Practical method for the absolute configuration assignment of tert/tert 1,2-diols using their complexes with Mo2(OAc)4

Article abstract of DOI:10.1021/jo062445x

(Chemical Equation Presented) We describe here an application of the practical, simple, and reliable approach for the determination of the absolute configuration of sterically demanding tert/tert vic-diols. According to this method, it is only necessary t

Full text of DOI:10.1021/jo062445x

Practical Method for the Absolute Configuration Assignment of
tert/tert 1,2-Diols Using Their Complexes with Mo2(OAc)4
Marcin Go´recki,† Ewa Jabłon´ska,‡ Anna Kruszewska,§ Agata Suszczyn´ska,†
Zofia Urban´czyk-Lipkowska,† Michael Gerards,| Jacek W. Morzycki,§
Wojciech J. Szczepek,‡ and Jadwiga Frelek*,†
Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw, Poland,
Chair of Organic Chemistry, Technical UniVersity of Radom, Chrobrego 27, 26-600 Radom, Poland,
Institute of Chemistry, UniVersity of Bialystok, al. Pilsudskiego 11/4, 15-443 Bialystok, Poland,
and Merck KGaA, 64271 Darmstadt, Germany
frelek@icho.edu.pl
ReceiVed NoVember 28, 2006
We describe here an application of the practical, simple, and reliable approach for the determination of
the absolute configuration of sterically demanding tert/tert Vic-diols. According to this method, it is only
necessary to mix dimolybdenum tetraacteate and a chiral diol in DMSO and record the CD spectra in the
250-650 nm spectral range. From the sign of the CD bands occurring at around 310, 350, and 400 nm,
it is possible to establish the chirality of the diol unit expressed by the sign of the O-C-C-O torsion
angle. Because the preferred conformation of the diol in the formed complex is known, we are able to
determine the absolute configuration of the carbon atoms in the diol subunit even in flexible tert/tert
Vic-diols.
Introduction
products. Among these products are brassinolides, very active
plant growth promoters,3,4 a variety of antibiotics, for example,
erythromycin A,5 oligomycin A,6 and olivomycin A,7 or steroidal
hormones.8
Because the biological activity is closely related to the
stereostructure of bioactive compounds, the access to the
methods allowing simple and unequivocal determination of their
absolute configuration is of great importance. Circular dichroism
Chiral Vic-diols represent an important group of organic
compounds due to their common occurrence in nature both in
a free form and as their respective esters. Many of them are
bioactive natural products, which display very interesting and
in many cases important biological activity. Moreover, Vic-diols
play a key role in organic chemistry being widely used as chiral
building blocks1 and controllers in asymmetric processes.2 In
general, Vic-diol moiety is present in carbohydrates, many
antibiotics, vitamins, steroids, and other bioactive natural
(3) Takatsuto, S.; Ikekawa, N. J. Chem. Soc., Perkin Trans. 1 1983,
2133-2137.
(4) Creelman, R.; Mullet, J. Plant Cell 1997, 9, 1211-1223.
(5) Thadepalli, H.; Chuah, S. K.; Iskandar, L.; Gollapudi, S. Int. J.
Antimicrob. 2002, 20, 180-185.
† Institute of Organic Chemistry of the Polish Academy of Sciences.
‡ Technical University of Radom.
§ University of Bialystok.
(6) Nakakita, Y.; Nakagawa, M.; Sakai, H. E. J. Antibiot. 1980, 33, 514-
516.
| Merck KgaA.
(1) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon: New York, 1983.
(2) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(7) Roush, W. R.; Hartz, R. A.; Gustin, D. J. J. Am. Chem. Soc. 1999,
121, 1990-1991.
(8) Fieser, L. F.; Fieser, M. Steroids; Reinhold Publishing Corp.: New
York, 1959.
10.1021/jo062445x CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/22/2007
2906
J. Org. Chem. 2007, 72, 2906-2916

Configuration Assignment of tert/tert 1,2-Diols
spectroscopy (CD) seems to be a method of choice for this
purpose, especially useful in solution. This approach requires
that the compounds under study exhibit measurable absorption
in an accessible frequency range. Because Vic-diols absorb below
the range generally available to commercial instruments (<190
nm), a suitable chromophoric system should be introduced into
the molecule prior to recording the spectra.
The exciton-coupled circular dichroism (ECCD), based on
the quantum mechanical theory of coupled oscillators,9 belongs
to the methods most frequently applied to the absolute stereo-
chemical assignment to Vic-diols. The “dibenzoate chirality
rule”, introduced by Harada and Nakanishi,10,11 was originally
formulated to assign the stereochemistry of glycols. A modifica-
tion made by Wiesler and Nakanishi12 utilizes two different
chromophoric systems added at two hydroxy moieties. Several
suitable red-shifted chromophores have been proposed to convert
hydroxyl groups of diols into derivatives that absorb light in
the visible spectral region.13,14 The ECCD method has been
applied successfully also to the absolute stereochemical assign-
ment of Vic-diols in the form of their macrocyclic host-guest
complexes with a host porphyrin tweezer.15,16 Recently, new
chromophoric systems applicable in the ECCD configurational
analysis of various classes of compounds, including Vic-diols,
were reviewed.17
The broad applicability of the exciton chirality method is due
to the very characteristic shape of the CD bands, the large CD
effects in most cases, and its nonempirical character. There are,
however, some limitations for cases undergoing conformational
changes and for applications to acyclic compounds. The perfect
solution to circumvent the problem of conformational mobility
of flexible diols could be their transformation into conforma-
tionally defined derivatives. Although attempts have been made
to obtain such derivatives,16,18,19 a correct application of the
exciton chirality method becomes difficult in some cases,20,21
or the methods proposed do not have general applicability.19,22
In the course of our study on the application of dinuclear
transition metal complexes as auxiliary chromophores in the
determination of the absolute configuration of transparent
molecules by means of circular dichroism spectroscopy, it was
demonstrated that, until now, only dimolybdenum tetraacetate
is able to form chiral complexes with diols.23 An empirically
based rule correlating a positive/negative helicity expressed by
the O-C-C-O torsion angle with the sign of Cotton effects
occurring in the 400-260 nm spectral range has been formulated
for 1,2-diols.23 Recently, the successful applicability of the
method was further corroborated by Italian authors24 who
confirmed the dimolybdenum method to be “a very reliable,
versatile, and elastic procedure for the assignment of the absolute
configuration of that fundamental class of molecules, no
exceptions being known to the empirical rule.”
Up until now, however, the methodology was applied to
sterically nonhindered prim/sec, sec/sec, and prim/tert 1,2-diols
only. We decided therefore to fill in the gap. In our very recent
study, the method was successfully used on sec/tert Vic-diols.25
In this paper, we decided to check the applicability of the
methodology to the sterically most demanding tert/tert Vic-diols.
This study is undertaken for two main reasons. First, such a
1,2-diol subunit is present in many bioactive natural products.
Among these products, hepatotoxic alkaloid monocrotaline, a
representative of pyrrolizidine alkaloids,26,27 or the peptide-
polyketide antibiotic aurantimycin, displaying strong activity
against Gram-positive bacteria,28 can be mentioned. Second, to
the best of our knowledge, a method for the determination of
the absolute configuration of tert/tert 1,2-diols based on CD
spectroscopy is lacking in the literature. This is most probably
due to the fact that derivatization of these diols is very difficult.
It is well known that esterification reactions of tertiary alcohols,
in contrast to primary and secondary ones, are relatively slow
and particularly susceptible to steric factors. Although some
esters of tertiary alcohols such as nitrates,29 trifluoroacetates,30
or methanesulfonates31 may be easily obtained, in general,
esterification reaction of tertiary alcohols requires application
of proper catalysts.32,33 In many cases, however, esterification
reactions of tertiary alcohols may not be successful. Sometimes
they lead to a partial or complete epimerization at the chiral
center.
Results
Synthesis. To achieve our goal, we have undertaken the
chiroptical studies on a variety of tert/tert diols 1-14, most of
them specially synthesized for this purpose (Figure 1). The only
exception constitutes monocrotaline (1), which is commercially
available. In the case of synthesis of compounds 2-9, the crucial
step was dihydroxylation of a tetrasubstituted double bond with
osmium tetraoxide. It was usually the final step of synthesis,
except for compounds 3 and 7.
(9) Mason, S. F.; Seal, R. H.; Roberts, R. D. Tetrahedron 1974, 30,
1671-1682.
(10) Harada, N.; Nakanishi, K. J. Am. Chem. Soc. 1969, 91, 3989-3991.
(11) Harada, N.; Nakanishi, K. Acc. Chem. Res. 1972, 5, 257-263.
(12) Wiesler, W. T.; Nakanishi, K. Croat. Chem. Acta 1989, 62, 211-
226.
(13) Cai, G.; Bozhkova, N.; Odingo, J.; Berova, N.; Nakanishi, K. J.
Am. Chem. Soc. 1993, 115, 7192-7198.
(14) Matile, S.; Berova, N.; Nakanishi, K.; Novkova, S.; Philipova, I.;
Blagoev, B. J. Am. Chem. Soc. 1995, 117, 7021-7022.
(15) Huang, X.; Nakanishi, K.; Berova, N. Chirality 2000, 12, 237-
255.
(23) Frelek, J.; Klimek, A.; Rus´kowska, P. Curr. Org. Chem. 2003, 7,
1081-1104 and literature cited therein.
(24) di Bari, L.; Pescitelli, G.; Pratelli, D.; Pini, D.; Salvadori, P. J. Org.
Chem. 2001, 66, 4819-4825.
(25) Go´recki, M.; Kamin´ska, A.; Rus´kowska, P.; Suszczyn´ska, A.; Frelek,
J. Pol. J. Chem. 2006, 80, 523-534.
(26) Yee, S. B.; Hanumegowda, U. M.; Hotchkiss, J. A.; Ganey, P. E.;
Roth, R. A. Toxicol. Sci. 2003, 72, 43-56.
(16) Huang, X.; Fujioka, N.; Pescitelli, G.; Koehn, F. E.; Williamson,
R. T.; Nakanishi, K.; Berova, N. J. Am. Chem. Soc. 2002, 124, 10320-
10335.
(27) Lee, Y.-S.; Byun, J.; Kim, J.-A.; Lee, J.-S.; Kim, K. L.; Suh, Y.-
L.; Kim, J.-M.; Jang, H.-S.; Lee, J.-Y.; Shin, I.-S.; Suh, W.; Jeon, E.-S.;
Kim, D.-K. Exp. Mol. Med. 2005, 37, 27-35.
(17) Gawronski, J.; Skowronek, P. Curr. Org. Chem. 2004, 8, 65-82.
(18) Superchi, S.; Casarini, D.; Summa, C.; Rosini, C. J. Org. Chem.
2004, 69, 1685-1694.
(28) Graefe, U.; Schlegel, R.; Ritzau, M.; Ihn, W.; Dornberger, K.;
Stengel, C.; Fleck, W. F.; Gutsche, W.; Hartl, A.; Paulus, E. F. J. Antibiot.
1995, 48, 119-125.
(19) Superchi, S.; Casarini, D.; Laurita, A.; Bavoso, A.; Rosini, C. Angew.
Chem., Int. Ed. 2001, 40, 451-454.
(29) Snatzke, G.; Laurent, H. R. W. Tetrahedron 1969, 25, 761-769.
(30) Jabłon´ska, E.; Szczepek, W. J., unpublished results.
(31) Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970, 35, 3195-
3196.
(20) Specht, K. M.; Nam, J.; Ho, D. M.; Berova, N.; Kondru, R. K.;
Beratan, D. N.; Wipf, P.; Pascal, R. A., Jr.; Kahne, D. J. Am. Chem. Soc.
2001, 123, 8961-8966.
(21) Kuball, H.-G. D. E.; Ho¨fer, T.; Tu¨rk, O. Monatsh. Chem. 2005,
136, 289-324.
(32) Steglich, W.; Hofle, G. Angew. Chem., Int. Ed. Engl. 1969, 8, 981-
981.
(33) Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43,
5436-5441.
(22) Superchi, S.; Donnoli, M. I.; Rosini, C. Org. Lett. 1999, 1, 2093-
2096.
J. Org. Chem, Vol. 72, No. 8, 2007 2907

Go´recki et al.
FIGURE 1. Investigated compounds.
SCHEME 1
SCHEME 2
Compound 3 was obtained from diol 2 by oximation reaction
of the C-6 ketone 2 with hydroxylamine in pyridine (Scheme
1), and compound 7 was obtained by cycloreversion of the
i-steroid ether 6 (Scheme 2).
one34 with OsO4 and careful reductive decomposition of the
formed osmate with sodium bisulfite. On the basis of the
literature data on dihydroxylation of the analogous 3,6-dike-
tone,35 the configuration of hydroxyl groups at C-9 and C-10
The vicinal cis-diol 2 was obtained by dihydroxylation of
the known 3â-acetoxy-5-methyl-19-nor-5â-cholest-9(10)-en-6-
(34) Szczepek, W. J. Acta Chim. Hung. 1986, 123, 77-82.
2908 J. Org. Chem., Vol. 72, No. 8, 2007

Configuration Assignment of tert/tert 1,2-Diols
SCHEME 3
1
was assumed to be R, and this fact was additionally proved by
the X-ray analysis (see Supporting Information). Further reaction
of the diol 2 with hydroxylamine hydrochloride in pyridine
afforded (E)-oxime 3 as the only product.
However, careful analysis of the crude product by H NMR
proved the presence of a minor product, the 13(14)-olefin.
Because the rearrangement involves formation of a carbocation
at C-13, it is not surprising that both tetra-substituted olefins
were formed as the reaction products. Before reaction with
OsO4, the C(5)-C(6) double bond had to be protected against
oxidation. For this reason, the olefin mixture was converted into
6â-methoxy-3R,5R-cyclosteroids (so-called i-steroid deriva-
tives). The reaction with OsO4 proceeded smoothly, affording
the corresponding vicinal cis-diols 6 and 8, which were separated
by silica gel chromatography. Because the i-steroid ethers are
usually oily compounds, compound 6 was subjected to cyclo-
reversion in a routine manner to the crystalline triol 7. The
configuration of the C-13 and C-17 hydroxyl groups as well as
the conformation of rings C and D was established by an X-ray
analysis (see Supporting Information).
Compound 4 was also synthesized by treatment of the
corresponding olefin with OsO4 (Scheme 1). The tetra-
substituted 5(6)-olefin, 3â-acetoxy-6-methylcholest-5-ene, was
obtained according to the well-known procedure described by
Fieser and co-workers.36 The configuration of hydroxyl groups
at C-5 and C-6 in the isolated product 4 was determined on the
basis of its 1H NMR spectrum. The presence of a characteristic
septet of an axial proton corresponding to the 3R-H signal
proved the R configuration of hydroxyl group at C-5 and,
consequently, R configuration of hydroxyl group at C-6.
Cis-hydroxylation of 5-methyl-B,19-dinor-5â-cholest-9(10)-
ene-3â,6R-diol, synthesized according to Sˇorm and co-work-
ers,37 with OsO4 gave diol 5a as the main product (Scheme 1).
Its 1H NMR spectrum showed a characteristic septet of an axial
proton, which corresponds to the 3R-H signal. Conformational
analysis by molecular mechanics calculations38 made for both
potential 9R,10R- and 9â,10â-dihydroxylated products allowed
one to establish the 9â,10â-configuration of the isolated diol
5a, because only in this product 3R-proton adopts an axial
orientation. It seems that the determining factor of the stereo-
chemical outcome of the dihydroxylation reaction is the presence
of 6R-hydroxyl group, which hinders an approach of osmium
tetraoxide from the R-side of the starting 9(10)-olefin. To
confirm the stereostructure of compound 5a, it was converted
into its crystalline monoacetate 5b. The X-ray analysis un-
equivocally proved 9â,10â-diol configuration and a chair
conformation of ring A with axial hydrogen atom at C-3 as a
consequence of equatorial orientation of the 3â-acetoxyl sub-
stituent (see Supporting Information).
Compound 9 was also obtained by reaction of the corre-
sponding olefin with OsO4 (Scheme 3). The tetra-substituted
13(14)-olefin was obtained by rearrangement of 16R,17R-
epoxide that was described a few years ago.40 However, during
the acid-catalyzed rearrangement, cycloreversion took place.
Therefore, i-steroid protection for the ring B double bond and
the 3â-OH group was reintroduced. Also, partial isomerization
at C-20 took place (the epimeric ratio 20R:20S was 2:3 as
1
established by integration of H-16â signals in the H NMR
spectrum of the mixture) under the reaction conditions. The 20R/
20S epimeric mixture was subjected to dihydroxylation, and the
isomeric vicinal cis-diols were separated.
The configuration at C-20 in the 20R-diol (compound 9) was
unequivocally established by a series of H difference NOE
experiments (Scheme 4). The irradiation of 17â-methyl protons
in the less polar 20R diol 9 caused a 3% NOE enhancement of
the H-16â signal at δ 4.60. There was also a weak NOE effect
(1%) for the H-20 signal at 2.54 upon irradiation of H-16â.
The more polar 20S epimer of diol 9 (compound 9a) showed a
5% enhancement of the H-20 signal at 2.38 and 1.6% of the
H-16â signal at 4.46 upon irradiation of 17â-methyl protons.
However, the 20S-diol appeared to be unstable and was lost
during final purification by silica gel column chromatography.
Compound 10 was obtained from the triol containing the
hydroxyl groups in the positions 16â, 17R, and in the side chain
1
Compounds 6 and 8 were obtained by dihydroxylation of the
mixture of 13(17)- and 13(14)-olefins with OsO4 (Scheme 2).
The mixture of olefins was obtained by Wagner-Meerwein
rearrangement of 17â-tosyloxy-androst-5-en-3â-ol promoted by
ethylmagnesium chloride. According to the original paper by
Madaeva,39 the reaction proceeds selectively to the 13(17)-olefin.
(35) Slates, H. L.; Wendler, N. L. Experientia 1961, 17, 161-161.
(36) Fieser, L. F.; Rigaudy, J. J. Am. Chem. Soc. 1951, 73, 4660-4662.
(37) Joska, J.; Fajkosˇ, J.; Sˇorm, F. Collect. Czech. Chem. Commun.
1963, 28, 82-100.
(38) HyperChem for Windows, Release 7.5 ed.; Hypercube, Inc.:
Gainesville, 2003.
(39) Madaeva, O. S. Zh. Obshch. Khim. 1955, 25, 1427-1431.
(40) Morzycki, J. W.; Gryszkiewicz, A.; Jastrze¸bska, I. Tetrahedron 2001,
57, 2185-2193.
J. Org. Chem, Vol. 72, No. 8, 2007 2909

Go´recki et al.
SCHEME 4
(Scheme 3).41 The reaction with sodium hydride unexpectedly
led to dehydrogenation of a secondary alcohol to the corre-
sponding 16-ketone. The product was formed, most likely, via
a cyclic mechanism outlined in Scheme 3, assuming participa-
tion of the side-chain OH group. Compound 10 exists in a
hemiketal form, which is presumably in equilibrium with a
hydroxy-ketone form. However, the cyclic form (the one with
hydroxyl groups at C-16 and C-17 configured cis) seems to be
by far more thermodynamically stable.
FIGURE 2. CD spectra of in situ formed Mo-complexes of mono-
crotaline (1) (-) and 5â-cholestane-3â,5,6â-triol (- - -). CD curve
of 5â-cholestane-3â,5,6â-triol is 1.5 times enhanced.
of chiral Mo-complexes of tert/tert Vic-diols is much slower
than that of other Vic-diols (even in comparison with sec/tert
Vic-diols (Figure 3)).
The replacement of carboxylate ligands of the stock complex
by the chiral 1,2-diol ligand produces no significant differences
in the absorption curve (Figure 4). In general, the shape and
position of particular bands remain unchanged. This indicates
that no considerable change of the chromophoric system of
Mo2O8 results from such a ligand exchange and additionally
may indicate that only one acetate group of the Mo2-core is
replaced by a diol ligand. However, the presence of two types
of complexes, chelating (R-form) and bridging (â-form), cannot
be excluded.23,25 Their existence in solution might explain the
observed time-dependence of the spectra.
To establish whether the shape of CD curves depends on the
concentration ratio, the CD spectra of monocrotaline (1) with
the Mo2-core in 1:1, 3:1, 5:1, and 10:1 ligand-to-metal ratios
were recorded. The increase of the ligand concentration resulted
in an increase of the band intensity (Figure 5). CD bands at
around 300 (band IV), 350 (band III), and 415 (band II) nm are
well developed and clearly visible even in the ligand-to-metal
ratio of 1:1. On the basis of the above-mentioned results, we
decided to measure the CD spectra of other tert/tert Vic-diols
with the Mo2-core in DMSO solution with a ligand-to-metal
ratio of 1:1 and after approximately 3 h after mixing the
components.
According to the X-ray data and conformational analysis by
molecular mechanics calculations,38 the torsion angle of the diol
unit in cis-diol 2 is positive and amounts to +20.6°. Therefore,
on the basis of the helicity rule, a positive sign of Cotton effects
at around 310 and 400 nm accompanied by a negative one
between both are expected in its CD spectrum with Mo2(OAc)4.
As can be seen in Figure 6, the signs of CEs at 350 and 405
nm are in agreement with the predicted ones, whereas CE at
298 nm is negative, in contradiction to the expectation. This is
due to the presence of the oxo group at C-6, which contributes
oppositely to the overall CD spectrum in the same spectral
region. After subtraction of the contributions from the oxo group,
the CD band at around 300 nm becomes positive (Figure 6).
After transformation of the oxo group in diol 2 into its oxime
derivative 3, all three diagnostic CD bands behave as predicted,
that is, follow the helicity rule (Figure 6).
Chiroptical Studies. As mentioned in the Introduction, the
helicity rule correlates a stereostructure of a Vic-diol and the
sign of the Cotton effects occurring between 300 and 400 nm
in its CD spectra recorded in the presence of dimolybdenum
tetraacetate. Until now, the rule was successfully applied to all
classes of Vic-diols, except the sterically more demanding tert/
tert diols.25 To fill in the gap, the chiroptical investigations on
tert/tert Vic-diols 1-14 were undertaken. According to the X-ray
diffraction analysis,42 the O-C-C-O torsion angle of the diol
unit in monocrotaline in the solid state is positive and equals
+46.9°. According to this and in agreement with the helicity
rule developed before,23 a positive sign of the Cotton effect at
around 310 and 400 nm should be present in the CD spectrum
of monocrotaline recorded in the presence of Mo2(OAc)4. This
is indeed the case, as can be seen in Figure 2, additionally
presenting the CD spectrum of the Mo-complex of 5â-
cholestane-3â,5,6â-triol, a representative of sec/tert Vic-diols,
for comparison. In the case of the latter diol (5â-cholestane-
3â,5,6â-triol) with a negative sign of the O-C-C-O torsion
angle of the diol unit, the Cotton effect at 313 nm is visible as
a positive minimum only.43 Nevertheless, the tendency to form
a minimum by this band is clearly visible. The shapes of CD
spectra of both compounds are similar, indicating that the
complexation modes for both the sec/tert and the tert/tert diols
are similar.
The stability of the chiral Mo-complex of monocrotaline in
solution was also investigated. In general, the signs and the
relative intensities of the bands are not time-dependent. How-
ever, the intensity of all CD bands does change with time. A
significant increase in intensity of all bands is observed in the
first 3-5 h, whereas a very small intensity change is evident
within the following hours. The time-dependent measurements
at λ ) 350 nm showed that the CD band intensity of chiral
Mo-complex of monocrotaline becomes stabile in solution after
approximately 5 h. This result demonstrates that the formation
(41) Kruszewska, A.; Wilczewska, A. Z.; Wojtkielewicz, A.; Morzycki,
J. W. Pol. J. Chem. 2006, 80, 611-615.
As mentioned before, the configuration of the hydroxyl groups
in compound 4 is 5R,6R. Thus, the O-C-C-O torsion angle
of the diol subunit is negative, and accordingly a negative sign
of the CD bands at around 310 and 400 nm should be present
in its CD spectrum with dimolybdenum tetraacetate. This is
(42) Stoeckli-Evans, H. Acta Crystallogr. 1979, B35, 231-234.
(43) Ciardelli, F.; Salvadori, P. An Introduction to Chiroptical Tech-
niques: Basic Principles, Definitions and Applications. In Fundamental
Aspects and Recent DeVelopments in Optical Rotatory Dispersion and
Circular Dichroism; Ciardelli, F., Salvadori, P., Eds.; Heyden & Son Ltd.:
London, New York, Rheine, 1973; Chapter 1.1, p 12.
2910 J. Org. Chem., Vol. 72, No. 8, 2007

Configuration Assignment of tert/tert 1,2-Diols
FIGURE 3. (A) Time-dependent measurements at 350 nm of in situ formed Mo-complex of monocrotaline (1) recorded in DMSO every 30′; (B)
time-dependent measurements at 350 nm of in situ formed Mo-complex of 5â-cholestane-3â,5,6â-triol recorded every 30′.
FIGURE 4. UV-vis spectra of dimolybdenum tetraacetate (-) and
FIGURE 7. CD spectra of in situ formed Mo-complexes of Vic-diols
its in situ formed chiral complexes with monocrotaline (1) (- - -)
4 (-), 5a (- ‚ - ‚ -), 6 (‚ ‚ ‚), and 7 (- - -) recorded in DMSO.
and 5â-cholestane-3â,5,6â-triol (‚ ‚ ‚), recorded in DMSO 3 h after
dissolving the components.
sides. Nevertheless, the tendency to form a maximum is clearly
visible.
An opposite situation is found in the case of diols 5a and 5b
in which the O-C-C-O torsion angle of the 9â,10â-diol
subunit is computed to be positive for 5a. The X-ray analysis
for compound 5b also showed a positive torsion angle of the
diol subunit (+17.2°) (see Supporting Information). In such
cases, the helicity rule predicts the presence of positive CEs at
around 310 and 400 nm and a negative one between both. The
experimental curves, which consist of positive CEs for bands
II and IV and of the negative band III, corroborate perfectly
with the above prediction (Figure 7).
FIGURE 5. CD spectra of in situ formed Mo-complexes of mono-
Compounds 6 and 7 possess the same 1,2-diol subunit in very
crotaline (1) at ligand-to metal ratios of 1:1 (-), 3:1 (- - -), 5:1
similar surroundings, and therefore the shapes of their CD curves
(‚ ‚ ‚), and 10:1 (- ‚ - ‚ -).
recorded in the presence of Mo2(OAc)4 are analogous (Figure
7). The positive signs of CEs at around 310 and 400 nm
undeniably indicate a positive sign of the O-C-C-O torsion
angle. The X-ray analysis showed the 13R,17R-configuration
of hydroxyl groups in compound 7, and consequently in
compound 6, because compound 7 was prepared from 6. This
assignment is consistent with the mechanism of cis-hydroxy-
lation reaction, which predicts an approach of osmium tetraoxide
from the less crowded R-side of the molecule, that is, from the
side opposite to the existing 6â- and 10â-substituents. The
molecular mechanics calculations indicated positive O-C-
C-O torsion angles for compound 7 (+32.3°) and compound
6 (+29.3°), while a negative one for its local stereoisomer 8
(-26.4°).38 Moreover, the molecular mechanics calculations
revealed a boat conformation of ring C for 7 being slightly lower
in energy as compared to its chair conformer. Unexpectedly,
the O-C-C-O torsion angle in the X-ray structure appeared
to be negative and amounted to -37.8° (see Supporting
Information). The conformation of ring C in the solid state was
also a boat, like for the computed structure, but the difference
was for the ring D conformation. The molecular mechanics
FIGURE 6. CD spectra of in situ formed Mo-complexes of Vic-diols
2 (-) and 3 (- ‚ - ‚ -). CD spectrum of diol 2 without Mo2(OAc)4
(- - -) and differential curve of Mo-complex of 2 minus CD spectrum
of diol 2 in DMSO (‚ ‚ ‚).
indeed the case, as can be seen from Figure 7. The third decisive
CE at around 350 nm is predicted to be positive. In this case,
however, this CD band is not well developed to a maximum,
most likely due to the presence of strong minima at both its
J. Org. Chem, Vol. 72, No. 8, 2007 2911

Go´recki et al.
FIGURE 8. Root-mean-square fit for the X-ray structure and the
calculated optimal conformation of compound 7 and overlay.
FIGURE 10. CD spectra of in situ formed Mo-complexes of Vic-
diols 11 (-), 12 (‚ ‚ ‚), 13 (- ‚ - ‚ -), 14 (- ‚‚ - ‚‚ -) and of (1R,2S)-
1-methylcyclohexane-1,2-diol (- - -) recorded in DMSO (top) and
preferred conformation of the diols in the chiral Mo-complexes
(bottom). CD curves of diols 13 and 14 are 2-fold enhanced.
FIGURE 9. CD spectra of in situ formed Mo-complexes of Vic-diols
8 (‚ ‚ ‚), 9 (- - -), and 10 (-) recorded in DMSO.
molecule becomes substantially reduced due to the steric
requirements of the stock complex.44,45 As a result, the molecule
appears to exist only as a single conformer, in most cases. The
energetically preferred conformation of a Vic-diol molecule in
the chiral Mo-complexes is the one with an antiperiplanar
orientation of both O-C-C-R units. This is very reasonable,
because only in such a conformation the bulky R-groups point
away from the rest of the complex and do avoid the close
interaction with the remaining acetate ligands in the stock
complex. Additional evidence in support of such preferred
conformation is given by quantum-mechanical calculations.46
These calculations made for the model systems of Vic-diols
indicate that the best gauche conformer (O-C-C-O ≈ 60°)
is ca. 8 kJ mol-1 lower in energy than the best trans conformer
(O-C-C-O ≈ 180°). Thus, the relative configuration of Vic-
diol after ligation to the Mo2-core is established to be gauche
with an antiperiplanar orientation of each O-C-C-R group.
In the CD spectra of diols 11 and 12, two negative CD bands
at around 310 and 370 nm can be seen (Figure 10). The negative
sign of these CD bands corresponds to a negative torsion angle
of the O-C-C-O moiety in its preferred antiperiplanar
conformation, as presented in the bottom of Figure 10. The
shape of the CD curves of 11 and 12 resembles the one for
sec/tert 1,2-diols, for example, for (1R,2S)-1-methylcyclohexane-
1,2-diol shown also in Figure 10. (1R,2S)-1-Methylcyclohexane-
1,2-diol exhibits positive CEs at around 310 and 370 nm
corresponding to the positive sign of the O-C-C-O torsion
angle in its complexed form.
calculations show preference for an envelope conformation of
the five-membered ring D with carbon atoms C-17, C-13, C-14,
and C-15 in one plane and the remaining C-16 carbon atom
above the plane. In the X-ray structure, ring D also assumed
slightly distorted envelope conformation with C-16 out of the
plane, but this time below the plane (Figure 8). Such conforma-
tion with pseudo-equatorial methyl and pseudo-axial hydroxyl
groups is advantageous for intermolecular hydrogen bonding,
but MM+ calculations show that it is less favored in the case
of isolated molecule by about 1.2 kcal/mol. The X-ray structure
is stabilized by three intermolecular hydrogen bonds: between
3â-OH and oxygen atom at C-17, between 17R-OH and oxygen
atom at C-13 of the second molecule, and between 13R-OH
and oxygen atom of the solvating water molecule. The CD
measurements were made in diluted DMSO (anhydrous) solu-
tions, and the positive signs of CEs at around 310 and 400 nm
unequivocally indicate that the conformation in solution is
different from that in solid state in agreement with the MM+
calculations.
According to the conformational analysis and molecular
mechanics calculations,38 the O-C-C-O torsion angle of the
diol unit in compounds 8 and 9 is negative and equals -26.4°
and -32.1°, respectively. Thus, a negative sign of the CD bands
at around 310 and 400 nm is expected in the CD spectra of
their Mo-complexes. The experimental CD curves agree with
this expectation, although band III is not developed to a
maximum for compound 8 (Figure 9). This can be explained
by the presence of relatively strong minima at both sides of
this band. Also, in the case of diol 10, the signs of the CD
bands in experimental curve fit the requirements of the helicity
rule. In the last case, the signs of the CEs at around 310, 350,
and 380 nm are positive, negative, and positive, respectively,
in accordance with the calculated positive sign of the O-C-
C-O torsion angle (Figure 9).
A preferred conformation of the diol unit in compound 13 in
its complexed form depends on the configuration at the C-7
carbon atom. So, for a (7S) configuration, the O-C-C-O
torsion angle is positive, while for its local enatiomer, that is,
a (7R) isomer, it is negative. Consequently, in the CD spectrum
of its Mo-complex, the CEs with a positive or a negative sign
at around 310 and 400 nm should be present, respectively.
Because the sign of the relevant CEs is negative (Figure 10),
Diols 11-14 belong to a conformationally flexible group of
compounds. Therefore, the determination of their absolute
configuration requires knowledge of their conformation in the
complexed form. It is well known that after ligation to the Mo2-
core an internal conformational mobility of the flexible diol
(44) Frelek, J.; Perkowska, A.; Snatzke, G.; Tima, M.; Wagner, U.; Wolff,
H. P. Spectrosc. Int. J. 1983, 2, 274-295.
(45) Frelek, J.; Majer, Z.; Perkowska, A.; Snatzke, G.; Vlahov, I.;
Wagner, U. Pure Appl. Chem. 1985, 57, 441-451.
(46) Brock, C. P. Acta Crystallogr. 2002, B58, 1025-1031.
2912 J. Org. Chem., Vol. 72, No. 8, 2007

Configuration Assignment of tert/tert 1,2-Diols
TABLE 1. CD Data of in Situ Formed Mo-Complexes of Wic-Diols 1-12a
comp.
Ab
Bc
CD band V
CD band IV
CD band III
CD band II
CD band I
d
1
2
3
+
+
+
+
-
+
+
+
+
-
-
+
-
-
-
-
+5.95 (299.0)
+0.10 (323.5)
+0.56 (305.0)
-0.30 (316.5)
+0.69 (300.0)
+0.39 (310.0)
+0.37 (306.5)
+0.71 (313.0)
-0.41 (321.0)
-0.31 (293.5)
+0.28 (307.0)
-0.76 (318.5)
-1.48 (324.5)
-0.32 (307.8)
-0.17 (298.5)
-2.65 (353.0)
-0.50 (344.5)
-0.18 (337.0)
ae (331.5)
-1.43 (350.5)
-0.21 (353.0)
-0.03 (344.0)
+0.93 (358.2)
ae (342.5)
+0.44 (414.0)
+1.32 (396.0)
+1.02 (393.0)
-1.02 (375.5)
+0.36 (417.0)
+0.21 (399.5)
+0.18 (389.0)
+0.14 (424.2)
-0.53 (376.0)
-0.03 (414.5)
+0.23 (380.5)
-0.88 (379.5)
-1.51 (381.5)
-0.15 (417.0)
-0.11 (420.5)
+
+
-
+
+
+
+
-
-
+
-
-
-
-
-2.05 (294.5)
-0.08 (275.5)
+0.41 (266.0)
4
-0.07 (482.0)
+0.14 (433.0)
5a
5b
6
7
8
-0.43 (276.0)
-0.11 (268.5)
-0.85 (264.2)
-0.40 (274.5)
-0.11 (436.0)
+0.07 (512.0)
9
+0.52 (348.5)
-0.05 (342.5)
ae (349.0)
10
11
12
13
14
-1.28 (262.0)
+2.07 (272.2)
+0.41 (269.0)
ae (350.5)
+0.38 (368.0)
+0.28 (369.0)
+0.10 (486.2)
+0.07 (478.0)
a Values are given as ∆ꢀ′(nm). For explanation of term ∆ꢀ′, see text. b A, calculated sign of the O-C-C-O torsion angle. c B, sign of the O-C-C-O
torsion angle from CD. d X-ray data. e a, negative inflection point.
thus we are able to assign the absolute configuration at C-7 in
13 to be (R). This assignment was additionally proven to be
correct by the X-ray analysis.47
the usual way as ∆ꢀ′ ) ∆A/c × d, where c is the molar
concentration of the chiral ligand, assuming 100% complexation
(∆A ) the difference in absorption of left and right circularly
polarized light; d ) path length of the cell). This, however,
creates no disadvantage for the method because, for the purpose
of absolute configuration determination, only the sign of the
appropriate Cotton effects is important and the magnitude of
∆ꢀ is irrelevant. In addition, provided that the appropriate
complexation takes place, CD spectra of chiral Mo-complexes
allow one to match both pattern and sign with absolute
configuration of diol ligand. On account of this, it is recom-
mended to measure the CD spectra for one class of compounds
always at similar concentration ratios.
The present study demonstrates that: (1) the scope of the
dimolybdenum CD method can be extended to tert/tert 1,2-
diols; (2) the absolute configuration can be determined un-
equivocally by means of the empirical helicity rule relating the
sign of the CEs arising in the 300-400 nm spectral region with
the helicity of the O-C-C-O subunit; (3) the method also
allows one to establish the preferred conformation of compound
in solution, if its absolute configuration is known; (4) no
exception to the helicity rule has as yet been found; and (5)
despite its empirical character, this simple methodology allows
easy, fast, and effective determination of the absolute config-
uration of a variety of classes of Vic-diols, including even
sterically demanding tert/tert diols, in a reliable and versatile
manner.
Cis-hydroxylation reaction of the respective oxacepham
bearing an exo isopropylene group at C-7 gave an inseparable
mixture of diols in a ratio of 4.5:1. The absolute configuration
at the bridgehead carbon atom in the major product 14 was
established to be (6S) by NMR and CD spectroscopies.48
However, the absolute configuration at C-7 could not be ascribed
unequivocally by these methods. Thus, we decided to apply the
CD dimolybdenum methodology for this purpose. As can be
seen from Figure 10, CD spectrum of the Mo-complex of 14 is
very similar to that of compound 13 in both signs of particular
CEs and in the shape of the CD curve. This points definitely to
the same (7R) absolute configuration in both compounds.
The results discussed above perfectly reflect the stereochem-
ical situation in chiral Mo-complexes of flexible Vic-diols and
the relationship with their CD spectra. On these grounds, we
came to the conclusion that flexible tert/tert Vic-diols 11-14
also fall under our empirical helicity rule established previously
for other classes of glycols.
Discussion and Conclusions
The chiroptical data for Vic-diols 1-14 collected in Table 1
demonstrate that the sign of the O-C-C-O torsion angle
predicted by the helicity rule is in excellent agreement with the
one resulting from their stereostructure. This statement holds
equally for rigid (compounds 1-10) as well as for flexible tert/
tert 1,2-diols (compounds 11-14). Thus, the results obtained
validate profitable applicability of the dimolybdenum methodol-
ogy to tert/tert 1,2-diols too. In other words, the empirical rule
finds application for determining the 3D molecular structure of
this class of Vic-diols with confidence.
On the other hand, the nature of the equilibrium formed in
solution and the complexes involved still remains unknown. It
means that by using the in situ dimolybdenum CD method one
does not obtain quantitative values because the real complex
structure as well as the concentration of the chiral complex
formed in solution are not known. Therefore, the CD data are
presented as the ∆ꢀ′ values. These ∆ꢀ′ values are calculated in
Experimental Section
3â-Acetoxy-9r,10-dihydroxy-5-methyl-19-nor-5â,10r-cholestan-
6-one (2). To a solution of 3â-acetoxy-5-methyl-19-nor-5â-cholest-
9(10)-en-6-one34 (1.0 g; 2.26 mmol) in pyridine (25 mL) was added
OsO4 (500 mg; 1.97 mmol), and the mixture was left standing at
room temperature for 2 weeks. The mixture was evaporated to
dryness under reduced pressure, and the residue was dissolved in
ethanol (30 mL). The obtained solution was treated with a saturated
aqueous solution of NaHSO3 at 50 °C for 5 h. Next, it was diluted
with water (75 mL) and extracted with chloroform (2 × 30 mL).
The organic extracts were combined, dried over anhydrous MgSO4,
filtered, and evaporated to dryness. The residue was chromato-
graphed on silica gel (30 g). The column was washed with hexane-
dichloromethane (50:50 and 25:75) mixtures, dichloromethane, and
dichloromethane-ethyl acetate (90:10, 80:20, 70:30, and 60:40)
mixtures. Fractions containing the main product were combined
and evaporated to dryness. The residue was crystallized twice from
(47) Łysek, R.; Urban´czyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron
2001, 57, 1301-1309.
(48) Danh, T. T.; Borsuk, K.; Solecka, J.; Chmielewski, M. Tetrahedron
2006, 62, 10928-10936.
J. Org. Chem, Vol. 72, No. 8, 2007 2913

Go´recki et al.
methanol to give 262 mg (28%) of the title compound; mp 217-
12.1 (CH3/CH). EI MS (70 eV): 476 (M+, 9.7%), 461 (9.7%), 440
(13.1%), 416 (7.4%), 398 (62.2%), 380 (52.2%), 365 (10.4%), 355
(12.6%), 329 (15.2%), 285 (15.3%), 263 (100%). EI HRMS: calcd
for C30H52O4, 476.38656; found, 476.38579. Anal. Calcd for
C30H52O4: C, 75.58%; H, 10.99%. Found: C, 75.37% and 75.34%;
H, 10.99% and 11.15%.
1
219 °C. IR (KBr): 3428, 3388, 1706, 1280, 1024, 962 cm-1. H
NMR (500 MHz): 0.73 (3H, s, 18-H), 1.43 (3H, s, 5â-Me), 2.03
(3H, s, OAc), 5.15 (1H, narrow m, 3R-H equatorial). 13C NMR
(125.758 MHz): 214.5 (C, CdO ketone), 170.1 (C, CdO acetate),
75.5 (C), 74.3 (C), 69.5 (CH3/CH), 55.8 (CH3/CH), 50.2 (C), 46.3
(CH3/CH), 43.5 (C), 39.4 (CH2), 36.9 (CH2), 36.4 (CH3/CH), 36.2
(CH2), 36.0 (CH2), 35.7 (CH3/CH), 35.6 (CH2), 31.7 (CH2), 28.3
(CH2), 28.0 (CH3/CH), 25.4 (CH2), 24.1 (CH2), 23.8 (CH2), 23.0
(CH2), 22.8 (CH3/CH), 22.5 (CH3/CH), 22.4 (CH3/CH), 21.6 (CH3/
CH), 18.5 (CH3/CH), 12.0 (CH3/CH). EI MS (70 eV): 476 (M+,
1.4%), 458 (3.2%), 430 (5.8%), 416 (15.2%), 388 (45.0%), 370
(21.0%), 305 (17.9%), 264 (19.0%), 193 (36.8%), 150 (100%). EI
HRMS: calcd for C29H48O5, 476.35017; found, 476.35166.
(6E)-6-Hydroxyimino-5-methyl-19-nor-5â,10r-cholestanetriol-
3â,9r,10 3-Acetate (3). 3â-Acetoxy-9R,10-dihydroxy-5-methyl-
19-nor-5â,10R-cholestan-6-one (2; 262 mg; 0.55 mmol) and
NH2OH.HCl (267 mg; 3.84 mmol) were dissolved in pyridine (15
mL), and the obtained solution was left standing at room temper-
ature for 1 week. The reaction mixture was diluted with water (100
mL) and extracted with chloroform (2 × 30 mL). The combined
organic extracts were dried over anhydrous MgSO4, filtered, and
evaporated to dryness. The residue was chromatographed on silica
gel (15 g). The column was washed with dichloromethane and
dichloromethane-ethyl acetate (95:5, 90:10, 85:15, 80:20, and 70:
30) mixtures. Fractions containing the substrate were combined and
evaporated to dryness to give 129 mg (49%) of the solid. Fractions
containing the product were combined and evaporated to dryness.
The residue was crystallized from methanol to give 118 mg (44%)
of the title compound; mp 184-185 °C. IR (KBr): 3530, 3419,
5-Methyl-B,19-dinor-5â,10r-cholestane-3â,6r,9r,10-tetraol (5a).
To a solution of 5-methyl-B,19-dinor-5â-cholest-9(10)-ene-3â,6R-
diol37 (806 mg; 2.07 mmol) in pyridine (25 mL) was added OsO4
(500 mg; 1.97 mmol), and the mixture was left standing at room
temperature for 1 week. The mixture was then evaporated to dryness
under reduced pressure, and the residue was dissolved in ethanol
(50 mL). The obtained solution was treated with a saturated aqueous
solution of NaHSO3 at 50 °C for 3 h. Next, it was diluted with
water (75 mL) and extracted with chloroform (2 × 30 mL). The
organic extracts were combined, dried over anhydrous MgSO4,
filtered, and evaporated to dryness. The residue was chromato-
graphed on silica gel (24 g). The column was washed with
dichloromethane-ethyl acetate (60:40, 50:50, 30:70, 20:80, and 10:
90) mixtures and ethyl acetate. Fractions containing the main
product were combined and evaporated to dryness to give 349 mg
(42%) of the title compound as a glassy oil. IR (KBr): 3430, 1067,
1021 cm-1. 1H NMR (500 MHz): 0.90 (3H, s, 18-H), 1.05 (3H, s,
5â-Me), 2.08 (1H, ddd, J ) 13.6, 5.2, and 1.9 Hz), 2.20 (1H, dd,
J ) 12.6 and 6.3 Hz), 2.28 (1H, s, -OH), 2.66 (1H, d, J ) 0.9 Hz,
-OH), 3.79 (1H, dd, J ) 6.3 and 3.5 Hz, 6â-H), 4.08 (1H, septet,
J1 ≈ J2 ≈ 10.9 Hz and J3 ≈ J4 ≈ 5.5 Hz, 3R-H axial). 13C NMR
(125.758 MHz): 80.7 (C), 80.3 (CH3/CH), 79.5 (C), 68.1 (CH3/
CH), 56.1 (CH3/CH), 51.0 (CH3/CH), 49.9 (C), 43.5 (CH3/CH),
43.0 (CH2), 41.3 (C), 39.5 (CH2), 36.03 (CH3/CH), 35.97 (CH2),
32.6 (CH2), 32.4 (CH2), 30.9 (CH2), 29.3 (CH2), 28.9 (CH2), 28.0
(CH3/CH), 25.0 (CH2), 24.1 (CH3/CH), 23.8 (CH2), 22.8 (CH3/
CH), 22.5 (CH3/CH), 18.5 (CH3/CH), 16.3 (CH3/CH). EI MS (70
eV): 404 (M+ - H2O, 5.2%), 386 (63.1%), 371 (6.7%), 345 (8.5%),
318 (9.5%), 293 (100%), 263 (94.9%), 193 (9.6%), 163 (21.8%),
141 (20.4%), 128 (32.3%). EI HRMS: calcd for C26H46O4,
422.33961; found, 422.34099.
1
3361, 1715, 1648, 1278, 908 cm-1. H NMR (500 MHz): 0.71
(3H, s, 18-H), 1.51 (3H, s, 5â-Me), 2.03 (3H, s, OAc), 3.48 (1H,
s, -OH), 5.13 (1H, narrow m, 3R-H equatorial), 7.96 (1H, narrow
m, -OH). 13C NMR (125.758 MHz): 170.2 (C, CdO acetate),
165.6 (C, CdN), 75.5 (C), 74.4 (C), 69.3 (CH3/CH), 55.8 (CH3/
CH), 46.8 (CH3/CH), 43.7 (C), 43.5 (C), 39.5 (CH2), 37.8 (CH2),
36.2 (CH2), 36.1 (CH2), 35.8 (CH3/CH), 35.3 (CH3/CH), 31.9 (CH2),
28.4 (CH2), 28.0 (CH3/CH), 25.5 (CH2), 25.3 (CH3/CH), 24.2 (CH2),
23.8 (CH2), 23.2 (CH2), 22.8 (CH3/CH), 22.5 (CH3/CH), 22.4 (CH2),
21.6 (CH3/CH), 18.5 (CH3/CH), 12.0 (CH3/CH). EI MS (70 eV):
491 (M+, 3.7%), 474 (43.1%), 456 (10.6%), 431 (8.3%), 414
(27.9%), 397 (47.0%), 386 (22.6%), 357 (10.1%), 227 (10.7%),
150 (16.0%), 110 (100%). EI HRMS: calcd for C29H49NO5,
491.36107; found, 491.36277.
5-Methyl-B,19-dinor-5â,10r-cholestane-3â,6r,9r,10-tetraol
3-Acetate (5b). A solution of 5-methyl-B,19-dinor-5â,10R-choles-
tane-3â,6R,9R,10-tetraol (5a; 245 mg) in pyridine (5 mL) was
treated with acetic anhydride (3 mL), heated to reflux, and then
left standing at room temperature for 2 h 15 min. The reaction
mixture was evaporated to dryness under reduced pressure. The
residue was treated with water (60 mL) and extracted with
chloroform (2 × 30 mL). The organic extracts were combined, dried
over anhydrous MgSO4, filtered, and evaporated to dryness. The
residue was chromatographed on silica gel (10 g). The column was
washed with dichloromethane and dichloromethane-ethyl acetate
(95:5, 92.5:7.5, 90:10, and 85:15) mixtures. Fractions containing
the main product were combined and evaporated to dryness.
Crystallization of the residue from hexane-dichloromethane gave
240 mg (89%) of the title compound; mp 192-193 °C. IR (KBr):
3â-Acetoxy-6â-methyl-5r-cholestan-5,6r-diol (4). To a solu-
tion of 3â-acetoxy-6-methylcholest-5-ene36 (0.411 g; 0.93 mmol)
in pyridine (30 mL) was added OsO4 (250 mg; 0.98 mmol), and
the mixture was left standing at room temperature for 1 week. The
mixture was then evaporated to dryness under reduced pressure,
and the residue was dissolved in ethanol (30 mL). The obtained
solution was treated with a saturated aqueous solution of NaHSO3
at 50 °C for 2 h and then extracted with chloroform (4 × 15 mL).
The organic extract was dried over anhydrous MgSO4, filtered, and
evaporated to dryness. The residue was chromatographed on silica
gel (13 g). The column was washed with dichloromethane and
dichloromethane-ethyl acetate (97.5:2.5, 95:5, 92.5:7.5, 90:10, and
80:20) mixtures. Fractions containing the main product were
combined and evaporated to dryness to give 154 mg (35%) of the
title compound as a glassy oil. IR (KBr): 3504, 1736, 1717, 1268,
1
3452, 3377, 1711, 1273, 1014 cm-1. H NMR (500 MHz): 0.89
(3H, s, 18-H), 1.03 (3H, s, 5â-Me), 2.01 (3H, s, OAc), 2.10 (1H,
ddd, J ) 13.5, 5.4 and 2.0 Hz), 2.19 (1H, dd, J ≈ 12.7 and 6.4
Hz), 2.26 (1H, s, -OH), 2.75 (1H, d, J ) 1.3 Hz, -OH), 3.80
(1H, dd, J ) 6.4 and 4.1 Hz, 6â-H), 5.16 (1H, septet, J1 ≈ J2 ≈
10.9 Hz and J3 ≈ J4 ≈ 5.4 Hz, 3R-H axial). 13C NMR (125.758
MHz): 171.0 (C, CdO acetate), 80.8 (C), 80.0 (CH3/CH), 79.4
(C), 71.7 (CH3/CH), 56.1 (CH3/CH), 50.8 (CH3/CH), 49.8 (C), 43.5
(CH3/CH), 41.3 (C), 39.5 (CH2), 38.6 (CH2), 36.05 (CH3/CH), 35.98
(CH2), 32.6 (CH2), 32.1 (CH2), 29.2 (CH2), 28.9 (CH2), 28.0 (CH3/
CH), 26.9 (CH2), 24.9 (CH2), 23.87 (CH2), 23.86 (CH3/CH), 22.8
(CH3/CH), 22.5 (CH3/CH), 21.5 (CH3/CH), 18.5 (CH3/CH), 16.3
(CH3/CH). EI MS (70 eV): 446 (M+ - H2O, 2.2%), 404 (12.0%),
386 (39.7%), 371 (6.3%), 331 (11.3%), 293 (85.0%), 263 (100%),
193 (16.0%), 163 (25.0%), 151 (20.5%), 123 (31.0%), 110 (57.5%).
ESI HRMS: calcd for C28H48O5Na, 487.3394; found, 487.3417.
1
1245, 1036 cm-1. H NMR (500 MHz): 0.66 (3H, s, 18-H), 1.06
(3H, s, 19-H), 1.27 (3H, s, 6â-Me), 2.02 (3H, s, OAc), 2.56 (1H,
s, -OH), 5.17 (1H, septet, J1 ≈ J2 ≈ 11.0 Hz and J3 ≈ J4 ≈ 5.5
Hz, 3R-H axial). 13C NMR (125.758 MHz): 170.6 (C, CdO
acetate), 78.8 (C), 74.1 (C), 71.7 (CH3/CH), 56.2 (CH3/CH), 55.5
(CH3/CH), 45.1 (CH3/CH), 42.7 (C), 42.0 (CH2), 39.8 (CH2), 39.5
(CH2), 39.4 (C), 36.1 (CH2), 35.8 (CH3/CH), 33.4 (CH2), 33.2 (CH3/
CH), 32.1 (CH2), 28.2 (CH2), 28.0 (CH3/CH), 26.6 (CH2), 25.0
(CH3/CH), 24.3 (CH2), 23.9 (CH2), 22.8 (CH3/CH), 22.5 (CH3/
CH), 21.5 (CH3/CH), 21.1 (CH2), 19.1 (CH3/CH), 18.6 (CH3/CH),
2914 J. Org. Chem., Vol. 72, No. 8, 2007

Configuration Assignment of tert/tert 1,2-Diols
6â-Methoxy-3r,5r-cyclo-18-nor-17-methylandrost-13(17)-
ene and 6â-Methoxy-3r,5r-cyclo-18-nor-17â-methylandrost-13-
(14)-ene. 17â-Tosyloxy-androst-5-en-3â-ol (11.80 g, 26.6 mmol)
was dissolved in dry ether (150 mL) and gradually added to a
solution of ethylmagnesium chloride in ether (100 mL), prepared
from 5.5 g of magnesium and ethyl chloride (it is a slightly modified
literature procedure39). The majority of ether (about 70 mL) was
distilled from the stirred solution, and dry benzene (150 mL) was
added. The reaction mixture was refluxed for 4 h at 60-62 °C,
cooled to room temperature, and quenched with water and 5% H2-
SO4. Organic layer was separated, dried over anhydrous MgSO4,
and evaporated in vacuo. A mixture of two olefins (∆13(17) and
evaporated in vacuo. The product was purified by silica gel column
chromatography. With a hexane:ethyl acetate (80:20) mixture, 18-
nor-17-methylandrost-5-ene-3â,13R,17R-triol (7) was eluted (100
mg, 91%) and crystallized from methanol; mp 160-162 °C. IR:
ν
max 3608, 3524, 1044, 995 cm-1. 1H NMR: δ 0.98 (3H, s, H-19),
1.22 (3H, s, 17â-CH3), 3.55 (1H, m, H-3R), 5.36 (1H, m, H-6).
13C NMR: δ 141.0 (C), 121.2 (CH), 80.8 (C), 80.5 (C), 71.6 (CH),
51.5 (CH), 45.4 (CH), 41.9 (CH2), 38.3 (CH2), 37.8 (C), 36.8 (CH2),
36.2 (CH), 32.7 (CH2), 31.3 (CH2), 29.0 (CH2), 26.3 (CH2), 23.5
(CH3), 19.0 (CH2), 17.9 (CH3). MS-EI, m/z (%) 306 (M+, 67), 288
(45), 270 (24), 255 (54), 230 (100). EI HR: calcd for C19H30O3,
306.2195; found, 306.2203.
(20R/S)-6â-Methoxy-18-nor-17â-methyl-3r,5r-cyclopregn-13-
ene-20,16r-carbolactone. Ethyl (20S)-6â-methoxy-16R,17R-oxido-
3R,5R-cyclopregnane-20-carboxylate (500 mg, 1.24 mmol) prepared
as previously described40 was subjected to slow column chroma-
tography on silica gel impregnated with 50% H2SO4 (7% weight).
3â-Hydroxy-18-nor-17â-methylpregna-5,13-diene-20,16R-carbolac-
tone (as a mixture of C-20 epimers) was eluted with a hexane:
ethyl acetate (80:20) mixture in 64% yield. The epimeric ratio (20R:
20S) 2:3 was established by integration of H-16â signals at δ 4.56
and 4.62, respectively, in the NMR spectrum.
∆
13(14)) was obtained in 96% yield (6.94 g). The 1H NMR spectrum
showed that the former olefin prevailed as it was evident from
integration of the signals of 17-methyl group (a broadened singlet
at 1.61 ppm deriving from 13(17)-olefin and a doublet at 0.98 ppm
(J ) 6.2 Hz) from 13(14)-olefin).
The mixture of olefins was treated with p-toluenesulphonic
chloride in pyridine, and the resulting 3â-tosylates were subjected
to a buffered methanolysis (in the presence of potassium acetate),
as previously described.49 A mixture of 6â-methoxy-3R,5R-cyclo-
18-nor-17-methylandrost-13(17)-ene and 6â-methoxy-3R,5R-cyclo-
18-nor-17-methylandrost-13(14)-ene was obtained in 51% yield
(3.7 g).
The epimeric mixture (203 mg, 0.6 mmol) was dissolved in
anhydrous pyridine (10 mL), and p-toluenesulphonic chloride (208
mg, 1.1 mmol) was added. The reaction mixture was stirred at room
temperature for 14 h, poured into iced water, and extracted with
benzene:ethyl ether (1:1). The extract was dried (anhydrous MgSO4)
and evaporated in vacuo. The crude product (289 mg, 98% yield)
was dissolved in methanol (15 mL) containing anhydrous (freshly
melted) potassium acetate (548 mg, 5.6 mmol), and the reaction
mixture was refluxed for 4 h. After being cooled, the mixture was
poured into water, and the product was extracted with chloroform.
Evaporation of the solvent from dried (anhydrous MgSO4) extract
followed by silica gel column chromatography afforded the title
compound as an epimeric mixture at C-20. The product was eluted
with a hexane:ethyl acetate (90:10) mixture in 54% yield (113 mg).
(20R)-6â-Methoxy-18-nor-17â-methyl-3r,5r-cyclopregna-
13r,14r-diol-20,16r-carbolactone (9). To a stirred solution of
mixture (20R/S)-6â-methoxy-3R,5R-cyclo-18-nor-17â-methylpregn-
13-ene-20,16R-carbolactone (113 mg, 0.32 mmol) in pyridine (15
mL) was added osmium tetraoxide (105 mg, 0.41 mmol) dissolved
in pyridine (1 mL) at room temperature. The reaction mixture was
stirred for 18 h at 25 °C. The obtained osmate complex was reduced
with aqueous solution of sodium hydrogen sulfite (40% NaHSO3).
The reaction mixture was stirred for 2 days at room temperature,
poured into water, and extracted with benzene:ether (1:1) and then
with ethyl acetate. Both extracts were dried with anhydrous MgSO4,
and the solvents were evaporated in vacuo. TLC control (chloroform-
methanol 9:1) showed two spots (less polar product predominated)
in the first extract, while the second one contained the more polar
product only. Column chromatography purification of the first
extract afforded (20R)-6â-methoxy-18-nor-17â-methyl-3R,5R-cy-
clopregna-13R,14R-diol-20â,16R-carbolactone (18 mg, 15%) eluted
6â-Methoxy-3r,5r-cyclo-18-nor-17-methylandrostan-13r,17r-
diol (6) and 6â-Methoxy-3r,5r-cyclo-18-nor-17â-methyland-
rostan-13r,14r-diol (8). To a stirred solution of the described
above olefin mixture (560 mg, 1.96 mmol) in pyridine (30 mL)
was added a solution of OsO4 (648 mg, 2.55 mmol) in pyridine (7
mL) at room temperature. The reaction mixture was stirred for 6
days at 25 °C. Next, an aqueous solution of sodium bisulfite (20
mL of 40% NaHSO3) was added, and the reaction mixture was
stirred for 3 days at room temperature, poured into water, and
extracted with dichloromethane. The extract was dried with
anhydrous MgSO4, and the solvent was evaporated in vacuo. The
products were separated by silica gel column chromatography.
Elution with ethyl acetate-hexane (10:90) mixture afforded
consecutively 275 mg (44%) of 6â-methoxy-3R,5R-cyclo-18-nor-
17-methylandrostan-13R,17R-diol (6) and 45 mg (7%) of 6â-
methoxy-3R,5R-cyclo-18-nor-17â-methylandrostan-13R,14R-diol (8).
Compound 6. An oil. IR: νmax 3618, 3556, 1092, 1076 cm-1
.
1H NMR: δ 0.46 (1H, m, H-4), 0.66 (1H, m, H-3), 0.99 (3H, s,
H-19), 1.27 (s, 3H, 17â-CH3), 2.28 (2H, broad s, HO-), 2.78 (1H,
m, H-6R), 3.32 (3H, s, CH3O-). 13C NMR: δ 82.1 (CH), 81.1
(C), 80.4 (C), 56.5 (CH3), 51.3 (CH), 44.1 (C), 43.1 (CH), 38.1
(CH2), 36.5 (CH2), 36.3 (CH), 35.3 (C), 33.6 (CH2), 30.9 (CH2),
26.5 (CH2), 24.8 (CH2), 23.9 (CH3), 22.4 (CH2), 21.6 (CH), 18.6
(CH3), 12.9 (CH2). MS-ESI, m/z (%) 343 (M + Na+, 100), 663
(2M + Na+, 28). EI HRMS calcd for C20H32O3Na, 343.2249; found,
343.2239.
Compound 8. An oil. IR: νmax 3610, 3532, 1085, 1011 cm-1
.
1H NMR: δ 0.48 (1H, m, H-4), 0.66 (1H, m, H-3), 1.02 (3H, s,
H-19), 1.08 (3H, d, J ) 7.1 Hz, 17â-CH3), 2.87 (1H, m, H-6R),
3.34 (3H, s, CH3O-). 13C NMR: δ 83.8 (C), 82.1 (CH), 79.2 (C),
56.4 (CH3), 43.7 (C), 43.3 (CH), 42.3 (CH), 38.3 (CH2), 37.2 (CH),
35.0 (C), 33.8 (CH2), 30.3 (CH2), 29.4 (CH2), 28.9 (CH2), 25.0
(CH2), 22.4 (CH2), 21.7 (CH), 19.3 (CH3), 18.7 (CH3), 13.2 (CH2).
MS-ESI, m/z (%) 343 (M + Na+, 100). ESI HRMS: calcd for
C20H32O3Na, 343.2249; found, 343.2239.
1
with a hexane:ethyl acetate (80:20) mixture. An oil. H NMR: δ
0.50 (1H, m, H-4), 0.68 (1H, m, H-3), 0.99 (3H, s, H-19), 1.38
(3H, d, J ) 7.3 Hz, H-21), 1.59 (3H, s, 17â-CH3), 2.54 (1H, q,
H-20R, J ) 7.3 Hz), 2.89 (1H, m, H-6R), 3.34 (3H, s, CH3O-),
4.60 (1H, dd, J1 ) 8.1 Hz, J2 ) 3.1 Hz, H-16â). 13C NMR δ
(ppm): 178.8 (C), 86.3 (CH), 85.4 (C), 81.8 (CH), 80.7 (C), 56.6
(CH3), 55.3 (C), 47.0 (CH), 43.4 (C), 43.0 (CH), 38.7 (CH), 37.4
(CH2), 34.3 (C), 33.8 (CH2), 31.7 (CH2), 30.5 (CH2), 24.8 (CH2),
23.1 (CH3), 21.9 (CH2), 21.3 (CH), 19.1 (CH3), 13.4 (CH2), 8.8
(CH3). MS-EI, m/z (%) 390 (M+, 2), 335 (19), 299 (4), 231 (100).
EI HR: calcd for C23H34O5, 390.2406; found, 390.2389.
18-Nor-17-methylandrost-5-ene-3â,13r,17r-triol (7). To a
stirred solution of 6â-methoxy-3R,5R-cyclo-18-nor-17-methylan-
drostan-13,17-diol (115 mg, 0.36 mmol) in a dioxane-water (4:1)
mixture (15 mL) was added p-TsOH‚H2O (23 mg, 0.12 mmol).
The reaction mixture was stirred at 70 °C for 1.5 h, poured into
water, and extracted with ethyl acetate. The extract was washed
with water, dried (anhydrous MgSO4), and the solvent was
In the ethyl acetate extract, (20S)-6â-methoxy-18-nor-17â-
methyl-3R,5R-cyclopregna-13R,14R-diol-20â,16R-carbolactone (9a)
was found as a 1:1 complex with pyridine. 1H NMR: δ 0.47 (1H,
m, H-4), 0.66 (1H, m, H-3), 1.02 (3H, s, H-19), 1.36 (3H, d, J )
7.1 Hz, H-21), 1.52 (3H, s, 17â-CH3), 2.89 (1H, m, H-6R), 3.36
(49) Rodewald, W. J.; Morzycki, J. W. Pol. J. Chem. 1978, 52, 2361-
2368.
J. Org. Chem, Vol. 72, No. 8, 2007 2915

Go´recki et al.
(3H, s, CH3O-), 4.46 (1H, dd, J1 ) 6.2 Hz, J2 ) ∼1 Hz, H-16â),
7.49 (2H, m, H-Pyr), 7.86 (2H, m, H-Pyr), 8.8 (1H, d, J ) 5.2 Hz,
H-Pyr). However, all attempts to remove pyridine (acid extraction
or column chromatography) led to the decomposition of the product.
6â-Methoxy-3r,5r-cyclo-23,24,25,26,27-pentanorfurostan-
16r,17r-diol (10). A stirred solution of (20R)-20-hydroxymethyl-
6â-methoxy-3R,5R-cyclopregnan-16â,17R-diol (30 mg, 0.08 mmol)
in dry THF was treated with NaH (15.8 mg, 0.4 mmol) at 25 °C.
The reaction mixture was refluxed for 24 h, quenched with water,
and the product was extracted with dichloromethane. The organic
extract was dried (anhydrous MgSO4) and evaporated in vacuo.
The product was purified by silica gel column chromatography.
6â-Methoxy-3R,5R-cyclo-23,24,25,26,27-pentanorfurostan-16R,-
17R-diol (10) was eluted with a hexane:ethyl acetate (80:20) mixture
(18 mg, 60%). An oil. IR: νmax 3604, 3416, 1090, 1006 cm-1. 1H
NMR: δ 0.45 (1H, m, H-4), 0.67 (1H, m, H-3), 0.92 (3H, d, J )
7.1 Hz, H-21), 0.95 (3H, s, H-18), 1.04 (3H, s, H-19), 2.46 (1H,
m, H-20), 2.78 (1H, m, H-6R), 3.33 (3H, s, CH3O-), 3.67 (1H,
def. t, Jgem ) 8.7 Hz, JVic ) 9.4 Hz), 4.15 (1H, def. t, Jgem ) 8.7
Hz, JVic ) 8.4 Hz). 13C NMR: δ 112.8 (C), 89.3 (C), 82.1 (CH),
76.6 (CH2), 56.6 (CH3), 52.0 (CH), 47.5 (CH), 45.8 (C), 43.5 (C),
39.8 (CH2), 35.12 (CH2), 35.08 (C), 34.0 (CH), 33.3 (CH2), 31.8
(CH2), 30.2 (CH), 24.9 (CH2), 21.9 (CH2), 21.3 (CH), 19.3 (CH3),
16.5 (CH3), 13.3 (CH3), 13.1 (CH2). MS-EI, m/z (%) 376 (M+,
13), 361 (33), 344 (22), 321 (74), 214 (54), 41 (100). EI HR calcd
for C23H36O4, 376.2614; found, 376.2598.
Acknowledgment. We are deeply indebted to Dr. R. Łysek
and Dr. T. T. Danh for providing us with samples of compounds
13 and 14, respectively.
Supporting Information Available: General experimental
1
methods, IR, H, 13C, MS spectra for reported compounds, X-ray
crystallographic structures (ORTEP) of compounds 2, 5a, and 7,
and computational details including hin files. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO062445X
2916 J. Org. Chem., Vol. 72, No. 8, 2007