Total synthesis of fuligocandines A and B

Article abstract of DOI:10.1016/j.tetlet.2009.10.134

A practical synthesis of the biologically active cycloanthranilylproline derivatives fuligocandines A and B is described, starting from l-proline and isatoic anhydride, employing an Eschenmoser episulfide contraction as the key step.

Full text of DOI:10.1016/j.tetlet.2009.10.134

Tetrahedron Letters 51 (2010) 238–239
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Total synthesis of fuligocandines A and B
*
Birgitta Pettersson, Vedran Hasimbegovic, Jan Bergman
Karolinska Institute, Department of Biosciences at Novum, Unit of Organic Chemistry, SE-141 57 Huddinge, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical synthesis of the biologically active cycloanthranilylproline derivatives fuligocandines A and B
Received 31 August 2009
Revised 19 October 2009
Accepted 28 October 2009
Available online 3 November 2009
is described, starting from
tion as the key step.
L
-proline and isatoic anhydride, employing an Eschenmoser episulfide contrac-
Ó 2009 Elsevier Ltd. All rights reserved.
O
O
(i)
Fuligocandines A (1) and B (2) (Scheme 1) are two cyclo-
anthranilylproline derivatives isolated in 2004 from the myxomy-
cete Fuligo candida by Nakatani et al. who also established their
structures, largely by extensive NMR and MS studies.1 A recent
study has shown that fuligocandin B (2) sensitizes leukaemia cells
to apoptosis caused by a tumour necrosis factor-related apoptosis-
inducing ligand (TRAIL).2 Intrigued by the interesting biological
activity and our ongoing interest in cycloanthranilylproline-de-
rived natural products we have developed practical syntheses of
both these alkaloids.
Cl
Cl
O
P(Ph)3
Cl
Cl
4
O
5
O
(ii)
(iii)
N
R
N
N
R
H
6
7a: R = SO2Ph
7b: R = 4-NO2-SO2Ph
8a: R = SO2Ph
8b: R = 4-NO2-SO2Ph
Herein, we report the synthesis of fuligocandines A and B using
an Eschenmoser episulfide contraction as the key step. This trans-
formation represents a versatile and efficient method to prepare
vinylogous amides by alkylation of thioamides with an appropriate
electrophilic reactant followed by extrusion of sulfur.3 Although
Scheme 2. Synthesis of the indole fragment of fuligocandin B. Reagents and
conditions: (i) (a) PPh3, THF, reflux, 24 h, (98%); (b) Na2CO3, H2O/MeOH, rt, ꢀ1 h
(90%); (ii) For 7a: NaOH, TBAHS (tetrabutylammonium hydrogen sulfate), PhSO2Cl,
CH2Cl2, rt, 2 h (80%), for 7b: NsCl, Et3N, DMAP, CH2Cl2, rt, 12 h (90%); (iii) compound
5, MeOH, reflux, 48 h (8a: 60%, 8b: 80%).
O
HO
O
+
N
H
O
N
O
H
O
N
O
O
N
N
N
H
N
N
S
H
H
O
O
3
1: fuligocandin A
2: fuligocandin B
N
H
Scheme 1. Retrosynthetic analysis of fuligocandines A and B.
* Corresponding author.
E-mail address: jan.bergman@ki.se (J. Bergman).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.134

B. Pettersson et al. / Tetrahedron Letters 51 (2010) 238–239
239
O
O
O
(i)
(ii)
N
N
OH
O
O
+
H
S
N
H
H
N
N
H
O
N
H
O
H
9
3
isatoic anhydride
-proline
(iii)
L
(iv; b)
(iv; a)
O
O
N
N
O
N
11a
H
H
N
N
H
H
H
O
N
O
O
H
9
1
2
N
H
Scheme 3. Synthesis of fuligocandines A and B. Reagents and conditions: (i)
L
-proline, DMSO, 100 °C, 4 h (95%); (ii) P2S5–Py2, ꢀ60 °C, MeCN, 4 h, (75%); (iii) NaH, DMSO, rt,
30 min, (quant.); (iv) (a) chloroacetone, rt, 40 min then P(OMe)3, DABCO, 100 °C, 24 h (60%, unoptimized); (b) 8a or 8b, rt, 40 min then P(OMe)3, DABCO, 100 °C, ꢀ30 h (20%,
for both, unoptimized).
the episulfide contraction was first studied by Knott,4 it has gained
as a base also gave the desired product, but in inferior yields as
compared with DABCO.
widespread use ever since the Eschenmoser–Woodward collabora-
5
tion on vitamin B12
.
As outlined in Scheme 2 (en route to 2 via 8), 1,3-dichloroace-
tone 4 was selectively combined with triphenylphosphine and
the resulting intermediate phosphonium salt was neutralized with
a base to give the desired mono ylide 5.6 The aldehyde 6 was pro-
tected with benzenesulfonyl chloride to give 7a and with p-nitro-
benzenesulfonyl chloride (NsCl) to give 7b. Both aldehydes 7a
and 7b underwent a smooth Wittig reaction with the phosphorus
ylide 5 when the reaction was conducted in refluxing methanol;
other solvents gave no reaction or poor yields of the required in-
dole derivatives 8. Attempts to obtain this molecule by halogena-
tion of the readily available7 3-(3-oxo-1-butenyl)indole failed.
Next, the pyrrolo-1,4-benzodiazepine derivative 9 was readily
References and notes
1. Nakatani, S.; Yamamoto, Y.; Hayashi, M.; Komiyama, K.; Ishibashi, M. Chem.
Pharm. Bull. 2004, 52, 368–370.
2. Hasegawa, H.; Yasuaki, Y.; Komiyama, K.; Hayashi, M.; Ishibashi, M.; Sunazuka,
T.; Izuhara, T.; Sugahara, K.; Tsuruda, K.; Masuda, M.; Takasu, N.; Tsukasaki, K.;
Tomonaga, M.; Kamihira, S. Blood 2007, 110, 1664–1674.
3. Roth, M.; Dubs, P.; Goetschi, E.; Eschenmoser, A. Helv. Chim. Acta 1971, 54, 710–
734.
4. Knott, E. B. J. Chem. Soc. 1955, 916–927.
5. Woodward, R. B. Pure Appl. Chem. 1968, 17, 519–547.
6. Boeckman, R. K., Jr.; Zhang, J.; Reeder, M. R. Org. Lett. 2002, 4, 3891–
3894.
7. Bergman, J. Acta Chem. Scand. 1972, 26, 970–974.
8. Wright, W. B., Jr.; Brabander, H. J.; Greenblatt, E. N.; Day, I. P.; Hardy, R. A., Jr. J.
Med. Chem. 1978, 21, 1087–1089.
prepared by heating isatoic anhydride and L
-proline in DMSO.8 This
9. (a) Kamal, A.; Howard, P. W.; Reddy, N.; Reddy, P.; Thurston, D. E. Tetrahedron
1997, 53, 3223–3230; (b) Schmidt, A.; Anika, S.; Shilabin, A. G.; Nieger, M.
Tetrahedron 2008, 64, 2048–2056.
diamide was selectively thionated to give the known monothi-
one9a,b 3, using the P2S5–Py2 complex (Scheme 3).
10. Fuligocandin A gave the following 1H NMR data (300 MHz, CDCl3) d ppm: 2.00–
2.10 (m, 2H), 2.11–2.29 (m, 4H), 2.34–2.46 (m, 1H), 3.64–3.70 (m, 1H), 3.80–
3.85 (m, 1H), 4.30 (dd, 1H, J = 7.9, 1.6 Hz), 5.30 (s, 1H), 7.02–7.05 (m, 1H), 7.19–
7.24 (m, 1H), 7.43–7.48 (m, 1H), 7.96–7.98 (m, 1H), 12.6 (br s, 1H); 13C NMR
(75 MHz, DMSO-d6) d ppm: 23.6 (t), 27.2 (t), 30.0 (q), 47.2 (t), 55.6 (d), 91.4 (d),
122.4 (d), 124.8 (d), 127.3 (s), 131.4 (d), 132.8 (d), 137.2 (s), 159.3 (s), 165.9 (s),
198.4 (s).These NMR data are in agreement with data previously reported by
Nakatani et al.1
Finally, one-pot alkylation of the thione 3 and subsequent sulfur
extrusion gave fuligocandin A (as the required Z-isomer).10 The
racemate of this compound has recently been synthesized in six
steps starting from azide derivatives.11 Employing our Eschenmo-
ser coupling strategy we also obtained fuligocandin B (as the re-
quired Z- and E-isomer) using the convergent route outlined in
Scheme 3.12 As a bonus, under the conditions employed, the indole
N-protecting group was also removed. Determination of the optical
purities of compounds 1–3, somewhat surprisingly showed that
the chirality at C-11a (Scheme 3) was lost in the last step, probably
due to tautomerization brought on by the basic reaction condi-
tions. We are currently optimizing this final step and are studying
the general applicability of this one-pot alkylation-sulfur extrusion
protocol. Previously used standard conditions (such as t-butoxide
or triethylamine and triphenylphosphine in benzene or xylene at
high temperature) failed in these cases. The use of DBU or DBN
11. More, S.; Shanmughapriya, D.; Lingam, Y.; Patel, N. B. Synth. Commun. 2009, 39,
2058–2066.
12. Fuligocandin B gave the following 1H NMR (300 MHz, acetone-d6) d ppm: 2.06–
2.17 (m, 2H), 2.27–2.30 (m, 1H), 2.57–2.62 (m, 1H), 3.55–3.65 (m, 2H), 4.46
(dd, 1H, J = 8.0, 1.6 Hz), 5.82 (s, 1H), 7.02 (d, 1H, J = 15.1 Hz), 7.13–7.16 (m, 1H),
7.19–7.23 (m, 3H), 7.50–7.62 (m, 2H), 7.82–7.85 (m, 1H), 7.87–7.91 (m, 1H),
7.93 (d, 1H, J = 15.1 Hz), 8.02–8.05 (m, 1H), 10.9 (br s, 1H), 13.4 (br s, 1H); 13C
NMR (75 MHz, DMSO-d6) d ppm: 24.1 (t), 29.0 (t), 47.6 (t), 56.2 (d), 93.6 (d),
113.0 (d), 114.1(s), 121.4 (d), 121.7 (d), 122.7 (d), 123.6 (d), 124.0 (d), 124.5 (d),
126.5 (s), 128.3 (s), 131.5 (d), 131.6 (d), 133.2 (d), 135.0 (d), 138.6 (s), 138.7 (s),
160.6 (s), 165.9 (s), 190.4 (s). These NMR data are in agreement with the data
previously reported by Nakatani et al.1