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3.2.9. Cyclohexanedione adduct (8i). Yield: 53% as a pale
yellow solid. 1H NMR (CDCl3) d: 10.5 (s, 1H, OH); 9.02 (b,
1H, NH); 6.94 (b, 1H); 5.87 (d, J¼3.1 Hz, 1H, pyrrole); 3.98
(s, 3H, OCH3); 3.79 (s, 3H, OCH3); 2.57 (dd, kJl¼6.5 Hz,
2H, CH2); 2.52 (dd, kJl¼6.5 Hz, 2H, CH2); 1.98 (dd,
kJl¼6.6 Hz, 2H, CH2); 1.57 (s, 9H, But); 1.47 (s, 9H, But).
13C NMR (CDCl3) d: 205.9, 202.4, 175.6, 167.4, 163.3,
159.6, 152.2, 123.7, 109.7, 104.6, 95.3, 93.3, 86.2, 81.0,
71.1, 60.5, 58.3, 34.6, 33.6, 28.4, 27.7. HRMS: Calcd for
C26H34N2O8: MþHþ 503.2393; found 503.2389.
3.2.13. Ethyl bipyrrole ester (15). A solution of 5
(92.3 mg, 0.47 mmol) in CH2Cl2 (47 mL) containing a
catalytic amount of methylene blue was photolyzed for
15 min at 278 8C with a steady stream of oxygen passing
through the reaction mixture. The flow of oxygen was then
stopped, the light turned off and 2-ethylpyrrole (0.247 g,
2.34 mmol) was added to the mixture in a single aliquot.
The reaction was stirred for a further thirty minutes and then
the volatiles were removed. The residue was chromato-
graphed (EtOAc–hexane 15:85, silica gel) and the product
1
isolated as a white powder. Yield: 33 mg, 24%. H NMR
3.2.10. Dimedone adduct (8j). Yield: 78% as a pale tan
1
solid. H NMR (CDCl3) d: 10.5 (b, 1H, OH); 9.03 (b, 1H,
(DMSO d6) d: 10.81 (b, 1H, NH); 10.64 (b, 1H, NH); 6.40,
(m, 1H, pyrrole); 6.09 (d, J¼2.47 Hz, 1H, pyrrole); 5.75 (m,
1H, pyrrole); 3.71 (s, 3H, OCH3); 2.55 (q, J¼7.57 Hz, 2H,
NH); 6.95 (s, 1H, HCv); 5.88 (d, J¼3.1 Hz, 1H, pyrrole);
3.98 (s, 3H, OCH3); 3.80 (s, 3H, OCH3); 2.46 (s, 2H, CH2);
2.41 (s, 2H, CH2); 1.57 (s, 9H, But); 1.47 (s, 9H, But); 1.09
(s, 3H, CH3); 1.08 (s, 3H, CH3). 13C NMR (CDCl3) d: 199.6,
196.9, 174.3, 170.9, 163.7, 159.6, 152.2, 124.5, 109.4,
105.1, 96.8, 95.3, 85.6, 80.8, 70.6, 60.1, 58.3, 52.8, 52.1,
30.4, 28.5, 27.8. HRMS: Calcd for C28H38N2O8: MþHþ
531.2706; found 531.2718.
CH2); 1.48 (s, 9H, But); 1.18 (t, J¼7.57 Hz, 3H, CH3). 13
C
NMR (DMSO d6) d: 159.8, 153.2, 34.9, 128.7, 122.7, 106.3,
105.8, 105.3, 90.9, 78.5, 57.6, 28.3, 20.3, 13.8. HRMS:
Calcd for C16H22N2O3: MþHþ 290.1630; found 290.1637.
3.2.14. Ethyl bipyrrole aldehyde (16). McFadyen–Stevens
reduction of 15 was performed according to the method
given for the reduction of 7e Yield: 41%. 1H NMR (DMSO
d6) d: 11.24 (b, 1H, CHO); 10.93 (b, 1H, NH); 9.25 (b, 1H,
NH); 6.60, (m, 1H, pyrrole); 6.21 (d, J¼2.43 Hz, 1H,
pyrrole); 5.83 (m, 1H, pyrrole); 3.82 (s, 3H, OCH3); 2.57 (q,
J¼7.55 Hz, 2H, CH2); 1.18 (t, J¼7.55 Hz, 3H, CH3). 13C
NMR (DMSO d6) d: 171.1, 158.7, 136.6, 133.5, 121.9,
117.1, 108.6, 106.1, 90.4, 57.7, 20.5, 13.7. HRMS: Calcd for
C12H14N2O2: MþHþ 219.1133; found 219.1143.
3.2.11. Cyclopentanedione adduct (8k). Yield: 55% as a
1
pale solid. H NMR (CDCl3) d: 10.1 (b, 1H, OH); 9.15 (b,
1H, NH); 6.55 (s, 1H); 5.87 (d, J¼3.1 Hz, 1H, pyrrole); 4.01
(s, 3H, OCH3); 3.79 (s, 3H, OCH3); 2.57 (m, 4H, CH2); 1.55
(s, 9H, But); 1.47 (s, 9H, But). 13C NMR (CDCl3) d: 200.2,
197.3, 174.3, 171.3, 163.6, 159.6, 152.2, 124.5, 109.4,
106.2, 96.9, 95.2, 85.7, 80.8, 70.6, 60.1, 58.2, 39.0, 38.5,
28.4, 27.7, 19.4. HRMS: Calcd for C26H35N2O8:
MþHþ503.2393; found 503.2391.
3.2.15. Ethyl prodigiosin analog HCl (17). The coupling of
16 with ethylpyrrole to yield 17 was carried out under acid
catalysis by known methods.15,16 Yield: 43% 1H NMR
(CDCl3) d: 12.64 (b, 1H, vCH); 12.58 (b, 2H,); 6.91, (s,
1H, pyrrole); 6.89 (dd, J¼3.69 Hz, 2.47, 1H, pyrrole); 6.76
(dd, J¼3.53, 2.51 Hz, 1H, pyrrole); 6.17 (d, J¼3.53 Hz, 1H,
pyrrole); 6.11 (dd, J¼3.69, 2.10 Hz, 1H, pyrrole); 6.01 (d,
J¼1.55 Hz, 1H, pyrrole); 3.99 (s, 3H, OCH3); 2.95 (q,
J¼7.60 Hz, 2H, CH2); 2.80 (q, J¼7.64 Hz, 2H, CH2);1.37
3.2.12. McFadyen–Stevens reduction forming the
methoxy bipyrrole aldehyde (14). A solution of 7e
(51 mg, 0.19 mmol) was suspended in anhydrous hydrazine
(4 mL) in a 10 mL round bottom flask and the apparatus was
purged with argon The flask was fitted with a reflux
condenser and the reaction mixture was heated to reflux for
14 h under a balloon of argon, during which time the starting
material dissolved to give a clear solution. The solution was
cooled and the volatile components removed to give a light-
brown oil. This oil was dissolved in pyridine (4.0 mL) and
treated with a solution of TsCl (41.6 mg, 0.22 mmol) in
pyridine (0.25 mL) for 30 min at room temperature.
Methylene chloride (100 mL) was added to the reaction
mixture and the solution was washed with water (100 mL).
The aqueous phase was extracted with CH2Cl2 (2£100 mL)
and the combined organic phases were washed with water
(10 mL), dried over Na2SO4 and concentrated. The dark
green material was dissolved in diethylene glycol (3.0 mL)
and Na2CO3 was added. The green suspension was purged
with argon and, under vigorous stirring, the mixture was
lowered into a heating bath at 170 8C. The color changed
rapidly from green to brown. After 5 min, the heating was
discontinued and after the reaction had cooled to room
temperature, water (20 mL) was added. The green solution
was extracted with CH2Cl2 (3£20 mL) and the combined
organic phases were washed with water (1£5 mL) and
dried over Na2SO4. Removal of the volatiles gave a
green solid that was chromatographed over silica
(EtOAc–hexane 50:50) to give 14. Yield: 8.4 mg, 21%.
The compound was spectroscopically identical to the known
material.16
(t, J¼7.60 Hz, 3H, CH3); 1.34 (t, J¼7.64 Hz, 3H, CH3). 13
C
NMR (CDCl3) d: 166.1, 152.7, 148.7, 146.8, 127.8, 125.9,
122.0, 120.9, 119.5, 114.9, 111.2, 110.3, 92.8, 58.7, 21.7,
21.6, 13.5, 13.3. HRMS: Calcd for C18H21N3O: MþHþ
296.1760; found 296.1760.
Acknowledgements
This work was supported by grants from the National
Institutes of Health, the National Science Foundation and
Pfizer, Inc. We thank Drs. Walter McMurray and Kathy
Stone of the Yale Cancer Center Mass Spectrometry
Resource for determining HRMS spectra.
References and notes
1. Blum, H. R. Photodynamic Action and Diseases Caused by
Light; Van Nostrand-Reinhold: New York, 1941.
2. Wasserman, H. H.; Power, P.; Petersen, A. K. Tetrahedron
Lett. 1996, 37, 6657–6659, and references cited therein.
3. Wasserman, H. H.; Lipshutz, B. H. In Singlet Oxygen;