Syntheses of the macrolide subunits of merremoside-type resin glycosides

Article abstract of DOI:10.1055/s-2006-956493

The 20- and 21-membered macrolide subunits of merremoside-type resin glycosides with interesting bioactivity were synthesized via a macrolactonization approach using Corey-Nicolaou protocol in 14 steps with overall yields of 0.7% for 17 and 3.5% for 18 fr

Full text of DOI:10.1055/s-2006-956493

3510
LETTER
Syntheses of the Macrolide Subunits of Merremoside-type Resin Glycosides
M
acrolide Subunit
i
s
of
M
e
n
rremoside-ty
g
pe
R
esin
G
l
-
ycosidesMei Zhu,1 Li-Li He, Guang-Li Yang, Ming Lei, Si-Shi Chen, Jin-Song Yang*
Department of Chemistry of Medicinal Natural Products and Key Laboratory of Drug Targeting, School of Pharmacy, Sichuan University,
Chengdu 610041, P. R. of China
Fax +86(28)85503723; E-mail: yjs@scu.edu.cn
Received 30 July 2006
C5H11
Abstract: The 20- and 21-membered macrolide subunits of merre-
moside-type resin glycosides with interesting bioactivity were syn-
thesized via a macrolactonization approach using Corey–Nicolaou
protocol in 14 steps with overall yields of 0.7% for 17 and 3.5% for
18 from (R)-glycidol. Further debenzylation of the macrolide 18 led
to diol 19 that might act as the key substrate for transformation into
merremosides A–G.
O
11S
O
O
HO
O
OH
O
O
O
OH
O
R2O
OR1
R3O
O
O
R1
R2
R3
Key words: resin glycoside, merremoside, macrolide, synthesis,
macrolactonization
HO
merremoside A
Mba
Iba
H
H
H
Mba
Iba
OH
B
C
D
Mba Iba
Iba Iba
H
Me
Me
F
Mba β-Glu Iba
Iba β-Glu Iba
Merremoside-type resin glycosides, a class of structurally
complex plant glycolipids consisting of a characteristic
macrolactone backbone, were isolated by Kitagawa from
the fresh tuber of Merremia mammosa (Lour.) Hall. f.
(Convolvulaceae), a plant used in Indonesia for treating
diabetes and illnesses involving the throat and respiratory
system.2 The hydrophobic aglycon found in these con-
stituents is monohydroxy C16 fatty acid, namely, (S)-11-
hydroxyhexadecanoic acid (jalapinolic acid), whose
hydroxyl group is linked to the reducing end of the sugar
unit, while the carboxyl function intramolecularly esteri-
fies with rhamnose 2¢- or 3¢-hydroxyl to form the macro-
cycle (Figure 1). Bioassays exhibited that merremosides
A, B, C, D, F, G, H1 and H2 displayed ionophoretic activ-
ity capable of transporting Na+, K+ and Ca2+ across human
erythrocyte membranes.3 Moreover, merremosides B and
D possessed significant antiserotonic activity [ED80
(mice): 10 mg/mL for B and 2 mg/mL for D].2a
Mba = Et
CO
Iba =
Me
CO
G
H
C5H11
O
O
O
HO
O
O
OH
O
HO
O
O
O
O
O
RO
HO
OR
OH
O
OH
HO
merremoside H1 R = Mba
H2 R = Iba
OH
OH
Figure 1 Structures of merremoside-type resin glycosides
(1)6 was treated with p-tosyl chloride to afford tosylate
2.4d Treatment of 2 with potassium tert-butoxide at –40 °C
in diethyl ether furnished the key intermediate (S)-1,2-ep-
oxyheptane (3)4d in 68% yield. Meanwhile, the bromide 4
was prepared from 1,9-nonanediol according to a known
procedure.7 Elongation of the carbon chain was carried
out through the nucleophilic coupling of the Grignard
reagent derived from 4 with epoxide 3 in the presence of
catalytic copper iodide to give the (S)-1-benzyloxy-11-
hexadecanol (5) in 63% yield based on consumed 3.
Protection of the alcohol 5 with acetyl chloride, followed
by debenzylation and Jones oxidation, provided the corre-
sponding (S)-11-acetoxyhexadecanoic acid (8). Finally,
the desired methyl (S)-11-jalapinolate (9)2a,4a–d,4g was ob-
tained by treatment of 8 with boron trifluoride–diethyl
ether complex in methanol with the removal of acetyl in
one pot [12% total yield over eight steps from (R)-
glycidol].
We chose merremoside-type resin glycosides as synthetic
targets due to the synthetic challenge posed by the intri-
cate macrolide structure and the lack of systematic survey
of their biological functions. In recent studies aimed at the
formation of the macrocyclic framework of resin glyco-
sides, macrolactonization4 and ring-closing metathesis
(RCM)5 strategies were typically employed as the key
steps. Described herein are the syntheses of the 20- and
21-membered macrolide subunits of merremoside-type
resin glycosides using a similar macrolactonization
approach.
The synthesis of the aglycon moiety is illustrated in
Scheme 1. Commercially available (R)-glycidol was em-
ployed as the chiral resource to react with excess n-butyl-
magnesium bromide and the resulting (S)-1,2-heptanediol
SYNLETT 2006, No. 20, pp 3510–3512
1
8
.1
2
.2
0
0
6
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956493; Art ID: W15906ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Macrolide Subunits of Merremoside-type Resin Glycosides
3511
OH
C5H11
O
a
b
OH
HO
O
OTCA
d
O
a
O
(R)-glycidol
1
R1O
AcO
AcO
9
+
R2O
OR2
OAc
10
OH
O
MeO
c
TsO
OTCA
O
11 R1, R2 = Ac
2
3
O
BnO
b
c
14
12 R1, R2 = H
AcO
OAc
NH
ref. 7
Br
R1 = H, R2 = isopropylidene
d
13
1,9-nonanediol
OBn
TCA =
C5H11
CCl3
4
O
OR
OR
O
O
g
O
C5H11
O
O
CH2OR1
COOR1
BnO
O
HO
O
O
O
5
6
7
R = H, R1 = Bn
O
8
9
R = Ac, R1 = H
R = H, R1 = Me
17
O
e
f
h
O
f
O
R = Ac, R1 = Bn
R = Ac, R1 = H
+
BnO
R1O
C5H11
OR1
O
R2O
O
O
O
Scheme 1 Preparation of methyl (S)-11-jalapinolate (9). Reagents
and conditions: (a) n-BuMgBr (3 equiv), CuI (cat.), THF, –40 °C,
73%; (b) p-TsCl, Et3N, CH2Cl2, 0 °C, 85%; (c) t-BuOK, Et2O, –40 °C,
68%; (d) Mg, THF, reflux, then CuI (cat.), 3 (0.77 equiv), –78 °C to
r.t., 63%; (e) Ac2O, pyridine, r.t., 95%; (f) H2 (1 atm), 10% Pd/C,
EtOH, 60 °C, 85%; (g) Jones reagent, acetone, r.t., 67%; (h) BF3·OEt2
(2.8 equiv), MeOH, 40 °C, 85%.
O
O
O
R1 = Ac, R2 = Me
RO
15
e
O
OH
16 R1
, R2 = H
O
18 R = Bn
R = H
g
19
Scheme 2 Construction of the macrolide subunits of merremoside-
type resin glycosides. Reagents and conditions: (a) 9 (1 equiv), 10
(1.8 equiv), BF3·Et2O (1.2 equiv), CH2Cl2, –78 °C to r.t., 66%; (b)
NaOMe, MeOH, –20 °C; (c) (CH3)2C(OCH3)2, p-TsOH, DMF, r.t.,
84% (two steps); (d) 14 (1.6 equiv), TMSOTf (cat.), 4 Å molecular
sieves, CH2Cl2, –78 °C to r.t., 96%; (e) 2% KOH, MeOH–H2O (9:1),
55 °C, 94%; (f) (PyS)2, Ph3P, toluene, reflux, 7 d, 11% for 17, 58%
for 18; (g) H2 (1 atm), 10% Pd/C, EtOH, 60 °C, 86%.
In order to construct the target macrocycle, two required
monosaccharide synthons, 2,3,4-tri-O-acetyl-a-L-rham-
nopyranosyl trichloroacetimidate (10)8 and 2,3-di-O-
acetyl-4-O-benzyl-a-L-rhamnopyranosyl trichloroacet-
imidate (14)9 were prepared, all of which were glycosyl
donors containing neighboring participation groups to
ensure the high selective a-glycosidation.
We then examined the Corey–Nicolaou protocol.12 Thus,
the glycosidic acid 16 was subjected to condensation with
2,2¢-pyridyl disulfide (PySSPy) and triphenylphosphine
(TPP). The resulting intermediate 2-pyridyl thioester was
heated under reflux in toluene using high dilution condi-
tions (7.2 × 10–4 M) to achieve selective macrolactoniza-
tion, giving rise to the 2¢- and 3¢-hydroxyl lactonized
products 1713 and 1813 in the yields of 11% and 58%, re-
spectively. The site of closure was unambiguously con-
firmed by NMR and the regioselectivity was attributed
reasonably to the steric hindrance of the glycosidic link-
age between the two rhamnose cores. This reaction pat-
tern, i.e. the high degree of activity of O-3¢ over O-2¢, in
the disaccharide system is in full accordance with the
observations made in macrolactonization approach.4a–d
Further transformation of macrolide 18 by catalytic
hydrogenolysis led to diol 1914 that might act as the key
substrate for transformation into merremosides A, B, C,
D, F and G, since the apparent different reactivity of the
free 2¢- and 4¢-hydroxyl groups in 19 allows direct attach-
ment of the missing saccharide residues without resorting
to protecting-group manipulations.
With the intermediates 9, 10 and 14 in hand, we made an
effort directing toward the construction of the macrolide
(Scheme 2). Thus, glycosidation of hydroxy ester 9 with
the rhamnosyl donor 10 utilizing Schmidt’s method10
gave the a-L-rhamnopyranoside 11 in moderate yield.
Through successive deacetylation and selective aceton-
ization of the rhamnose 2,3-hydroxyls under routine con-
ditions, conjugate 11 was transferred to 13 with the 4-
hydroxyl group free which could serve as the acceptor for
the next glycosidation. Subsequent coupling of 13 with
the imidate 14 proceeded smoothly in dichloromethane at
–78 °C in the presence of catalytic amounts of trimethyl-
silyl trifluoromethanesulfonate (TMSOTf) to afford the
disaccharidic fragment 15 having a-glycosidic linkages in
excellent yield. Then, the 2¢- and 3¢-hydroxyl groups
along with the aglycon carboxyl in 15 were completely
exposed by saponification with 2% potassium hydroxide
in methanol–water (9:1) to give the macrolactonization
precursor 16 in 94% yield.
Initial attempts to accomplish the cyclization via the
Yamaguchi mixed anhydride procedure (2,4,6-trichlo-
robenzoyl chloride–DMAP–Et3N)11 were unsuccessful.
Synlett 2006, No. 20, 3510–3512 © Thieme Stuttgart · New York

3512
X.-M. Zhu et al.
LETTER
(13) Typical Procedure for Macrolactonization: Under argon,
a solution of glycosidic acid 16 (150 mg, 0.22 mmol), (PyS)2
(225 mg, 1.0 mmol), and Ph3P (303 mg, 1.2 mmol) in anhyd
toluene (6 mL) was stirred for 6 h at r.t. The mixture was
diluted with deoxygenated anhyd toluene (20 mL) and then
was added dropwise by a syringe pump to refluxing anhyd
toluene (280 mL) for 12 h. The solution was refluxed under
argon for 7 d until the complete disappearance of 16 (judged
by TLC analysis). The reaction mixture was concentrated
under reduced pressure. The residue was subjected to silica
gel column chromatograph (PE–EtOAc, 6:1) to afford the
macrolides 17 (20 mg, 11%) as a colorless syrup together
with 18 (75 mg, 58%) as a colorless syrup. Spectral data for
17: Rf 0.11 (PE–EtOAc, 6:1); [a]D21 –8.09 (c = 0.68, CHCl3).
IR (KBr): 3436, 3063, 2906, 1737, 1602, 1496, 1081, 1052
cm–1. 1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 6.8 Hz, 3
H), 1.16–1.34 (m, 28 H), 1.45–1.68 (m, 2 H), 1.34, 1.50 (s,
6 H, 2 × CH3), 2.34 (t, J = 6.4 Hz, 2 H), 3.37–3.46 (m, 1 H),
3.55–3.60 (m, 2 H), 3.91–4.02 (m, 2 H), 4.05–4.07 (m, 2 H),
4.22 (t, J = 4.8 Hz, 1 H), 4.60 (d, J = 10.8 Hz, 1 H), 4.68 (d,
J = 10.8 Hz, 1 H), 4.91 (s, 1 H), 5.13 (s, 1 H), 5.35 (dd, J =
2.4, 9.6 Hz, 1 H), 7.26–7.35 (m, 5 H). 13C NMR (50 MHz,
CDCl3): d = 14.1, 17.8, 19.7, 22.6, 22.7, 23.8, 24.5, 24.8,
25.9, 26.1, 27.1, 27.7, 29.3, 30.0, 31.9, 32.7, 33.9, 37.1, 66.2,
69.2, 71.0, 73.9, 74.1, 74.7, 76.6, 78.5, 78.9, 80.3, 96.7, 98.0,
109.7, 127.7, 127.8, 128.3, 173.2. HR–ESI–MS: m/z [M +
Na]+ calcd for C38H60O10: 699.4084; found: 699.4079. 18: Rf
0.12 (PE–EtOAc, 6:1); [a]D21 –24.55 (c = 0.5, CHCl3). IR
(KBr): 3438, 3066, 2926, 1735, 1602, 1494, 1080, 1051
cm–1. 1H NMR (400 MHz, CDCl3): d = 0.88 (t, J = 6.8 Hz,
3 H), 1.23 (d, J = 6.0 Hz, 3 H), 1.28 (d, J = 6.4 Hz, 3 H),
1.24–1.43 (m, 22 H), 1.61–1.73 (m, 2 H), 1.34, 1.52 (s, 6 H,
2 × CH3), 2.32–2.39 (m, 1 H), 2.45–2.52 (m, 1 H), 3.36 (dd,
J = 2.8, 8.4 Hz, 1 H), 3.46–3.51 (m, 1 H), 3.52 (dd, J = 7.2,
10.0 Hz, 1 H), 3.85–3.94 (m, 2 H), 4.02 (d, J = 5.2 Hz, 1 H),
4.15 (br s, 1 H), 4.19 (dd, J = 5.6, 6.8 Hz, 2 H), 4.53 (d, J =
11.2 Hz, 1 H), 4.73 (d, J = 11.6 Hz, 1 H), 5.01 (s, 1 H), 5.10
(dd, J = 2.8, 5.2 Hz, 1 H), 5.29 (d, J = 5.2 Hz, 1 H), 7.26–
7.38 (m, 5 H). 13C NMR (50 MHz, CDCl3): d = 14.0, 17.7,
19.0, 22.6, 22.7, 23.0, 24.9, 25.7, 26.6, 27.7, 28.0, 28.1, 29.3,
29.7, 32.0, 32.8, 33.9, 34.9, 64.3, 67.9, 69.7, 72.4, 73.4, 75.9,
77.7, 77.9, 81.0, 83.5, 95.5, 96.5, 109.5, 127.9, 128.0, 128.5,
137.7, 173.2. HR–ESI–MS: m/z [M + Na]+ calcd for
In conclusion, we have succeeded in the syntheses of the
macrolide subunits bearing 20- and 21-membered rings of
merremoside-type resin glycosides via a macrolactoniza-
tion approach. The synthesis required 14 steps overall and
the total yield was 0.7% for 17 and 3.5% for 18 from (R)-
glycidol. Further introductions of suitably functionalized
rhamnopyranose building blocks for assembly of the
whole molecules are currently underway.
Acknowledgment
Financial support from the National Natural Science Foundation of
China (No. 30300434) is gratefully appreciated.
References and Notes
(1) Current address: Department of Chemistry, Fourth Military
Medical University, Xi’an 710032, P. R. of China.
(2) (a) Kitagawa, I.; Baek, N. I.; Kawashima, K.; Yokokawa, Y.;
Yoshikawa, M.; Ohashi, K.; Shibuya, H. Chem. Pharm.
Bull. 1996, 44, 1680. (b) Kitagawa, I.; Baek, N. I.;
Yokokawa, Y.; Yoshikawa, M.; Ohashi, K.; Shibuya, H.
Chem. Pharm. Bull. 1996, 44, 1693.
(3) Kitagawa, I.; Ohashi, K.; Kawanishi, H.; Shibuya, H.;
Shinkai, K.; Akedo, H. Chem. Pharm. Bull. 1989, 37, 1679.
(4) For the syntheses of resin glycosides by macrolaconization,
see: Tricolorins: (a) Larson, D. P.; Heathcock, C. H. J. Org.
Chem. 1996, 61, 5208. (b) Larson, D. P.; Heathcock, C. H.
J. Org. Chem. 1997, 62, 8406. (c) Lu, S.-F.; O’Yang, Q.-Q.;
Guo, Z.-W.; Yu, B.; Hui, Y.-Z. Angew. Chem., Int. Ed. Engl.
1997, 36, 2344. (d) Lu, S.-F.; O’Yang, Q.-Q.; Guo, Z.-W.;
Yu, B.; Hui, Y.-Z. J. Org. Chem. 1997, 62, 8400. (e) Brito-
Arias, M.; Pereda-Miranda, R.; Heathcock, C. H. J. Org.
Chem. 2004, 69, 4567. Calonyctins: (f) Jiang, Z.-H.;
Geyer, A.; Schmidt, R. R. Angew. Chem., Int. Ed. Engl.
1995, 34, 2520. (g) Furukawa, J.; Kobayashi, S.; Nomizu,
M.; Nishi, N.; Sakairi, N. Tetrahedron Lett. 2000, 41, 3453.
(5) (a) For RCM method in the syntheses of resin glycosides,
see a review: Fürstner, A. Eur. J. Org. Chem. 2004, 943.
Tricolorins: (b) Fürstner, A.; Müller, T. J. Org. Chem. 1998,
63, 424. (c) Fürstner, A.; Müller, T. J. Am. Chem. Soc. 1999,
121, 7814 . Woodrosins: (d) Fürstner, A.; Jeanjean, F.;
Razon, P. Angew. Chem. Int. Ed. 2002, 41, 2097.
(e) Fürstner, A.; Jeanjean, F.; Razon, P.; Wirtz, C.; Mynott,
R. Chem. Eur. J. 2003, 9, 307. (f) Fürstner, A.; Jeanjean, F.;
Razon, P.; Wirtz, C.; Mynott, R. Chem. Eur. J. 2003, 9, 320.
(6) Barry, J.; Kagan, H. B. Synthesis 1981, 453.
(7) Menezra, C.; Mattes, H. J. Med. Chem. 1987, 30, 165.
(8) Zhang, J.-J.; Kong, F.-Z. J. Carbohydr. Chem. 2002, 21, 89.
(9) Mulard, L. A.; Ughetto-Monfrin, J. J. Carbohydr. Chem.
2000, 19, 503.
(10) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
(11) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(12) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96,
5614.
C38H60O10: 699.4084; found: 699.4079.
(14) Spectral data for 19: Rf 0.15 (PE–EtOAc, 2:1); [a]D21 –19.1
(c = 0.44, CHCl3). IR (KBr): 3394, 2924, 1740, 1079, 1051
cm–1. 1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3
H), 1.26 (d, J = 7.8 Hz, 3 H), 1.35 (d, J = 7.2 Hz, 3 H), 1.24–
1.52 (m, 24 H), 1.31, 1.50 (s, 6 H, 2 × CH3), 2.34–2.43 (m, 2
H), 3.51 (dd, J = 8.1, 9.9 Hz, 2 H), 3.91–4.05 (m, 5 H), 4.47
(dd, J = 6.0, 6.6 Hz, 1 H), 4.97 (t, J = 7.8 Hz, 1 H), 5.00 (s,
1 H), 5.07 (s, 1 H). 13C NMR (50 MHz, CDCl3): d = 14.0,
17.7, 22.5, 22.7, 23.6, 25.0, 25.3, 27.6, 28.2, 28.6, 28.7, 29.3,
30.0, 31.7, 32.0, 33.1, 33.4, 34.5, 63.5, 66.7, 71.0, 73.1, 74.4,
75.3, 75.9, 79.7, 80.0, 93.5, 95.3, 109.4, 173.7. HR–ESI–
MS: m/z [M + Na]+ calcd for C31H54O10: 609.3615; found:
609.3609.
Synlett 2006, No. 20, 3510–3512 © Thieme Stuttgart · New York