A facile entry to bicyclic systems from L-glutamic acid

Article abstract of DOI:10.3987/com-01-9308

An efficient synthesis of bicyclic heterocycles has been realized from L-glutamic acid. The key step is the construction of the pyrrole ring in a single step, using tosylmethyl isocyanide (TosMIC) methodology. Structures of reaction intermediates and final products were investigated using density functional theory calculations.

Full text of DOI:10.3987/com-01-9308

HETEROCYCLES, Vol. 55, No. 11, 2001, pp. 2099 - 2108, Received, 30th July, 2001
A FACILE ENTRY TO BICYCLIC SYSTEMS FROM L-GLUTAMIC
ACID
Bryan A. Frieman, Charles W. Bock, and Krishna L. Bhat*
Department of Chemistry, School of Science and Health, Philadelphia University,
Philadelphia, PA 19144, USA
Abstract - An efficient synthesis of bicyclic heterocycles has been realized from
L-glutamic acid. The key step is the construction of the pyrrole ring in a single
step, using tosylmethyl isocyanide (TosMIC) methodology. Structures of reaction
intermediates and final products were investigated using density functional theory
calculations.
INTRODUCTION
Optically active α-amino aldehydes,1 as well as the corresponding α-amino acids,2 have potential as chiral
building blocks for the synthesis of novel polyfunctional amino acids, amino polyols, and peptide mimics,
that include enzyme inhibitors, aminosugar antibiotics, and sympathomimetic amines. For example, the
use of amino acids as synthons for various heterocyclic systems, including pyrroles, has been
documented.3 Recently, a titanium mediated cyclization reaction has been reported that provides an
efficient and practical method for synthesizing N-heterocycles from amino acids.4 In spite of the fact that
numerous synthetic routes exist for the preparation of this important class of heterocyclic compounds,
many of these procedures provide limited access in terms of substituents and substitution patterns.5 Thus
the development of new methodologies for the synthesis of substituted pyrroles is an area of continued
interest.
L-Glutamic acid (1) is a naturally occurring, inexpensive amino acid and is a well-known substrate from
the chiral pool. The synthetic pathway described here utilizes construction of a pyrrole ring system, in a
single step, using TosMIC methodology. This procedure provides an easy entry to bicyclic substituted
pyrroles and their oxygen analogs from readily available chiral starting material via conventional
transformations of functional groups.

RESULTS AND DISCUSSION
L-Glutamic acid (1) was first converted to the lactam (2) and then to the α,β-unsaturated protected lactam
(3) following literature procedures6,7 with minor modifications as described in EXPERIMENTAL. All the
reagents used in the synthetic sequence are inexpensive, non-hazardous and the resulting products are
obtained in pure form without any chromatographic purification. All reaction products in the intermediate
steps were characterized by spectral data (IR and NMR). The structures of 1, 2 and 3 were investigated
using density functional theory (DFT) at the BP/DN** computational level, as implemented in Spartan
5.0.8 In each case several different conformers were optimized. The lowest-energy structures of 1-3 we
found are shown in Figure 1.
1) H2O, NaNO3, HCl
2) Dry THF,
Borane-Methyl Sulfide Reagent
O
1) H2O, ∆
2)CH3OH, SOCl2
3) NaBH4, C2H5OH
O
O
O
O
NH
HO
OH
NH2
H
H
H
1
HO
HO
5
2
1) TBDMS-Cl, NEt3, CH2Cl2
2) (Boc)2O, DMAP, NEt3
3) LDA, PhSeCl
1) TBDMS-Cl, NEt3, CH2Cl2
2) LDA, PhSeCl
3) H2O2, DMAP, CH2Cl2
4) H2O2, DMAP, CH2Cl2
O
O
O
N-Boc
H
TBDMSO
H
TBDMSO
3
6
1) NaH, TosMIC, DMSO-Et2O
NaH, TosMIC, DMSO-Et2O
O
O
HN
O
HN
N-Boc
H
H
TBDMSO
TBDMSO
7
4
The second step in the synthetic sequence involves the construction of the pyrrole ring system using the
procedure developed by Van Leusen et al.9 and subsequently employed by us10 and others.11 This general

route to substituted pyrroles involves conjugate addition of isocyanide-derived carbanions stabilized by an
additional electron withdrawing group to a variety of α,β-unsaturated functional groups, e.g. ester, ketone,
nitro and sulfone. Substituted TosMIC reagents have also found synthetic uses.12 Reaction of 3 with 3.6
equivalents of sodium hydride and 3 equivalents of TosMIC generated the bicyclic derivative (4) in 97.8%
yield. The BP/DN** optimized structure is shown in Figure 1.
For the synthesis of the oxygen analog, L-glutamic acid was first converted to γ-butyrolactone (5).13 The
hydroxyl group was then protected and the resulting silyl derivative was subjected to selenylation-
deselenylation using conditions we developed during the course of this study for the lactam (2) to afford
the α, β-unsaturated lactone (6) in 61% yield for the three step sequence. Treatment of 6 with 1.2
equivalents of NaH and 1 equivalent of TosMIC gave the bicyclic derivative (7) in 87% yield. The
corresponding structures are shown in Figure 2.
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 was distilled from sodium benzophenone ketyl. DMF and DMSO
were distilled under reduced pressure and stroed over 4Å molecular sieves. The melting points reported
1
are uncorrected. H NMR spectra were measured at 60 and 500 MHz using acetone-d6 as solvent. TLC
was performed on 0.25 mm precoated silica plates (60F-254); the plates were initially examined under UV
light and spots were then visualized with iodine and a 7% solution of phospomolybdic acid in ethanol.
Silica gel (70-230 mesh) was used for column chromatography. Optical rotations were recorded on a
Perkin-Elmer Model 241 Polarimeter.
Computational Methods
All optimizations were performed using the highly efficient Becke-Perdew (BP) density functional with
the numerical DN** basis set, as implemented in Spartan 5.0.8 This non local (gradient corrected)
BP/DN** method14 incorporates the effects of electron correlation into the optimization and the DN**
basis set includes d-type polarization functions on all the heavy atoms and p-type polarization functions
on all the hydrogen atoms. No symmetry constraints were employed during the optimizations.
(+)-(2S)-2-Hydroxymethyl-5-pyrrolidinone (2)- L-Glutamic acid (25 g, 194 mmol) was refluxed in
water (125 mL) for 48 h. The solvent was evaporated and the residue was azeotropically dried with
methanol. The resulting thick viscous liquid was suspended in dry methanol (100 mL) and freshly

distilled thionyl chloride (2 mL) was added and the solution was stirred for 48 h at rt. Sodium bicarbonate
was then added until the mixture was of a neutral pH and then the solvent was rotary evaporated. The
residue was extracted with ethyl acetate (100 mL) and washed with water (20 mL). The organic layer was
dried over sodium sulfate and evaporated to afford (+)-methyl (2S)-5-oxopyrrolidine-2-carboxylate (27.48
g, 90.1%). A portion of this ester (5.89 g, 37.5 mmol) was dissolved in dry ethanol (236 mL) and sodium
borohydride (2.59 g, 68.5 mmol) was added. The reaction mixture was stirred for 3 h at rt. Acetone (11.8
mL) was added to the solution and allowed to stir for an additional 30 min. The reaction mixture was
acidified using conc. hydrochloric acid (4.2 mL) to pH 4.0 The residue was extracted with ethyl acetate
(100 mL) and washed with water (15 mL). The organic layer was dried over sodium sulfate and
evaporated to yield 2 (4.012 g, 82.9 %) as a viscous liquid.
(5S)-N-(tert-Butoxycarbonyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-pyrrolin-2-one (3)
Compound (2) (2.0 g, 17.4 mmol) was dissolved in acetone (15 mL) by gentle warming. To this solution,
dry dichloromethane (30 mL), tert-butyldimethylsilyl chloride (3.142 g, 20.8 mmol), and triethylamine
(5.924 mL, 43.4 mmol) were added and the reaction mixture was stirred for 12 h at rt. The solvent was
evaporated and the residue was extracted with ethyl acetate (100 mL) and washed with water (20 mL).
The organic layer was dried over sodium sulfate and evaporated to yield yellowish crystals (1.750 g, 7.6
mmol). This solid was dissolved in THF (30 mL) and then cooled to 0°C. Triethylamine (2.13 mL, 15.3
mmol), 4-dimethylaminopyridine (1.025 g, 8.4 mmol), and di-tert-butyl dicarbonate (1.832 g, 8.4 mmol)
were added to the mixture at 0°C and then stirred overnight at rt. The reaction was quenched with 5%
aqueous citric acid (15 mL); the organic layer was dried over sodium sulfate and the solvent was
25
evaporated to give solid yellowish crystals (2.41g; 7.3 mmol); [α]D23 –60° (c 1.0, CHCl3) (lit.,15 [α]D
–
61° (c 1.1, CHCl3)).
A solution of this compound (1.6 g, 4.85 mmol) in dry THF (5 mL) was added drop by drop to a solution
of LDA [prepared from iPr2NH (2.38 mL, 17 mmol) and n-BuLi (2.5 M in hexane solution, 0.54 mL, 5.87
mmol) at -78°C under nitrogen. The solution was stirred for 30 min at -78°C. Then a solution of
phenylselenenyl chloride (1.125 g, 5.87 mmol) in dry THF (5 mL) was added and the reaction mixture
was stirred for an additional 30 min. It was then quenched with 5% aqueous ammonium chloride (5 mL),
allowed to warm to rt and extracted with ethyl acetate. The organic layer was dried over sodium sulfate
and concentrated to yield the phenylselenyl compound as an orange colored solid (0.778 g, 1.6 mmol).
The product, without any purification, was dissolved in dichloromethane (15 mL) and 30% hydrogen
peroxide (3 mL, 126.98 mmol), and 4-dimethylaminopyridine (0.787 g, 6.44 mmol) were added. The
reaction mixture was allowed to stir overnight. The reaction was quenched using 5% hydrochloric acid

(10 mL) and an additional amount of dichloromethane (10 mL) was used to extract the product. The
organic layer was dried over sodium sulfate and then concentrated to yield 3 (1.391 g, 86.9%). An
analytical sample was obtained by column chromatography on silica gel using ether; hexane (1:4) as
eluant, mp 92-94°C. (lit.,7 mp 64-65˚C); [α]D23 –170.2° (c 1.0, CHCl3) (lit.,7 [α]D25 –175.6° (c 0.9,
CHCl3)); IR and NMR spectra identical to the reported values.7
Reaction of Compound (3) with TosMIC
Pentane (5 mL) was added to sodium hydride (60% mineral oil, 0.220 g, 5.50 mmol). After stirring for 5
min the pentane was decanted off. To the dry sodium hydride under a nitrogen atmosphere was added
TosMIC (0.895 g, 4.58 mmol) in dry ether (5 mL) and DMSO (2.5 mL). Compound (3) (0.500 g, 1.53
mmol) was then added to the mixture in dry ether (5 mL) and DMSO (2.5 mL) over a period of 10 min.
The mixture was stirred at rt for 2 h. The residue was extracted with ether (20 mL) and washed with
water (20 mL). The organic layer was dried over sodium sulfate and evaporated to yield 4, (0.548 g, 97.8 %)
as colorless crystals; mp 90°C. An analytical sample was prepared by passing through a short path of
silica gel using hexane-ethyl acetate (7:3) as eluant. NMR δ 0.08-0.10 (6H, m), 1.00-1.10 (9H, m), 1.52
(9H, s), 3.70 (1H, m), 4.30 (2H, m), 6.50 (1H, m), 7.20 (2H, m). Anal. Calcd for C18H30N2O4Si: C,
58.98; H, 8.25; N, 7.64. Found: C, 58.88; H, 8.29; N, 7.60; [α]D23 – 20.6° (c 0.9, CHCl3).
(S)–(+)-γ-Hydroxymethyl-γ-butyrolactone (5)
A solution of sodium nitrite (7 g, 100 mmol) in water (15 mL) was added dropwise to a mixture of L-
glutamic acid (10 g, 68 mmol) in water (26.67 mL) and conc. hydrochloric acid (14 mL) at 0-5˚C under
vigorous stirring (6 h). The clear solution was stirred at rt overnight. The solvent was rotary evaporated
and then extracted with ethyl acetate (33 mL). The insoluble material was filtered by suction and the
organic solution was dried over sodium sulfate. Evaporation of the solvent affored s(+)-γ-carboxy-γ-
butyrolactone as thick viscous oil (4.334 g, 49%). This product without purification was dissolved in dry
THF (30 mL) and under nitrogen atmosphere borane-methyl sulfide reagent (3.81 mL, 38.1 mmol) was
added slowly (50 min). The reaction mixture was stirred for 3 h and cautiously quenched with dry
methanol (2.7 mL). Evaporation of solvent afforded 5 as thick liquid (4.20 g, 53.1%). An analytical
sample was obtained by purification on silica gel column using chloroform: ethanol (90:10) as eluant.
26
NMR δ 2.00-2.80 (4H, m); 3.60-4.00 (3H, m); 4.65 (1H, m); [α]D20 +30.1° (c 0.4, EtOH) (lit.,13 [α]D
+31.3° (c 2.92, EtOH)).

5-0-(tert-butyldimethylsilyl)-2, 3-dideoxy-L-glyceropentonic Acid γ-Lactone (6)
A mixture of 5 (4.20 g, 36.1 mmol), dry dichloromethane (50 mL), tert-butyldimethylsilyl chloride (6.537
g, 43.32 mmol), and triethylamine (12.59 mL, 90.25 mmol) were stirred at rt for 12 h. Solvent was
evaporated and the residue was extracted with ethyl acetate (100 mL) and washed with water (20 mL).
The organic layer was dried over sodium sulfate and evaporated to yield the corresponding silyl derivative
(7.863 g, 94.5%). A solution of this compound in dry THF (15 mL) was added to a solution of LDA
[prepared from iPr2NH (5.26 mL, 37.51 mmol) and n-BuLi (1.6 M in Hexane solution, 21.35 mL] at -
78˚C. Then a solution of phenylselenium chloride (7.837 g, 40.92 mmol) in dry THF (15 mL) was added
and the reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched with
5% ammonium chloride (15 mL) and allowed to warm to rt. The mixture was then extracted with THF
(30 mL) and the organic layer was dried over sodium sulfate, concentrated to yield the phenylselenyl
compound (10.157 g, 26.3 mmol). This product without any purification was dissolved in dry
dichloromethane (30 mL) and 30% hydrogen peroxide (7.77 mL, 262.8 mmol), and 4-
dimethylaminopyridine (12.843 g, 105.12 mmol) were added. The reaction mixture was allowed to stir
overnight. It was then quenched with 5% hydrochloric acid (20 mL) and an additional amount of
dichloromethane (20 mL) was used to extract the product. The organic layer was dried over sodium
sulfate and then concentrated. Recrystallization of the crude product using methanol gave 6 (5.021 g,
84%), mp 87-88˚C. IR 3027, 2925, 1601, 1492, 1452, 901; NMR δ 0.04 (6H, s), 0.90 (9H, s), 4.20 (2H,
m), 4.50 (1H, m), 6.50 (1H, m), 7.00 (1H, m). Anal. Calcd for C11H20O3Si: C, 57.86; H, 8.83. Found: C,
57.78; H, 8.78; [α]D23 – 73.5° (c 2.3, CH3OH).
Reaction of Compound (6) with TosMIC
Pentane (5 mL) was added to sodium hydride (60% mineral oil, 0.0525 g, 2.63 mmol). After stirring for 5
min at 0˚C, the pentane was decanted off. To the dry sodium hydride under a nitrogen atmosphere was
added TosMIC (0.427 g, 2.19 mmol) in dry ether (5 mL) and DMSO (2.5 mL). Compound (6) (0.500 g,
2.19 mmol) was then added to the mixture in dry ether (5 mL) and DMSO (2.5 mL) over a period of 10
min. The mixture was stirred at rt for 2 h. The residue was extracted with ether (20 mL) and washed with
water (20 mL). The organic layer was dried over sodium sulfate and evaporated to yield 7 as colorless
crystals. An analytical sample was prepared by passing through a short path of silica gel using a 3:1 ethyl
acetate:hexane as eluant; mp 89-90˚C [solvent of recrystallization (ethylacetate:hexane)]. NMR δ 0.30
(6H, m), 0.90 (9H, s), 3.80 (3H, m), 7.00 (1H, brs), 7.80 (1H, m), 8.20 (1H, m). Anal. Calcd for
C13H21NO3Si: C, 58.33; H, 7.91; N 5.23. Found: C, 58.42; H, 7.97; N, 5.33; [α]D23 – 14.8° (c 1.2,
CH3OH).

ACKNOWLEDGEMENTS
The authors would like to thank Dr. Timothy Shea of Temple University for technical assistance.
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