Stereospecific synthesis of eight-membered polyhydroxy carbocycles via TIBAL-promoted claisen rearrangement

Article abstract of DOI:10.1055/s-2008-1077965

The stereoselective synthesis of novel eight-membered polyhydroxy carbocycles was achieved from D-glucose via mercuriocyclization and triisobutylaluminum (TIBAL)-promoted Claisen rearrangement. Along with rearrangement, TIBAL also promoted debenzylation a

Full text of DOI:10.1055/s-2008-1077965

LETTER
1985
Stereospecific Synthesis of Eight-Membered Polyhydroxy Carbocycles via
TIBAL-Promoted Claisen Rearrangement
Synthesis of
E
ig
i
ht-Me
a
mbered Pol
n
yhydroxy Ca
x
r
bocycle iang Han, Yi Liu, Zhenjun Yang, Liangren Zhang,* Lihe Zhang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
38 Xueyuan Road, Beijing 100083, P. R. of China
Fax +86(10)82802724; E-mail: liangren@bjmu.edu.cn
Received 7 April 2008
cose derivative (Figure 1). In the synthesis of compound
1, stereospecific mercuriocyclization was observed. This
study provides a practical approach to synthesize eight-
membered polyhydroxy carbocycles. The new method
Abstract: The stereoselective synthesis of novel eight-membered
polyhydroxy carbocycles was achieved from D-glucose via mercu-
riocyclization and triisobutylaluminum (TIBAL)-promoted Claisen
rearrangement. Along with rearrangement, TIBAL also promoted
debenzylation and cycloaddition, and
a
3,9-dioxa-bicy- could be used for the synthesis of novel bioactive agents.
clo[3.3.1]nonane derivative was formed. The stereoselectivity of
mercuriocyclization was attributed to the interaction between me-
curio and vinyl moities, and this interaction also assisted the mercu-
rio derivative to exist in an abnormal conformation. The
configuration and/or conformation of intermediates and products
were identified by NMR spectral analyses.
OH
OH
BnO
BnO
OBn
OBn
BnO
OBn
BnO
OBn
1
2
Key words: carbocycle, carbasugar, mercuriocyclization, TIBAL,
Claisen rearrangement, debenzylation
Figure 1 Structures of eight-membered polyfunctional carbocycles
BnO
BnO
BnO
BnO
The eight-membered polyfunctional carbocycle structure
is present in numerous biologically important molecules
and natural products, such as paclitaxel,1 poitediol,2 fusi-
coccin H,3 and kalmanol,4 etc. Because of the diverse bio-
logical properties, their syntheses have been extensively
investigated. Various methods have been developed for
the construction of eight-membered polyfunctional car-
bocycles. They include oxidation and hydroxylation of
cyclooctene derivatives,5 cycloadditions,6 ring expan-
sions,7 fragmentations,8 and intramolecular cross-cou-
pling,9 etc. The discovery of ring-closing metathesis
(RCM) has also greatly advanced the development of the
synthesis of eight-membered carbocycles.10
Ph3PMeBr
n-BuLi, THF
55 °C, 2 h
OH
O
D-glucose
OH
OBn
BnO
OBn
BnO
4
3
BnO
BnO
BnO
BnO
O
PCC, 4 Å MS
CH2Cl2, r.t., 2 h
CH2=CHMgBr
THF, –78 °C, 1 h
OH
BnO
OBn
BnO
OBn
6
5
a) Hg(OAc)2
THF, reflux
10 h
The polyhydroxy carbacycle (carbasugar) is a carbocyclic
mimic of carbohydrate. Comparing furanose to pyranose,
carbasugar are more resistant to hydrolysis because of the
absence of acetal moiety and they show inhibition activity
to glycosidase and glycosyl transferase.11 It is a superior
method to prepare carbasugars via the conversion of car-
bohydrate because the configurations of the functional
groups could be maintained and the specific spatial distri-
bution of hydroxy groups could be achieved.12 Five- and
six-membered carbasugars can be synthesized in many
ways, but only a few methods are available for the forma-
tion of seven- and eight-membered carbasugars.13 In this
report, we disclose a synthesis of hydroxymethyl-
branched polyhydroxy cyclooctene via triisobutylalumi-
num (TIBAL) promoted Claisen rearrangement of D-glu-
BnO
BnO
BnO
I2, CH2Cl2
r.t., 3 h
O
O
I
HgCl
BnO
BnO
b) aq KCl
THF, reflux
2 h
OBn
BnO
OBn
7
8
1 M TIBAL
toluene
80 °C, 2 h
BnO
BnO
NaH, DMF
r.t., 1 h
O
1
BnO
OBn
9
Scheme 1 Synthesis of compound 1
The synthesis route is presented in Scheme 1. Starting
from D-glucose, intermediate 6 could be obtained via hy-
droxy protection, Wittig olefination,14 Swern oxidation,15
and Grignard reaction15 in an overall yield of 56%. In the
SYNLETT 2008, No. 13, pp 1985–1988
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077965; Art ID: W05508ST
x
x
.x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

1986
T. Han et al.
LETTER
presence of Hg(OAc)2, stereoselective mercuriocycliza- tween H-1 and H-3 and hence confirming the
tion of 6 proceeded to give the mecurio derivative 716 in configuration.
almost quantitative yield. In this reaction, mercuriocy-
clization was used for the formation of the six-membered
pyran ring. It was noted that iodocyclization generally
In TIBAL-promoted Claisen rearrangement reaction, be-
sides the formation of compound 1, an unexpected benzyl
elimination byproduct 1020 was also isolated. The struc-
gives the five-membered furan ring as the major prod-
ture was identified by NMR spectroscopy. The different
coupling constants of J5,6 and J6,7 (J5,6 = 5 Hz, J6,7 = 9 Hz)
uct.17
1
Structural characterization of compound 7 by H NMR indicated that H-5 and H-6 had a cis spatial relationship
spectroscopy showed identical coupling constants of 3 Hz and C-5 is in an R configuration. This configuration was
for J2,3 and J3,4. The result indicated that H-2 and H-3 had further confirmed by the existence of NOE interactions
the same spatial relationship as H-3 and H-4, which are in between H-7 and H-2, as well as between H-7 and H-4.
trans configuration in glucose. Hence, H-2 and H-3
NOE
should also be in a trans configuration, and C-2 has an R
OH
H
absolute configuration. In addition, the small coupling
constants indicated that all neighbor protons on the pyran
ring of compound 7 should possess an equatorial–equato-
rial relationship (Figure 2). This conformation is in con-
flict with the general observation with substituted pyrans,
wherein the large group prefers to occupy the equatorial
position and the small group the axial position. The result
is also different from other organomercurial compounds
reported in literature.17 This unique conformation was at-
tributed to the existence of a vinyl group at C-6. When the
vinyl group was located at the axial position, the mercury
atom could coordinate to the double bond. The favorable
interaction lowers the energy and places the large groups
at the axial positions. It is also because of the coordination
interaction, the mercuriocyclization proceeded stereose-
lectively and in high yield. The conformation of com-
pound 7 was further proved by NOE experiments
(Figure 2). The existence of a strong NOE between H-8
and H-1 also supported that CH2HgCl and vinyl group are
located at the axial positions.
OH
H
BnO
H
BnO
BnO
OBn
OBn
NOE
BnO
OBn
BnO
H
1
2
Figure 3 Configurations of compounds 1 and 2 as confirmed by
NOESY experiments
OBn
O
BnO
BnO
OBn
a
9
b
OBn
BnO
BnO
BnO
+
O
–AlR3
R2Al–
+
Ph
O
H
BnO
BnO
BnO
OBn
O
BnO
BnO
BnO
H
HgCl
–
8
1
O+ AlR2
7
Hg2+
OBn
OH
H
H
H
H
6
OBn
O
BnO
BnO
2
5
4
O
3
OBn
OBn
OBn
OBn
BnO
BnO
BnO
Figure 2 Coordination interaction between vinyl and mercurio af-
forded stereospecific cyclization (left) and stabilized the unique con-
formation (right)
OBn
O
BnO
BnO
BnO
OH
H
1
10
After the organomercury functionality in compound 7 was
substituted by iodine, compound 8 was obtained in 87%
yield. The NMR spectral analysis indicated that com-
pound 8 existed in a similar conformation as compound 7.
Elimination of HI by NaH gave compound 918 in 83%
yield. Conversion of compound 9 into the polyhydroxy
eight-membered carbocycle 119 was achieved in good
stereoselectivity, in 87% yield, via TIBAL-promoted
Claisen rearrangement (Scheme 1). The configuration of
Scheme 2 Proposed mechanism for the TIBAL-promoted Claisen
rearrangement and debenzylation cycloaddition
The mechanism of the formation of compound 1 and 10 is
illustrated in Scheme 2. Triisobutylaluminum bound
strongly to the oxygen atom of the benzyloxy group and
promoted debenzylation and cycloaddition to form 3,9-di-
oxabicyclo[3.3.1]nonane (route b). It was also found that
the amount of byproduct 10 was increased and even be-
came the main product as the amount of TIBAL decreased
(Table 1). This may be resulted from the competition be-
tween route a and route b (Scheme 2). Based on the stabil-
ity of their respective transition states, it appeared that
route a should proceed faster because of the less sterically
1
C-1 of compound 1 was identified by H NMR and 2D
NOESY experiments. The coupling constants between H-
2 and its neighboring protons (J1,2 = 7 Hz, J2,3 = 6 Hz)
showed that the H-1 had a trans relation with H-2, and C-
1 was in an R configuration. The 2D NOESY NMR spec-
tra also showed strong NOE (Figure 3) interactions be-
Synlett 2008, No. 13, 1985–1988 © Thieme Stuttgart · New York

LETTER
Synthesis of Eight-Membered Polyhydroxy Carbocycles
1987
hindered coordination state. At low TIBAL concentration,
route b was favored but needed longer reaction time to
complete the reaction. At high TIBAL concentration,
route a was favored with the increasing opportunity to
form a higher sterically hindered coordination state.
References and Notes
(1) (a) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
McPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325.
(b) Magri, N. F.; Kingston, D. G. I.; Jitrangsri, C.;
Piccariello, T. J. Org. Chem. 1986, 51, 3239. (c) Holton,
R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.; Harusawa, S.;
Lowenthal, R. E.; Yogai, S. J. Am. Chem. Soc. 1988, 110,
6558. (d) Chauviere, G.; Guenard, D.; Pascard, C.; Picot, F.;
Potier, P.; Prange, T. J. Chem. Soc., Chem. Commun. 1982,
495.
(2) Fenical, W.; Shulte, G. R.; Finer, J.; Clardy, J. J. Org. Chem.
1978, 43, 3628.
(3) Barrow, K. D.; Barton, D. H. R.; Chain, E.; Ohnsorge, U. F.
W.; Sharma, R. P. J. Chem. Soc., Perkin Trans. 1 1973,
1590.
(4) Burke, J. W.; Doskotch, R. W.; Ni, C.-Z.; Clardy, J. J. Am.
Chem. Soc. 1989, 111, 5831.
(5) (a) Cope, A. C.; Keough, A. H.; Peterson, P. E.; Simmons,
H. E. Jr.; Wood, G. W. J. Am. Chem. Soc. 1957, 79, 3900.
(b) Cope, A. C.; Fournier, A. Jr.; Simmons, H. E. Jr. J. Am.
Chem. Soc. 1957, 79, 3905. (c) Kulkarni, S. U.; Brown, H.
C. J. Org. Chem. 1979, 44, 1747.
(6) (a) Shea, K. J.; Wise, S. Tetrahedron Lett. 1979, 20, 1022.
(b) Shea, K. J.; Wise, S.; Burke, L. D.; Davis, P. D.; Gilman,
J. W.; Greely, A. C. J. Am. Chem. Soc. 1982, 104, 5708.
(c) Brown, P. A.; Jenkins, P. R. J. Chem. Soc., Perkin Trans.
1 1986, 1303. (d) Sieburth, S. M.; Chen, J.; Ravindran, K.;
Chen, J. J. Am. Chem. Soc. 1996, 118, 10803. (e) Sieburth,
S. M.; Siegel, B. Chem. Commun. 1996, 2249.
(7) (a) Martin, S. F.; White, J. B.; Wagner, R. J. Org. Chem.
1982, 47, 3190. (b) Snider, B. B.; Allentoff, A. J. J. Org.
Chem. 1991, 56, 321.
Table 1 TIBAL-Promoted Formation of Compounds 1 and 10 un-
der Different Conditions
Entry
9/TIBAL Solvent
(mol:mol)
Time
(h)
Yield (%)
1
10
2
1
2
3
4
1:10
1:5
1:2
1:1
toluene
toluene
toluene
toluene
2
2
6
6
87
58
30
14
26
33
37
The configuration of C-1 of compound 1 could be easily
converted into the S-isomer in 97% yield via Mitsunobu
reaction. After hydrolysis of the benzoyl group, com-
pound 221 was afforded in 83% yield (Scheme 3). The
coupling constants between H-2 and its neighboring pro-
tons (J1,2 = 2 Hz, J2,3 = 8 Hz) indicated that H-1 had a cis
relation with H-2. Strong NOE (Figure 3) between H-1
and H-4 in 2D NOESY spectra also supported that C-1 of
compound 2 has an S-configuration.
OBz
BzOH, Ph3P
DEAD, THF
40 °C, 3 h
K2CO3
MeOH
r.t., 12 h
(8) (a) Neh, H.; Blechert, S.; Schnick, W.; Jansen, M. Angew.
Chem. Int. Ed. Engl. 1984, 23, 905. (b) Blechert, S.; Kleine-
Klausing, A. Angew. Chem. Int. Ed. Engl. 1991, 30, 412.
(c) Pradhan, T. K.; Hassner, A. Synlett 2007, 1071.
(9) Kawada, H.; Iwamoto, M.; Utsugi, M.; Miyano, M.; Nakada,
M. Org. Lett. 2004, 6, 4491.
BnO
OBn
OBn
1
2
BnO
11
Scheme 3 Synthesis of compound 2
(10) Michaut, A.; Rodriguez, J. Angew. Chem. Int. Ed. 2006, 45,
5740.
(11) (a) Mehta, G.; Ramesh, S. S. Chem. Commun. 2000, 24,
2429. (b) Ogawa, S.; Funayama, S.; Okazaki, K.; Ishizuka,
F.; Sakata, Y.; Doi, F. Bioorg. Med. Chem. Lett. 2004, 14,
5183. (c) Grondal, C.; Enders, D. Synlett 2006, 3507.
(12) (a) Das, S. K.; Mallet, J.-M.; Sinaÿ, P. Angew. Chem. Int. Ed.
Engl. 1997, 36, 493. (b) Sollogoub, M.; Mallet, J.-M.;
Sinaÿ, P. Angew. Chem. Int. Ed. 2000, 39, 362. (c) Shing,
T. K. M.; Cheng, H. M. J. Org. Chem. 2007, 72, 6610.
(d) Shing, T. K. M.; Wong, W. F.; Cheng, H. M.; Kwok, W.
S.; So, K. H. Org. Lett. 2007, 9, 753.
(13) (a) Blériot, Y.; Giroult, A.; Mallet, J.-M.; Rodriguez, E.;
Vogel, P.; Sinaÿ, P. Tetrahedron: Asymmetry 2002, 13,
2553. (b) Liu, Y.; Han, T. X.; Yang, Z. J.; Zhang, L. R.;
Zhang, L. H. Tetrahedron: Asymmetry 2007, 18, 2326.
(c) Jia, C.; Zhang, Y.; Zhang, L. Tetrahedron: Asymmetry
2003, 14, 2195. (d) Shing, T. K. M.; Wong, A. W. F.; Ikeno,
T.; Yamada, T. J. Org. Chem. 2006, 71, 3253. (e) Shing, T.
K. M.; Wong, A. W. F.; Ikeno, T.; Yamada, T. Org. Lett.
2007, 9, 207.
In conclusion, we have developed an efficient, highly ste-
reospecific method for the syntheses of hydroxymethyl-
branched polyhydroxy cyclooctene compounds. The co-
ordination interaction between mercurio group and vinyl
group allowed the mercuriocyclization to proceed stereo-
selectively and the formed mecurio derivative was found
to exist in an all-axial conformation. The hydroxy groups,
the side chains, and the double bonds in the carbocycles
could be converted into other functional groups. These
carbocycles with unique conformations could be used for
the synthesis of bioactive compounds and analogues of
natural products. The formation of dioxabicyclic com-
pounds also provides a way to build mimics of related nat-
ural products.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(14) Liu, P. S. J. Org. Chem. 1987, 52, 4717.
(15) Kapferer, P.; Sarabia, F.; Vasella, A. Helv. Chim. Acta 1999,
82, 645.
(16) Synthesis of 7
Acknowledgment
To alkene 6 (1.30 g, 2.30 mmol) dissolved in anhyd THF (20
mL) was added Hg(OAc)2 (0.73 g, 2.31 mmol) under argon.
The reaction mixture was stirred and refluxed for 10 h, then
sat. aq KCl (1 mL) was added, stirred, and refluxed for
another 2 h, quenched by the addition of brine at r.t., and
This work was supported by National Natural Science Foundation
of China (20672010, 90713005) and The Ministry of Science and
Technology of China (2004CB518904). We thank Dr. Jundong
Zhang for help in revising the manuscript.
Synlett 2008, No. 13, 1985–1988 © Thieme Stuttgart · New York

1988
T. Han et al.
LETTER
column chromatography (PE–acetone, 20:1) to give 1 as
extracted three times with EtOAc. Organic extracts were
combined, dried by Na2SO4, filtered, and evaporated. The
residue was purified by column chromatography on SiO2
(PE–EtOAc, 20:1) to give 7 as a colorless oil (1.85 g,
99.9%). 1H NMR (400 MHz, CDCl3): d = 7.33–7.18 (m, 20
H, arom. H), 5.96 (dd, J7,8a = 11.0 Hz, J7,8b = 17.5 Hz, 1 H,
H-7), 5.23–5.27 (m, J8a,7 = 11.0 Hz, J8b,7 = 17.5 Hz,
J8a,8b = J8b,8a = 1.5 Hz, 2 H, H-8a, H-8b), 4.66, 4.59 (dd,
J = 11.5 Hz, 2 H, HCH2Ph), 4.57, 4.51 (dd, J = 12.0 Hz, 2 H,
HCH2Ph), 4.35, 4.23 (dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.42
(m, J2,3 = 3.0 Hz, J2,1a = 6.0 Hz, J2,1b = 4.0 Hz, 1 H, H-2),
3.90 (t, J4,3 = 3.0 Hz, J4,5 = 4.0 Hz, 1 H, H-4), 3.87, 3.41 (dd,
J = 8.5 Hz, 2 H, H-9a, H-9b), 3.67 (d, J5,4 = 4.0 Hz, 1 H,
H-5), 3.16 (t, J3,2 = 3.0 Hz, J3,4 = 3.0 Hz, 1 H, H-3), 1.94 (dd,
J1a,2 = 6.0 Hz, J1a,1b = 12.0 Hz, 1 H, H-1a), 1.65 (dd,
J1b,2 = 4.0 Hz, J1b,1a = 12.0 Hz, 1 H, H-1b). 13C NMR (100
MHz, CDCl3): d = 139.2 (C-7), 138.5, 138.4, 138.0, 137.3
(4 × Cipso), 129.1–127.5 (arom. C), 114.6 (C-8), 79.6 (C-6),
76.2 (C-3), 76.0 (C-5), 75.9 (C-9), 74.2 (C-4), 73.9, 73.7,
72.5, 72.1 (4 × CH2Ph), 67.4 (C-2), 31.6 (C-1). MS (ESI-
TOF+): m/z = 818 [M + NH4]+, 823 [M + Na]+, 839 [M + K]+.
Anal. Calcd for C37H39O5HgCl: C, 55.57; H, 4.92. Found: C,
55.83; H, 5.10.
colorless oil (571 mg, 86.5%). 1H NMR (300 MHz, CDCl3):
d = 7.32–7.18 (m, 20 H, arom. H), 6.02 (t, J6,7a = J6,7b = 8 Hz,
1 H, H-6), 4.73 (d, J4,3 = 6 Hz, 1 H, H-4), 4.61 (dd, J = 12
Hz, 2 H, HCH2Ph), 4.58 (dd, J = 12 Hz, 2 H, HCH2Ph), 4.48
(dd, J = 12 Hz, 2 H, HCH2Ph), 4.33 (dd, J = 12 Hz, 2 H,
HCH2Ph), 4.11 (t, J1,2 = 7 Hz, J1,8a = 7 Hz, 1 H, H-1), 4.00
(dd, J = 12 Hz, 2 H, H-9), 3.90 (t, J3,2 = J3,4 = 6 Hz, 1 H,
H-3), 3.63 (dd, J2,3 = 6 Hz, J2,1 = 7 Hz, 1 H, H-2), 3.39 (s, 1
H, OH), 2.42 (br, 1 H, H-7a), 2.22 (br, 1 H, H-7b), 2.04 (t,
J8b,8a = 13 Hz, 1 H, H-8b), 1.71 (m, J8a,8b = 13 Hz, J8a,1 = 7
Hz, 1 H, H-8a). 13C NMR (75 MHz, CDCl3): d = 138.6,
138.4, 138.1, 138.1 (4 × Cipso), 134.2 (C-5), 131.4 (C-6),
128.4-127.4 (arom. C), 84.4 (C-3), 81.3 (C-2), 78.7 (C-4),
74.2, 72.5, 72.2, 71.2 (4 × CH2Ph), 70.4 (C-1), 32.9 (C-8),
21.3 (C-7). MS (ESI-TOF+): m/z = 565 [M + H]+, 582 [M +
NH4]+, 587 [M + Na]+, 603 [M + K]+. Anal. Calcd for
C37H40O5: C, 78.69; H, 7.14. Found: C, 78.84; H, 6.91.
(20) Compound 10: white solid. 1H NMR (500 MHz, CDCl3):
d = 7.26–7.19 (m, 15 H, H-arom.), 5.74 (dd, J10,11a = 18 Hz,
J10,11b = 11 Hz, 1 H, H-10), 5.26 (dd, J11a,10 = 18 Hz,
J11a,11b = 2 Hz, 1 H, H-11a), 5.09 (dd, J11b,10 = 11 Hz,
J11b,11a = 2 Hz, 1 H, H-11b), 4.87 (dd, J = 12 Hz, 2 H,
HCH2Ph), 4.82 (dd, J = 12 Hz, 2 H, HCH2Ph), 4.66 (dd,
J = 12 Hz, 2 H, HCH2Ph), 4.58 (t, J7,6 = J7,8 = 9 Hz, 1 H,
H-7), 4.13 (d, J2a,2b = 12 Hz, 1 H, H-2a), 4.02 (d, J4a,4b = 12
Hz, 1 H, H-4a), 3.79 (dd, J6,5 = 5 Hz, J6,7 = 9 Hz, 1 H, H-6),
3.75 (dd, J5,6 = 5 Hz, J5,4b = 3 Hz, 1 H, H-5), 3.54 (dd,
J4b,4a = 12 Hz, J4b,5 = 3 Hz 1 H, H-4b), 3.39 (d, J8,7 = 9 Hz, 1
H, H-8), 3.22 (d, J2b,2a = 12 Hz, 1 H, H-2b). 13C NMR (125
MHz, CDCl3): d = 139.0, 138.6, 138.3 (3 × Cipso), 136.8 (C-
10), 128.4–127.4 (arom. C), 115.5 (C-11), 84.4 (C-8), 83.7
(C-7), 80.9 (C-6), 75.5, 75.3, 73.2 (3 × CH2Ph), 74.6 (C-1),
69.6 (C-5), 68.8 (C-2), 63.8 (C-4). MS (ESI-TOF+): m/z =
490 [M + NH4]+, 495 [M + Na]+, 511 [M + K]+. Anal. Calcd
for C37H40O5: C, 76.25; H, 6.83. Found: C, 76.50; H, 7.05.
(21) Synthesis of 2
(17) (a) Nicotra, F.; Ronchetti, F.; Russo, G. J. Org. Chem. 1982,
47, 4459. (b) Nicotra, F.; Ronchetti, F.; Russo, G. J. Chem.
Soc., Chem. Commun. 1982, 470. (c) Nicotra, F.; Perego,
R.; Ronchetti, F.; Russo, G.; Toma, L. Carbohydr. Res.
1984, 131, 180. (d) Nicotra, F.; Panza, L.; Ronchetti, F.;
Russo, G.; Toma, L. Carbohydr. Res. 1987, 171, 49.
(18) Synthesis of 9
Compound 8 (559 mg, 0.81mmol) dissolved in anhyd DMF
(5 mL) was treated with NaH (60% in oil, 323 mg, 8.10
mmol) under argon. The reaction mixture was stirred for 1 h
at r.t., quenched with MeOH, and concentrated. The residue
was added H2O and extracted with CH2Cl2. The organic
extracts were washed twice with brine, dried by Na2SO4,
filtered, and evaporated. The residue was purified by column
chromatography (PE–EtOAc–Et3N, 15:1:0.02) to yield 9 as
a colorless oil (377 mg, 82.7%). 1H NMR (300 MHz,
CDCl3): d = 7.02–6.78 (m, 20 H, arom. H), 5.88 (dd,
J7,8a = 17.5 Hz, J7,8b = 11.0 Hz, 1 H, H-7), 5.43 (ss,
J8a,7 = 17.5 Hz, J8a,8b = 1.5 Hz, 1 H, H-8a), 4.88 (dd,
J8b,7 = 17.5 Hz, J8b,8a = 1.5 Hz, 1 H, H-8b), 4.70 (d,
J1a,1b = 1.5 Hz, 1 H, H-1a), 4.66 (d, J1b,1a = 1.5 Hz, 1 H,
H-1b), 4.52 (dd, J = 11.5 Hz, 2 H, HCH2Ph), 4.39 (dd,
J = 11.5 Hz, 2 H, HCH2Ph), 4.35 (dd, J = 11.5 Hz, 2 H,
HCH2Ph), 4.20 (dd, J = 11.5 Hz, 2 H, HCH2Ph), 3.81 (m,
J5,4 = 8.0 Hz, J4,5 = 8.0 Hz, J4,3 = 8.0 Hz, 2 H, H-5, H-4),
3.58 (dd, J = 10.0 Hz, 2 H, H-9a, H-9b), 3.34 (d, J3,4 = 8.0
Hz, 1 H, H-3). 13C NMR (75 MHz, CDCl3): d = 156.0 (C-2),
139.3 (C-7), 139.0, 138.8, 138.7, 138.5 (4 × Cipso), 128.6–
127.7 (arom. C), 115.3 (C-8), 94.7 (C-1), 84.2 (C-6), 82.8
(C-3), 82.2 (C-5), 80.6 (C-4), 75.6 (C-9), 74.7, 73.9, 73.5,
71.1 (4 × CH2Ph). MS (ESI-TOF+): m/z = 585 [M + Na]+,
601 [M + K]+. Anal. Calcd for C37H38O5: C, 78.98; H, 6.81.
Found: C, 78.80; H, 7.02.
To the solution of Ph3P (296 mg, 1.13 mmol) in anhyd THF
(3 mL) previously cooled in an ice bath was added dropwise
2.2 M DEAD in toluene (0.5 mL, 1.13 mmol) under argon.
After 30 min, this solution was added dropwise to the
solution of compound 1 (254 mg, 0.45 mmol) and benzoic
acid (100 mg, 0.82 mmol) in anhyd THF under argon in an
ice bath. The mixture was stirred for 30 min at 0 °C, then
stirred at 45 °C for 3 h. When the volatiles were removed, the
residue was purified by column chromatography (PE–
acetone, 40:1) to yield 10 as colorless oil (290 mg, 96.5%).
Compound 10 (362 mg, 0.54 mmol) dissolved in MeOH (10
mL) was treated with K2CO3 (372 mg, 2.69 mmol) and
stirred at r.t. for 12 h. The reaction mixture was subsequently
filtered and concentrated, and the residue was purified by
column chromatography (PE–acetone, 20:1) to afford 2 as
colorless oil (254 mg, 82.7%). 1H NMR (500 MHz, CDCl3):
d = 7.31–7.21 (m, 20 H, arom. H), 6.03 (t, J6,7a = J6,7b = 8.5
Hz, 1 H, H-6), 4.67 (dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.62
(dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.47 (dd, J = 12.0 Hz, 2 H,
HCH2Ph), 4.43 (dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.41 (m,
J2,1 = 2.5 Hz, J2,3 = 6.0 Hz, 1 H, H-2), 4.07–3.98 (m, 3 H,
H-1, H-9a, H-9b), 3.83 (t, J3,2 = 6.0 Hz, J3,4 = 5.0 Hz, 1 H,
H-3), 3.69 (d, J4,3 = 5.0 Hz, 1 H, H-4), 2.36 (br, 1 H, H-7a),
2.10 (m, 1 H, H-7b), 2.00 (m, 1 H, H-8a), 1.70 (m, 1 H, H-
8b). MS (ESI-TOF+): m/z = 565 [M + H]+, 582 [M + NH4]+,
587 [M + Na]+, 603 [M + K]+. Anal. Calcd for C37H40O5: C,
78.69; H, 7.14. Found: C, 78.64; H, 7.02.
(19) Synthesis of 1
To the solution of compound 9 (660 mg, 1.17 mmol) in
toluene (20 mL) was added dropwise 1 M TIBAL (11.7 mL,
11.7 mmol) in toluene at r.t. under argon. The mixture was
stirred at 80 °C for 2 h, cooled to 0 °C, and quenched with
20% aq NaOH solution. The mixture was extracted with
toluene, and the organic layers were combined, dried with
Na2SO4, and concentrated. The residue was purified by
Synlett 2008, No. 13, 1985–1988 © Thieme Stuttgart · New York