-dioxane. In another embodiment, it is heated at an elevated temperature. The allyl alcohol oxidation of 3 gave alcohol 4, which was obtained in 82-83% yield even on 10 grams scale (Scheme 4 and Table 2). Importantly, the substantially pure alcohol 4 was obtained by simple work-up procedures, i.e., removal of DDQ stuffs with 1 M aqueous NaOH solution, followed by filtration through a silica gel plug. Alternatively, compound 4 can be recovered, isolated and purified using techniques known to one of ordinary skill in the art, such as by chromatography, such as column chromatography or gas chromatography , HPLC and the like.

Scheme 4. H

3b = 1 :3)

Table 2. Allylic oxidation of diol 3a and 3b. run 3a + 3b (3a:3b=1 :3) time (h) 4 yield (%) ^a

1 9.97 g (38.0 mmol) 14 8.16 g (31.4 mmol) 83

2 8.76 g (33.4 mmol) 14 7.18 g (27.6 mmol) 83

3 14.9 g (57.0 mmol) 12 12.1 g (46.5 mmol) 82

Isolated yield.

Reductive methylation of 4

[0034] Reductive methylation of 4 produces compound 5. (Scheme 5 and Table 3). ²² It was conducted by reacting an alkali metal, such as lithium or sodium, with ammonia and then reacting the product thereof with compound 4 and water. The reaction is effected in an inert solvent, such as THE In addition, the reaction is performed under cooling temperatures, preferably at temperatures ranging from aboiut-15 °C to about -50 °C. Regardless of the reaction scale, the desired alcohol 5 was constantly obtained in good yields. The alcohol 5 could be purified by simple filtration through a silica gel plug.

Scheme 5.

Table 3. Reductive methylation of alcohol 4. run 4 5 yield (%)

1 1.04 g (4.00 mmol) 772 mg (2.79 mmol) 70

2 2.08 g (8.00 mmol) 1.72 g (6.22 mmol) 78

3 4.16 g (16.0 mmol) 3.34 g (12.1 mmol) 75

4 4.67 g (17.9 mmol) 3.71 g (13.4 mmol) 75

5 8.32 g (32.0 mmol) 6.82 g (24.7 mmol) 77

6 8.32 g (32.0 mmol) 6.77 g (24.5 mmol) 76

7 12.5 g (48.0 mmol) 10.1 g (36.4 mmol) 76

8 12.5 g (48.0 mmol) 10.3 g (37.2 mmol) 77 total 53.6 g (206 mmol) 43.5 g (157 mmol) 76

[0035] Although each of the compounds 4 and 3, e.g., 3a and 3b, could be used without further purification in the present process, compounds 4 and 3, i.e., 3a and 3b, can be separated and purified by techniques known to one of ordinary skill in the art to form substantially pure compounds of 3a, 3b and 4. Moreover, since 3a and 3b are diastereomers, they could be separated in the mixture by techniques known to one or ordinary skill in the art, such as column chromatography, HPLC, gas chromatography and the like to form enantiomerically pure compounds 3a and 3b. Thus, substantially pure and enatiomerically pure compounds of 3a, substantially pure and enatiomerically pure compounds of 3b and substantially pure and enatiomerically pure compounds of 4 can be produced and isolated and recovered from the present process, if desired.

[0036] Compound 2 was prepared from 2-carbomethoxycyclohexanone (1) and l-chloro-3- pentanone via Robinson annulations (Scheme 6) in the presence of a base, such as an alkali metal or a strong base. The reaction is conducted in an inert solvent, such as methanol. The reaction is conducted at elevated temperatures, for e.g., reflux temperature of the solvent, such as methanol and the like. In an embodiment, the reaction was conducted in methanol under reflux in the presence of a base. The desired compound 2 (27 g) was obtained from 1 (20 g) in 77% yield without column chromatography purification. The purity of 2 was confirmed by Ή NMR to be good enough for use without further purification.

Scheme 6.

20.0 g (128 mmol) 27.1 g (77%)

[0037] Compound 1 is prepared from cyclohexanone and dimethyl carbonate in the presence of a strong base, for example, sodium hydride and/or potassium hydride. The reaction is conducted in an inert solvent, such as methanol. In addition, the reaction is conducted at elevated temperatures, such as at the reflux temperature of the solvent. In an embodiment, the reaction is conducted at reflux temperatures in methanol in the presence of an alkali hydride, such as sodium hydride and potassium hydride and the like. The reaction is depicted below:

C ₆ H ₁₀ O ( W: 98.14) 1, C ₈ H ₁₂ 0 ₃ ( W: 156.18)

[0038] From compound 5, the strategy is to add a carbon atom to position 8a of the ring of compound 5 by converting the hydroxymethyl substituent at position 8a of the ring to an aldehyde and then adding via a Wittig reaction a carbon atom to the 8a position followed by dehydrochlorination to form the ethyne group at position 8a of the ring. [0039] The keto group in position 2 of the ring is next protected using techniques known in the art so that it does not react with the reagents used in the next few steps. In an embodiment, it is ketalized. For example, it is ketalized with an alkylene diol in a solvent that is non-reactive under ketalization forming conditions. For example, in an embodiment, compound 4 is ketalized with ethylene glycol in the presence of pyridinium p- toluenesulfonate ('PPS") in an inert solvent, such as benzene and toluene. The reaction takes place at temperatures sufficient to affect the ketalization. The temperature for this reaction may range from room temperature until the reflux temperature of the solvent. Thus, for example, reacting 4 with ethylene glycol in benzene under reflux in the presence of PPS affords compound 5 in quantitative yield, regardless of the reaction scale (Scheme 7 and Table 4). This material was used for the next step without column chromatography purification.

Scheme 7.

Table 4. Ketalization of ketone 4 using ethylene glycol. run 4 5 yield (%)

I .11 g (4.00 mmol) 1 .28 g 100

2 I I .1 g (40.0 mmol) 13.6 g 100 3 22.2 g (80.0 mmol) 27.2 g 100 4 10.1 g (36.5 mmol) 12.8 g 100

Crude yield. [0040] A series of reactions follow in order to add a carbon atom to carbon 8a of the ring. To effect this objective, the next step in the process is to convert the hydroxymethylene functionality in 5 to an aldehyde. This is effected by oxidizing 5 with an oxidizing agent without the formation to the corresponding carboxylic acid. In an embodiment, 5 is oxidized under Swern oxidation reaction conditions using an oxidizing agent. This is effected by oxidizing 5 under conditions to form the corresponding aldehyde substantially free of the formation of the corresponding carboxylic acid. For example, this oxidation may be achieved by the treatment of 5 with DMSO, DCC and anhydrous phosphoric acid under Moffatt oxidation reaction conditions. Other reagents include DMSO with any of the following: acetic anhydride, S0 ₃ -pyridine-triethylamine, trifluoroacetic anhydride, tosyl chloride, P ₂ 0 ₅ -Et ₃ N, trichloromethyl chloroformate, trimethylamine N-oxide, KI and

NaHC0 ₃ and methanesulfonic anhydride, and oxalyl chloride, and the like. In an

embodiment, the reaction is conducted under Swern oxidation conditions using oxalyl chloride and DMSO. In another embodiment, the Swern oxidation of 5 is conducted using oxalyl chloride and DMSO in the presence of Et ₃ N in an inert solvent, such as CH ₂ C1 ₂ .

(Scheme 8 and Table 5). The reaction may be conducted under cooling temperature, such as at a temperature ranging from -20 °C to about -80 °C Regardless of the reaction scale, desired aldehyde 6 was obtained in quantitative yield. In an embodiment, it is conducted at - 60 °C. This material was used for the next step without column chromatography purification.

Scheme 8.

Table 5. Swern oxidation of alcohol 5. run 5 6 yield (%)'

1.28 g (4.00 mmol) 1.30 g 100

2 13.6 g (40.0 mmol) 13.6 g 100 3 27.2 g (80.0 mmol) 26.0 g 100 4 12.7 g (36.5 mmol) 12.4 g 100

³ Crude yield.

[0041] The addition of the carbon atom to the molecule at position 8a is effected by a Wittig reaction. More specifically, aldehyde 6 is reacted with the ylide, which is generated from (chloromethyl)triphenylphoshonium chloride in the presence of a strong base, such as butyllithium, sodium amide, and sodium hydride or sodium alkoxide under Wittig reaction conditions. In an embodiment, the base used is ^-butyllithium. In another embodiment, the Wittig reaction was conducted using «-butyllithium in the presence of HMPA as the strong base in an inert solvent, such as diethyl ether, THF and the like. (Scheme 9 and Table 6). The reaction may be conducted at a temperature ranging from room temperature up to the reflux temperature of the solvent, although in an embodiment, it may be conducted at temperatures ranging from about room temperature until about 50 °C. The following scheme illustrates an embodiment for the Wittig reaction used in this process. In runs 1 and 2, the corresponding chloroalkene 7 was obtained in 80-81% yield. Scheme 9.

Table 6. Wittig reaction of aldehyde 6. run 6 7 yield (%) ^a

1 13.6 g (40.0 m mol) 11.3 g (32.2 mmol) 81

2 12.4 g (36.5 mmol) 10.2 g (29.1 mmol) 80 a Isolated yield.

[0042] Compound 7 was next dehydrochlorinated to form the corresponding alkyne at position 2 of the ring under conditions effective to form the alkyne. Dehydrochlorination reaction was conducted in the presence of a strong base, such as alkyl lithium or sodium alkoxide, sodium hydride, and the like. In one embodiment, the strong base is MeLi. The reaction is effected in an inert solvent, such as ether, such as in THF. The reaction may be conducted at a temperature ranging from about room temperature up to the reflux temperature of the solvent, although in an embodiment, it may be conducted at temperatures ranging from about room temperature to about 50 °C. Quenching of the acetylide thus produced with a Lewis acid, such as aqueous NH ₄ C1 solution provided terminal alkyne 8 in 95-96% yield, regardless of the reaction scale (Scheme 10 and Table 7). This material was used for the next step as a crude product. Scheme 10.

Table 7. Dehydrochlorination of 7 with methyllithium. run 7 time (h) 8 yield (%) ^a

1 1 .12 g (3.19 mmol) 16 961 mg (3.06 mmol) 96

2 1 1.3 g (32.2 mmol) 14 9.68 g (30.8 mmol) 96

3 10.2 g (29.1 mmol) 16 8.65 g (27.5 mmol) 95

4 18.2 g (51.9 mmol) 16 15.5 g (49.2 mmol) 95 a Crude yield.

[0043] The protecting group, for example, the ketal, was removed using techniques known in the art. In an embodiment, the ketal of 8 was removed under acidic conditions to produce 9 in excellent yield (Scheme 11 and Table 8). It is conducted under conditions effective for removal of the ketal. For example, it is conducted in an inert solvent, such as THF or MeOH/THF mixture. The reaction may be conducted at a temperature ranging from about room temperature up to the reflux temperature of the solvent, although in an embodiment, it may be conducted at temperatures ranging from about room temperature until about 50 °C. This material was used in the next step without column chromatography purification.

Scheme 11.

Table 8. Deketalization of 8. run yield (%) ^a

961 mg (3.06 mmol) 830 mg (3.06 mmol) 100

2 9.68 g (30.8 mmol) 8.13 g (30.1 mmol) 98 3 8.65 g (27.5 mmol) 7.33 g (27.1 mmol) 99 4 11.5 g (36.6 mmol) 9.65 g (35.7 mmol) 98

Crude yield.

[0044] The next strategy is to form the dicyano substituents, which is effected in several steps.

[0045] The next step is the oxidation of 9 to form an oxo substituent at the 6-position of the ring, i.e., the position on the ring which is allylic to the carbon-carbon double bond in the ring. Compound 9 is subjected to allylic oxidation using an oxidizing agent, such as Cr0 ₃ , and organic peroxide, t-BuOOH. The reaction is conducted under oxidizing conditions. In an embodiment, it is conducted in an inert solvent, such as methylene chloride. The reaction is conducted at cooling temperatures such as, in one embodiment, ranging from about 0 °C to about -50 °C. For example, in an embodiment, 9 is reacted with chromium oxide (1.4 equiv) and t-BuOOH (10 equiv) in CH ₂ C1 ₂ afforded the corresponding diketone 10 in 60- 63% isolated yield, regardless of the reaction scale (Scheme 12 and Table 9). In this step, column chromatography purification was necessary.

Scheme 12.

Table 9. Allylic oxidation of 9 using Cr0 ₃ and t-BuOOH. run 9 10 yield (%) ^a

1 830 mg (3.06 mmol) 545 mg (1.92 mmol) 63

2 8.13 g (30.1 mmol) 5.13 g (18.0 mmol) 60

3 7.33 g (27.1 mmol) 4.70 g (16.5 mmol) 61

4 9.65 g (35.7 mmol) 6.14 g (21.6 mmol) 61

⁹ Isolated yield.

[0046] The next step is double a-formylation of 10 with an alkyl formate or formic acid in the presence of a strong base, such as NaOMe, and the like; this reaction affords the desired compound 11. This reaction is conducted under effective conditions to form compound 11. It may be conducted in an inert solvent, such as benzene, toluene and the like. It is conducted at temperatures ranging from about room temperature to the reflux temperature of the solvent, although in an embodiment, it is conducted at a temperature ranging from about room temperature to about 50 °C. For example, double alpha-formylating 10 with an HC0 ₂ Et (11 equiv) in the presence of NaOMe (11 equiv) in an inert solvent, e.g., benzene, afforded the desired compound 11 in 95-100% yield (Scheme 13 and Table 10). This crude material was used in the next step.

Scheme 13.

Table 10. α-Formylation of 10 using HC0 ₂ Et. run 10 11 yield (%) ^a

1 1.00 g (3.50 mmol) 1.20 g (3.50 mmol) 100

2 9.37 g (32.9 mmol) 1 1.1 g (32.9 mmol) 100

3 6.14 g (21.6 mmol) 6.95 g (20.4 mmol) 95

Crude yield.

[0047] The next step is forming the δ/ ^' s-isoxazole under effective conditions. In one embodiment, 11 is treated with an hydroxylamine acid salt. The treatment of 11 with acid such as hydroxylamine hydrochloride, NH ₂ 0H-HC1, gives the corresponding Zw-isoxazole 12. The reaction can be conducted at a temperature ranging from about room temperature to the refluxing temperature of the solvent. Thus, for example, in an embodiment, the treatment of 11 with N¾0H.HC1 (16 equiv) in an inert solvent, such as aqueous EtOH gave the corresponding to-isoxazole 12 in 94-99% yield, regardless of the reaction scale (Scheme 14 and Table 11). This material was used for the next step without column chromatography purification.

Scheme 14.

Table 11. Condensation of 11 with NH ₂ OH-HCl. run 11 12 yield (%) ^a

1 1.20 g (3.50 mmol) 1.11 g (3.33 mmol) 94

2 11.1 g (32.9 mmol) 10.8 g (32.9 mmol) 98

3 6.95 g (20.4 mmol) 6.72 g (20.1 mmol) 99 a Crude yield. [0048] The next step is cleaving the isoxazole ring of 12 with strong base, such as hydroxide, alkali amide, or alkali alkoxide, to give the nitrile. This reaction is conducted under effective conditions. It is conducted in an inert solvent, such as ethers, e.g., diethyl ether, methyl ethyl ether, THF and the like. It is conducted at a temperature ranging from about room temperature to the reflux temperature of the solvent. For example, cleavage of the isoxazole ring with sodium methoxide gave nitrile 13 in 97-100% yield (Scheme 15 and Table 12). This material was used for the next step without column chromatography purification.

Scheme 15.

Table 12. Isoxazole ring cleavag run 12 13 yield (%) ^a

1 1.1 1 g (3.33 mmol) 1 .10 g (3.33 mmol) 100

2 10.8 g (32.9 mmol) 10.9 g (32.3 mmol) 100

3 6.72 g (20.1 mmol) 6.49 g (19.4 mmol) 97 a Crude yield.

[0049] Finally, in the last step, nitrile 13 was selenated and the resulting product was treated with an oxidizing agent, such as hydrogen peroxide, sodium iodate, and the like to afford a, β-unsaturated ketones, that is, TBE-31. In an embodiment, nitrile 13 was treated with PhSe hal, where hal is a halide. The reaction is conducted in the presence of a weak base, such as pyridine and the like. It is conducted in an inert solvent, such as methylene chloride and the like. Further, it is conducted at effective temperatures, such as cooling temperatures. In an embodiment, it is conducted at a temperature ranging from room temperature to -20 °C.

[0050] Subsequent oxidation/elimination of the selenated intermediate with an oxidizing agent, such as 30% aqueous H ₂ 0 ₂ solution affords TBE-31. The reaction is conducted in an inert solvent, such as methylene chloride. Further, it is conducted at effective temperatures, such as cooling temperatures. In an embodiment, it is conducted at a temperature ranging from room temperature to -20 °C. The overall yield was 59%, regardless of the reaction scale (Scheme 16 and Table 13). As this is the last step in the process, the product was purified. For example, TBE-31 is purified using techniques known to one of ordinary skill in the art, such as chromatography, for example column chromatography, GC or HPLC.

Scheme 16.

Table 13. ot-Phenylselenation and subsequent oxidation/elimination of 13. run 13 TBE-31 yield (%) ^a

1 1.10 g (3.33 mmol) 644 mg (1.95 mmol) 59

2 10.9 g (32.3 mmol) 6.25 g 18.9 mmol) 59

3 6.49 g (19.4 mmol) 3.78 g (11.4 mmol) 59 total 10.67 g (32.3 mmol)

a Isolated yield. [0051] This process forms TBE-31 in higher yield than heretofore. More specifically according to the present process, TBE is synthesized in 15 steps and has a greater than 10% yield from cyclohexanone, which is a very inexpensive material. Because the molecular weight of TBE-31 (330.38 g) is three times larger than that of cyclohexanone (98.14 g), 10 g. of TBE-31 can be synthesized from 30 grams cyclohexanone.

[0052] Another embodiment of the present invention is directed to the novel intermediates in the synthetic process described hereinabove. For example, an aspect of the present invention is directed to the intermediate products, 8a-(hydroxymethyl)-l ,4a-dimethyl- 2,3,4,4a,6,7,8,8a,9, 10-decahydrophenanthren-2-ol and 8a-(hydroxymethyl)-l ,4a-dimethyl- 4,4a,6,7,8,8a,9, 10-octahydrophenanthren-2(3H)-one, e.g., (4aS ^, ,8a5)-8a-(hydroxymethyl)- l ,4a-dimethyl-4,4a,6,7,8,8a,9,10-octahydrophenanthren-2(3H)-o ne (4). Another

embodiment is directed to the products (±)-(2i?,4a ₁ S ^, ,8a5)-8a-(hydiOxymethyl)-l ,4a-dimethyl- 2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol (3a) and (±)-(2£4aS,8aS)-8a- (hydroxymethyl)- 1 ,4a-dimethyl-2,3 ,4,4a,6,7,8,8a,9, 10-decahydrophenanthren-2-ol (3b). Although these latter two compounds are not isolated from each other in the schemes described hereinabove, both of them can be individually isolated using techniques known in the art, such as column chromatography, and the like, as described hereinabove.

[0053] The present invention is further illustrated by the following non-limiting example, which provides the synthetic route for preparing TBE-31 , in accordance with the present invention. EXAMPLE General procedures.

[0054] In the procedure for the preparation of TBE-31 outlined below, physical data were obtained as follow: The melting points were determined on a Thomas Hoover capillary melting point apparatus melting point apparatus and are uncorrected. H (300 MHz) and C (75 MHz) NMR spectra were recorded on a Varian XL-300 Fourier transform spectrometer. The chemical shifts are reported in δ (ppm) using the δ 7.27 signal of CHC1 ₃ (Ή NMR) and the δ 77.23 signal of CDC1 ₃ ( C NMR) as internal standards. Low-resolution mass spectra and high resolution MS data were obtained on a Micromass 70-VSE (EI method) and Micromass Q-Tof Ultima (ESI+ method). Elemental analyses were performed by Atlantic Microlab Inc. All samples prepared for elemental analysis or supplied for biological evaluation were dried at 50-60 °C at reduced pressure (< 0.1 Torr) in a National Appliance Company model 5831 vacuum oven unless otherwise stated. TLC was performed using plates precoated with silica gel 60 F254. Flash column chromatography was done with silica gel (230-400 mesh). Anhydrous THF and CH ₂ C1 ₂ were obtained from a solvent purification system. All other solvents (analytical grade) including anhydrous solvents and reagents were used as received.

[0055] All experiments were performed under a nitrogen atmosphere unless otherwise stated. I. (±)-2-Methoxycarbonylcyclohexanone (1).

C ₆ H ₁₀ O ( W: 98.14) 1, C ₈ H ₁₂ 0 ₃ (MW: 156.18) [0056] To sodium hydride (60% oil dispersion, 10 g, 250 mmol, 3.1 equiv) was added a solution of dimethyl carbonate (18.02 g, 200 mmol, 2.5 equiv) in dry THF (50 mL). The mixture was stirred at reflux temperature (100 °C), and then, a solution of cyclohexanone (7.8 g, 80 mmol) in dry THF (20 mL) was added dropwise to the mixture using a syringe pump. After two minutes of addition, potassium hydride (30% oil dispersion, 0.9 g) was added to initiate the reaction. The addition of cyclohexanone was continued over a period of 1 h. The mixture was refluxed and stirred for an additional 30 min after complete addition of cyclohexanone, when the reaction mixture lumped. It was cooled down in an ice bath for 20 min. The mixture was hydrolyzed by the slow addition of 3 M aqueous acetic acid (75 mL), then poured into brine (100 mL) and extracted with CH ₂ C1 ₂ (150 mL χ 4). The combined organic layers were dried over MgS0 ₄ and filtered. The filtrate was evaporated in vacuo to give a thick yellow liquid (17.2 g). The liquid was distilled under reduced pressure to give 2 (11.3 g, 91%) as a colorless liquid [bp 38-43 °C (0.05 -0.075 mmHg, bath temp: 75-78 °C)].

II. (±)-(4aS,8aS)-l,4a-dimethyl-2-oxo-2,3,4,4a,6,7,8,8a,9,10- decahydrophenanthrene-8a-carboxylic acid (2)

1, C ₈ H ₁₂ 0 ₃ ( W: 156.18) 2 C ₁₇ H ₂₂ 0 ₃ (MW: 27 ₄ .35)

[0057] To dry methanol (256 mL) was added sodium metal (11.8 g, 0.512 mol, 2.3 equiv) in an ice bath. After the sodium was completely dissolved in methanol, 2- carbomethoxycyclohexanone (20.0 g, 0.128 mol) was added. The mixture was heated under reflux. Then, to the mixture was added l-chloro-3-pentanone (40 mL, 0.30 mol, 4.0 equiv) using a syringe pump under reflux over 14 h. After the complete addition, the mixture was stirred for an additional 6 h. After removal of methanol in vacuo, C¾C1 ₂ (200 mL) and 5% aqueous HC1 solution (200 mL) were added to acidify the mixture. The acidic mixture was extracted with CH ₂ C1 ₂ (200 mL). The organic solution was extracted with 1 M aqueous NaOH solution (300 mL 2). The basic solution was washed with CH ₂ C1 ₂ (500 mL) and acidified with concentrated aqueous HC1 solution (100 mL) to give a precipitate. It was extracted with CH ₂ C1 ₂ (300 mL χ 2). The extract was washed with brine (500 mL), dried over MgS0 ₄ , and filtered. The filtrate was concentrated in vacuo to give 2 (27.1 g, 77%) as a crystalline solid: Ή NMR (400 MHz, CDC1 ₃ ) δ 5.88 (1H, dd, J= 3.8, 3.8 Hz), 2.66-2.43 (5H, s), 2.25 (1H, ddd, J= 2.2, 2.2, 18.5 Hz), 2.20-2.07 (2H, m), 2.07-1.97 (2H, m), 1.88- 1.76 (1H, m), 1.77 (3H, s), 1.73-1.62 (3H, m), 1.55 (1H, ddd, J= 3.4, 13.7, 13.7 Hz), 1.46- 1.36 (3H, m), 1.29 (3H, s). This material was used for the next reaction without further purification.

III. (±)-(2R,4aS,8aS)-8a-(Hydroxymethyl)-l,4a-dimethyl-2,3,4,4a, 6,7,8,8a,9,10- decahydrophenanthren-2-ol (3a) and (±)-(2S,4aS,8a5)-8a-(hydroxymethyl)-l,4a- dimethyl-2,3)4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol (3b).

2 C ₁₇ H _Z2 0 ₃ ( W: 274.35) 3a 3b

Ci ₇ H ₂₆ 0 ₂ (MW: 262.39)

[0058] To a solution of 2 (10.6 g, 38.6 mmol) in toluene (430 mL) was added sodium bis(2- methoxy-ethoxy)aluminium hydride (Red-AI ^® , 3.5 M in toluene, 44.1 mL, 154 mmol, 4.0 equiv) at 110 °C. The solution was stirred at the same temperature for 14 h. The reaction mixture was cooled with an ice bath and water (11 mL), 1 M aqueous NaOH solution (3.7 mL), and water (11 mL) were added. The organic layer was washed with 1 M aqueous NaOH solution (500 mL), water (500 mL), and brine (500 mL), dried over MgS0 ₄ , filtered, and concentrated in vacuo to give a residue. The residue was roughly purified with a short silica gel pad (Si0 ₂ , 200 mL (8 cm diameter column, 4 cm height); hexanes/AcOEt (3/1), 2 L) to give 3a and 3b [8.76 g, 77% as a mixture of two diastereomers (1 :3)] as a colorless solid. [Analytical samples, 3a and 3b, were obtained by flash column chromatography (hexanes/AcOEt: 3/1).]

[0059] 3a: mp 145-146 °C; Ή NMR (400 MHz, CDC1 ₃ ) δ 5.80 (IH, dd, J= 3.8, 3.8 Hz), 3.87 (IH, s), 3.78 and 3.76 (each IH, ABq, J= 11.0 Hz), 2.45 (IH, ddd, J= 1.5, 1.5, 14.6 Hz), 2.19-2.08 (3H, m), 1.99-1.74 (5H, m), 1.78 (3H, d, J= 0.7 Hz), 1.69 (IH, m), 1.67- 1.52 (2H, m), 1.47 (IH, brs), 1.33 (IH, brs), 1.23-1.13 (2H, m), 1.14 (3H, s); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 147.1, 140.6, 125.6, 123.9, 69.5, 66.6, 40.4, 39.5, 36.3, 35.1, 31.6, 28.3, 28.2, 25.9, 22.3, 17.91, 17.85.

[0060] 3b: mp 147-150 °C; Ή NMR (400 MHz, CDC1 ₃ ) δ 5.71 (IH, dd, J= 3.8, 3.8 Hz), 4.01 (IH, dd, J= 7.2, 7.2 Hz), 3.76 (2H, s), 2.44 (IH, ddd, J= 3.9, 3.9, 14.6 Hz), 2.19 (IH, m), 2.13 (IH, dd, J= 3.9, 4.9 Hz), 2.11 (IH, dd, J= 1.1, 4.0 Hz), 2.04 (1H, m), 1.92-1.70 (5H, m), 1.73 (3H, s), 1.63-1.52 (2H, m), 1.39 (IH, brs), 1.30 (IH, brs), 1.22 (3H, s), 1.25- 1.05 (2H, m); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 146.6, 139.7, 127.1, 123.6, 71.4, 66.9, 40.9, 39.6, 36.6, 35.6, 34.3, 29.8, 29.7, 25.8, 22.8, 17.9, 15.2; MS (ESI+) m/z 285.2 [M+Na] ⁺ ; HRMS (ESI+) calcd for Ci ₇ H ₂₆ 0 ₂ + Na 285.1830, found 285.1825. IV. (±)-(4aS,8aS)-8a-(Hydroxymethyl)-l,4a-dimethyl-4,4a,6,7,8,8 a,9,10- octahydrophenanthren-2(3H)-one (4).

3a 3b 4 C ₁₇ H ₂₄ 0 ₂ (MW: 260.37)

Ci ₇ H ₂₆ 0 ₂ (MW: 262.39)

[0061] To a solution of 3 (14.9 g, 57.0 mmol) in 1 ,4-dioxane (710 mL) was added DDQ (19.4 g, 85.5 mmol, 1.5 equiv) and stirred at 40 °C for 12 h. After removal of 1 ,4-dioxane in vacuo, the resulting residue was dissolved in CH ₂ C1 ₂ (500 mL). The mixture was washed with 1 M aqueous NaOH solution (500 mL), water (500 mL), and brine (500 mL), dried over MgS0 ₄ , and concentrated in vacuo. The residue was roughly purified with a short silica gel pad (Si0 ₂ , 300 mL (8 cm diameter column, 6 cm height); hexanes/AcOEt (2/1), 1.8 L) to give 4 as a crystalline solid (12.1 g, 82%): mp 135-136 °C; Ή NMR (400 MHz, CDC1 ₃ ) δ 5.74 (1H, dd, J= 3.8, 3.8 Hz), 3.85 and 3.74 (each 1H, ABq, J= 11.2 Hz), 2.59 (1H, ddd, J = 4.2, 5.7, 15.7 Hz), 2.58-2.41 (3H, m), 2.20-2.13 (2H, m), 2.10-2.05 (2H, m), 2.01 (1H, ddd, J= 4.2, 5.7, 13.6 Hz), 1.86-1.80 (2H, m), 1.78 (3H, d, J= 0.9 Hz), 1.67-1.58 (2H, m), 1.32 (3H, s), 1.30-1.14 (2H, m); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 198.6, 163.4, 145.3, 128.4, 124.6, 66.3, 41.1 , 39.4, 35.0, 34.2, 34.1, 33.1 , 27.6, 25.6, 25.0, 17.5, 11.4; MS (ESI+) m/z 261.2 [M+H] ⁺ ; HRMS (ESI+) calculated for Ci ₇ H ₂₄ 0 ₂ + H 261.1855, found 261.1849.

V. (±)-(4aS,8aS)-8a-(Hydroxymethyl)-l,l,4a-trimethyl-3,4,4a,6, 7,8,8a,9,10,10a- decahydrophenanthren-2(lH)-one (5).

4 C ₁₇ H ₂₄ 0 ₂ (MW: 260.37) 5 C ₁₈ H _2e 0 ₂ (MW: 276.41 )

[0062] To liquid ammonia (400 mL) was added lithium (sliced ribbon, 2.40 g, 339 mmol,

7.2 equiv). The solution was stirred at -78 °C for 1 h. Compound 4 (12.5 g, 48.0 mmol) and water (864 mg, 48.0 mmol, 1.0 equiv) in THF (192 mL) were added dropwise and the mixture was stirred under reflux at -33 °C (bp of ammonia) (with the aid of a CC1 ₄ bath) for

1 h. The mixture was cooled to -78 °C and isoprene (approx. 10.5 mL) was injected until the blue color disappeared turning the solution cloudy white. To this mixture were successively added THF (69.6 mL) and iodomethane (69.6 mL, 1.12 mol, 23 equiv) dropwise. The reaction mixture was stirred under reflux at -33 °C for 1 h. After removal of the ammonia with the aid of a nitrogen stream, saturated aqueous NH ₄ C1 solution (100 mL) was added and the aqueous mixture was extracted with AcOEt (100 mL χ 2). The extract was dried over MgS0 ₄ , filtered, and concentrated in vacuo. The residue was roughly purified with a short silica gel pad (Si0 ₂ , 250 mL (8 cm diameter column, 5 cm height); hexanes/AcOEt (3/1), 1.3 L) to give 5 as a crystalline solid (10.3 g, 78%): Ή NMR (300

MHz, CDC1 ₃ ) δ 5.67 (1H, dd, J= 3.8, 3.8 Hz), 3.68 (2H, s), 2.68 (1H, ddd, J= 6.6, 12.5,

15.7 Hz), 2.43 (1H, ddd, J= 3.3, 5.9, 15.7 Hz), 2.20-1.00 (14H, m), 1.20 (3H, d, J= 0.6 Hz),

1.08 (3H, s), 1.06 (3H, s); ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 217.0, 148.0, 123.0, 67.0, 54.1 ,

47.9, 39.7, 39.0, 38.0, 37.1, 36.7, 34.9, 26.1, 26.0, 22.6, 21.8, 19.7, 18.1; MS (EI) m/z 276

[M] ⁺ , 245, 227, 203; HRMS (EI) calcd for C ₁₈ H ₂₈ 0 ₂ 276.2089, found: 276.2082. VI. (ii^a'S^a'SaOa'^-l l'^a'-Trimethyl-S'^'^aSe T S Sa'^ lO lOa'- decahydro-l'H-spiro[[l,3]dioxoIane-2,2'-phenanthrene]-8a'-yl )methanol (6).

5 C ₁₈ H ₂₈ 0 ₂ (MW: 276.41) 6 C20H32O3 (MW: 320.47)

[0063] A mixture of 5 (11.1 g, 40.0 mmol), PPTS (2.01 g, 8.00 mmol), and ethylene glycol (16 mL) in benzene (143 mL) was heated under reflux with a Dean-Stark apparatus for 3 h. The mixture was washed with saturated aqueous NaHC0 ₃ solution (150 mL χ 2), and brine (150 mL), dried over MgS0 ₄ , filtered, and concentrated to give 6 (12.8 g, 100%) as an amorphous solid: Ή NMR (300 MHz, CDC1 ₃ ) δ 5.66 (1H, t, J= 3.8 Hz), 3.98 (4H, m), 3.67, 3.60 (each 1H, ABq, J= 11.0 Hz), 2.07 (2H, m), 1.89-1.15 (13H, m), 1.09, 0.96, 0.86 (each 3H, s); ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 148.9, 121.9, 113.2, 67.6, 65.1, 65.0, 51.8, 42.6, 39.6, 39.2, 37.6, 37.4, 36.0, 27.4, 26.0, 23.1, 22.8, 20.1, 18.8, 18.3; MS (ESI+) m/z 321 [M+H] ⁺ ; HRMS (ESI+) calcd for C ₂₀ H ₃₂ O ₃ + H 321.2430, found 321.2442. This material was used for the next reaction without further purification.

VII. (ii^a'S^a'SaOa'Ri-l l'^a'-Trimeth l-S'^'^a'^' SS Sa'^'aO'aOa'- decahydro-l'H-spiro[[l,3]dioxolane-2,2'-phenanthrene]-8a'-ca rbaldehyde (7).

6 C ₂ oH320 ₃ (MW: 320.47) 7 C ₂₀ H ₃₀ O ₃ (MW: 318.45)

[0064] To anhydrous CH ₂ C1 ₂ (100 mL) in a pre-dried round bottomed flask was added oxalyl chloride (3.77 mL, 44.0 mmol, 1.1 equiv). The solution was cooled to -78 °C for 20 min. A solution of DMSO (6.82 mL, 96.0 mmol, 2.4 equiv) in CH ₂ C1 ₂ (20 mL) was added slowly to the reaction flask. The reaction mixture was stirred at -78 °C for 10 min. Then a solution of 6 (12.8 g, 40.0 mmol) in CH ₂ C1 ₂ (40 mL) was added slowly over 5 min. The reaction mixture was stirred for 20 min at -60 °C, followed by slow addition of

triethylamine (28 mL, 200 mmol, 5.0 equiv) at that temperature. The cooling bath was removed and water (150 mL) was added when at room temperature. Stirring was continued for 10 min, and then the organic layer was separated. The aqueous layer was extracted with CH ₂ C1 ₂ (100 mL χ 2). The organic layers were combined and washed with 5 % aqueous HC1 solution (300 mL), water (300 mL), saturated aqueous Na ₂ C0 ₃ solution (300 mL), water (300 mL), then dried over MgS0 ₄ , filtered, and concentrated in vacuo to give 7 (12.7 g, 100%) as a pale yellow crystalline solid: Ή NMR (300 MHz, CDC1 ₃ ) δ 9.69 (1H, d, J= 1.1 Hz), 5.80 (1H, t, J= 4.0 Hz), 3.98 (4H, m), 2.39 (1H, dt, J= 13.2, 2.9 Hz), 2.14 (2H, m), 1.84 (2H, m), 0.90, 0.89, 0.83 (each 3H, s); ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 206.4, 146.2, 121.8, 113.2, 65.3, 65.0, 51.3, 50.6, 42.6, 39.9, 35.7, 35.2, 34.8, 27.3, 25.9, 23.2, 21.1, 20.0, 19.5, 18.5; MS (ESI+) m/z 319 [M+H] ⁺ ; HRMS (ESI+) calcd for C ₂₀ H ₃₀ O ₃ + H 319.2273, found 319.2276. This material was used for the next reaction without further purification.

VIII. (±)-(4a'S,8a'R,10a'R)-8a ^, -(2-Chlorovinyl)-l ^, ,l',4a ^, -trimethyI- S'^'^a'^'^ S Sa'^ lO lOa'-decahydro-l'H-s irotll^ldioxolane-l^'-phenanthrene]

(8).

7 C ₂ oH ₃₀ 03 (MW: 318.45) 8 C ₂₁ H ₃₁ CI0 ₂ (MW: 350.92) [0065] To a suspension of (chloromethyl)triphenylphosphonium chloride (61.4 g, 168 mmol, 4.2 equiv) in anhydrous THF (182 mL) was added «-BuLi (105 mL, 1.6 M in hexane, 168 mmol, 4.2 equiv) dropwise in an ice bath. To the mixture was added

hexamethylphosphoramide (HMPA, 29.2 mL, 168 mmol, 4.2 equiv). The mixture was stirred at room temperature for 30 min and then a solution of 7 (12.7 g, 40.0 mmol) in anhydrous THF (180 mL) was added at 0 °C. The mixture was stirred at room temperature for 1 h. Saturated aqueous NH ₄ C1 solution (300 mL) was added and the aqueous mixture was extracted with CH ₂ Cl ₂ -Et ₂ 0 (1 :2, 200 mL χ 2). The extract was washed with brine (500 mL x 2), dried over MgSC filtered, and concentrated to give a brown residue. The residue was dissolved in CH ₂ C1 ₂ (50 mL), and silica gel (100 g) was added to afford homogeneous powder. It was roughly purified with a short silica gel pad (Si0 ₂ , 250 mL (8 cm diameter column, 5 cm height); hexanes/Et ₂ 0 (10/1), 1.8 L) to give 8 (E-isomer: Z- isomer =1 :4, 11.3 g, 81%) as a colorless oil: ^! H NMR (300 MHz, CDC1 ₃ ) δ 6.32 (0.2H, d, J = 13.9 Hz), 5.89 (1.6H, s), 5.86 (0.2H, d, J= 13.9 Hz), 5.52 (0.2H, t, J= 4.0 Hz), 5.49 (0.8H, t, J= 4.0 Hz), 3.97 (4H, m), 2.85 (1H, dt, J= 13.6, 3.1 Hz), 1.13 (2.4H, s), 1.04 (0.6H, s), 0.96 (2.4H, s), 0.95 (0.6H, s), 0.85 (3H, s); MS (FAB) m/z 387 [M+Na] ⁺ and 351 [M+H] ⁺ .

IX. (±)-(4a'S,8a'R,10a ^, R)-8a ^, -Ethynyl-l',l ^, ,4a ^, -trimethyI-

3S4 4a ^, ,6 ^, ,7 ^, ,8',8a ^, ,9 ^, ,10',10a ^, -decahydro-l'H-spiro[[l,3]dioxolane-2,2 ^, -phenanthrene]

(9).

8 C ₂₁ H ₃₁ CI0 ₂ (MW: 350.92) 9 C ₂₁ H ₃ o0 ₂ (MW: 314.46) [0066] To a solution of 8 (11.3 g, 32.2 mmol) in anhydrous THF (81 mL) was added MeLi (1.6 M in Et ₂ 0, 50.3 mL, 80.5 mmol, 2.5 equiv) dropwise in an ice bath. The mixture was stirred at room temperature for 14 h. To the reaction mixture was added saturated aqueous NH ₄ C1 (50 mL) solution dropwise in an ice bath. The aqueous mixture was extracted with CH ₂ C1 ₂ -Et ₂ 0 (1 :2, 50 mL χ 3). The extract was washed with brine (150 mL), dried over MgS0 ₄ filtered, and concentrated in vacuo to give 9 (9.68 g, 96%) as a crystalline solid: 1H NMR (300 MHz, CDC1 ₃ ) δ 5.48 (1H, t, J= 3.67 Hz), 3.97 (4H, m), 2.15 (1H, s), 1.36, 1.00, 0.86 (each 3H, s); ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 147.9, 119.2, 113.3, 93.0, 68.8, 65.1, 65.0, 52.0, 43.2, 42.6, 41.0, 40.4, 35.5, 35.2, 27.3, 26.2, 23.3, 23.2, 20.3, 19.6, 19.2; MS (ESI+) m/z 315 [M+H] ⁺ ; HRMS (ESI+) calcd for C ₂ iH ₃₀ O ₂ + H 315.2324, found 315.2335. This material was used for the next reaction without further purification.

X. (±)-(4aS,8aR,10aR)-8a-Ethynyl-l,l,4a-trimethyl-3,4,4a,6,7,8 ,8a,9,10,10a- decahydrophenanthren-2(lH)-one (10).

9 C ₂₁ H ₃₀ O ₂ (MW: 314.46) 10 C ₁₉ H ₂₆ O (MW: 270.41 )

[0067] To a solution of compound 9 (8.65 g, 27.5 mmol) in MeOH (280 mL) and THF (55 mL) was slowly added 10% aqueous HCI solution (55 mL) at room temperature. The mixture was stirred at the same temperature for 1 h. The reaction mixture was concentrated in vacuo to remove the solvents. To the resulting mixture were added water (30 mL) and AcOEt (80 mL). The aqueous mixture was extracted with AcOEt (80 mL χ 3). The extract was combined with the original organic solution. It was washed with saturated aqueous NaHC0 ₃ solution (300 mL 2) and brine (300 mL), dried over MgS0 ₄ , filtered, and concentrated in vacuo to give 10 (7.33 g, 99%) as a crystalline solid: Ή NMR (300 MHz, CDC1 ₃ ) δ 5.52 (1H, t, J= 3.8 Hz), 2.72 (1H, ddd, J= 6.8, 12.6, 15.9 Hz), 2.42 (1H, ddd, J= 2.9, 5.9, 15.9 Hz), 2.20 (1H, s), 1.48, 1.10, 1.09 (each 3H, s); ^I3 C NMR (75 MHz, CDC1 ₃ ) δ 217.1, 146.8, 120.5, 92.4, 69.4, 54.2, 47.9, 42.5, 40.8, 40.2, 37.3, 35.3, 34.9, 26.2, 26.1 , 22.7, 22.0, 20.7, 19.1 ; MS (ESI+) m/z 271 [M+H] ⁺ ; HRMS (ESI+) calcd for Ci ₉ H ₂₆ 0 + H

271.2062, found 271.2070. This material was used for the next reaction without further purification.

XI. (±)-(4aS,8aS,10aR)-8a-Ethynyl-l,l,4a-trimethyl-4,4a,7,8,8a, 9,10,10a- octahydrophenanthrene-2,6(lH,3 /)-dione (H).

10 C ₁₉ H ₂₆ 0 (MW: 270. ₄ 1 ) 11 0 ₁₉ Η ₂ 4θ ₂ (MW: 284.39)

[0068] To a solution of 10 (9.65 g, 35.7 mmol) in CH ₂ C1 ₂ (255 mL) was added -BuOOH

(70% in water, 48 mL, 357 mmol, 10 equiv) at 0 °C. Cr0 ₃ (5.00 g, 50.0 mmol, 1.4 equiv) was added portionwise to the mixture over a period of 30 min at the same temperature. The mixture was stirred at the same temperature for initial 1 h and then at room temperature for an additional 3 h. After the aqueous layer was removed, the organic layer was washed with

5% aqueous NaOH solution (200 mL ^χ 2). The basic washings and the original aqueous layer were combined and then were extracted with CH ₂ C1 ₂ (200 mL ^χ 3). The extract and the original organic solution were combined. It was washed with saturated aqueous NH ₄ C1 solution (500 mL) and brine (500 mL), dried over MgS0 ₄ , filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (750 mL (8 cm diameter, 15 cm height); hexanes/AcOEt (3/1) 3.6 L) to give 11 (6.14 g, 61%) as a crystalline solid: 1H NMR (300 MHz, CDC1 ₃ ) δ 5.90 (1H, s), 2.85 (1H, ddd, J= 4.8, 15.0, 17.2 Hz), 2.72 (1H, ddd, J= 7.0, 11.7, 16.1 Hz), 2.50 (1H, ddd, J= 3.7, 6.6, 16.1 Hz), 2.43 (1H, m), 2.28 (1H, s), 1.53 (3H, d, J= 0.9 Hz), 1.14, 1.13 (each 3H, s); ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 215.5, 200.2, 170.3, 123.7, 86.7, 71.2, 52.8, 47.9, 41.8, 41.2, 39.1, 36.4, 35.9, 34.7, 34.2, 26.4, 22.9, 22.0, 20.2; MS (ESI+) m/z 285 [M+H] ⁺ ; HRMS (ESI+) calcd for C ₁₉ H ₂₄ 0 ₂ + H 285.1855, found 285.1853.

XII. (±)-(3Z,4aS,7Z,8aS,10aR)-8a-Ethynyl-3,7-^M(hydroxymethylene )-l,l,4a- trimethyl-4,4a,7,8,8a,9,10,10a-octahydrophenanthrene-2,6(lH, 3^)-dione (12).

11 C ₁₉ H ₂₄ 0 ₂ ( W: 284.39) 12 C ₂₁ H ₂₄ 04 (MW: 340.41 )

[0069] To a solution of 11 (9.37 g, 32.9 mmol) in benzene (150 mL) were successively added ethyl formate (29.2 mL, 362 mmol, 11 equiv) and NaOMe (19.6 g, 362 mmol, 11 equiv) in an ice bath. The mixture was stirred at room temperature for 1 h and acidified with

5% aqueous HC1 solution (50 mL). After NaCl was added to the aqueous layer, it was extracted with CH ₂ C1 ₂ -Et ₂ 0 (1 :2, 50 mL 3). The extract and the original organic layer were combined, washed with brine (300 mL), dried over MgS0 ₄ , filtered, and concentrated in vacuo to give 12 as a crystalline solid ( 11.1 g, 100%) : ¹ H NMR (300 MHz, CDC1 ₃ ) δ

14.92 (1H, d, J= 2.4 Hz), 13.67 (1H, brs), 8.79 (1H, d, J= 2.4 Hz), 7.61 (1H, s), 6.11 (1H, s), 2.65, 2.38 (each 1H, ABq, J= 14.1 Hz), 2.52 (2H, s), 2.30 (1H, dt, J= 3.1 , 12.4 Hz), 2.21 (1H, s), 1.97 (1H, ddd, J = 2.9, 13.2, 13.2 Hz), 1.70 (1H, ddd, J= 3.1, 6.2, 13.9 Hz), 1.52 (1H, ddd, J= 3.3, 13.2, 13.2 Hz), 1.44 (1H, m), 1.35, 1.25, 1.22 (each 3H, s); ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 189.9, 188.5, 188.4, 168.2, 167.8, 123.2, 106.1, 104.9, 86.5, 71.4, 49.6, 40.84, 40.76, 40.0, 36.54, 36.46, 28.7, 23.7, 21.3, 20.0; MS (ESI+) m/z 341 [M+H] ⁺ ; HRMS (ESI+) calcd for C _2] H ₂₄ 0 ₄ + H 341.1753, found 341.1747. This material was used for the next reaction without further purification.

XIII. (±)-(4aS,8aS,10aR)-8a-Ethynyl-l,l,4a-trimethyl-4,4a,7,8,8a, 9,10,10a- octahydrophenanthren[3,2-< :7,6-</|diisoxazole (13).

12 C ₂₁ H ₂₄ 0 ₄ (MW: 340.41) 13 C ₂₁ H ₂₂ N ₂ 0 ₂ (MW: 334.41)

[0070] To a solution of compound 12 (6.95 g, 20.4 mmol) in EtOH (314 mL) was added a solution of hydroxylamine hydrochloride (22.7 g, 326 mmol, 16 equiv) in water (68 mL).

The mixture was heated under reflux for 1 h. After removal of the solvents, the resulting mixture was diluted with AcOEt (100 mL) and then the organic layer was separated. The aqueous mixture was extracted with AcOEt (100 mL ^χ 3). The combined organic layer was washed with brine (300 mL), dried over MgS0 ₄ , filtered, and concentrated in vacuo to give

13 (6.72 g, 99%) as an amorphous solid: 1H NMR (300 MHz, CDC1 ₃ ) δ 8.12, 8.11, 6.60

(each 1H, s), 3.02, 2.69 (each 1H, ABq, J= 15.6 Hz), 2.89, 2.55 (each 1H, ABq, J = 14.6

Hz), 2.40 (lH, dt, J= 3.1 , 12.8 Hz), 2.12 (1H, s), 2.00 (1H, ddd, J= 2.7, 13.2, 13.2 Hz), 1.82

(lH, ddd, J= 3.3, 6.2, 13.9 Hz), 1.65 (2H, m), 1.37, 1.35, 1.31 (each 3H, s); ¹³ C NMR (75

MHz, CDC1 ₃ ) δ 172.5, 165.8, 155.8, 150.3, 148.2, 110.6, 108.6, 108.2, 87.6, 70.4, 50.7, 42.7, 41.3, 37.2, 36.0, 35.4, 33.8, 29.2, 25.7, 21.7, 19.5; MS (ESI+) m/z 335 [M+H] ⁺ ; HRJV1S (ESI+) calcd for C21H22N2O2 + H 335.1760, found 335.1764. This material was used for the next reaction without further purification.

XIV. (±)-(4bS,8aR,10aS)-10a-Ethynyl-4b,8,8-trimethyl-3,7-dioxo- l,2,3 _? 4b,5,6,7,8,8a,9,10,10a-dodecahydrophenanthrene-2,6-dic arbonitrile (14).

13 C ₂₁ H ₂₂ N ₂ 0 ₂ (MW: 334.41 ) 14 C _Z1 H ₂₂ N ₂ 0 ₂ (MW: 334.41 )

[0071] To a solution of NaOMe (52.3 g, 969 mmol, 30 equiv) in MeOH (388 mL) were successively added Et ₂ 0 (162 mL) and a solution of 13 in MeOH (258 mL) in an ice bath. The mixture was stirred at room temperature for 1 h, and acidified with 10% aqueous HCl solution (350 mL). After removal of the solvents, the resulting aqueous mixture was extracted with AcOEt (300 mL x 3). The organic layer was washed with water (800 mL) and brine (800 mL), dried over MgS0 ₄ , filtered, and concentrated in vacuo to give 14 as an amorphous solid (10.9 g, 100%). This material was used for the next reaction without further purification.

XV. (±)-(4bS,8aR,10aS)-10a-Ethynyl-4b,8,8-trimethyl-3,7-dioxo-3 ,4b,7,8,8a,9,10,10a- octahydrophenanthrene-2,6-dicarbonitrile (TBE-31).

14 C ₂₁ H ₂₂ N ₂ 0 ₂ (MW: 334.41) TBE-31 : C ₂₁ H ₁₈ N ₂ 0 ₂ (MW: 330.38) [0072] To a solution of PhSeCl (26.0 g, 136 mmol, 4.2 equiv) in anhydrous CH ₂ C1 ₂ (630 niL) was added a solution of anhydrous pyridine (12.0 niL, 149 mmol, 4.6 equiv) in anhydrous CH ₂ C1 ₂ (210 mL) in an ice bath. The mixture was stirred in the ice bath for 20 min. To the mixture in the ice bath was added a solution of 14 (10.9 g, 32.3 mmol) in anhydrous CH2CI2 (240 mL) using a syringe pump over 30 min. The mixture was stirred in the ice bath for 1 h. The mixture was washed with 10% aqueous HC1 solution (200 mL ^χ 2). To the resulting organic solution was added 30% aqueous ¾(¾ solution (27 mL) in the ice bath. After the mixture was stirred for 10 min, 30% aqueous H ₂ 0 ₂ solution (16 mL) was added four times at 10 min interval (total 91 mL) in the ice bath. The reaction mixture was washed with water (500 mL ^χ 2), saturated aqueous NaHC0 ₃ solution (500 mL ^χ 2), and brine (500 mL), dried over MgSC^, filtered, and concentrated in vacuo. The solid was purified by flash column chromatography (Si0 ₂ (8 cm diameter column, 15 cm height); hexanes/AcOEt (2/1), 3.5 L) to give TBE-31 (6.25 g, 59%) as a pale yellow crystalline solid: mp 217-220 °C dec; Ή NMR (300 MHz, CDC1 ₃ ) δ 7.92 (IH, s), 7.44 (IH, s), 6.28 (IH, s), 2.63 (IH, s), 2.53 (IH, dt, J= 12.8, 3.1 Hz), 2.28 (IH, m), 1.99 (IH, m), 1.84 (3H, s), 1.64 (2H, m), 1.27, 1.22 (each 3H, s); ^,3 C NMR (75 MHz, CDC1 ₃ ) δ 195.9, 178.6, 162.5, 160.3, 160.0, 122.5, 115.2, 114.4, 114.2, 113.0, 79.6, 77.0, 51.4, 45.4, 45.3, 40.2, 39.5, 26.3, 22.7, 21.8, 19.0; MS (FAB) m/z 331 [M+H] ⁺ ; HRMS (FAB) calcd for C ₂ iH, ₈ N ₂ 0 ₂ + H 331.1447, found 331.1434; Anal. Calcd for C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.21 ; H, 5.53; N, 8.48.

[0073] The above preferred embodiments and examples were given to illustrate the scope and spirit of the present invention. These embodiments and examples will make apparent to those skilled in the art other embodiments and examples. The other embodiments and examples are within the contemplation of the present invention. Therefore, the present invention should not be limited only by the preferred embodiments and examples.