Merged Conjugate Addition/Oxidative Coupling Sequence
A R T I C L E S
Scheme 3. Enantioselective Synthesis of Prodigiosin R1 (2)
organic extracts were washed with brine (20 mL), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude
material was used directly in the subsequent oxidation. To a solution
of CAN (1.21 g, 2.2 mmol) in MeCN (23 mL) at -25 °C was
added dropwise 2,6-di-tert-butylpyridine (972 µL, 4.4 mmol). After
several minutes, to the resulting solution was added the silyl bis-
enol ether 10 as a solution in MeCN (5 mL, then 2 mL rinse, cooled
to -25 °C prior to addition). The reaction was stirred at -20 °C
(unless otherwise noted) until deemed complete by TLC analysis
(typically between 12 and 24 h). The mixture was then poured into
saturated NaHCO3 (30 mL) and extracted with CHCl3 (3 × 30 mL).
The combined organic extracts were then washed with brine (30
mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel provided the desired
diketones as inseparable mixtures of diastereomers.
General Procedure for Pyrrole Synthesis. To a solution of 1,4-
diketone (0.15 mmol) in EtOH (1.5 mL) was added ammonium
acetate (116 mg, 1.15 mmol); the mixture was heated to reflux until
the reaction was deemed complete by TLC analysis (typically
between 30 min and 24 h). The resulting solution was then cooled
to ambient temperature, diluted with CHCl3 (5 mL), and poured
into 1:1 saturated NH4Cl:water (10 mL total), and the organic layer
was extracted. The aqueous phase was washed with CHCl3 (5 mL),
and the combined organic extracts were washed with brine (10 mL),
dried (Na2SO4), filtered, and concentrated under reduced pressure.
Flash chromatography (plug) on silica gel provided the desired
pyrroles.
two syntheses represent the first time that any members of the
prodigiosin alkaloids have been prepared in enantioenriched
form.
Conclusions
By developing a merged conjugate addition/oxidative cou-
pling sequence, we have been able to access diverse pyrrole
structures through the combination of three readily accessible
components (i.e., Grignard reagent, enone, and enol silane).
Crucial to the success of this procedure was the generation of
a silyl bis-enol ether intermediate, which ensured selective cross-
coupling during the oxidative bond-forming step, rather than
potential dimerization pathways. When the conjugate addition
was conducted with a chiral catalyst, efficient asymmetric
induction could be achieved, and this allowed for the first
enantioselective total syntheses of metacycoprodigiosin and
prodigiosin R1. This general strategy for preparing enantioen-
riched prodigiosins has important implications for future
biological studies of these intriguing molecules. Additionally,
the merged process we have developed generates pyrroles
possessing a stereocenter attached to C3 and is complementary
to the enantioselective Friedel-Crafts alkylation of pyrroles,
which produces a stereocenter at C2.26
Metacycloprodigiosin (1): IR (film) 3431, 2936, 2848, 1595,
1
1235 cm-1; H NMR (500 MHz, CDCl3) 12.79 (bs, 1H), 12.65
(bs, 1H), 12.59 (bs, 1H), 7.23 (t, 1H, J ) 0.7 Hz), 7.06 (s, 1H),
6.93-6.92 (m, 1H), 6.36-6.35 (m, 1H), 6.27 (d, 1H, J ) 1.6 Hz),
6.10 (s, 1H), 4.03 (s, 3H), 3.23-3.20 (m, 1H), 2.78-2.75 (m, 1H),
2.57-2.55 (m, 1H), 1.82-1.58 (m, 5H), 1.55-1.32 (m, 3H),
1.25-1.23 (m, 2H), 1.08-1.05 (m, 2H), 0.89 (t, 3H, J ) 6.2 Hz),
0.88 (obs m, 2H), 0.26-0.24 (m, 1H); 13C NMR (100 MHz, CDCl3)
165.7, 154.3, 150.4, 147.4, 126.8, 126.0, 122.3, 120.6, 116.8, 113.3,
112.4, 111.6, 92.7, 58.7, 39.4, 34.4, 29.9, 29.0, 27.3, 26.8, 26.6,
25.6, 24.5, 22.8, 12.6; HMRS (ESI), exact mass calcd for
C25H33N3O [M + H+] 391.2624, found 391.2621.
Experimental Section27
General Procedure for the Merged Conjugate Addition/
Oxidative Coupling Sequence. To a vigorously stirred suspension
of CuI (232 mg, 1.22 mmol) in THF (7 mL) at 0 °C was added
dropwise the Grignard reagent (1.20 mmol, solution in diethyl
ether). The resulting suspension was stirred for 20 min at that
temperature, and then the enone (1.0 mmol) was added dropwise
as a solution in THF (2 mL, then 1 mL rinse). The mixture was
allowed to stir for 30 min prior to dropwise addition of the
(chloro)silyl enol ether [generated in situ by dropwise addition of
acetyl chloride (85 µL, 1.20 mmol) to a solution of the appropriate
(diethylamino)silyl enol ether (1.22 mmol) in THF (5 mL) at 0 °C,
followed by stirring for 20 min], followed by dropwise addition of
triethylamine (420 µL, 3 mmol). The reaction mixture was allowed
to stir at 0 °C until deemed complete by thin-layer chromatography
(TLC) (typically between 1 and 5 h) and then quenched by slow
addition of saturated NH4Cl (1 mL). The mixture was diluted with
pentane (15 mL), poured into 20% NH4OH (20 mL), and shaken
vigorously, and the organic layer removed. The aqueous phase was
further extracted with pentane (2 × 15 mL), and the combined
Prodigiosin R1 (2): IR (film) 3135, 2920, 2856, 1610 cm-1; 1H
NMR (500 MHz, CDCl3) 12.76 (bs, 1H), 12.62 (bs, 1H), 12.54
(bs, 1H), 7.21 (s, 1H), 7.06 (s, 1H), 6.91-6.90 (m, 1H), 6.34-6.33
(m, 1H), 6.24 (s, 1H), 6.08 (d, 1H, J ) 1.8 Hz), 4.00 (s, 3H),
3.20-3.18 (m, 1H), 2.75-2.73 (m, 2H), 1.84-1.63 (m, 4H), 1.58
(td, 1H, J ) 3.7, 1.7 Hz), 1.56-1.35 (m, 6H), 1.34-1.13 (m, 2H),
1.10-0.98 (m, 2H), 0.88 (d, 3H, J ) 6.4 Hz), 0.84 (d, 3H, J ) 6.
Hz), 0.19-0.17 (m, 1H); 13C NMR (100 MHz, CDCl3) 165.7, 154.3,
150.6, 147.5, 126.9, 125.7, 122.3, 120.6, 116.8, 113.2, 112.4, 111.6,
92.7, 58.8, 46.6, 35.5, 35.2, 29.0, 27.5, 26.8, 26.6, 26.0, 25.5, 24.5,
23.7, 22.4, 22.1; HMRS (ESI), exact mass calcd for C27H38N3O
[M + H+] 420.3009, found 420.3030.
Acknowledgment. This paper is dedicated to Prof. Lewis N.
Mander on the occasion of his 70th birthday. Support for this work
was provided by Northwestern University (NU) and the NIH/
NIGMS (1R01GM085322). We thank Prof. Gu (Ocean University
of China) for providing authentic NMR spectra of metacyclopro-
digiosin, and Solvias AG (Dr. Matthias Lotz) for a gift of ligands.
(26) For examples, see: (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 4370–4371. (b) Palomo, C.; Oiarbide, M.; Kardak,
B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154–
4155. (c) Evans, D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249–
2252. (d) Trost, B. M.; Muller, C. J. Am. Chem. Soc. 2008, 130, 2438–
2439.
Supporting Information Available: Detailed experimental
procedures and spectral data for all compounds. This material
(27) See Supporting Information for full experimental procedures.
JA906122G
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J. AM. CHEM. SOC. VOL. 131, NO. 40, 2009 14583