Solid-phase synthesis of levoglucosan derivatives

Article abstract of DOI:10.1055/s-1998-1874

Levoglucosan was decorated with a variety of substituents at various sites while being bound to a solid support.

Full text of DOI:10.1055/s-1998-1874

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Solid-Phase Synthesis of Levoglucosan Derivatives
Wolfgang K.-D. Brill*, Alain De Mesmaeker, Sebastian Wendeborn
Combinatorial Chemistry, Novartis Pharma AG, S-507.3.12, CH-4002-Basle, Switzerland
Fax: +41 61 3244236; wolfgang_k-d.brill@pharma.novartis.com
Received 11 May 1998
11
Abstract: Levoglucosan was decorated with a variety of substituents at
to decomposition. The RAM-resin , which was used to obtain 7b, was
various sites while being bound to a solid support.
found to be too labile to hydrolysis, leading to low yields. Ammonia,
primary and secondary amines were used to open the epoxides under
12
catalysis of LiClO or LiBPh , the latter being equally potent, more
4
4
Levoglucosan has frequently been used as building block in the de novo
soluble, but not explosive (Scheme 3, Table 2). Unfortunately 8i and 8j
1
2
3
synthesis of natural products their analogs and polymers . Here we
describe the use of the 6,8-dioxa-bicyclo[3.2.1]octane skeleton as a
scaffold for the generation of a compound library. Herein the carbons 2,
3 and 4 on the levoglucosan scaffold were decorated with various
alkoxy, thioxy or amino groups using epoxide opening and alkylation
could not be afforded without side products. The reaction with
13
multifunctional amines like ammonia or piperazine was accompanied
by very few crosslinking products. Various thiols could be used to open
the epoxide when they were deprotonated by LiHMDS or DBU (for
14
9a) with Li-ions acting as Lewis acid (Scheme 4, Table 3).
1
2
3
reactions. Moieties (R , R or R ) bearing another amino or an aromatic
iodo-function, were derivatized further using acylations or Pd-mediated
Compounds 7a and 7i were alkylated at their 4-positions with n-dodecyl
iodide, benzyl bromide and m-iodobenzyl chloride in presence of
coupling reactions (Scheme 1). We immobilized the scaffold onto
15,16
1
KOtBu to afford 10a-c (Scheme 5, Table 4).
The products of
“Rink”-amide resin ( ) via various spacers (R ). The levoglucosan-
5
epoxide openings with piperazine or ammonia (8f-h) could be
exhaustively acylated using standard conditions. Thus, treatment of 8h
with a solution of acetic anhydride (1M) and DMAP (0.05M) in
pyridine at r. t. for 16 hours gave the diacetylated sugar 11d. In turn,
selective N-acylations with 4-iodobenzenesulfonyl chloride were
performed after exhausive silylation of the polymer bound sugars
spacer adducts (
4a-d
dianhydro-2-O-p-toluenesulfonyl-β-D-galactopyranose ( ) upon BF -
) were synthesized off bead from 1,6: 3,4-
4
1
3
catalyzed epoxide opening with various methylester bearing alcohols
5
(
).
2a-d
The tosylated levoglucosan spacer conjugates (3a-d) were then treated
with LiOH to hydrolyze their methyl ester and generate the 2,3-epoxides
(4a-d). These lithium salts were then coupled to polystyrene or RAM-
resin bearing “Rink”-NH (5) using standard techniques. The TFA-
cleavage protocol prevented build up of high TFA concentrations during
the evaporation, thus glycosidic scission. Subsequent diversification on
the 2-position of the scaffold were performed using epoxide opening
17
(Scheme 6, Table 5, Method A). The epoxide openings of 13 with 8f
gave 11e, while 8h rendered unreactive under identical conditions.
6,7
2
1
2
Compounds bearing iodine atoms in R (6d, 8d), R (7a, 8b, 8c) or
3
R (10c) were used as substrates for various Pd-mediated reactions
18-21
(Scheme 7).
The catalysts tolerated the potentially chelating
scaffold with amide, sulfonamide (11a-c), amine (8b,c), hydroxy,
epoxide (6d) and ether functionalities (Scheme 7, Table 6). Coupling
reactions with electron poor aryl iodides were facile, while electron less
deficient or sterically crowded residues (6d, 7a, 8d) required two or
9
reactions with alcohols, amines and thiols (Scheme 2).
Epoxide openings with alcohols were mediated by KOtBu or P<t/4>-t-
10
Bu (Scheme 2, Table 1). The reactions involving the “Schwesinger
base” were always found to be free of precipitates, which readily occur
with other bases upon absorption of even traces of water or CO .
Opening reactions with pentenyl alcohol (7e) and cholesterol (7h),
failed due to double bond migrations leading to enol ethers unstable to
22
more consecutive couplings separated by crucial resin washes. While
1
2
the spacer R was of minor importance for the coupling, pyridyl
stannanes or boronates (Table 6, entry 6,7) gave sluggish conversion.
Coupling of methyl propargylic alcohol with 7a gave a complex
2
TFA-cleavage. Attempts to synthesize 7c (R = 2-iodobenzyl) failed due

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mixture, probably due to decomposition during the TFA-cleavage
protocol.
References and Notes:
(1) For example: a) Takatori, K.; Kajiwara, M. Synlett 1995, 280-282;
b) Ichikawa, Y.; Mondan, R.; Kuzuhara, H. Tetrahedron Lett.
1986, 27, 611-614; c) Frazer-Reid, B.; Magdzinski, L.; Molino, B.
J. Am. Chem. Soc. 1984, 106, 731-734;
21
The success of the multiple coupling protocol led us to perform two
different couplings within the same reaction sequence.Thus 6d could be
coupled with tributylvinyl stannane to afford 18b, which could be
+
transformed into 20 upon Li -mediated epoxide opening with 3-iodo
d)
Ogawa, T.; Kawano, T.; Matsui, M. Carbohydrate Research 1977,
57, C31-35; e) Sviridov, A. F.; Ermolenko, N. S.; Yashunsky, D.
V.; Borodkin, V. S.; Kochetkov, N. K. Tetrahedron Lett. 1987, 28,
3835-3838.
benzylamine. The latter could undergo another Pd-coupling reaction to
21
give 21( Scheme 8).
In conclusion, we have demonstrated epoxide opening reactions of a
very stable epoxide as a key step to obtain novel carbohydrate structures
on a polymeric support. The residues introduced by the epoxide
opening, could be modified further by a variety of transformations. Most
prominent were the Pd-mediated couplings. The presented reaction
sequences, which avoid complex protection schemes, provide a valuable
basis for many currently ongoing library projects.
(2) For example: Paulsen, H.; Schüller, M. Liebigs Ann. Chem. 1987,
249-258.
(3) For instance: a) Kriecheldorf, H. R.; Delius, U. Makromol. Chem.
1989, 190, 1289-1301; b) Gorkovenko, A. A.; Berman, E. L.;
Ponomarenko, V. A. Bioorg. Khim. 1987, 13, 218-222; (English
translation: 126-129); c) Uryu, T.; Hatanaka, K.; Matsuzaki, K.;
Kuzuhara, H. Macromolecules 1983, 16, 853-858.
Acknowledgement: We thank Dr. Tammo Winkler for many NMR-
structural assignments and the Central Analytical Laboratories for mass
spectra, Josette Schaub and Fabienne Andelfinger for technical
assistance.
(4) a) Cerny, M.; Gut, V.; Pacak, J. Collect. Czech, Chem. Commun.
1961, 26, 2542-2550; b) Szeja, W. Carbohydrate Res. 1988, 183,
135-139; Cerney, M.; Stanek Jr., J.; Pacak, J. Collect. Czech.
Chem. Commun. 1969, 34, 849-856.

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(5) For review: Cerny, M. Levoglucosanone and Levoglucosanes,
Chemistry and Applications, Witczak, Z. J. (ed.). ATL PRESS
1994, 121-146.
(14) 0.05M LiPF (2eq.),0.2M thiol (10eq.), 2,6-lutidine/DBU 9/1(V/
6
V), 100°C, 16h.
(15) Kataoka, S.; Imai, J.; Yamaji, N.; Kato, M.; Kawada, T.; Imai, S.
(6) Caprino, L. A.; El-Faham, A. J. Org. Chem. 1995, 60, 3561-3564.
Chem. Pharm. Bull. 1990, 38, 1596-1600.
(7) All described reactions were performed in a glass “frit reactor”. Its
top was closed by a rubber septum, connected to an Ar-balloon.
The bottom contained a P3-glass frit, leading to a narrow outlet,
which could either be sealed by a small septum or rubber stopper
or fastened tightly onto a PTFE valve to perform washing
procedures. This “frit reactor”, could be placed in a heating block,
mounted on an orbital shaker to allow agitation of the resin during
the reactions. Washings were performed in a “flow through”
manner when the reactor was mounted on a PTFE valve.
(16) 7i: 201mg of resin bearing 0.104mmol of 7i was treated with 5ml
of 3-iodobenzyl chloride 5ml of 1.002M KOtBu in THF. KCl
precipitated within 1h. After a wash as under epoxide openings
1
and TFA-cleavage 10c was obtained. HNMR (DMSO D ): sugar:
6
5.33 (H1), 3.2, 3.3 (H2, H4), 3.36 (H3), 3.5, 3.77 (H6), 4.5-4.63
2
3
1
(H5, CH (R ,R )); R : 1.05 (Me), 3.35, 3.53 (CH ), 6.85, 7.05
2
2
2
3
(CONH); R : 7,25, 7.35: (benzyl); R : 7.14, 7.65, 7.68
(iodobenzyl).
(17) Gaffney, B. L.; Marki, L. A.; Jones, R. A. Tetrahedron 1984, 40,
(8) The resins were treated 10 times with TFA/ClCH CH Cl 1/4(V/
3-13.
2
2
V) for 2min. each. To the combined cleavage solutions were added
1/4 volume eq. of toluene prior to evaporation in vacuo (T>40°C).
(18) a) Wellow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034-5037,
b) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.; Naeslund, C.
G. M. J. Chem. Soc. Chem. Commun. 1994, 2395.
(9) Representative procedure for epoxide opening with
nucleophiles: All reaction mixtures were washed using 5
alternating washes with 5ml MeOH and DMF/1M TEAA 4/1 (V/
(19) Hodgson, D. M.; Witherington, J.; Moloney, B. A.; Richards, I.
C.; Brayer, J.-L. Synlett 1995, 32-34.
V) each, 5 alternating washes with 5ml MeOH and ClCH CH Cl/
2
2
(20) Fancelli, D.; Fagnola, M. C.; Severino, D.; Bedeschi, A.
HOAc 4/1 (V/V) each, 5 alternating washes with 5ml MeOH and
DCM each and 5 alternating washes with 5ml DCM and n-pentane
each.
Tetrahedron Lett. 1997, 38, 2311-2314.
(21) Representative procedure for Pd-mediated couplings: All Pd-
mediated coupling reactions require vigorous exclusion of oxygen
and the use of oxygen free solvents. The resins were washed
successively with 10x 5ml DMA/1M aq. TEAA 4/1(V/V) and 10x
5ml 0.05M sodium N,N-diethyl dithiocarbamate, 10x 5ml NMP.
Then 5 alternating washes were performed with 5ml MeOH and
5ml DCM each and 5 alternating washes with 5ml DCM and 5ml
n-pentane each.
9e (Scheme 2): To 500mg of “Rink”-resin bearing 0.235mmol of
6c was added 751mg (5mmol) 2-mercaptobenzimidazole, 5ml 1M
LiHMDS in THF and 15ml dry dioxane. The reaction mixture was
agitated at 80°C for 16h and then washed. TFA cleavage resulted
1
in the isolation of amide 9e in quantitative yields. HNMR
(DMSO D ): sugar: 5.49 (H1), 3.88 (H2), 3.83 (H3), 3.21 (H4),
6
1
4.6 (H5), 3.56, 4.06 (H6); R : 3,38, 3.58 (CH ), 1.05 (CH ); 6.8,
7.0 (CONH ), 7.28, 7.47(AA’BB’): benzothiazole. C-NMR
2
3
20 (Scheme 4): 300mg of “Rink”-amide resin bearing 0.216mmol
of 20 was washed 10x with 5ml of oxygen-free dioxane. To this
washed support was added under Ar a solution consisting of
262.5mg (1.727mmol) of p-methoxybenzeneboronic acid, 537mg
13
2
(DMSO D ): 50.2, J =147Hz C2 (sugar).
6
CH
(10) a) Schwesinger, R.; Schlemper, H. Angew. Chem. 1987, 99, 1212-
1214; Angew. Chem. Int. Ed. Engl. 1987, 26, 1167-1168 ;
b)Esswein, B.; Steidel, N. M.; Moeller, M. Macromol. Rapid
Commun. 1996, 17, 143-148; c) Schwesinger, R.; Hasenfratz, C.;
Schlemper, H.; Walz, L.; Peters, E. M.; Peters, K.; von Schnering,
H. G. Angew. Chem. 1993, 105, 1420-1422; Angew. Chem. Int. Ed.
Engl. 1993, 32, 1361-1363.
(3.88mmol) K CO in 1.23ml water. To this suspension was added
2
3
10mg (0.044mmol) of Pd(OAc) and 7.4ml of dioxane. The
2
reaction mixture was agitated at 110°C for 17h. The resulting
resin was blackened by Pd deposits. After deprotection with TFA
1
89mg (72%) the amide 21 was obtained: HNMR(CDCl ): sugar:
3
5.45 (H1), 3.2 (H2), 4.1 (H3), 3.45 (H4), 4.72 (H5), 4.22, 4.41
1
4
2
5
(11) RAM-resin is produced by Rapp Polymere GmbH, Ernst-Simon-
Str. 9, D-72072 Tübingen, Germany.
(H6); R : 7.15, 7.8 (CONH ), 4.85 (CH ); R : 1.29; R , R : 3.79,
2
2
4.22, 4.35, 6.93, 7.45.
(12) Chini, M.; Crotti, P.; Maccia, F. Tetrahedron Lett. 1990, 32, 4661-
(22) Multiple couplings: After a coupling reaction as under ref. 21.
the resin is washed 10x with oxygen-free dioxane and is
subsequently subjected with the reagents for a subsequent
coupling reaction.
4664.
(13) 0.05M LiBPh (2eq.), 30% aq. NH /2,6-lutidine 1/4 (V/V),
4
3
100°C, sealed tube.