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Tetrahedron 69 (2013) 9663e9674

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Tetrahedron

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a-Methoxymethyl ketones via aldol reaction

Alexander Kasal *, Milos BudesinskyInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo 2, CZ 166 10 Prague 6, Czech Republic

a r t i c l e i n f o

Article history:Received 11 June 2013Received in revised form 28 August 2013Accepted 9 September 2013Available online 14 September 2013

Keywords:NMRSteroidsSynthesisAldol reaction

* Corresponding author. E-mail address: kasal@uoc

0040-4020/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2013.09.022

a b s t r a c t

Paraformaldehyde in a methanolic solution of KOH converts ketones into a-methoxymethylated anda- hydroxymethylated products. The method was tested on nine steroidal ketones. On prolongedtreatment the ketones formed are reduced to alcohols.

� 2013 Elsevier Ltd. All rights reserved.

1. Introduction

In our search for new potential neuroactive steroids that act viag-aminobutyric acid receptors (GABAA), a series of analogues of 3a-hydroxy-5a-pregnan-20-one (1, allopregnanolone, see Scheme 1)were prepared and tested.1e5 In this context, additional analoguescontaining two methoxy-methyl groups in position 21 were re-quired. A suitable intermediate, compound 2 would be hydrox-ymethylated (3) and then O-methylated (4) to reduce the numberof free hydroxyl groups in themolecule.6,7 Aldol reaction seemed tobe a method of choice. This CeC bond forming reaction has beenwidely used since it was discovered by L. Claisen and J. G. Schmidt130 years ago.8,9 New media, new reagents, new protocols havebeen designed to achieve useful patterns, such as chemoselectivity,stereoselectivity and asymmetric course of the reaction.10e28 Insteroid chemistry, the aldol reactionwas used both in the synthesisof the steroid nucleus (e.g., Robinson annulation reaction29,30) andof the side chain.31e33

2. Results and discussion

Even an old reaction can bring a surprise; the treatment ofcompound 2 with paraformaldehyde in a methanolic solution ofpotassium hydroxide yielded no diol 3, but the target compound 4as the major product (45%). The other major component wasidentified by 1H and 13C NMR, IR and MS spectra as the product ofan additional aldol reaction, compound 5 (29%). A minor side-

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product, compound 6, was identified as the C17-epimer of themajor product 5. Another minor product 7 was formed by enoli-sation of the starting ketone 2 in the less accessible position 17.Under modified reaction conditionsdwhenmethanol was replacedwith 2-propanoldthe above methoxy derivatives were formed inaddition to the isopropoxy derivative 8. Selected NMR data ofcompounds 4e8 are in Table 1.

To test the scope of this reaction, we carried it out using someother ketones. Thus, 5a-cholestane-2-one (9) was mainly convertedinto a mixture of bis-aldol and tris-aldol products (50 and 39%, re-spectively) from which compounds 10e13 were obtained by chro-matography and crystallisation (see Scheme 2). The 3b-substitutedproducts were found to prevail over their 3a-counterparts. SelectedNMR data of compounds 10e13 are in Table 2.

The 3-oxo group in steroids is the least hindered steroidal oxogroup, thus a very complex mixture was expected upon similartreatment of 5a-cholestane-3-one (14, see Scheme 3). Indeed, themajor product, isolated by chromatography and crystallisation,turned out to be a tris-aldol with the oxo group reduced to an equa-torial hydroxyl group (15, 34%). Substitution of one of the twoa-methylene groups with bromine did not affect the aldol reactionsubstantially: 2a-bromo-5a-cholestan-3-one (16) yielded the sametris-aldol (15, 54%). Neither did the introduction of a double bond inposition 1(2) make the reaction more selective: cholest-1-en-3-one(17) was converted into the same tris-aldol 15 (22%), the majorproducts being this time bis-aldol derivatives, i.e., 2-methoxymethyl-4-methyleno-5a-cholest-1-en-3-one and 2,4a-bis-methoxymethyl-5a-cholest-1-en-3-one (compounds 18 and 19, 53 and 22%,respectively). A similar a-alkylation of a,b-enones was described byRezgui.34SelectedNMRdataof compounds15,18and19are inTable3.

H

H

H H

H

COCH3

H

H

H H

H

COCH3

HO

H

H

H H

H

H

H

H H

H

O

CH2OH

CH2OH OCH2OMe

CH2OMe

12

34, R = H5, R = CH2OH

R

H

H

H H

COCH3

CH2OH

7

H

H

H H

HO

CH2OMe

CH2OMe

CH2OH

6

H

H

H H

H

O

8

O

(i)

Scheme 1. Aldol reaction with 5a-pregn-2-en-20-one. Reagents and conditions: (i) Polyoxymethylene (64 equiv), KOH (32 equiv), MeOH, 40 �C, 20 h. Exceptionally, MeOH wasreplaced with 2-propanol.

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e96749664

The introductionof a 4(5)-doublebond into a3-oxo steroid20 (seeScheme 4) caused additional complications: product of the mono-methoxymethylation 21was only the minor product (13%). Evidencefor a range of products that reacted with between 2 and 4 equiv offormaldehyde (compounds 22e30) was only obtained from partiallyseparatedmixtures. In summary, the aldol alkylationoccurred atbotha-carbon atoms 2 and 4, but also at the g-position 6 (compounds25e30); in addition, the rigid steroid system made intramolecularparticipation possible (compounds 22 and 27). Selected NMR data ofcompounds 21, 22, 26 and 27 are in Table 4 and proton NMR data ofcompounds 23e25 and 28e30 are shown in Fig. 1.

Another steroidal ketone studied was 5a-cholest-2-en-6-one(31, Scheme 5). Monotopic products with substituents at thea-side (33e36) were mostly formed (80%), while the 7b-product 32was only obtained in a low yield (11.4%).

Ditopic products consisted of 7a-hydroxymethyl-7b-methox-ymethyl-5a-cholest-2-en-6-one (36, 5%) and 5-hydroxymethyl-7b-methoxymethyl-5a-cholest-2-en-6-one (37, 3%). Selected NMRdata of compounds 32e35, 37 and 38 are in Table 5.

It was considered that the reaction mixture should become lesscomplex with the 5a position blocked: indeed, 3a,5-cyclo-5a-cho-lestan-6-one (39, Scheme 6) mostly yielded monotopic products:a 7-exomethyleno derivative 40 (21%) and 7a-methoxymethyl and7b-methoxymethyl derivatives 41 and 42 (31 and 20%, re-spectively). Selected NMR data of compounds 40e42 are in Table 6.

Even a less reactive 7-oxo group could be forced to react withparaformaldehyde in the presence of potassium hydroxide, givingmostly monotopic aldol products. The prolonged treatment of5a-cholestan-7-one (43) under the usual conditions yieldeda 6-methyleno product 44 (9%, see Scheme 7), 6a-methoxymethyland 6a-hydroxymethyl ketones 45 and 46 (27 and 17%, re-spectively), 6a-hydroxymethyl-7a- and 7b-alcohols 47 and 48(7% and 25%, respectively) and 6a-methoxymethyl-6b-hydrox-ymethyl-7a-hydroxy derivative 49 (3%). Selected NMR data ofcompounds 44e49 are in Table 7.

Besides the above cyclohexanone derivatives, a steroidal cyclo-pentanone was also tested. Under the conditions used, 5a-androst-2-en-17-one (50) yielded all possible aldol and bis-aldol products(51e55, see Scheme 8), some with the oxo group reduced to a 17bhydroxyl (compounds 51 and 52). Selected NMR data of compounds51e55 are in Table 8. In general, yields of the 16b-hydroxymethyl-16a-methoxymethyl isomers (52 and 53) were lower than thoseof 16a-hydroxymethyl-16b-methoxymethyl derivatives (e.g., 54).Under the conditions used, 17-ketones predominated over 17b-al-cohols, although a longer reaction time favoured the oxo groupreduction, with the proportion of other types of products unaltered.

Potential for selective transformation of one oxo group besidesanother one was tested on 5a-androstane-7,17-dione (56). A com-plex mixture of substituted 7-oxo derivatives was formed fromwhich compounds 57 and 58 could easily be isolated (Scheme 9).Selected NMR data of compounds 57 and 58 are in Table 9.

3. Conclusions

In conclusion, we have reported on a direct a-bismethox-ymethylation of methyl ketones A, which apparently proceeds viathe corresponding conjugated ketones B and D (see Scheme 10).

The final aldolisation ends up with a hydroxymethyl group at-tached (type F): Alicyclic ketones, unable to produce intermediatesof type D, yielded a-methoxymethyl products, the second aldolreaction at the same carbon ended up as a primary product of aldolreaction, i.e., as a hydroxymethyl derivative (e.g., 54).

Less reactive cyclic ketones (e.g., 7-oxo steroids, 43), were slowlytransformed into mono-substituted ketones (type 44 to 46), whosestereochemistry was controlled by particular steric factors.

The oxo groups of the product were partly reduced to hydroxylgroups, whose configuration was largely consistent with stericalpreferences of the given ketone; this reduction can be prevented bysuitable shortening of the reaction time. These reactions were not

H

O

H

O

R3

R2

R1

9 10, R1 = CH2OMe, R2 = CH2OH, R

3 = H

11, R1 = CH2OH, R2 = CH2OMe, R

3 = H

12, R1 = CH2OCH2OMe, R2 = CH2OH, R

3 = H

13, R1 = CH2OMe, R2 = CH2OH, R

3 = CH2OH

Polyoxymethelene

KOH, MeOH,

40 0C, 72 h

Scheme 2. Aldol reaction with 5a-cholestan-2-one: 10þ11 (50%), 12 (10%), 13 (29%).

Table 1Selected carbon and proton NMR chemical shifts of compounds 4e8 in CDCl3. Coupling constants J(H,H) are given in brackets

Position 4 5 6 7 8

13C 1H 13C 1H 13C 1H 13C 1H 13C 1H

11 20.9 1.54 m 1.38 m 20.8 1.48 m1.33 m

20.8 1.49 m1.37 m

20.5 1.55 m1.38 m

21.0 1.51 m1.29 m

12 38.9 2.07 m1.42 m

33.9 1.44 m1.33 m

38.7 1.82 m1.23 m

33.0 1.86 m1.49 m

39.4 1.79 m1.29 m

13 44.9 d 47.1 d 46.2 d 45.5 d 44.8 d

14 56.8 1.16 m 51.8 1.76 m 56.8 1.10 m 52.9 1.36 m 57.1 1.21 m15 24.3 1.66 m

1.19 m26.2 1.77 m

1.25 m24.9 1.69 m

1.30 m24.5 1.75 m

1.28 m24.7 1.72 m

1.26 m16 22.9 2.16 m

1.62 m28.2 1.92 m

1.58 m28.5 1.83 m 26.1 2.53 m

1.62 m23.6 2.27 m

1.63 m17 63.3 2.73 t (9.1) 55.1 3.11 dd

(9.2, 3.4)57.2 2.88 t

(9.4)67.2 d 56.7 3.20 t

(9.0, 9.2)18 13.5 0.64 s 20.7 0.86 s 13.6 0.80 s 16.0 0.67 s 13.7 0.56 s19 11.7 0.75 s 11.6 0.73 s 11.6 0.75 s 11.6 0.74 s 11.7 0.74 s20 212.3 d 217.6 d 215.2 d 212.0 d 202.5 d

21 53.2 3.15 m 58.7 d 58.7 d 29.2 2.22 s 147.6 d

21-CH2OCH3 72.0 3.48 dd (9.2, 5.5)3.45 dd(9.2, 5.8)

73.3 3.67 d (9.3)3.54 d (9.3)

72.9 3.67 d (9.2)3.59 d (9.2)

d d d d

59.1 3.30 s 59.4 3.32 s 59.3 3.31 s d d d d

70.4 3.62 dd(9.3, 7.0)3.42 dd(9.3, 6.4)

72.6 3.67 d(9.3)3.54 d(9.3)

72.9 3.67 d (9.2)3.57 d(9.2)

d d d d

59.0 3.28 s 59.4 3.30 s 59.3 3.31 s d d d d

21-CH2OH d d 64.3 3.89 dd(11.3, 6.0)3.79 dd(11.3, 5.8)

64.0 3.86 d(11.2)3.83 d(11.2)

d d d d

17-CH2OH d d d d d d 66.1 4.18 dd(10.4, 1.6)3.60 d (10.4)

d d

21]CH2 d d d d d d d d 123.6 6.00 t(1.6)

21-CH2OCH(CH3)2 d d d d d d d d 66.3 4.21 dt(14.5, 1.6)4.16 dt(14.5, 1.6)

71.9 3.64 h(6.1)

22.1 1.18 d(6.1)

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e9674 9665

stereospecific; in many cases, however, one epimer prevailed andcould be isolated by crystallisation.

The above modification of the aldol reaction could not bestopped at a given stage, although softer conditions could beelaborated to yield primary aldol products.35 This reaction is stillwidely used in organic synthesis, often, however, alternatives (e.g.,Claisen condensation followed by hydrogenation36) are more ex-pedient for the synthesis of monotopic aldols.

4. Experimental section

4.1. General experimental methods

Melting points were determined on a Boetius micro meltingpoint apparatus (Germany). Optical rotations were measured at25 �C in chloroform using an Autopol IV (Rudolf Research Analyt-ical, USA, [a]D values are given in 10�1 deg cm2 g�1).

H HO

CH2CH2

HO

15

R

14, R = H16, R = Br

HO

17

HO

HO

1918

CH2OMe

MeOHO

CH2MeO CH2MeO

Scheme 3. Aldol reaction with 5a-cholestan-3-one (14) and 2a-bromo-5a-cholestan-3-one (16) (34% and 54%, respectively) and with cholest-1-en-3-one (17). Reagents andconditions: polyoxymethylene (64 equiv), KOH (32 equiv), MeOH, 40 �C, 22 h.

Table 2Selected carbon and proton NMR chemical shifts of compounds 10e13 in CDCl3. Coupling constants J(H,H) are given in brackets

Position 10 11 12 13

13C 1H 13C 1H 13C 1H 13C 1H

1 51.7 2.35 d (13.5)2.22 d (13.5)

52.4 2.36 d (13.2)2.16 d (13.2)

51.7 2.37 d (13.6)2.24 d (13.6)

62.2 2.69 dd(11.8, 7.3)

2 213.0 d 216.1 d 212.8 d 214.2 d

3 54.2 d 54.6 d 54.1 d 54.7 d

4 34.4 1.68 dd (14.0, 4.0)1.39 dd 14.0, 13.4)

34.0 1.68 t (14.0)1.50 (14.0, 4.0)

34.6 1.63 dd (14.0, 4.0)1.43 dd (14.0, 13.4)

34.7 1.49 dd (14.4, 12.8)1.38 dd (14.4, 4.4)

5 41.1 1.74 m 41.3 1.81 m 41.2 1.75 m 35.3 1.94 m6 27.7 1.44 m

1.19 m27.7 1.44 m

1.19 m27.7 1.44 m

1.22 m28.0 1.49 m

1.23 m7 31.6 1.72 m

0.95 m31.6 1.72 m

0.95 m31.6 1.72 m

0.95 m31.3 1.70 m

8 34.8 1.26 m 34.8 1.26 m 34.8 1.27 m 34.5 1.28 m9 53.6 0.91 m 53.6 0.91 m 53.7 0.91 m 47.8 0.84 m10 41.0 d 41.2 d 41.0 d 41.3 d

19 12.5 0.72 s 12.5 0.72 s 12.5 0.73 s 14.8 0.77 s1-CH2OH d d d d d d 60.3 4.16 t (11.8)

3.84 dd (11.8, 7.3)3-CH2OH 66.4 3.94 d (11.2)

3.82 d (11.2)65.8 3.87 d (11.5)

3.35 d (11.5)66.2 3.99 dd (11.2, 7.1)

3.82 dd (11.2, 5.4)66.3 4.12 d (11.8)

3.70 d (11.8)3-CH2OCH3 77.3 3.78 d (9.2)

3.28 d (9.2)74.9 3.64 d (9.2)

3.40 d (9.2)d d 76.5 3.64 d (9.0)

3.34 d (9.0)59.6 3.38 s 59.5 3.31 s d d 59.5 3.38 s

3-CH2OeeCH2OCH3

d d d d 71.8 3.89 d (9.5)3.46 d (9.5)

d d

d d d d 97.0 4.66 d (6.5)4.64 d (6.5)

d d

d d d d 55.5 3.40 s d d

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e96749666

Infrared spectra (wave numbers in cm�1) were recorded ona Bruker IFS 88 spectrometer. Thin-layer chromatography (TLC),used for monitoring of reactions, was performed on silica gel G(ICN Biochemicals, detection by spraying with concentrated sul-furic acid monitored by heating). Preparative TLC (PLC) was carriedout on 200�200 mm plates coated with a 0.7 mm thick layer of thesame material. For column chromatography, Silica gel 60 (Merck,63e100 m) was used. Prior to evaporation on a rotary evaporator invacuo (0.25 kPa, bath temperature 40 �C), solutions in organicsolvents were dried over anhydrous sodium sulfate. The NMRspectra were measured on Bruker AVANCE-600 instrument (1H at600.13 MHz and 13C at 150.9 MHz) with a cryo-probe in CDCl3at 27 �C. Spectra are referenced to TMS (1H) or solvent peak

(13C, using dC(CDCl3)¼77.0 ppm). Complete structural assignmentof proton and carbon signals was achieved combining 1D-1H and13C-spectra with 2D-H,H-COSY, 2D-H,C-HSQC and 2D-H,C-HMBCspectra. The 2D-H,H-ROESY spectra were used to determine theconfiguration of newly introduced substituents (CH2OR groups).The presence of hydroxyl groups was confirmed by NMR spectra ofTAC-derivatives (after addition of small molar excess of tri-chloroacetyl isocyanate (TAI) into CDCl3 solution). The signals ofmethylene hydrogens of eCH2eOH and eCH2OMe group could bedistinguished on the basis of characteristic difference in theirgeminal coupling constants (11.0e12.5 Hz in CH2OH and9.0e10.5 Hz in CH2OMe group). The 1H and 13C chemical shifts aregiven in Supplementary data.

O

20

HO

CH2

R1

CH2OHR3O

R2

OMeOCH2

R1

R2

HO

CH2

HOH2C

CH2O

HOH2C

22

OO

OMe

+

24, R1 = CH2OMe, R2 = H, R3 = Me25, R1 = R2 = H, R3 = Me26, R1 = CH2OMe, R2 = CH2OH, R3 = Me29, R1 = H, R2 = CH2OH, R3 = Me30, R1 = R2 = R3 = H

21, R1 = R2 = H23, R1 = CH2OH, R2 = H28, R1 = R2 = CH2OH

27

Scheme 4. Aldol reaction with cholest-4-en-3-one: 21 (13%), 22 (28%), 23 (3%), 24 (1.4%), 25 (2.6%), 26 (5%), 27 (6%), 28 (7%), 29 (5%), 30 (3%). Reagents and conditions: poly-oxymethylene (64 equiv), KOH (32 equiv), MeOH, 40 �C, 45 min.

Table 3Selected carbon and proton NMR chemical shifts of compounds 15, 18 and 19 in CDCl3. Coupling constants J(H,H) are given in brackets

Position 15 18 19

13C 1H 13C 1H 13C 1H

1 43.0 1.83 d (14.2)0.96 d (14.2)

154.5 7.22 t (1.6) 153.7 7.13 t (1.5)

2 46.1 d 133.6 d 133.3 d

3 78.8 4.11 t (1.8) 188.4 d 198.4 d

4 150.3 d 146.2 d 48.3 2.27 ddd (13.0, 3.1, 2.6)5 50.9 1.65 m 49.6 2.49 dq (12.0, 2.5) 44.2 2.02 m6 23.7 1.50 m

1.41 m23.4 1.75 m

1.48 m24.1 1.73 m

1.28 m7 31.4 1.72 m

0.88 m30.6 1.79 m

0.97 m31.2 1.74 m

0.97 m8 35.0 1.32 m 35.6 1.41 m 35.3 1.42 m9 56.2 0.74 m 49.8 1.11 m 50.2 1.02 m10 38.4 d 40.0 d 38.3 d

19 15.3 0.76 s 14.5 0.89 s 13.8 1.01 s2-CH2OH 73.2 3.76 d (10.7)

3.69 d (10.7)d d d d

2-CH2OMe 70.6 3.76 d (9.6)3.29 d (9.6)

69.3 4.15 dd (13.3, 1.6)4.11 dd (13.3, 1.6)

69.4 4.10 dd (13.2, 1.5)4.05 dd (13.2, 1.5)

59.0 3.30 s 58.7 3.41 s 58.7 3.29 s4]CH2 105.2 5.18 td (1.8, 1.0)

4.77 q (1.7)118.6 6.11 dd (2.5, 1.5)

5.19 dd (2.5, 1.5)d d

4-CH2OMe d d d d 68.2 4.00 dd (9.4, 2.6)3.57 dd (9.4, 3.1

d d d d 59.3 3.28 s

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e9674 9667

1H and 13C NMR spectra and their structure interpretation aresummarised in Supplementary data.

4.2. General procedure

Ketone (0.73 mmol) was dissolved in hot methanol (15 mL),then paraformaldehyde (1.409 g, 46.6 mmol) and a solution of KOH(1.312 g, 23.2 mmol) in methanol (15 mL) were added. The reaction

mixture was kept at 40 �C for a given time (mostly 20 h) underargon. The mixture was neutralised with an aqueous solution ofcitric acid (20%), methanol was removed on a rotary evaporator.Product, precipitated on addition of water (ca. 15 mL), was extrac-ted with dichloromethane. Separation of the components on PLCyielded corresponding methoxymethyl- and hydroxymethyl de-rivatives. Products formed are given in the increasing polarityorder.

CH3

O

CH2

H

HO

CH3

O

23

CH2 CH2MeO MeO CH2 OH

H H

17.96

1.26 s

39.56

38.02

43.02

201.49

128.75

171.80

64.07

64.00

1.85 dd 1.46 dd

13.4

58.25

3.32 s

4.22 d4.09 d 10.3

11.33.76 dd3.68 dd

CH2

HH H

19.27

38.75

40.55

42.00

197.10

131.83

170.57

40.97

H63.55

65.01

2.15 m 1.60 m

2.70 m

4.60 d3.85 d 10.0

3.72 m (2H)

3.17 m

1.33 s

H H

2.58 m7.6

4.0

27.92

2.86 m 2.18 m

MeO71.9559.10

3.72 dd3.64 dd9.2

6.2

3.8

3.35 s

58.44

3.38 s

24

CH3

O

H

CH2MeO CH2 OH

H HH

H

18.82

38.83

36.86

33.58

197.44

131.92

170.89

41.01

65.10

63.40

58.43

1.31 s

3.38 s

4.59 d3.86 d 9.9

3.70 m (2H)

3.17 m

2.03 m 1.66 m2.43 m

2.57 m

25

CH3

O

CH2

CH2

HO

HO

CH2MeO

H H

21.52

1.33 s

42.45

38.16

49.27

202.83

64.16

127.44

172.13

64.20

66.79

1.95 d 1.43 d

13.4

58.12

3.30 s

4.18 d4.12 d

11.2

10.4

3.94 d3.64 d

11.03.72 d3.59 d

28

CH3

O

CH2HO

CH2MeO CH2 OH

H HH

H

19.23

42.25

39.84

43.23

200.71

131.57

171.75

41.00

64.93

63.21

58.44

1.34 s

3.38 s

4.58 d3.88 d 10.0

~3.74 m (2H)

3.19 m

1.90 1.52

2.70 m

~3.74 m (2H)

63.89

29

CH3

O

CH2HO CH2 OH

H

HH H

19.09

42.25

36.53

33.53

198.25

134.72

168.88

40.65

H54.52

61.64

2.02 m 1.66 m

2.55 m

2.43 m

4.68 d4.09 d 12.0

~3.75 m (2H)

3.30 m

1.27 s

30

28.21

H H2.82 m 2.21 m

Fig. 1. Selected carbon and proton NMR data of compounds 23e25 and 28e30 in CDCl3.

Table 4Selected carbon and proton NMR data of compounds 21, 22, 26 and 27 in CDCl3. Coupling constants J(H,H) are given in brackets

Position 21 22 26 27

13C 1H 13C 1H 13C 1H 13C 1H

1 34.9 1.98 ddd (13.4, 5.0, 3.8)1.68 ddd (14.0, 13.4, 5.0)

41.2 1.98 d (13.4)1.34 dd (13.5, 3.0)

39.9 2.21 d (13.9)1.47 d (13.9)

38.2 2.01 d (14.3)1.45 d (14.3)

2 33.6 2.44 ddd (16.6, 14.0, 5.0)2.39 ddd (16.6, 5.0, 3.8)

47.4 d 49.0 d 49.2 d

3 197.9 d 200.4 d 200.8 d 201.7 d

4 129.0 d 146.3 d 130.9 d 127.1 d

5 171.2 d 77.4 d 171.8 d 163.3 d

6 28.0 2.85 ddd (14.8, 4.0, 2.8)2.19 tdd (14.8, 5.0, 0.8)

26.8 1.76 m 41.4 3.20 m 33.6 2.46 m

7 32.2 1.89 m1.02 m

25.5 1.52 m1.37 m

33.4 1.68 m1.22 m

36.0 1.75 m1.33 m

8 35.3 1.56 m 35.0 1.26 m 30.4 1.65 m 34.4 1.61 m9 54.2 0.97 m 48.5 1.47 m 56.1 0.95 m 56.7 0.95 m10 39.3 d 38.0 d 38.0 d 37.4 d

19 17.9 1.21 s 20.4 0.77 s 21.2 1.43 s 21.2 1.31 s4-CH2OMe 64.1 4.21 dd (10.3, 0.8)

4.13 d (10.3)d d 63.5 4.54 d (10.2)

3.89 d (10.2)d d

58.2 3.31 s d d 58.4 3.37 s d d

2-CH2OMe d d 71.9 3.49 d (9.9)3.38 d (9.9)

72.2 3.61 d (9.2)3.49 d (9.2)

d d

d d 59.6 3.34 s 58.9 3.32 s d d

2-CH2eOe d d 67.8 3.98 d (8.9)3.83 dd (8.9, 3.0)

d d d d

4]CH2 d d 117.7 6.15 d (1.0)5.31 d (1.0)

d d d d

2-CH2OH d d d d 67.3 3.66 d (11.0)3.59 d (11.0)

66.9 3.73 d (11.0)3.60 d (11.0)

d d d d d d 64.3 3.96 d (11.2)3.67 d (11.2)

4-CH2OH d d d d d d 64.4 4.31 dd (15.7, 2.0)4.24 dd (15.7, 2.1)

6-CH2OH d d d d 64.9 3.73 m3.21 m

69.9 3.82 dd (11.5, 5.2)3.38 dd (11.4, 5.6)

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e96749668

Table 5Selected carbon and proton NMR data of compounds 32e35, 37 and 38 in CDCl3. Coupling constants J(H,H) are given in brackets

Position 32 33 34 35 37 38

13C 1H 13C 1H 13C 1H 13C 1H 13C 1H 13C 1H

1 39.5 2.00 m1.94 m

39.1 2.02 m(2H)

39.1 2.02 m(2H)

41.9 1.90 m1.77 m

39.8 n.d. 35.6 1.90 m1.82 m

2 124.9 5.68 m 125.2 5.70 m 125.0 5.70 m 125.8 5.70 m 124.9 5.69 m 124.6 5.66 m3 124.3 5.56 m 124.4 5.57 m 124.4 5.57 m 125.7 5.58 m 123.9 5.54 m 124.4 5.56 m4 22.2 2.27 m

2.10 m21.5 2.36 m

1.96 m21.5 2.33 m

1.98 m26.4 2.34 m

1.84 m21.8 2.41 m

1.99 m25.0 2.29 m

(2H)5 53.6 2.27 m 49.7 2.66 dd

(11.1, 5.0)49.9 2.70 dd

(11.0, 5.0)39.3 1.65 m 50.0 2.77 dd (10.6, 5.0) 55.7 d

6 211.4 d 211.4 d 214.1 d 71.3 4.02 t (2.5) 212.6 d 212.9 d

7 54.8 2.08 m 52.9 2.72 dt (10.8, 5.7) 55.6 2.60 dt(11.0, 5.5)

46.4 1.86 m 57.4 d 51.4 2.39 ddd(10.7, 4.4, 1.5)

8 38.3 1.90 m 38.8 1.85 m 38.8 1.87 m 31.6 1.95 m 40.6 1.68 t (10.7) 37.9 1.93 t(10.7)

9 54.1 1.35 m 47.1 1.59 m 47.1 1.57 m 47.3 0.93 m 50.2 1.56 m 46.3 1.69 m10 39.4 d 40.6 d 40.5 d 34.9 d 39.3 d 38.9 d

19 13.6 0.69 s 13.0 0.71 s 13.1 0.72 s 15.0 0.98 s 13.5 0.64 s 16.3 0.74 s7-CH2OMe 69.2 3.81 dd

(9.2, 1.7)3.60 dd(9.2, 4.5)

70.4 3.87 dd(10.8, 9.5)3.57 dd (9.5, 5.7)

d d d d 74.3 3.78 d (8.9)3.68 d (8.9)

69.0 3.84 dd(9.3, 1.5)3.59 dd(9.3, 4.4)

58.8 3.30 s 59.0 3.30 s d d d d 59.3 3.37 s 58.8 3.31 s7-CH2OH d d d d 60.7 4.05 t (11.0)

3.96 dd (11.0, 5.8)60.2 3.86 dd (10.9, 4.2)

3.60 dd(10.9, 10.3)

63.9 4.16 d (11.3)3.96 d (11.3)

d d

5-CH2OH d d d d d d d d d d 63.00 4.14 d (10.8)3.64 d (10.8)

O

R2

R1O

39 40

O

+

41, R1 = CH2OMe, R2 = H42, R1 = H, R2 = CH2OMe

Scheme 6. Aldol reaction with 3a,5-cyclo-5a-cholest-2-en-6-one: 40 (21%), 41 (31%), 42 (20%). Reagents and conditions: polyoxymethylene (64 equiv), KOH (32 equiv), MeOH,40 �C, 20 h.

HO

31

R1O

R3

R2

35

H CH2OHOH

+

32, R1 = R2 = H, R3 = CH2OMe33, R1 = H, R2 = CH2OMe, R3 = H34, R1 = H, R2 = CH2OH, R3 = H36, R1 = CH2OH, R2 = R3 = H37, R1 = H, R2 = CH2OH, R3 = CH2OMe38, R1 = CH2OH, R2 = H, R3 = CH2OMe

Scheme 5. Aldol reaction with 5a-cholest-2-en-6-one: 32 (11%), 33 (16%), 34 (29%), 35 (30%), 36 (5%), 37 (5%), 38 (3%). Reagents and conditions: polyoxymethylene (64 equiv), KOH(32 equiv), MeOH, 40 �C, 22 h.

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e9674 9669

4.3. Reaction of 5a-pregn-2-en-20-one (2) in methanol(40 �C, 20 h)

21,21-Bismethoxymethyl-5a-pregn-2-en-20-one (4, 45%).White crystals, mp 91e92 �C (MeOH), [a]D25 þ160.7 (CHCl3, c 0.3). IR(CHCl3) 3065, 1655 (C]CH); 2843, 1108 (OMe); 1700 (C]O). IR(CCl4) 3065, 3023, 1657 (C]CH), 1707 (C]O). For C25H40O3 (388.6)

calcd 77.27 %C, 10.38 %H; found: 77.08 %C, 10.31 %H. HRMS (ESI)411.28735; for C25H40NaO3 calcd 411.28697.

21-Hydroxymethyl-21,21-bismethoxymethyl-5a-pregn-2-en-20-one (5, 28%). White crystals, mp 119e120 �C (MeOH). [a]D25

þ108.3 (CHCl3, c 0.5). IR (CCl4) 3637, 3522, 1048 (OH), 3064, 3023,1656 (C]CH), 1697 (C]O). For C26H42O4 (418.6) calcd 74.60 %C,10.11 %H; found: 74.38 %C, 10.28 %H.

OH

4344

CH2

OH

CH2OH

R2

R1H

OCH2OR

H

HCH2OMeOH

CH2HO

+

45, R = Me46, R = H

47, R1 = H, R2 = OH48, R1 = OH, R2 = H

+

49

+

Scheme 7. Aldol reaction with 5a-cholestan-7-one: 44 (9%), 45 (27%), 46 (17%), 47 (7%), 48 (25%), 49 (3%). Reagents and conditions: polyoxymethylene (64 equiv), KOH (32 equiv),MeOH, 40 �C, 14 days.

Table 6Selected carbon and proton NMR data of compounds 40e42 in CDCl3. Coupling constants J(H,H) are given in brackets

Position 40 41 42

13C 1H 13C 1H 13C 1H

1 33.2 1.87 m; 1.03 m 33.7 1.88 m; 0.98 m 33.6 1.73 m; 0.99 m2 24.8 1.78 m; 1.65 m 24.8 1.76 m; 1.61 m 26.5 1.98 m; 1.76 m3 37.0 1.83 m 38.6 1.73 m 32.9 1.55 m4 16.8 1.63 m; 0.97 m 16.2 1.75 m; 0.93 m 9.8 1.50 m; 0.60 t (4.7)5 43.9 d 43.6 d 44.8 d

6 203.0 d 212.8 d 210.8 d

7 147.6 d 52.6 1.99 dt (8.6, 2.8) 51.2 2.63 dt (9.5, 5.0)8 39.6 2.60 tt (11.2, 2.1) 34.7 2.16 ddd (11.2, 10.5, 8.6) 37.4 2.03 td (11.6, 5.0)9 47.2 1.32 m 45.8 1.20 m 40.3 1.65 m10 46.7 d 46.7 d 48.5 d

19 18.5 1.02 s 18.8 1.08 s 19.4 0.97 s7]CH2 120.6 5.81 t (1.9);5.20 t (1.9) d d d d

7-CH2OMe d d 74.5 3.91 dd (8.8, 2.8)3.42 dd (8.8, 2.8)

70.8 3.68 dd (9.5, 9.3)3.56 dd (9.3, 5.0)

d d 59.2 3.25 s 58.8 3.26 s

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e96749670

21-Hydroxymethyl-21,21-bismethoxymethyl-5a,17b-pregn-2-en-20-one (6, 10%) White crystals, mp 89e91 �C (MeOH). [a]D25

�37.3 (CHCl3, c 0.2). IR (CHCl3) 3624, 3499, 1042 (OH); 3065, 1655(C]C); 2833, 1104 (OMe); 1694 (C]O). For C26H42O4 (418.62)calcd 74.60 %C, 10.11 %H; found: 74.53 %C, 10.25 %H.

17a-Hydroxymethyl-5a-pregn-2-en-20-one (7, 11%). Whitecrystals, mp 172e174 �C (MeOH). [a]D25þ65.3 (CHCl3, c 0.4). IR (CCl4)3626, 3620, 3485, 1057, 1041 (OH); 3064, 3023, 1546 (C]C); 1704(C]O). For C22H34O2 (330.5) calcd 79.95 %C, 10.37 %H; found: 79.25%C, 10.26 %H.

4.4. Reaction of 5a-pregn-2-en-20-one (2) in 2-propanol andTHF (40 �C, 20 h)

A solution of compound 2 (100 mg, 0.33 mmol) and para-formaldehyde (700mg, ca. 4.8mmol) in THF (8mL) wasmixedwitha solution of potassium tert-butoxide (700 mg, 6.24 mmol) in2-propanol (8mL). Themixturewas heated at 40 �C under argon for20 h. The usual work-up yielded:

22-Methyleno-21-nor-24-oxa-5a-cholest-2-en-20-one (8, 9%).White needles, mp 86e88 �C (MeOH). [a]D25þ89.3 (CHCl3, c 0.21). IR(CHCl3) 3092, 3065, 1632, 1649, 898 (C]C); 2973 (iso-propyl); 1660

(C]O). For C26H40O2 (384.6) calcd 81.20 %C, 10.48 %H; found: 81.87%C, 10.72 %H. HRMS: 407.29199; For C26H40NaO2 calcd 407.29205.

21-Hydroxymethyl-21,21-bismethoxymethyl-5a,17a-pregn-2-en-20-one (6, 20%). White crystals, mp, [a]D25 and NMR spectrumidentical with properties of the sample prepared above. IR (CCl4)3625, 3474, 1082, 1037 (OH); 3068, 3025, 1655 (C]C); 1692 (C]O).

4.5. Reaction of 5a-cholestan-2-one (9) (40 �C, 72 h)

3x-Hydroxymethyl-3x-methoxymethyl-5a-cholestan-2-one(10þ11, 44%). White crystals, mp 84e86 �C (acetone/heptane). [a]D25

þ98 (CHCl3, c 0.6); IR 3623, 3504, 1042 (OH); 1697 (C]O); 1450,1108, 1100 (OMe). For C30H52O3 (460.7) calcd 78.21 %C, 11.38 %H;found: 78.09 %C, 11.45 %H.

3a-Hydroxymethyl-(3b-methoxy-methoxy)-methyl-5a-choles-tan-2-one (12, 8%). White solid. IR (CHCl3) 3624, 3516, 1046 (OH);1152, 1109, 1046 (COCOC); 1700 (C]O). HRMS: 513.39111; forC31H54NaO4 calcd 513.39143.

1a,3a-Bis(hydroxymethyl)-3b-methoxymethyl-5a-cholestan-2-one (13, 35%). White crystals, mp 137e138 �C (ether/heptane); [a]D25

þ89 (CHCl3, c0.3); IR 3614, 3590, 3456,1050 (OH); 1692 (C]O); 1449,1110,1100 (OMe). HRMS: 513.39128. For C31H54NaO4 calcd 513.39143.

H

O OR1

H

R2

OH

H

R1

R2

50

+

51, R1 = R2 = CH2OH52, R1 = CH2OMe, R2 = CH2OH

53, R1 = CH2OH, R2 = CH2OMe54, R1 = CH2OMe, R2 = CH2OH55, R1 = R2 = CH2OH

Scheme 8. Aldol reaction with 5a-androst-2-en-17-one (3 and 18 h): 51 (5e21%), 52 (23e40%), 53 (3e0%), 54 (39e11%), 55 (9e1%). Reagents and conditions: polyoxymethylene(64 equiv), KOH (32 equiv), MeOH, 40 �C, 3 h and 18 h.

Table 7Selected carbon and proton NMR data of compounds 44e49 in CDCl3. Coupling constants J(H,H) are given in brackets

Position 44 45 46 47 48 49

13C 1H 13C 1H 13C 1H 13C 1H 13C 1H 13C 1H

1 37.7 1.77 m1.05 m

38.6 1.75 m0.92 m

38.5 1.76 m0.94 m

38.9 1.71 m0.84 m

38.7 1.71 m0.99 m

42.0 1.67 m0.98 m

2 21.3 1.66 m1.43 m

21.3 1.62 m1.44 m

21.3 1.63 m1.44 m

21.5 1.48 m1.37 m

20.6 1.57 m1.24 m

20.4 1.56 m1.28 m

3 26.0 1.83 m1.24 m

26.6 1.76 m1.17 m

26.3 1.76 m1.19 m

26.5 1.73 m1.13 m

26.6 1.75 m1.26 m

27.5 1.74 m1.25 m

4 23.7 1.62 m1.35 m

25.6 1.60 m1.34 m

25.0 1.60 m1.27 m

24.3 1.58 m1.13 m

23.9 1.63 m1.33 m

21.6 1.34 m(2H)

5 51.5 2.03 m 51.8 1.34 m 50.2 1.44 m 44.4 0.96 m 45.9 1.22 m 50.3 1.47 m6 152.7 d 52.1 2.43 dddd

(12.2, 5.0, 4.1, 1.1)52.8 2.41 dddd

(12.5, 6.5, 2.9, 1.1)45.1 1.44 m 41.9 1.35 m 45.9 d

7 207.0 d 212.1 d 216.4 d 78.7 3.37 t (9.5) 73.7 3.96 t (2.5) 68.7 3.98 t (2.9)8 50.0 2.31 dd

(12.1, 10.6)50.2 2.37 ddd

(12.2, 10.8, 1.1)50.3 2.40 ddd

(12.2, 10.6, 1.1)42.6 1.48 m 39.8 1.43 m 35.1 1.57 m

9 53.3 1.33 m 56.3 1.14 m 56.6 1.16 m 52.5 0.74 m 50.0 1.29 m 45.1 1.29 m10 37.4 d 36.9 d 36.6 d 35.6 d 36.2 d 36.6 d

19 11.7 0.89 s 12.8 1.09 s 12.8 1.09 s 13.2 0.84 s 12.2 0.80 s 16.4 0.83 s6-CH2OMe d d 69.1 3.64 dd (9.5, 5.2)

3.42 dd(9.5, 4.2)

d d d d d d 80.6 3.62 d (8.9)3.59 dd(8.9, 1.5)

d d 59.0 3.31 s d d d d d d 59.2 3.26 s6-CH2OH d d d d 59.7 3.82 ddd

(11.8, 7.0, 2.9)3.64 ddd(11.8, 7.2, 6.5)

63.9 4.00 dd (10.8, 2.6)3.57 dd (10.8, 5.8)

64.7 3.85 dd (11.0, 4.2)3.79 dd (11.0, 2.2)

65.2 3.78 ddd(11.2, 7.5, 1.5)3.69 dd(11.2, 2.3)

6]CH2 113.1 5.38 dd (2.2, 1.4)4.81 dd(2.5, 1.4)

d d d d d d d d d d

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e9674 9671

4.6. Reaction of 5a-cholestan-3-one (14) (40 �C, 22 h)

2x-Hydroxymethyl-2x-methoxymethyl-4-methyleno-5a-cho-lestan-3b-ol (15, 34%). White crystals, mp 138e140 �C (MeOH).[a]D25 þ36 (CHCl3, c 0.3). IR (CHCl3) 3626, 3602, 3451, 1099, 1088,1048 (OH); 3094, 1653, 899, 543 (C]CH2). HRMS: 474.4073; ForC31H54O3 calcd 474.4072.

4.7. Reaction of cholest-1-en-3-one (17) (40 �C, 22 h)

2-Methoxymethyl-4-methyleno-5a-cholest-1-en-3-one (18,53%). White solid, mp 78e80 �C. [a]D25 þ35 (CHCl3, c 0.2). IR(CHCl3) 3101, 1615, 894 (C]CH2); 1667 (C]O); 1446 (OMe).For C30H48O2 (440.7) calcd 81.76 %C, 10.98H%; found: 81.78 %C,11.08 %H.

2,4a-Bis-methoxymethyl-5a-cholest-1-en-3-one (19, 12%).White solid, mp 63e65 �C. [a]D25þ27.6 (CHCl3, c 0.35). IR 2820,1445,1116, 1105 (MeO); 1666 (C]O). HRMS: for C31H52O3 calcd 472.3916,found: 472.3910.

2a-Hydroxymethyl-2b-methoxymethyl-4-methylene-5a-cho-lestan-3b-ol (15, 22%). White crystals, mp 138e140 �C (MeOH).[a]D25 þ36.1 (CHCl3, c 0.3). IR (CHCl3) 3626, 3602, 3451, 1088, 1044(OH); 3094, 1653, 543 (C]C); 2820 (OMe). For C31H54O3 (474.8)calcd 78.43 %C, 11.46 %H; found: 78.58 %C, 11.37 %H.

4.8. Reaction of 2a-bromo-5a-cholestan-3-one (16)(40 �C, 20 h)

2a-Hydroxymethyl-2b-methoxymethyl-4-methylene-5a-cho-lestan-3b-ol (15, 54%). White crystals were found identical with theabove sample.

4.9. Reaction of cholest-4-en-3-one (20) (40 �C, 45 min)

2a-Methoxymethyl-2b-methyl-4-methyleno-2a,5-oxido-5b-cholestan-3-one (22, 28%). White crystals, mp 139e141 �C (crude).For C30H50O3 (458.7) calcd 78.55 %C, 10.99 %H; found: 78.29 %C,11.13 %H.

4-Methoxymethyl-cholest-4-en-3-one (21, 13%). White solid.HRMS (ESI) found: 428.3644; for C29H48O2 calcd 428.3654.

FractionA (7%), amorphous solid consisting of 2b-hydroxymethyl-4-methoxymethylcholest-4-en-3-one (23), 6x-hydroxymethyl-4-methoxymethylcholest-4-en-3-one (25) and 6x-hydroxymethyl-2b,4-bis-methoxymethylcholest-4-en-3-one (24) in proportion43:37:20.

Fraction B (11%), crystalline mixture consisting of 2a,6x-bis-hydroxymethyl-2b,4-bis-methoxymethylcholest-4-en-3-one (26)and 2,2-bis-hydroxymethyl-4a,6a-oxido-4,6a-dimethyl-cholest-4-en-3-one (27) in proportion 45:55.

H

O

OH

OHCH2OH

CH2OH

O

56 57

H

OHCH2OMe

CH2OH

OCH2OMe

58

+

Scheme 9. Aldol reaction with 5a-androstan-7,17-dione: 57 (29%), 58 (14%). Reagents and conditions: polyoxymethylene (64 equiv), KOH (32 equiv), MeOH, 40 �C, 21 h.

Table 9Carbon and proton NMR data of compounds 57 and 58 in CDCl3. Coupling constants J(H,H) are given in brackets

Position 57 58 Position 57 58

13C 1H 13C 1H 13C 1H 13C 1H

1 38.2 1.73 m0.93 td (13.0, 4.2)

38.5 1.76 m0.93 td (13.0, 4.5)

13 45.0 d 44.6 d

2 21.7 1.57 m1.45 m

21.3 1.54 m1.45 m

14 41.7 1.40 m 41.4 1.46 m

3 26.4 1.73 m1.23 m

26.4 1.76 m1.18 m

15 32.7 1.89 dd (12.8, 5.8)0.84 t (12.8)

33.0 1.92 dd (12.8, 5.6)0.93 t (12.8)

4 29.0 1.37 m1.32 m

26.5 1.59 m1.32 m

16 48.0 d 48.3 d

5 48.8 1.44 m 51.0 1.37 m 17 85.8 3.76 s 84.6 3.64 s6 46.4 2.28 ddd

(13.4, 12.6, 1.1)2.01 dd (12.6, 3.2)

51.8 2.41 m 18 12.2 0.86 s 12.1 0.83 s

7 211.9 d 211.6 d 19 11.7 1.05 s 12.7 1.09 s8 49.0 2.37 ddd

(12.0, 10.6, 1.1)48.9 2.42 m 16-CH2OH 72.2 4.02 dd (11.3, 1.5) 3.68 d (11.3) 70.9 3.72 d (11.2)

3.50 d (11.2)9 56.1 1.15 td (12.0, 4.4) 56.2 1.18 m 69.9 3.85 d (11.1)

3.64 dd (11.1, 1.5)d d

10 36.7 d 36.9 d 16-CH2OMe d d 78.659.2

3.68 d (9.0)3.47 d (9.0) 3.35 s

11 20.7 1.69 m1.49 m

20.8 1.69 m1.46 m

6-CH2OMe d d 68.659.0

3.57 dd (9.3, 5.3)3.45 dd (9.3, 2.5)3.31 s

12 36.7 1.82 ddd(12.8, 4.2, 2.8)1.07 m

37.0 1.88 ddd(12.8, 3.8, 3.0)1.10 m

Table 8Carbon and proton NMR data of compounds 51e55 in CDCl3. Coupling constants J(H,H) are given in brackets

Position 51 52 53 54 55

13C 1H 13C 1H 13C 1H 13C 1H 13C 1H

11 20.2 1.53 m1.38 m

20.3 1.52 m1.37 m

20.0 1.61 m1.42 m

20.1 1.61 m1.42 m

20.0 1.62 m1.42 m

12 37.7 1.81 ddd (12.5, 4.2, 2.7)1.11 td(12.5, 4.4)

38.0 1.88 ddd(12.5, 4.2, 2.7)1.13 td(12.5, 4.4)

31.8 1.81 m1.25 m

32.1 1.81 m1.25 m

31.8 1.82 ddd (13.0, 4.2, 2.5)1.27 td (13.0, 4.3)

13 48.0 d 48.1 d 49.0 d 49.3 d 49.5 d

14 48.5 0.95 ddd(13.1, 10.6, 5.4)

48.4 0.94 ddd(13.2, 10.1, 5.2)

48.3 1.50 m 48.4 1.39 m 48.5 1.43 m

15 31.9 1.27 dd(11.9, 5.4)0.90 dd(13.1, 11.9)

32.4 1.35 dd(11.9, 5.2)1.00 dd(13.2, 11.9)

29.1 2.09 dd(11.9, 4.9)1.54 m

29.3 1.89(13.0, 5.9)1.74 t(13.0)

29.2 1.88 dd(12.9, 5.6)1.56 t(12.9)

16 45.0 d 44.8 d 56.0 d 55.2 d 55.8 d

17 86.8 3.68 s 85.6 3.55 s 222.7 d 222.6 d 224.2 d

18 12.1 0.86 s 12.1 0.85 s 14.3 0.94 s 13.4 0.93 s 13.9 0.95 s16-CH2OMe d d 78.6 3.72 dd

(9.0, 1.0)3.49 d (9.0)

75.5 3.50 dd(9.0, 1.0)3.40 d (9.0)

76.5 3.60 d (9.0)3.55 d (9.0)

d d

d d 59.3 3.36 s 59.6 3.34 s 59.4 3.34 s d d

16-CH2OH 71.8 4.05 dd(11.4, 1.5)3.65 d(11.4)

71.0 3.61 d(10.8)3.48 dd(10.8, 1.0)

67.7 3.75 d (11.0)3.66 dd(11.0, 1.0)

65.6 3.64 d (11.0)3.54 d (11.0)

66.7 3.82 d(11.0)3.78 d(11.0)

69.6 3.71 d (10.9)3.60 dd(10.9, 1.5)

d d d d d d 65.0 3.75 d (11.0)3.63 d (11.0)

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e96749672

R

O

R

O

OMeR

O

OMe

B

R CH3

O

R

O

CH2OMeCH2OMe

R

A C D E, R = HF, R = CH2OH

Scheme 10. Reagents and conditions: polyoxymethylene (64 equiv), KOH (32 equiv), MeOH.

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e9674 9673

Fraction C (15%), amorphous solid consisting of 2,2-bis-hydroxymethyl-4-methoxymethylcholest-4-en-3-one (28), 2a,6x-bis-hydroxymethyl-4-methoxymethylcholest-4-en-3-one (29) and4,6x-bis-hydroxymethyl-cholest-4-en-3-one (30) in proportion46:32:22.

4.10. Reaction of 5a-cholest-2-en-6-one (31) (40 �C, 22 h)

7b-Methoxymethyl-5a-cholest-2-en-6-one (32, 11%), colourlessoil. [a]D25 þ65.2 (CHCl3, c 0.39). IR (CHCl3) 3067, 3027, 1660 (C]CH);1702 (C]O); 1106 (COC). HRMS (ESI): 429.37266; for C29H48O2calcd C29H49O2 429.37271; 451.35458; for C29H48NaO2calcd 451.35465.

7a-Methoxymethyl-5a-cholest-2-en-6-one (33, 16%). Whitecrystals, mp 100e101 �C (MeOH). [a]D25 þ24.1 (CHCl3, c 0.5). IR(CHCl3) 3065, 3029, 1656 (C]CH); 1705 (C]O); 1107 (COC). HRMS(ESI): 451.35466; for C29H48NaO2 calcd 451.35465.

7a-Hydroxymethyl-5a-cholest-2-en-6-one (34, 29%). Whitecrystals, mp 180e183 �C (MeOH). [a]D25 þ35.5 (CHCl3, c 0.1). IR(CHCl3) 3623, 3473, 1044 (OH); 3065, 3028, 1656 (C]CH); 1702(C]O). HRMS (ESI): 437.33889; for C28H46NaO2 calcd 437.33900.

Mother liquors contain some 19% of 5a-hydroxymethyl-5a-cholest-2-en-6b-one (36), which was not studied further.

7a-Hydroxymethyl-7b-methoxymethyl-5a-cholest-2-en-6-one(37, 5%). White solid; IR (CHCl3) 3620, 3502, 1042 (OH); 3063, 3027,1660 (C]CH); 2955 (OMe); 1707 (C]O). [a]D25 þ29.4 (CHCl3, c 0.17).HRMS (ESI) 481.36522; for C30H50NaO3 calcd 481.36522.

5-Hydroxymethyl-7b-methoxymethyl-5a-cholest-2-en-6-one(38, 3%). Colourless oil, IR (CHCl3) 3624, 3491, 1050 (OH); 3063,3028, 1658 (C]CH); 2954 (OMe), 1703 (C]O). [a]D25 þ33.2 (CHCl3, c0.25). HRMS (ESI) 481.36524; for C30H50NaO3 calcd 481.36522.

7a-Hydroxymethyl-5a-cholest-2-en-6b-ol (35, 30%). Whitecrystals, mp 172e174 �C (EtOH). [a]D25 þ12.7 (CHCl3, c 0.18). IR(CHCl3) 3623, 3453, 1042, 998 (OH); 3062, 3027, 1655 (C]CH).HRMS (ESI) 439.35458; for C28H48NaO2 calcd 439.35465.

4.11. Reaction of 3a,5-cyclo-5a-cholestan-6-one (39) (40 �C,20 h)

3a,5-cyclo-7-Methyleno-5a-cholestan-6-one (40, 21%); colour-less oil. [a]D25 þ28.7 (CHCl3, c 0.17). IR (CCl4) 3026 (cp); 1674 (C]O);1599, 1409, 884 (C]C). HRMS (ESI): 397.34642; For C28H45Ocalcd 397.34649.

3a,5-cyclo-7a-Methoxymethyl-5a-cholestan-6-one (41, 31%);colourless oil. [a]D25 þ19.9 (CHCl3, c 0.29). IR (CHCl3) 3085 (cp); 1666(C]O); 1189(OMe). IR (CCl4) 3082 (cp); 1676 (C]O); 1109 (OMe).HRMS (ESI): 429.37237; For C29H49O2 calcd 429.37271.

3a,5-cyclo-7b-Hydroxymethyl-5a-cholestan-6-one (42, 20%);colourless oil. [a]D25 þ42.5 (CHCl3, c 0.28). IR (CCl4) 3078 (cp); 1699and 1680 (C]O); 1106 (OMe). HRMS (ESI): 451.35458. ForC29H48NaO2 calcd 451.35465.

4.12. Reaction of 5a-cholestan-7-one (43) (40 �C, 14 days)

6-Methyleno-5a-cholestan-7-one (44, 9.2%). White crystals, mp114e116 �C (heptane), [a]D25 �25.4 (CHCl3, c 0.13). IR (CHCl3) 3095,

1624,1405 (C]C); 1693 (C]O). For C28H46O (398.7) calcd 84.36 %C,11.63 %H; found: 84.20 %C, 11.58 %H.

6a-Methoxymethyl-5a-cholestan-7-one (45, 26.9%). Whitecrystals, mp 61e63 �C (MeOH). [a]D25 �32 (CHCl3, c 0. 9). IR (CHCl3)1705 (C]O), 1107 (CeOeC). HRMS (ESI): 417.37264. For C28H49O2calcd 417.37271. For C29H50O2 (430.7) calcd 80.87 %C, 11.70 %H;found: 81.16 %C, 11.51 %H.

6a-Hydroxymethyl-5a-cholestan-7-one (46, 17.3%). White solid,mp 105e107 �C. [a]D25 �34 (CHCl3, c 0.19). IR (CHCl3): 3569, 1035,1262 (OH); 1692 (C]O). HRMS (ESI) 417.37264; for C28H49O2calcd 417.37271.

6a-Hydroxymethyl-5a-cholestan-7b-ol (47, 6.7%). White solid,mp 68e69 �C. [a]D25 þ46.7 (CHCl3, c 0.18). IR (CHCl3) 3631, 3455,1055, 1015 (OH). HRMS (ESI) 441.37012; for C28H50NaO2calcd 441.37030.

6a-Hydroxymethyl-5a-cholestan-7a-ol (48, 25.0%). Whitecrystals, mp 142e144 �C. [a]D25 þ20.6 (CHCl3, c 0.20). IR (CHCl3)3622, 3504 (OH). HRMS (ESI): 441.36996; for C28H50NaO2calcd 441.37030.

6a-Hydroxymethyl-6b-methoxymethyl-5a-cholestan-7a-ol(49, 3%). White crystals, mp 128e132 �C. IR (CHCl3): 3615, 1261,1052, 1027 (OH); 2820 (OMe). HRMS (ESI) 485.39637; forC30H54NaO3 calcd 485.39652.

4.13. Reaction of 5a-androst-2-en-17-one (50) (40 �C, 3 h)

16a-Hydroxymethyl-16b-methoxymethyl-5a-androst-2-en-17-one (54, 39.2%). White crystals; mp 157e158 �C (acetone/heptane).[a]D25 þ88.9 (CHCl3, c 0.3). IR: 3625, 3512, 1050 (OH); 2834, 1107(OMe); 1725(C]O); 1655 (C]C). For C22H34O3 (346.5) calcd 76.26 %C, 9.89 %H; 75.98 %C, 9.96 %H;

16b-Hydroxymethyl-16a-methoxymethyl-5a-androst-2-en-17-one (53, 3.3%). White solid.

16a-Hydroxymethyl-16b-methoxymethyl-5a-androst-2-en-17b-ol (52, 22.7%). White crystals, mp 161e162 �C (acetone). [a]D25

þ46 (CHCl3, c 0.27). IR (CHCl3) 3623, 3521, 1053 (OH); 2835, 1091(OMe); 1655, 3061 (C]C). For C22H36O3 (348.6) calcd 75.82 %C,10.41 %H; found: 75.82 %C, 10.73 %H. HRMS (ESI) for C22H36NaO3calcd 371.25567; found: 371.25561.

16,16-Bis-hydroxymethyl-5a-androst-2-en-17-one (55, 9.4%),White crystals, mp 162e164 �C (acetone/heptane). [a]D25 þ104.8(CHCl3, c 0.1). IR (CHCl3) 3623, 3519, 3420, 1050 (OH); 3067, 1657(C]C); 1718 (C]O). HRMS: 355.22436. For C21H32NaO3 found:355.22437.

16,16-Bis-hydroxymethyl-5a-androst-2-en-17b-ol (51, 5.2%).White crystals, mp 222e223 �C (acetone, 9.1%). [a]D25 þ56.5(CHCl3, c 0.1) IR (CHCl3) 3620, 3529, 3482, 1093, 1955, 1027 (OH);1655 (C]C). For C21H34O3 (334.5) calcd 75.41 %C, 10.25 %H; found:75.60 %C, 10.42 %H. HRMS (ESI), for C21H34NaO3 calcd 357.24002;found: 357.23996.

4.14. Reaction of 5a-androst-2-en-17-one (50) (40 �C, 18 h)

16a-Hydroxymethyl-16b-methoxymethyl-5a-androst-2-en-17-one (54, 11%). White crystals, mp 158e160 �C (acetone/heptane).

A. Kasal, M. Budesinsky / Tetrahedron 69 (2013) 9663e96749674

[a]D25 þ88.9 (CHCl3, c 0.25). IR 3623, 3516, 1050 (OH); 3062 (C]C);1091 (OMe); 1718 (C]O).

16x-Hydroxymethyl-16x-methoxymethyl-5a-androst-2-en-17x-ols (59%), a 2:1 mixture of compound 52 and its isomer.

16,16-Bis-hydroxymethyl-5a-androst-2-en-17b-ol (51, 21%),identical with the sample prepared above.

4.15. Reaction of 5a-androstane-7,17-dione (56) (40 �C, 21 h)

17ß-Hydroxy-16,16-bis-hydroxymethyl-5a-androstan-7-one(57, 29%). White crystals, mp 182e184 �C (acetone/heptane). [a]D25

�60 (CHCl3, c 0.15). IR 3620, 3533, 3496, 1082, 1048, 1025 (OH);1703 (C7]O). For C21H34O4 (350.5) calcd 71.96 %C, 9.78 %H; found:71.69 %C, 9.53 %H;

17b-Hydroxy-16a-hydroxymethyl-6a,16ß-bis-methoxymethyl-5a-androstan-7-one (58, 13.6%). White crystals, mp 138e140 �C(MeOH); [a]D25 �37.5 (CHCl3, c 0.3). IR 3620, 3531, 1046, 1025 (OH);2836, 1446, 1093 (OMe); 1706 (C7]O). HRMS (ESI) found:431.27657; for C24H40NaO5 calcd 431.27680.

Acknowledgements

We are indebted to Dr. P. Fiedler for the measurement andinterpretation of the IR spectra.

The optical rotations and elemental analyses were measured inthe Analytical Laboratory (Dr. S. Mat�ejkov�a, Head). This work wassupported by grants RVO 61388963 and TACR TE01020028.

Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2013.09.022.

References and notes

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