An approach to highly oxygenated monocyclic derivatives with large rings

Article abstract of DOI:10.1016/j.tetasy.2013.03.009

Abstract Coupling of the d-glucose and d-xylose derivatives via a phosphonate methodology provided a C12 higher sugar enone, which was converted into the protected dodecitol with both terminal free OH groups. This compound was used as a starting material

Full text of DOI:10.1016/j.tetasy.2013.03.009

Tetrahedron: Asymmetry 24 (2013) 468–473
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An approach to highly oxygenated monocyclic derivatives with large rings
⇑
Anna Osuch-Kwiatkowska, Sławomir Jarosz
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 January 2013
Accepted 13 March 2013
Coupling of the D-glucose and D-xylose derivatives via a phosphonate methodology provided a C12 higher
sugar enone, which was converted into the protected dodecitol with both terminal free OH groups. This
compound was used as a starting material for the preparation of highly oxygenated macrocyclic
derivatives.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
OH
Sug1
OR
OR
O
PPh3
P
Highly functionalized macrocyclic derivatives with a large ring
are interesting synthetic targets. In general, they can be divided
into two classes: carbo- and heterocyclic. The synthesis of such
derivatives can be carried out by several routes. One of the most
common methods for the preparation of heterocyclic derivatives
is macrolactonization.1,2 Many natural macrocyclic compounds
contain double bond(s); this allows us to plan their synthesis based
on a Wittig type reaction, McMurry reaction,3 or other similar reac-
tions in which this double bond is created during the cyclization
step. A classical version for the preparation of such systems is
the intramolecular Horner–Wadsworth–Emmons (HWE) reaction,
which has been applied to the synthesis of 16-,4 17-,5 18-,6 28-,7
and 36-8 membered rings. In all cases, this reaction was highly
stereoselective and afforded macrocyclic olefins with an E-config-
uration across the double bond. In 2010, a method for the construc-
tion of macrocyclic olefins with a Z-geometry was proposed.9
Another route to the synthesis of unsaturated macrocyclic com-
pounds is the ring closing metathesis (RCM) reaction.1,10 The pio-
neering work of Fürstner was particularly important in the
preparation of such complex structures via RCM.11,12 The key-as-
pect of the construction of the new double bond is in the E/Z-selec-
tivity.13 It has been reported that the temperature and the solvent
have great influence on the selectivity of this process.11,14 The nat-
ure of the catalyst plays also a crucial role.15,16 The configuration of
the olefin is also dependent on the substituents of the compound
involved in the RCM process.17
or
Sug1
Sug1
+
3
2
1
Sug2-CHO
OH
OH
O
Sug1
Sug2
Sug1
Sug2
OH
4
OR
OR
???
activation of
terminal positions
then coupling
Sug'
Sug''
OR
6
Figure 1. Synthesis of higher sugar precursors by Wittig type methodology and
(possible) route to carbocycles.
The monosaccharide-derived phosphoranes 2 or phosphonates
3 upon reaction with sugar aldehydes provided the higher enones,
which were then converted into fully hydroxylated compounds
5.18 Proper functionalization of both terminal positions should
allow us to ‘close’ the molecule and obtain the polyhydroxylated
carbocylic derivative with a large ring. Herein we report a model
synthesis of such compounds.
2. Results and discussion
Recently we became interested in the synthesis of carbocyclic
polyhydroxylated derivatives with large rings. Higher carbon sug-
ars (HCS) seem to be convenient starting materials for the prepara-
tion of such targets. A general route to HCS is shown in Figure 1.
As a starting material for the model synthesis of polyhydroxy-
lated carbocyclic compounds with large rings, the known19 C12
alcohol 10 was chosen.
The target compound was obtained by the stereoselective trans-
formation of the higher sugar enone 9, previously prepared by the
phosphorane methodology20 or (more conveniently and in higher
yield) by coupling of phosphonate 721 with the corresponding alde-
hyde 822 under mild PTC conditions (Fig. 2).
⇑
Corresponding author. Tel.: +48 22 343 23 22; fax: +48 22 632 66 81.
E-mail address: slawomir.jarosz@icho.edu.pl (S. Jarosz).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.03.009

A. Osuch-Kwiatkowska, S. Jarosz / Tetrahedron: Asymmetry 24 (2013) 468–473
469
OBn
O
O
P
OBn
OBn OBn OBn
CHO
O
OBn
OMe
OMe
12
BnO
BnO
11
BnO
BnO
a
X
10
O
O
OBn OBn OBn
O
+
O
7
8
11 X = O
PTC
b
OMe
OMe
12 X = CH2
OBn
O
O
OBn
BnO
1. hydrolysis
2. steps
12
OBn OBn OBn OBn
O
O
1
BnO
BnO
9
11O
BnO
OH
OMe
OR
OBn OBn OBn
OBn OBn OBn OBn
OH
OBn OBn OBn OBn
BnO
13 R = H
BnO
BnO
11
14 R = Bn
OH
12
OBn
OBn OBn OBn
BnO
1
O
OBn OBn OBn
15
10
OMe
Figure 3. Synthetic strategies to polyhydroxylated di-olefin 15, 75%.
Figure 2. Synthesis of the key-starting material for the preparation of cyclic
polyhydroxylated compounds with large ring.
OBn OBn OBn OBn
BnO
Our synthetic strategy required the conversion of this derivative
into linear di-olefin 15 either stepwise or simultaneously (Fig. 3
route a or b respectively). The first route involves the elaboration
of an efficient method for the synthesis of mono-olefin 12 (by olef-
ination of the aldehyde 11), followed by further transformations of
the molecule. The most demanding step is the hydrolysis of the
glycosidic bond in 12.
a
OAc
O
OBn OBn OBn
BnO
16
OAc
b
10
13 (main)
+
17 (ratio: 65:15)
Oxidation of alcohol 10 was achieved almost quantitatively by
PCC; the Swern oxidation,23 commonly used in our laboratory for
the oxidation of such complex systems, was not effective. The reac-
tion of 11 with Ph3P@CH2 provided the corresponding olefin 12 in
only 35% yield. Replacement of this simplest phosphorane for other
reagents (e.g., Tebbe reagent24) was unsuccessful.
As expected, hydrolysis at the C-1 position (removal of methyl
group) in 12 caused a large problem. We have already reported
that the hydrolysis of the glycosidic bond in higher sugars can be
performed most conveniently under acetolysis conditions; how-
ever, when unsaturation is placed at the terminal position, such a
reaction was not effective.25 This was also the case here; that is,
compound 12 was completely resistant towards hydrolysis
(Ac2O/H2SO4) even after 24 h.
Scheme 1. Reagents: (a) Ac2O/AcOEt, cat. H2SO4; (b) NaBH4, THF/MeOH.
The first step involved the hydrolysis of the acetates with the
formation of the free sugar 18a, which is in equilibrium with the
open-chain derivative 18b. Reduction of the carbonyl group and at-
tack of the free C5–OH (or its anion) at the C3-position (with elim-
ination of BnOH) affords the oxetane 19. Next, opening of the 4-
membered ring with the C1–O(ꢂ) provided derivative 17, which
was finally converted into the di-acetate 17-Ac.
Compound 13 was transformed into diol 14 using the standard
sugar methodology: protection of the primary OH (at the C1 and
C12 positions) as trityl ethers to give 21 followed by benzylation
of the C5–OH to give 22 and deprotection (Scheme 2).
We therefore decided to synthesize di-olefin 15 via route b. Ace-
tolysis of compounds 10 afforded diacetate 16 as a mixture of
a
/b
Oxidation of both terminal hydroxyl groups was achieved with
PCC and provided the di-aldehyde 23 in good yield. Double olefin-
ation was carried out with Ph3P@CH2 and afforded the di-olefin 15
in excellent yield (Scheme 3).
anomers (in the ratio ꢀ4.5:1 as detected by integration of the ace-
1
tate signals in the H NMR spectrum) in good yield.
Treatment of 16 with LiAlH4 or DIBAL-H led only to the decom-
position of the starting material. However, reduction of 16 with a
large excess of sodium borohydride provided the desired diol 13
together with the side product 17 (Scheme 1; ratio 13:17 = 65:15).
The determination of the structure of 17 was not easy. The MS
spectrum indicated the elimination of one molecule of benzyl alco-
hol during the reduction stage; this suggests that the product has a
double bond or cyclic structure. Our first assumption is that it was
an olefin that was excluded, since 17 was resistant towards ozone.
Acetylation of crude 17 gave a product containing two acetate
groups: one primary and one secondary as assigned by the signals
at d: 3.93 (dd, H-12a), 4.11 (H-12b) and 5.85 (dd, H-3) ppm respec-
tively. Furthermore, we found (with help of 2D correlation: COSY,
HSQC, HMBC and DEPT experiments), characteristic signals at d:
3.80 (dd, H-1a) and 4.14 (H-1b) in the 1H NMR, and in the 13C
NMR spectra at d: 20.8 and 21.2 [2 ꢁ C(O)Me], 64.2 (C-12), 71.53
(C-3), 71.55 (C-1), 169.4 and 170.5 (2 ꢁ C@O). On the basis of these
data, structure of 17-Ac was proposed for this compound. Plausible
mechanism of its formation is shown in Figure 4.
Attempts to cyclize di-olefin 15 in the presence of Grubbs (I and
II generation; A and B in Figure 5), Hoveyda-Grubbs (II generation;
C in Figure 5) catalysts, as well as modified complex: D or E were
unsuccessful. After 24 h (in CH2Cl2 at rt or in toluene at 80 °C), no
product 24 was formed.
It is reported that conducting the ‘challenging’ RCM cases in
perfluorinated solvents can solve the problem of the low reactivity
of certain olefins.26 However, cyclization of di-olefin 15 in per-fluo-
robenzene was not effective either. The same failure was noted in
the McMurry cyclization of the dialdehyde 23 (Scheme 4).
We cannot explain why the RCM for 15 and McMurry for 23
cyclizations did not. One of the reasons may be the size of the tar-
get ring; because there are ten benzyl groups present in the mole-
cule, and the 12-membered ring could be too small to form easily.
We decided, therefore, to enlarge the size of the ring. Alcohol 14
was allylated and the resulting di-olefin 25 was subjected to the
RCM reaction (Scheme 5). In order to avoid the cross-metathesis,
this reaction was performed under high dilution conditions.

470
A. Osuch-Kwiatkowska, S. Jarosz / Tetrahedron: Asymmetry 24 (2013) 468–473
OBn
OBn OBn OBn OBn
BnO
R
5
3
3
2
BnO
BnO
5
OH
R
OH
BnO
OBn OBn
O
OBn
1
base
O
OH
18b
NaBH4
THF/MeOH
1. reduct.
2. - BnOH
18a
16
OBn OBn OBn OBn
OBn
RO
3
5
5
R
OR
12
3
OBn
1
O
OBn OBn
O
BnO
BnO
19
17 R = H 17-Ac R = Ac
-
O
C=O δ = 169.4 ppm, δ = 170.5 ppm
CH3C=O δ = 1.84 ppm (s), δ = 1.98 ppm (s)
H-3 δ = 5.85 ppm (dd)
Figure 4. The (proposed) mechanism for the formation of compound 17.
OBn
OBn OBn OBn OBn
OBn
OBn
R1O
1
5
OBn
OBn
OR1
12
OBn OR2 OBn
OBn OBn
OBn
OBn
BnO
1 = R2 = H
1 = Tr, R2 = H
1 = Tr, R2 = Bn
H
13
21
22
R
R
R
a
b
c
a
b
BnO
OBn
23
15
1 = H, R2 = Bn
OBn
24
14
R
Scheme 2. Reagents: (a) TrCl, py; (b) BnCl/Bu4NCl/50% NaOH; (c) p-TsOH/MeOH–
ether (78% overall).
Scheme 4. Reagents: (a) RCM (see: Section 4); (b) TiCl4/Zn, THF, reflux.
OBn OBn OBn OBn OBn
OBn OBn OBn OBn OBn
X
O
a
X
O
14
a
OBn OBn OBn OBn OBn
23 X = O 15 X = CH2
OBn OBn OBn OBn OBn
14
25
b
b
OBn
OBn
OBn
O
O
Scheme 3. Reagents: (a) PCC, CH2Cl2, 72%; (b) Ph3P@CH2, 75%.
OBn
OBn
O
BnO
OBn
BnO
BnO
BnO
c
BnO
BnO
BnO
BnO
OBn
OBn
N
Cl
N
N
N
Mes
Mes
Mes
Ph
Mes
Cy3P
Ru
OBn
OBn
Cl
Cl
Ru
O
Ru
O
OBn
Cl
Cl
Ph
PCy3
27
Cl
PCy3
OBn
26a/26b
B
A
C
Scheme 5. Reagents: (a) AllBr, toluene/50% NaOH/Bu4NCl, 80 °C, 80%; (b) RCM (see:
Table 1); (c) H2NNH2, O2, cat. AcOH, EtOH, 60 °C, 72–77%.
iPr
iPr
N
N
N
N
Cl
Mes
Cl
Mes
Ind
Table 1
Cl
The RCM reaction of di-allyl derivative 25
Ru
iPr
Cl
iPr
Ph
Ru
cat. (mol %)
Concn (10ꢂ3 M)
Temp
Time (h)
Yield 26a/26b (%)
PCy3
PCy3
A, 20 mol %
A, 20 mol %
A, 30 mol %
B, 20 mol %
4.5
0.7
0.7
0.7
rt
85 °C
rt
24
4.5
9
9/50
9/56
D
E
20/65
Figure 5. Catalysts used for RCM reaction.
rt
24
6/40a
a
16% of isomerized starting material was isolated.
We carried out several attempts; in all cases, two products 26a
and 26b were formed. The results are shown in Table 1. Cyclization
of 25 with Grubbs-I catalyst A at room temperature in toluene at
low concentrations (4.5 ꢁ 10ꢂ3 M) afforded two cyclic products
(as detected by MS) in 9% yield for 26a and 50% yield for 26b. After
24 h, complete conversion of the di-olefin and decomposition of
the catalyst was achieved.

A. Osuch-Kwiatkowska, S. Jarosz / Tetrahedron: Asymmetry 24 (2013) 468–473
471
The same results were obtained at a higher temperature (entry
4.1.1. Methyl 2,3,4,6,7,8,9,10,11-nona-O-benzyl-
L-threo-L-
2), although the time of the reaction was shortened significantly.
The reaction was more effective when 30 mol % of the catalyst
was used (entry 3). Changing the catalyst to B (Grubbs-II) resulted
in a decreased yield; significant isomerization of the starting mate-
rial was also observed.
Although isomeric olefins 26a and 26b could be easily sepa-
rated, we were unable to assign the geometry across the double
bond. Even the high resolution 1H NMR spectra (600 MHz) were
not clear enough; the signals (especially in the olefinic region at
d: 5.52–5.75 ppm) were broadened, which did not allow us to pre-
cisely assign the coupling constants.
manno- -gluco-dodeca-1,5-pyranoside 10
a-D
This compound was prepared according to the literature;19
½
a rDt
ꢃ
¼ þ14 (c 0.5, CHCl3); 1H NMR (600 MHz) d: 4.59 (d, J1,2 = 3.5,
H-1), 4.23 (d, H-5), 3.97 (t, H-3), 3.83 (dd, J3,4 = 9.1, J4,5 = 10.2,
H-4), 3.79 (t, H-10), 3.57 (m, H-12a i H-11), 3.45 (m, H-12b), 3.40
(dd, J2,3 = 9.6, H-2), 3.30 (s, OMe), 1.68 (br s, OH); 13C NMR
(150 MHz) d: 97.8 (C-1), 82.8 (C-3), 80.5 (C-10), 80.1 (C-2), 79.3
(C-11), 78.5 (C-4), 69.6 (C-5), 61.6 (C-12), 55.0 (OMe); HR-MS
(ESI) m/z: 1207.5558; calcd for C76H80O12 [M+Na+]: 1207.5542;
analysis: calcd for C76H80O12: C, 77.00; H, 6.80; found: C, 77.11;
H, 6.76.
This might be due to the presence of trace amounts of ruthe-
nium species in the product, which can cause significant broaden-
ing of the lines in the spectrum. However, using known methods
for oxidative termination of the RCM process27 (which should re-
move traces of the catalyst) did not improve the spectra. Moreover,
the spectrum of di-olefin 25 (recovered from post-reaction mix-
ture), which did contain trace amounts of the catalyst did not show
significant broadening of the lines.
A possible explanation for the phenomenon of the broad lines in
the NMR spectra may be connected with the large number of con-
formers of the macrocyclic skeleton (substituted with ten bulky
benzyloxy groups), which may be relatively stable. However, the
1H NMR spectrum recorded at a higher temperature (80 °C) in
DMSO-d6 did not improve the quality of the spectrum. Recording
at a low temperature (ꢂ40 °C in CDCl3 or ꢂ60 °C in CD2Cl2) was
also not helpful for obtaining a spectrum of good quality.
These cyclic compounds were therefore characterized by HRMS
and elemental analysis, as well as, their conversion into the satu-
rated product 27. Compound 26a or (separately) 26b upon treat-
ment with hydrazine in the presence of air afforded the same
compound 27.
4.1.2. Methyl 2,3,4,6,7,8,9,10,11-nona-O-benzyl-
-gluco-dodeca-1,5-pyranosid-12-ulose 11
This compound was prepared previously19 in lower yield and
was not characterized. Alcohol 10 (0.51 g, 0.43 mmol) was dis-
solved in methylene chloride to which PCC (1.4 g, 6.5 mmol) was
added and the mixture was stirred for 7 h. The excess oxidant
was filtered off and the filtrate was concentrated. The crude prod-
uct was purified by column chromatography (hexane/ethyl acetate,
8:1 to 6:1) to yield 11 in 0.49 g (95%). LR–MS (ESI) m/z: 1205.7;
calcd for C76H78O12 [M+Na+]: 1205.
L-threo-L-manno-
a-D
4.1.3. Methyl 2,3,4,6,7,8,9,10,11-nona-O-benzyl-12,13-dideoxy-
12,13-didehydro-L-threo-L-manno-a-D-gluco-tridec-1,5-pyrano-
side 12
To
a
cooled (ꢂ78 °C) suspension of Ph3PCH3I (0.182 g,
0.45 mmol) in dry THF (20 mL), BuLi (0.17 mL 2.5 M solution in
hexane, 0.43 mmol) was added and the mixture was stirred for
30 min. Next, aldehyde 11 (0.18 g, 0.15 mmol) in THF (4 mL) was
added dropwise over 5 min, and the stirring was prolonged for an-
other 30 min, after which the mixture was allowed to reach room
temperature. After 24 h, saturated ammonium chloride was added,
after which the mixture was stirred for 10 min and partitioned be-
tween water (10 mL) and ether (25 mL). The organic phase was
separated and the aqueous phase extracted with ether
(3 ꢁ 10 mL). The combined organic solutions were washed with
water (10 mL), dried and concentrated; column chromatography
(hexane/ethyl acetate, 99:1 to 8:1) of the crude product afforded
pure 12 (62 mg, 35%). 1H NMR (600 MHz) d: 5.72 (ddd,
The NMR spectra (1H and 13C), also in case of 27, were also un-
clear; most of the signals were broadened. However, in the 13C
NMR spectrum recorded in CD2Cl2 at ꢂ60 °C, two signals of the sec-
ondary carbons (CH2–) at d: 26.2 and 27.1 ppm were seen. More-
over, in the 1H NMR spectra the olefinic signals at d: 5.52–5.75
observed for unsaturated products 26a and 26b disappeared.
3. Conclusion
J11,12 = 7.4, J12,13 = 10.2, J12,13 = 17.5, H-12), 5.11 (m, H-13 i H-130),
0
4.59 (d, J1,2 = 3.6, H-1), 4.23 (d, H-5), 3.97 (t, H-3), 3.82 (m, H-4),
3.40 (dd, J2,3 = 9.7, H-2), 3.30 (s, OMe); 13C NMR (150 MHz) d:
135.5 (C-12), 118.7 (C-13), 97.8 (C-1), 82.8 (C-3), 80.1 (C-2), 78.5
(C-4), 69.7 (C-5), 55.0 (OMe); HR-MS (ESI) m/z: 1203.56059; calcd
for C77H80O11 [M+Na+]: 1203.55929.
The higher sugar dodecitol with ten O-benzyl groups at the
C2–C11 positions was converted into the C14-di-olefin, which
was completely resistant towards RCM reactions most likely due
to the steric hindrance created by ten benzyl units. Allylation of
this dodecitol provided another di-olefin, which did undergo
RCM cyclization. However, the cyclic products were very difficult
to characterize even using 600 NMR spectroscopy.
4.1.4. 1,12-Di-O-acetyl-2,3,4,6,7,8,9,10,11-nona-O-benzyl-
eo- -manno- -gluco-dodeca-1,5-pyranose 16
Methyl glycoside 10 (1.83 g, 1.54 mmol) was dissolved in ethyl
L-thr-
L
D
4. Experimental
4.1. General
acetate (12 mL) to which acetic anhydride (24 mL) and sulfuric
acid [4.3 mL of the solution: conc. H2SO4 (0.05 mL) in ethyl acetate
(100 mL)] were added. The mixture was then stirred at rt until
completion [3 d; TLC monitoring in hexane/ethyl acetate, 3:1; also
1H NMR (200 MHz)]. The mixture was then diluted with ether
(50 mL), washed with satd aq NaHCO3 (5 ꢁ 40 mL) and water
(40 ml), dried and concentrated. The crude product was purified
by column chromatography (hexane/ethyl acetate, 95:5 to 8:1) to
The NMR spectra were recorded with a Varian 600 MHz or Bru-
ker 500 MHz in CDCl3 at 25 °C unless otherwise stated. The struc-
tures were assigned, whenever necessary, with help of 2D
correlation experiments (COSY, HSQC and HMBC). Chemical shifts
(in most cases only diagnostic signals were shown) were reported
with reference to TMS. Optical rotations were measured with a Jas-
co P 1020 polarimeter (sodium light) in chloroform at room temp.
The MS spectra were recorded with a Mariner PerSeptive Biosys-
tems spectrometer. Thin layer chromatography was performed
on pre-coated plates (0.25 mm, silica gel 60 F254). Column chroma-
tography was carried out with silica gel (230–400 mesh).
yield 1.64 g (85%) of 16 (mixture of
1H NMR (600 MHz) d: 6.34 [d, J1,2 = 3.6, H-1(
J1,2 = 8.2, H-1(b)], 3.89 [t, H-3( )], 3.66 [t, H-3(b)], 3.46 [dd, H-
a/b anomers in the ratio 4.5:1).
a)], 5.63 [d,
a
2(
a
)], 3.42 [t, H-2(b)], 1.97 and 1.83 [2s, 2 ꢁ OAc(
a)], 1.96 and
1.82 [2s, 2 ꢁ OAc(b)]; 13C NMR (150 MHz) d: 170.6 and 169.5
[2 ꢁ C@O(
a
)], 169.6 and 168.9 [2 ꢁ C@O(b)], 94.2 [C-1(b)], 89.6
[C-1(
a
)], 85.3 [C-3(b)], 82.3 [C-3(a)], 81.2 [C-2(b)], 79.1 [C-2(a)],

472
A. Osuch-Kwiatkowska, S. Jarosz / Tetrahedron: Asymmetry 24 (2013) 468–473
64.3 [C-12(
21.0 and 20.8 [2 ꢁ OC(O)CH3(
a
)], 64.1 [C-12(b)], 21.1 and 20.7 [2 ꢁ OC(O)CH3(b)],
)]; HR-MS (ESI) m/z: 1277.55987;
calcd for C79H82O14 [M+Na+]: 1277.55968.
Crude 22 was dissolved in ether/methanol (v/v 1:1; 40 mL) to
a
which p-TsOHꢄH2O (3 g, 15 mmol) was added, and the mixture
was stirred and heated at reflux for 5 h. After cooling to rt, it was
partitioned between ethyl acetate (50 mL) and water (50 mL).
The organic phase was separated, and the aqueous phase extracted
with ethyl acetate (2 ꢁ 25 mL). The combined organic solutions
were washed with water (50 mL) and brine (50 mL), dried and con-
centrated and the product was isolated by column chromatogra-
phy (hexane/ethyl acetate, 7:1 to 4:1) to afford 14 (1.45 g, 78%
after three steps). HR-MS (ESI) m/z: 1285.5983; calcd for
4.1.5. 2,3,4,6,7,8,9,10,11-Nona-O-benzyl-
co-dodecitol 13
L-threo-L-manno-D-glu-
To a solution of compounds 16 (0.41 g, 0.33 mmol) in THF/
methanol (3:1 v/v, 40 mL) NaBH4 (3 g, 78 mmol) was added por-
tionwise and the mixture was stirred for 24 h (TLC monitoring in
hexane/ethyl acetate, 3:1). Next, the mixture was partitioned be-
tween ether (30 mL) and water (15 mL). The organic phase was
separated, and the aqueous phase extracted with ether
(2 ꢁ 15 mL). The combined organic solutions were washed with
water (10 mL), dried and concentrated and the residue was sub-
jected to column chromatography (hexane/ethyl acetate, 5:1 to
3:1) to give two products. Compound 13 (0.304 g, 78%) was iso-
lated as an oil; HR-MS (ESI) m/z: 1195.55420; calcd for C75H80O12
[M+Na+]: 1195.55781; analysis: calcd for C75H80O12: C, 76.77; H,
6.87; found: C, 76.84; H, 7.07. This compound was also character-
ized as a tri-acetate; 1H NMR (600 MHz) d: 5.82 (dd, J = 3.5, J = 7.2,
H-5), 1.85, 1.82, and 1.81 (3s, 3 ꢁ OAc); 13C NMR (150 MHz) d:
170.6, 170.5, and 169.5 (3 ꢁ C@O), 64.1 and 64.0 (C-1 and C-12);
HR-MS (ESI) m/z: 1321.59163; calcd for C81H86O15 [M+Na+]:
C
82H86O12 [M+Na+]: 1285.60115. Analysis: calcd for C82H86O12: C,
77.95; H, 6.86; found: C, 78.17; H, 6.46%; ½a Drt
ꢃ ¼ þ2:0 (c 0.5, CHCl3).
1
This diol was further characterized as a di-acetate 14-Ac. H NMR
(600 MHz): 1.79 and 1.78 (2s, 2 ꢁ OAc); 13C NMR (150 MHz) d:
170.6 and 170.5 (2 ꢁ C@O), 139.8–138.2 (10 ꢁ 4°Caromat.), 74.8–
71.6 (10 ꢁ CH2Ph), 64.3 and 64.1 (C-1 and C-12), 20.8 and 20.7
[2 ꢁ OC(O)CH3]; HR-MS (ESI) m/z: 1369.62598; calcd for
C
86H90O14 [M+Na+]: 1369.62228.
4.2.2. (2R,3S,4R,5R,6R,7S,8R,9R,10S,11R)-2,3,4,5,6,7,8,9,10,11-
Deca(benzyloxy)-dodecanedial 23
Diol 14 (0.41 g, 0.32 mmol) was dissolved in methylene chloride
(60 mL), and then PCC (2.6 g, 12 mmol) was added and the mixture
was stirred for 6 h at rt. The inorganic material was filtered off, the
filtrate was concentrated and the crude product was isolated by
column chromatography (hexane/ethyl acetate, 95:5 to 9:1) to af-
ford pure dialdehyde 23 (0.294 g, 72%) as an oil. 1H NMR
(600 MHz) d: 9.56–9.37 (2 ꢁ HC@O); 13C NMR (150 MHz) d:
201.6–201.3 (2 ꢁ HC@O), 139.2–127.2 (10 ꢁ 4°Caromat.), 75.1–72.0
(10 ꢁ CH2Ph). HR-MS (ESI) m/z: 1281.57168; calcd for C82H82O12
[M+Na+]: 1281.56985. Analysis: calcd for C82H82O12: C, 78.20; H,
1321.59163.
1-Deoxy-2,4,6,7,8,9,10,11-octa-O-benzyl-L-threo-L-
manno-a-D-allo-dodeca-1,5-pyranoside 17 (0.070 g, 20%); HR-MS
(ESI) m/z: 1087.50165; calcd for C68H72O11 [M+Na+]: 1087.49669;
Analysis: calcd for C68H72O11: C, 76.67; H, 6.81; found: C, 76.81;
H, 6.58.
½ ꢃ ¼ ꢂ28:0 (c 1.3, CHCl3).
a rDt
4.2. Determination of the structure of 17
6.56; found: C, 78.38; H, 6.62; ½a Drt
ꢃ ¼ þ20 (c 1.0, CHCl3).
Ozonolysis of this derivative under standard conditions was
unsuccessful, which excluded the presence of the double bond in
the molecule. Acetylation of this compound provided the acetate
17-Ac. 1H NMR (600 MHz) d: 5.85 (dd, J2,3 = 7.1, J3,4 = 3.6, H-3),
4.37 (dd, J4,5 = 7.1, H-4), 4.28 (dd, J = 3.2, J = 9.6, H-6), 4.14–4.07
(m, H-1a, H-12a, H-9, H-2), 3.93 (dd, J = 6.6, J = 11.8, H-12b), 3.80
(dd, J1b,2 = 4.3, J1a,1b = 12.2, H-1b), 3.76 (m, H-11), 3.63 (dd, J = 4.3,
J = 5.8, H-10), 1.99 and 1.84 (2s, 2 ꢁ OAc); 13C NMR (150 MHz) d:
170.5 and 169.4 (2 ꢁ C@O), 80.5 (C-5), 80.0 (C-6), 78.5 (C-10),
77.7 (C-2), 77.5 (C-11), 71.5 (C-1 and C-3), 64.2 (C-12), 21.2 and
20.8 (2 ꢁ OC(O)CH3). LR-MS (ESI) m/z: 1171.6; calcd for
4.2.3. (3S,4R,5S,6S,7S,8R,9S,10S,11R,12S)-3,4,5,6,7,8,9,10,11,12-
Deca(benzyloxy)-tetradeca-1,13-diene 15
This reaction was conducted under an argon atmosphere. To a
cooled (at ꢂ78 °C) suspension of Ph3PCH3I (0.407 g, 1 mmol) in
dry THF (12 mL), BuLi (0.38 mL of a 2.5 M solution in hexane,
0.95 mmol) was added and the mixture was stirred for 45 min.
Next, di-aldehyde 23 (0.126 g, 0.1 mmol) in THF (8 mL) was added
dropwise (during 15 min) and the mixture was allowed to reach rt.
Saturated ammonium chloride (10 mL) was added, stirring was
continued another 15 min, after which the mixture was partitioned
between ether (20 mL) and water (15 mL). The organic phase was
separated and the aqueous phase extracted with ether
(3 ꢁ 10 mL). The combined organic solutions were washed with
water (15 mL), brine (15 mL), dried and concentrated and the prod-
uct was isolated by column chromatography (hexane/ethyl acetate,
99:1 to 95:5) to afford pure di-olefin 15 (0.0941 g, 75%) as an oil. 1H
NMR (600 MHz) d: 5.74 (m, J = 7.6, JZ = 10.4, JE = 17.3, H-2 or H-13),
5.63 (m, H-13 or H-2), 5.08–4.92 (m, H-1a, H-1b, H-14a and H-
14b), 4.05 (dd, J = 5.2, J = 7.7, H-3 or H-12), 3.96 (dd, J = 5.2,
J = 7.2, H-3 or H-12), 3.82 (t, H-4 or H-11); 13C NMR (150 MHz) d:
139.6–138.4 (10 ꢁ 4°Caromat.), 135.8 and 135.7 (C-2 and C-13),
118.6 and 118.4 (C-1 and C-14), 82.9 (C-4 or C-11), 81.8 and 81.3
(C-3 and C-12), 75.0–70.1 (10 ꢁ CH2Ph). HR-MS (ESI) m/z:
1277.61071; calcd for C84H86O10 [M+Na+]: 1277.61132. Analysis:
calcd for C84H86O10: C, 80.35; H, 6.90; found: C, 80.50; H, 6.77
C
72H76O13 [M+Na+].
4.2.1. 2,3,4,5,6,7,8,9,10,11-Deca-O-benzyl-L-threo-L-manno-D-
gluco-dodecitol 14
Compound 13 (1.71 g, 1.46 mmol) was dissolved in methylene
chloride (25 mL), containing triethylamine (3 mL), trityl chloride
(3 g, 10 mmol) and DMAP (25 mg). The mixture was heated at re-
flux for 5 h (TLC monitoring in hexane/ethyl acetate, 4:1), then
cooled to rt and partitioned between ether (50 mL) and water
(50 mL). The organic phase was separated and the aqueous phase
extracted with ether (2 ꢁ 20 ml). The combined organic solutions
were washed with water (40 mL) and brine (40 mL), dried and con-
centrated and the crude product 21 (LR MS; m/z: 1679.8; calcd for
C
113H108O12 [M+Na+]: 1679) was used in the next step without
purification.
To a solution of crude 21 in toluene (30 mL), benzyl chloride
½ ꢃ ¼ þ23 (c 0.5, CHCl3).
a rDt
(8.4 mL, 73 mmol) was added, followed by 50% aq NaOH (40 mL)
and Bu4NBr (50 mg). The mixture was vigorously stirred for 5 days
(TLC monitoring in hexane/ethyl acetate, 5:1) and partitioned be-
tween ether (50 mL) and water (50 mL). The organic phase was
separated, dried and concentrated and the crude 22 (LR MS; m/z:
1769.9; calcd for C120H114O12 [M+Na+]: 1769) was used in the next
step without purification.
4.2.4. (6S,7R,8S,9S,10S,11R,12S,13S,14R,15S)-6,7,8,9,10,11,12,13,
14,15-Deca(benzyloxy)-4,17-dioxan-icosa-1,19-diene 25
To a solution of diol 14 (107.9 mg, 0.0855 mmol) in toluene
(5 mL), allyl bromide (0.3 mL, 3.5 mmol) and 50% aq NaOH
(5 mL) were added followed by tetrabutylammonium chloride
(30 mg). This heterogeneous mixture was vigorously stirred at

A. Osuch-Kwiatkowska, S. Jarosz / Tetrahedron: Asymmetry 24 (2013) 468–473
473
80 °C for 24 h and, after cooling to rt, partitioned between ether
[M+Na+]: 1337.63245; analysis for 26a/26b: calcd for C86H90O12
:
(10 mL) and water (10 mL). The organic phase was separated and
the aqueous phase extracted with ether (10 mL). The combined or-
ganic solutions were washed with water (10 mL) and brine
(10 mL), dried and concentrated and the product was isolated by
column chromatography (hexane/ethyl acetate, 98:2 to 95:5) to
yield pure di-olefin 25 (92 mg, 80%) as an oil. 1H NMR (600 MHz)
d: 5.75 (m, H-2 and H-17), 5.14 (m, J = 1.7, J = 3.1, JE = 13.9, H-1b
or H-18b), 5.11 (m, J = 1.7, J = 3.1, JE = 13.9, H-1b or H-18b), 5.07
(m, J = 1.0, J = 3.1, JZ = 10.4, H-1a or H-18a), 5.04 (m, J = 1.0,
J = 3.1, JZ = 10.4, H-1a or H-18a), 3.72 (m, H-3 or H-16) and 3.68
(m, H-3 or H-16); 13C NMR (150 MHz) d: 139.6–138.4 (10 ꢁ 4°Caro-
mat.), 135.0 and 134.5 (C-2 and C-17), 116.6 and 116.4 (C-1 and C-
18), 72.0 and 71.9 (C-3 and C-16). HR-MS (ESI) m/z: 1365.6691;
calcd for C88H94O12 [M+Na+]: 1365.66375. Analysis: calcd for
C, 78.51; H, 6.90; found: C, 78.49; H, 6.96.
4.6. Reduction of the double bond in 26a
Cyclic olefin 26a (54 mg, 0.041 mmol) was dissolved in ethanol
(5 mL) to which hydrazine hydrate (98%; 0.2 mL) was added fol-
lowed by 3 drops of acetic acid, and the mixture was stirred at
60 °C for 3 h. After this time, TLC (hexane/ethyl acetate, 5:1)
showed the disappearance of the starting material and the forma-
tion of a new, slightly less polar product. After cooling to rt, water
(5 mL) was added, the organic phase was separated and the aque-
ous phase extracted with ether (3 ꢁ 5 mL). The combined organic
solutions were dried and concentrated, and the product was iso-
lated by preparative TLC (benzene/ether, 100:2) to afford macrocy-
clic derivative 27 (41.6 mg, 77%). 13C NMR (125 MHz, CD2Cl2,
ꢂ60 °C) d: 27.1 and 26.2 (C-1 and C-16); HR-MS (ESI) m/z:
1339.64451; calcd for: C86H92O12 [M+Na+]: 1339.64810. Analysis:
calcd for C86H92O12: C, 78.39; H, 7.04; found: C, 78.57; H, 7.05;
C
88H94O12: C, 78.66; H, 7.05; found: C, 78.45; H, 7.09; ½a Drt
ꢃ ¼ ꢂ5
(c 0.25, CHCl3).
4.3. General procedure for the RCM reaction of polyhydrox-
ylated di-olefins
½ ꢃ ¼ þ7 (c 0.6, CHCl3). Reduction of 26b under the same condi-
a rDt
tions (t = 9 h) provided the same derivative 27 in 72% yield.
This reaction was conducted in dry solvents under an argon
atmosphere. To a solution of the corresponding diene in an appro-
priate solvent the catalyst for the RCM reaction, dissolved in the
minimum amount of the same solvent, was added, and the reaction
(carried out at given temp.) was monitored by TLC. After comple-
tion, the solvent was removed in vacuo, and the residue was puri-
fied by column chromatography or preparative TLC.
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To a solution of diene 15 (15 mg, 0.0119 mmol) in methylene
chloride (25 mL; c = 4.5 ꢁ 10ꢂ3 M/L), Grubbs-I catalyst (or B–D;
15 mol%) was added and the mixture was kept at rt for 24 h. Only
the starting material was recovered.
To a solution of the diene 15 (72 mg, 0.0571 mmol) in toluene
(80 mL; c = 0.7 ꢁ 10ꢂ3 M/L), Grubbs-I catalyst (or B, E; 20 mol %)
was added and the mixture was kept at 80 °C for 72 h. After this
time, the unchanged starting material (61.8 mg) was recovered to-
gether with small amounts of an isomerized derivative (as de-
tected by MS). Similar results were obtained with cat. E in C6F6
(c = 4.5 ꢁ 10ꢂ3 M; t = 75 °C).
4.5. Cyclization of the di-O-allyl derivative 25
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(7.8 mg, 9%) and 26b (41.8 mg, 50%). Similar results were obtained
after 4.5 h at 85 °C. When this reaction was conducted at lower
concentrations (118.1 mg, 0.0879 mmol of 25 in 125 mL of tolu-
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´
To a solution of diene 25 (91 mg, 0.0677 mmol) in toluene
(125 mL) Grubbs-II catalyst (20 mol%) was added and the mixture
was kept at rt for 24 h. The products were isolated by preparative
TLC to yield: 26a (5.7 mg, 6%), 26b (35.5 mg, 40%) and a mixture of
isomerized starting material (as detected by (ESI) MS; m/z; 1365.7;
for C88H94O12 [M+Na+]: 1365). Data for 26a: HR-MS (ESI) m/z:
1337.63625; calcd for C86H90O12 [M+Na+]: 1337.63245. Data for
26b: 1H NMR (600 MHz, ꢂ40 °C) d: 5.66 and 5.47 (2 bm, H-1 and
27. Vougioukalakis, G. C. Chem. Eur. J. 2012, 18, 8868–8880.
H-16); HR-MS (ESI) m/z: 1337.63447; calcd for
C86H90O12