Synthetic approaches toward the marine alkaloid prenostodione

Article abstract of DOI:10.1016/j.tetlet.2013.02.116

An efficient synthesis of the core of prenostodione (3) is described herein featuring the base condensation of BOC-protected indole diesters 21 and 24 with p-methoxybenzaldehyde (22) and 4-[(t-butyldimethylsilyl)oxy]benzaldehyde (26). Attempts at selective saponification of the resultant diesters yielded isoprenostodione (3a) bearing the ester functionality at the C-3 position of the indole ring.

Full text of DOI:10.1016/j.tetlet.2013.02.116

Tetrahedron Letters 54 (2013) 2759–2762
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic approaches toward the marine alkaloid prenostodione
Jeanese C. Badenock a, , Jason A. Jordan a, Gordon W. Gribble b
⇑
a Department of Biological and Chemical Sciences, University of the West Indies, Cave Hill, Barbados
b 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 the core of prenostodione (3) is described herein featuring the base condensation
of BOC-protected indole diesters 21 and 24 with p-methoxybenzaldehyde (22) and 4-[(t-butyldimethyl-
silyl)oxy]benzaldehyde (26). Attempts at selective saponification of the resultant diesters yielded isopre-
nostodione (3a) bearing the ester functionality at the C-3 position of the indole ring.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 3 January 2013
Revised 3 February 2013
Accepted 8 February 2013
Available online 25 March 2013
Keywords:
Indole
Prenostodione
Cyanobacteria
2-Vinylindoles
Recently, a number of blue-green algae (cyanobacteria) have
been found to possess various bioactive components,1 some of
which exhibit antibacterial,2 antimicrobial,3 and cytotoxic effects.4
Additional interest in some of these pigments stems from their
reported protective role against high solar radiation,5 and their
potential use as active ingredients in sunblock and sunscreen lo-
tions. We have been interested in three such indole alkaloids
namely scytonemin (1),6 nostodione A (2),7 and prenostodione
(3) (Fig. 1).8
OH
N
O
O
CO2H
CO2Me
O
O
N
N
H
N
H
H
Of these three alkaloids, prenostodione (3) is of particular
interest mainly in view of its presumed role in the biosynthesis
of nostodione A (2) and scytonemin (1). The UV-absorbing natural
product prenostodione (3) was isolated by Ploutno et al. in 2001 as
the minor pigment from Nostoc sp. and determined to be the E
isomer of the indole-3-carboxylic acid derivative.8 The combina-
tion of acid and ester functionalities led us to first consider the
introduction of the 3-carboxylic acid group in the final stages of
the synthesis.9 As such, we envisioned the installation of the
p-hydroxyphenyl moiety using either a Wittig reaction,10 or a
suitable modification, such as the Shapiro, Schlosser, or Horner–
Emmons–Wadsworth reactions (Scheme 1).11
HO
HO
HO
3
1
2
Figure 1. Cyanobacteria based indole natural products.
CO2H
CO2Me
CO2Me
H
CO2Me
N
N
R
N
R
H
H
O
Keto ester 6 was therefore generated from indole (7) in two
steps utilizing standard C-2 lithiation chemistry.12 Unfortunately,
attempts to couple 6 with phosphorus ylide 9a resulted in poor
yields of the desired alkene (10a), as a 1:1 mixture of isomers
(14% overall yield). Furthermore, reaction of 6 with p-methoxyben-
zyl ylide 9b and with commercially available diethyl 4-methoxy-
HO
R1O
3
4
5
Scheme 1. Initial retrosynthetic approach.
benzyl phosphonate (9c) failed to yield the desired alkenes
(Scheme 2). The poor stereoselectivity and the low yields of the
reaction caused us to abandon this route.
⇑
Corresponding author. Tel.: +1 246 417 4336; fax: +1 246 417 4325.
E-mail address: jeanese.badenock@cavehill.uwi.edu (J.C. Badenock).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.116

2760
J. C. Badenock et al. / Tetrahedron Letters 54 (2013) 2759–2762
CO2R
CO2R
CO2R
CO2R
ii.
CO2R
CO2R
i.
i./ii.
iii./iv.
N
H
N
N
Bn
N
H
O
But
O
O
7
8
16: R = Et
19: R = Me
18: R = Et
20: R = Me
14a: R = Et
14b: R = Me
O
O
iii.
Scheme 5. Synthesis of indole diesters 14. Reagents and conditions: (i) Compound
17, EtOH, d (18: 54%); (ii) Compound 17, MeOH, (20: 57%); (iii) AlCl3, PhH, rt, 3.5 h
(14a: 40%); (iv) AlCl3, PhH, , 0.5 h (14b: 85%).
N
OMe
N
OMe
D
tBu
O
tBu
R1P
O
O
O
O
D
OR2
OR2
9a: R1 = Ph3+Br-, R2 = TBS
9b: R1 = Ph3+Br-, R2 = Me
9c: R1 = (O)OEt2, R2 = Me
6
10
indole 20 as a white fluffy solid in 57% yield. Removal of the benzyl
group seemed promising based on a number of reports describing
debenzylation from indole nitrogens.20 Gratifyingly, treatment of
indole 18 with anhydrous aluminum chloride (AlCl3) in anhydrous
benzene at room temperature resulted in indole 14a (R1 = Et, and
R2 = H), albeit in only 40% yield after 3 h at room temperature.21,22
We fared better with dimethyl indole 20, which was converted
smoothly into the parent indole 14b (R1 = Me, and R2 = H), in 85%
yield, with AlCl3 at reflux after 30 min (Scheme 5).23
Reprotection of the indole nitrogen of 14a, using di-tert-butyl
dicarbonate and DMAP generated t-butoxy carbamate 21 in 85%
yield.24 The Macor-precedented condensation reaction was
performed with LDA and the resulting anion was treated with
commercially available p-methoxybenzaldehyde (22). Pleasingly,
we obtained the coupled alkene (23), after stirring with sodium hy-
dride in refluxing THF, in 54% yield. The 1H NMR spectrum of 23
indicated a predominance of one isomer and only trace (<5%)
amounts of the other (Scheme 6). From NOE experiments, we con-
cluded that alkene 23 possesses the Z geometry (opposite to the
natural product) based on the observation that irradiation of the
indole NH singlet (d = 8.84) showed a positive NOE enhancement
of the vinyl singlet (d = 7.88) in addition to the C-7 multiplet.
With sufficient 23 in hand, we preliminarily investigated the
selective hydrolysis of the ethyl ester functionalities of this indole
alkene. Using 1 N KOH in methanol, we were pleasantly surprised
when after 1 h at reflux we observed the cleavage of one ethyl
group in 93% yield.16b,25 However, we have been unable to deter-
mine conclusively which ester was removed.
Scheme 2. Unsuccessful Wittig reaction. Reagents and conditions: (i)
((CH3)3CO2C)2O, DMAP, THF (98%); (ii) t-BuLi, THF, (CO2Me)2 (71%); (iii) n-BuLi,
9a, THF (14%).
O
O
CO2H
CH3
OEt
CH3
O
i.
ii.
CH3
Ph
N
CH3
N
N
CH3
Ph
CH3
11
12
13
Scheme 3. Synthesis of 2-vinylindole 13. Reagents and conditions: (i) LDA, THF,
À78 °C, CH3COPh (60%); (ii) NaH, THF (80%).
We were then drawn to a procedure by Mouaddib et al. which
features
a base-catalyzed condensation en route to tetra-
hydrobenzo[4,5]cyclohept[b]indol-12-one derivatives, necessary
for the development of new effective chemotherapeutic agents.13
In that work, initially elaborated by Macor et al.,14 the vinyl group
was installed by LDA-catalyzed condensation of acetophenone and
2-methylindole 11 followed by treatment with sodium hydride
(Scheme 3).
Therefore, we surmised that this precedent might be useful in a
biomimetic approach to prenostodione (3) and proposed that
coupling of diester 14 with a benzaldehyde derivative could pro-
duce the desired alkene (15). Furthermore, this approach would
eliminate the need for the installation of the C-3 acid and would
only necessitate selective hydrolysis of the ester already installed
at that position.15 Indeed Bahadur et al. and others16 utilized this
chemistry with indoles and in all cases generated the desired
monoesters with the acid at C-3 on the indole core. Our initial tar-
get was therefore the N-BOC derivatives of diesters 14 (R2 = CO2-
But) (Scheme 4).
The results of this hydrolysis attempt and the perceived diffi-
culty associated with the transesterification of the remaining ethyl
ester to the methyl ester found in the natural product prompted us
to utilize dimethyl ester 24 for the coupling. Thus, 14b was
protected as the N-BOC derivative (24) in quantitative yield, and
then condensed with p-methoxybenzaldehyde (22) under identical
conditions to those used with diethyl ester 21 to give the coupled
alkene 25, in an overall yield of 69% (Scheme 7). Alkene 25
contained one major isomer (16% minor isomer) determined to
be the Z-isomer based on NOE experiments.26
While the Fischer indole reaction17 of phenylhydrazine with
diethyl acetone-1,3-dicarboxylate (16) in concentrated sulfuric
acid gave the diethyl ester indole 14a (R1 = Et, and R2 = H) in only
6% yield,18 treatment of N-benzyl phenylhydrazine hydrochloride
(17) with 16 in refluxing ethanol gave the desired indole 18, in
one step, as a white solid in 54% yield.19 Likewise, heating 17 with
dimethyl acetone-1,3-dicarboxylate (19) in methanol generated
Attempts at cleavage of the methyl ester and methyl ether in 25
were unsuccessful27,28 but a change in the protecting group of the
phenolic coupling unit, however, from the methyl ether to the
CO2Et
CO2Et
CO2Et
CO2Et
ii.
N
R
N
H
7
CO2H
CO2Me
CO2R1
CO2R1
CO2R1
CO2R1
H
OMe
N
H
N
H
N
14a: R = H
23
H
H
R2
i.
21: R = CO2But
HO
R3O
3
15: R1 = Me, Et
14: R1 = Me, Et
Scheme 6. Coupling of diethylindole 21 with 22. Reagents and conditions: (i)
((CH3)3CO2C)2O, DMAP, THF, rt (85%); (ii) LDA, THF, p-OMeC6H4CHO (22), À78 °C;
Scheme 4. New retrosynthetic analysis.
NaH, THF, D, 1 h (54%).

J. C. Badenock et al. / Tetrahedron Letters 54 (2013) 2759–2762
2761
CO2Me
CO2Me
CO2Me
CO2Me
In summary, we have synthesized a number of C-2 vinyl in-
doles,33 some of which possess the desired E stereochemistry
found in prenostodione (3). Efforts are ongoing in our laboratory
to regioselectively hydrolyze dimethyl esters 27 and 28 to provide
the natural product.
ii.
N
R
N
H
H
OMe
14b: R = H
25
Acknowledgments
i.
24: R = CO2But
This work was supported by the Donors of the Petroleum Re-
search Fund (PRF), administered by the American Chemical Society,
Wyeth, the UWI, and the Government of Barbados. The authors
would like to thank Prof. Sean McDowell for assistance with the
molecular modeling experiments.
Scheme 7. Coupling of dimethylindole 24 with 22. Reagents and conditions: (i)
((CH3)3CO2C)2O, DMAP, THF, rt (100%); (ii) LDA, THF, p-OMeC6H4CHO (22), À78 °C;
NaH, THF,
D, 1 h (69%).
CO2Me
CO2Me
CO2Me
CO2Me
References and notes
i.
N
H
N
1. (a) Skulberg, O. M. J. Appl. Phycol. 2000, 12, 341; (b) Schaeffer, D. J.; Krylov, V. S.
Ecotoxicol. Environ. Saf. 2000, 45, 208; (c) Burja, A. M.; Banaigs, B.; Abou-
Mansour, E.; Grant Burgess, J.; Wright, P. C. Tetrahedron 2001, 57, 9347; (d) Tan,
L. T. Phytochemistry 2007, 68, 954; (e) Gademann, K.; Portmann, C. Curr. Org.
Chem. 2008, 12, 326; (f) Martins, R. F.; Ramos, M. F.; Herfindal, L.; Sousa, J. A.;
Skærven, K.; Vasconcelos, V. M. Mar. Drugs 2008, 6, 1.
2. (a) MacMillan, J. B.; Ernst-Russell, M. A.; de Ropp, J. S.; Molinski, T. F. J. Org.
Chem. 2002, 67, 8210; (b) Mundt, S.; Kreitlow, S.; Jansen, R. J. Appl. Phycol. 2003,
15, 263; (c) Rao, M.; Malhotra, S.; Fatma, T.; Rattan, A. Pharm. Biol. 2007, 45, 88.
3. (a) Matern, U.; Oberer, L.; Erhard, M.; Herdman, M.; Weckesser, J.
Phytochemistry 2003, 64, 1061; (b) Shanab, S. M. M. Int. J. Agric. Biol. 2007, 9,
617.
tBu
O
O
H
R1O
ii.
27: R1 = TBS
28: R1 = H
24
Scheme 8. Coupling of dimethylindole 24 with 26. Reagents and conditions: (i)
LDA, THF, 26, À78 °C; CaH2, THF, , 1 h (46%); (ii) TBAF, THF, rt, 3 h (98%).
D
4. Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J.; Mooberry, S. L. J. Nat. Prod.
2000, 63, 611.
5. (a) Tripathi, S. N.; Talpasayi, E. R. S. Curr. Sci. 1980, 49, 31; (b) Castenholz, R. W.;
Garcia-Pichel, F. In The Ecology of Cyanobacteria; Whitton, B. A., Potts, M., Eds.;
Kluwer Academic Publishers: Dordrecht, The Netherlands, 2000; p 591.
6. (a) Nägeli, C. Neue Denkschrift. Allg. Schweiz. Nat. Ges. 1849, 10, 1; (b) Nägeli, C.;
Schwenderer, S. Das Mikroskop, 2nd ed.; Willhelm Engelmann: Leipzig, 1877;
(c) Garcia-Pichel, F.; Castenholz, R. W. J. Phycol. 1991, 27, 395; (d) Garcia-Pichel,
F.; Sherry, N. D.; Castenholz, R. W. Photochem. Photobiol. 1992, 56, 17; (e)
Proteau, P. J.; Gerwick, W. H.; Garcia-Pichel, F.; Castenholz, R. Cell. Mol. Life Sci.
1993, 49, 825; (f) Balskus, E. P.; Walsh, C. T. J. Am. Chem. Soc. 2008, 130, 15260;
(g) Balskus, E. P.; Walsh, C. T. J. Am. Chem. Soc. 2009, 131, 14648; (h) Ekebergh,
A.; Karlsson, I.; Mete, R.; Pan, Y.; Börje, A.; Mårtensson, J. Org. Lett. 2011, 13,
4458.
t-butyldimethylsilyl ether gave us more favorable results. When 4-
[(t-butyldimethylsilyl)oxy]benzaldehyde (26)29 was condensed
with indole 24 we obtained the desired OTBS-alkene (27) in 46%
yield, as a single isomer. The orientation of alkene 27 was deter-
mined once again using NOE experiments but surprisingly unlike
alkenes 23 and 25, the E geometry was observed.30,31 With alkene
27 in hand, deprotection with tetra-n-butyl ammonium fluoride
(TBAF) in THF32 afforded alkene 28 in almost quantitative yield
(Scheme 8).
7. (a) Kobayashi, A.; Kajiyama, S.-I.; Inawaka, K.; Kanzaki, H.; Kawazu, K. Z. Z.
Naturforsch., C Biosci. 1994, 49, 464; (b) Shim, S. H.; Chlipala, G.; Orjala, J. J.
Microbiol. Biotechnol. 2008, 18, 1655; (c) Ekebergh, A.; Börje, A.; Mårtensson, J.
Org. Lett. 2012, 14, 6274.
We were elated to find that refluxing 28 with stoichiometric
amounts of KOH in methanol for 4 hours resulted in the selective
hydrolysis of one of the methyl esters in 25% yield after column
chromatography. Comparison of the UV, 1H and 13C NMR data of
this compound and naturally occurring 3, indicated a close correla-
tion. In our revisit of this experiment, silyl ether 27 was subjected
to a solution of excess potassium hydroxide in methanol and
generated a yellow oil with identical spectral data to the one
formed from the hydrolysis of 28, indicating the lost of the silyl
ether and one of the methyl esters. Extensive 2D NMR experiments
of this monoester confirmed the E geometry of the alkene, however
the expected ROESY correlation between the vinylic H-9 proton
(d = 7.77) and the methoxy (1-OMe) protons (d = 3.69) was not
observed.8 Instead we observed an unmistakeable correlation
between the methoxy (1-OMe) protons (d = 3.69) and the indole
aromatic (H-7) proton (d = 8.03) (Scheme 9) indicating that the
isomer of the natural product, isoprenostodione (3a), had been
synthesized.
8. Ploutno, A.; Carmeli, S. J. Nat. Prod. 2001, 64, 544.
9. (a) Snieckus, V. Chem. Rev. 1990, 90, 879; (b) Delgado, A.; Clardy, J. Tetrahedron
Lett. 1992, 33, 2789; (c) Delgado, A.; Clardy, J. J. Org. Chem. 1993, 58, 2862.
10. (a) Maryanoff, B. E.; Reitz, A. B. Tetrahedron Lett. 1985, 26, 4587; (b) Maryanoff,
B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863; (c) Maryanoff, B. E.; Reitz, A. B.; Duhl-
Emswiler, B. A. J. Am. Chem. Soc. 1985, 107, 217.
11. Modi, S. P.; Zayed, A. H.; Archer, S. J. Org. Chem. 1989, 54, 3084.
12. Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy, A. B. J. Org. Chem.
1981, 46, 157.
13. Mouaddib, A.; Joseph, B.; Hasnaoui, A.; Merour, J.-Y.; Leonce, S. Heterocycles
1999, 51, 2127.
14. (a) Macor, J. E.; Newman, M. E.; Ryan, K. Tetrahedron Lett. 1989, 30, 2509; (b)
Macor, J. E.; Ryan, K.; Newman, M. E. J. Org. Chem. 1989, 54, 4785.
15. (a) Groves, J. K.; Cundasawmy, N. E.; Anderson, H. J. Can. J. Chem. 1973, 51,
1089; (b) Li, J.; Zhang, J.; Chen, J.; Luo, X.; Zhu, W.; Shen, J.; Liu, H.; Shen, X.;
Jiang, H. J. Comb. Chem. 2006, 8, 326.
16. (a) Bahadur, G. A.; Bailey, A. S.; Middleton, N. W.; Peach, J. M. J. Chem. Soc.,
Perkin Trans. 1 1980, 1688; (b) Karrick, G. L.; Peet, N. P. J. Heterocycl. Chem.
1986, 23, 1055; (c) Monge, A.; Palop, J. A.; Goni, T.; Martinez, A.; Fernandez-
Alvarez, E. J. Heterocycl. Chem. 1984, 21, 381; (d) Kita, Y.; Akai, S.; Ajimura, N.;
Yoshigi, M.; Tsugoshi, T.; Yasuda, H.; Tamura, Y. J. Org. Chem. 1986, 51, 4150; (e)
Monge, A.; Palop, J. A.; Recalde, J. I.; Fernandez-Alvarez, E. An. de Quim. Ser. C
Quim. Org. y Bioquim. 1989, 85, 72.
17. (a) Robinson, B. Chem. Rev. 1963, 373; (b) Robinson, B. Chem. Rev. 1969, 69, 227;
(c) Robinson, B. The Fischer Indole Synthesis; Wiley-Interscience: New York,
1982.
18. Mills, K.; Al Khawaja, I. K.; Al-Saleh, F. S.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1
1981, 636.
7
CO2Me
CO2Me
CO2Me
CO2H
i.
N
H
N
H
4
H9
H
19. Perni, R. B.; Gribble, G. W. Org. Prep. Proced. Int. 1982, 14, 343.
20. Hirano, S.; Akai, R.; Shinoda, Y.; Nakatsuka, S.-i. Heterocycles 1995, 41, 255; (b)
Murphy, W. S.; Bertrand, M. J. Chem. Soc., Perkin Trans. 1 1998, 4115; (c)
Haddach, A. A.; Kelleman, A.; Deaton-Rewolinski, M. V. Tetrahedron Lett. 2002,
43, 399; (d) Izawa, T.; Nishiyama, S.; Yamamura, S. Tetrahedron 1994, 50,
13593.
R'O
28: R' = H
27: R' = OTBS
HO
3a
Scheme 9. Synthesis of isoprenostodione (3a). Reagents and conditions: (i) KOH,
MeOH, , 4 h (25% from 28; 23% from 27).
21. Murakami, Y.; Watanabe, T.; Kobayashi, A.; Yokoyama, Y. Synthesis 1984, 738.
D

2762
J. C. Badenock et al. / Tetrahedron Letters 54 (2013) 2759–2762
22. Attempts to improve this yield by increasing the reaction time (to overnight) as
well as increasing the temperature (to reflux temperatures) were unsuccessful;
in all cases the yield decreased significantly.
23. Arai, S.; Yamauchi, S.; Yamagishi, T.; Hida, M. Bull. Chem. Soc. Jpn. 1991, 64, 324.
24. Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. 1984, 23, 296.
25. Murakami, Y.; Watanabe, T. J. Chem. Soc., Perkin Trans. 1 1988, 3005.
3H); 13C NMR (CDCl3) d 167.8, 165.0, 159.4, 141.9, 140.9, 135.8, 132.2, 126.7,
125.1, 122.8, 121.6, 121.1, 120.5, 115.8, 112.2, 104.8, 50.8; IR (film) 3657,
m
3525, 2951, 2847, 1697, 1601, 1508, 1457 cmÀ1; UV (MeOH) 215, 229, 285,
317 nm. HRMS Calcd for C20H17NO5 (M+Na)+ 360.0848. Found 360.0842.
Compound 23: mp 123–124 °C; 1H NMR (CDCl3) d 8.84 (s, 1H), 8.26–8.27 (d, 1H,
J = 7.6 Hz), 7.88 (s, 1H), 7.21–7.31 (m, 3H), 6.88–6.91 (d, 2H, J = 8.9 Hz), 6.63–
6.65 (d, 2H, J = 8.8 Hz), 4.25–4.30 (q, 2H, J = 7.0 Hz), 4.17–4.21 (q, 2H,
J = 7.0 Hz), 3.69 (s, 3H), 1.31–1.34 (t, 3H, J = 7.0 Hz), 1.20–1.22 (t, 3H,
J = 7.0 Hz); 13C NMR (CDCl3) d 167.0, 165.1, 161.0, 142.7, 138.6, 135.5, 132.3,
127.2, 126.4, 123.3, 122.1, 121.9, 121.8, 114.3, 111.7, 107.2, 61.4, 59.9, 55.4,
26. Irradiation of the alkene singlet (d = 7.91) displayed
a positive NOE
enhancement of the indole NH singlet (d = 8.54) in addition to protons on
the phenolic subunit (d = 6.92–6.93).
27. Basic hydrolysis with 1 N KOH in methanol, and LiOH in aqueous THF gave only
starting material even at reflux temperatures. Additional attempts were made
with trimethylsilyl bromide (trimethylsilyl chloride and lithium bromide) and
HI in acetic acid, which returned starting materials and decomposed the
sample in respective experiments.
28. (a) Black, D. S. C.; Kumar, N.; Wong, L. C. H. Aust. J. Chem. 1986, 39, 15; (b) Pryor,
K. E.; Shipps, W., Jr.; Skyler, D. A.; Rebek, J., Jr. Tetrahedron 1998, 54, 4107; (c)
Edstrom, E. D.; Yu, T. Tetrahedron 1997, 53, 4549; (d) Bhatt, M. V.; Kulkarni, S.
U. Synthesis 1983, 249; (e) Mouaddib, A.; Joseph, B.; Hasnaoui, A.; Merour, J.-Y.
Tetrahedron Lett. 1999, 40, 5853; (f) Chandran, S. S.; Frost, J. W. Bioorg. Med.
Chem. Lett. 2001, 11, 1493.
14.5, 14.3; IR
m (film) 3298, 3055, 2982, 2901, 1695, 1601, 1539, 1501,
1443 cmÀ1; UV kmax (95% EtOH) 216, 232, 290, 316 nm. MS m/z 393.2 (M+,
100%), 346.1, 319.1, 274.1, 247.1, 220.1, 195.1, 165.1, 138.1, 121.1. HRMS Calcd
for C23H23NO5 (M+) 393.1573. Found 393.1576.
Compound 25: mp 79–81 °C; 1H NMR (CDCl3) d 9.20 (s, 1H), 9.13 (s, 1H, minor
isomer), 8.21–8.23 (d, 1H, J = 7.9 Hz), 7.87 (s, 1H), 7.18–7.29 (m, 3H), 6.86–6.88
(d, 2H, J = 8.9 Hz), 6.60–6.62 (d, 2H, J = 8.9 Hz), 3.79 (s, 3H), 3.68 (s, 3H), 3.67 (s,
3H); 13C NMR (CDCl3) d 167.7, 165.6, 161.2, 143.2, 138.7, 135.7, 132.5, 127.2,
126.4, 123.5, 122.3, 122.0, 121.4, 114.5, 111.9, 107.2, 55.5, 52.7, 51.2; IR m (film)
3431, 3301, 3054, 2951, 1697, 1602, 1573, 1539, 1510, 1459 cmÀ1; UV kmax
(95% EtOH) 192, 214, 288, 318 nm. MS m/z 365.1 (M+, 100%), 332.1, 305.1,
274.1, 247.1, 231.1, 203.1, 151.1. HRMS Calcd for C23H23NO5 (M+) 365.1263.
Found 365.1272.
29. Akita, H.; Chen, C. Y.; Kato, K. Tetrahedron 1998, 54, 11011.
30. Irradiation of the indole N-H singlet (d = 8.42) showed no NOE to the vinyl
proton (d = 7.92) but instead an NOE was observed for H-7 (d = 7.33) as well as
protons of the phenolic subunit. Moreover, irradiation of the vinyl proton
displayed an NOE for a methyl ester singlet (d = 3.76) as well as a strong signal
with the ortho protons of the phenolic subunit (d = 6.89–6.90). Finally,
irradiation of the methyl singlet at 3.76 ppm produced an observed NOE to
the other methyl ester singlet (d = 3.85) as well as to the vinyl proton
(Scheme 8).
Compound 27: mp 196.5–198 °C; 1H NMR (CDCl3) d 8.40 (s, 1H), 8.24–8.27 (d,
1H, J = 8.1 Hz), 7.92 (s, 1H), 7.25–7.35 (m, 3H), 6.87–6.90 (d, 2H, J = 8.8 Hz),
6.61–6.65 (d, 2H, J = 8.8 Hz), 3.84 (s, 3H), 3.75 (s, 3H), 0.93 (s, 9H), 0.15 (s, 6H);
13C NMR (CDCl3) d 167.6, 165.5, 157.9, 143.3, 138.5, 135.5, 132.5, 127.2, 126.9,
123.7, 122.4, 122.1, 121.5, 120.7, 111.7, 107.5, 52.7, 51.3, 25.8, 18.4, À4.2; IR
m
;
(film) 3292, 3055, 2952, 2855, 1727, 1666, 1631, 1598, 1534, 1506, 1447 cmÀ1
31. Theoretical molecular modeling experiments of the Z- and E-isomers of alkenes
25 and 27 performed using the B3LYP/6-311G basis set revealed that the Z-
isomers were of lower energy when compared to the corresponding E-isomers,
UV kmax (95% EtOH) 206, 286 nm. MS m/z 465.2 (M+, 100%), 432.2, 406.2, 376.1,
348.1. HRMS Calcd for C26H31NO5Si (M+) 465.1972. Found 465.1978.
Compound 28: mp 215–216 °C; 1H NMR (CDCl3) d 9.02 (s, 1H), 8.18–8.21 (d, 1H,
J = 7.7 Hz), 7.78 (s, 1H), 7.19–7.30 (m, 3H), 6.70–6.72 (d, 2H, J = 8.8 Hz), 6.49–
6.52 (d, 2H, J = 8.8 Hz), 3.79 (s, 3H), 3.66 (s, 3H); 13C NMR (CDCl3) d 168.5,
166.5, 159.2, 144.3, 139.5, 136.0, 133.1, 127.4, 125.8, 124.0, 122.7, 122.3, 120.5,
with dE values of 1.859 Â 10À04 KJ molÀ1 and 2.935 Â 10À03 KJ molÀ1
,
respectively.
32. Clavier, S.; Khouili, M.; Bouyssou, P.; Coudert, G. Tetrahedron 2002, 58, 1533.
33. All final compounds were characterized by 1H, 13C NMR, IR, UV and HRMS.
Selected spectral data:
116.6, 112.3, 107.2, 53.1, 51.9; IR m(film) 3315, 3054, 1697, 1603, 1541, 1511,
1457 cmÀ1; UV kmax (95% EtOH) 214, 290, 322 nm. MS m/z 351.1 (M+), 318.1
(100%), 291.1, 260.1, 233.1, 142.1. HRMS Calcd for C20H17NO5 (M+) 351.1107.
Found 351.1105.
Compound 3a: Yellow oil: 1H NMR (CDCl3) d 11.93 (s, 1H), 10.04 (s, 1H), 8.00–
8.03 (d, 1H, J = 8.7 Hz), 7.77 (s, 1H), 7.38–7.41 (m, 1H), 7.18–7.22 (d, 2H,
J = 8.0 Hz), 6.81–6.84 (d, 2H, J = 8.6 Hz), 6.57–6.60 (d, 2H, J = 8.6 Hz), 3.69 (s,