A short total synthesis of sulfobacin A

Article abstract of DOI:10.1016/S0040-4039(03)01600-9

A total synthesis of the von Willebrand factor receptor antagonist sulfobacin A is described. Key steps for this short route to sulfobacin A include ruthenium-catalyzed asymmetric hydrogenation and diastereoselective electrophilic amination for the construction of the three stereogenic centers.

Full text of DOI:10.1016/S0040-4039(03)01600-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6383–6386
A short total synthesis of sulfobacin A
Olivier Labeeuw, Phannarath Phansavath and Jean-Pierre Geneˆt*
Laboratoire de Synthe`se Se´lective Organique et Produits Naturels-UMR CNRS 7573,
Ecole Nationale Supe´rieure de Chimie de Paris, 11, rue Pierre et Marie Curie, 75231 Paris cedex 05, France
Received 4 June 2003; accepted 27 June 2003
Abstract—A total synthesis of the von Willebrand factor receptor antagonist sulfobacin A is described. Key steps for this short
route to sulfobacin A include ruthenium-catalyzed asymmetric hydrogenation and diastereoselective electrophilic amination for
the construction of the three stereogenic centers.
© 2003 Elsevier Ltd. All rights reserved.
Two syntheses of sulfobacin A have been reported by
Shioiri4,5 and Mori.6,7 As part of our ongoing efforts
towards the synthesis of biologically active natural
products,8–10 we report herein a short synthesis of sul-
While screening for novel von Willebrand factor (vWF)
receptor antagonists, Kamiyama and co-workers1,2 iso-
lated in 1995 sulfobacins A and B in the culture broth
of Chryseobacterium sp. NR 2993, a strain isolated
from a soil sample collected in Iriomote Island (Scheme
1). These compounds showed potent inhibitory activity
against the binding of vWF to its receptor in a compet-
itive manner with IC50 of 0.47 mM for sulfobacin A and
2.2 mM for sulfobacin B. The same year, Kobayashi
fobacin
A using sequential catalytic asymmetric
hydrogenation11,12 and electrophilic amination13,14 for
the construction of the three stereogenic centers.
Scheme 2 shows our retrosynthetic analysis for sul-
fobacin A. Our approach is based on the use of b-
and co-workers3 isolated sulfobacin
A
and
flavocristamide A from a marine bacterium Flavobac-
terium sp., separated from the marine bivalve Cristaria
plicata collected in Ishikary Bay (Scheme 1). These
compounds exhibited inhibitory activity against DNA
polymerase a.
Scheme 1. Structures of flavocristamide A and sulfobacins A
and B.
* Corresponding author. Tel.: +33-1-44-27-67-43; fax: +33-1-44-27-
10-62; e-mail: genet@ext.jussieu.fr
Scheme 2. Retrosynthetic analysis for sulfobacin A.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01600-9

6384
O. Labeeuw et al. / Tetrahedron Letters 44 (2003) 6383–6386
hydroxy ester 6 as a key intermediate for the synthesis
of both fragments 7 and 14 whose coupling reaction
would afford the desired sulfobacin A (1). Thus, b-
hydroxy acid 7 would be obtained from 6 by simple
alkaline treatment while 14 would be prepared via
compound 9, easily obtainable by diastereoselective
electrophilic amination of 6. Asymmetric hydrogena-
tion of b-keto ester 5 using chiral ruthenium complexes
would furnish the key intermediate 6 with high enan-
tiomeric excess.
The synthesis of the desired b-hydroxy ester 6 began
with the commercially available 10-bromodecan-1-ol 2
which was converted into alcohol 3 by treatment with
isoamylmagnesium bromide in the presence of dilithium
tetrachlorocuprate7 in 95% yield (Scheme 3). Oxidation
of 3 using Jones’ reagent then furnished the corre-
sponding carboxylic acid 4, which was converted into
the b-keto ester 5 using Masamune’s procedure.15
Thus, the addition of carbonyl diimidazole to 4 fol-
lowed by treatment with the magnesium salt of
monomethyl malonic acid gave the requisite b-keto
ester 5 in 81% yield. For the asymmetric hydrogenation
of 5, we used our recently reported simple procedure
for the in situ preparation of chiral ruthenium catalysts
starting directly from anhydrous RuCl3.16 Thus, hydro-
genation of 5 was carried out at 80°C in methanol
under a low pressure of hydrogen (6 bar), using 1 mol%
of the RuCl3/(R)-MeO-BIPHEP system.
Scheme 4. Reagents and conditions: (a) MeZnBr (1 equiv.),
0°C, 1 h; LDA (2 equiv.), −78°C, 1 h; DTBAD (2 equiv.),
−78°C, 2 h, 72%, d.e. >95%; (b) TFA, CH2Cl2, rt, 3 h; (c) H2
(1 atm), Raney Ni, MeOH, ultrasound, rt, 14 h; (d) Boc2O,
NaHCO3, MeOH, ultrasound, rt, 3.5 h, 80% from 8; (e)
Me2C(OMe)2, Et2O·BF3, CH2Cl2, rt, 1 h, 93%; (f) Ca(BH4)2,
THF, EtOH, −15°C to rt, 22 h, 94%; (g) CH3COSH,
iPrOCONꢀNCO2 Pr, PPh3, THF, 0°C, 1 h, then rt, 16 h, 95%;
i
(h) H2O2, TFA, rt, 1 h.
boxylic acid 7, [h]2D5 −11.6 (c 1.0, CHCl3), lit.17 [h]2D0
−12.0 (c 1.0, CHCl3).
Under these conditions, b-hydroxy ester 6 was obtained
in 96% yield and excellent enantiomeric excess (e.e.
>99%, determined by HPLC analysis, Chiralcel OD-H
column, hexane/propan-2-ol: 99/1, flow rate: 1.0 mL/
min, detection: 215 nm), [h]2D5 −14.3 (c 0.51, CHCl3),
lit.2 [h]D20 −12.7 (c 0.52, CHCl3). Finally, alkaline treat-
ment of 6 furnished the corresponding b-hydroxy car-
The synthesis of 13 involved again b-hydroxy ester 6 as
shown in Scheme 4. The anti-N,N-Boc-a-hydrazino-b-
hydroxy ester 8 was readily obtained from 6 by elec-
trophilic amination with di-tert-butylazodicarboxylate
(DTBAD).18,19 Treatment of 6 with methylzinc bromide
followed by lithium diisopropylamide at −78°C fur-
nished the resulting zinc enolate which was reacted with
DTBAD to give 8 in 72% yield and with high
diastereoselectivity (d.e. >95%, determined by 1H
NMR). After deprotection of the hydrazine function,
the NꢁN bond was cleaved by hydrogenolysis using
Raney nickel and ultrasound.20 Subsequent protection
of the resulting amine with di-tert-butyl dicarbonate
and ultrasound21 afforded compound (2R,3R)-9 in 80%
overall yield starting from 8.
Protection of
9
was performed using 2,2-
catalytic amount of
dimethoxypropane with
a
Et2O·BF3, and the resulting oxazolidine 10 was then
reduced to the primary alcohol 1122 by treatment with
calcium borohydride. After conversion of 11 into the
corresponding mesylate, all attempts to perform nucle-
ophilic substitution with sodium sulfite failed to afford
the expected sulfonic acid. Finally, Mitsunobu23,24 reac-
tion of 11 with thioacetic acid afforded thioester 1225 in
95% yield and subsequent oxidation with hydrogen
peroxide in trifluoroacetic acid led to the target com-
pound 13.
Scheme 3. Reagents and conditions: (a) Me2CH(CH2)2MgBr,
Li2CuCl4 (1 mol%), THF, −78°C to rt, 12 h, 95%; (b) Jones’
reagent, acetone, rt, 1 h, 88%; (c) carbonyl diimidazole, THF,
rt, 6 h; Mg(O2CCH2CO2Me)2, THF, rt, 16 h, 81%; (d) H2 (6
bar), RuCl3/(R)-MeO-BIPHEP (1 mol%), MeOH, 80°C, 23 h,
96%, e.e. >99%; (e) 1N NaOH, MeOH, 0°C, 30 min, then rt,
3 h, 89%.

O. Labeeuw et al. / Tetrahedron Letters 44 (2003) 6383–6386
6385
9. Poupardin, O.; Ferreira, F.; Geneˆt, J.-P.; Greck, C. Tet-
rahedron Lett. 2001, 42, 1523–1526.
10. Phansavath, P.; Duprat de Paule, S.; Ratovelomanana-
Vidal, V.; Geneˆt, J.-P. Eur. J. Org. Chem. 2000, 3903–
3907.
11. For a review, see: Geneˆt, J.-P. In Reductions in Organic
Synthesis; Abdel-Magid, A. F., Ed.; ACS Symposium
Series 641; American Chemical Society: Washington, DC,
1996; pp. 31–51.
Scheme 5. Reagents and conditions: (a) HONB, DCC, THF/
dioxane, 0°C, 40 min, rt, 24 h then 13, NaHCO3, dioxane/
H2O, rt, 20 h, 20% from 12.
12. For a review, see: Ohkuma, T.; Kitamura, M.; Noyori, R.
In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley:
VCH, 2000; pp. 1–110.
13. For a review, see: Geneˆt, J.-P.; Greck, C.; Lavergne, D.
In Modern Amination Methods; Ricci, A., Ed.; Wiley-
VCH: Weinheim, 2000; pp. 65-102.
14. Greck, C.; Bischoff, L.; Ferreira, F.; Pinel, C.; Piveteau,
E.; Geneˆt, J.-P. Synlett 1993, 475–477.
15. Brooks, D. W.; Lu, L. D. L.; Masamune, S. Angew.
Coupling of 13 with carboxylic acid 7 was carried out
using HONB and DCC to form the corresponding
active ester of 7, which was coupled with the sodium
salt of 13 in a mixture of dioxane and water at room
temperature (Scheme 5).26 After treatment with Amber-
lite IR-120B (H+ form), sulfobacin A (1) was obtained
in 20% yield from 12. Spectral data of 127 were found to
be in agreement with those reported,2,5,6 [h]D25 −15.5 (c
0.14, MeOH) {lit.1 [h]D24 −35 (c 0.14, MeOH), lit.3 [h]D20
−7.9 (c 0.18, MeOH), lit.6 [h]D25 −15 (c 0.14, MeOH)}.28
Chem., Int. Ed. Engl. 1979, 18, 72–74.
16. Madec, J.; Pfister, X.; Phansavath, P.; Ratovelomanana-
Vidal, V.; Geneˆt, J.-P. Tetrahedron 2001, 57, 2563–2568.
17. Uchida, I.; Yoshida, K.; Kawai, Y.; Takase, S.; Itoh, Y.;
Tanaka, H.; Kohsaka, M.; Imanaka, H. J. Antibiot. 1985,
38, 1476–1486.
18. Geneˆt, J.-P.; Juge´, S.; Mallart, S. Tetrahedron Lett. 1988,
29, 6765–6768.
19. Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron 1988, 44,
5553–5562.
20. Alexakis, A.; Lensen, N.; Mangeney, P. Synlett 1991,
625–626.
21. Einhorn, J.; Einhorn, C.; Luche, J.-L. Synlett 1991, 37–
38.
In summary, in spite of the moderate yield obtained in
the final coupling reaction between compounds 7 and
13, our route to sulfobacin A is a very short one and
compares favorably with the other reported syntheses.
The ruthenium-catalyzed asymmetric hydrogenation of
b-keto ester 5 followed by diastereoselective elec-
trophilic amination allowed the stereocontrolled con-
struction of the three stereogenic centers. Preparation
of analogs of sulfobacin A is currently underway in our
laboratory and will be reported in due course.
22. Characteristic data for compound 11: Rf 0.29 (20%
Acknowledgements
AcOEt in cyclohexane); [h]2D5 −6.5 (c 0.79, CHCl3); IR
wmax (CH2Cl2): 3459, 2927, 2852, 1680 cm−1 1H NMR
;
(400 MHz, CDCl3, 50°C) l=4.05–3.95 (m, 2H), 3.81 (m,
1H), 3.65 (m, 1H), 1.58 (s, 3H), 1.57 (s, 3H), 1.49 (s, 9H),
1.60–1.15 and 1.25 (m and bs, 23H), 0.86 (d, 6H, J=6.6
Hz); 13C NMR (50 MHz, CDCl3) l=155.0, 92.5, 81.0,
75.6, 63.2, 61.1, 38.9, 29.8, 29.5, 28.8, 28.3, 27.8, 27.3,
26.8, 26.3, 24.4, 22.5; MS (CI, NH3): m/z (%) 428 [M++1]
(100); C25H49NO4 (427.6) calcd C, 70.21; H, 11.55; N,
3.28; found C, 70.30; H, 11.57; N, 3.18.
We thank Dr. R. Schmid (Hoffmann La Roche) for
samples of (R)-MeO-BIPHEP: (R)-(+)-6,6%-dimethoxy-
2,2%-bis(diphenyl-phosphinoyl)-1,1%-biphenyl. O.L. is
grateful to the Ministe`re de l’Education Nationale et de
la Recherche for a grant (2001-2004).
References
23. Volante, R. P. Tetrahedron Lett. 1981, 22, 3119–3122.
24. For a review, see: Mitsunobu, O. Synthesis 1981, 1–28.
25. Characteristic data for compound 12: Rf 0.66 (20%
AcOEt in cyclohexane); [h]2D5 +3.0 (c 1.11, CHCl3); IR
1. Kamiyama, T.; Umino, T.; Satoh, T.; Sawairi, S.; Shi-
rane, M.; Ohshima, S.; Yokose, K. J. Antibiot. 1995, 48,
924–928.
1
(film) 2925, 2854, 1702, 1455, 1379 cm−1; H NMR (400
2. Kamiyama, T.; Umino, T.; Itezono, Y.; Nakamura, Y.;
Satoh, T.; Yokose, K. J. Antibiot. 1995, 48, 929–936.
3. Kobayashi, J.; Mikami, S.; Shigemori, H.; Takao, T.;
Shimonishi, Y.; Izuta, S.; Yoshida, S. Tetrahedron 1995,
51, 10487–10490.
MHz, CDCl3), major conformer, l=4.12 (m, 1H), 4.00
(m, 1H), 3.19 (dd, 1H, J=13.7 and 6.6 Hz), 3.06 (dd, 1H,
J=13.7 and 4.1 Hz), 2.33 (s, 3H), 1.60 (s, 3H), 1.58 (s,
3H), 1.48 (s, 9H), 1.39–1.03 and 1.25 (m and bs, 23H),
0.85 (d, 6H, J=6.6 Hz); minor conformer, l=4.12 (m,
1H), 3.94 (m, 1H), 3.25 (dd, 1H, J=13.5 and 6.3 Hz),
3.02 (dd, 1H, J=13.5 and 5.5 Hz), 2.31 (s, 3H), 1.58 (s,
3H), 1.55 (s, 3H), 1.48 (s, 9H), 1.39–1.03 and 1.25 (m and
bs, 23H), 0.85 (d, 6H, J=6.6 Hz); 13C NMR (50 MHz,
CDCl3), two conformers: l=(195.0, 194.6), (152.3,
151.6), (92.9, 92.5), (80.2, 80.0), (58.5, 57.8), 39.0, 30.5,
30.1, 29.9, 29.7, 29.6, 29.5, 29.4, 29.2, 28.9, 28.7, 28.3,
27.9, 27.6, 27.4, 26.9, 26.8, 26.4, 24.6, 23.3, 22.6; MS (CI,
NH3): m/z (%) 486 [M++1] (100).
4. Irako, N.; Shioiri, T. Tetrahedron Lett. 1998, 39, 5793–
5796.
5. Shioiri, T.; Irako, N. Tetrahedron 2000, 56, 9129–9142.
6. Takikawa, H.; Muto, S.; Nozawa, D.; Kayo, A.; Mori,
K. Tetrahedron Lett. 1998, 39, 6931–6934.
7. Takikawa, H.; Nozawa, D.; Kayo, A.; Muto, S.; Mori,
K. J. Chem. Soc., Perkin Trans. 1 1999, 2467–2477.
8. Desroy, N.; Le Roux, R.; Phansavath, P.; Chiummiento,
L.; Bonini, C.; Geneˆt, J.-P. Tetrahedron Lett. 2003, 44,
1763–1766.
26. Higashiura, K.; Ienaga, K. Synthesis 1992, 353–354.

6386
O. Labeeuw et al. / Tetrahedron Letters 44 (2003) 6383–6386
27. Characteristic data for compound 1: Rf 0.22 (low layer of
CHCl3–MeOH–H2O/65:25:10); [h]2D5 −15.5 (c 0.14,
MeOH); IR wmax (KBr) 3356, 2950, 2850, 1642, 1554,
2.09 (dd, 1H, J=13.5 and 5.5 Hz), 1.45 (m, 2H), 1.35 (m,
2H), 1.23 (m, 38H), 1.13 (m, 4H), 0.83 (d, 12H, J=6.6
Hz); 13C NMR (100 MHz, DMSO-d6) l 170.4, 72.1, 67.8,
52.0, 51.3, 45.0, 38.7, 36.8, 33.5, 29.6, 29.5, 29.4, 29.3,
27.6, 27.0, 25.7, 25.4, 22.7.
1
1467, 1198, 1054 cm−1; H NMR (400 MHz, DMSO-d6)
l=7.66 (d, 1H, J=8.8 Hz), 4.79 (d, 1H, J=5.6 Hz); 4.68
(d, 1H, J=4.4 Hz), 3.91 (m, 1H), 3.75 (m, 1H), 3.47 (m,
1H), 2.74 (dd, 1H, J=14.1 and 6.7 Hz), 2.69 (dd, 1H,
J=14.1 and 4.3 Hz), 2.13 (dd, 1H, J=13.5 and 6.7 Hz),
28. As mentioned earlier by Mori6 the specific rotation value
of sulfobacin A seems to fluctuate depending on the
concentration or the pH of the solution.