Synthesis of L-cladinose using enantioselective desymmetrization

Article abstract of DOI:10.1055/s-2008-1078046

L-Cladinose, a neutral sugar found in erythromycins and azithromycins, has been synthesized efficiently using enantioselective monobenzoylation of 2-propenylglycerol in the presence of the imine-CuCl₂ catalysts to elaborate the stereogenic quaternary center. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078046

2526
LETTER
Synthesis of L-Cladinose Using Enantioselective Desymmetrization
S
ynthesis of
L-Cla
y
dinose oung Cheul Kim,a Joo-Hack Youn,b Sung Ho Kang*a
a
Department of Chemistry, School of Molecular Science (BK21), KAIST, Daejeon 305-701, Korea
Fax +82(42)8692810; E-mail: shkang@kaist.ac.kr
Department of Chemical Engineering, Sun Moon University, Asan Si, Chung-Nam 336-840, Korea
b
Received 8 July 2008
HO
O
Abstract: L-Cladinose, a neutral sugar found in erythromycins and
azithromycins, has been synthesized efficiently using enantioselec-
tive monobenzoylation of 2-propenylglycerol in the presence of the
imine-CuCl2 catalysts to elaborate the stereogenic quaternary cen-
ter.
OH
RO
1: R = H L-mycarose
2: R = Me L-cladinose
Key words: L-mycarose, L-cladinose, desymmetrization, quaterna-
ry centers, imine-CuCl2
OH
OH
HO
HO
HO
O
O
c
a, b
O
71%
BzO
3
4
(R)-8
A branched neutral sugar L-mycarose (1, 2,6-dideoxy-3C-
methyl-L-ribohexose; Scheme 1) is present1 in magnamy-
cin (cabomycin),2 erythromycins C and D,3 tylosin,4 mith-
ramycin,5 spiramycin,6 leucomycin,7 and kedarcidin
chromophore.8 Its 3-methyl ether L-cladinose (2;
Scheme 1) is attached to erythromycins A, B, F, and G.3
Since the first nonstereoselective synthesis of mycarose
disclosed from acetoacetaldehyde dimethyl acetal,9 their
several synthetic routes have been reported through
methyl Grignard additions to ketones10 and aldol
condensation11 in the formation of the tertiary alcohol
functionality. All the approaches have exploited the pre-
existing asymmetric center(s) to induce the desired stere-
ochemistry with relatively low stereoselectivity. In
connection with our recently developed enantioselective
desymmetrization to install hydroxyl-containing quater-
nary centers,12 we have been engaged in synthetic studies
on natural products embedded with the stereogenic qua-
ternary centers. One of our on-going targets is azithro-
mycin A, an erythromycin A derived semisynthetic
macrolide antibiotic comprising L-cladinose.13 Herein, we
describe an enantioselective synthesis of L-cladinose (2;
Scheme 1) using the desymmetrizing monobenzoylation
to introduce the requisite tertiary alcohol functionality.
d, b
70%
h
98%
e, f 65%
OH
HO
OH
HO
HO
OH
BzO
HO
HO
9
(S)-8
e, g
11
c
e, g
66%
OH
70%
OH
OH
HO
BzO
e, f
73%
10
13
12
t-Bu
O
O
O
N
N
N
N
N
Cu
Cl2
Cu
Cl2
Ph
Bn
Bn
Br
5: (R)-Ph, (S)-t-Bu
6: (S)-Ph, (R)-t-Bu
7
Scheme 1 Reagents and conditions: a) trans-MeCH=CHBr, t-BuLi,
THF, –78 °C; b) dilute aq HCl, MeOH, r.t.; c) 5 (20 mol%) or 7 (5
mol%), BzCl, Et3N, THF, r.t.; d) cis-MeCH=CHBr, t-BuLi, THF, –78
°C; e) MsCl, Et3N, CH2Cl2, –78 °C, then DBU, r.t.; f) Red-Al, THF,
0 °C; g) CH2=CHMgBr, CuI, THF, –40 to –20 °C; h) 6 (20 mol%),
BzCl, Et3N, THF, r.t.
The synthesis began with preparation of the desymmetri-
zation substrate glycerol 4 (Scheme 1). The known ketone
314 was coupled with the propenyllithium generated by
transmetalation of trans-1-bromo-1-propene and then hy-
drolyzed to afford the triol 4 in 71% overall yield
(Scheme 1). While the desymmetrization of 4 using the
imine-CuCl2 catalyst 5 furnished 98% of the monoben-
zoate (R)-8 with 91% ee,12a the bisoxazoline-CuCl2 cata-
lyst 7 induced much inferior stereoselectivity (28% ee)
and 91% chemical yield. Due to the potential utility of the
desymmetrization product, the cis-isomeric triol 9, pro-
cured by the similar sequence to 4, was also subjected to
the monobenzoylation to give the expected monobenzoate
10 in 85–90% yield with 82% ee using 5 but merely 29%
ee in the presence of 7 (Scheme 1).
For the synthesis of the target L-cladinose, the enantio-
merically enriched diol (R)-8 was mesylated and then cy-
clized with DBU in one pot to give rise to the epoxide in
81% yield (Scheme 1). Subsequently, it was reductively
deoxygenated and concomitantly debenzoylated by Red-
Al to deliver the allylic alcohol 11 in 80% yield
(Scheme 1).
SYNLETT 2008, No. 16, pp 2526–2528
x
x
.x
x
.2
0
0
8
Advanced online publication: 10.09.2008
DOI: 10.1055/s-2008-1078046; Art ID: U07208ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of L-Cladinose
2527
After conversion of 11 into the corresponding epoxide in
79% yield by the one-pot mesylation–cyclization process,
the epoxide was exposed to vinyl Grignard reagent in the
presence of CuI to offer the diene 12 in 89% yield
(Scheme 1).15 Alternatively, 12 could be derived from the
monobenzoate (S)-8 enantiomeric to (R)-8 by switching
the orders of the reductive epoxide opening and the cu-
prate-driven epoxide substitution. The desymmetrization
of 4 with the catalyst 6 supplied (S)-8 with the expected
level of enantioselectivity (91% ee), which was function-
alized to the epoxide in 81% yield by the one-pot opera-
tion. Treatment of the generated epoxide with vinyl anion
effected substitution as well as debenzoylation to render
the diol 13 in 81% yield (Scheme 1). Reductive removal
of the primary hydroxyl group of 13 was carried out via
epoxide formation with Red-Al to provide the diene 12 in
73% overall yield (Scheme 1).
OH
H
MeO
O
c, d
O
a, b
12
O
66%
74%
OMe
14
15
HO
O
2-pyS
O
e
f, g
81%
63%
OH
OTBS
MeO
MeO
16
2
Scheme 2 Reagents and conditions: a) VO(acac)2, t-BuO2H,
CH2Cl2, 0 °C to r.t. (83%); b) NaH, MeI, THF, 0 °C to r.t. (80%);
c) RuCl3(H2O)n, NaIO4, CH2Cl2, MeCN, H2O, 15 °C (80%); d) BF3·OEt2,
CH2Cl2, 0 °C to r.t. (86%); e) DIBAL-H, THF, –78 °C (81%);
f) TBSCl, AgNO3, pyridine, THF, r.t.; g) (2-pyS)2, (n-Bu)3P, CH2Cl2,
r.t.
The allylic alcohol 12 was epoxidized not only chemose-
lectively but also stereoselectively in 83% yield using
V(IV)-promoted tert-butyl hydroperoxide (Scheme 2).16
The tertiary hydroxyl group of the resultant epoxy alcohol
was methylated to produce the methyl ether 14 in 80%
yield (Scheme 2).17 After ozonolysis of 14, the generated
aldehyde was unsuccessfully attempted to form the de-
sired pyranose or pyranoside via the corresponding fura-
nosyl derivative under various acidic conditions in the
presence of several nucleophiles such as H2O, alcohol,
thiol, etc. The ineffective synthetic plan led us to employ
carboxylic acid rather than the aldehyde. The olefinic
double bond of 14 was oxidatively cleaved in 86% yield
and the resulting carboxylic acid was most efficiently cy-
clized to the butyrolactone 15 in 86% yield in the presence
of 0.3 equivalents of BF3·OEt2 (Scheme 2).18 The requi-
site rearrangement of 15 to the six-membered lactone
failed under various acidic or basic conditions. When 15
was reduced to the corresponding furanose with DIBAL-
H, it was spontaneously rearranged to the pyranose to im-
part L-cladinose (2) in 81% yield (Scheme 2),19 the spec-
tral data of which were found to be identical with the
reported.11 In order to prepare the known glycosyl donor
for our azithromycin synthesis, the synthetic L-cladinose
(2) was silylated in the presence of AgNO3 and then cou-
pled with 2,2¢-dithiodipyridine under Mitsunobu condi-
tions to produce the thiocladinoside 16 in 63% overall
yield (Scheme 2).20
Acknowledgment
This work was supported by the Korea Science and Engineering
Foundation (KOSEF) grant funded by the Korean government
(MOST) (R01-2007-000-10051-0).
References and Notes
(1) Johnson, D. A.; Liu, H.-w. In Comprehensive Chemistry of
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P. F. Antibiot. Chemother. 1961, 11, 328. (b) Achenbach,
H.; Regel, W.; Karl, W. Chem. Ber. 1975, 108, 2481.
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1997, 119, 12012.
In summary, a practical synthesis of L-cladinose has been
completed through twelve steps from the readily available
ketone 3 in 12.5% overall yield. The synthesis culminated
in setting up the C4-stereogenic quaternary center by our
developed enantioselective desymmetrization of 2-substi-
tuted glycerols, which is considered of great synthetic
utility to settle the abstruse installation of the hydroxyl-
containing quaternary asymmetric carbons.
(9) Lemal, D. M.; Pacht, P. D.; Woodward, R. B. Tetrahedron
1962, 18, 1275.
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Soc. C 1966, 398. (b) Howarth, G. B.; Jones, J. K. N. Can. J.
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T.; Mukaiyama, S.; Tatsuta, K. Tetrahedron Lett. 1991, 32,
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Synlett 2008, No. 16, 2526–2528 © Thieme Stuttgart · New York

2528
H. C. Kim et al.
LETTER
column chromatography (SiO2, 230–400 mesh, EtOAc–
(11) Montgomery, S. H.; Pirrung, M. C.; Heathcock, C. H.
Carbohydr. Res. 1990, 32, 13.
(12) (a) Jung, B.; Kang, S. H. Proc. Natl. Acad. Sci. U. S. A. 2007,
104, 1471. (b) Jung, B.; Hong, M. S.; Kang, S. H. Angew.
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(13) (a) Bright, G. M.; Nagel, A. A.; Bordner, J.; Desai, K. A.;
Dibrino, J. N.; Nowakowska, J.; Vincent, L.; Watrous,
R. M.; Sciavolino, F. C.; English, A. R.; Retsema, J. A.;
Anderson, M. R.; Brennan, L. A.; Borovoy, R. J.;
Cimochowski, C. R.; Faiella, J. A.; Girard, A. E.; Girard, D.;
Herbert, C.; Manousos, M.; Mason, R. J. Antibiot. 1988, 41,
1029. (b) Retsema, J. A.; Girard, A. E.; Schelkly, W.;
Manousus, M.; Anderson, M. R.; Bright, G. M.; Borovoy, R.
J.; Brennan, L. A.; Mason, R. Antimicrob. Agents
Chemother. 1987, 31, 1939. (c) Kirst, H. A.; Sides, G. D.
Antimicrob. Agents Chemother. 1989, 33, 1419.
hexane, 1:2) to give the corresponding carboxylic acid
(267 mg, 80%). The carboxylic acid (267 mg, 1.53 mmol) in
CH2Cl2 (4 mL) was stirred in the presence of BF3·OEt2
(58 mL, 0.46 mmol) at 0 °C for 10 min and then at r.t. for 5
h. After addition of H2O (3 mL), the resulting solution was
extracted with EtOAc (3 × 5 mL), the organic layer was dried
over MgSO4 (400 mg), filtered and evaporated in vacuo. The
residue was separated by column chromatography (SiO2,
230–400 mesh, EtOAc–hexane, 1:2) to afford the lactone 15
(229 mg, 86%).
Compound 15: 1H NMR (400 MHz, CDCl3): d = 1.28 (d,
J = 6.3 Hz, 3 H), 1.42 (s, 3 H), 2.52 (d, J = 17.1 Hz, 1 H),
2.66 (d, J = 17.1 Hz, 1 H), 3.24 (s, 3 H), 3.88–3.95 (m, 1 H),
4.06 (d, J = 7.1 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
d = 17.6, 20.4, 41.5, 51.1, 66.5, 80.6, 87.9, 174.0. HRMS
(EI): m/z calcd for C8H14O4: 174.0892; found: 174.0889.
(19) Synthesis of L-Cladinose (2)
(14) Hoppe, D.; Schmincke, H.; Kleemann, H.-W. Tetrahedron
1989, 45, 687.
(15) Compound 12: 1H NMR (400 MHz, CDCl3): d = 1.26 (s, 3
H), 1.64 (br s, 1 H), 1.70 (d, J = 5.2 Hz, 3 H), 2.11–2.48 (m,
2 H), 5.07–5.21 (m, 2 H), 5.59 (d, J = 14.0 Hz, 1 H), 5.71–
5.92 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 17.6, 27.7,
47.2, 71.8, 118.7, 122.9, 133.9, 137.6. HRMS (EI): m/z calcd
for C8H14O: 126.1044; found: 126.1041.
Diisobutylaluminum hydride (1.0 M in THF, 2.87 mL, 2.87
mmol) was added to 15 (200 mg, 1.15 mmol) in THF (5 mL)
dropwise at –78 °C and the resulting mixture was stirred at
that temperature for 3 h. The reaction was quenched with a
4:1 mixture of MeOH and H2O at –78 °C, and then the
temperature was raised to r.t. After addition of sat. NaHCO3
(0.5 mL) and MgSO4 (200 mg) to the mixture, it was filtered
using EtOAc (10 mL), and the organic layer was evaporated
in vacuo. The remaining residue was purified by column
chromatography (SiO2, 230–400 mesh, EtOAc–hexane, 1:1)
to deliver L-cladinose (2, 164 mg, 81%).
(16) Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharpless, K. B.;
Michaelson, R. C.; Cutting, J. D. J. Am. Chem. Soc. 1974,
96, 5254.
(17) Synthesis of Epoxide 14
Vanadyl(acetylacetonate) (25 mg, 0.095 mmol) and
t-BuO2H (2.0 M in CH2Cl2, 2.38 mL, 4.76 mmol) were
added to diene 12 (400 mg, 3.17 mmol) in CH2Cl2 (3 mL) at
0 °C in sequence. The mixture was stirred at 0 °C for 30 min
and then at r.t. for 6 h. After quenching the excess peroxide
with 10% aq Na2S2O3 (10 mL), the following extraction with
EtOAc (3 × 5 mL), drying over MgSO4 (500 mg), filtration
and evaporation under reduced pressure gave the crude
product, which was separated by column chromatography
(SiO2, 230–400 mesh, EtOAc–hexane, 1:3) to furnish the
desired epoxide (374 mg, 83%) along with the regioisomeric
epoxide (35 mg, 7%). Sodium hydride (60% dispersion in
mineral oil, 126 mg, 3.16 mmol) was added to the
disubstituted epoxide (374 mg, 2.63 mmol) in THF (3 mL)
at 0 °C portionwise. To the generated alkoxide was injected
MeI (0.25 mL, 4.0 mmol), and the resulting solution was
stirred at 0 °C for 15 min and then at r.t. for 3 h. After
quenching the methylation with sat. NH4Cl (3 mL), the
workup was done by extraction with EtOAc (3 × 4 mL),
drying with MgSO4 (300 mg), filtration and evaporation in
vacuo. The residual material was purified chromato-
graphically (SiO2, 230–400 mesh, EtOAc–hexane, 1:4) to
render the epoxy methyl ether 14 (329 mg, 80%).
Compound 14: 1H NMR (400 MHz, CDCl3): d = 1.21 (s, 3
H), 1.33 (d, J = 5.2 Hz, 3 H), 1.91–2.10 (m, 2 H), 2.71 (d,
J = 2.3 Hz, 1 H), 3.12 (qd, J = 5.2, 2.3 Hz, 1 H), 3.31 (s, 3
H), 5.10–5.25 (m, 2 H), 5.78–5.94 (m, 1 H). 13C NMR (100
MHz, CDCl3): d = 17.3, 25.1, 39.1, 51.5, 52.6, 62.4, 63.5,
118.1, 133.6. HRMS (EI): m/z calcd for C9H16O2: 156.1150;
found: 156.1145.
(20) (a) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan,
K.; Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne,
L. J.; Card, P. J.; Chen, C. H.; Chenevert, R. B.; Fliri, A.;
Frobel, K.; Gais, H.-J.; Garratt, D. G.; Hayakawa, K.;
Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt,
J. A.; Ikeda, D.; Jacobi, P. A.; Kim, K. S.; Kobuke, Y.;
Kojima, K.; Krowicki, K.; Lee, V. J.; Leutert, T.;
Malchenko, S.; Martens, J.; Matthews, R. S.; Ong, B. S.;
Press, J. B.; Rajan Babu, T. V.; Rousseau, G.; Sauter, H. M.;
Suzuki, M.; Tatsuta, K.; Tolbert, L. M.; Truesdale, E. A.;
Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.;
Vladuchick, W. C.; Wade, P. A.; Williams, R. M.; Wong,
H. N.-C. J. Am. Chem. Soc. 1981, 103, 3210.
(b) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan,
K.; Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne,
L. J.; Card, P. J.; Chen, C. H.; Chenevert, R. B.; Fliri, A.;
Frobel, K.; Gais, H.-J.; Garratt, D. G.; Hayakawa, K.;
Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt,
J. A.; Ikeda, D.; Jacobi, P. A.; Kim, K. S.; Kobuke, Y.;
Kojima, K.; Krowicki, K.; Lee, V. J.; Leutert, T.;
Malchenko, S.; Martens, J.; Matthews, R. S.; Ong, B. S.;
Press, J. B.; Rajan Babu, T. V.; Rousseau, G.; Sauter, H. M.;
Suzuki, M.; Tatsuta, K.; Tolbert, L. M.; Truesdale, E. A.;
Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.;
Vladuchick, W. C.; Wade, P. A.; Williams, R. M.; Wong,
H. N.-C. J. Am. Chem. Soc. 1981, 103, 3213.
(c) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan,
K.; Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne, L.
J.; Card, P. J.; Chen, C. H.; Chenevert, R. B.; Fliri, A.;
Frobel, K.; Gais,
(18) Synthesis of Lactone 15
To epoxide 14 (300mg, 1.92 mmol), dissolved in a mixture
of CH2Cl2 (4 mL), MeCN (4 mL), and H2O (6 mL), were
added NaIO4 (1.68 g, 7.87 mmol) and RuCl3·3H2O (16 mg)
sequentially at r.t., and the mixture was stirred at that
temperature for 8 h. After addition of CH2Cl2 (50 mL) to the
mixture, the resulting solution was washed with aq HCl
(1.0 M, 30 mL) twice and then brine (20 mL) once. The
remaining organic layer was dried over MgSO4 (1 g), filtered
and evaporated in vacuo. The residue was purified by
H.-J.; Garratt, D. G.; Hayakawa, K.; Heggie, W.; Hesson, D.
P.; Hoppe, D.; Hoppe, I.; Hyatt, J. A.; Ikeda, D.; Jacobi, P.
A.; Kim, K. S.; Kobuke, Y.; Kojima, K.; Krowicki, K.; Lee,
V. J.; Leutert, T.; Malchenko, S.; Martens, J.; Matthews, R.
S.; Ong, B. S.; Press, J. B.; Rajan Babu, T. V.; Rousseau, G.;
Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Tolbert, L. M.;
Truesdale, E. A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella,
A. T.; Vladuchick, W. C.; Wade, P. A.; Williams, R. M.;
Wong, H. N.-C. J. Am. Chem. Soc. 1981, 103, 3215.
Synlett 2008, No. 16, 2526–2528 © Thieme Stuttgart · New York