Oxidative Functionalization of Trinor-18α-olean-17(22)-ene Derivatives. Annulation of the E-Ring by an Intramolecular Aldol Reaction

Article abstract of DOI:10.1021/acs.joc.1c00697

cis-Dihydroxylation of trinor-18α-olean-17(22)-ene 2 with osmium tetroxide led to diol 9. Its cleavage with lead tetraacetate gave tetracyclic ketoaldehyde 10. By comparison, the ozonation of trinor-18α-olean-17(22)-ene 2 in the presence of p-toluenesulfonic acid gave the corresponding ketoacetal 12. Both products were subjected to an intramolecular aldol reaction under the acidic conditions and yielded unusual triterpenes bearing a bicyclo[4.3.1]decane fragment (22). Further manipulation of the protective groups afforded compounds useful in triterpene synthesis, especially in the preparation of potentially biologically active saponins based on a tetracyclic terpene core.

Full text of DOI:10.1021/acs.joc.1c00697

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Article
Oxidative Functionalization of Trinor-18α-olean-17(22)-ene
Derivatives. Annulation of the E‑Ring by an Intramolecular Aldol
Reaction
́
́
Kinga Kuczynska,* Jarosław Jazwinski, Zbigniew Pakulski,* Piotr Cmoch, and Roman Luboradzki
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ABSTRACT: cis-Dihydroxylation of trinor-18α-olean-17(22)-ene
2 with osmium tetroxide led to diol 9. Its cleavage with lead
tetraacetate gave tetracyclic ketoaldehyde 10. By comparison, the
ozonation of trinor-18α-olean-17(22)-ene 2 in the presence of p-
toluenesulfonic acid gave the corresponding ketoacetal 12. Both
products were subjected to an intramolecular aldol reaction under
the acidic conditions and yielded unusual triterpenes bearing a
bicyclo[4.3.1]decane fragment (22). Further manipulation of the
protective groups afforded compounds useful in triterpene
synthesis, especially in the preparation of potentially biologically
active saponins based on a tetracyclic terpene core.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Transformation of betulin diacetate (5) into 3β-O-acetyl-19α-
isopropyl-28,29,30-trinor-18α-olean-17(22)-ene (2) was real-
ized according to the modified literature methods. The key
compound, 3β-O-acetyl-dihydrobetulin (8) can be prepared by
several methods summarized in Scheme 2. Selective
deacetylation of 5 gave monoacetate 6.25 Hydrogenation of 5
or 6 yielded dihydrobetulin derivatives 7 or 8, respectively.
Similarly, selective deacetylation of 7 gave monoacetate 8.
Treatment of 8 with POCl3 in pyridine caused the rearrange-
ment and an expansion of the E-ring in olean-17(22)-ene core
(2) almost quantitatively.
In the first attempt, the dihydroxylation of 2 with an excess
of OsO4 in pyridine afforded cis-diol 9 in high yield (80%) as a
single diastereoisomer; the complete oxidation of the double
bond took 7 days (Scheme 3). Catalytic dihydroxylation of 2 in
catalytic version (OsO4/NMO) gave no product.26,27 Accord-
ing to the well-known mechanism of dihydroxylation with
OsO4, only the cis-diol was formed. We expected that the steric
interaction of D- and E-ring protons precluded formation of
17β,22β-diol (Figure 1). By a comparison, no steric interaction
influenced the OsO4 attack from the α-side. The 17α,22α
configuration of the new stereogenic centers in 9 was
Birch is a hardwood tree of the genus Betula widespread in the
Northern Hemisphere, particularly in areas of temperate and
boreal climates. Its wood has had important historical and
cultural significance since ancient times.1,2 Nowadays, birch
wood is widely used in the paper industry. The outer part of
birch bark (the waste generated during paper production) is an
extremely rich source of lupane-type triterpenes, mostly betulin
(1, Scheme 1), which are isolated in appreciable amounts (up
to 30% of dry mass).3,4 Betulin has interesting biological
properties, including antiviral and antitumor activities.5−8
Lupane triterpenoids have also been used as intermediates in
the synthesis of triterpenoids employed for biological
studies.9−18
In the pursuit of new, flexible starting materials for the
functionalization of the lupane core,19−22 we guessed that the
easily available 3β-O-acetyl-trinor-18α-olean-17(22)-ene (2)23
is a candidate for further transformation (Scheme 1). Special
interests for us were the tetracyclic compounds with the
general formula 3, which can be obtained by oxidative cleavage
of the double bond in 2. They are structural analogues of
radermasinin (4), a cytotoxic triterpene lactone isolated from
Radermachia sinica.24
Received: March 24, 2021
Published: May 25, 2021
In the present paper, we report on a simple and high yield
conversion of the olean-17(22)-ene scaffold by an oxidative
functionalization of the double bond. The obtained derivatives
may be used as starting materials for the synthesis of saponins
and more complex triterpene derivatives.
© 2021 The Authors. Published by
American Chemical Society
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Scheme 1. Proposed Transformation of Betulin
a
Scheme 2
a
Reagents and conditions: i. 10% Pd/C, H2 (7 bar, quantitatively); ii. i-PrOH, Al(i-PrO)3, reflux, 75%; iii. POCl3, pyridine (98%).
a
Scheme 3
a
Reagents and conditions: i. OsO4, pyridine (80%); ii. NaIO4 supported on SiO2 (27%); iii. Pb(OAc)4, pyridine (78% of 10, 7% of 11); iv.
Pb(OAc)4, benzene (90% of 10); v. O3, methanol, CH2Cl2 (45−59% of 12, 15−21% of 11, 3−7% of 13, and 11−15% of 14); vi. O3, p-TsOH,
methanol, CH2Cl2 (71% of 12); vii. NaClO2, amylene; viii. Jones reagent, acetone; ix. MeOH, HCl (75% of 17 after two steps; 98% of 20); x. MeI,
K2CO3, DMF (75% of 13 after two steps; 80% of 19 after two steps); xi. Ac2O, Py (95%); xii. (a) LiAlH4, (b) Ac2O, Py (79% after two steps).
the −CHO proton was detected at δ = 9.81 ppm.
Unexpectedly, only one signal of the carbonyl group at δ =
206.5 ppm, belonging to the aldehyde moiety, was observed in
the 13C NMR spectra. Analysis of HMBC and NOE
correlations suggested that a pentacyclic product 11 was
obtained (in 27% yield) instead of the expected tetracyclic 10.
Therefore, in the next attempt, we used lead tetraacetate in
Figure 1. Steric interactions influencing the OsO4 attack.
pyridine as an oxidizer. At room temperature, two products
were obtained. In the 1H NMR spectrum of the main product,
determined by the NMR experiments (see Supporting
Information).
Then, we studied the oxidative cleavage of the 1,2-diol group
a typical multiplet of the −CHO proton was observed at δ =
9.75 ppm, whereas both expected signals of the carbonyl
groups belonging to the ketone (δ = 202.4 ppm) and aldehyde
in 9, which, as we expected, should afford ketoaldehyde 10 as a
groups (δ = 213.7 ppm) were present in the 13C NMR spectra.
Further analysis of HMBC and NOE correlations confirmed
that, in this case, compound 10 was isolated as the main
product (78%), whereas 11 (7%) was identified as the minor
main product. Treatment of 9 with NaIO4 on silica gel28 for 7
days, gave a single product (Scheme 3). Despite a prolonged
time of the reaction, most of the starting material (53%) was
recovered. In the 1H NMR spectra of the product, a doublet of
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Scheme 4. Tentative Mechanism of the Formation of Acetal and Ester
Figure 2. X-ray structure of 21 (left), 23 (middle), and 24 (right). Contour probability level: 50%.
a
Scheme 5
a
Reagents and conditions: i. p-TsOH, acetone (10 → 20% of 11 and 56% of 22; 12 → 18% of 11 and 59% of 22); ii. p-TsOH, toluene (10 → 74%
of 22; 12 → 50% of 22); iii. Ac2O, pyridine.
product. Presumably, the pentacyclic compound 11 was
formed in an intramolecular pyridine catalyzed aldol reaction
as the basic component of this reaction. To confirm this
assumption, we kept aldehyde 10 in pyridine at 50 °C for 12 h.
However, no cyclization was observed. Apparently, the
mechanism of this reaction is more complex and requires the
presence of a metal ion. To avoid formation of 11, we have
tested benzene as a neutral solvent. As a result, tetracyclic
aldehyde 10 was obtained as a sole product in 90% yield. No
traces of 11 were detected in the reaction mixture. Both
products (10 and 11) have limited shelf life.
Further optimization was focused on excluding the use of
toxic OsO4. With alkene 2 in hand, we tried to run ozonation
of the C17(22) double bond to prepare 10. Because of the low
solubility of 2 at −78 °C, we used a dichloromethane−
methanol mixture as a solvent system to provide sufficient
solubility of the starting material. Under these conditions, the
ozonation of 2 was fast; however, a mixture of products was
obtained (Scheme 3).29,30 Careful separation of the reaction
mixture and analysis of the isolated products revealed that four
compounds were obtained in this reaction. It must be noted
that the composition of the mixture and the yields of the
products changed significantly from batch to batch. Usually,
acetal 12 (45−59%) and pentacyclic aldehyde 11 (15−21%)
were isolated as the main products. In some cases, 13 (3−7%)
and 14 (11−15%) were also isolated as byproducts.
Surprisingly, the expected aldehyde 10 was not formed during
the ozonation of 2.
his seminal publication, Schreiber has shown31 that the
incorporation of an acid or base during the ozonolysis of
cycloalkenes, followed by a reductive workup, promoted a
formation of differently substituted products, including acetals
and esters, in high yields.32,33 As suggested, such products were
formed by the addition of methanol, a participating solvent, to
the carbonyl oxide 15, reactive intermediate in the Criegee
mechanism,34 and subsequent transformation of α-alkoxy
hydroperoxide 16 during workup (Scheme 4). It is interesting
that, in the case of ozonation of 2, acetal 12 and ester 13 were
formed in the absence of a catalyst. We supposed that the
unpredictability of the ozonation of 2 and fluctuation in the
product proportions were caused by an uncontrolled
decomposition of α-alkoxy hydroperoxide 16 under neutral
conditions. To confirm the above assumption, we repeated this
reaction under the Schreiber’s conditions. The ozonation of 2
in the presence of NaHCO3 caused decomposition of the
starting material. By comparison, the reaction performed in the
presence of p-TsOH (approximately 10% w/w) afforded acetal
12 as a sole product in high yield (71%, Scheme 3).
All compounds prepared above (10−12) are valuable
starting materials in the synthesis of differently substituted
analogues. Therefore, in the next step, we have tested their
reactivity and scope of possible transformations. We were
especially interested in the synthesis of compounds bearing the
free −OH groups, starting materials for the preparation of
saponins (triterpene glycosides).35 Then, we initially converted
aldehyde 10 into acid 14 by its oxidation using a procedure
developed by Clive.36 The same reaction can be performed
using the Jones reagent. Acid 14 was then transformed into
The formation of acetals and esters is rather unexpected
during the ozonolysis under neutral conditions. However, in
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methyl ester by treatment with acidic methanol which afforded
17, bearing a free 3β-OH group (75% yield after two steps).
Moreover, treatment of 14 with methyl iodide in the presence
of potassium carbonate afforded fully protected ester 13 in
75% yield. The same compound 13 was obtained by
acetylation of 17 under the standard conditions in 95% yield.
Similar oxidation of 11 to free acid 18 with the Clive’s
method, followed by esterification with methyl iodide, gave
ester 19 (80% yield after two steps). Treatment of 19 with
acidic methanol afforded ester 20 with the free 3-OH group
(98%). The reduction of 11 with LiAlH4, followed by
acetylation of the crude reaction mixture, yielded diacetate
21 (79% after two steps). Its structure was confirmed by a
single-crystal X-ray analysis (Figure 2).
Scheme 6. Tentative Reaction Mechanism
Finally, we have attempted the hydrolysis of acetal 12 into
aldehyde 10 by a treatment with p-TsOH in acetone. This
reaction required high loading of acid (at least 40% w/w) for a
complete transformation. Column chromatography of the
reaction mixture gave two fractions. The first contained a
compound which was identified as 11 (18%, Scheme 5). The
second fraction was composed of an inseparable mixture of two
epimeric compounds (22, 56%). They were chromato-
graphically separated after acetylation under standard con-
ditions. On the basis of the analysis of the NMR spectra, we
proposed their structures as diacetates 23 (46%, after two
steps) and 24 (28%, after two steps). Both structures were
confirmed by single-crystal X-ray analysis (Figure 2). Similarly,
treatment of aldehyde 10 with p-TsOH in acetone afforded the
same products in an identical ratio. Notably, the subjecting of
12 to acidic conditions led to the hydrolysis of the acetal
function and the formation of aldehyde 10, which immediately
cyclized by intramolecular aldol reaction,37 affording cyclic
products 11 and 22. When acetone was replaced by toluene,
the cyclization of 10 was highly selective toward 22 (74%).
Similarly, cyclization of acetal 12 in toluene solution gave the
epimers 22, but in lower yield (50%). In both cases, only traces
of 11 were detected. Neither equilibration nor retro-aldol
reactions were observed when compounds 11 and 22 were
subjected to acidic conditions.
Compounds 22−24 belong to modified triterpenes with an
unusual bicyclo[4.3.1]decane framework.38−43 To the best of
our knowledge, compounds bearing the bicyclo[4.3.1]decane
motif in their structure have never been synthesized by an
intramolecular aldol reaction. This methodology was, however,
used for the preparation of derivatives with the bicyclo[3.3.1]-
nonane fragment,44−46 found in some natural com-
pounds.47−50
The possible reaction mechanism is presented in Scheme 6.
When an aldehyde’s carbonyl group is protonated (structures
A and B), cyclization leads to product 22 having a seven-
membered ring. Protonation of the ketone’s carbonyl group
(structures C and D) should result in the formation of five-
membered ring products. In this case, however, compound
11α was formed selectively. Probably, the formation of 11β is
precluded by steric interactions of the aldehyde group with
protons of the ring D and the angular methyl group at the C8.
Stereochemistry of the newly generated stereogenic center at
C16 (in 22) and C17 (in 11) was determined by the structure
of aldehyde 10; formation of the new carbon−carbon bond is
possible only from the β-side of the D-ring.
DFT CALCULATIONS
■
Initially, 18 structures of 10 differing in the arrangement of the
side chains were considered, while the remaining part of the
molecules were unchanged. The analysis of energy revealed
that only three structures have a significant population (0.22,
0.13, and 0.48 molar fractions, Figure 2S, rotamers I, II, and
III), having an aldehyde group far from the ketone fragment.
In the next step, the structures of four tautomers derived from
III (i.e., from the low-energy structure) were optimized, and
their molecular energies were estimated (Figure 3S). An
analysis of the molecular energies of III and its tautomers
together with the assumption of equilibrium between species
indicated a negligible molar fraction of tautomeric forms.
In the third step, calculations were performed for the
protonated compounds. All input structures (cations) were
constructed starting from the most stable rotamer III and
related tautomers. A proton was located at either the ketone or
aldehyde groups (Figure 4S). The structure with H+ at the
ketone group appeared to be the most stable. However, the
most interesting results were obtained starting from formally
unfavorable rotamers. Optimization resulted in structures
stabilized by hydrogen bonds (HB) and/or other weak
interactions, such as C···O, CH···O, and OH···C (Figure 3).
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Figure 3. Rotamers stabilized by hydrogen bonds (dotted lines) or the O···C interaction. The bond lengths are as follows: 1.032 and 1.514 Å (O···
H, IV), 1.032 and 1.555 Å (O···H, V), and 1.591 Å (O···CH(OH+), VI).
Figure 4. Formation of enol during structure optimization. The H atom from CH2 (red arrow) of the protonated aldehyde moved to the CO
group, forming the rotamer VII (enol) stabilized by OH···−CH interaction (dotted line, dOH 1.022 Å, dHC 1.795 Å).
Figure 5. Transformation of 10 (enole form) to cyclic product 22. Depending on the orientation of the CH(OH+) group, two configurations of
the CH(OH) center have been obtained.
In one case, we observed the transformation of aldehyde to
enol, forced by the transfer of H (Figure 4). Twice, the ring
closure occurred during optimization (Figure 5).
The last series of calculations concerned the analysis of the
hydrogen bonds expected for 11. Three initial structures
differing in the arrangements of the OH bonds were
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Figure 6. Two structures of 11 with (X) and without (XI) hydrogen bonds (top). The structure of 11 with different hydrogen bond patterns
transformed to linear isomer XII during optimization (bottom). At right: linear structure is stabilized by various intramolecular weak interactions,
O···O, C···C, and OH···σ*(CH3).
considered (Figure 6), the first with the aldehyde group
CH(OH+) involved in HB formation, the second structure
without HBs, and the third one HB formed by the ketone
group (COH+). Surprisingly, an open chain product has
been obtained during optimization in the last case, with
molecular energy lower than cyclic XI without HB. This
“linear” form was stabilized by the C···C, O···O, and OH···C
interactions. The optimization process appeared to be
reversible; cyclic 11 with HB has been obtained during
optimization when a “linear” reagent with the right OH bonds
pattern was used as the input structure.
Concluding, the first calculations revealed that rotamers of
10 having the CHO and CO functionalities far from one
another seem to be preferential ones. However, the
optimization and examination of seemingly disadvantageous
rotamers of protonated 10 resulted in some structures having
both CO groups close to each other. Analysis by Atom-In-
Molecule (AIM) methodology shows that these rotamers are
stabilized by numerous weak interactions, such as OH···O,
CH···O, and C···HO hydrogen bonds, and/or interactions
between C and O atoms. Weak interactions preorganize 10,
enabling the reacting fragments to come closer, and facilitating
certain reactions. In particular, the ring closure leads to 11 or
22, depending on the conformation of the reagent. The results
of the calculations are in agreement with the proposed reaction
mechanism.
synthesis of tetracyclic terpene analogues, especially the
synthesis of saponins. The most interesting achievement is
the synthesis of triterpenes bearing a bicyclo[4.3.1]decane
fragment. To our best knowledge, this is the first observation of
an intramolecular aldol reaction leading to this unusual
structure.51 As with recently reported bicyclo[3.3.1]nonane
derivatives,52 the bicyclo[4.3.1]decane derivatives may be
considered as precursors of chiral macrocycles and highly
sterically hindered ligands.
EXPERIMENTAL SECTION
■
General Procedures. Silica gel HF254 and Silica gel 230−400
mesh (E. Merck) were used for TLC and column chromatography,
1
respectively. H and 13C{1H} NMR spectra were recorded at 298 K
with Varian NMR-vnmrs600 or vnmrs500 spectrometers, using
standard experimental conditions and Varian software (ChemPack
4.1). Configurational assignments were based on the NMR measure-
ments generated using two-dimensional techniques like COSY and
1H−13C gradient selected HSQC (g-HSQC), as well as 1H−13C
gradient selected HMBC (g-HMBC). Internal TMS was used as the
1H and 13C NMR chemical shift standard. J values are given in Hertz.
High-resolution mass spectra (HRMS ESI) were acquired with
Mariner and MaldiSYNAPT G2-S HDMS (Waters) mass spectrom-
eters. Optical rotations were measured with a Jasco P-2000 automatic
polarimeter. Single crystal X-ray diffraction measurements were
carried out on an Agilent Supernova diffractometer at 100 K with
monochromated Cu Kα radiation (1.54184 Å). The structures of
compounds 21, 23, and 24 were determined on crystals prepared in a
chloroform/methanol solvent system by slow evaporation at room
temperature.
All DFT calculations have been performed using the Gaussian
program suite.53 Molecular energies (a.u.) have been estimated at the
B3LYP/6-311++G(2d,p) level of theory, using B3LYP/6-31G(2d,p)
optimized structures. All calculations were performed assuming
isolated molecules. The protonated compounds were calculated as
cations. Topological analysis: detection of the weak interactions,
hydrogen bonds, and bond critical points was performed by the
AIMAll program package.54 Some preliminary calculations were
CONCLUSIONS
■
The presented results clearly show that the oxidative
functionalization of the double bond of trinor-18α-olean-
17(22)-ene derivatives led to synthetically useful products. The
proper choice of oxidants and reaction conditions gave highly
functionalized tetracyclic triterpenes and unusual products
with the bicyclo[4.3.1]decane fragment. In all cases, the key
compounds were obtained as the major products. Prepared
derivatives are convenient starting materials for further
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performed using simplified structures (Figure 1S) to save computa-
tional time; then the results were used to plan the calculations for full
molecules 10, 11, and 22. The population of a series of rotamers was
estimated on the basis of molecular energy, using the Boltzmann
distribution. The details of the calculations, some key figures as well as
atomic coordinates are enclosed in the Supporting Information.
20,29-Dihydrobetulin 3β,28-di-O-acetate (7). Betulin diac-
etate (5) was converted to dihydrobetulin diacetate (7) by a modified
procedure of Lehn.55 To a solution of betulin diacetate (5, 5.27 g,
10.00 mmol) in THF (70 mL) and methanol (70 mL) was added
10% Pd/C (300 mg), and the mixture was hydrogenated under 7 bar
of hydrogen for 48 h. Then, the whole mixture was filtered through a
short silica pad (hexane−ethyl acetate−methanol, 5:3:1 as an eluent)
to afford dihydrobetulin diacetate (7, 5.25 g, quant) as a white solid.56
−31 (c 1.40). νmax (film): 2946, 2869, 1732, 1451, 1370, 1247, 1026,
981, 740 cm−1. 1H NMR (500 MHz, CDCl3) δ: 5.32−5.33 (bs, 1 H,
H-22), 4.49 (dd, 1 H, J 5.6 and 10.8 Hz, H-3), 2.04 (s, 3 H, CH3),
1.05 (s, 3 H, CH3), 0.95 (s, 3 H, CH3), 0.88 (d, 3 H, J 6.5 Hz, CH3),
0.87 (d, 3 H, J 6.6 Hz, CH3), 0.86 (s, 3 H, CH3), 0.85 (s, 3 H, CH3),
0.84 (s, 3 H, CH3), 1.96−2.14 (m, 23 H), 0.80−1.07 (m, 3 H).
13C{1H} NMR (125 MHz, CDCl3) δ: 171.0, 141.6 (C-17), 117.5 (C-
22), 80.9 (C-3), 55.4, 50.3, 43.3, 42.6 (C), 40.9 (C), 40.2, 38.5 (CH,
CH2), 37.8 (C), 37.1 (C), 34.5 (CH2), 34.0 (CH2), 33.2 (CH2), 28.1,
27.9, 25.6 (CH2), 23.7 (CH2), 22.1 (CH2), 21.3, 21.2 (CH2), 21.1
(CH2), 20.8 (CH2), 20.7, 18.2 (CH2), 16.5, 16.3, 15.8, 14.8. Anal.
Calcd for C32H52O2: C, 81.99; H, 11.18. Found: C, 82.09; H, 11.20.
3-O-Acetyl-19α-isopropyl-28,29,30-trinor-17α,18α-ole-
anan-3β,17α,22α-triol (9).58 To a solution of 2 (1.000 g, 2.133
mmol) in pyridine (30 mL) was added OsO4 (600 mg, 2.36 mmol),
and the mixture was stirred in the dark for 7 days. Then, pyridine was
co-evaporated with toluene under reduced pressure, and the residue
was dissolved in ethyl acetate. Water (40 mL), Na2S2O5 (2.0 g), and
Na2S2O3·5H2O (3.0 g) were added, and the mixture was stirred until
decomposition of osmate ester was detected on TLC (2−3 days).
Then, water (100 mL) was added, and the product was extracted with
chloroform (3 × 30 mL). Combined organic extracts were
concentrated and the residue was purified by column chromatography
(hexane−ethyl acetate, 20:1 to 7:3) to afford 860 mg (80%) of the
title compound as a foam. [α]2D0 +36.2 (c 0.2, chloroform). νmax (film):
3479, 2946, 2868, 1730, 1716, 1451, 1374, 1248, 1032, 979, 736
1
No further purification was necessary. H NMR (600 MHz, CDCl3)
δ: 4.48 (dd, 1 H, J 5.6 and 10.8 Hz, H-3), 4.24 (dd, 1 H, J 1.8 and
11.2 Hz, H-28), 3.82 (d, 1 H, J 10.9 Hz, H-28), 2.06 (s, 3 H,
COCH3), 2.04 (s, 3 H, COCH3), 1.17−1.88 (m, 23 H), 0.87−1.03
(m, 2 H), 1.04 (s, 3 H, CH3), 0.95 (s, 3 H, CH3), 0.86 (s, 3 H, CH3),
0.85 (s, 3 H, CH3), 0.84 (s, 3 H, CH3), 0.84 (d, 1 H, J 6.8 Hz, CH3),
0.78−0.80 (m, 1 H, H-5), 0.77 (d, 1 H, J 6.8 Hz, CH3). 13C{1H}
NMR (150 MHz, CDCl3) δ: 171.6 (CO), 171.0 (CO), 80.9 (C-
3), 62.8 (CH2), 55.3, 49.9, 48.1, 46.4 (C), 44.5, 42.8 (C), 40.9 (C),
38.3 (CH2), 37.8 (C), 37.1, 37.0 (C), 34.6 (CH2), 34.2 (CH2), 29.8
(CH2), 29.4, 27.9, 26.9 (CH2), 26.8 (CH2), 23.7 (CH2), 22.9, 21.6
(CH2), 21.3, 21.0, 20.8 (CH2), 18.2 (CH2), 16.5, 16.1, 16.0, 14.9,
14.6.
1
cm−1. H NMR (600 MHz, CDCl3) δ: 4.48 (dd, 1 H, J 5.3 and 11.1
20,29-Dihydrobetulin 3β-O-acetate (8). Method A. To a
solution of betulin 3β-O-acetate (6, 3.15 g, 6.50 mmol) in THF (35
mL) and methanol (55 mL) was added 10% Pd/C (230 mg), and the
mixture was hydrogenated under 7 bar of hydrogen for 3 days. Then,
the whole mixture was filtered through a syringe filter to remove the
catalyst and evaporated to dryness under reduced pressure. No further
purification was necessary. Dihydrobetulin 3β-acetate (8) was
obtained quantitatively as a white solid.56
Hz, H-3), 3.79 (dd, 1 H, J 5.3 and 10.8 Hz, H-22), 2.29−2.35 (m, 1
H, H-19a), 2.05 (s, 3 H, COCH3), 2.00−2.03 (m, 1 H, H-16), 1.88−
1.90 (m, 1 H, H-18), 1.74 (H-12), 1.69 (H-1), 1.69 (H-20), 1.68 (H-
21), 1.67 (H-13), 1.65 (H-2), 1.61 (H-2), 1.61 (H-21), 1.57 (H-15),
1.52 (H-6), 1.52 (H-11), 1.44 (H-20), 1.40 (H-7), 1.40 (H-16), 1.39
(H-6), 1.36 (H-9), 1.24 (H-11), 1.22 (H-19), 1.16 (H-15), 1.02 (H-
1), 1.01 (s, 3 H, H-27), 0.98 (s, 3 H, H-26), 0.91 (d, J 6.4 Hz, H-19b),
0.88 (H-12), 0.87 (s, 3 H, H-25), 0.85 (d, J 6.6 Hz, H-19c), 0.85 (s, 3
H, H-23), 0.84 (s, 3 H, H-24), 0.80−0.82 (m, 1 H, H-5). 13C{1H}
NMR (150 MHz, CDCl3) δ: 171.0 (CO), 80.9 (C-3), 74.9 (C-17),
68.0 (C-22), 55.4 (C-5), 50.1 (C-9), 43.2 (C-18), 41.3 (C-14), 40.9
(C-8), 40.3 (C-19), 38.4 (C-1), 37.8 (C-4), 37.0 (C-10), 36.5 (C-13),
34.0 (C-7), 31.8 (C-16), 28.1 (C-19a), 28.0 (C-15), 27.9 (C-23),
26.6 (C-21), 25.8 (C-12), 23.7 (C-2), 22.4 (C-19c), 22.3 (C-19b),
21.4 (C-20), 21.3 (C-11). 18.2 (C-6), 16.5 (C-24), 16.3 (C-25), 15.6
(C-26), 15.0 (C-27). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C32H54O4Na 525.3920; found 525.3908.
Compounds 10 and 11. Method C. To a vigorously stirred
suspension of silica gel (230−400 mesh, 400 mg) in CH2Cl2 (4 mL)
was added a solution of NaIO4 (56 mg, 0.26 mmol) in water (1 mL),
and the heterogeneous mixture was stirred for 15 min to form a flaky
suspension. Diol 9 (100 mg, 0.200 mmol) in CH2Cl2 (5 mL) was
then added and stirred for 7 days. The mixture was filtered through
sintered glass, silica gel was washed with CH2Cl2, and the solvents
were evaporated under reduced pressure. The residue was purified by
column chromatography (hexane−ethyl acetate, 9:1 to 5:1) to afford
11 (27 mg, 27%) as a foam and recovered diol 9 (53 mg, 53%).
Method D. A mixture of diol 9 (201 mg, 0.400 mmol) and lead
tetraacetate (320 mg, 0.65 mmol) in pyridine (10 mL) was stirred at
room temperature for 30 min. Then, two drops of glycerin were
added to decompose an excess of lead tetraacetate and the solvents
were co-evaporated with toluene under diminished pressure. The
residue was purified by column chromatography (hexane−ethyl
acetate, 9:1 to 5:1) to afford 10 (156 mg, 78%) and 11 (14 mg, 7%),
both as a foams.
Method B. Dihydrobetulin 3β-O-acetate (8) was prepared from
dihydrobetulin 3β,28-di-O-acetate (7) by selective deacetylation
according to a modified procedure of Thibeault.25 A mixture of
dihydrobetulin 3β,28-di-O-acetate (7, 10.00 g, 18.91 mmol), Al(i-
OPr)3 (11.65 g, 57.04 mmol), and i-PrOH (300 mL) was stirred
under reflux for 24 h. The crude mixture was concentrated under
reduced pressure and water (300 mL) was added. The suspension was
slightly acidified with 2 M HCl and extracted with chloroform (3 ×
100 mL). The combined organic layers were washed with saturated
NaHCO3 (20 mL) and concentrated under reduced pressure.
Column chromatography of the residue (hexane−ethyl acetate, 15:1
1
to 10:1) afforded 6.86 g (75%) of 8 as a white solid. H NMR (500
MHz, CDCl3) δ: 4.48 (dd, 1 H, J 5.3 and 11.1 Hz, H-3), 3.77 (bd, 1
H, J 10.9 Hz, H-28), 3.30 (bd, 1 H, J 10.9 Hz, H-28), 2.04 (s, 3 H,
CH3), 0.97−1.97 (m, 26 H), 1.03 (s, 3 H, CH3), 0.95 (s, 3 H, CH3),
0.86 (s, 3 H, CH3), 0.83−0.85 (m, 9 H, 3 x CH3), 0.79−0.82 (m, 1
H), 0.77 (d, 3 H, J 6.7 Hz, CH3). 13C{1H} NMR (125 MHz, CDCl3)
δ: 171.0 (CO), 80.9 (C-3), 60.5 (CH2), 55.3, 49.9, 48.0, 47.9 (C),
44.5, 42.8 (C), 40.9 (C), 38.3 (CH2), 37.8 (C), 37.0 (C), 36.8, 34.2
(CH2), 34.0 (CH2), 29.4, 29.3 (CH2), 27.9, 26.9 (CH2), 26.8 (CH2),
23.7 (CH2), 22.9, 21.7 (CH2), 21.3, 20.8 (CH2), 18.2 (CH2), 16.5,
16.1, 15.9, 14.9, 14.6.
3β-O-Acetyl-19α-isopropyl-28,29,30-trinor-18α-olean-
17(22)-ene (2). Compound 2 was prepared from dihydrobetulin 3-
O-acetate (8) according to the procedure published for betulin 3-O-
acetate.57 POCl3 (19.5 mL, 210 mmol) was added to a solution of
dihydrobetulin 3-acetate (8, 6.33 g, 13.00 mmol) in anhydrous
pyridine (50 mL) and heated at 60 °C in an oil bath for 24 h. Then,
the mixture was carefully poured onto ice (500 g). The product was
extracted with chloroform (3 × 100 mL), and the organic extracts
were concentrated under reduced pressure and filtered through a
short silica path. Organic solvents were evaporated; column
chromatography of the residue (hexane−ethyl acetate, 40:1 to 20:1)
gave the title compound (2, 5.98 g, 98%) as a foam, sufficiently pure
for further transformation. [α]2D0 −20.5 (c 0.2, chloroform); lit.23 [α]2D0
Method E. A mixture of diol 9 (402 mg, 0.800 mmol) and lead
tetraacetate (600 mg, 1.20 mmol) in benzene (15 mL) was stirred at
room temperature for 30 min. Then, two drops of glycerin were
added to decompose an excess of lead tetraacetate and the solvents
were evaporated under diminished pressure. The residue was purified
by column chromatography (hexane−ethyl acetate, 9:1 to 5:1) to
afford 10 (360 mg, 90%) as a foam.
7642
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Article
Data for 10. [α]2D0 +29.0 (c 0.2, chloroform). νmax (film): 2948,
52.8, 52.5, 50.7, 45.1, 41.4, 41.1 (C), 40.6 (C), 38.7 (CH2), 38.5
(CH2), 37.8 (C), 37.1 (C), 34.1 (CH2), 33.9 (CH2), 31.2, 30.6
(CH2), 27.9, 27.6 (CH2), 25.5 (CH2), 23.6 (CH2), 21.9 (CH3, CH3),
21.3, 21.1 (CH2), 18.1 (CH2), 16.5 (CH3, CH3), 15.6, 14.8. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C34H58O5Na 569.4182; found
569.4167.
1
2872, 1728, 1451, 1369, 1247, 1026, 981, 737 cm−1. H NMR (600
MHz, CDCl3) δ: 9.74−9.75 (m, 1 H, H-22), 4.49 (dd, 1 H, J 5.3 and
11.2 Hz, H-3), 2.48−2.54 (m, 1 H, H-21), 2.35−2.42 (m, 2 H, H-16,
H-21) 2.26−2.29 (m, 1 H, H-18), 2.23−2.26 (m, 1 H, H-16), 2.05
(CH3CO), 2.00 (H-13), 2.00 (H-19a), 1.84 (H-15), 1.83 (H-20),
1.72 (H-1), 1.70 (H-12), 1.68 (H-20), 1.64 (H-2), 1.58 (H-15), 1.56
(H-6), 1.55 (H-11), 1.46 (H-7), 1.42 (H-6), 1.40 (H-9), 1.31 (H-11),
1.22 (H-19), 1.12 (H-12), 1.09 (s, 3 H, H-27), 1.05 (H-1), 1.02 (s, 3
H, H-26), 0.93 (d, 1 H, J 6.7 Hz, H-19c), 0.90 (s, 3 H, H-25), 0.87 (s,
3 H, H-23), 0.86 (s, 3 H, H-24), 0.84 (H-5), 0.82 (d, 1 H, J 6.7 Hz,
H-19b). 13C{1H} NMR (150 MHz, CDCl3) δ: 213.7 (C-17), 202.4
(C-22), 171.0 (CH3CO), 80.8 (C-3), 55.6 (C-5), 52.6 (C-18), 50.7
(C-9), 44.6 (C-21), 44.2 (C-19), 41.4 (C-13), 41.2 (C-8), 40.8 (C-
14), 38.8 (C-16), 38.6 (C-1), 37.8 (C-4), 37.1 (C-10), 34.1 (C-7),
30.9 (C-15), 30.7 (C-19a), 27.9 (C-23), 27.5 (C-12), 23.7 (C-2),
22.2 (C-20), 21.9 (C-19c), 21.8 (C-19b), 21.3 (CH3CO), 21.1 (C-
11), 18.1 (C-6), 16.5 (C-24, C-25), 15.7 (C-26), 14.7 (C-27). HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C32H52O4Na 523.3763; found
523.3761.
Data for 13. [α]2D0 +32.5 (c, 0.2 chloroform). νmax (film): 2949,
2872, 1736, 1706, 1451, 1368, 1245, 1170, 1026, 756 cm−1. 1H NMR
(600 MHz, CDCl3) δ: 4.49 (dd, 1 H, J 5.2 and 11.3 Hz, H-3), 3.66 (s,
3 H, COCH3), 2.36 (H-16), 2.35 (H-21), 2.26 (H-21), 2.25 (H-16),
2.25 (H-18), 2.05 (s, 3 H, CH3CO), 1.98 (H-13), 1.97 (H-19a), 1.85
(H-15), 1.85 (H-20), 1.72 (H-1), 1.71 (H-12), 1.66 (H-20), 1.62 (H-
2), 1.60 (H-2), 1.56 (H-6), 1.56 (H-15), 1.55 (H-11), 1.48 (H-7),
1.43 (H-7), 1.42 (H-6), 1.39 (H-9), 1.30 (H-11), 1.21 (H-19), 1.11
(H-12), 1.07 (s, 3 H, H-27), 1.05 (H-1), 1.02 (s, 3 H, H-26), 0.93 (d,
3 H, J 6.7 Hz, H-19b), 0.90 (s, 3 H, H-26), 0.87 (s, 3 H, H-23), 0.85
(s, 3 H, H-24), 0.84 (H-5), 0.82 (d, 3 H, J 6.7 Hz, H-19c). 13C{1H}
NMR (150 MHz, CDCl3) δ: 213.7 (C-17), 174.1 (C-22), 171.0
(CH3CO), 80.7 (C-3), 55.5 (C-5), 52.7 (C-18), 51.5 (CO2CH3),
50.7 (C-9), 44.2 (C-19), 41.3 (C-13), 41.1 (C-8), 40.7 (C-14), 38.7
(C-16), 38.5 (C-1), 37.8 (C-4), 37.1 (C-10), 34.8 (C-21), 34.1 (C-7),
30.8 (C-19a), 30.7 (C-15), 27.9 (C-23), 27.5 (C-12), 25.7 (C-20),
23.6 (C-2), 21.8 (C-19c), 21.8 (C-19b), 21.3 (CH3CO), 21.1 (C-11),
18.1 (C-6), 16.5 (C-25), 16.5 (C-24), 15.6 (C-26), 14.7 (C-27).
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C33H54O5Na 553.3869;
found 553.3863.
Data for 11. [α]2D0 +30.6 (c 0.2, chloroform). νmax (film): 3486,
1
2948, 2870, 1712, 1450, 1374, 1248, 1024, 981, 756 cm−1. H NMR
(500 MHz, CDCl3) δ: 9.81 (d, 1 H, J 2.7 Hz, H-22), 4.48 (dd, 1 H, J
5.3 and 11.1 Hz, H-3), 2.80 (ddd, 1 H, J 2.8, 8.1, and 11.3 Hz, H-21),
2.04 (s, 3 H, CH3CO), 2.01 (H-20), 1.96 (H-20), 1.94 (H-16),
1.70 (H-1), 1.69 (H-12), 1.69 (H-16), 1.66 (H-19a), 1.65 (H-2), 1.61
(H-2), 1.54 (H-11), 1.52 (H-6), 1.50 (H-19), 1.49 (H-15), 1.44 (H-
18), 1.40 (H-6), 1.40 (H-7), 1.36 (H-9), 1.27 (H-15), 1.19 (H-11),
1.08 (H-13), 1.02 (H-1), 0.95 (H-12), 0.95 (s, 3 H, H-27), 0.94 (s, 3
H, H-26), 0.91 (d, 3 H, J 6.5 Hz, H-19c), 0.90 (d, 3 H, J 6.7 Hz, H-
19b), 0.87 (s, 3 H, H-25), 0.85 (s, 3 H, H-23), 0.84 (s, 3 H, H-24),
0.81 (H-5). 13C{1H} NMR (125 MHz, CDCl3) δ: 206.5 (C-22),
171.0 (CH3CO), 83.1 (C-17), 80.8 (C-3), 55.5 (C-5), 55.5 (C-21),
53.6 (C-18), 51.1 (C-9), 50.2 (C-19), 42.7 (C-13), 40.8 (C-14), 40.5
(C-8), 38.6 (C-1), 37.8 (C-4), 37.1 (C-10), 34.8 (C-19a), 33.9 (C-7),
31.3 (C-16), 29.0 (C-20), 28.1 (C-15), 27.9 (C-23), 26.7 (C-12),
23.6 (C-2), 22.7 (C-19b), 21.4 (C-11), 21.3 (CH3CO), 20.7 (C-
19c), 18.1 (C-6), 16.6 (C-25), 16.5 (C-24), 15.5 (C-26), 14.6 (C-27).
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C32H52O4Na 523.3763;
found 523.3757.
Ozonolysis of 2. Method F. Ozone was bubbled through a
solution of 2 (4.69 g, 10.00 mmol) in MeOH (100 mL) and CH2Cl2
(100 mL) at −78 °C until the disappearance of the starting material
on TLC (30 min). Oxygen was passed through the solution for an
additional 15 min to remove an excess of ozone, and Me2S2 (10 mL)
was added. The mixture was then left to warm to room temperature
and stirred overnight. Solvents were evaporated under reduced
pressure and the residue was purified by column chromatography
(hexane−ethyl acetate, 9:1 to 5:1) to afford 13 (320 mg, 6%),58 12
(3.06 g, 56%), 11 (902 mg, 18%), and crude 14 (565 mg, 11%) in
order of appearance, all as foams.
Selected Data for 14. 13C{1H} NMR (125 MHz, CDCl3) δ: 213.9
(C-17), 179.5 (C-22), 171.0 (CH3CO), 80.8 (C-3), 55.5, 52.7,
50.8, 44.3, 41.2, 41.1 (C), 40.7 (C), 38.7 (CH2), 38.6 (CH2), 37.8
(C), 37.1 (C), 34.8 (CH2), 34.1 (CH2), 30.8, 30.7 (CH2), 27.9, 27.5
(CH2), 25.5 (CH2), 23.6 (CH2), 21.9, 21.8, 21.3, 21.0 (CH2), 18.1
(CH2), 16.5 (2 × CH3), 15.6, 14.7.
Compound 14. Method H. Aldehyde 10 (201 mg, 0.400 mmol)
was dissolved in a mixture of THF (5 mL), tert-BuOH (15 mL), and
2-methyl-2-butene (5 mL). The solution was cooled in an ice bath,
and a solution of NaH2PO4·2H2O (600 mg) and NaClO2 (720 mg)
in water (10 mL) was added. The solution was stirred at 0 °C for 10
min; then the temperature was raised to room temperature and
stirring was continued for 30 min. A saturated solution of NH4Cl (0.5
mL) and 15 mL of water were added. Product was extracted with
dichloromethane (3 × 100 mL), and the combined organic extracts
were evaporated to dryness. Short column chromatography of the
residue (hexane−ethyl acetate, 9:1 to 5:1, and hexane−ethyl acetate−
methanol, 5:3:1) gave crude acid 14 (202 mg) as an amorphous
powder.58
Method I. To a cooled in an ice bath solution of 10 (100 mg, 0.200
mmol) in acetone (10 mL) was added Jones reagent (0.8 mL)
dropwise, and the mixture was stirred at room temperature for 1 h.
Then, isopropanol (1 mL) was added and stirring was continued for
an additional 20 min. The solution was decanted, and the precipitated
solid mass was washed with acetone (4 × 10 mL). Combined organic
extracts were evaporated under reduced pressure and the residue was
purified by column chromatography (hexane−ethyl acetate, 5:1, to
hexane−ethyl acetate−methanol, 5:3:1) to afford crude acid 14 (100
mg) as amorphous powder.
Compound 17. Crude acid 14 (100 mg, 0.194 mmol) was
dissolved in methanol (6 mL), and acetyl chloride (50 μL) was added.
The mixture was stirred at room temperature for 24 h. The reaction
was quenched with Et3N (0.3 mL), and the solvents were evaporated
under reduced pressure. Column chromatography of the residue
(hexane−ethyl acetate, 7:3 to 1:1) gave 17 (76 mg, 75% after two
steps) as a glass.58 [α]D20 +17.4 (c, 0.2 chloroform). νmax (film): 3461,
2947, 2870, 1736, 1704, 1449, 1384, 1254, 1172, 1038, 755 cm−1. 1H
NMR (500 MHz, CDCl3) δ: 3.66 (s, 3 H, OCH3), 3.21 (dd, 1 H, J
5.0 Hz, 11.5 Hz, H-3), 2.32−2.40 (m, 2 H), 2.22−2.29 (m, 3 H),
1.95−2.01 (m, 2 H), 1.82−1.88 (m, 2 H), 1.19−1.74 (m), 1.07 (s, 3
H, CH3), 1.02 (s, 3 H, CH3), 0.99 (s, 3 H, CH3), 0.93 (d, 3 H, J 6.7
Hz, H-19b), 0.87 (s, 3 H, CH3), 0.82 (d, 3 H, J 6.7 Hz, H-19c), 0.78
(s, 3 H, CH3), 0.72−1.35 (m). 13C{1H} NMR (125 MHz, CDCl3) δ:
213.8 (C-17), 174.1 (C-22), 78.8 (C-3), 55.4, 52.7, 51.5, 50.8, 44.3,
Method G. Ozone was bubbled through a solution of 2 (910 mg,
1.94 mmol) and p-TsOH (100 mg) in MeOH (25 mL) and CH2Cl2
(25 mL) at −78 °C until the disappearance of the starting material on
TLC (30 min). Oxygen was passed through the solution for an
additional 15 min to remove an excess of ozone. Then, the mixture
was stirred for 1 h at room temperature to ensure the complete acetal
formation and Me2S2 (1 mL) was added. The reaction was worked up
following Method F. Acetal 12 (754 mg, 71%) was obtained as the sole
product.
Data for 12. [α]2D0 +35.2 (c, 0.3 chloroform). νmax (film): 2949,
1
2873, 1732, 1708, 1452, 1370, 1246, 1126, 1026, 980, 736 cm−1. H
NMR (600 MHz, CDCl3) δ: 4.49 (dd, 1 H, J 5.1 and 11.3 Hz, H-3),
4.28−4.30 (m, 1 H, H-22), 3.31 (s, 3 H, OCH3), 3.30 (s, 3 H,
OCH3), 2.33−2.39 (m, 1 H), 2.22−2.27 (m, 2 H), 2.05 (s, 3 H,
COCH3), 1.93−1.98 (m, 2 H), 1.84 (ddd, 1 H, J 6.1, 6.1, and 13.0
Hz), 0.96−1.77 (m), 1.06 (s, 3 H, CH3), 1.01(s, 3 H, CH3), 0.93 (d, 3
H, J 6.7 Hz, CH3), 0.89 (s, 3 H, CH3), 0.86 (s, 3 H, CH3), 0.85 (s, 3
H, CH3), 0.82 (d, 3 H, J 6.7 Hz, CH3). 13C{1H} NMR (150 MHz,
CDCl3) δ: 214.0 (C-17), 171.0, 104.7 (C-22), 80.7 (C-3), 55.5, 52.9,
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41.3, 41.1 (C), 40.7 (C), 38.9 (C, CH2), 38.7 (CH2), 37.2 (C), 34.8
(CH2), 34.2 (CH2), 30.8, 30.7 (CH2), 27.9, 27.6 (CH2), 27.4 (CH2),
25.7 (CH2), 21.8, 21.8, 21.1 (CH2), 18.2 (CH2), 16.4, 15.6, 15.4,
14.8. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C31H52O4Na
511.3763; found 511.3767.
Compound 13. Method J. Crude acid 14 (100 mg, 0.194 mmol)
was dissolved in DMF (5 mL), to which K2CO3 (150 mg), and MeI
(100 μL) were added. The mixture was stirred at room temperature
for 24 h, and the solvents were evaporated under reduced pressure.
Column chromatography of the residue (hexane−ethyl acetate, 7:3 to
1:1) gave 13 (80 mg, 75% after two steps) as a glass.
Method K. Acetylation of ester 17 (35 mg, 0.072 mmol) with acetyl
anhydride (1.0 mL) in pyridine (2 mL) at room temperature for 24 h,
followed by the usual workup and column chromatography (hexane−
ethyl acetate, 9:1 to 7:3), gave 13 (36 mg, 95%) as a glass.
Compound 19. Aldehyde 11 (495 mg, 0.988 mmol) was
dissolved in THF (5 mL), tert-BuOH (25 mL), and 2-methyl-2-
butene (8 mL). The solution was cooled in an ice bath, and a solution
of NaH2PO4·2H2O (1.3 g) and NaClO2 (1.0 g) in water (12 mL) was
added. The solution was stirred at 0 °C for 30 min; then the
temperature was raised to room temperature and the mixture was
stirred for 2 h. The mixture was poured into 10 mL of a saturated
solution of NH4Cl and 50 mL of water. The product was extracted
with dichloromethane (4 × 30 mL), and the combined organic
extracts were evaporated to dryness. Column chromatography of the
residue (hexane−ethyl acetate, 9:1 to 5:1, and finally hexane−ethyl
acetate−methanol, 5:3:1) gave crude acid 18 (449 mg, 88%) as an
amorphous powder. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C32H52O5 539.3712; found 539.3693.
47.8, 42.5, 40.9 (C), 40.4 (C), 38.9 (CH2), 38.8 (C), 37.2 (C), 34.6,
34.0 (CH2), 32.2 (CH2), 30.9 (CH2), 28.1 (CH2), 27.9, 27.4 (CH2),
26.8 (CH2), 22.8, 21.4 (CH2), 20.7, 18.2 (CH2), 16.5, 15.6, 15.3,
14.5. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C31H52O4Na
511.3763; found 511.3764.
Compound 21. A solution of aldehyde 11 (100 mg, 0.200 mmol)
in THF (8 mL) was added to a suspension of LiAlH4 (100 mg, 2.6
mmol) in THF (2 mL), and the mixture was stirred at room
temperature under an argon atmosphere for 2.5 h. Then, sat. NH4Cl
(few drops) and ethyl acetate (5 mL) were added. The whole mixture
was filtered through a short silica pad, eluted with hexane−ethyl
acetate (1:1), and evaporated to dryness. To the residue were added
pyridine (3 mL) and acetic anhydride (2 mL), and the mixture was
stirred at room temperature for 24 h. Solvents were co-evaporated
with toluene under reduced pressure. Column chromatography
(hexane−ethyl acetate, 5:1 to 7:3) of the residue afforded diacetate
21 (86 mg, 79% after two steps) as a white solid. mp 224−226 °C;
[α]2D0 +32.2 (c, 0.25 chloroform). H NMR (600 MHz, CDCl3) δ:
1
4.48 (dd, 1 H, J 5.2 and 11.2 Hz, H-3), 4.28 (dd, 1 H, J 6.0 and 11.2
Hz, H-22), 4.07 (dd, 1 H, J 6.8 and 11.2 Hz, H-22), 2.22−2.28 (m, 1
H, H-21), 2.05 (s, 3 H, CH3CO), 2.04 (s, 3 H, CH3CO), 1.91−1.96
(m, 1 H, H-20), 1.88 (m, 1 H, H-16), 1.71 (H-1), 1.68 (H-12), 1.65
(H-2), 1.61 (H-2), 1.60 (H-16), 1.54 (H-19a), 1.53 (H-11), 1.52 (H-
6), 1.44 (H-15), 1.43 (H-7), 1.40 (H-18), 1.39 (H-6), 1.37 (H-7),
1.37 (H-9), 1.37 (H-19), 1.35 (H-20), 1.21 (H-15), 1.18 (H-11), 1.12
(H-13), 1.03 (H-1), 0.96 (s, 3 H, H-27), 0.94 (H-12), 0.94 (s, 3 H,
H-26), 0.88 (H-19c), 0.87 (H-19b), 0.87 (s, 3 H, H-25), 0.85 (s, 3 H,
H-23), 0.84 (s, 3 H, H-24), 0.81 (H-5). 13C{1H} NMR (150 MHz,
CDCl3) δ: 171.1 (CH3CO), 171.0 (CH3CO), 80.9 (C-3), 80.7
(C-17), 64.6 (C-22), 55.6 (C-5), 53.6 (C-18), 51.1 (C-9), 49.0 (C-
19), 42.9 (C-13), 41.9 (C-21), 41.0 (C-14), 40.5 (C-8), 38.6 (C-1),
37.8 (C-4), 37.1 (C-10), 35.0 (C-19a), 33.9 (C-7), 31.8 (C-20), 30.5
(C-16), 28.0 (C-15), 27.9 (C-23), 26.7 (C-12), 23.7 (C-2), 22.6 (C-
19c), 21.5 (C-11), 21.3 (CH3CO), 21.1 (CH3CO), 20.6 (C-
19b), 18.1 (C-6), 16.6 (C-25), 16.5 (C-24), 15.6 (C-26), 14.8 (C-
27). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C34H56O5Na
567.4025; found 567.4006.
Cyclization of 10 and 12 by Intramolecular Aldol Reaction.
Method L. A solution of 12 (273 mg, 0.500 mmol) and p-TsOH (150
mg) in acetone (10 mL) was stirred at room temperature for 24 h.
The whole mixture was then filtered through a short silica gel pad and
concentrated under reduced pressure, and the residue was purified by
column chromatography (hexane−ethyl acetate, 9:1 to 7:3) to give 11
(45 mg, 18%) and a mixture of epimers 22 (148 mg, 59%), both as
foams.
Crude 18 (422 mg, 0.817 mmol) was then dissolved in DMF (5
mL), K2CO3 (300 mg), and MeI (500 μL) was added. The mixture
was stirred at room temperature for 2 h. Then, the solvents were
evaporated under reduced pressure. Column chromatography of the
residue (hexane−ethyl acetate, 9:1 to 5:1) gave 19 (346 mg, 80%) as
a foam. [α]2D0 +60.3 (c, 0.4 chloroform). νmax (film): 3508, 2949, 2871,
1
1728, 1449, 1368, 1247, 1198, 1175, 1023, 982, 756 cm−1. H NMR
(500 MHz, CDCl3) δ: 4.48 (dd, 1 H, J 5.1 and 11.4 Hz, H-3), 3.71 (s,
3 H, OCH3), 2.89 (dd, 1 H, J 7.7 and 12.5 Hz, H-21), 2.05 (H-20),
2.04 (s, 3 H, CH3CO), 1.83 (H-20), 1.75 (H-16), 1.70 (H-1), 1.68
(H-12), 1.65 (H-2), 1.61 (H-2), 1.53 (H-11), 1.52 (H-6), 1.49 (H-
19), 1.42 (H-19a), 1.40 (H-15), 1.38 (H-6), 1.37 (H-7), 1.37 (H-9),
1.22 (H-15), 1.19 (H-11), 1.07 (H-13), 1.02 (H-1), 0.97 (H-12), 0.96
(s, 3 H, H-27), 0.94 (s, 3 H, H-26), 0.88 (d, 3 H, J 6.9 Hz, H-19c),
0.87 (s, 3 H, H-25), 0.86 (d, 3 H, J 6.7 Hz, H-19b), 0.85 (s, 3 H, H-
23), 0.84 (s, 3 H, H-24), 0.81 (H-5). 13C{1H} NMR (125 MHz,
CDCl3) δ: 176.1 (C-22), 171.0 (CH3CO), 80.8 (C-17), 80.8 (C-
3), 55.5 (C-5), 51.7 (CO2CH3), 51.0 (C-9), 51.0 (C-19), 50.2 (C-
19a), 47.8 (C-21), 42.4 (C-13), 40.8 (C-8 or C-14), 40.4 (C-8 or C-
14), 38.5 (C-1), 37.7 (C-4), 37.1 (C-10), 34.5 (C-18), 33.8 (C-7),
32.3 (C-20), 30.8 (C-16), 28.1 (C-15), 27.9 (C-23), 26.7 (C-12),
23.6 (C-2), 22.8 (C-19c), 21.4 (C-11), 21.3 (CH3CO), 20.7 (C-
19b), 18.1 (C-7), 16.6 (C-25), 16.4 (C-24), 15.5 (C-26), 14.5 (C-
27). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C33H54O5Na
553.3869; found 553.3873.
Method M. Starting from 10 (250 mg, 0.500 mmol), and following
the Method L, 11 (50 mg, 20%) and 22 (140 mg, 56%) were obtained,
both as foams.
Method N. Starting from 12 (273 mg, 0.500 mmol) and p-TsOH
(150 mg) in toluene (10 mL), and following the Method L, 22 (125
mg, 50%) was obtained as foam.
Method O. Starting from 10 (250 mg, 0.500 mmol) and p-TsOH
(150 mg) in toluene (10 mL), and following the Method L, 22 (185
mg, 74%) was obtained as foam.
Compounds 23 and 24. The acetylation of 22 (751 mg, 1.500
mmol) with acetyl chloride (2.0 mL) in pyridine (4 mL) at room
temperature for 24 h, followed by the usual workup and column
chromatography (hexane−ethyl acetate, 20:1 to 5:1), gave 23 (374
mg, 46%) and 24 (228 mg, 28%), both as a white solid. Crystals
suitable for X-ray structure analysis were obtained by slow
evaporation of a chloroform/methanol solution at room temperature.
Data for 23. mp 214−216 °C; [α]2D0 +45.3 (c 0.4, chloroform);
νmax (film): 2948, 2871, 1736, 1699, 1466, 1448, 1369, 1246, 1208,
1027, 982, 757 cm−1. 1H NMR (600 MHz, CDCl3) δ: 4.81 (ddd, 1 H,
J 3.7, 5.9, and 11.5 Hz, H-22), 4.48 (dd, 1 H, J 5.0 and 11.5 Hz, H-3),
3.01−3.05 (m, 1 H, H-16), 2.15 (dd, 1 H, J 7.0 and 14.3 Hz, H-15),
2.07 (H-13), 2.05 (s, 3 H, COCH3), 2.03 (s, 3 H, COCH3), 2.00 (H-
21), 1.94 (H-18), 1.82 (H-21), 1.78 (H-20), 1.73 (H-1), 1.73 (H-12),
1.66 (H-2), 1.62 (H-2), 1.58 (H-19a), 1.54 (H-6), 1.51 (H-11), 1.48
(H-15), 1.47 (H-7), 1.44 (H-7), 1.41 (H-19), 1.40 (H-6), 1.31 (H-9),
Compound 20. Ester 19 (103 mg, 0.194 mmol) was dissolved in
methanol (5 mL), and acetyl chloride (50 μL) was added. The
mixture was stirred at room temperature for 24 h. The reaction was
quenched with Et3N (0.3 mL), and the solvents were evaporated
under reduced pressure. Column chromatography of the residue
(hexane−ethyl acetate, 5:1 to 7:3) gave 20 (94 mg, 98%) as a foam.
[α]2D0 +56.1 (c, 0.3 chloroform). νmax (film): νmax (film): 3489, 2946,
2870, 1713, 1450, 1374, 1212, 1197, 1175, 1031, 756 cm−1. 1H NMR
(600 MHz, CDCl3) δ: 3.72 (s, 3 H, OCH3), 3.20 (dd, 1 H, J 4.8, 11.5
Hz, H-3), 2.89 (dd, 1 H, J 7.7, 12.5 Hz, H-3), 2.03−2.08 (m, 1 H),
1.80−1.86 (m, 1 H), 1.48−1.76 (m, 11 H), 1.34−1.45 (m, 6 H),
1.14−1.24 (m, 2 H), 1.05−1.09 (m, 1 H), 0.97 (s, 3 H, CH3), 0.96 (s,
3 H, CH3), 0.94 (s, 3 H, CH3), 0.88 (d, 3 H, J 6.7 Hz, H-19b), 0.86
(d, 3 H, J 6.5 Hz, H-19c), 0.84 (s, 3 H, CH3), 0.76 (s, 3 H, CH3),
0.69−0.71 (m, 1 H, H-5). 13C{1H} NMR (150 MHz, CDCl3) δ:
176.1 (CO), 80.9 (C-17), 78.9 (C-3), 55.4, 51.7, 51.2, 51.1, 50.2,
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Article
1.29 (H-11), 1.12 (s, 3 H, H-26), 1.10 (H-20), 1.09 (H-12), 1.04 (H-
1), 0.91 (s, 3 H, H-25), 0.90 (d, 3 H, J 6.7 Hz, H-19b), 0.85 (d, 3 H, J
6.3 Hz, H-19c), 0.86 (s, 3 H, H-23), 0.85 (s, 3 H, H-24), 0.84 (s, 3 H,
H-27), 0.81 (H-5). 13C{1H} NMR (150 MHz, CDCl3) δ: 215.7 (C-
17), 170.9 (CO), 169.9 (CO), 80.7 (C-3), 75.4 (C-28), 55.4 (C-
5), 54.4 (C-18), 50.7 (C-9), 49.9 (C-19), 49.0 (C-16), 47.5 (C-13),
41.0 (C-8), 39.7 (C-14), 38.5 (C-1), 37.7 (C-4), 37.1 (C-10), 34.1
(C-7), 33.8 (C-20), 29.9 (C-15), 29.8 (C-12), 27.9 (C-23), 27.7 (C-
22), 25.5 (C-21), 23.6 (C-2), 21.3 (CH3), 21.2 (CH3), 21.2 (C-11),
20.7 (C-29), 19.7 (C-30), 18.0 (C-6), 16.6 (C-25), 16.5 (C-24), 16.0
(C-26), 15.7 (C-27). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C34H54O5Na 565.3869; found 565.3856.
Authors
́
́
Jarosław Jazwinski − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; orcid.org/
0000-0003-2346-5815
Piotr Cmoch − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; orcid.org/
0000-0002-8413-9290
Roman Luboradzki − Institute of Physical Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; orcid.org/
0000-0001-8910-230X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00697
Data for 24. mp 279−282 °C; [α]2D0 +44.2 (c 0.2, chloroform);
νmax (film): 2948, 2871, 1736, 1699, 1466, 1448, 1369, 1246, 1208,
1027, 982, 757 cm−1. 1H NMR (600 MHz, CDCl3) δ: 4.80 (ddd, 1 H,
J 2.8, 2.8, and 5.7 Hz, H-22), 4.47 (dd, 1 H, J 5.0 and 11.5 Hz, H-3),
2.68−2.71 (m, 1 H, H-16), 2.08 (H-18), 2.06 (s, 3 H, COCH3), 2.05
(H-21), 2.04 (s, 3 H, COCH3), 2.00 (H-13), 1.88 (H-21), 1.86 (H-
15), 1.73 (H-15), 1.72 (H-1), 1.72 (H-12), 1.69 (H-20), 1.65 (H-2),
1.65 (H-19a), 1.61 (H-2), 1.56 (H-20), 1.53 (H-6), 1.51 (H-11), 1.43
(H-7), 1.41 (H-7), 1.37 (H-6), 1.28 (H-9), 1.28 (H-11), 1.25 (H-19),
1.10 (H-12), 1.07 (H-1), 1.05 (s, 3 H, H-26), 0.95 (d, 3 H, J 6.7 Hz,
H-19b), 0.90 (s, 3 H, H-25), 0.88 (d, 3 H, J 6.8 Hz, H-19c), 0.86 (s, 3
H, H-27), 0.85 (s, 3 H, H-23), 0.84 (s, 3 H, H-24), 0.80 (H-5).
13C{1H} NMR (150 MHz, CDCl3) δ: 215.0 (C-17), 170.9 (CO),
170.5 (CO), 80.7 (C-3), 73.5 (C-28), 55.4 (C-5), 55.4 (C-18),
50.7 (C-9), 50.2 (C-16), 47.6 (C-19), 46.1 (C-13), 40.8 (C-8), 39.7
(C-14), 38.5 (C-1), 37.8 (C-4), 37.1 (C-10), 35.0 (C-15), 34.2 (C-7),
32.2 (H-20), 29.6 (C-12), 27.9 (C-23), 26.3 (C-22), 23.6 (C-2), 23.2
(C-21), 21.4 (CH3), 21.3 (CH3), 21.2 (C-30), 21.1 (C-11), 20.2 (C-
29), 18.0 (C-6), 16.5 (C-25), 16.5 (C-24), 16.0 (C-26), 15.7 (C-27).
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C34H54O5Na 565.3869;
found 565.3867.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Science
Centre, Poland (grant No. 2016/21/B/ST5/02141).
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* Supporting Information
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CCDC 2031169, 2031957, and 2055466 contain the
supplementary crystallographic data for this paper. These
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Kinga Kuczynska − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; orcid.org/
0000-0002-7526-177X; Email: kinga.kuczynska@
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Zbigniew Pakulski − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; orcid.org/
0000-0002-8085-0050; Email: zbigniew.pakulski@
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