Total synthesis of lycogarubin C utilizing the Kornfeld-Boger ring contraction

Article abstract of DOI:10.1016/j.tetlet.2009.11.085

An efficient synthesis of lycogarubin C (3) was completed in seven steps from the known 1-(phenylsulfonyl)indole-3-carbaldehyde in 30% overall yield, via a Diels-Alder reaction between (Z)-1,2-di(1H-indol-3-yl)ethene 9b and dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7), followed by a Kornfeld-Boger ring contraction to form the pyrrole ring.

Full text of DOI:10.1016/j.tetlet.2009.11.085

Tetrahedron Letters 51 (2010) 537–539
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Tetrahedron Letters
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Total synthesis of lycogarubin C utilizing the Kornfeld–Boger ring contraction
*
Liangfeng Fu, Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of lycogarubin C (3) was completed in seven steps from the known 1-(phenylsul-
fonyl)indole-3-carbaldehyde in 30% overall yield, via a Diels–Alder reaction between (Z)-1,2-di(1H-indol-
3-yl)ethene 9b and dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7), followed by a Kornfeld–Boger ring
contraction to form the pyrrole ring.
Received 22 October 2009
Revised 18 November 2009
Accepted 19 November 2009
Available online 26 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Lycogarubins A–C (1–3) and lycogalic acid A (4) are marine
natural products isolated from the fruit bodies of the slime mold
Lycogala epidendrum independently by Asajawa and co-workers1
and Steglich and co-workers2 in 1994 (Fig. 1). Previous syntheses
of lycogarubins include a one-pot reaction from methyl 3-(indol-
3-yl)pyruvate,2 a palladium-catalyzed Suzuki cross-coupling reac-
tion,3 the oxidative condensation of 3-arylpyruvic acid with
ammonia,4 and a one-step synthesis from indole-3-pyruvic acid
catalyzed by hemoprotein StaD5 and by the cytochrome P450 en-
zymes StaP, RebP,6 RebO, and RebD.7
The requisite (Z)-1,2-di(1H-indol-3-yl)ethene 9a11 (R1 = H,
R2 = SO2Ph) and 9b12 (R1 = R2 = SO2Ph) were prepared from the
known indole-3-carbaldehyde 11.13 Reduction of 11 with NaBH4
in EtOH provided alcohol 12 in 97%. Bromination of 12 with PBr3
afforded the corresponding bromide 1314 in 95% yield. A Wittig
Our recent synthesis of 1,2-di(1H-indol-3-yl)ethyne 68
prompted us to utilize this substrate in a novel synthesis of lyco-
garubin C (3). Thus, an inverse-electron demand Diels–Alder reac-
tion between 6 and the well-known 1,2,4,5-tetrazine ester 79
should give bisindole 5, which by a subsequent Kornfeld–Boger
reductive ring contraction reaction9,10 should provide a simple
route to lycogarubin C (3) (Scheme 1).
In our initial attempt, heating 6 (R = SO2Ph) and tetrazine 7 in
toluene only resulted in recovered starting alkyne 6 and the
decomposition of 7. Likewise, reactions in refluxing xylene, mesit-
ylene, dichlorobenzene, and diphenyl ether were unsuccessful
(Scheme 2).
Figure 1.
We reasoned that the electron-withdrawing phenylsulfonyl-
protecting groups might be deactivating the dienophilic alkyne.
However, attempted Diels–Alder reactions between 6 (R = H) and
7 in refluxing toluene led to the recovery of ethyne 6 (Scheme 2).
Believing that steric hindrance in the ethyne 6 was the reason
for the failure of the Diels–Alder reaction, we redirected our ap-
proach to the corresponding (Z)-1,2-di(1H-indol-3-yl)ethene 9 as
the dienophile (Scheme 3).
Thus, a Diels–Alder reaction of alkene 9 with tetrazine 7 should
give intermediate 10 (or a tautomer), which upon treatment with
zinc in acetic acid followed by N-deprotection should give lyco-
garubin C (3) (Scheme 3).
* Corresponding author.
E-mail address: ggribble@dartmouth.edu (G.W. Gribble).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.085

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L. Fu, G. W. Gribble / Tetrahedron Letters 51 (2010) 537–539
Scheme 2.
Scheme 5.
Scheme 3.
reaction protocol of 13 with indole-3-carbaldehyde (14)15 gave al-
kene 9a (cis:trans, 4:1) in 87% from 13. Similarly, alkene 9b was
obtained in 65% from 13 using aldehyde 11 (Scheme 4).
Scheme 6.
The Diels–Alder reaction between 9a and tetrazine 7 afforded a
mixture of the corresponding Diels–Alder product 15 (not shown),
which upon treatment with zinc in acetic acid gave a mixture of
three different products 16,16 1717, and 1818 in 21%, 25%, and
29% yield, respectively (Scheme 5). We believe that 17 is formed
by acid-catalyzed loss of indole from the initial Diels–Alder adduct.
Deprotection of 16 under mild conditions using Mg and NH4Cl
in methanol provided lycogarubin C (3)19 in 93% yield (Scheme 6).
Since the unprotected indole in 9a is clearly unsatisfactory for
the zinc reductive ring contraction (cf. Scheme 5), we turned to
the use of fully protected bisindolealkene 9b. To our delight, the
Diels–Alder reaction between 9b and tetrazine 7 followed by
reduction with zinc and acetic acid provided the desired bisindol-
ylpyrrole 2020 in 54% yield from 9b. Cleavage of the phenylsulfonyl
groups with Mg and NH4Cl gave lycogarubin C (3)19 in 91% yield
(Scheme 7).
Scheme 7.
In summary, we have described a convenient synthesis of the
bis(indolyl)pyrrole lycogarubin C (3) that features a Diels–Alder
reaction between bis(indolyl)ethene 9b and dimethyl 1,2,4,5-tet-
razinedicarboxylate (7) followed by a Kornfeld–Boger zinc reduc-
tive ring contraction.
Acknowledgments
This work was supported by the Donors of the Petroleum Re-
search Fund (PRF), administrated by the American Chemical Soci-
ety, and by Wyeth. We thank Professor Alois Fürstner for copies
of spectra of lycogarubin C for comparison with our material.
References and notes
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Lett. 1994, 35, 1689.
Scheme 4.

L. Fu, G. W. Gribble / Tetrahedron Letters 51 (2010) 537–539
539
3. Furstner, A.; Krause, H.; Thiel, O. R. Tetrahedron 2002, 58, 6373.
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7.60 (m, 4H), 7.34–7.42 (m, 4H), 7.10–7.34 (m, 2H), 6.86 (s, 2H); 13C NMR
(500 MHz, acetone-d6) d 137.9, 134.8, 134.6, 130.0, 129.7, 127.0, 125.3, 124.8,
123.7, 121.4, 120.5, 119.6, 113.7.
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15. James, P. N.; Snyder, H. R. Org. Synth. 1959, 39, 30.
16. Compound 16: 1H NMR (500 MHz, acetone-d6) d 11.45 (br s, 1H), 10.15 (br s,
1H), 7.80 (d, J = 8.6 Hz, 1H), 7.56–7.64 (m, 4H), 7.44–7.50 (m, 2H), 7.37 (d,
J = 8.2 Hz, 1H), 7.22–7.26 (m, 1H), 7.09–7.20 (m, 3H), 6.97–7.07 (m, 2H), 6.85–
6.88 (m, 1H), 3.64 (s, 3H), 3.60 (s, 3H); 13C NMR (500 MHz, acetone-d6) d 160.6,
160.4, 138.2, 136.2, 134.6, 134.1, 131.6, 129.8, 129.7, 126.8, 126.3, 125.4, 125.3,
124.3, 123.6, 123.5, 123.1, 122.0, 121.3, 121.0, 119.7, 119.1, 116.6, 113.2, 111.4,
107.9, 51.1, 51.0; HRMS (ESI): m/z calcd for C30H23O6N3S: 554:1386. Found:
554.1372.
8. Roy, S.; Gribble, G. W. Synth. Commun. 2007, 37, 829.
9. Although Kornfeld first described this particular useful reductive ring
contraction: Bach, N. J.; Kornfeld, E. C.; Jones, N. D.; Chaney, M. O.; Dorman,
D. E.; Paschal, J. W.; Clemens, J. A.; Smalstig, E. B. J. Med. Chem. 1980, 23, 481; it
is Boger who has exploited it: Boger, D. L.; Panek, J. S.; Patel, M. Org. Synth.
1992, 70, 79; Boger, D. L.; Coleman, R. S.; Panek, J. S.; Huber, F. X.; Sauer, J. J. Org.
Chem. 1985, 50, 5377; Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D. J.
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Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 11418; Boger, D. L.;
Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54;
Boger, D. L.; Soenen, D. R.; Boyce, C. W.; Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000,
65, 2479; Boger, D. L.; Hong, J. J. Am. Chem. Soc. 2001, 123, 8515; Yeung, B. K. S.;
Boger, D. L. J. Org. Chem. 2003, 68, 5249; Hamasaki, A.; Zimpleman, J. M.;
Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2005, 127, 10767.
17. Compound 17: 1H NMR (500 MHz, acetone-d6) d 11.59 (br s, 1H), 8.07–8.12 (m,
4H), 7.57–7.69 (m, 4H), 7.37–7.41 (m, 1H), 7.28–7.32 (m, 1H), 7.14 (d,
J = 2.8 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H); 13C NMR (500 MHz, acetone-d6) d
160.4, 160.3, 138.2, 135.0, 134.5, 130.7, 129.8, 127.2, 126.4, 125.9, 124.9, 123.9,
123.1, 121.8, 120.8, 116.6, 115.9, 113.8, 51.5, 51.3; HRMS (ESI): m/z calcd for
C22H18O6N2S: 439.0964. Found: 439.0953.
18. Compound 18: 1H NMR (500 MHz, acetone-d6) d 11.56 (br s, 1H), 10.40 (br s,
1H), 8.00 (d, J = 8.2 Hz, 1H), 7.85–7.88 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.60–
7.64 (m, 1H), 7.44–7.54 (m, 4H), 7.35–7.39 (m, 1H), 7.21–7.31 (m, 3H), 7.10–
7.15 (m, 1H), 6.96–7.05 (m, 1H), 5.38 (s, 1H), 3.73 (s, 3H), 3.60 (s, 3H); 13C NMR
(500 MHz, acetone-d6) d 165.1, 163.9, 137.8, 136.5, 135.9, 134.5, 129.8, 129.4,
127.3, 127.1, 126.9, 126.5, 125.4, 125.3, 125.1, 123.9, 123.1, 122.0, 120.9, 120.1,
119.5, 113.9, 113.8, 112.2, 110.8, 51.9, 51.8, 35.2.
10. Other groups have also employed this reaction in synthesis: Daly, K.; Nomak,
R.; Snyder, J. K. Tetrahedron Lett. 1997, 38, 8611; Joshi, U.; Josse, S.; Pipelier, M.;
Chevallier, F.; Pradère, J.-P.; Hazard, R.; Legoupy, S.; Huet, F.; Dubreuil, D.
Tetrahedron Lett. 2004, 45, 1031; Müller, J.; Troschütz, R. Synthesis 2006, 1513;
Naud, S.; Pipelier, M.; Chaumette, C.; Viault, G.; Huet, F.; Legoupy, S.; Dubreuil,
D. Synlett 2007, 403; Naud, S.; Pipelier, M.; Viault, G.; Adjou, A.; Huet, F.;
Legoupy, S.; Aubertin, A.-M.; Evain, M.; Dubreuil, D. Eur. J. Org. Chem. 2007,
3296; Moisan, L.; Odermatt, S.; Gombosuren, N.; Carella, A.; Rebek, J., Jr. Eur. J.
Org. Chem. 2008, 1673.
19. Lycogarubin C (3): yellowish solid; mp 123–125 °C (Lit.3 mp 122–125 °C); 1H
NMR (500 MHz, acetone-d6) d 11.06 (br s, 1H), 10.04 (br s, 2H), 7.26–7.30 (m,
2H), 7.16–7.20 (m, 2H), 7.07 (d, J = 2.8 Hz, 2H), 6.95–6.99 (m, 2H), 6.79–6.83
(m, 2H), 3.64 (s, 6H); 13C NMR (500 MHz, acetone-d6) d 160.8, 136.3, 128.2,
125.4, 125.3, 123.0, 120.9, 119.9, 118.7, 111.2, 108.6, 50.9.
11. Compound 9a: yellow oil (cis:trans, 4:1); 1H NMR (500 MHz, acetone-d6) (cis-
isomer) d 8.05 (br s, 1H), 7.94 (m, 1H), 7.66 (m, 2H), 7.20–7.43 (m, 8H), 7.06–
7.13 (m, 2H), 6.95–6.99 (m, 1H), 6.80–6.88 (m, 2H), 6.44 (d, 1H); 13C NMR
(500 MHz, acetone-d6) d 138.2, 135.9, 135.1, 134.1, 130.3, 129.6, 127.1, 126.6,
125.2, 124.2, 124.1, 123.6, 122.6, 121.0, 120.9, 120.3, 120.0, 116.5, 113.8, 113.5,
111.7.
20. Compound 20: yellow solid; mp 205–207 °C; 1H NMR (500 MHz, acetone-d6) d
11.79 (br s, 1H), 7.86–7.89 (m, 2H), 7.67–7.71 (m, 6H), 7.56–7.60 (m, 2H), 7.44–
7.48 (m, 4H), 7.16–7.24 (m, 4H), 6.96–7.03 (m, 2H), 3.57 (s, 6H); 13C NMR
(500 MHz, acetone-d6) d 160.2, 138.1, 134.5, 134.2, 131.4, 129.7, 126.7, 126.4,
124.6, 124.0, 123.3, 121.9, 120.8, 115.7, 113.3, 51.2.
12. Compound 9b: white solid; mp 152–155 °C; 1H NMR (500 MHz, acetone-d6) d
8.00–8.07 (m, 2H), 7.85–7.89 (m, 4H), 7.64–7.72 (m, 2H), 7.61 (s, 2H), 7.54–