Synthesis of methyl α-L-callipeltoside

Article abstract of DOI:10.1016/S0008-6215(98)00086-X

The synthesis of callipeltose, a novel amino sugar with the proposed structure, 4-amino-4,6-dideoxy-2,O-3-C-dimethyl-L-talopyranosyl-3,4- urethane, from L-rhamnose is described. Oxime reduction, carbamate cyclization and selective methylation are key steps. The synthesis supports the assignment of the relative stereochemistry of callipeltose.

Full text of DOI:10.1016/S0008-6215(98)00086-X

Carbohydrate Research 308 (1998) 223±227
Note
Synthesis of methyl ꢀ-l-callipeltoside
Garry R. Smith, John J. Finley IV, Robert M. Giuliano *
Department of Chemistry, Villanova University, Villanova, PA 19085, USA
Received 10 February 1998; accepted 23 March 1998
Abstract
The synthesis of callipeltose, a novel amino sugar with the proposed structure, 4-amino-4,6-dideoxy-
2,O-3-C-dimethyl-l-talopyranosyl-3,4-urethane, from l-rhamnose is described. Oxime reduction, car-
bamate cyclization and selective methylation are key steps. The synthesis supports the assignment of
the relative stereochemistry of callipeltose. # 1998 Elsevier Science Ltd. All rights reserved
Keywords: Callipeltose; Methyl ꢀ-l-callipeltoside
Callipeltins are a new class of cyclodepsipeptides
recently isolated by Minale and co-workers from
the marine sponge Callipelta sp. Extracts of the
sponge were found to inhibit in vitro proliferation
of KB and P388 cells and to protect cells infected
with HIV. Further studies of the same extract led to
the isolation of three biologically active macrolides,
callipeltosides A±C, which consist of a macrocyclic
lactone linked to a dienyne cyclopropane side chain
[1]. The novel macrocycle is also linked, in each
case, to a di€erent deoxy sugar. In callipeltoside A,
the carbohydrate component is a new amino sugar
whose structure has been proposed as 4-amino-4,6-
dideoxy-2,O-3-C-dimethyl-l-talopyranosyl-3,4-ure-
thane (1). Callipeltoside B contains an analogous N-
formyl amino sugar 2, while the authors have pro-
posed that callipeltoside C contains 6-deoxy-2,O-3-C-
dimethyl-ꢁ-mannopyranose (3) [2]. The 2-hydroxy,
d-form of 3 is known as evalose and is found in the
oligosaccharide antibiotic everninomicin [3] B; how-
ever, only the relative con®gurations of the carbohy-
drates found in callipeltosides A±C have been
established.
The synthesis of callipeltose (1) has not been
reported. As part of our ongoing e€orts to synthe-
size carbohydrate components of antibiotics, we
have synthesized methyl ꢀ-l-callipeltoside 11 from
1
l-rhamnose. The H NMR data obtained for 11
match that assigned for the carbohydrate
component in the naturally occurring glyco-
side, providing con®rmation of the structure
proposed.
* Corresponding author. Tel.: 001 215 645 4868; fax: 001
0008-6215/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00086-X

224
G.R. Smith et al./Carbohydrate Research 308 (1998) 223±227
The 3-C-methyl branched sugar 4 was prepared
presence of 10% palladium-on-charcoal, to give
the product with the l-talo con®guration. We
observed that reduction of 5 under these conditions
proved to be extremely slow. The use of reduced
platinum oxide as the catalyst resulted in facile
reduction to give amino sugar 6, which was iso-
lated as its benzyl carbamate derivative 7 in 87%
yield. Consistent with the previously reported
results, the reduction of the oxime occurred with
complete stereoselectivity to give 8 as the only iso-
mer. Partial cleavage of the isopropylidene group
from methyl ꢀ-l-rhamnopyranoside [4] as descri-
bed by Klemer [5], by alkylation of the lithium
enolate of methyl 6-deoxy-2,3-O-isopropylidene-ꢀ-
l-lyxo-hexopyranoside-4-ulose. The resulting 3-C-
methyl-branched derivative was converted to the
oxime 5 (Scheme 1), which was previously synthe-
sized [6] by Yoshimura and co-workers as a pre-
cursor to the amino sugar sibirosamine. Reduction
of the oxime was attempted using the method
described by the authors, with hydrogen in the
Scheme 1. Synthesis of methyl ꢀ-l-callipeltoside.

G.R. Smith et al./Carbohydrate Research 308 (1998) 223±227
occurred during reduction to give diol 8, which 1. Experimental
225
could be separated for purposes of characterization
of both 7 and 8. Products resulting from transgly-
cosylation with solvent (ethanol) were not observed.
Treatment of the crude reduction product with
60% acetic acid resulted in complete removal of
the isopropylidene group. Completion of the
synthesis of callipeltose required selective methyla-
tion of the C-2 hydroxyl group in the presence of
the carbamate nitrogen and cyclization. The con-
ditions used for these transformations proved to be
problematic, owing to the propensity of the nitro-
gen to undergo alkylation. The cyclization of 8 to 9
occurred eciently in the presence of sodium
hydride, using conditions described by Sugawara
and Narisada [7] for a di€erent system. However, 9
underwent conversion to its N-methyl derivative
when treated with sodium hydride and one
equivalent of iodomethane. It was found that
methylation of either 8 or 9 occurred selectively
using silver oxide and iodomethane in DMF [6,8]
to give the corresponding 2-O-methyl derivatives
10 and 11. Methylation of 8 stopped short of
completion, and the formation of side products
was observed. The yield of 77% for this step is
based on recovered starting material. Methylation
of 9 occurred more cleanly to give methyl ꢀ-l-cal-
lipeltoside 11. The 1H NMR spectrum of 11
was remarkably similar to that reported for the
carbohydrate in the natural glycoside. A compari-
son is given in Table 1. These data support the
original assignment of relative stereochemistry for
callipeltose.
General methods.Ð1H NMR spectra were recor-
ded on a Varian XL 300 spectrometer at 300 MHz
with Me4Si as an internal reference in CDCl3,
unless otherwise noted. 13C NMR spectra were
recorded on a Varian XL 300 spectrometer at
75 MHz and referenced with CDCl3. Melting
points were determined in an open capillary tube
with a Thomas±Hoover apparatus and are uncor-
rected. TLC analyses were conducted on silica gel
(Kieselgel 60 F254, E. Merck) glass plates and
visualized by UV254 nm or with ammonium molyb-
date±ceric sulfate reagent. Column chromatog-
raphy was carried out with J. T. Baker's silica
gel. Optical rotations were recorded on a ꢀPerkin±
Elmer 241 polarimeter as [ꢀ]d values at 23 C. Ele-
mental analysis were carried out at Merck Research
Laboratories. High-resolution mass spectra were
measured at Merck Research Laboratories using
ES-FT/ICR/MS with propylene glycol as internal
standard on a Bruker ES-FT mass spectrometer.
Methyl 4-(benzyloxycarbonylamino)-4,6-dideoxy-
2,3-O-isopropylidene-3-C-methyl-a-l-talopyranoside
(7). A solution of methyl 6-deoxy-2,3-O-iso-
propylidene-3-C-methyl-ꢀ-l-lyxo-hexopyranosid-4-
ulose oxime5 (5, 3.1 g) in 95% ethanol (120 mL)
containing HCl (1 M, 25 mL) and platinum(IV)
oxide (1.4 g) was shaken on a Parr apparatus for
48 h. The reaction was ®ltered over Celite and was
made neutral with basic ion-exchange resin
(hydroxide, 6 g) and was again ®ltered through
Celite. The reaction mixture was concentrated
Table 1
Comparison of NMR data for methyl ꢀ-l-callipeltoside and the carbohydrate portion of callipeltoside A
Methyl ꢀ-l-callipeltoside
Callipeltoside A
H-1
H-2
H-4
H-5
H-6
3-CH3
2-OCH3
4.74 (d, J 6.1 Hz)
3.42 (d, J 6.1 Hz)
3.48 (d, J 1.7 Hz)
3.99 (dq, J 6.5, 1.7 Hz)
1.12 (d, J 6.5 Hz)
1.54 (s)
4.48 (d, J 6.2 Hz)
3.39 (d, J 6.2 Hz)
3.46 (d, J 1.7 Hz)
3.94 (dq, J 6.4, 1.7 Hz)
1.12 (d, J 6.4 Hz)
1.50 (s)
3.63 (s)
3.53 (s)
C-1
C-2
C-3
C-4
C-5
C-6
3-CH3
2-OCH3
C=O
103.6
83.2
83.8
62.7
65.3
15.9
23.0
62.0
161.2
103.5
82.3
83.7
62.6
65.5
15.9
23.1
61.0
161.1

226
G.R. Smith et al./Carbohydrate Research 308 (1998) 223±227
at reduced pressure, and the resulting methyl
4-amino-4,6-dideoxy-2,3-O-isopropylidene-3-C-
methyl-ꢀ-l-talopyranoside (6) (2.9 g, 12.5 mmol)
OCH3), 1.40 (s, 3 H, 3-CH3), 1.17 (d, J5,6 6.5 Hz, 3
H, H-6); 13C NMR (75 MHz) ꢂ 157.65 (C=O),
136.33 (Ar ipso), 127.83, 127.91, 128.28, 128.33
(Ar), 101.39 (C-1), 72.75 (C-2), 69.28 (C-3), 66.80
(PhCH2), 64.26 (C-5), 58.59 (C-4), 55.11 (OCH3),
24.39 (3-CH3), 17.05 (C-6). Anal. Calcd for
C16H23NO6: C, 59.07; H, 7.13, N, 4.30. Found: C,
58.87; H, 7.16; N, 4.20.
ꢀ
was dissolved in dichloromethane (60 mL) at 0 C
and treated with benzyl chloroformate (2.15 mL,
15.0 mmol) and diisopropylethylamine (3.1 mL,
17.6 mmol). The resulting solution was allowed to
warm to ambient temperature for 1.5 h, after which
time it was diluted with dichloromethane (50 mL)
and poured into satd aq NaHCO3 (50 mL). The
layers were separated, and the aqueous layer was
extracted again with dichloromethane (30 mL).
The organic layers were combined, dried (Na2SO4),
®ltered and concentrated at reduced pressure. The
resulting oil was puri®ed by ¯ash chromatography
on silica gel with 1:4 ethyl acetate±hexane to give
3.3 g of a colorless oil as well as 0.60 g of the 2,3-
deprotected product (87%): [ꢀ]d 37.4ꢀ (c 1.00;
chloroform); Rf 0.82 in 1:1 hexanes±ethyl acetate;
1H NMR (300 MHz) ꢂ 7.40±7.25 (m, 5 H, Ar), 5.18
(br. d, JNH,4 10.3 Hz, 1 H, NH), 5.12 (d, J 2.5 Hz, 2
H, PhCH2), 4.85 (s, 1 H, H-1), 3.97 (br q, J5,6
6.6 Hz, 1 H, H-5), 3.71 (s, 1 H, H-2), 3.52 (br d,
JNH,4 10.4 Hz, 1 H, H-4), 3.37 (s, 3 H, OCH3), 1.47
(s, 3 H, 3-CH3), 1.34, 1.39 (each s, 3 H, CH3), 1.21
(d, J5,6 6.5 Hz, 3 H, H-6); 13C NMR (75 MHz) ꢂ
155.64 (C=O), 127.86, 128.02, 128.09 (Ar), 135.52
(Ar ipso), 108.46 (Cq, acetal), 98.37 (C-1),
77.77 (C-2), 66.62 (PhCH2), 63.27 (C-5), 57.55
(C-3), 56.22 (C-4), 54.84 (OCH3), 25.38, 25.87
(2xCH3), 24.62 (3-CH3), 17.28 (C-6). HRMS:
Calcd for C19H28NO6 (M+1), 366.1911. Found,
366.1917.
Methyl 4-amino-3-O,4-N-carbonyl-4,6-dideoxy-
3-C-methyl-a-l-talopyranoside (9). A stirred solu-
tion of methyl 4-(benzyloxycarbonylamino)-4,6-
dideoxy-3-C-methyl-ꢀ-l-talopyranoside (500 mg,
1.54 mmol) in tetrahydrofuran (14 mL) under
ꢀ
nitrogen was cooled to 0 C. To this solution was
added sodium hydride (44 mg, 1.84 mmol) in one
portion, and the resulting suspension was allowed
to warm to ambient temperature for 1.5 h. The
reaction was quenched with satd aq NaHCO3
(5 mL), and the resulting mixture was extracted
with ethyl acetate (6Â30 mL). The organic layers
were combined, dried (Na2SO4), decanted, and
concentrated at reduced pressure to yield a solid.
This solid was triturated with ethyl ether (5 mL)
and ®ltered to yield 297 mg of a white powder
(89%): mp 234±236 ꢀC; [ꢀ]d
87.5ꢀ (c 0.92;
methanol); Rf 0.38 in 95:5 ethyl acetate±methanol;
1H NMR (300 MHz, CD3OD) ꢂ 4.41 (d, 1 H, H-1),
3.93 (dq, 1 H, H-5), 3.65 (d, J1,2 6.3 Hz, 1 H, H-2),
3.45 (d, J4,5 1.7 Hz, 1 H, H-4), 3.40 (s, 3 H, OCH3),
1.49 (s, 3 H, 3-CH3), 1.11 (d, J5,6 6.4 Hz, 3 H, H-6);
13C NMR (75 MHz, CD3OD) ꢂ 161.1 (CO), 103.8
(C-1), 83.9 (C-3), 73.0 (C-2), 65.5 (C-5), 62.7 (C-4),
55.7 (OCH3), 23.2 (3-CH3), 16.0 (C-6). Anal. Calcd
for C9H15NO5: C, 49.76; H, 6.96; N, 6.45. Found:
C, 49.36; H, 6.76; N, 6.26.
Methyl 4-(benzyloxycarbonylamino)-4,6-dideoxy-
3-C-methyl-a-l-talopyranoside (8). A stirred solu-
tion of methyl 4-(benzyloxycarbonylamino)-4,6-
dideoxy-2,3-O-isopropylidene-3-C-methyl-ꢀ-l-talo-
pyranoside (700 mg) in 60% acetic acid (15 mL)
was heated at 70±75 ꢀC for 13 h. The reaction
mixture was then concentrated at reduced pressure
to yield an amber oil that was concentrated from
toluene (3 mL) twice. The resulting oil was puri®ed
by ¯ash chromatography on silica gel (200 g) with
2:3 ethyl acetate±hexane to give 540 mg of a color-
less oil which crystallized on standing (87%): mp
Methyl 4-amino-3-O,4-N-carbonyl-4,6-dideoxy-
3-C,2-O-dimethyl-a-l-talopyranoside (11). To a
stirring solution of methyl 4-amino-3-O,4-N-car-
bonyl-4,6-dideoxy-3-C-methyl-ꢀ-l-talopyranoside
(50 mg, 0.23 mmol) in N,N-dimethylformamide
(0.5 mL) was added silver oxide (213 mg,
0.92 mmol) and iodomethane (143 ꢃL, 2.3 mmol),
ꢀ
and the resulting mixture was warmed at 40±45 C
for 20 h. The reaction mixture was allowed to cool
to room temperature and was then diluted with
ethyl acetate and ®ltered through Celite. The
resulting clear solution was washed with deionized
water (2 mL) and extracted with ethyl acetate
(5Â5 mL). The organics were combined, dried
(Na2SO4), decanted, and concentrated at reduced
pressure to yield 46 mg of a white solid (86%): mp
ꢀ
111±113 C; [ꢀ]d 72.5ꢀ (c 1.13, chloroform); Rf
0.31 in 1:1 hexanes±ethyl acetate; 1H NMR
(300 MHz) ꢂ 7.38±7.25 (m, 5 H, Ar), 5.85 (br d,
JNH,4 10.3 Hz, 1 H, NH), 5.10 (ABq, J 21.3 Hz,
12.2 Hz, 2 H, PhCH2), 4.71 (s, 1 H, H-1), 4.03 (br
q, J5,6 6.6 Hz, 1 H, H-5), 3.55 (br d, JNH,4 10.3 Hz,
1 H, H-4), 3.39 (br s, 1 H, H-2), 3.34 (s, 3 H,
ꢀ
147±148 C; [ꢀ]d= 88.5ꢀ (c 0.76; methanol); Rf

G.R. Smith et al./Carbohydrate Research 308 (1998) 223±227
227
0.49 in 95:5 ethyl acetate±methanol; 1H NMR
(300 MHz, CD3OD) ꢂ 4.48 (d, J1,2 6.2 Hz, 1 H,
H-1), 3.94 (dq, J4,5 1.7 Hz, J5,6 6.4 Hz, 1 H, H-5),
3.53 (s, 3 H, 2-OCH3), 3.46 (d, J4,5 1.7 Hz, 1 H, H-
4), 3.40 (s, 3 H, 1-OCH3), 3.39 (d, J1,2 6.2 Hz, 1 H,
H-2), 1.50 (s, 3 H, 3-CH3), 1.12 (d, J5,6 6.4 Hz, 3 H,
H-6); 13C NMR (75 MHz, CD3OD) ꢂ 161.1 (CO),
103.5 (C-1), 83.7 (C-3), 82.3 (C-2), 65.5 (C-5), 62.6
(C-4), 61.0 (2-OCH3), 55.2 (1-OCH3), 23.1 (3-
CH3), 15.9 (C-6). Anal. Calcd for C10H17NO5: C,
51.94; H, 7.41; N, 6.06. Found: C, 52.13; H, 7.06;
N, 5.93. HRMS: Calcd for C10H18NO5 (M+1):
232.1182. Found: 232.1179.
for elemental analyses and HRMS measurements,
respectively.
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The authors thank Merck Research Labora-
tories and Villanova University for ®nancial sup-
port, including a research fellowship for G. Smith
from the Medicinal Chemistry Department. We also
thank Patrice Ciecko and C.W. Ross III of Merck
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