Synthesis of novel macrocyclic derivatives with a sucrose scaffold by the RCM approach

Article abstract of DOI:10.1016/j.tet.2015.10.046

1′2,3,3′4,4′-Hexa-O-benzylsucrose was esterified at both terminal positions with an unsaturated acid derived from d-glucose. Cyclization of the resulting di-olefin under the RCM conditions afforded the corresponding 21-membered macrocyclic unsaturated di-

Full text of DOI:10.1016/j.tet.2015.10.046

Accepted Manuscript
Synthesis of novel macrocyclic derivatives with a sucrose scaffold by the RCM
approach
Katarzyna Łęczycka, Sławomir Jarosz
PII:
S0040-4020(15)30146-0
10.1016/j.tet.2015.10.046
TET 27218
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 July 2015
Revised Date: 2 October 2015
Accepted Date: 16 October 2015
Please cite this article as: Łęczycka K, Jarosz S, Synthesis of novel macrocyclic derivatives with a
sucrose scaffold by the RCM approach, Tetrahedron (2015), doi: 10.1016/j.tet.2015.10.046.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Synthesis of novel macrocyclic derivatives with a sucrose scaffold by the RCM approach
Katarzyna Łęczycka and Sławomir Jarosz*
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw, Poland
slawomir.jarosz@icho.edu.pl
Abstract
1’2,3,3’4,4’-Hexa-O-benzylsucrose was esterified at both terminal positions with an
unsaturated acid derived from D-glucose. Cyclization of the resulting di-olefin under the RCM
conditions afforded the corresponding 21-membered macrocyclic unsaturated di-ester. The
same sequence of reactions performed for 6,6’-diamino-6,6’-dideoxy-1’2,3,3’4,4’-hexa-O-
benzylsucrose gave a 21-membered macrocyclic unsaturated di-amide. The cyclization in
both cases was highly selective and provided a cyclic olefin with the E-geometry exclusively.
Dihydroxylation of the olefin provided only one diol with relative configuration is consistent
with the Kishi’s rule. The absolute configuration was determined by CD spectroscopy.
Keywords: sucrose, ring-closing metathesis, macrocycles, dihydroxylation
Introduction
Metal-catalyzed olefin metathesis is one of the most powerful tools for the creation of the
carbon-carbon bond in modern synthetic chemistry.1 This methodology allows the
preparation, often in large scale, of a variety of complex fine chemicals including natural
products. It has also found an application in materials chemistry and chemical biology.1b Most
of the catalysts applied in such transformations are commercially available and can be used
without special precautions.
The synthesis of macrocyclic compounds with a sucrose scaffold is one of the main research
areas in our laboratory.2 Our strategy is based on the connection of the terminal positions of
appropriately protected sucrose via a -X-CH2CH2-Y- unit (X and Y = O, NR). Representative
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examples of such compounds, some of which possess interesting complexing properties, are
shown in Figure 1. We have also started to explore more complex sucrose macrocycles which
contain the amide type units (Fig. 1),3 as it is known that macrocyclic di-lactams can
selectively complex chiral anions.4
Figure 1. Examples of sucrose-based crown- and aza-crown ether analogs and di-lactams.
In this paper we present the synthesis of a new type of sucrose macrocycle, in which the
terminal positions: C6 and C6’ are connected via a highly functionalized long carbon bridge
(1 in Fig. 2).
Figure 2. New type of sucrose macrocycles.
Results and Discussion
The synthesis of our target, schematically depicted as 1, can be initiated either from known
1',2,3,3',4,4'-hexa-O-benzylsucrose5 (2a) or 6,6’-dideoxy-6,6’-diamino-1',2,3,3',4,4'-hexa-O-
benzylsucrose (2b). It can be realized via two routes: 1) direct reaction of compounds 2 with
long-chain alditols (or their derivatives; route a, Scheme 1) or 2) a stepwise sequence
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involving conversion of 2 into di-olefin 3 by reaction with relatively short unsaturated
fragments, followed by cyclization under the RCM conditions (route b, Scheme 1).
Scheme 1. Synthetic plan towards a new type of sucrose macrocycles.
Although we have access to the selectively protected C12-alditol (e.g. 46) with the terminal
positions unprotected, this route is not convenient, since only the C2-symmetrical alditols can
react in a selective manner. We have decided, therefore, to carry out the synthesis following
route b which should be more convenient and simpler, and may allow the preparation of
different derivatives just by simple changing the olefins attached to the glucose and/or
fructose ‘end’ of the sucrose starting material.
Planning the synthesis, we required a good method for the efficient preparation of both
starting materials: diol 2a and di-amine 2b. Diol 2a has been usually prepared in our
laboratory by deprotection of di-tritylated derivative 5 (route a in Scheme 2); however, this
procedure is challenging, since the glycosidic bond in sucrose is very labile in acidic media
and the yield of the diol is only moderate.5
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Scheme 2. Synthesis of hexa-O-benzylsucrose and hexa-O-benzyl-6,6'-diaminosucrose.
An alternative route to 2a can be realized from known7 di-chlorosucrose 5 (route b); it is,
however, rather capricious, since benzylation of 5, realized in strongly basic media, is often
accompanied by elimination of HCl and – moreover – regeneration of the hydroxyl functions
at the C6 and C6’ positions may be also demanding.8
We now report an alternative preparation of 2a, by selective removal of the trityl protecting
groups in 7 using a heterogeneous, silica-supported sodium hydrogen sulfate (NaHSO4/SiO2)
catalyst.9 The yield of 2a was higher (60% vs 52%) than in our original procedure (acetic acid
in toluene, 2 h, reflux)5 and the process is much easier to control (see Experimental). Di-
amine 2b was prepared by reduction of known10 azide 6 with LiAlH4 (see Scheme 2 and
Experimental).
We first decided to prepare the “symmetrical” derivative of type 3, i.e. to place the same
unsaturated unit at the C6 (glucose) and C6’ (fructose) terminal positions of our sucrose
building block.
The required olefinic unit was prepared by a reductive dehalogenation (commonly known as
the Vasella reaction11) of iodosugar 8 which was prepared by the standard methodology from
methyl α-D
-glucopyranoside (Scheme 3).12
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Scheme 3. Preparation of the olefinic unit 8.
The esterification of unsaturated acid 9 with diol 2a, under the conditions introduced by
Steglich,13 afforded di-ester 3a in 83% yield. The analogous reaction of 9 with di-amine 2b
gave di-amide 3b also in good yield 75% (see Scheme 4).
Scheme 4. Preparation of unsaturated sucrose di-ester 3a and di-amide 3b and their
cyclization under RCM conditions.
Ring-closing metathesis macrocyclisation can be very demanding,14 especially for highly
oxygenated long-chain di-olefins.6 The control of stereochemistry of the resulting olefin is
also problematic. A variety of factors can determine the stereochemical outcome and general
strategies leading to either Z- or E-configured products remain a significant challenge.15 Our
primary efforts were focused, therefore, on the construction of the desired macrocyclic
skeleton rather than the geometry of the newly created double bond.
We initiated our studies by investigating the cyclization of di-ester 3a. The Grubbs’ catalysts
(either I or II generation) were ineffective. We therefore tested other commercially available
catalysts (A-G; see Fig. 3) in the RCM reaction leading to 10a.
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Figure 3. Catalysts used in the RCM reaction.
The results of the optimization of this cyclization process are summarized in Table 1. On the
basis of our results, the Hoveyda-Grubbs' II catalyst (G) was chosen as the best one. It is
characterized by low sensitivity to air and moisture, as well as the tolerance to a variety of
common organic functional groups.16
Table 1 Optimization of the RCM reaction (c= 6 x 10-3 mol L-1) of 3a and 3b.
entry
catalyst
solvent
time (h)
temp.
MW
Isolated yield (%)
diester (10a) diamide (10b)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
24
24
15
10
10
10
10
10
48
48
46
49
8
rt.
-
-
-
-
-
-
-
36
-
50
43
60
74
83
83
84
-
-
-
-
-
-
-
15
-
45
40
50
69
79
76
80
A
A
B
40 °C
50 °C
80 °C
60 °C
70 °C
70 °C
70 °C
60 °C
100 °C
70 °C
95 °C
60 °C
70 °C
70 °C
70°C
B
C
D
E
F
G
G
G
G
G
G
G
G
toluene
perfluorobenzene
perfluorotoluene
toluene
toluene
perfluorobenzene
perfluorotoluene
+
+
+
+
8
8
8
In the RCM reaction of 3a with the Hoveyda-Grubbs’ II catalyst (toluene, 60 °C, 48 h; entry 9
Table 1) the corresponding cyclization product was not observed; the starting material
remained unchanged. At higher temperature (100 °C; entry 10 in Table 1) 50% of the olefin
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was formed. Cyclization performed in perfluorotoluene was more effective than in toluene
and provided 10a in 60% yield at 95 °C (entry 12 in Table 1). As discussed by Grela in his
recent paper “The use of fluorinated aromatic hydrocarbons (FAH) as solvents for olefin
metathesis reactions catalysed by standard commercially available ruthenium precatalysts
allows substantially higher yields of the desired products especially in the case of demanding
polyfunctional molecules”.17
The yields were even higher under microwave irradiation and reached 84% at 70 °C (entry 16
in Table 1). Moreover, because the reaction time under MW irradiation was significantly
shorter (8 h vs 48 h without MW), we required less catalyst (15 mol %), since significant
decomposition of the catalyst is observed only upon prolonged reaction times at high
temperatures. Cyclization of 3a or 3b under MW conditions should be performed below 90
°C, since significant decomposition of the starting material was noted above this temperature.
Reaction of diol 3a gave olefin 10a as the single E-isomer; the configuration was proven by
1
the H NMR spectra in which a large coupling constant between the olefinic protons was
observed (J = 15.6; see Scheme 4). The same optimization of the reaction conditions was
applied to the cyclization of di-amide 3b (see Table 1) and we were able to obtain di-amide
10b in 80% yield, again as a single E-isomer (J = 16.0 Hz; Scheme 4).
To accomplish the synthesis of our target, the macrocyclic derivatives 10a and 10b were
subjected to syn-dihydroxylation according to the standard procedure [OsO4 (cat.), NMO,
THF-tert.-BuOH-H2O].18 Reaction of the olefin 10a under these conditions did not provide
the expected diol(s); only a product of hydrolysis i.e. sucrose diol 2a, was isolated from the
post-reaction mixture. This may result from the high sensitivity of the ester linkage to base,
even as mild as N-methylmorpholine, which is liberated during the oxidation process.
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Dihydroxylation of the double bond in di-amide 10b was more successful; we isolated only
one diol to which structure 11 was assigned. This assignment can be predicted by Kishi’s rule,
according to which the attack of osmium tetraoxide takes place from the side opposite the
hydroxyl (alkoxyl) function(s) in the close vicinity of the double bond.19 In the case of 10b,
both methoxyl groups flanking the double bond act in the same direction; the highly selective
formation of diol 11 can, therefore, be expected (Scheme 5).
Scheme 5. Complelety diastereoselective syn-dihydroxylation of the double bond in 10b.
Final proof of the structure of this diol was provided by circular dichroism spectroscopy (CD).
It is well established that CD spectroscopy using the in situ dimolybdenum methodology,
provides hard proof of the absolute configuration of the optically pure vic-diols with the
relative threo-configuration.20 Recently, based on this method, we were able to propose
structure 13 to the oxidation product of olefin 12 (Figure 4).21
Figure 4. Assignment of the absolute configuration of diol 13.
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A positive Cotton effect was observed in the CD spectrum of the complex of diol 11 with
Mo2(OAc)4 (Figure 5) which is the same, as observed for diol 13; thus the arrangement of
both hydroxyl groups in 11 is the same as in 13 (see Figure 6).
Figure 5. CD spectrum of in situ-formed chiral complex of 11 with
dimolybdenum tetraacetate recorded in DMSO.
HO
OH
HO
HO
OH
OH
OH
HO
11
13
Figure 6. The arrangement of the diol grouping in 1321 and diol 11.
CONCLUSION
The synthesis of macrocyclic derivatives with a sucrose scaffold having the terminal positions
connected with a long polyhydroxylated carbon bridge is presented. The strategy of the
preparation of such derivatives was realized by placing the relatively short unsaturated unit
via an ester or amide linkage at both sucrose ‘ends’ (C6 and C6’) and cyclization of such
precursors by the RCM approach. This process gave the single E-isomers; conducting the
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cyclization under the microwave irradiation the cyclic olefins in high yields. The resulting
olefin derived from a di-amide was highly selectively syn-dihydroxylated providing the diol,
configuration of which was consistent with Kishi’s rule. Its absolute configuration was
assigned by CD spectroscopy.
The methodology presented in this paper may open a convenient route to a new class of
sucrose macrocycles in which the terminal positions (C6 and C6’) are connected with a long
polyhydroxylated carbon bridge.
Experimental
General methods
All reported NMR spectra were recorded with a Varian AM-600 (600 MHz 1H, 150 MHz 13C)
1
or with a Varian AM-400 (400 MHz H, 100 MHz 13C) for solutions in CDCl3 at room
1
temperature. Chemical shifts (
residual chloroform (
δ
) are reported in ppm relative to TMS (
δ
0.00) for H and
δ
77.0) for 13C. All significant resonances (carbon skeleton) were
assigned by COSY (1H-1H), HSQC (1H-13C) and HMBC (1H-13C) correlations. IR spectra
(CH2Cl2 film or KBr disc) were recorded with a JASCO FT/IR 6200. Mass spectra were
recorded with a ESI/MS Mariner (PetSeptive Biosystem) mass spectrometer. Optical rotations
were measured with a Jasco P 2000 apparatus in CHCl3 using sodium light (c = 0.3) at room
temperature. Elemental analyses were obtained with a Perkin–Elmer 2400 CHN analyzer. The
ECD spectra were acquired at room temperature in DMSO (for UV-spectroscopy, Fluka) on a
Jasco J-715 spectropolarimeter. Microwave synthesizer: Discover SP. Reagents were
purchased from Sigma–Aldrich, Alfa Aesar, or ABCR, and used without further purification.
Dry solvents were purchased from Sigma–Aldrich and used as obtained. The solvents were
degassed by bubbling with argon for 10 min. Organic solutions were dried over anhydrous
MgSO4 and concentrated under reduced pressure. Flash chromatography was performed on
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Grace Resolv or Grace Reveleris cartridges, using a Grace Reveleris X2 system (UV and
ELSD detection). Analytical and preparative TLC were performed on Silica Gel 60 F254
(Merck).
Preparation of 2(R),3(S),4(R)-2,3,4-trimethoxy-5-ene-hexanoic acid (9). To a solution of
iodosugar 712 (500 mg, 1.44 mmol) in a THF-water mixture (9:1 v/v; 15 mL) activated zinc
dust* (10 equiv.) was added, and the reaction mixture was stirred under reflux until all of the
starting material disappeared (~1 h, TLC monitoring in: hexane-EtOAc, 2:1). The mixture
was filtered through a Celite pad to remove solid inorganic material and the filtrate was
concentrated under reduced pressure. The residue was dissolved in acetone (15 mL) to which
Jones’ reagent (1.5 mL of a 1.25 M solution) was added, the mixture was stirred at rt. for 2 h,
filtered, concentrated, and partitioned between EtOAc (20 mL) and brine (10 mL). The
organic layer was separated, washed with water (10 mL), dried, and the crude acid 9 (250 mg,
85% yield, colorless oil) was used in the next step without further purification. 1H NMR (400
MHz)
δ 5.77 (ddd, J = 16.4, 11.2, 8.0 Hz, 1H), 5.39 – 5.31 (m, 2H), 3.92 (d, J = 3.3 Hz, 1H),
3.88 (dd, J = 7.5, 6.9 Hz, 1H), 3.59 (dd, J = 6.4, 3.3 Hz, 1H) 3.53 (s, 3H), 3.45 (s, 3H), 3.32
(s, 3H); 13C NMR (100 MHz)
δ
174.83, 134.78, 119.98, 83.91, 83.66, 80.28, 61.19, 59.44,
Na]+ 227.0895; found: 227.0900 [M+Na]+.
57.04. ESI-MS: m/z Calcd for C9H16O5 [M
+
Improved procedure for the preparation of 1’,2,3,3’,4,4’-hexa-O-benzylsucrose (2a).
Trityl ether 75 (1g, 0.73 mmol) was dissolved in a CH2Cl2-MeOH mixture (10:1 v/v; 11 mL)
and the solution was stirred at room temperature for 5 min. NaHSO4 (1.5 g) embedded on
silica (1.5 g) was added and the mixture was stirred at rt. until TLC (hexane–AcOEt, 9:1)
*Zinc activation: Zinc dust was stirred in a 1 M aqueous HCl soln. (0.5 mL/1.0 mmol of zinc) for 1 min, then
filtered, and used directly in the reaction.
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indicated disappearance of the starting material (ca 20 h). Then it was filtered and the residue
was purified by flash chromatography (hexane–AcOEt, 9:1) to afford diol 2a (colorless oil;
385 mg, 60 %) identical in all respect with the material prepared independently.5
Preparation of 6,6’-diamino-6,6’-dideoxy-1’,2,3,3’,4,4’-hexa-O-benzylsucrose (2b). To a
cooled (0 °C) and stirred solution of azide 610 (4.66 g, 5 mmol) in dry THF (70 mL), LiAlH4
(0.45 g, 12 mmol) was added in small portions over 5 min. The mixture was warmed to room
temperature and stirring was continued for 2 h. After cooling in an ice bath, the reaction was
quenched by the addition of sat. aq. Na2SO4 and Celite. It was then filtered through a Celite
pad, the layers were separated, and the aqueous phase extracted with EtOAc (3 x 30 mL). The
combined organic solutions were washed with brine (20 mL), dried, and concentrated under
reduced pressure to afford di-amine 2b (3.78 g, 86 %) as a colorless oil. [
(400 MHz) 7.36 – 7.19 (m, 30H), 5.57 (d, J = 3.6 Hz, 1H), 4.88 (dd, J = 15.0, 11.0 Hz, 2H),
α
]D = +45; 1H NMR
δ
4.80 – 4.36 (m, 9H), 4.14 – 3.83 (m, 4H), 3.78 – 3.65 (m, 3H), 3.56 – 3.30 (m, 3H), 3.02 –
2.76 (m, 2H), 2.67 (dd, J = 13.6, 5.6 Hz, 2H); 13C NMR (100 MHz)
δ
138.79, 138.31, 138.27,
138.25, 138.07, 137.82, 128.45 - 127.54, 104.27, 90.33, 84.15, 82.00, 81.84, 80.10, 78.34,
75.48, 74.80, 73.46, 72.79, 72.74, 72.44, 72.07, 71.12, 62.62, 44.71, 42.6; IR (film)
3030, 2918, 2867, 1584, 1454, 1089, 1072, 1028, 736, 698 cm-1; ESI-MS: m/z Calcd for
Na]+ 903.4197; found: 903.4156 [M+Na]+.
νmax 3375,
C54H60N2O9 [M
+
Synthesis of di-ester 3a. To a stirred solution of acid 9 (0.81g, 3.97 mmol) in dry CH2Cl2 (6
mL), diol 2a (0.87 g, 0.99 mmol) was added followed by DCC (4.95 mL of 1 M solution in
CH2Cl2; 4.95 mmol) and DMAP (60 mg, 0.50 mmol). The mixture was stirred for 1 h at room
temperature, filtered, and the filter cake was washed with dry CH2Cl2 (10 mL). The filtrates
were combined, concentrated under reduced pressure and the residue was purified by column
chromatography (hexane–EtOAc, 4:1) to afford 3a (1.03 g, 83%) as colorless oil. [
α]D = +33;
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1H NMR (600 MHz)
δ
7.36 – 7.19 (m, 30H), 5.75 – 5.66 (m, 2H), 5.62 (d, J = 3.5 Hz, 1H),
5.36 – 5.27 (m, 4H), 4.93 (d, J = 10.9 Hz, 1H), 4.87 (d, J = 10.9 Hz, 1H), 4.90 – 4.74 (m, 3H),
4.77 (d, J = 10.9 Hz, 1H), 4.68 – 4.47 (m, 7H), 4.47 – 4.37 (m, 3H), 4.32 (dd, J = 11.7, 3.6
Hz, 1H), 4.24 (s, 2H), 4.19 – 4.11 (m, 2H), 4.10 – 3.93 (m, 2H), 3.86 – 3.75 (m, 3H), 3.69 (d,
J = 11.0 Hz, 2H), 3.57 – 3.45 (m, 3H), 3.45 (s, 3H), 3.42 (s, 3H), 3.35 (s, 3H), 3.29 (s, 3H),
3.27 (s, 6H); 13C NMR (150 MHz)
δ 170.45, 170.22, 138.65, 138.14, 138.10, 137.85, 137.76,
137.70, 134.84, 134.83, 128.40 - 127.56, 119.36, 119.23, 105.06, 90.00, 83.97, 83.90, 83.87,
83.63 (double intensity), 83.61, 82.55, 81.73, 80.42, 80.35, 79.85, 78.50, 75.59, 74.93, 73.40,
73.00, 72.64, 72.53, 70.92, 69.06, 66.06, 63.00, 60.84, 60.79, 58.96, 58.81, 56.83, 56.81; IR
(film) νmax 2928, 1758, 1736, 1454, 1094, 738, 699 cm-1; ESI-MS: calcd for C72H86O19
[M+Na]+ 1277.5661; found: 1277.5643 [M+Na]+; anal. calcd for C72H86O19: C, 68.88; H,
6.90; found: C, 68.74; H, 6.83.
Synthesis of di-amide 3b. To a stirred solution of acid 9 (0.69 g, 3.38 mmol) in dry CH2Cl2
(7.2 mL), di-amine 2b (1 g, 1.13 mmol) was added followed by DCC (5.65 mL of 1 M
solution in CH2Cl2; 5.65 mmol) and DMAP (69 mg, 0.56 mmol). The mixture was stirred for
1 h at room temperature, filtered, and the filter cake was washed with dry CH2Cl2 (10 mL).
The filtrates were combined, concentrated under reduced pressure and the residue was
purified by column chromatography (hexane–EtOAc, 1:1) to afford 3b (1.06 g, 75%) as
1
colorless oil. [
α
]D = +31; H NMR (600 MHz)
δ
7.42 – 7.16 (m, 30H), 7.04 (dd, J = 7.5, 4.3
Hz, 1H), 6.86 (dd, J = 9.5, 2.2 Hz, 1H), 5.81 – 5.66 (m, 2H), 5.56 (d, J = 3.4 Hz, 1H), 5.38 –
5.25 (m, 3H), 4.94 – 4.86 (m, 2H), 4.80 – 4.75 (m, 2H), 4.74 – 4.65 (m, 2H), 4.66 – 4.56 (m,
3H), 4.56 – 4.44 (m, 4H), 4.38 (t, J = 8.8 Hz, 3H), 4.26 – 4.16 (m, 2H), 4.13 – 3.81 (m, 6H),
3.83 – 3.72 (m, 3H), 3.72 – 3.63 (m, 3H), 3.56 (s, 3H), 3.54 – 3.45 (m, 2H), 3.39 (s, 3H), 3.38
(s, 3H), 3.31 (s, 3H), 3.29 (s, 3H), 3.26 (s, 3H); 13C NMR (150 MHz)
δ 170.87, 170.71,
139.02, 138.53, 138.17, 138.01, 137.76, 137.75, 135.07, 135.02, 128.51 - 127.16, 119.60,
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119.42, 105.30, 90.68, 84.54, 84.26, 83.86, 83.69, 83.65, 83.26, 82.47, 82.12, 81.68, 79.90,
79.80, 77.58, 75.08, 75.07, 73.40, 72.93, 72.75, 72.28, 70.83, 69.91, 61.26, 61.18, 59.59,
59.21, 56.82, 56.62, 42.63, 38.34; IR (film) ν
max 3425, 2932, 1676, 1526, 1092, 737, 699 cm-1;
ESI-MS: calcd for C72H88N2O17 [M+Na]+ 1275.5981; found: 1275.5973 [M+Na]+.
General procedure for RCM reaction. To a solution of the corresponding diene (3a or 3b;
0.02 mmol) in degassed, anhydrous solvent (3.3 mL which makes the concentration ca. 6 x
10-3 mol L-1), the catalyst (A-G; 10 mol %) was added, and the mixture was stirred and
heated. The progress of the reaction was monitored by TLC (hexane–AcOEt, 1:1 for 3a or
hexane–AcOEt, 1:3 for 3b); the precise conditions of the process are shown in Table 1. For
prolonged reaction times additional portions of the catalyst were required.
General procedure for the RCM reaction induced with microwaves. Experiments were
carried out in 20 mL closed microwave glass process vials. A solution of the corresponding
diene 3a or 3b (25 mg; 0.02 mmol) and Hoveyda-Grubbs-II catalyst (1.3 mg, 0.002 mmol, 10
mol %) in toluene (3.3 mL; c = 6 x 10-3 mol L-1 degassed, anhydrous) was stirred and
irradiated for 5 h at 70°C. Another portion of the catalyst (0.6 mg, 0.001 mmol, 5 mol %) was
added and the reaction was continued for another 3 h.
Olefin 10a. This compound was obtained from 3a and purified by preparative TLC (benzene-
1
Et2O, 1:3) to afford 10a (20.5 mg, 84%) as a white amorphous foam. [
(600 MHz)
α
]D = +68; H NMR
δ
7.53 – 7.08 (m, 30H), 6.03 (d, J = 3.6 Hz, 1H), 5.87 (dd, J = 15.6, 5.8 Hz, 1H),
5.61 (dd, J = 15.4, 6.2 Hz, 1H), 4.93 (d, J = 10.9 Hz, 1H), 4.82 (d, J = 10.5 Hz, 1H), 4.74 (t, J
= 10.8 Hz, 2H), 4.67 – 4.42 (m, 4H), 4.34 – 4.23 (m, 3H), 4.19 – 4.01 (m, 3H), 3.97 – 3.73
(m, 7H), 3.73 – 3.39 (m, 10H), 3.53 (s, 3H), 3.51 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 3.30 (s,
3H), 3.24 (s, 3H); 13C NMR (150 MHz)
δ
170.55, 169.68, 138.85, 138.36, 138.04, 137.73,
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ACCEPTED MANUSCRIPT
137.67, 137.24, 129.82, 129.71, 128.52 - 127.33, 103.96, 88.06, 83.06, 82.89, 82.36 (double
intensity), 81.96, 81.23, 81.22, 80.62, 80.43, 78.98, 77.21, 76.49, 75.58, 75.08, 73.72, 73.53,
73.07, 72.94, 71.94, 69.36, 62.90, 62.58, 60.90, 60.73, 58.95, 58.50, 57.47, 57.36; IR (KBr)
νmax 3088, 3063, 3031, 1744, 1093 cm-1; ESI-MS: calcd for C70H82O19 [M+Na]+ 1249.5348;
found: 1249.5360 [M+Na]+; anal. calcd for C70H82O19 ·H2O: C, 67.51; H, 6.80; found: C,
67.96; H, 6.87.
Olefin 10b. This compound was obtained from 3b and purified by preparative TLC (acetone-
CH2Cl2, 1:5) to afford 10b (19.7 mg, 80%) as a colorless oil; [
α
]D = +70; 1H NMR (600 MHz)
δ
7.36 – 7.18 (m, 30H), 7.16 (s, 1H), 6.64 (s, 1H), 5.60 – 5.57 (m, 2H), 5.52 (d, J = 3.2 Hz,
1H), 4.97 – 4.33 (m, 17H), 4.21 – 3.44 (m, 14H). 3.48 (s, 3H), 3.42 (s, 3H), 3.35 (s, 3H), 3.34
(s, 3H), 3.33 (s, 3H), 3.24 (s, 3H); 13C NMR (150 MHz)
δ
170.68, 170.62, 138.61, 138.59,
138.14, 137.90, 137.89, 137.86, 131.60, 131.37, 128.38 - 127.51, 105.01, 90.29, 83.71, 83.04,
82.27, 81.77, 81.57, 81.38, 81.13, 81.01, 79.81, 79.51, 79.22, 79.21, 75.26, 74.93, 73.37,
72.88, 72.87, 72.75, 72.15, 70.27, 60.08, 60.04, 58.85, 58.24, 56.96, 56.94, 40.93, 39.77; IR
(film) ν
max 3418, 3375, 1680, 1524, 1092, 699 cm-1; ESI-MS: calcd for C70H84N2O17 [M+Na]+
1247.5668; found: 1247.5647 [M+Na]+; anal. calcd for C70H84N2O17 ·H2O: C, 67.62; H, 6.97;
N, 2.25; found: C, 67.26; H, 6.96; N, 2.28.
syn-Dihydroxylation of cyclic olefin 10b with OsO4. To a solution of compound 10b (55
mg, 0.045 mmol) in THF-tert.-BuOH-H2O (1 mL, 0.1 mL, 0.02 mL), NMO (6.3 mg, 0.054
mmol) was added followed by OsO4 (0.1 mL of a ~ 2.5% solution in tert.-butyl alcohol) and
the mixture was stirred at rt. until TLC indicated the disappearance of the starting material
and formation of a new, more polar product (TLC monitoring in hexane–AcOEt, 1:4). Then
MeOH (1 mL) and sat. aq. NaHSO3 (0.5 mL) were added and the mixture was stirred for 15
min at rt. and then filtered through Celite. The layers were separated, and the aqueous phase
15

ACCEPTED MANUSCRIPT
extracted with EtOAc (3 x 5 mL). The combined organic solutions were washed with brine (3
mL), dried, concentrated under reduced pressure and the product was purified by preparative
TLC (CH2Cl2-MeOH, 10:1) to afford diol 11 (29 mg, 52%) as a white amorphous powder.
[α]D = +35; ESI-MS: calcd for C70H86N2O19 [M+
Na]+ 1281.5722; found: 1281.5736 [M+Na]+;
anal. calcd for C70H86N2O19·H2O: C, 65.81; H, 6.94; N, 2.19; found: C, 65.97; H, 7.03; N,
2.23.
Compound 11 was characterized as its diacetate:1H NMR (600 MHz)
δ 7.38 – 7.13 (m, 31H),
6.72 (s, 1H), 5.57 (dd, J = 5.2, 3.4 Hz, 1H), 5.47 (d, J = 3.7 Hz, 1H), 4.88 (d, J = 11.0 Hz,
1H), 4.84 (d, J = 10.7 Hz, 1H), 4.80 – 4.67 (m, 3H), 4.66 – 4.56 (m, 4H), 4.46 (dd, J = 11.9,
3.2 Hz, 3H), 4.39 (d, J = 12.0 Hz, 2H), 4.33 (d, J = 4.9 Hz, 1H), 4.24 (s, 1H), 4.20 – 4.14 (m,
2H), 4.05 – 3.93 (m, 2H), 3.88 (d, J = 6.7 Hz, 1H), 3.79 – 3.62 (m, 6H), 3.60 – 3.53 (m, 2H),
3.48 – 3.45 (m, 3H), 3.49 (s, 3H), 3.45 (s, 3H), 3.44 (s, 3H), 3.41 (s, 3H), 3.35 (s, 3H), 3.24 (s,
3H), 2.14 (s, 3H), 2.09 (s, 3H); 13C NMR (150 MHz)
δ 170.84, 170.11 (double intensity),
169.95, 138.52, 138.32, 138.19, 137.96, 137.88, 137.71, 128.50 - 127.45, 106.38, 89.98,
84.57, 83.34, 81.83, 81.72, 81.58, 81.56, 80.71, 79.81 (double intensity), 78.85, 75.60, 74.77,
73.34, 72.79, 72.76, 72.60, 72.14, 71.02, 69.22, 69.14, 69.13, 68.19, 60.82, 60.47 (double
intensity), 59.37, 59.09, 58.45, 43.01, 38.91, 21.07, 21.01.
syn-Dihydroxylation of olefin 10a. To a solution of 10a (63 mg, 0.051mmol) in THF-tert.-
BuOH-H2O (1 mL, 0.1 mL, 0.02 mL), NMO (7.2 mg, 0.061 mmol) was added followed by
OsO4 (0.1 mL of a ~ 2.5% solution in tert.-butyl alcohol) and the mixture was stirred at rt.
until TLC indicated the disappearance of the starting material (TLC monitoring in hexane–
AcOEt, 1:2). Then MeOH (1 mL) and sat. aq. NaHSO3 (0.5 mL) were added and the mixture
was stirred for 15 min at rt. and then filtered through Celite. The layers were separated and the
aqueous phase extracted with AcOEt (3 x 5 mL). The combined organic solutions were
16

ACCEPTED MANUSCRIPT
washed with brine (3 mL), dried, concentrated under reduced pressure and the product was
purified by preparative TLC (CH2Cl2-MeOH,10:1); only the diol 2a (resulted from hydrolysis
of the macrocycle) was isolated (35 mg, 78%).
Acknowledgement
The support. from the Grant of National Science Centre UMO-2012/05/B/ST5/00377 is
acknowledged.
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