Towards stable di-carba analogues of guanofosfocins

Article abstract of DOI:10.1016/j.tetlet.2011.02.102

Guanofosfocins are strong inhibitors of chitin synthases, but also very prone to hydrolytic cleavage. Two advanced intermediates 15 and 20 for the synthesis of stable di-carba-guanofosfocins were prepared via ester 11. Acylation of the allylic C-glycoside

Full text of DOI:10.1016/j.tetlet.2011.02.102

Tetrahedron Letters 52 (2011) 2940–2942
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Tetrahedron Letters
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Towards stable di-carba analogues of guanofosfocins
⇑
Jan Duchek, Mu-Hua Huang, Andrea Vasella
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, HCI, CH-8093 Zürich, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Guanofosfocins are strong inhibitors of chitin synthases, but also very prone to hydrolytic cleavage. Two
advanced intermediates 15 and 20 for the synthesis of stable di-carba-guanofosfocins were prepared via
ester 11. Acylation of the allylic C-glycoside 6 with riburonic acid chloride 10 afforded ester 11 in 79%
yield. This ester was converted to 15 in four steps and in 54% yield and to 20 in eight steps and in 20%
yield.
Received 27 January 2011
Revised 21 February 2011
Accepted 23 February 2011
Available online 1 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Antifungals
Synthesis
Carbohydrates
Heterocycles
Guanofosfocins (Fig. 1) were isolated in 1996 by Nippon Roche
from the fermentation broth of Streptomyces and Trichoderma
spp.1 They strongly inhibit chitin synthases from Saccharomyces
cerevisiae and Candida albicans and b-glucan synthase from C. albi-
cans. The investigation of their mode of action was hampered by
their high instability. The structure of the guanofosfocins is charac-
terised by a C(8) substituted guanosine moiety, a 1,3-di-O-substi-
we opted for an intramolecular N-glycosylation, and report on the
synthesis of intermediates suitable to explore this approach.
The allyl C-glycoside 6 (Scheme 1) was prepared from methyl
a-
D-mannopyranoside (3) that was selectively protected via the
stannylene acetal and methoxybenzylated to form 4. The remain-
ing hydroxy groups were benzylated to obtain 5 in a yield of 49%
from 3.5 Treating
5 with allylTMS (3.4 equiv) and TMSOTf
tuted
a
-
D
-mannopyranosyl residue, an 11-membered ring, and a
(0.5 equiv) resulted both in allylation and deprotection of the
PMB–OR group to yield 73% of 6.6 The cleavage of the PMB–OR
group preceded allylation, as treating 5 with 1 equiv of allylTMS
and 0.5 equiv of TMSOTf led selectively to 7.
pyrophosphate substituent. We assume that the two activated
O,O-acetal moieties of the guanofosfocins are responsible for their
instability, and, for this reason, designed the C-glycoside analogue
1 (Fig. 1) as a synthetic target. An approach towards a different,
carba-sugar type, analogue was reported by Sugimura and
Hosogai.2
The main challenges in the synthesis of 1 may be characterised
as follows: incorporation of a methylene group between the man-
nosyl and guanyl moieties, formation of an ether bond between the
O–C(3) of the mannosyl moiety and C(5) of the ribosyl unit, and
cyclisation to an 11-membered ring.
The problem of incorporating a methylene group between the
mannosyl and guanyl moieties was solved earlier in our group.3
The guanine ring was constructed by cyclising 4-acylamino-5-nitr-
osopyrimidines.4 This strategy led to the acid 2 which, however, did
not undergo the planned macrolactonisation. The mannopyranosyl-
C-glycoside unit of 2 adopts a 1C4 and the guanosine unit a syn con-
formation, favoured by an intramolecular hydrogen bond between
COOH and N(3), both factors disfavouring the macrolactonisation.
Looking for an alternative strategy to close the 11-membered ring,
The known riburonic acid 9 (Scheme 2) was prepared by perio-
date cleavage of the C(5)–C(6) bond of the vicinal diol 8,7 and oxi-
dation of the resulting aldehyde with sodium chlorite–hydrogen
peroxide.8 Diol 8 was prepared in five steps and in 21% overall yield
from D
-glucose.9
The common intermediate 11 was synthesised by acylating
alcohol 6 (Scheme 2) with the acid chloride 10, and then sub-
jected to ozonolysis. Reductive workup with dimethyl sulfide
and oxidation of the resulting aldehyde furnished the carboxylic
acid 12 that was converted to the acyl chloride 13 using oxalyl
chloride/DMF. The amide 14 was obtained upon treating 13 with
6-(benzyloxy)-5-nitrosopyrimidine-2,4-diamine in the presence
of K2CO3. These conditions greatly facilitated the workup, merely
filtration through Celite and evaporation being sufficient, and fur-
nished very pure crude 14 that was used directly in the next step.
This procedure is preferred to chromatography on silica gel that
resulted in low yields of 14 contaminated with impurities, as
shown by the 1H NMR spectra. The formation of 14 proceeds pre-
sumably via the O-acylated (O-acyloximino) intermediate,4 as
indicated by an initial colour change from blue to green (in
⇑
Corresponding author. Tel.: +41 446325130.
E-mail address: vasella@org.chem.ethz.ch (A. Vasella).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.102

J. Duchek et al. / Tetrahedron Letters 52 (2011) 2940–2942
2941
BnO
HO
HO
OH
OH
O
N
N
NCOiPr
H
O
BnO
N
O
O
OH
O
HO
HO
N
N
O
O
O
O
N
O
H O
O
OBn
NR1
NHR2
NH
NH2
N
N
P
O
O
O
P
RO
C
OBn
O
HO
HO
O
N
N
H2
O
OH
O
HO
OH
HO
OH
Guanofosfocin A R1 = Me, R2 = H
Guanofosfocin B R1 = R2 = H
Guanofosfocin C R1 = H,
1
2
Di-carba analogue of guanofosfocin B
R = pyrophosphate or mimic thereof
R2 = Ser-β−Asp-Ser-Ser
Figure 1. Structure of guanofosfocins, analogues, and an advanced intermediate 2.
Scheme 1. Reagents and conditions: (a) (1) Bu2SnO, MeOH, reflux; (2) PMBCl, CsF, DMF; (b) BnBr, NaH, TBAI, DMF; 49% from 3; (c) allylTMS (3.4 equiv), TMSOTf (0.5 equiv),
MeCN, ꢁ10°?25°; 73%; (d) allylTMS (1 equiv), TMSOTf (0.5 equiv), MeCN, ꢁ15°?5°; 73%.
Scheme 2. Reagents and conditions: (a) (1) NaIO4, MeOH, H2O; (2) H2O2, NaClO2, NaH2PO4, CH3CN, H2O; 73%; (b) (COCl)2, DMF, CH2Cl2; (c) 6+10, py, DMAP, CH2Cl2; 79%; (d)
(1) O3, CH2Cl2, n-pentane, ꢁ90°; (2) Me2S; (3) 2-methyl-2-butene, t-BuOH, NaClO2, NaH2PO4, H2O; 85%; (e) (1) (COCl)2, DMF, CH2Cl2; (f) 13, 2,4-diamino-6-(benzyloxy)-5-
nitrosopyrimidine, K2CO3, THF, ꢁ60°?25°; (g) DPPE, p-xylene, reflux; 63% from 12.
THF) in the course of the reaction. The isolated amide 14 is blue
oil. It was treated with 1,2-bis(diphenylphosphino)ethane (DPPE)
in boiling p-xylene to provide guanine 15 in a yield of 63% from
12. The transformation of the nitroso group in the course of the
diastereoisomers which were not separated. Selective hydrolysis
with aqueous acetic acid of the more labile dioxolane ring of 19,
periodate cleavage of the resulting diol, and oxidation of the result-
ing aldehyde led to the desired carboxylic acid 20 that was ob-
tained as ca. 1:1 mixture of two diastereoisomers in a yield of
20% from 11.
reaction was accompanied by
blue-green to brown.
a typical colour change from
The second intermediate was synthesized as shown in Scheme
3. The double bond of 11 was dihydroxylated, and the resulting
diol protected as isopropylidene acetal 16 that was obtained in a
yield of 79% as a mixture of two diastereoisomers. The carbonyl
group of 16 was methylenated with Petasis’ reagent to yield 68%
of 17. Hydroboration (BH3ꢀTHF) and workup with H2O2/NaOH
provided 18 that was acetylated to afford 19 as a mixture of four
In conclusion, we have prepared two advanced intermediates
for the synthesis of analogues of guanofosfocins.10 Both intermedi-
ates derive from ester 11 which was readily obtained in gram
quantities. This divergent route allows selecting the order of the
final key steps in our projected synthesis of di-carba guanofosfoc-
ins (formation of the guanine ring, N-glycosylation, and methyle-
nation of the ester group).

2942
J. Duchek et al. / Tetrahedron Letters 52 (2011) 2940–2942
Scheme 3. Reagents and conditions: (a) OsO4, NMO, acetone, H2O; 93%; (b) 2,2-dimethoxypropane, p-TsOH, acetone; 85%; (c) Cp2TiMe2, toluene, reflux; 68%; (d) (1) BH3ꢀTHF,
CHCl3; (2) H2O2, NaOH, H2O, 0°; 60%; (e) Ac2O, DMAP, Et3N, CH2Cl2; 98%; (f) AcOH, H2O; (g) NaIO4, MeOH, H2O; (h) H2O2, NaClO2, NaH2PO4, CH3CN, H2O; 62% from 19.
spectrum): d 7.34–7.16 (m, 20 arom. H), 5.88–5.72 (m, overlapped with d of H–
C(1’), CH2CH@CH2), 5.75 (d, J = 3.7 Hz, H–C(1’)), 5.51 (dd, J = 5.6, 3.1 Hz, H–
C(4)), 5.16–5.04 (m, CH2CH@CH2), 4.67–4.42 (m, 8PhCH, H–C(4’)), 4.27 (br t,
Acknowledgements
We thank ETH Zürich for generous support and Dr. Bruno Ber-
net for checking the experimental data.
J = 3.7 Hz, H–C(2’)), 3.98–3.88 (m, irrad. at 2.39?change, H–C(2)), H–C(6)),
3.85 (br t, J = 5.6 Hz, irrad. 5.51?d, J = 5.0 Hz, irrad. at 3.93?change, H–C(3)),
3.79–3.73 (m, H–C(5), H–C(3’)), 3.72 (dd, J = 10.6 Hz, 5.6, Ha–C(1)), 3.67 (dd,
J = 10.6, 5.0 Hz, Hb–C(1)), 2.42 (br dd, J ꢃ 14.8, 6.8 Hz, CHaCH@CH2), 2.36 (br dd,
J ꢃ 14.9, 7.5 Hz, CHbCH@CH2), 1.57, 1.32 (2s, Me2C); 13C NMR (CDCl3, 75 MHz;
assignments based on a HSQC spectrum): d 169.68 (s, C@O), 138.40, 137.97,
137.90, 137.53 (4s), 134.30 (d, CH2CH@CH2), 128.59–127.69 (several d, arom.
CH), 117.56 (t, CH2CH@CH2), 113.67 (s, Me2C), 104.93 (d, C(1’)), 80.66 (d, C(3’)),
78.16 (d, C(2’)), 77.60 (d, C(4’)), 75.21 (d, C(5)), 74.37 (d, C(3)), 73.79 (d, C(2)),
73.44, 73.26, 72.80, 71.98 (4t, 4 PhCH2), 71.39 (d, C(6)), 71.06 (d, C(4)), 68.61 (t,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.102.
C(1)), 35.16 (t, CH2CH@CH2), 27.15, 26.76 (2q, Me2C). HR-MALDI-MS: 789.3059
References and notes
(73, [M+K]+, C45H50KO10
;
calcd 789.3041), 773.3284 (100, [M+Na]+,
þ
C
45H50NaO10þ; calcd 773.3302). Anal. calcd for C45H50O10 (750.87): C, 71.98;
1. Katoh, H.; Yamada, M.; Lida, K.; Aoki, M.; Itezono, Y.; Nakayama, N.; Suzuki, Y.;
Watanabe, M.; Shimada, H.; Fujimari, H.; Nagata, M.; Ohshima, S.; Watanabe, J.;
Kamiyama, T.; ‘Isolation and Structure Elucidation of Novel Chitin Synthase
Inhibitors, Guanofosfocins Produced by Microorganisms’, in ‘Abstracts of the
38th Symposium on the Chemistry of Natural Products, Sendai, Japan 1996,
p.115’, 1996; Kamiyama, T.; Nippon Nogeikagaku Kaishi-Journal of the Japan
Society for Bioscience Biotechnology and Agrochemistry 1997, 71, 535.
2. Sugimura, H.; Hosogai, N. Chem. Lett. 2007, 36, 36–37.
3. George, T. G.; Szolcsányi, P.; Koenig, S. G.; Paterson, D. E.; Isshiki, Y.; Vasella, A.
Helv. Chim. Acta 2004, 87, 1287–1298.
4. Xu, M.; De Giacomo, F.; Paterson, D. E.; George, T. G.; Vasella, A. Chem. Commun.
2003, 1452–1453.
5. Izumi, M.; Suhara, Y.; Ichikawa, Y. J. Org. Chem. 1998, 63, 4811–4816.
6. The origin of the stereoselectivity of analogous allylations has been discussed:
(a) Lucero, C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641–2647; For
discussion of effects of individual substituents in related reactions of six-
membered oxo-carbenium ions see: (b) Ayala, L.; Lucero, C. G.; Romero, J. A. C.;
Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521–15528; (c)
Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168–
169; (d) Miljkovic´, M.; Yeagley, D.; Deslongchamps, P.; Dory, Y. L. J. Org. Chem.
1997, 62, 7597–7604; Related computational studies: (e) Winkler, D. A.; Holan,
G. J. Med. Chem. 1989, 32, 2084–2089; (f) Amat, L.; Carbó-Dorca, R. J. Chem. Inf.
Comput. Sci. 2000, 40, 1188–1198; (g) Nukada, T.; Bérces, A.; Wang, L. J.;
Zgierski, M. Z.; Whitfield, D. M. Carbohydr. Res. 2005, 340, 841–852; (h) Vasella,
A.; Davies, G. J.; Böhm, M. Curr. Opin. Chem. Biol. 2002, 6, 619–629; (i) Woods, R.
J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc. 1992, 114, 859–864.
7. Rosenthal, A.; Nguyen, L. J. Org. Chem. 1969, 34, 1029–1034.
H, 6.71. Found: C, 71.95; H, 6.78. Compound 15: Yellowish oil; Rf (CHCl3/AcOEt
1:4) 0.22; IR (CHCl3): mmax 3527 (w), 3421 (w), 3362 (w), 3257 (w), 3090 (w),
3067 (w), 3034 (w), 3008 (w), 2994 (w), 2938 (w), 2872 (w), 1951 (w), 1877
(w), 1809 (w), 1758 (m), 1625 (s), 1591 (s), 1524 (w), 1496 (w), 1466 (m), 1455
(m), 1409 (m), 1385 (m), 1376 (m), 1356 (m), 1324 (m), 1268 (m), 1219 (m),
1163 (m), 1147 (m), 1091 (s), 1038 (m), 1029 (m), 991 (m), 912 (w) cmꢁ1 1H
;
NMR (CDCl3, 400 MHz; assignments based on a DQFCOSY spectrum): d 11.35
(br s, exchange with CD3OD, H–N(900)); 7.54–6.94 (m, 25 arom. H); 5.77 (d,
J = 3.5 Hz, H–C(1’)); 5.68 (br t, J ꢃ 2.5 Hz, H–C(4)); 5.54 (br s, PhCH2); 4.84 (br s,
exchange with CD3OD, NH2); 4.65–4.28 (m, 7 PhCH, H–C(4’)); 4.25 (br t,
J = 4.0 Hz, H–C(2’)); 4.19–4.13 (m, PhCH, H–C(2)); 4.08 (br t, J = 9.3 Hz, H–C(6));
3.74–3.64 (m, Ha–C(1), H–C(5), H–C(3’)); 3.53 (br s, H–C(3)); 3.39 (br d,
J ꢃ 14.6 Hz, Hb–C(1), Ha–C(7)); 2.96 (dd, J = 15.6, 9.8 Hz, Hb–C(7)); 1.57, 1.30
(2s, Me2C). 13C NMR (CDCl3, 100 MHz; assignments based on
a HSQC
spectrum): d 169.48 (s, C@O), 160.30, 158.87, 155.70 (3s, C(2’’), C(4’’), C(6’’));
148.38 (s, C(8’’)); 137.68, 137.33, 137.28, 137.19, 136.89 (5s); 130–127 (several
d); 114.89 (s, C(5’’)); 113.65 (s, Me2C); 105.15 (d, C(1’)); 80.68 (d, C(3’)); 77.77
(d, C(2’)); 77.23 (d, C(4’)); 74.81 (d, C(3)); 74.42 (d, C(2)); 74.34 (d, C(5)); 73.16,
72.68, 72.47, 72.07 (4t, 4 PhCH2); 68.25 (d, C(6)); 67.93 (t, PhCH2); 67.26 (d,
C(4)); 66.64 (t, C(1)); 31.49 (t, C(7)); 27.17, 26.78 (2q, Me2C). HR-MALDI-MS:
1024.363 (4, [MꢁH+K+Na]+, C55H56KN5NaO11þ; calcd 1024.3511), 1008.386
(24, [MꢁH+2Na]+, C55H56N5Na2O11þ; calcd 1008.3772), 1002.378 (21, [M+K]+,
C
55H57KN5O11þ; calcd 1002.3692), 986.3976 (73, [M+Na]+, C55H57N5NaO
;
þ
calcd 986.3952); 964.4109 (100, [M+H]+, C55H58N5O11
;
calcd 964.411313).
þ
Compound 20 (mixture of 2 diastereoisomers): Colourless gum; IR (CHCl3):
max 2962 (w), 1740 (m), 1494 (m), 1454 (w), 1371 (m), 1259 (s), 1092 (s), 1026
(s) cmꢁ1 1H NMR (CDCl3, 300 MHz):
7.38–7.12 (m, arom. H), 5.76 (d,
m
;
d
8. (a) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567–569; (b) Dhavale, D.
D.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Org. Chem. 1989, 54, 4100–
4105.
J = 3.7 Hz), 5.62 (dd, J = 3.4, 3.8 Hz), 5.57 (d, J = 3.6 Hz), 5.22 (d, J = 3.7 Hz), 4.70–
4.41 (m), 4.32–3.99 (m), 3.92–3.60 (m,), 3.51 (dd, J = 3.9, 10.6 Hz), 2.77–2.50
(m), 1.93 (s), 1.80 (s), 1.59 (s,), 1.55 (s), 1.33 (s), 1.21 (s); 13C NMR (CDCl3, 75 M)
9. (a) Lohri, B. ‘Dissertation No. 5783’, ETH Zürich, 1976.; (b) Baker, D. C.; Horton,
D.; Tindall, C. G. Carbohydr. Res. 1972, 24, 192–197.
d
171.02, 170.44, 169.48, 137.79, 137.51, 137.30, 129.09, 128.57, 128.55,
128.51, 128.46, 128.41, 128.38, 128.36, 128.22, 128.20, 128.16, 128.13, 127.94,
127.92, 127.88, 127.82, 127.78, 127.70, 127.03, 113.00, 112.61, 104.09, 77.54,
77.41, 77.12, 76.95, 76.86, 76.69, 76.26, 75.97, 73.30, 71.85, 71.46, 67.85, 63.95,
63.57, 36.61, 27.07, 26.87, 26.67, 26.19, 21.51, 20.91, 20.71; HR-MALDI-MS:
849.3475 ([M+Na]+, C47H54NaO13þ; calcd 849.3462); 871.3288 [MꢁH+2Na]+,
10. All compounds gave satisfactory analytical data (1H NMR, 13C NMR, IR, and
elemental analysis or HR-MS). Data of key compounds follow. Compound 11:
Colourless oil; Rf (cyclohexane/AcOEt 5:1) 0.17; ½a D25
ꢂ
+30.2 (c 1.15, CHCl3); IR
(CHCl3): mmax 3088 (w), 3067 (w), 3033 (w), 3010 (m), 2937 (w), 2871 (w),
1951 (w), 1873 (w), 1810 (w), 1752 (m), 1642 (w), 1606 (w), 1586 (w), 1496
(w), 1454 (m), 1384 (m), 1375 (m), 1219 (m), 1163 (m), 1094 (s), 1029 (s), 917
C
47H53Na2O13þ; calcd 871.3282).
(w) cmꢁ1 1H NMR (CDCl3, 300 MHz; assignments based on
; a DQFCOSY