Synthesis of chiral 3,4-disubstituted pyrroles from L-amino acids

Article abstract of DOI:10.3987/com-02-9679

A general methodology for the conversion of naturally occurring amino acids to 3,4-disubstituted pyrroles is described. A suitably protected amino acid (1) was first converted to the corresponding aldehyde (2). Homer-Emmons olefination afforded a facile entry to the corresponding α,β-unsaturated ester (3). The construction of the pyrrole ring system was accomplished in a single step, using an intramolecular cyclization reaction with tosylmethyl isocyanide (TOSMIC).

Full text of DOI:10.3987/com-02-9679

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Received, 28th November, 2002, Accepted, 28th January, 2003, Published online, 4th February, 2003
SYNTHESIS OF CHIRAL 3,4-DISUBSTITUTED PYRROLES
FROM L-AMINO ACIDS
Jocelyn A. Hover, Charles W. Bock, and Krishna L. Bhat*
Department of Chemistry and Biochemistry, School of Science and Health,
Philadelphia University, Philadelphia, PA 19144, USA
E-mail: BhatK@philau.edu
Abstract – A general methodology for the conversion of naturally occurring
amino acids to 3,4-disubstituted pyrroles is described. A suitably protected
amino acid (1) was first converted to the corresponding aldehyde (2). Horner-
Emmons olefination afforded a facile entry to the corresponding α,β-
unsaturated ester (3). The construction of the pyrrole ring system was
accomplished in a single step, using an intramolecular cyclization reaction with
tosylmethyl isocyanide (TOSMIC).
INTRODUCTION
Amino acids are one of the most important classes of compounds in the pool of chiral molecules and they
have been a source for the preparation of natural products and complex biologically active compounds.1
The pyrrole ring is an important heterocycle in biological systems being incorporated into the porphyrin
ring systems of chlorophyll, heme, vitamin B12, and the bile pigments. Additionally, there are a number
of pyrrole-containing small molecules that exhibit useful biological activities.2 As such, a lot of effort has
been spent developing practical methods for the synthesis of pyrrole units that incorporate appropriate
functionality.3 Many of these procedures, however, are limited in terms of substituents and/or substitution
patterns.4 Recently,5 we reported a facile entry to bicyclic systems from L-glutamic acid, involving the
construction of the pyrrole ring in a single step, using tosylmethyl isocyanide (TOSMIC) methodology.
This paper describes a general synthesis of 3,4-disubstituted chiral pyrroles from naturally occurring
amino acids.
RESULTS AND DISCUSSION
Our synthetic reaction sequence is shown in Scheme 1. The carboxylic acid group in 1 was first
converted to the corresponding methyl ester and the amine functional group was protected as the tert-
butyloxycarbonyl derivative. Reduction of the ester functionality to the corresponding aldehydes (2) was

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achieved by using diisobutylaluminum hydride (DIBAL).6 A somewhat less satisfactory route to the
aldehydes (2) was the reduction of the ester group to the corresponding alcohols using lithium aluminum
hydride in tetrahydrofuran and subsequent Swern oxidation using oxalyl chloride and activated dimethyl
sulfoxide.7 The reaction products in each step were characterized by spectral data (IR and NMR) and
comparison with literature values wherever possible. Since α-amino aldehydes are not configurationally
stable, they were prepared immediately prior to use.
Reaction of the aldehydes (2) with triethyl phosphonoacetate,8 using potassium tert-butoxide as the base,
afforded the corresponding α, β-unsaturated esters (3) in yields ranging from 91 to 95%; the physical
properties of some of the derivatives were compared to reported values.9 The crucial step in the synthesis
is the construction of the pyrrole ring in one step using an intramolecular cyclization reaction with
tosylmethyl isocyanide (TOSMIC). This methodology developed by Van Leusen et al.10 and
subsequently employed by us5,10 and others,11 involving the reaction of TOSMIC with Michael acceptors,
offers a facile entry to substituted pyrroles. Thus, reaction of 3 with 3.6 equivalents of sodium hydride
and 3 equivalents of TOSMIC generated the chiral heterocycles (4) in yields ranging from 77 to 98%.
The physical properties for compounds (3) and (4) are listed in Table 1. No effort has been made to
establish the stereochemical integrity of the final products or intermediates.
In conclusion, we have developed a simple and convenient preparative method for the synthesis of chiral
heterocycles from readily available optically active starting materials via conventional transformations of
functional groups. Since amino acids are relatively inexpensive and often available commercially in both
enantiomeric forms, the approach we have described can easily be extended to the D-series of amino
acids. Clearly, this methodology possesses considerable potential in the development of heterocyclic
libraries for drug screening, especially in the search for new anti-inflammatory agents.1
EXPERIMENTAL
GENERAL METHODS
All reactions were carried out under a nitrogen atmosphere. Glassware was oven dried and cooled to rt
under a nitrogen atmosphere. Ether and THF were distilled from sodium benzophenone ketyl. DMSO
1
was distilled under reduced pressure and stored over 4A molecular sieves. H NMR spectra were
measured at 60 and 500 MHz using acetone-d6 as solvent. TLC was performed on 0.25 mm precoated
silica gel plates (60F-254); the plates were initially examined under UV light and spots were then
visualized with iodine and a 7% solution of phosphomolybdic acid in ethanol. Silica gel (70-230 mesh)

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was used for column chromatography. Specific rotations were recorded on a Perkin-Elmer Model 241
Polarimeter.
GENERAL PROCEDURE FOR PREPARATION OF ALDEHYDES [2 (a-d)]
Acetyl chloride (20 mL, 281mmol) was added drop wise to methanol (150 mL) over 8 min under nitrogen
atmosphere. The solution was stirred for 5 min at rt and compound (1) (114 mmol) was added in one
portion at rt. The reaction mixture was refluxed for 2 h. Solvent was removed in vacuo to yield the
corresponding methyl esters. To a cooled solution of this methyl ester (64.3 mmol) in THF (200 mL),
under nitrogen atmosphere, triethylamine (19.2 mL, 138 mmol) and di-tert-buyl dicarbonate (14.3 g, 363
mmol) in tetrahydrofuran (100 mL) were added over 1 h. The reaction mixture was stirred overnight at rt
and at 50˚C for an additional 3 h. The solvent was removed in vacuo and the residue was extracted with
ether. The ether layer was washed with saturated aqueous NaHCO3 (250 mL). The aqueous phase was
extracted with ether (3x150 mL) and the combined organic layers were dried over sodium sulfate and
concentrated. The corresponding tert-butyloxycarbonylamino acid methyl esters were obtained in good to
moderate yields usually as thick oils.
METHOD A
The solution of ester (37.5 mmol) in dry toluene (75 mL) under nitrogen atmosphere was cooled to -78˚C.
A solution of DIBAL in toluene (43.75 mL, 1.5 M) was added at an adjustable rate in order to keep the
internal temperature of the system below -65˚C (~1 h). The reaction mixture was stirred at -78˚C for 2 h
and then quenched with methanol (15 mL). It was then allowed to come to rt and poured into aqueous
hydrochloric acid solution (1 N, 250 mL). The aqueous layer was extracted with ethyl acetate (3x250
mL) and the combined organic layers were washed with brine (250 mL) and dried over anhydrous
magnesium sulfate. Removal of solvent under reduced pressure yielded the aldehydes [2 (a-d)] as
yellowish oils.
METHOD B
The solution of ester (38.2 mmol) in THF (50 mL) was slowly added to lithium aluminum hydride (0.16
g, 57 mmol) in THF (100 mL) under nitrogen atmosphere. The suspension was stirred for an additional
20 min and then cooled to 0˚C. Aqueous potassium hydroxide (10%, 20 mL) was added drop-wise and
the reaction mixture was stirred at rt for 1 h. The white precipitate formed was removed by filtration and
washed with ether (3x30 mL). The combined organic layers were washed with a phosphate buffer (100
mL, pH=7), dried over sodium sulfate and concentrated under reduced pressure to afford the
corresponding alcohols as yellow oils.

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A flask charged with oxalyl chloride (6.58 g, 51.9 mmol) in methylene chloride (80 mL) was cooled to
-78˚C under nitrogen atmosphere. DMSO (8.10 g, 103.71 mmol) in methylene chloride (10 mL) was then
added over a period of 25 min. A solution of the alcohol (34.6 mmol) in methylene chloride (60 mL) was
added to this reaction mixture. It was stirred at -45˚C for 30 min and quenched by adding N,N-
diisopropylethylamine (36 mL, 200 mmol) in methylene chloride (5 mL). The solution was warmed to
0˚C and an aqueous solution of hydrochloric acid (1 M, 130 mL) was added. The mixture was extracted
with methylene chloride (3x30 mL) and the organic layers were washed with a phosphate buffer (4x80
mL, pH=7), dried over sodium sulfate and concentrated to yield the corresponding aldehydes as thick oils.
GENERAL PROCEDURE FOR PREPARATION OF UNSATURATED ESTERS [3 (a-d)]
Potassium tert-butoxide (12 mL, 12 mmol, 1 M in THF) was added to solution of triethyl
phosphonoacetate (2.69 g, 13.4 mmol) in THF (50 mL) at 0˚C. The mixture was stirred at rt for 1 h.
Compound (2) (12 mmol) in THF (20 mL) was added to it at 5˚C and further stirred at rt for 2 h. The
solvent was removed under reduced pressure and the residue was extracted with ether (2x100 mL), dried
over sodium sulfate and concentrated under reduced pressure. The residue was then purified by column
chromatography using hexane:ethyl acetate (9:1) as eluant to yield 3 as colorless oil.
GENERAL PROCEDURE FOR PREPARATION OF PYRROLES [4 (a-d)]
Pentane (15 mL) was added to sodium hydride (60% mineral oil, 0.660 g, 16.5 mmol). After stirring for 5
min at 0˚C, the pentane was decanted off. TOSMIC (2.685 g, 13.74 mmol) in dry ether (15 mL) and
DMSO (7.5 mL) was added to the dry sodium hydride under a nitrogen atmosphere. Compound (3) (4.59
mmol) was then added to the mixture in dry ether (15 mL) and DMSO (7.5 mL) over a period of 15 min.
The reaction mixture was stirred at rt for 2 h. The residue was extracted with ether (60 mL) and washed
with water (60 mL). The organic layer was dried over sodium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography using hexane-ethyl acetate (7:3) as eluant.
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