Synthesis of fused heteroarylprolines and pyrrolopyrroles

Article abstract of DOI:10.1021/jo049612i

Fused heteroarylprolines were prepared starting from 4-oxo-N-(PhF)proline benzyl ester (6, PhF = 9-(9-phenylfluorenyl) following two approaches. First, allylation of oxoproline 6 followed by Wacker oxidation gave 1,4-dione 8 that was selectively converted

Full text of DOI:10.1021/jo049612i

Syn th esis of F u sed Heter oa r ylp r olin es a n d P yr r olop yr r oles
Guillaume J eannotte and William D. Lubell*
De´partement de chimie, Universite´ de Montre´al, C.P. 6128, Succursale CentreVille,
Montre´al, Que´bec, Canada H3C 3J 7
lubell@chimie.umontreal.ca
Received March 9, 2004
Fused heteroarylprolines were prepared starting from 4-oxo-N-(PhF)proline benzyl ester (6, PhF
) 9-(9-phenylfluorenyl)) following two approaches. First, allylation of oxoproline 6 followed
by Wacker oxidation gave 1,4-dione 8 that was selectively converted to pyrroloproline 10b,
pyrrolopyrrole 12, and pyridazinoproline 9. Second, aldol condensation of oxoproline 6 with a series
of N-(Boc)-R-amino aldehydes 15a -e and acid-catalyzed cyclization gave pyrroloprolines 17a -e
possessing a variety of pyrrole 5-position substituents. Conditions for the selective deprotection
and alkylation of the pyrrole nitrogen of pyrroloprolines 17 were developed to expand the diversity
of the heteoaryl systems. Finally, hydrogenolytic cleavage of the PhF and benzyl groups followed
by subsequent protection with Boc, Fmoc, and Moz groups was performed to obtain analogues
suitable for peptide synthesis. The enantiomeric purity of N-(Boc)pyrrolo-proline 21a was ascertained
by coupling to L- and D-phenylalanine methyl ester and examination of the diastereotopic pyrrole
protons, which demonstrated the dipeptides to be of >99% diastereomeric purity. These approaches
have thus delivered the first series of enantiopure fused arylprolines for application as arylglycine-
proline chimeras in structure-activity studies of biologically active compounds.
In tr od u ction
Fused arylprolines, such as 1 and 2 (Figure 1), are
challenging synthesis targets that have potential to serve,
respectively, as phenylalanine-proline and phenylglycine-
proline chimeras in structure-activity studies of biologi-
cally relevant compounds. For example, asymmetric
synthesis,1-3 enzymatic resolution, and fractional recrys-
tallization4 all have furnished enantiomerically enriched
analogues of indoline-2-carboxylate 1, which has been
used to develop angiotensin-converting enzyme inhibitors
related to the drugs captopril5,6 and enalapril.7 Isoindo-
line-1-carboxylic acid 2 has been less well studied, and
there exist presently no methods for its synthesis in
enantiomerically pure form. Methyl isoindoline-1-car-
boxylates have been isolated as hydrochlorides yet re-
ported to be “highly sensitive to air” and presumed to
oxidize to the corresponding 1-carbomethoxyphthalim-
idines 3 and isoindoles 4.8 In light of the importance of
F IGURE 1. Representative fused arylproline analogues.
arylglycines in medicine, such as their presence in
common â-lactam antibiotics such as ampicillin9 and
amoxicillin,10 enantiopure, conformationally rigid aryl-
glycine analogues, like 2, have desirable utility for
studying and improving the pharmacological properties
of contemporary drugs.
(1) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J . Am. Chem. Soc.
1997, 119, 8451-8458.
Prior to our studies, the synthesis of fused heteroaryl-
prolines had yet to be reported. Pyrrole-prolines of
general structure 5 were pursued as novel heteroarylg-
lycine-proline chimeras that could be amenable for
diversity oriented synthesis. In particular, N-alkylation
was expected to allow synthesis of a variety of fused
arylproline analogues from a common intermediate. The
(2) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J . Am.
Chem. Soc. 2000, 122, 7614-7615.
(3) Viswanathan, R.; Prabhakaran, E. N.; Plotkin, M. A.; J ohnston,
J . N. J . Am. Chem. Soc. 2003, 125, 163-168.
(4) Ramos Tombo, G. M.; Scha¨r, H.-P.; Ghisalba, O. Agric. Biol.
Chem. 1987, 51, 1833-1838.
(5) Kim, D. H.; Guinosso, C. J .; Buzby, G. C. J .; Herbst, D. R.;
McCaully, R. J .; Wicks, T. C.; Wendt, R. L. J . Med. Chem. 1983, 26,
394-403.
(6) Stanton, J . L.; Gruenfeld, N.; Babiarz, J . E.; Ackerman, M. H.;
Friedmann, R. C.; Yuan, A. M.; Macchia, W. J . Med. Chem. 1983, 26,
1267-1277.
(8) Cignarella, G.; Cerri, R.; Grella, G.; Sanna, P. Gazz. Chim. Ital.
1976, 106, 65-75.
(9) Austin, K. W. B.; Marshall, A. C.; Smith, H. Nature 1965, 208,
999-1000.
(7) Gruenfeld, N.; Stanton, J . L.; Yuan, A. M.; Ebetino, F. H.;
Browne, L. J .; Gude, C.; Huebner, C. F. J . Med. Chem. 1983, 26, 1277-
1282.
(10) Long, A. A. W.; Nayler, J . H. C.; Smith, H.; Taylor, T.; Ward,
N. J . Chem. Soc. C 1971, 1920-1922.
10.1021/jo049612i CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/08/2004
4656
J . Org. Chem. 2004, 69, 4656-4662

Synthesis of Fused Heteroarylprolines and Pyrrolopyrroles
SCHEME 1. P a a l-Kn or r Ap p r oa ch to
Heter oa r ylp r olin es
directionality of the pyrrole was expected to retard
racemization and oxidation of the neighboring pyrrolidine
ring. A methodology for making enantiopure pyrrole-
prolines 5 has now been developed that allows modifica-
tion of the steric and electronic properties of the aromatic
component of the arylproline. Furthermore, conditions
have been developed for alkylation of the pyrrole nitro-
gen. In addition to novel methodology for the synthesis
of enantiopure pyrrole-prolines, protocols have been
conceived for the preparation of pyridazinoproline and
pyrrolopyrroles. A novel series of amino acid scaffolds has
thus been synthesized for the study of biologically active
compounds.
Resu lts a n d Discu ssion
Past syntheses of dihydroisoindole-2-carboxylic acid 2
and its analogues have constructed the chiral R-center
by amine alkylation with an R-halo acid equivalent,8 by
carbonylation of metalated phthalimidine11 and isoindo-
line12 intermediates, and by intramolecular arylation of
glycine precursors.13 Such approaches have thus far failed
to deliver enantiopure product due to the inherent
difficulty of constructing this stereocenter stereoselec-
tively. In contrast, we pursued a route to heteroarylpro-
lines in which hydroxyproline was used as chiral educt
to provide enantiopure product. This approach was based
on our previous methodology for the enolization and
alkylation of 4-oxo-N-(PhF)proline benzyl ester to make
a variety of ∆3-dehydroproline analogues without loss of
the configurational integrity at the R-center.14,15
Alkylation of the enolate of 6 with R-halo ketones was
first pursued to construct a suitable 1,4-dione for pyr-
roloproline synthesis by condensation with amines ac-
cording to the Paal-Knorr pyrrole synthesis.16,17 Methyl
bromoacetate had previously reacted with the potassium
enolate of 6 to install the 3-position substituent for the
synthesis of ∆3-dehydrokainic acid analogues.14,18 In
contrast, attempts to perform similar chemistry with
R-bromo ketones, such as R-bromo acetophenone, gave
only trace amounts of 1,4-diones, perhaps due to depro-
tonation of the electrophile. Desired 1,4-dione 8 was
synthesized from ketone 6 in 64% overall yield by
alkylation with allyl iodide, followed by oxidation of the
terminal olefin by a Wacker process using oxygen, PdCl2,
and CuCl in a mixture of DMF and water (Scheme 1).19
Considering the Paal-Knorr pyrrole synthesis with
1,4-dione 8 and our recently reported synthesis of 4-ami-
nopyrrole-2-carboxylates20 from 4-oxo-N-(PhF)proline es-
ters such as 6, we realized that there was a competition
at hand and sought to develop selective conditions to
prepare either pyrroloproline 10b or pyrrolopyrroles 12.
The latter was expected to be a thermodynamic product
because of its fully aromatic character. To the best of our
knowledge, the 2,4-dihydropyrrolo[3,4-b]pyrrole ring sys-
tem had been reported only once before,21 and the parent
heterocycle was predicted to be unstable according to
theoretical calculations of its resonance energy.22 N-p-
Methoxyphenysulfonylpyrrolo[3,4-b]pyrroles were syn-
thesized by a retro-malonate addition reaction; however,
attempts to deprotect the arylsulfonyl group led to
decomposition of the product.21 Condensation of 1,4-dione
8 with benzylamine was explored in different solvents
(EtOH, CH3CN, THF, toluene) with both p-toluene-
sulfonic and acetic acids. Varying ratios of pyrroloproline
10b and pyrrolopyrrole 12 were obtained along with PhF-
protected pyrrolopyrrole 11,23 as measured by proton
NMR spectroscopy and integration of the pyrrole proton
signals at 5.31, 6.35, and 6.12 ppm, respectively. The
formation of PhF-protected 11 was minimized by per-
forming the condensation under inert atmosphere in
degassed solvent. The thermodynamic pyrrolo[3,4-b]-
pyrrole 12 was obtained in a >14:1 ratio with pyrrolo-
proline 10b by reacting 1,4-dione 8 with 500 mol % of
benzylamine in toluene at 50 °C for 24 h in the presence
of 10 mol % of p-toluenesulfonic acid. After column
chromatography, pure pyrrolopyrrole 12 was isolated in
60% yield as a yellow solid that turned brown when
exposed to air and as a solution in CDCl3. The presence
of the electro-attractive ester moiety on the ring of the
pyrrolopyrrole 12 may account for its enhanced stability.
On the other hand, pyrroloproline 10b was obtained in
(11) Couture, A.; Deniau, E.; Ionescu, D.; Grandclaudon, P. Tetra-
hedron Lett. 1998, 39, 2319-2320.
(12) Beeley, L. J .; Rockell, C. J . M. Tetrahedron Lett. 1990, 31, 417-
420.
(13) Gaertzen, O.; Buchwald, S. L. J . Org. Chem. 2002, 67, 465-
475.
(14) Gill, P.; Lubell, W. D. J . Org. Chem. 1995, 60, 2658-2659.
(15) Rondeau, D.; Gill, P.; Chan, M.; Curry, K.; Lubell, W. D. Bioorg.
Med. Chem. Lett. 2000, 10, 771-773.
(16) Paal, C. Chem. Ber. 1884, 17, 2756.
(17) Knorr, L. Chem. Ber. 1884, 17, 2863.
(21) Sha, C.-K.; Liu, J .-M.; Chiang, R.-K.; Wang, S.-U. Heterocycles
1990, 31, 603-609.
(22) Gutman, I.; Milun, M.; Trinajstic´, N. J . Am. Chem. Soc. 1977,
99, 1692-1704.
(23) 1-Benzyl-2-methyl-5-(PhF)-1,5-dihydropyrrolo[3,4-b]pyrrole-4-
carboxylic acid benzyl ester (11): 1H NMR (300 MHz, CDCl3) 2.25 (s,
3 H), 4.89 (s, 2 H), 5.12 (s, 2 H), 6.12 (s, 1 H), 7.0-7.7 (m, 23 H); 13C
NMR (75 MHz, CDCl3) 13.5, 49.1, 65.4, 78.1, 160.6; HRMS calcd for
(18) Sharma, R.; Lubell, W. D. J . Org. Chem. 1996, 61, 202-209.
(19) Tsuji, J . Synthesis 1984, 369-384.
(20) Marcotte, F.-A.; Lubell, W. D. Org. Lett. 2002, 4, 2601-2603.
C
41H32N2O2 (MH+) 584.2464, found 584.2487.
J . Org. Chem, Vol. 69, No. 14, 2004 4657

J eannotte and Lubell
SCHEME 2. Syn th esis of P r otected
P yr r olop r olin es 17
SCHEME 3. P yr r ole Dep r otection a n d Alk yla tion
indicated by the presence of a characteristic pyrrole
aromatic singlet at around 5.5 ppm in the proton NMR
spectrum.
With effective methodology for preparing pyrrolopro-
lines 17 in hand, our next objectives were the selective
removal of the Boc group and alkylation of the pyrrole
nitrogen to demonstrate the potential of our strategy for
diversity-oriented synthesis (Scheme 3). Initially, pyr-
roloproline 17a was treated with sodium methoxide in
THF at room temperature and a 66% yield of deprotected
product was isolated; however, trans-esterification oc-
curred to give the pyrroloproline methyl ester.28 Selective
Boc group deprotection without trans-esterification was
later accomplished by thermolysis at 180 °C for 30 min
under a flow of argon.29 All five pyrroloprolines 17a -e
were effectively converted to their NH-pyrrole counter-
parts 18a -e by this method in 77-89% yields on a scale
of 60 mg and 60-65% yields on 400 mg scale. The
diversity of the pyrroloproline analogues was expanded
by N-alkylation of the pyrrole ring. Alkylation of the
nitrogen of both pyrrole 18a and its 5-methyl counterpart
18b was effectively accomplished in dimethyl sulfoxide
at room temperature by sequential treatments with
powdered potassium hydroxide and an alkyl halide
followed by stirring at room temperature, aqueous work-
up, and purification by chromatography.30 N-Alkylpyr-
role-prolines 10a and 10b, 19a and 19b, and 20b were
prepared in 49-92% overall yields from 18 by this
method using methyl iodide, benzyl bromide, and tert-
butyl bromoacetate as electrophiles, respectively.
The next objective was to transform N-PhF-pyrrolo-
proline benzyl ester 18 into analogues suitable for peptide
synthesis. Previously, a one-pot hydrogenolytic cleavage
of the PhF-amine and benzyl ester protecting groups in
the presence of di-tert-butyl dicarbonate was used to
synthesize Boc-protected proline-valine and hydroxypro-
line-valine chimeras suitable for peptide synthesis.18,31
When pyrrole-proline 18a was submitted to a similar
hydrogenation protocol in the presence of (Boc)2O and
a >3:1 ratio with pyrrolopyrrole 12 by reacting 1,4-dione
8 with 500 mol % of benzylamine and 3000 mol % of
acetic acid in EtOH at 60 °C for 1.5 h. These mildly acidic
conditions suppressed R-deprotonation with elimination
of the PhF aromatic anion which leads to 4-aminopyrrole-
2-carboxylates related to 12,20 such that pyrroloproline
10b was isolated in 23% yield after column chromatog-
raphy.
A more generally successful method for preparing
pyrroloprolines was developed that involved the aldol
condensation of ketone 6 with N-(Boc)-R-amino aldehydes
15, followed by acid-induced cyclization of the â-hydroxy-
ketone intermediate to yield the pyrrole24 (Scheme 2).
R-Substituted R-amino aldehydes 15b-e were synthe-
sized in >80% yields from their corresponding N-(Boc)-
amino acids by acylation of N,O-dimethylhydroxylamine
using TBTU, followed by reduction of the hydroxamate
with lithium aluminum hydride.25 Glycinal 15a was
prepared in two steps and 65% overall yield from
3-amino-1,2-propanediol by protection with (Boc)2O fol-
lowed by periodate oxidation of the crude protected diol.26
Previously, aldol adducts had been obtained by enoliza-
tion of N-PhF-4-oxoproline esters with n-BuLi in THF
at -55 °C and condensations with ordinary aromatic and
aliphatic aldehydes.27 Enolization of 4-oxoproline 6 under
these conditions followed by treatment with N-Boc-R-
amino aldehydes 15 at -78 °C gave crude mixtures that
were observed by proton NMR spectroscopy and mass
spectrometry to contain diastereomeric aldol products 16,
as well as starting 4-oxoproline 6 which could be recov-
ered by column chromatography and recycled. Treatment
of crude â-hydroxy ketone 16 with concentrated HCl in
methylene chloride at room temperature afforded pyr-
roles 17a -e in 10-37% overall yields accounting for
recovered 6 (Scheme 2). Formation of the heterocycle was
(28) (4S)-5-(PhF)-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrole-4-carboxy-
lic acid methyl ester: 1H NMR (400 MHz, CDCl3) 3.43 (s, 3 H), 3.99
(d, 21 H, J ) 12.4 Hz), 4.27 (d, 1 H, J ) 2.4 Hz), 4.35 (dd, 1 H, J )
12.4, 2.4 Hz), 5.75 (s, 1 H), 6.54 (s, 1 H), 7.11-7.71 (m, 13 H), 7.89 (s,
1 H); 13C NMR (100 MHz, CDCl3) 49.8, 51.8, 63.2, 77.8, 174.9; HRMS
calcd for C27H22N2O2 (M+) 406.1681, found 406.1652.
(29) Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985, 26, 6141-
6142.
(30) Heaney, H.; Ley, S. V. J . Chem. Soc., Perkin Trans. 1 1973,
499-500.
(31) Beausoleil, E.; Sharma, R.; Michnick, S. W.; Lubell, W. D. J .
Org. Chem. 1998, 63, 6572-6578.
(24) Nagafuji, P.; Cushman, M. J . Org. Chem. 1996, 61, 4999-5003.
(25) Fehrentz, J .-A.; Castro, B. Synthesis 1983, 676-678.
(26) Dueholm, K. L.; Egholm, M.; Buchardt, O. Org. Prep. Proc. Int.
1993, 25, 457-461.
(27) Blanco, M.-J .; Paleo, M. R.; Penide, C.; Sardina, F. J . J . Org.
Chem. 1999, 64, 8786-8793.
4658 J . Org. Chem., Vol. 69, No. 14, 2004

Synthesis of Fused Heteroarylprolines and Pyrrolopyrroles
SCHEME 4. Syn th esis of P r otected
P yr r olop r olin es for P ep tid e Syn th esis
SCHEME 5. En a n tiom er ic P u r ity of
P yr r olop r olin e 21a
dioxane gave the Moz-protected pyrrole-proline 25b in
60% yield after work-up and chromatography.
Finally, the potential for pyrroloprolines 21a to serve
in amide bond synthesis was evaluated in experiments
to determine enantiomeric purity. N-(Boc)-Pyrroloproline
21a was coupled to both L- and D-phenylalanine methyl
ester using O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-
uronium tetrafluoroborate (TBTU) and triethylamine in
acetonitrile (Scheme 5). Measurement of the dia-
stereotopic pyrrole proton signals at 6.69 and 6.59 ppm
during incremental additions of the (S,R)-isomer into the
(S,S)-dipeptide established the limits of detection of any
(R,S)-isomer from racemization of the pyrroloproline
during synthesis and coupling. In this way, N-(Boc)-
pyrroloprolylphenylalanine methyl ester (S,S)-26 was
demonstrated to be of >99% diastereomeric purity. Fused
pyrroloproline 21a is thus considered to be of similarly
high enantiomeric purity.
palladium-on-carbon, in THF at 7 atm of hydrogen,
starting material was predominantly recovered along
with (4S)-5-(PhF)-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrole-
4-carboxylic acid 23a 32 from loss of the benzyl ester.
Changing to palladium hydroxide as catalyst in a mixed
MeOH/THF solvent system at 7 atm of hydrogen en-
hanced conversion; however, a considerable amount of
bis-acylated reduced pyrrole 22a was isolated as a
mixture of diastereomers that were characterized by
Con clu sion
The first examples of enantiomerically pure fused
heteroarylprolines have been synthesized by two ap-
proaches starting from 4-oxo-N-(PhF)proline benzyl ester
6. In the first method, allylation of 6 followed by Wacker
oxidation gave 1,4-dione 8 which was condensed with
hydrazine to afford pyridazinoproline 9, and with ben-
zylamine to provide pyrroloproline 10b and pyrrolopyr-
role 12. The competition between the Paal-Knorr con-
densation and the formation of aminopyrrole carboxylate20
was controlled such that it was possible to obtain
predominantly pyrroloproline 10b or pyrrolopyrrole 12
by regulating the concentration of acid and amine nu-
cleophile. Pyrroloprolines 17a -e were synthesized by a
general process featuring the aldol condensation of
oxoproline 6 and N-(Boc)-R-amino aldehydes followed by
acid-catalyzed cyclization. Selective modification of the
pyrrole nitrogen of 17 was achieved by thermolytic
cleavage of the Boc-group and N-alkylation. Diversity
oriented methodology was thus developed for synthesiz-
ing a variety of fused heteroaryl-prolines from a common
intermediate. N-(PhF)-pyrroloproline benzyl ester 18 was
transformed into a series of analogues suitable for peptide
synthesis, as demonstrated by the introduction of N-
(Boc)pyrroloproline 21a into a dipeptide of >99% dia-
stereomeric purity. Pyrroloprolines are now being studied
in model peptides to examine the influences of the aryl
moiety and flattened pyrrolidine ring puckering on
conformation and biological activity.
1
mass spectrometry (m/z ) 352.2) and H NMR spectros-
copy.33 To date, our best conditions for this one-pot
conversion have featured hydrogenation of pyrrole-pro-
line 18a in the presence of di-tert-butyl dicarbonate and
palladium hydroxide in a MeOH/THF mixture at 1 atm
of hydrogen for 24 h to furnish the desired N-(Boc)amino
acid 21a in 40% yield along with 10% of the reduced
pyrrole 22a after purification by preparative liquid
chromatography (Scheme 4).
Two alternative protecting groups, the Fmoc and
p-methoxybenzyloxycarbonyl groups, were also installed
on the proline nitrogen by a two-step processs featuring
hydrogenation of pyrrole-proline 18 in the presence of
palladium hydroxide at 1 atm of H2 in 1:1 MeOH/THF
for 3 h, followed by amine acylation after filtration of the
catalyst and solvent exchange. (4S)-5-(Fmoc)-1,4,5,6-
Tetrahydro-pyrrolo[3,4-b]pyrrole-4-carboxylic acid 24a
and its 5-methyl analogue 24b were prepared in 71% and
73% overall yields, respectively, from 18a and 18b by
suspension of the crude hydrogenation mixture in a
dioxane/aqueous sodium carbonate solution, treatment
with FmocOSu in dioxane at 0 °C for 30 min, aqueous
workup, and chromatography on silica gel. Similar
hydrogenation of 18b and treatment with Moz-azide in
(32) (4S)-5-(PhF)-1,4,5,6-tetrahydropyrrolo[3, 4-b]pyrrole-4-carboxy-
lic acid (23a ): 1H NMR (400 MHz, CD3OD) 4.14 (m, 2 H), 4.54 (dd, 1
H, J ) 13.4, 3.9 Hz), 5.69 (d, 1 H, J ) 2.6 Hz), 6.58 (d, 1 H, J ) 2.6
Hz), 7.1-7.8 (m, 13 H); 13C NMR (100 MHz, CD3OD) 50.7, 65.1, 78.7,
176.3; HRMS calcd for C26H21N2O2 (MH+) 393.1603, found 393.1589.
(33) (4S)-1,5-Bis-(Boc)-octahydropyrrolo[3, 4-b]pyrrole-4-carboxylic
acid (22a ): 1H NMR (400 MHz, CD3OD) 1.46 (m, 18 H), 1.95 (m, 2 H),
3.26 (m, 2 H), 3.40 (m, 1 H), 3.42 (m, 1 H), 3.93 (m, 1 H), 4.31 (q, 1 H,
J ) 7.3 Hz), 4.44 (d, 1 H, J ) 8.8 Hz); HRMS calcd for C17H29N2O6
(MH+) 357.2026, found 357.1992.
Exp er im en ta l Section
(2S)-3-Allyl-4-oxo-N-(P h F )p r olin e Ben zyl Ester (7). A
solution of (2S)-4-oxo-N-(PhF)proline benzyl ester (6, 4 g, 8.7
mmol) in a 10:1 mixture of THF/HMPA (34 mL/3.4 mL) was
treated dropwise with n-BuLi (3.76 mL, 2.5 M in hexanes, 9.14
mmol) at -55 °C, stirred for 1 h, treated with allyl iodide (2.4
J . Org. Chem, Vol. 69, No. 14, 2004 4659

J eannotte and Lubell
mL, 26 mmol), and stirred for 2 h during which time the
temperature rose slowly to -10 °C. The reaction mixture was
treated with H3PO4 (10%, 6 mL) and poured into 150 mL of
diethyl ether. The organic layer was washed with saturated
sodium sulfite and brine, dried, and concentrated to a residue
that was chromatographed eluting with 10% EtOAc in hexanes
to furnish 3-allylproline 7 as a white foam that turned to dark
yellow on standing, a 1:5 mixture of diastereomers (3.44 g,
79%). Spectral data for the major isomer: 1H NMR (400 MHz,
CDCl3) δ 2.08 (m, 1 H), 2.32 (m, 1 H), 2.46 (m, 1 H), 3.45 (d,
1 H, J ) 18 Hz), 3.48 (s, 1 H), 3.85 (d, 1 H, J ) 18 Hz), 4.35
(d, 1 H, J ) 12.5 Hz), 4.53 (d, 1 H, J ) 12.5 Hz), 4.92 (m, 2 H),
4.52 (m, 1 H), 7.1-7.7 (m, 18 H); 13C NMR (100 MHz, CDCl3)
δ 33.8, 52.4, 55.5, 63.1, 66.3, 75.7, 117.9, 172.7, 213.2.
(d, 1 H, J ) 16.9 Hz), 4.83 (d, 1 H, J ) 16.9 Hz), 4.90 (d, 1 H,
J ) 12.5 Hz), 5.98 (d, 1 H, J ) 12.5 Hz), 5.31 (s, 1 H), 6.7-7.6
(m, 23 H); 13C NMR (75 MHz, CDCl3) δ 12.6, 48.7, 49.9, 64.1,
66.1, 78.2, 174.3; HRMS calcd for C41H35N2O2 (MH+) 587.2699,
found 587.2685.
1-Ben zyl-2-m eth yl-1,5-d ih yd r op yr r olo[3,4-b]p yr r ole-4-
ca r boxylic Acid Ben zyl Ester (12). A solution of dione 8
(50 mg, 0.097 mmol) in toluene (5 mL) was treated with
benzylamine (44 µL, 0.4 mmol) and p-toluenesulfonic acid
monohydrate (2 mg, 0.01 mmol), heated to 50 °C under argon
atmosphere for 24 h, cooled, and concentrated to a residue that
was dissolved in EtOAc (10 mL) and washed with 2 M NaH2-
PO
4, saturated NaHCO3 and brine, dried, and concentrated.
The residue was chromatographed eluting with 10-30%
EtOAc in hexanes. Evaporation of the collected fractions gave
pyrroloproline 12 (20 mg, 60%): 1H NMR (400 MHz, CDCl3) δ
2.30 (s, 3 H), 5.03 (s, 2 H), 5.34 (s, 2 H), 6.10 (s, 1 H), 6.35 (s,
1 H), 7.0-7.5 (m, 10 H), 9.3 (br s, 1 H); 13C NMR (100 MHz,
CDCl3) 13.3, 48.7, 65.4, 95.2, 105.3, 126.8, 127.6, 127.9, 128.6,
128.8, 134.4, 137.3, 137.7, 142.8; HRMS calcd for C22H21N2O2
(MH+) 345.1603, found 345.1557.
(2S)-4-Oxo-3-(2′-oxop r op yl)-1-(P h F )-p r olin e Ben zyl Es-
ter (8). In a 25 mL round-bottom flask under a rubber balloon
filled with oxygen was stirred a mixture of palladium(II)
chloride (14 mg, 0.08 mmol), copper(I) chloride (80 mg, 0.8
mmol), water (1 mL), and dimethylformamide (6 mL) for 1 h
at room temperature during which time the solution turned
to green. A solution of (2S)-3-allyl-4-oxo-N-(PhF)proline benzyl
ester (7, 400 mg, 0.08 mmol, a 1:5 mixture of diastereomers)
in DMF (3 mL) and water (0.3 mL) was added to the green
solution, and the mixture was stirred vigorously for 24 h under
oxygen, poured into cold 1 N HCl (50 mL), and extracted three
times with EtOAc (50 mL). The combined organic layer was
washed with saturated sodium bicarbonate and brine, dried,
and concentrated to a residue that was chromatographed
eluting with 10-25% EtOAc in hexanes to give dione 8 (336
mg, 81%) as a 1:5 mixture of diastereomers. First to elute was
the minor isomer: 1H NMR (300 MHz, C6D6) δ 1.34 (s, 3 H),
1.64 (dd, 1 H, J ) 7.8, 18.6 Hz), 2.49 (dd, 1 H, J ) 5.0, 18.6
Hz), 3.30 (m, 1 H), 3.59 (d, 1H, J ) 17.0 Hz), 3.94 (d, 1 H, J )
17 Hz), 4.17 (d, 1 H, J ) 8.3 Hz), 4.39 (d, 1 H, J ) 12.3 Hz),
4.50 (d, 1 H, J ) 12.3 Hz), 6.9-7.4 (m, 18 H); 13C NMR (75
MHz, C6D6) δ 29.2, 38.6, 47.6, 54.3, 62.4, 66.1, 76.2, 171.6,
203.9, 211.8; HRMS calcd for C34H30NO3 (MH+) 515.2097,
found 515.2077. Next to elute was the major isomer:1H NMR
(300 MHz, C6D6) δ 1.26 (s, 3 H), 1.89 (dd, 1 H, J ) 7.4, 18.4
Hz), 2.16 (dd, 1 H, J ) 3.8, 18.4 Hz), 3.08 (m, 1 H), 3.46, (d, 1
H, J ) 7.4 Hz), 3.55 (d, 1 H, J ) 17.8 Hz), 3.81 (d, 1 H, J )
17.8 Hz), 4.47 (d, 1 H, J ) 12.4 Hz), 4.70 (d, 1 H, J ) 12.4 Hz),
6.9-7.6 (m, 18 H); 13C NMR (75 MHz, C6D6) δ 28.9, 41.4, 48.9,
57.1, 65.1, 66.7, 77.2, 172.7, 203.6, 211.1; HRMS calcd for
Typ ica l P r oced u r e for P yr r ole P r ep a r a tion . (4S)-1-N-
Boc-5-(P h F )-1,4,5,6-t et r a h yd r op yr r olo[3,4-b]p yr r ole-4-
ca r boxylic Acid Ben zyl Ester (17a ). A stirred solution of
(2S)-4-oxo-N-(PhF)proline benzyl ester (6, 3 g, 6.5 mmol) in
17 mL of THF was cooled to -78 °C under argon atmosphere,
treated with n-BuLi (2.75 mL, 2.5 M in hexanes, 6.9 mmol),
and stirred for 1 h at -55 °C. The mixture was cooled to -78
°C, treated via cannula with a -78 °C solution of N-(Boc)-
glycinal (1.09 g, 6.9 mmol) in 5 mL of THF, stirred for 5 h at
-55 °C, and poured into an ice-cold solution of 1 M NaH2PO4
(50 mL). The aqueous solution was extracted with ether (3 ×
50 mL), and the combined organic phases were washed with
brine, dried, and evaporated to a foam. The foam was chro-
matographed using 15% EtOAc in hexanes as eluent to recover
0.62 g of starting oxoproline 6 and a more polar fraction, that
was isolated, dissolved in 50 mL of CH2Cl2, treated with 0.4
mL of conc HCl, and stirred for 12 h. The resulting brown
mixture was diluted with CH2Cl2 (50 mL), washed with
saturated NaHCO3 (3 × 30 mL) and brine, dried, and concen-
trated to a residue that was chromatographed eluting with
10% EtOAc in hexanes. Evaporation of the collected fractions
gave pyrroloproline 17a as a white foam (1.11 g, 30 (37%)):
[R]22D 107.7 (c 1.01, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.47
(s, 9 H), 4.23 (m, 2 H), 4.61 (m, 1 H), 4.80 (d, 1 H, J ) 12 Hz),
4.97 (d, 1 H, J ) 12 Hz), 5.73 (d, 1 H, J ) 3.1 Hz), 6.96 (s, 1
H), 7.0-7.7 (m, 18 H); 13C NMR (100 MHz, CDCl3) δ 28.0, 51.9,
63.1, 66.4, 77.8, 84.0, 147.0, 173.4; HRMS calcd for C38H35N2O4
(MH+) 583.2597, found 583.2608.
C
34H30NO3 (MH+) 515.2097, found 515.2085.
(5S)-3-Met h yl-6-(P h F )-6,7-d ih yd r o-5H -p yr r olo[3,4-c]-
p yr id a zin e-5-ca r boxylic Acid Ben zyl Ester (9). Hydrazine
hydrate (60 µL, 1.9 mmol) was added to a solution of dione 8
(100 mg, 0.19 mmol) in toluene (5 mL), and the mixture was
heated to a reflux for 12 h, cooled to room temperature, diluted
with EtOAc (10 mL), washed with 2 M NaH2PO4 and brine,
dried, and concentrated to a residue that was purified by
chromatography eluting with 50% EtOAc in hexanes to give
pyridazine 9 (52 mg, 54%): 1H NMR (400 MHz, CD2Cl2) δ 2.53
(s, 3 H), 4.47, (s, 1 H), 4.60 (d, 1 H, J ) 16.1 Hz), 4.82 (d, 1 H,
J ) 16.1 Hz), 4.88 (d, 1 H, J ) 12.2 Hz), 4.96, (d, 1 H, J ) 12.2
Hz) 6.86 (s, 1 H), 7.2-7.8 (m, 18 H); 13C NMR (100 MHz, CD2-
Cl2) δ 22.3, 55.0, 66.4, 67.3, 77.7, 171.1; HRMS calcd for
(4S)-1-N-Boc-2-m et h yl-5-(P h F )-1,4,5,6-t et r a h yd r op yr -
r olo[3,4-b]p yr r ole-4-ca r boxylic a cid ben zyl ester (17b)
was isolated as a white foam in 25(31)% yield: [R]22 104.8 (c
D
0.94, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9 H), 2.29
(s, 3 H), 4.20 (m, 2 H), 4.56 (dd, 1 H, J ) 5.6, 15.3 Hz), 4.79 (d,
1 H, J ) 12 Hz), 4.95 (d, 1 H, J ) 12 Hz), 5.47 (s, 1 H), 7.0-
7.9 (m 18 H); 13C NMR (75 MHz, CDCl3) δ 15.9, 27.8, 53.1,
63.0, 66.2, 77.6, 83.5, 147.1, 173.6; HRMS calcd for C39H37N2O4
(MH+) 597.2753, found 597.2773.
C
34H28N3O2 (MH+) 510.2812, found 510.2175.
(4S)-1-N-Boc-2-ben zyl-5-(P h F)-1,4,5,6-tetr ah ydr opyr r olo-
[3,4-b]p yr r ole-4-ca r boxylic a cid ben zyl ester (17c) was
(4S)-1-N-Ben zyl-2-m et h yl-5-(P h F )-1,4,5,6-t et r a h yd r o-
isolated as a white foam in 29(36)% yield: [R]22 96.0 (c 1.03,
D
p yr r olo[3,4-b]p yr r ole-4-ca r boxylic Acid Ben zyl Ester
(10b). A stirred solution of dione 8 (50 mg, 0.097 mmol) in
degassed anhydrous EtOH (2 mL) and acetic acid (150 µL, 3
mmol) was treated with benzylamine (24 µL, 0.2 mmol) in
EtOH (1 mL), heated to 60 °C under argon atmosphere for
1.5 h, poured into water (5 mL), and extracted three times
with EtOAc (5 mL). The combined organic phase was then
washed with saturated NaHCO3 and brine, dried, and evapo-
rated to a residue that was chromatographed eluting with 5%
EtOAc in hexanes. Evaporation of the collected fractions gave
pyrroloproline 10b (13 mg, 23%): 1H NMR (300 MHz, CDCl3)
δ 1.99 (s, 3 H), 3.78 (d, 1 H, J ) 11.6 Hz), 4.33 (m, 2 H), 4.72
1
CHCl3); H NMR (300 MHz, CDCl3) δ 1.35 (s, 9 H), 4.07 (s, 2
H), 4.22 (m, 2 H), 4.65 (dd, 1 H, J ) 4.4, 14.9 Hz), 4.78 (d, 1 H,
J ) 12.2 Hz), 4.96 (d, 1 H, J ) 12.2 Hz), 5.31 (s, 1 H), 7.0-7.7
(m, 23 H); 13C NMR (75 MHz, CDCl3) δ 27.9, 35.6, 53.2, 63.2,
66.3, 77.7, 83.9, 143.3, 173.5; HRMS calcd for C45H41N2O4
(MH+) 673.3066, found 673.3090.
(4S)-1-N-Boc-2-isopr opyl-5-(P h F)-1,4,5,6-tetr ah ydr opyr -
r olo[3,4-b]p yr r ole-4-ca r boxylic a cid ben zyl ester (17d )
was isolated as a white foam in 6(10)% yield: [R]22 105.5 (c
D
1
0.94, CHCl3); H NMR (400 MHz, CDCl3) δ 1.08 (d, 3 H, J )
2.6 Hz), 1.10 (d, 3 H, J ) 2.6 Hz), 1.42 (s, 9 H), 3.38 (m, 1 H),
4660 J . Org. Chem., Vol. 69, No. 14, 2004

Synthesis of Fused Heteroarylprolines and Pyrrolopyrroles
4.18 (m, 2 H), 4.54 (dd, 1 H, J ) 5.1, 14.9 Hz), 4.78 (d, 1 H, J
) 12.3 Hz), 5.01 (d, 1 H, J ) 12.3 Hz), 5.50 (s, 1H), 7.0-7.7
(m, 18 H); 13C NMR (100 MHz, CDCl3) δ 22.9, 23.3, 27.4, 27.9,
53.5, 63.2, 66.2, 77.7, 83.6, 146.8, 173.6; HRMS calcd for
temperature, a solution of KOH (9.3 mg, 0.17 mmol) in DMSO
(500 µL) was treated with (4S)-5-(PhF)-1,4,5,6-tetrahydropy-
rrolo[3,4-b]pyrrole-4-carboxylic acid benzyl ester (18a , 40 mg,
0.08 mmol), stirred for20 min, treated with iodomethane (20
µL, 0.32 mmol), and stirred for 2 h. Water (4 mL) was added
to the mixture, which was extracted with three portions of
EtOAc (10 mL). The combined organic phase was washed with
water and brine, dried, and concentrated to a residue that was
chromatographed eluting with 10% EtOAc in hexanes to give
N-methylpyrrole 19a (38 g, 92%): 1H NMR (400 MHz, CDCl3)
δ 3.40 (s, 3 H), 4.03 (d, 1 H, J ) 12.4 Hz), 4.30 (d, 1 H, J ) 2.4
Hz), 4.42 (dd, 1 H, J ) 2.4, 12.4 Hz), 4.78 (d, 1 H, J ) 12.4
Hz), 4.96 (d, 1 H, J ) 12.4 Hz), 5.61 (d, 1 H, J ) 2.1 Hz), 6.37
(s, 1 H), 7.0-7.7 (m, 18 H); 13C NMR (100 MHz, CDCl3) δ 34.8,
49.2, 63.6, 66.2, 77.8, 174.2; HRMS calcd for C34H29N2O2 (MH+)
497.2229, found 497.2222.
(4S)-1-N-Met h yl-2-m et h yl-5-(P h F )-1,4,5,6-t et r a h yd r o-
pyr r olo[3,4-b]pyr r ole-4-car boxylic acid ben zyl ester (19b)
was isolated from the reaction of pyrroloproline 18b (50 mg,
0.1 mmol) and iodomethane (25 µL, 0.4 mmol) in 72% yield:
1H NMR (300 MHz, CDCl3) δ 2.07 (s, 3 H), 3.26 (s, 3H), 4.03
(d, 1 H, J ) 12.1 Hz), 4.29 (dd, 1 H, J ) 1.5, 4.2 Hz), 4.42 (dd,
1 H, J ) 4.2, 12.1 Hz), 4.77 (d, 1 H, J ) 12.5 Hz), 4.94 (d, 1 H,
J ) 12.5 Hz), 5.39 (s, 1 H), 7.0-7.7 (m, 18 H); 13C NMR (75
MHz, CDCl3) δ 12.6, 31.9, 49.7, 63.8, 66.2, 77.3, 174.4; HRMS
calcd for C35H31N2O2 (MH+) 511.2386, found 511.2371.
C
41H41N2O4 (MH+) 625.3066, found 625.3083.
(4S)-1-N-Boc-2-(2-m eth ylth ioeth yl)-5-(P h F )-1,4,5,6-tet-
r a h yd r op yr r olo[3,4-b]p yr r ole-4-ca r boxylic a cid ben zyl
ester (17e) was isolated as a white foam in 19(22)% yield:
[R]22D 104.1 (c 0.94, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.44
(s, 9 H), 2.07 (s, 3 H), 2.63 (m, 2 H), 3.00 (t, 2 H, J ) 7.3 Hz),
4.19 (m 2 H), 4.57 (d, 1 H, J ) 9.5 Hz), 4.82 (d, 1 H, J ) 11.9
Hz), 5.00 (d, 1 H, J ) 11.9 Hz), 5.56 (s, 1 H), 7.0-7.7 (m, 18
H); 13C NMR (100 MHz, CDCl3) δ 15.7, 28.0, 29.8, 33.7, 53.3,
63.2, 66.4, 77.7, 83.9, 147.2, 173.5; HRMS calcd for C41H41N2O4S
(MH+) 657.2787, found 657.2774.
Typical P r ocedu r e for BOC Depr otection . (4S)-5-(P h F)-
1,4,5,6-tetr ah ydr opyr r olo[3,4-b]pyr r ole-4-car boxylic Acid
Ben zyl Ester (18a ). A round-bottom flask containing (4S)-
1-N-Boc-5-(PhF)-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrole-4-car-
boxylic acid benzyl ester (17a , 60 mg, 0.1 mmol) under an
argon atmosphere was placed into a 180 °C oil bath for 35 min.
The flask was removed from the oil bath, and the resulting
product was purified by chromatography using 20% EtOAc in
hexanes as eluent. Evaporation of the collected fractions gave
1
18a (39 mg, 79%): [R]22 61.8 (c 0.94, CHCl3); H NMR (400
D
MHz, CDCl3) δ 4.01 (d, 1 H, J ) 12.7), 4.33 (d, 1 H, J ) 3.3
Hz), 4.41 (dd, 1 H, J ) 3.8, 12.7), 4.82 (d, 1 H, J ) 12.4), 4.97
(d, 1 H, J ) 12.4), 5.73 (s, 1 H), 6.56 (s, 1 H), 6.5-7.7 (m, 18
H), 7.8 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 50.0, 63.4, 66.2,
78.0, 174.3; HRMS calcd for C33H27N2O2 (MH+) 483.2073, found
483.2081.
(4S)-1-N-Ben zyl-5-(P h F )-1,4,5,6-tetr a h yd r op yr r olo[3,4-
b]p yr r ole-4-ca r boxylic a cid ben zyl ester (10a ) was iso-
lated from the reaction of pyrroloproline 18a (40 mg, 0.082
mmol) and benzyl bromide (20 µL, 0.164 mmol) in 81% yield:
1H NMR (300 MHz, CDCl3) δ 3.76 (m, 1 H), 4.32 (m, 2 H),
4.81-4.90 (m, 3 H), 4.98 (d, 1 H, J ) 12.4 Hz), 5.71 (d, 1 H, J
) 2.7 Hz), 6.45 (d, 1 H, J ) 2.7 Hz), 6.8-7.6 (m, 23 H); 13C
NMR (75 MHz, CDCl3) δ 49.4, 51.9, 63.7, 66.2, 78.1, 174.0;
HRMS calcd for C40H33N2O2 (MH+) 573.2542, found 573.2541.
(4S)-2-Meth yl-5-(P h F)-1,4,5,6-tetr a h yd r o-p yr r olo[3,4-b]-
p yr r ole-4-ca r boxylic a cid ben zyl ester (18b) was prepared
from Boc-pyrroloproline 17b (61 mg, 0.10 mmol) and isolated
in 77% yield: [R]22 79.9 (c 1.21, MeOH); 1H NMR (400 MHz,
D
CDCl3) δ 2.12 (s, 3 H), 3.95 (d, 1 H, J ) 12.4 Hz), 4.34 (m, 2 H,
J ) 3.3 Hz), 4.81 (d, 1 H, J ) 12.4 Hz), 4.95 (d, 1 H, J ) 12.4
Hz), 5.40 (s, 1 H), 7.0-7.7 (m, 19 H); 13C NMR (100 MHz,
CDCl3) δ 13.7, 50.2, 63.6, 66.2, 77.9, 174.5; HRMS calcd for
(4S)-1-N-Ben zyl-2-m et h yl-5-(P h F )-1,4,5,6-t et r a h yd r o-
pyr r olo[3,4-b]pyr r ole-4-car boxylic acid ben zyl ester (10b)
was isolated from the reaction of pyrroloproline 18b (50 mg,
0.1 mmol) and benzyl bromide (24 µL, 0.2 mmol) in 63% yield
and possessed the same spectral and physical properties as
described above.
C
34H29N2O2 (MH+) 497.2229, found 497.2211.
(4S)-2-Ben zyl-5-(P h F )-1,4,5,6-tetr a h yd r op yr r olo[3,4-b]-
p yr r ole-4-ca r boxylic a cid ben zyl ester (18c) was prepared
from Boc-pyrroloproline 17c (60 mg, 0.089 mmol) and isolated
(4S)-1-N-(ter t-Bu tyl a ceta te)-2-m eth yl-5-(P h F )-1,4,5,6-
tetr a h yd r op yr r olo[3,4-b]p yr r ole-4-ca r boxylic a cid ben -
zyl ester (20b) was isolated from the reaction of pyrrolopro-
line 18b (40 mg, 0.08 mmol) and tert-butyl bromoacetate (35.4
µL, 0.24 mmol) in 49% yield: 1H NMR (300 MHz, CDCl3) δ
1.40 (s, 9 H), 2.05 (s, 3 H), 4.04 (d, 1 H, J ) 12.3 Hz), 4.15 (d,
1 H, J ) 17.3 Hz), 4.23 (m, 2 H), 4.41 (dd, 1 H, J ) 4.4, 12.4
Hz), 4.82 (d, 1 H, J ) 12.5 Hz), 4.93 (d, 1 H, J ) 12.5 Hz), 5.46
(s, 1 H), 7.0-7.7 (m, 18 H); 13C NMR (75 MHz, CDCl3) δ 12.5,
28.1, 47.9, 49.9, 63.8, 66.1, 77.9, 82.5, 167.5, 174.2; HRMS calcd
for C40H39N2O4 (MH+) 611.2910, found 611.2909.
in 78% yield: [R]22 80.3 (c 0.77, MeOH); 1H NMR (400 MHz,
D
CDCl3) δ 3.79 (s, 2 H), 3.91 (d, 1 H, J ) 11.1 Hz), 4.31 (m, 2
H), 4.81 (d, 1 H, J ) 12.4 Hz), 4.96 (d, 1 H, J ) 12.4 Hz), 5.48
(s, 1 H), 7.0-7.7 (m, 24 H); 13C NMR (100 MHz, CDCl3) δ 34.7,
50.1, 63.6, 66.1, 77.9, 174.3; HRMS calcd for C40H33N2O2 (MH+)
573.2542, found 573.2522.
(4S)-2-Isop r op yl-5-(P h F )-1,4,5,6-tetr a h yd r op yr r olo[3,4-
b]p yr r ole-4-ca r boxylic a cid ben zyl ester (18d ) was pre-
pared from Boc-pyrroloproline 17d (60 mg, 0.091 mmol) and
isolated in 79% yield: [R]22 79.9 (c 0.95, MeOH); 1H NMR
D
(4S)-5-(Boc)-1,4,5,6-tetr a h yd r op yr r olo[3,4-b]p yr r ole-4-
ca r boxylic Acid (21a ). A solution of (4S)-5-(PhF)-1,4,5,6-
tetrahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid benzyl ester
(18a , 210 mg, 0.43 mmol) and di-tert-butyl dicarbonate (122
mg, 0.56 mmol) in 1:3 THF/MeOH (5 mL/15 mL) was treated
with palladium hydroxide-on-carbon (60 mg, 20 wt % in
palladium (wet)) and stirred under 1 atm of hydrogen for 24
h. The catalyst was removed by filtration on Celite and washed
with MeOH. The filtrate was evaporated to dryness, and the
residue was partitioned between saturated NaHCO3 (10 mL)
and Et2O (15 mL). The aqueous phase was washed with Et2O
(2 × 15 mL), acidified to pH 2 with cold 1 N HCl, and extracted
with CHCl3 (4 × 15 mL). The combined organic extractions
were washed with brine, dried, and concentrated to a residue
that was purified by HPLC (20-80% CH3CN in water, 0.01%
TFA, C18 column) to provide pyrroloproline 21a (44 mg, 40%):
1H NMR (400 MHz, CDCl3) showed a 2:1 mixture of carbamate
isomers δ 1.44 (s, 6 H) [1.48 (s, 3 H)], 4.50 (m, 2 H), 5.22 (d,
0.66 H, J ) 2.9 Hz) [5.31 (d, 0.33, J ) 2.4 Hz)], 6.03 (s, 0.66
H) [6.10 (s, 0.33 H)], 6.69 (s, 1 H), 8.69 (s, 0.66 H) [8.49 (s,
(400 MHz, CDCl3) δ 1.12 (d, 6 H, J ) 6.8 Hz), 2.74 (m, 1 H),
3.98 (d, 1 H, J ) 12.2 Hz), 4.30 (d, 1 H, J ) 4.2 Hz), 4.35 (dd,
1 H, J ) 4.2, 12.2 Hz), 4.79 (d, 1 H, J ) 12.5 Hz), 4.97 (d, 1 H,
J ) 12.5 Hz), 5.39 (s, 1 H), 7.0-7.7 (m, 19 H); 13C NMR (100
MHz, CDCl3) δ 22.7, 22.8, 27.7, 50.1, 63.6, 66.0, 77.8, 174.4;
HRMS calcd for C36H33N2O2 (MH+) 525.2542, found 525.2559.
(4S)-2-(2-Meth ylth ioeth yl)-5-(P h F )-1,4,5,6-tetr a h yd r o-
pyr r olo[3,4-b]pyr r ole-4-car boxylic acid ben zyl ester (18e)
was prepared from Boc-pyrroloproline 17e (60 mg, 0.096) and
isolated in 89% yield: [R]22 81.2 (c 1.17, MeOH); 1H NMR
D
(300 MHz, CDCl3) δ 2.01 (s, 3 H), 2.59 (t, 2 H, J ) 6.7 Hz),
2.72 (t, 2 H, J ) 6.6 Hz), 3.94 (d, 1 H, J ) 11.1 Hz), 4.31 (m,
2 H), 4.80 (d, 1 H, J ) 12.4 Hz), 4.95 (d, 1 H, J ) 12.4 Hz),
5.44 (s, 1 H), 7.0-7.7 (m, 18 H), 8.00 (s, 1 H); 13C NMR (75
MHz, CDCl3) δ 15.7, 28.2, 34.6, 50.1, 63.5, 66.2, 77.9, 174.4;
HRMS calcd for C36H33N2O2S (MH+) 557.2263, found 557.2270.
Typ ica l P r oced u r e for N-Alk yla tion of th e P yr r ole.
(4S)-1-N-Meth yl-5-(P h F )-1,4,5,6-tetr a h yd r op yr r olo[3,4-b]-
p yr r ole-4-ca r boxylic Acid Ben zyl Ester (19a ). At room
J . Org. Chem, Vol. 69, No. 14, 2004 4661

J eannotte and Lubell
0.33 H)], 10.8 (br s, 1 H); 13C NMR (100 MHz, CDCl3) δ 28.4
(28.5), 46.5 (47.1), 61.1 (60.9), 81.2 (77.4), 102.4 (102.9), 119.3,
122.0, 130.4, 154.3 (155.2), 177.0, 175.4; HRMS calcd for
washed with brine, dried, and concentrated. Chromatography
eluting with 50-100% EtOAc in hexanes containing 1% AcOH
gave Moz-pyrroloproline 25b (40 mg, 60%): 1H NMR (400
MHz, MeOD) showed a 1:1 mixture of carbamate isomers δ
2.19 (s, 3 H), 4.43 (d, 1 H, J ) 12.3 Hz), 4.52 (d, 1 H, J ) 12.3
Hz), 5.00-5.15 (m, 3 H), 5.63 (s, 0.5 H) [5.66 (s, 0.5)], 6.87 (m,
2 H), 7.26 (d, 1 H, J ) 8.3 Hz) [7.30 (d, 1 H, J ) 8.4 Hz)], 10.1
(s, 0.5 H) [10.14 (s, 0.5 H]; 13C NMR (100 MHz, MeOD) δ 13.5,
48.0 (48.2), 55.8, 62.67 (62.75), 68.36 (68.39), 100.2, 114.9
(115.0), 120.0 (120.4), 129.4 (130.0), 129.92 (129.87), 130.7
(130.9), 133.63 (133.59), 156.7 (156.9), 161.2 (161.3), 175.0
(175.3); HRMS calcd for C17H19N2O5 (MH+) 331.1294, found
331.1281.
En a n tiom er ic P u r ity of (4S)-5-(Boc)-1,4,5,6-tetr a h y-
d r op yr r olo[3,4-b]p yr r ole-4-ca r boxylic Acid (21a ). At room
temperature, a solution of (4S)-5-(Boc)-1,4,5,6-tetrahydropy-
rrolo[3,4-b]pyrrole-4-carboxylic acid (21a , 5 mg, 0.02 mmol)
and the HCl salt of either L- or D-phenylalanine methyl ester
(4.3 mg, 0.02 mmol) in 0.5 mL of acetonitrile was treated with
O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluo-
roborate (7 mg, 0.02 mmol) and Et3N (5.5 µL, 0.04 mmol). After
being stirred for 12 h, the mixture was partitioned between
brine (0.7 mL) and EtOAc (3 mL). The organic layer was
washed with H2O (2 × 3 mL) and brine, dried, and concen-
trated to a residue that was directly examined by 1H NMR
spectroscopy. Measurement of the diastereotopic pyrrole proton
signals at 6.69 and 6.59 ppm during incremental additions of
(S,R)-26 in a sample of (S,S)-26 demonstrated N-(Boc)-pyr-
roloprolylphenylalanine methyl ester (S,S)-26 to be of >99%
diastereomeric purity. Hence, fused pyrrole-proline 21a is
considered to be of the same high enantiomeric purity.
(S,S)-N-(Boc)-P yr r olop r olylp h en yla la n in e m eth yl es-
ter ((S,S)-26): 1H NMR (400 MHz, MeOD) showed a 1:2
mixture of carbamate isomers δ 1.33 (s, 6 H) [1.49 (s, 3 H)],
3.04 (m, 2 H), 3.64 (s, 2 H) [6.62 (s, 1 H], 4.43-4.50 (m, 2 H),
4.67 (m, 1 H), 5.11 (d, 0.66 H, J ) 2.3 Hz) [5.14 (d, 0.33 H, J
) 2.0 Hz], 5.95 (s, 0.66 H) [5.98 (s, 0.33 H)], 6.69 (s, 0.66 H)
[6.71 (s, 0.33 H)], 7.0-7.2 (m, 5 H), 8.22 (d, 0.66 H, J ) 7.9
Hz) [8.08 (d, 0.33 H, J ) 7.5 Hz)], 10.4 (s, 1 H); MS m/z 414.2
[MH+].
C
12H16N2O4 (M) 252.1110, found 252.1112.
Typ ica l P r oced u r e for F m oc P r otection of P yr r olo-
p r olin e. (4S)-5-(F m oc)-1,4,5,6-tetr a h yd r op yr r olo[3,4-b]-
p yr r ole-4-ca r boxylic Acid (24a ). A solution of (4S)-5-(PhF)-
1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid benzyl
ester (18a , 68 mg, 0.14 mmol) in 1:1 THF/MeOH (8 mL) was
treated with palladium hydroxide-on-carbon (34 mg, 20 wt %
in palladium (wet)) and stirred under 1 atm of hydrogen for 3
h. The catalyst was removed by filtration onto Celite and
washed with MeOH. The filtrate was concentrated to a residue
that was suspended in water (3 mL) containing 9% aqueous
Na2CO3 (165 µL, 0.14 mmol), cooled to 0 °C, and treated with
FmocOSu (53 mg, 0.15 mmol) in dioxane (3 mL) with vigorous
stirring for 30 min. The reaction mixture was concentrated
and partitioned between saturated NaHCO3 (5 mL) and Et2O
(5 mL). The aqueous phase was washed with Et2O (2 × 5 mL),
acidified to pH 2 with cold 1 N HCl, and extracted with CHCl3
(4 × 8 mL). The combined organic extractions were washed
with brine, dried, and concentrated to a residue that was
chromatographed eluting with 50-100% EtOAc in hexanes
containing 1% AcOH to give Fmoc-pyrroloproline 24a (37 mg,
71%): 1H NMR (400 MHz, CDCl3) showed a 1:1 mixture of
carbamate isomers δ 4.13 (t, 0.5 H, J ) 6.1 Hz) [1.48 (t, 0.5 H,
J ) 6.6 Hz)], 4.41-4.63 (m, 4 H), 5.21 (d, 0.5 H, J ) 2.2 Hz)
[5.39 (d, 0.5, J ) 2.0 Hz)], 6.07 (s, 0.5 H) [6.15 (s, 0.5 H)], 6.68
(s, 1 H) [6.72 (s, 0.5 H], 7.2-7.8 (m, 8 H), 8.15 (br s, 1 H); 13
C
NMR (100 MHz, CDCl3) δ 46.9 (47.1), 47.2 (47.3), 61.0 (61.1),
67.8, 102.7 (103.0), 119.4 (119.3), 120.0 (120.1), 122.1 (122.2),
125.0 (124.9), 125.1 (125.3), 127.2 (127.1), 127.8 (127.9), 130.0,
141.4 (141.3), 143.4 (143.8), 143.97 (143.99), 154.8 (155.2),
175.4 (176.1); HRMS calcd for C22H19N2O4 (MH+) 375.1267,
found 375.1312.
(4S)-5-(F m oc)-2-m eth yl-1,4,5,6-tetr a h yd r op yr r olo[3,4-
b]p yr r ole-4-ca r boxylic a cid (24b) was isolated from reac-
tion of (4S)-2-methyl-5-(PhF)-1,4,5,6-tetrahydropyrrolo[3,4-
b]pyrrole-4-carboxylic acid benzyl ester 18b (170 mg, 0.34
mmol) in 73% yield: 1H NMR (400 MHz, CDCl3) showed a 1:1
mixture of carbamate isomers δ 2.17 (s, 1.5 H) [2.21 (s, 1.5
H], 4.12 (t, 0.5 H, J ) 6. Hz0) [4.26 (t, 0.5 H, J ) 6.9 Hz)],
4.32-4.66 (m, 4 H), 5.20 (d, 0.5 H, J ) 2.4 Hz) [5.32 (d, 0.5 H,
J ) 2.9 Hz)], 5.73 (s, 0.5 H) [5.79 (s, 0.5 H)], 7.2-7.8 (m, 8 H),
7.89 (s, 0.5 H) [7.94 (s, 0.5 H)]; 13C NMR (100 MHz, CDCl3) δ
13.57 (13.63), 47.03 (47.1), 47.2 (47.28), 60.9 (61.2), 67.78
(67.87), 100.3 (100.6), 119.3, 1210.1 (120.0), 125.0 (125.1), 125.2
(125.3), 127.2 (127.8), 127.9 (128.4), 132.5 (132.6), 141.4 (141.3)
143.8 (143.9), 144.0, 154.8 (155.2), 175.4 (176.1); HRMS calcd
for C23H21N2O4 (MH+) 388.1423, found 388.1492.
(4S)-5-(Met h oxyben zyloxyca r b on yl)-2-m et h yl-1,4,5,6-
tetr a h yd r op yr r olo[3,4-b]p yr r ole-4-ca r boxylic Acid (25b).
A solution of (4S)-2-methyl-5-(PhF)-1,4,5,6-tetrahydropyrrolo-
[3,4-b]pyrrole-4-carboxylic acid benzyl ester (18b, 100 mg, 0.2
mmol) in 1:1 THF/MeOH (6 mL) was treated with palladium
hydroxide-on-carbon (50 mg, 20 wt % in palladium (wet)),
stirred under 1 atm of hydrogen for 3 h, filtered onto Celite,
and washed with MeOH. The filtrate was concentrated to a
residue that was suspended in water (4 mL), treated with
NaHCO3 (51 mg, 0.6 mmol), cooled to 0 °C, treated with
4-methoxybenzyloxycarbonyl azide (83 mg, 0.4 mmol) in di-
oxane (4 mL), stirred for 12 h, and concentrated to a residue
that was partitioned between saturated NaHCO3 (5 mL) and
Et2O (5 mL). The aqueous phase was washed with Et2O (2 ×
5 mL), acidified to pH 2 with cold 1 N HCl, and extracted with
CHCl3 (4 × 8 mL). The combined organic extractions were
(S,R)-N-(Boc)-p yr r olop r olylp h en yla la n in e m eth yl es-
ter ((S,R)-26): 1H NMR (400 MHz, MeOD)) showed a 1:2
mixture of carbamate isomers δ 1.42 (s, 6 H) [1.48 (s, 3 H)],
2.99 (m, 1 H), 3.15 (m, 1 H), 4.37 (m, 1 H), 4.52 (m, 1 H), 4.65
(m, 1 H), 5.14 (d, 1 H, J ) 3.0 Hz), 5.57 (s, 0.66 H) [5.75 (s,
0.33 H)], 6.59 (s, 0.66 H) [6.63 (s, 0.33 H)], 7.1-7.3 (m, 5 H),
8.63 (d, 0.66 H, J ) 7.8 Hz) [8.36 (d, 0.33 H, J ) 7.7 Hz)], 10.3
(s, 1 H); MS m/z 414.2 [MH+].
Ack n ow led gm en t. This research was supported in
part by the Merck Frosst Center for Therapeutic Re-
search, Canada, the Natural Sciences and Engineering
Research Council of Canada (NSERC), and the Fonds
Que´be´cois de la Recherche sur la Nature et les Tech-
nologies (FQRNT). We thank Mr. Dalbir Sekhon for
performing LC-MS experiments.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information, 1H and 13C NMR spectra for compounds 7-12,
1
17a -e, 18a -e, 19a ,b, 20b, 21a , 23a , 24a ,b, and 25b, and H
NMR spectra for 22a and 26 along with the limits of detection
experiment for enantiomeric purity of 21a . This material is
available free of charge via the Internet at http://pubs.acs.org.
J O049612I
4662 J . Org. Chem., Vol. 69, No. 14, 2004