Preparation of an analogue of orbicuside A, an unusual cardiac glycoside

Article abstract of DOI:10.1016/j.tetasy.2004.11.028

A steroid containing a multi-linked glycoside, analogous to the bufadienolide orbicuside A, has been prepared. The key steps were (i) the preparation of a 2α-allyloxycarbonyloxy-3β-hydroxy steroid, (ii) a Ferrier reaction between the steroid and a rhamnal derivative, (iii) removal of protecting group and oxidation of the 2-hydroxy group, (iv) dihydroxylation of the pseudoglycal from the sterically more hindered side and finally (v) ring closure by acetal formation under acidic conditions.

Full text of DOI:10.1016/j.tetasy.2004.11.028

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 393–401
Preparation of an analogue of orbicuside A, an unusual
cardiac glycoside
John T. Dixon,a Fanie R. van Heerdenb,* and Cedric W. Holzapfela
aDepartment of Chemistry and Biochemistry, Rand Afrikaans University, PO Box 524, Auckland Park 2006, South Africa
bSchool of Chemistry, University of KwaZulu-Natal, Private Bag X01, Scottsville, 3209 Pietermaritzburg, South Africa
Received 3 November 2004; accepted 16 November 2004
Available online 25 December 2004
Abstract—A steroid containing a multi-linked glycoside, analogous to the bufadienolide orbicuside A, has been prepared. The key
steps were (i) the preparation of a 2a-allyloxycarbonyloxy-3b-hydroxy steroid, (ii) a Ferrier reaction between the steroid and a rham-
nal derivative, (iii) removal of protecting group and oxidation of the 2-hydroxy group, (iv) dihydroxylation of the pseudoglycal from
the sterically more hindered side and finally (v) ring closure by acetal formation under acidic conditions.
ꢀ 2004 Elsevier Ltd. All rights reserved.
O
O
1. Introduction
O
O
Several members of the Crassulaceae family are toxic to
animals and an investigation of the active metabolites of
some of these plants resulted in the isolation of a num-
ber of bufadienolide glycosides with unusual carbohy-
drate moieties,1 for example, orbicuside A 1 from
Cotyledon orbiculata2 and tyledoside A 2 and tyledoside
C 3 from Tylecodon grandiflorus3 (Fig. 1). Cardiac glyco-
sides are of the oldest drugs used by mankind4 and di-
goxin, the most commonly prescribed cardiac
glycoside, is still one of the most used prescription
drugs. However, these drugs are extremely toxic and
there is accordingly a demand for analogues with dimin-
ished toxicity, but with enhanced therapeutic activity.
The unusual features of the Crassulaceae cardiac glyco-
sides prompted us to attempt the syntheses of analogues
in order to evaluate the effect of the carbohydrate
arrangement on the biological activity of these com-
pounds. The glycosides isolated from the Cotyledon
and Tylecodon species, for example, 1, 2 and 3 have neu-
rotoxic side effects apart from the cardiac activity.5 Fur-
thermore, it is known that oxygen substituents on the
aglycone (except for the essential 14b-hydroxy group)
of cardiac glycosides are detrimental to the cardiac
O
O
HO
HO
H
OCH3
O
O
O
OH
O
OH
O
O
O
O
O
O
H
1
2
O
O
O
HO
OAc
OH
O
OH
O
O
O
H
H
3
Figure 1.
activity and that cardenolides are more reactive than
bufadienolides.1 Considering all these facts, we investi-
gated the synthesis of cardiac glycosides containing only
the essential substituents on the aglycone (i.e., a 14b-hy-
droxy group and a 17b-unsaturated lactone moiety), but
with unusual carbohydrate features. We have already
reported the preparation of the cardenolide aglycone,6
and we describe herein the synthesis of a model steroid
glycoside containing the carbohydrate moiety present
in orbicuside A (Fig. 1).
*
Corresponding author. Tel.: +27 33 2605326; fax: +27 33 2605009;
e-mail: vanheerdenf@ukzn.ac.za
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.028

394
J. T. Dixon et al. / Tetrahedron: Asymmetry 16 (2005) 393–401
2. Results and discussion
16-dehydropregnane derivative9 that can serve as a pre-
cursor to a 14b-hydroxy cardenolide.10 The transforma-
tion of diosgenin into a suitable 2,3-dioxygenated
steroid is illustrated in Scheme 2. Steroid 4 was trans-
formed into the 3-oxo-5,6-dihydro-5a-analogue by stan-
dard methodology, and the oxygen functionality was
introduced at C-2 by formation of the enol TMS ether
and subsequent epoxidation with dimethyldioxirane.
Huffman and Balke11 observed that, under thermody-
namic control, the 2,3-enol ether was formed from a 3-
keto-5a-steroid, whereas kinetically controlled condi-
tions yielded the 3,4-enol ether. By using TMSI in the
presence of hexamethyldisilisane, enol ether 5 was
obtained in a good yield and none of the 3,4-isomer
was detected. Under the experimental conditions used
for the epoxidation of 5, an in situ rearrangement of
the epoxide occurred and only the required 2a-hydroxy
ketone 6 was isolated.
A retrosynthetic analysis of the target compound A
(Scheme 1) yielded a 2-oxo-3-O-a-L-glycosyloxy steroid
with a 1,2,3-cis,cis configuration of the carbohydrate,
that is, a 4,6-dideoxyallopyranoside derivative C, as
the logical precursor. Two approaches to the 4,6-dide-
oxyallopyranoside were envisaged, direct glycosylation
with a suitable carbohydrate precursor or reaction of
the steroid with a glycal derivative followed by dihydr-
oxylation of the pseudoglycal. We have demonstrated
that the second approach is successful for the prepara-
tion of 3-O-a-L-allopyranosyl steroids.7 Therefore, the
challenges of the synthesis were reduced to (i) the prep-
aration of a 2,3-dioxygenated steroid, (ii) preparation of
a suitable glycal and (iii) coupling of the steroidal and
carbohydrate moieties via a Ferrier reaction8 and subse-
quent transformations of the glycoside. Since the meth-
odology for the deoxygenation of carbohydrate alcohols
is well developed, the target of this synthesis was a mul-
ti-linked glycoside of type B (Scheme 1).
Having the a-hydroxy ketone 6 in hand, the choice of
the protecting group for the hydroxy function was crit-
ical. Several criteria had to be fulfilled: the protection
and deprotection steps need to be performed under mild
conditions, the protected compound should be stable to-
wards epimerization, the protecting group must not mi-
grate to the C-3 hydroxy in the subsequent step (as was
observed for acetate12) or cause steric hindrance detri-
mental to a future glycosidation step. Both the hydroxy
derivative 6 and its acetate and benzoate derivatives
were found to be prone to epimerization under condi-
tions used for chromatography. Reaction of 6 with allyl-
oxycarbonyl chloride yielded carbonate derivative 7,
which satisfied all the above-mentioned criteria. Reduc-
tion of the ketone with sodium borohydride yielded two
OH
O
O
R
O
O
OH
O
R
O
O
H
H
C: R=H
A: R=H
D: R=OH
B: R=OH
Scheme 1.
Diosgenin 4 was used as the aglycone, since the D/E/F
ring system of this steroid can be transformed into a
O
1. H2, Pd/C, HOAc
2. H2CrO4 (83%)
O
O
O
1.
RO
O
96%
O
3. HN(TMS)2, TMSI (86%)
O
Cl
,Py
2.
TMSO
H
H
92%
5
6: R=H
HO
4
7: R=CO2Allyl
NaBH4
Me
BzO
BzO
O
RO
1.
O
O
,BF3.OEt2
73%
Dess-Martin (95%)
Me
AllylOCO2
HO
Me
BzO
O
O
O
2. Pd(dba)2, dppe (95%)
H
H
BzO
H
12
8: R=β-OH (63%)
9: R=α-OH (27%)
10: R=CO2Allyl
11: R=H
NBS/H2O
O
Cl
O
Me
O
O
EtO2CCH2COCl
O
H
Me
R1O
R2O
BzO
Py
O
O
H
74%
EtO2CCH2CO2
Br
Br
15
13: R1=Bz, R2=H 47%
14: R1=H, R2=Bz 39%
1. NaHCO3
2. Bu2SnO
3. BzCl
70%
Scheme 2.

J. T. Dixon et al. / Tetrahedron: Asymmetry 16 (2005) 393–401
395
products in a 7:3 ratio with the required 3b-hydroxy
derivative 8 as the major product. Efforts to increase
the ratio of the required product by using solvents such
as dioxane or isopropanol were unsuccessful.
rohydrin was added to the reaction as an acid scavenger.
Although the reaction formed the required bromohydrin
13, a side product 14, resulting from the migration of the
benzoyl protecting group was also formed. Fortunately,
this unwanted product could be recycled into 13 by
hydrolysis of the benzoyl ester followed by selective ben-
zoylation of the equatorial 4-hydroxy group of the cor-
responding stannylene derivative.
Our initial approach involved a Ferrier reaction of a 4-
deoxy glycal. Rhamnal was prepared by the method de-
scribed by Bredenkamp et al.13 and transformed to the
4-deoxyrhamnal derivative as described by Paquette
and Oplinger.14 However, this compound was extremely
unstable and we were forced to postpone the deoxygen-
ation of the 4-position of the carbohydrate to the last
step. Using rhamnal acetate in this synthesis presented
separation problems at a later stage,7 and 3,4-di-O-benz-
oylrhamnal was used as substrate in the Ferrier reaction
to furnish the pseudorhamnal 10 in a good yield
(Scheme 3). The challenge now was to dihydroxylate
the carbohydrate alkene from the sterically more hin-
dered side. To prevent competition between the two al-
kene functionalities in 10, the protecting group at C-3
was removed at this stage. Allyl carbonates are good
substrates for Pd(0)-catalyzed reactions,15 and the
deprotection of the hydroxy group proceeded under
neutral conditions. Initially Pd(PPh3)4 was used as cata-
lyst, but it was observed that the reaction stopped after
ca. 10% of the starting material was consumed. The lack
of further reaction was attributed to coordination of the
palladium to the 20,30-double bond of the carbohydrate.
This problem was solved by using a catalyst containing
the bidentate ligand 1,2-bis(diphenylphosphino)ethane,
and the deprotected glycoside 11 was now obtained in
almost quantitative yield. Oxidation with the Dess–
Martin periodinane16,17 yielded the ketone 12.
Preparation of the allose derivative 19 from 13 was pos-
sible by using a variation20 of the Corey method.19,21
Bromohydrin 13 was transformed into the mixed malon-
ate ester 15 (Scheme 2), which, upon treatment with so-
dium hydride in HMPA, yielded the ketene acetal 16.
Although NMR analysis of the crude product confirmed
the ketene acetal structure of 16, the compound was not
stable and in subsequent reactions this compound was
not isolated, but hydrolyzed in situ to 17 (Scheme 3).
Saponification of the esters was accomplished by treat-
ment of 17 with sodium methoxide. NMR analysis of
the product in CDCl3 revealed that it consists of a mix-
ture of two isomeric compounds, of which the major one
is the hemiacetal 18. However, when D2O was added to
simplify the spectrum, the chemical shifts indicted that
the equilibrium was reversed, and only the triol 19 was
detected.
The final step entails the formation of the intramolecu-
lar acetal to form the multi-linked glycosidic moiety that
is also present in orbicuside A 1. It can be envisaged that
in the treatment of 19 with acid two isomeric com-
pounds can form resulting from acetalization of the 2-
keto functionality with either the 20,30- or the 30,40-diol.
However, reaction with the 30,40-diol will form a com-
pound containing an unfavourable combination of
five- and seven-membered rings, whereas reaction with
the 20,30-diol will yield the more stable compound
containing two six-membered rings, both in the chair
conformation. As predicted, treatment of 19 with
p-toluenesulfonic acid in the presence of anhydrous cop-
per(II) sulfate resulted in the quantitative formation of
20, the target compound of this synthesis. Although
the NMR data were in agreement with structure 20, fur-
ther confirmation for the structure was obtained by add-
ing trichloromethylisocyanate to the NMR tube. The
In order to dihydroxylate the pseudoglycal 12 from the
more hindered side, an indirect approach first described
by Woodward and Brutscher18 and Corey and Das19
was followed in which a halohydrin is formed and the
halogen is then subsequently replaced by an oxygen
nucleophile. Initial attempts to form the bromohydrin
13 by treatment of 12 with NBS in dimethoxyethane/
water resulted in the quantitative hydrolysis of the sugar
and the formation of two isomeric vinylic a-ketols from
the aglycone. It was clear that the formation of HBr in
the reaction should be avoided, and, therefore, epichlo-
O
O
O
O
O
Me
Me
Me
O
O
NaH
O
O
p-TsOH
H
H
BzO
H
BzO
BzO
HMPT
64%
EtO2CCH2CO2
Br
O
O
O
OH
EtO2CCH2CO2
17
16
15
Et
1 eq. NaOMe
74%
O
OH
O
O
OH
HO
HO
O
O
O
p-TsOH
79%
O
O
H
HO
HO
O
O
H
H
OH
19
20
18
Scheme 3.

396
J. T. Dixon et al. / Tetrahedron: Asymmetry 16 (2005) 393–401
chemical shifts observed for the resultant trichlorometh-
ylcarbamate was in agreement with an acetal structure
containing a free 40-hydroxy group.
(C-26), 80.7 (C-16), 109.2 (C-22) and 211.8 (C-3); m/z
414 (M+, 21%), 399 (2) and 384 (1).
4.3. (25R)-3-Trimethylsilyloxy-5a-spirost-2-ene 5
3. Conclusion
Hexamethyldisilazane (4.3 g, 20.4 mmol) and TMSI
(2.8 mL, 20.4 mmol) was added consecutively to a solu-
tion of (25R)-5a-spirostan-3-one (7.7 g, 18.6 mmol) in
CH2Cl2 (100 mL) at À30 ꢁC under a N2 atmosphere.
The reaction mixture was stirred for 2 h at À30 ꢁC and
then stirred at room temperature for a further 24 h. It
The presence of multi-linked steroid glycosides presented
an interesting synthetic challenge. Herewith, it was pro-
ven that a viable approach to this problem involved the
formation of the glycosidic bond by a Ferrier reaction
between a steroid and a glycal, followed by indirect
dihydroxylation of the resulting pseudoglycal and acid-
catalyzed acetal formation to give the desired product.
was washed with
a saturated NaHCO3 solution
(2 · 30mL) and H 2O (30mL), the organic layer dried
over anhydrous Na2SO4 and the solvent removed under
reduced pressure. The residue was purified by flash chro-
matography (hexane–EtOAc, 20:1) to give the trimethyl-
4. Experimental
4.1. General
silyl enol ether 5 (7.8 g, 86%) as white crystals, mp 135–
22
137 ꢁC (hexane–CH2Cl2); ½aŠ ¼ À11:8 (c 1.22, CHCl3);
D
(found: M+, 486.355 C30H50O3Si requires M, 486.3529);
mmax (CHCl3)/cmÀ1 1684 (C@C); dH 0.15 [s, 9H,
(CH3)3SiO], 3.39 (t, 1H, J 10.5, 26b-H), 3.41–3.48 (m,
1H, 26a-H), 4.36 (q, 1H, J 7.0, 16H) and 4.71 (d, 1H,
J 5.5, 2H); dC 0.4 [(CH3)3Si], 11.6 (C-19), 14.5 (C-21),
16.4 (C-18), 17.1 (C-27), 21.0(C-11), 28.5 (C-6), 28.8
(C-24), 30.3 (C-25), 31.4 (C-23), 31.8 (C-15), 31.9 (C-
7), 34.6 (C-4), 34.6 (C-8), 35.2 (C-10), 38.5 (C-1), 40.1
(C-12), 40.5 (C-13), 41.6 (C-20), 42.0 (C-5), 53.8 (C-9),
56.3 (C-14), 62.2 (C-17), 66.8 (C-26), 80.8 (C-16),
102.9 (C-2), 109.2 (C-22) and 148.8 (C-3); m/z 486
(M+, 40%), 471 (5) and 457 (1).
Mps were determined on a Kofler hotplate apparatus
and are uncorrected. IR spectra were obtained as dilute
solutions in spectroscopic grade CHCl3 using a Perkin
Elmer 881 instrument. 1H (200 MHz) and 13C
(50MHz) NMR data were recorded on a Varian VXR
200 NMR spectrometer in CDCl3 solution with tetra-
methylsilane as internal standard. Mass spectra were
recorded on a Finnigan-MAT 8200 spectrometer at an
electron impact of 70eV. Column chromatography
was performed with silica gel 60 (0.040–0.063 mm,
230–400 mesh ASTM) and thin-layer chromatography
with Whatman silica gel 60A K6F.
4.4. (25R)-2a-Hydroxy-5a-spirostan-3-one 6
4.2. (25R)-5a-Spirostan-3-one
A
dimethyldioxirane–acetone solution22 (187 mL,
0.85 M, 15.9 mmol) was added to a cold solution
(0 ꢁC) of (25R)-3-trimethylsilyloxy-5a-spirost-2-ene 5
(7.8 g, 15.9 mmol) in CH2Cl2 (80mL) and the mixture
was stirred for 50min at 0 ꢁC. The volatile components
were removed under reduced pressure at room tempera-
ture to yield the crude a-ketol 6 (6.9 g, >98%) that was
used directly to prepare the allyl carbonate. Purification
of the crude product by crystallization from hexane–
Palladium (10%) on activated carbon (2.0 g) was added
to a solution of diosgenin 4 (20.0 g, 48.2 mmol) in
HOAc (1000 mL) and the resulting mixture was stirred
under a hydrogen atmosphere (2 bar) for 24 h. The reac-
tion mixture was filtered through Celite, cooled to 15 ꢁC
and then a chromic acid solution (24.2 mL, 2.0M,
48.2 mmol) was added over a period of 45 min while
the temperature was maintained between 15 and 20 ꢁC.
After the addition was completed, the reaction mixture
was stirred for 90min 15 ꢁC. H2O (750mL) was then
added to the reaction mixture and it was stirred for an-
other 10min. The mixture was extracted with CHCl 3
(2 · 750mL), the combined organic extracts washed
with a saturated solution of NaHCO3 (2 · 500 mL)
and H2O (500 mL), the organic layer dried over anhy-
drous Na2SO4 and the solvent evaporated under
reduced pressure. Chromatography of the residue (hex-
CH2Cl2 yielded pure (25R)-2a-hydroxy-5a-spirostan-
22
3-one 6 as white crystals, mp 178–180 ꢁC; ½aŠ
¼
D
À27:0 (c 1.58, CHCl3); (found: M+, 430.3087. C27H42O4
requires M, 430.3083); mmax (CHCl3)/cmÀ1 1076 (C–O),
1719 (C@O) and 3529 (O–H); dH 2.19 (dd, 1H, J 3.8
and 13.4, 4a-H), 2.35 (t, 1H, J 12.6, 1b-H), 2.40(dd,
1H, J 6.8 and 12.8, 1a-H), 3.29 (t, 1H, J 10.5, 26b-H),
3.36–3.42 (m, 1H, 26a-H), 4.16 (dd, 1H, J 7.3 and
12.2, 2H) and 4.33 (dt, 1H, J 6.2 and 7.4, 16H); dC
12.8 (C-19), 14.4 (C-21), 16.4 (C-18), 17.0(C-27), 21.3
(C-11), 28.4 (C-6), 28.7 (C-24), 30.2 (C-25), 31.3 (C-
23), 31.6 (C-7), 31.7 (C-15), 34.2 (C-8), 37.1 (C-10),
39.7 (C-12), 40.5 (C-13), 41.5 (C-20), 42.3 (C-4), 48.3
(C-5), 48.4 (C-1), 53.7 (C-9), 55.8 (C-14), 62.1 (C-17),
66.7 (C-26), 72.7 (C-2), 80.6 (C-16), 109.1 (C-22) and
ane–EtOAc, 10:1) gave the ketone (16.6 g, 83%) as white
22
crystals, mp 200–203 ꢁC; ½aŠ ¼ À34:1 (c 1.06, CHCl3);
D
mmax (CHCl3)/cmÀ1 1711 (C@O); dH 2.16–2.30(m, 2H,
2a-H and 4b-H), 2.32 (dt, 1H, J 6.2 and 13.0, 2b-H),
3.32 (t, 1H, J 10.5, 26b-H), 3.39–3.47 (m, 1H, 26a-H)
and 4.36 (dt, 1H, J 6.6 and 7.2, 16H); dC 11.5 (C-19),
14.4 (C-21), 16.4 (C-18), 17.1 (C-27), 21.2 (C-11), 28.8
(C-6), 28.8 (C-24), 30.3 (C-25), 31.4 (C-23), 31.7 (C-
15), 31.8 (C-7), 35.0(C-8), 35.7 (C-10), 38.1 (C-2), 38.5
(C-1), 39.9 (C-12), 40.5 (C-13), 41.6 (C-20), 44.6 (C-4),
46.6 (C-5), 53.8 (C-9), 56.1 (C-14), 62.2 (C-17), 66.8
+
210.8 (C-3); m/z 430(M , 9%), 415 (3) and 400 (1).
4.5. (25R)-2a-Allyloxycarbonyloxy-5a-spirostan-3-one 7
Crude (25R)-2a-hydroxy-5a-spirostan-3-one 6 (6.9 g, ca.
15.9 mmol) was dissolved in CH2Cl2 (80mL) and the

J. T. Dixon et al. / Tetrahedron: Asymmetry 16 (2005) 393–401
397
solution cooled to À40 ꢁC. Pyridine (5.1 mL, 63.6
mmol) and allyl chloroformate (6.7 mL, 63.6 mmol)
was added to the cold solution consecutively and the
reaction mixture was allowed to warm up to 0 ꢁC over
a period of 2 h. It was then washed with a cold (0 ꢁC)
HCl solution (10%, 80 mL) and H2O (2 · 50mL), the
organic layer dried over anhydrous Na2SO4 and the sol-
vent removed under reduced pressure. Chromatography
of the residue (hexane–EtOAc, 10:1) gave the allyl car-
(ROCH2CH@CH2) and 154.9 [ROC(O)OR0]; m/z 516
(M+, 6%), 501 (1) and 486 (1). (25R)-2a-Allyloxycarbon-
yloxy-5a-spirostan-3a-ol
8
had mp 171–173 ꢁC;
22
½aŠ ¼ À51:8 (c 1.00, CHCl3); (found: M+, 516.3449.
D
C31H48O6 requires M, 516.3451); mmax (CHCl3)/cmÀ1
1655 (C@C) and 1752 (C@O); dH 3.33 (t, 1H, J 10.8,
26b-H), 3.38–3.47 (m, 1H, 26a-H), 4.09 (br s, 1H, 3H),
4.36 (dt, 1H, J 6.4 and 7.8, 16H), 4.59 (dt, 2H, J 1.3
and 5.8, OCH2CH@CH2), 4.75 (ddd, 1H, J 3.0, 4.7
and 12.2, 2H), 5.25 [ddd, 1H, J 1.2, 2.5 and 10.4,
OCH2CH@CH2 (cis)], 5.33 [ddd, 1H, J 1.5, 2.9 and
17.2, OCH2CH@CH2 (trans)] and 5.91 (ddt, 1H, J 5.8,
10.4 and 17.2, OCH2CH@CH2); dC 12.3 (C-19), 14.5
(C-21), 16.4 (C-18), 17.1 (C-27), 20.8 (C-11), 27.4 (C-
6), 28.8 (C-24), 30.3 (C-25), 31.4 (C-23), 31.7 (C-15),
31.9 (C-7), 33.9 (C-4), 34.4 (C-8), 37.0(C-1), 37.3 (C-
10), 38.0 (C-5), 39.9 (C-12), 40.6 (C-13), 41.6 (C-20),
54.1 (C-9), 56.2 (C-14), 62.2 (C-17), 66.8 (C-26), 67.2
(C-3), 68.4 (ROCH2CH@CH2), 77.2 (C-2), 80.8 (C-16),
109.2 (C-22), 119.0 (ROCH2CH@CH2), 131.5
(ROCH2CH@CH2) and 154.2 [ROC(O)OR0]; m/z 516
(M+, 6%), 458 (5) and 444 (4).
bonate 7 as white crystals (7.5 g, 92% over two steps),
22
mp 174–177 ꢁC; ½aŠ ¼ À6:8 (c 1.40, CHCl3); (found:
D
M+, 514.3289. C31H46O6 requires M, 514.3294); mmax
(CHCl3)/cmÀ1 1659 (C@C), 1729 (C@O, cyclic) and
1756 (C@O, allyl carbonate); dH 2.19 (dd, 1H, J 3.6
and 14.2, 4a-H), 2.31 (dd, 1H, J 6.6 and 12.4, 1a-H),
2.39 (t, 1H, J 12.9, 1b-H), 3.32 (t, 1H, J 10.8, 26b-H),
3.39–3.45 (m, 1H, 26a-H), 4.35 (q, 1H, J 6.6, 16H),
4.61 (d, 2H, J 5.7, OCH2CH@CH2), 5.08 (dd, 1H, J
6.3 and 12.7, 2H), 5.23 [d, 1H, J 10.5, OCH2CH@CH2
(cis)], 5.34 [d, 1H, J 17.3, OCH2CH@CH2 (trans)] and
5.89 (ddt, 1H, J 5.6, 10.0 and 17.1, OCH2CH@CH2);
dC 12.7 (C-19), 14.4 (C-21), 16.4 (C-18), 17.0(C-27),
21.4 (C-11), 28.2 (C-6), 28.7 (C-24), 30.2 (C-25), 31.3
(C-23), 31.7 (C-15), 31.7 (C-7), 34.3 (C-8), 37.3 (C-10),
39.7 (C-12), 40.5 (C-13), 41.6 (C-20), 43.3 (C-4), 44.6
(C-1), 47.6 (C-5), 53.7 (C-9), 55.8 (C-14), 62.1 (C-17),
66.8 (C-26), 68.7 (ROCH2CH@CH2), 77.4 (C-2), 80.6
(C-16), 109.1 (C-22), 118.8 (ROCH2CH@CH2), 131.3
(ROCH2CH@CH2), 154.2 [ROC(O)OR0] and 203.4 (C-
3); m/z 514 (M+, 9%), 499 (1) and 484 (1).
4.7. 3,4-Di-O-acetyl-L-rhamnal
L-Rhamnose monohydrate (10.0 g, 54.9 mmol) was dis-
solved in a mixture of pyridine (52.0mL, 0.64 mol)
and Ac2O (64.0mL, 0.68 mol) the reaction mixture stir-
red at 40 ꢁC for three days. Evaporation of the solvents
under reduced pressure yielded an anomeric mixture
of crude tetra-O-acetyl-L-rhamnopyranose (18.1 g, ca.
99%) as a light yellow syrup. The crude tetra-O-acetyl-
L-rhamnopyranose (18.1 g, ca. 54.4 mmol), CH2Cl2
(20.0 mL) and Ac2O (1.0mL) were treated under a N 2
atmosphere with a solution of 30% HBr in HOAc
(16.3 mL, 81.7 mmol). The reaction mixture was stirred
for 2 h at room temperature and the volatile compo-
nents were removed under reduced pressure to give an
anomeric mixture of crude tri-O-acetyl-L-rhamnopyr-
anosyl bromide (18.2 g, ca. 95%) as a red syrup. Zinc
powder (6.8 g, 103.4 mmol) was added under a N2 atmo-
sphere to a mixture of anhydrous CuSO4 (675 mg,
10.3 mmol), NaOAc (3.8 g, 93.1 mmol), CH3CN
(10mL), HOAc (3.0mL, 103.4 mmol) and Ac 2O
(3.4 mL, 72.4 mmol). The mixture was stirred at room
temperature for 30min, a solution of crude tri- O-ace-
tyl-L-rhamnopyranosyl bromide (18.2 g, ca. 51.7 mmol)
in CH3CN (50mL) was added and the mixture was stir-
red for a further 2 h. CH2Cl2 (200 mL) was added to the
reaction mixture and all the solids removed by filtration
through a short column. The filtrate was washed with
saturated NaHCO3 solution (2 · 100 mL), dried over
anhydrous Na2SO4 and filtered through Celite and the
solvent evaporated under reduced pressure. Chromatog-
raphy of the residue (hexane–ethyl acetate, 7:1) gave di-
4.6. (25R)-2a-Allyloxycarbonyloxy-5a-spirostan-3b-ol 8
(25R)-2a-Allyloxycarbonyloxy-5a-spirostan-3-one
(7.4 mmol, 14.4 mmol) was dissolved in to a mixture
7
of MeOH (80mL) and THF (20mL). NaBH (544 mg,
4
14.4 mmol) was added and the resulting mixture was
stirred at room temperature for 30min. CH 2Cl2
(500 mL) was added and the mixture was washed with
ice H2O (2 · 250mL), the organic layers dried over
anhydrous Na2SO4 and the solvent removed under re-
duced pressure. Chromatography of the residue (hex-
ane–EtOAc, 4:1) resulted in the isolation of 8 (4.7 g,
63%) and 9 (2.0g, 27%). (25 R)-2a-Allyloxycarbonyl-
22
D
oxy-5a-spirostan-3b-ol 7 had mp 163–165 ꢁC; ½aŠ
¼
À75:7 (c 1.00, CHCl3); (found: M+, 516.3458.
C31H48O6 requires M, 516.3451); mmax (CHCl3)/cmÀ1
1688 (C@C) and 1751 (C@O); dH 2.09 (dd, 1H, J 4.9
and J 12.3, 1b-H), 3.33 (t, 1H, J 10.7, 26b-H), 3.40–
3.46 (m, 1H, 26a-H), 3.61 (ddd, 1H, J 5.6, J 9.5 and
11.0, 3H), 4.36 (dt, 1H, J 6.2 and 7.4, 16H), 4.59 (dt,
2H, J 1.3 and 5.8, OCH2CH@CH2), 4.62 (ddd, 1H, J
4.9, 9.5 and 11.7, 2H), 5.24 [ddd, 1H, J 1.1, 2.4 and
10.5, OCH2CH@CH2 (cis)], 5.33 [ddd, 1H, J 1.5, 2.9
and 17.3, OCH2CH@CH2 (trans)] and 5.91 (ddt, 1H, J
5.7, 10.3 and 17.2, OCH2CH@CH2); dC 13.1 (C-19),
14.4 (C-21), 16.4 (C-18), 17.1 (C-27), 21.2 (C-11), 27.6
(C-6), 28.8 (C-24), 30.2 (C-25), 31.3 (C-23), 31.7 (C-
15), 31.9 (C-7), 34.3 (C-8), 35.6 (C-4), 37.5 (C-10), 39.8
(C-12), 40.5 (C-13), 41.6 (C-20), 41.9 (C-1), 44.4 (C-5),
54.1 (C-9), 56.1 (C-14), 62.1 (C-17), 66.8 (C-26), 68.5
(ROCH2CH@CH2), 73.1 (C-3), 80.6 (C-2), 80.7 (C-16),
109.2 (C-22), 119.0 (ROCH2CH@CH2), 131.5
O-acetyl-L-rhamnal (8.8 g, 79%) as a colourless oil;
22
D
½aŠ ¼ þ55:2 (c 1.00, CHCl3); mmax (CHCl3)/cmÀ1 1236
(C–O) and 1732 (C@O); dH 1.29 (d, 3H, J 6.5, CH3),
2.01 and 2.06 (2 · s, 2 · 3H, 2 · OCOCH3), 4.08 (dq,
1H, J 6.6 and 8.5, 5H), 4.75 (dd, 1H, J 3.0and 6.2,
2H), 5.00 (dd, 1H, J 6.1 and 8.2, 4H), 5.29–5.35 (m,
1H, 3H) and 6.40(dd, 1H, J 1.4 and 6.2, 1H); dC 16.5
(C-6), 20.9 and 21.0 (2 · CH3CO2), 68.3 (C-3), 71.8

398
J. T. Dixon et al. / Tetrahedron: Asymmetry 16 (2005) 393–401
(C-4), 72.5 (C-5), 98.7 (C-2), 145.9 (C-1), 169.9 and
170.6 (2 · CH3CO2); m/z 214 (M+, 1%), 112 (25) and
43 (100).
5.81–5.97 (m, 2H, 30H and OCH2CH@CH2), 7.34–7.48
(m, 2H, meta-Ph), 7.50–7.59 (m, 1H, para-Ph) and
7.93–8.01 (m, 2H, ortho-Ph); dC 12.9 (C-19), 14.4 (C-
21), 16.4 (C-18), 17.1 (C-27), 17.9 (C-60), 21.2 (C-11),
27.8 (C-6), 28.8 (C-24), 30.3 (C-25), 31.4 (C-23), 31.7
(C-15), 32.0(C-7), 32.8 (C-4), 34.4 (C-8), 37.2 (C-10),
39.8 (C-12), 40.5 (C-13), 41.6 (C-20), 42.4 (C-1), 44.2
(C-5), 54.2 (C-9), 56.1 (C-14), 62.3 (C-17), 65.1 (C-50),
66.8 (C-26), 68.0(RO CH2CH@CH2), 71.3 (C-40), 76.9
(C-3), 77.3 (C-2), 80.7 (C-16), 91.4 (C-10), 109.2 (C-
22), 118.3 (ROCH2CH@CH2), 128.1 (C-20), 128.6 and
129.6 (ortho- and meta-Ph), 129.9 (C-30), 130.0 (ipso-
Ph), 131.8 (ROCH2CH@CH2), 133.1 (para-Ph), 154.8
[ROC(O)OR0] and 165.9 [RC(O)OR0]; m/z 732 (M+,
1%), 688 (16) and 673 (2).
4.8. 3,4-Di-O-benzoylrhamnal
K2CO3 (18 mg, 0.1 mmol) was added to a solution of di-
O-acetyl-L-rhamnal (2.79 g, 13.0mmol) in MeOH
(15 mL) and the mixture was stirred for 24 h at room
temperature. The mixture was filtered through a short
silica gel column, the solvent evaporated under reduced
pressure and the residue purified by crystallization (hex-
ane) to give pure L-rhamnal (1.64 g, 97%) as white crys-
tals. Pyridine (2.24 mL, 27.8 mmol) and benzoyl
chloride (3.22 mL, 27.8 mmol) were added successively
to a solution of L-rhamnal (1.64 g, 12.6 mmol) in
CH2Cl2 (20mL) at 0 ꢁC and the mixture stirred for
24 h at room temperature. CH2Cl2 (40mL) and H 2O
(40mL) were added, the mixture was shaken, the organ-
ic layer dried over anhydrous Na2SO4 and the removed
under reduced pressure. Chromatography of the residue
(hexane–ethyl acetate, 4:1) gave 3,4-di-O-benzoyl-L-
4.10. (25R)-3b-(40-O-Benzoyl-20,30-didehydro-20,30-dide-
oxy-a-L-rhamnopyranosyloxy)-5a-spirostan-2a-ol 11
Tris(dibenzylideneacetone)dipalladium(0)–CHCl3 ad-
duct (172 mg, 0.3 mmol) and 1,2-bis(diphenylphosph-
ino)ethane (120mg, 0.3 mmol) was added successively
to a solution of (25R)-2a-allyloxycarbonyloxy-3b-(40-
O-benzoyl-20,30-didehydro-20,30-dideoxy-a-L-rhamnopy-
ranosyloxy)-5a-spirostan 10 (2.2 g, 3.0mmol) in THF
(70mL) under a N 2 atmosphere. The mixture was stir-
red for 6 h at 50 ꢁC and then the solvent was removed
under reduced pressure. Chromatography (hexane–
EtOAc, 5:1) of the residue gave in addition to unreacted
starting material (462 mg, 21%) the alcohol 11 (1.4 g,
rhamnal (3.57 g, 84%) as
a
colourless oil;
22
D
½aŠ ¼ þ204:8 (c 1.00, CHCl3); mmax (CHCl3)/cmÀ1
1219 (C–O), 1529 (C@C), 1659 (C@C) and 1699
(C@O); dH 1.43 (d, 3H, J 6.6, CH3), 4.34 (q, 1H, J
6.8, 5H), 4.99 (dd, 1H, J 2.9 and 6.1, 2H), 5.49 (dd,
1H, J 6.0and 7.8, 4H), 5.68–5.73 (m, 1H, 3H), 6.52
(dd, 1H, J 1.4 and 6.1, 1H), 7.35–7.58 (m, 6H,
C6H5CO2) and 7.96–8.09 (m, 4H, C6H5CO2); dC 16.7
(C-6), 68.8 (C-3), 72.1 (C-4), 72.7 (C-5), 98.8 (C-2),
128.3, 128.4, 129.7 and 129.8 (ortho- and meta-Ph),
129.5 and 129.9 (ipso-Ph), 133.1 and 133.3 (para-Ph),
146.1 (C-1), 165.4 and 166.0(2 · C6H5CO2); m/z 217
(M+ÀOCOC6H5, 9%), 201 (4) and 105 (100).
73%) as a colourless glass, mp 176–178 ꢁC (CH2Cl2–hex-
22
ane); ½aŠ ¼ À114:9 (c 1.00, CHCl3); (found: M+,
D
648.4032. C40H56O7 requires M, 648.4026); mmax
(CHCl3)/cmÀ1 1457 (C@C, aromatic) and 1724 (C@O);
dH 2.04 (dd, 1H, J 5.0and 12.9, 1 b-H), 3.33 (t, 1H, J
10.4, 26b-H), 3.25–3.57 (m, 2H, 3H and 26a-H), 3.66
(ddd, 1H, J 5.0, 9.0 and 11.6, 2H), 4.20 (dq, 1H, J 6.3
and 9.4, 50H), 4.36 (q, 1H, J 7.3, 16H), 5.14 (s, 1H,
10H), 5.29 (dd, 1H, J 1.4 and 9.2, 40H), 5.79 (dt, 1H, J
2.5 and 10.3, 20H), 5.97 (d, 1H, J 10.3, 30H), 7.37–7.45
(m, 2H, meta-Ph), 7.51–7.59 (m, 1H, para-Ph) and
7.98–8.02 (m, 2H, ortho-Ph); dC 13.3 (C-19), 14.4 (C-
21), 17.1 (C-27), 17.9 (C-60), 17.9 (C-18), 21.1 (C-11),
27.9 (C-6), 28.8 (C-24), 30.3 (C-25), 31.4 (C-23), 31.8
(C-15), 32.1 (C-7), 33.5 (C-4), 34.5 (C-8), 36.8 (C-10),
40.0 (C-12), 40.6 (C-13), 41.6 (C-20), 44.6 (C-5), 44.7
(C-1), 54.3 (C-9), 56.2 (C-14), 62.3 (C-17), 65.7 (C-50),
66.8 (C-26), 70.8 (C-2), 70.9 (C-40), 80.8 (C-16), 85.1
(C-3), 93.8 (C-10), 109.2 (C-22), 127.8 (C-20), 128.4 and
129.7 (ortho- and meta-Ph), 129.8 (ipso-Ph), 129.8 (C-
30), 133.2 (para-Ph) and 165.9 [RC(O)OR0]; m/z 648
(M+, 4%), 618 (1) and 604 (13).
4.9. (25R)-2a-Allyloxycarbonyloxy-3b-(40-O-benzoyl-
20,30-didehydro-20,30-dideoxy-a-L-rhamnopyranosyloxy)-
5a-spirostan 10
A
solution of 3,4-di-O-benzoyl-L-rhamnal (3.5 g,
10.3 mmol) and (25R)-2a-allyloxycarbonyloxy-5a-spiro-
stan-3b-ol 8 (2.3 g, 4.5 mmol) in CH2Cl2 (30mL) were
cooled to 0 ꢁC under a N2 atmosphere and BF3ÆOEt
(138 lL, 1.1 mmol) was added. The reaction mixture
was stirred at 0 ꢁC for 35 min. A saturated NaHCO3
solution (100 mL) and CH2Cl2 (250mL) were added.
After shaking the mixture thoroughly, the two layers
were separated. The organic layer was dried over anhy-
drous Na2SO4 and all the solvent removed in vacuo.
Chromatography (hexane–EtOAc, 7:1) of the residue
afforded the pseudoglycal 10 (2.4 g, 74%) as a colourless
22
glass, mp 102–105 ꢁC (CH2Cl2–hexane); ½aŠ ¼ À118:9
D
(c 1.00, CHCl3); mmax (CHCl3)/cmÀ1 1457 (C@C, aro-
matic), 1656 (C@C), 1725 (C@O) and 1750(C @O); dH
2.12 (dd, 1H, J 4.5 and 12.4, 1b-H), 3.33 (t, 1H, J
10.3, 26b-H), 3.40–3.48 (m, 1H, 26a-H), 3.77 (dt, 1H,
J 5.4 and 10.9, 3H), 4.10 (dq, 1H, J 5.9 and 9.1, 50H),
4.36 (dt, 1H, J 6.2 and 7.4, 16H), 4.54 (ddt, 1H, J 1.3,
5.6 and 13.2, OCH2CH@CH2), 4.63 (ddt, 1H, J 1.3,
5.6 and 13.1, OCH2CH@CH2), 4.80(ddd, 1H, J 4.9,
9.5 and 11.7, 2H), 5.08–5.31 (m, 4H, 10H, 40H and
OCH2CH@CH2), 5.76 (dt, 1H, J 2.4 and 10.2, 20H),
4.11. (25R)-3b-(40-O-Benzoyl-20,30-didehydro-20,30-dide-
oxy-a-L-rhamnopyranosyloxy)-5a-spirostan-2-one 12
Dess–Martin periodinane16,17 (828 mg, 2.0mmol) was
added to a solution of (25R)-3b-(40-O-benzoyl-20,30-
didehydro-20,30-dideoxy-a-L-rhamnopyranosyloxy)-5a-
spirostan-2a-ol 11 (1.1 g, 1.7 mmol) in CH2Cl2 (20mL)
under a N2 atmosphere and the mixture was stirred
for 24 h at room temperature. The reaction mixture
was diluted with Et2O (150mL) and extracted with a

J. T. Dixon et al. / Tetrahedron: Asymmetry 16 (2005) 393–401
399
saturated NaHCO3 solution (150mL) containing so-
dium thiosulfate (1.9 g, 11.9 mmol). The organic layer
was washed with H2O (2 · 50mL), dried over anhy-
drous Na2SO4 and the solvent removed under reduced
Ph), 133.2 (para-Ph), 165.7 [RC(O)OR0] and 206.7 (C-
2); m/z 429 (M+ÀC13H14O4Br, 1%), 356 (1) and 314
(3). (25R)-3b-(30-O-Benzoyl-20-bromo-20,60-dideoxy-a-
L-altropyranosyloxy)-5a-spirostan-2-one 14 had mp
20
pressure to give the ketone 12 (1.04 g, 95%) as a colour-
156–158 ꢁC (diethyl ether–hexane); ½aŠ ¼ À51:4 (c
D
22
D
less glass, mp 185–187 ꢁC (CH2Cl2–hexane); ½aŠ
¼
1.00, CHCl3); mmax (CHCl3)/cmÀ1 1458 (C@C, aromatic)
and 1734 (C@O); dH 2.44 (d, 1H, J 12.7, 1b-H), 3.33 (t,
1H, J 10.4, 26b-H), 3.40–3.48 (m, 1H, 26a-H), 4.03 (dd,
À102:7 (c 1.00, CHCl3); mmax (CHCl3)/cmÀ1 1456
(C@C, aromatic), 1656 (C@C) and 1727 (C@O); dH
2.45 (d, 1H, J 12.6, 1b-H), 3.34 (t, 1H, J 10.3, 26b-H),
3.41–3.48 (m, 1H, 26a-H), 4.36 (dd, 1H, J 4.5 and 8.4,
3H), 4.38 (q, 1H, J 7.9, 16H), 4.44 (dq, 1H, J 5.9 and
9.5, 50H), 5.06 (s, 1H, 10H), 5.29 (ddd, 1H, J 1.8, 3.2
and 9.5, 40H), 5.84 (dt, 1H, J 2.5 and 10.2, 20H), 5.99
(d, 1H, J 10.2, 30H), 7.38–7.46 (m, 2H, meta-Ph),
7.50–7.59 (m, 1H, para-Ph) and 8.00–8.05 (m, 2H,
ortho-Ph); dC 12.4 (C-19), 14.4 (C-21), 16.3 (C-18),
17.1 (C-27), 17.8 (C-60), 21.1 (C-11), 27.6 (C-6), 28.8
(C-24), 30.3 (C-25), 31.4 (C-23), 31.7 (C-15), 31.8 (C-
7), 34.5 (C-4), 36.6 (C-8), 39.7 (C-12), 40.5 (C-13), 41.4
(C-10), 41.6 (C-20), 44.7 (C-5), 52.9 (C-1), 54.0 (C-9),
0
1H, J 3.0and 9.1, 4 H), 4.14 (dd, 1H, J 7.0and 10.9,
0
3H), 4.33 (dd, 1H, J 1.0and 3.7, 2 H), 4.37 (q, 1H, J
7.3, 16H), 4.58 (dq, 1H, J 6.3 and 9.0, 50H), 4.99 (s,
1H, 10H), 5.47 (t, 1H, J 3.3, 30H), 7.36–7.62 (m, 3H,
meta- and para-Ph) and 8.19–8.24 (m, 2H, ortho-Ph);
dC 12.4 (C-19), 14.4 (C-21), 16.3 (C-18), 17.1 (C-27),
17.5 (C-60), 21.1 (C-11), 27.5 (C-6), 28.8 (C-24), 30.3
(C-25), 31.4 (C-23), 31.7 (C-15), 31.7 (C-7), 34.4 (C-4),
36.2 (C-8), 39.7 (C-12), 40.5 (C-13), 41.2 (C-10), 41.6
(C-20), 44.4 (C-5), 45.9 (C-20), 53.00(C-1), 53.8 (C-9),
56.0(C-14), 62.2 (C-17), 66.2 (C-5 ), 66.9 (C-26), 68.0
(C-40), 72.4 (C-30), 80.7 (C-16), 80.8 (C-3), 98.7 (C-10),
109.2 (C-22), 128.3 and 130.4 (ortho- and meta-Ph),
129.8 (ipso-Ph), 133.3 (para-Ph), 166.3 [RC(O)OR0]
0
56.0(C-14), 62.2 (C-17), 65.5 (C-5 ), 66.8 (C-26), 71.1
(C-40), 80.7 (C-3), 80.8 (C-16), 93.7 (C-10), 109.2 (C-
22), 127.3 (C-20), 128.4 and 129.7 (ortho- and meta-
Ph), 129.9 (ipso-Ph), 130.6 (C-30), 133.1 (para-Ph),
+
and 206.3 (C-2); m/z 430(M ÀC13H15O4Br, 1%), 358
(1) and 316 (2).
+
0
166.0[RC(O)OR ] and 207.2 (C-2); m/z 646 (M , 1%),
602 (7) and 587 (1).
4.13. (25R)-3b-(40-O-Benzoyl-20-bromo-20,60-dideoxy-30-
O-ethylmalonyl-a-L-altropyranosyloxy)-5a-spirostan-2-
one 15
4.12. (25R)-3b-(40-O-Benzoyl-20-bromo-20,60-dideoxy-a-
L-altropyranosyloxy)-5a-spirostan-2-one 13
Pyridine (39 lL, 0.485 mmol) and ethyl (chloro-
formyl)acetate (62 lL, 0.485 mmol) was added to a solu-
tion of (25R)-3b-(40-O-benzoyl-20-bromo-20,60-dideoxy-
a-L-altropyranosyloxy)-5a-spirostan-2-one 12 (301 mg,
0.404 mmol) in CH2Cl2 (5 mL) at 0 ꢁC under a N2 atmo-
sphere and the mixture was stirred for 18 h at room tem-
perature. CH2Cl2 (100 mL) was added and the solution
washed successively with a cold 10% HCl solution
(40mL), H 2O (2 · 20mL), the organic layer dried over
anhydrous Na2SO4 and the solvent removed under
reduced pressure at room temperature. Chromatogra-
phy (hexane–EtOAc, 4:1) of the residue gave the mixed
H2O (567 lL, 32 mmol), epichlorohydrin (617 ll,
8 mmol) and NBS (2.8 g, 16 mmol) were added succes-
sively to a solution of (25R)-3b-(40-O-benzoyl-20,30-dide-
hydro-20,30-dideoxy-a-L-rhamnopyranosyloxy)-5a-spiro-
stan-2-one 12 (1.0g, 1.6 mmol) in 1,2-dimethoxyethane
(40mL) at 0 ꢁC. The mixture was stirred for 30min at
0 ꢁC and then for a further 2 h at room temperature.
The reaction mixture was diluted with Et2O (250mL)
and extracted with a saturated NaHCO3 solution
(150mL) containing sodium thiosulfate (1.9 g,
11.9 mmol). The organic layer was washed with H2O
(2 · 50mL), dried over anhydrous Na 2SO4 and the sol-
vent removed under reduced pressure. Chromatography
(hexane–EtOAc, 7:1) of the residue yielded 13 (492 mg,
42%) and 14 (340mg, 29%). (25 R)-3b-(40-O-benzoyl-20-
bromo-20,60-dideoxy-a-L-altropyranosyloxy)-5a-spiros-
malonyl ester 15 (257 mg, 74%) as a colourless glass,
20
D
½aŠ ¼ À48:2 (c 1.00, CHCl3); mmax (CHCl3)/cmÀ1 1457
(C@C, aromatic), 1737 (C@O) and 1754 (C@O); dH
2.43 (d, 1H, J 12.9, 1b-H), 3.33 (t, 1H, J 10.2, 26b-H),
3.36–3.49 (m, 1H, 26a-H), 3.48 (d, 1H, J 16.1,
ROCOCH2COOR0), 3.57 (d, 1H, J 16.1, ROCO-
CH2COOR0), 4.07 (dq, 2H, J 3.1 and 7.1, RCH2COO-
CH2CH3), 4.18 (dd, 01H, J 7.1 and 11.0, 3H), 4.35 (dd,
1H, J 2.0and 4.2, 2 H), 4.37 (q, 1H, J 7.4, 16H), 4.61
(dq, 1H, J 6.5 and 8.5, 50H), 5.03 (d, 1H, J 1.9, 10H),
5.39 (t, 1H, J 3.4, 30H), 5.45 (dd, 1H, J 3.2 and 8.6,
40H), 7.37–7.45 (m, 2H, meta-Ph), 7.51–7.59 (m, 1H,
para-Ph) and 7.98–8.07 (m, 2H, ortho-Ph); dC 12.5 (C-
tan-2-one 13 had mp 109–112 ꢁC (diethyl ether–hexane);
20
½aŠ ¼ À80:2 (c 1.00, CHCl3); mmax (CHCl3)/cmÀ1 1457
D
(C@C, aromatic) and 1729 (C@O); dH 2.52 (d, 1H, J
13.2, 1b-H), 3.34 (t, 1H, J 10.4, 26b-H), 3.42–3.49 (m,
1H, 26a-H), 4.20–4.44 (m, 5H, 20H, 30H, 50H, 3H and
16H), 5.12 (s, 1H, 10H), 5.38 (dd, 1H, J 2.7 and 10.3,
40H), 7.36–7.48 (m, 2H, meta-Ph), 7.50–7.58 (m, 1H,
para-Ph) and 8.03–8.10 (m, 2H, ortho-Ph); dC 12.7 (C-
19), 14.4 (C-21), 16.3 (C-18), 17.1 (C-27), 17.6 (C-60),
21.1 (C-11), 27.6 (C-6), 28.8 (C-24), 30.3 (C-25), 31.4
(C-23), 31.7 (C-15), 31.7 (C-7), 34.4 (C-4), 36.2 (C-8),
40.0 (C-12), 40.5 (C-13), 41.2 (C-10), 41.6 (C-20), 43.9
(C-5), 46.6 (C-20), 52.7 (C-1), 53.8 (C-9), 56.0(C-14),
62.2 (C-17), 62.7 (C-50), 66.9 (C-26), 69.5 (C-30), 70.9
(C-40), 77.7 (C-3), 80.7 (C-16), 97.3 (C-10), 109.2 (C-
22), 128.3 and 129.9 (ortho- and meta-Ph), 129.8 (ipso-
19), 14.0[RC(O)OCH CH3], 14.4 (C-21), 16.4 (C-18),
2
17.1 (C-27), 17.3 (C-60), 21.1 (C-11), 27.6 (C-6), 28.8
(C-24), 30.3 (C-25), 31.4 (C-23), 31.8 (C-15), 31.8 (C-
7), 34.4 (C-4), 35.6 (C-8), 39.7 (C-12), 40.5 (C-13), 41.3
(C-10), 41.3 [RC(O)CH2C(O)R0], 41.6 (C-20), 44.3 (C-
5), 45.1 (C-20), 53.0(C-1), 53.9 (C-9), 56.0(C-14), 61.4
[RC(O)OCH2CH3], 62.2 (C-17), 64.6 (C-50), 66.9 (C-
0
26), 69.5 (C-30), 71.0(C-4 ), 79.9 (C-3), 80.7 (C-16),

400
J. T. Dixon et al. / Tetrahedron: Asymmetry 16 (2005) 393–401
0
98.0(C-1 ), 109.2 (C-22), 128.4 and 129.6 (ortho- and
meta-Ph), 129.4 (ipso-Ph), 133.3 (para-Ph), 165.4
[RC(O)OR0], 166.0[RC(O)OR 0], 166.1 [RC(O)OR0]
and 206.0 (C-2); m/z 663 (M+ÀOCOC6H5 and
ÀCOOCH2CH3, 2%), 646 (3) and 429 (9).
of this solution (5 mL) was added to a solution of (25R)-
3b-(40-O-benzoyl-30-O-ethylmalonyl-60-deoxy-a-L-allo-
pyranosyloxy)-5a-spirostan-2-one 17 (115 mg, 0.144
mmol) in toluene (3 mL) at 0 ꢁC. The reaction was stir-
red for 80min at room temperature. CH 2Cl2 (25 mL)
was added and the mixture was extracted with H2O
(10mL), the organic layer dried over anhydrous Na 2SO4
and the solvent removed under reduced pressure at
room temperature. Chromatography (CHCl3–MeOH,
10:1) of the residue gave a mixture of the triol 19 and
the corresponding hemiacetal 18 (62 mg, 74%) as white
crystals, mmax (CHCl3, D2O)/cmÀ1 1723 (C@O); dH
(CDCl3+D2O) 2.49 (d, 1H, J 13.4, 1b-H), 3.12 (dd,
1H, J 3.2 and 10.2, 40H), 3.33 (t, 1H, J 10.5, 26b-H),
3.41–3.64 (m, 3H, 20H, 50H and 26a-H), 4.01 (t, 1H, J
2.7, 30H), 4.25 (dd, 1H, J 6.9 and 11.2, 3H), 4.37 (q,
1H, J 7.3, 16H) and 4.93 (d, 1H, J 2.9, 10H); dC (D2O)
12.7 (C-19), 14.4 (C-21), 16.3 (C-18), 17.1 (C-27), 17.3
(C-60), 21.1 (C-11), 27.5 (C-6), 28.8 (C-24), 30.3 (C-
25), 31.4 (C-23), 31.7 (C-15), 31.7 (C-7), 34.4 (C-4),
34.9 (C-8), 39.7 (C-12), 40.5 (C-13), 41.3 (C-10), 41.6
(C-20), 43.9 (C-5), 52.6 (C-1), 53.8 (C-9), 56.0 (C-14),
62.2 (C-17), 64.2 (C-50), 66.9 (C-26), 67.9 (C-40), 71.9
(C-20), 72.1 (C-30), 77.3 (C-3), 80.7 (C-16), 96.2 (C-10),
109.3 (C-22) and 207.3 (C-2).
4.14. (25R)-3b-(40-O-Benzoyl-60-deoxy-30-O-ethylmalon-
yl-a-L-allopyranosyloxy)-5a-spirostan-2-one 17
NaH (5 mg, ꢀ75% pure, ꢀ0.151 mmol) was added
under a N2 atmosphere to a solution of (25R)-3b-(40-
O-benzoyl-30-O-ethylmalonyl-20-bromo-20,60-dideoxy-
a-L-altropyranosyloxy)-5a-spirostan-2-one 15 (130mg,
0.151 mmol) in HMPA (9 mL) at room temperature.
The mixture was stirred for 5 min at room temperature
and then for a further 6 h at 60 ꢁC. Et2O (50mL) was
added to the reaction mixture, and it was then extracted
with H2O (2 · 25 mL), the organic layer dried over
anhydrous Na2SO4 and the solvent evaporated under re-
duced pressure. Chromatography (hexane–EtOAc, 1:1)
of the residue gave a single product 16 (128 mg) as a col-
ourless oil. The product (128 mg) was dissolved in
benzene (10mL) and H 2O (4 lL, 0.222 mmol) and p-
toluenesulfonic acid monohydrate (10 mg, 0.052 mmol)
were added. After stirring the mixture for 20min at
room temperature, it was diluted with benzene (20mL)
and washed with H2O (2 · 10mL). The organic layer
was dried over anhydrous Na2SO4 and all volatile com-
ponents removed under reduced pressure. Chromato-
graphy (hexane–EtOAc, 2:1) of the residue gave the
4.16. (25R)-2a,2b,3b-[(2S,3S,4S,5S,6S)-Tetrahydro-5-
hydroxy-6-methyl-2H-pyran-4,3,2-trioxytriyl]-5a-spiros-
tane 20
alcohol 17 (77 mg, 64%) as
a
colourless glass,
Anhydrous CuSO4 (60mg, 0.376 mmol) and p-toluene-
sulfonic acid monohydrate (8 mg, 0.042 mmol) was
added sequentially to a solution of a mixture of the triol
19 and the corresponding hemiacetal 18 (37.0mg,
0.064 mmol) in toluene (20 mL) under a N2 atmosphere
and the mixture was stirred for 45 min at 50 ꢁC. The
mixture was allowed to reach to room temperature,
Et3N (40 lL, 0.286 mmol) was added and the mixture
was stirred for a further 10min at room temperature.
CH2Cl2 (50mL) was added, the mixture was washed
with H2O (2 · 10mL), the organic layer dried over
anhydrous CuSO4 and all the volatile components re-
moved in vacuo at room temperature. Chromatography
of the residue (hexane–EtOAc, 1:2) gave the acetal 20
20
D
½aŠ ¼ À98:4 (c 1.00, CHCl3); mmax (CHCl3)/cmÀ1 1459
(C@C, aromatic), 1734 (C@O) and 1759 (C@O); dH
2.43 (d, 1H, J 12.9, 1b-H), 3.34 (t, 1H, J 10.6, 26b-H),
3.39 (d, 1H, J 16.2, ROCOCH2COOR0), 3.40–3.46 (m,
1H, 26a-H), 3.62 (d, 1H, J 16.2, ROCOCH2COOR0),
3.86 (t, 1H,
J
3.8, 20H), 4.02–4.21 (m, 3H,
RCH2COOCH2CH3 and 3H), 4.38 (q, 1H, J 7.6,
16H), 4.58 (dq, 1H, J 6.3 and 10.1, 50H), 4.86 (d, 1H,
J 3.6, 10H), 4.87 (dd, 1H, J 2.8 and 10.2, 40H), 5.70(t,
1H, J 2.9, 30H), 7.36–7.49 (m, 2H, meta-Ph), 7.52–7.57
(m, 1H, para-Ph) and 7.92–7.97 (m, 2H, ortho-Ph); dC
12.5 (C-19), 14.0[RC(O)OCH CH3], 14.4 (C-21), 16.3
2
(C-18), 16.9 (C-60), 17.1 (C-27), 21.1 (C-11), 27.5 (C-
6), 28.8 (C-24), 30.3 (C-25), 31.4 (C-23), 31.7 (C-7),
31.7 (C-15), 34.4 (C-4), 35.8 (C-8), 39.7 (C-12), 40.5
(C-13), 41.3 (C-10), 41.5 [RC(O)CH2C(O)R0], 41.6 (C-
20), 44.3 (C-5), 53.0(C-1), 53.9 (C-9), 56.0(C-14), 61.5
[RC(O)OCH2CH3], 61.7 (C-50), 62.2 (C-17), 66.8 (C-
(28.4 mg, 79%) as white crystals, mp 260–263 ꢁC;
20
½aŠ ¼ À37:1 (c 1.00, CHCl3); (found: M+, 558.3558.
D
C33H50O7 requires M, 558.3556); mmax (CHCl3)/cmÀ1
1164 (C–O, acetal); dH 3.32 (dd, 1H, J 3.5 and 9.9,
40H), 3.35 (t, 1H, J 10.9, 26b-H), 3.44–3.48 (m, 2H,
26a-H and OH), 3.78 (t, 1H, J 8.2, 3H), 3.92 (dq, 1H,
J 6.2 and 9.7, 50H), 4.16 (t, 1H, J 3.7, 30H), 4.35 (t,
1H, J 4.4, 20H), 4.38 (q, 1H, J 7.5, 16H) and 5.23 (d,
1H, J 5.4, 10H); dC 12.6 (C-19), 14.4 (C-21), 16.4 (C-
18), 17.1 (C-27), 17.3 (C-60), 21.1 (C-11), 27.5 (C-6),
28.8 (C-24), 30.3 (C-25), 31.4 (C-23), 31.7 (C-15),
32.0(C-7), 34.4 (C-4), 34.9 (C-8), 36.8 (C-1)0, 39.9
(C-12), 40.5 (C-13), 41.6 (C-20), 43.8 (C-5), 45.9 (C-1),
54.9 (C-9), 56.1 (C-14), 62.2 (C-17), 62.9 (C-50), 66.8
(C-26), 71.5 (C-40), 73.2 (C-30), 73.4 (C-20), 80.4
(C-3), 80.7 (C-16), 89.1 (C-10), 106.8 (C-2) and 109.2
(C-22); m/z 558 (M+, 10%), 541 (4) and 499
(5).
0
26), 67.2 (C-20), 71.0(C-3 ), 71.5 (C-40), 80.6 (C-16),
81.1 (C-3), 96.8 (C-10), 109.2 (C-22), 128.3 and 129.7
(ortho- and meta-Ph), 129.5 (ipso-Ph), 133.1 (para-Ph),
165.2
[RC(O)OR0],
166.0[RC(O)OR
0],
167.1
[RC(O)OR0] and 206.7 (C-2); m/z 776 (M+ÀH2O, 1%),
662 (2) and 644 (1).
4.15. (25R)-3b-(60-Deoxy-a-L-allopyranosyloxy)-5a-spi-
rostan-2-one 19
NaH (46 mg, ꢀ75% pure, ꢀ1.44 mmol) was dissolved in
MeOH (25 mL) under a N2 atmosphere. Twenty percent

J. T. Dixon et al. / Tetrahedron: Asymmetry 16 (2005) 393–401
401
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