Synthesis of densely functionalized pyrrolidinone templates by an intramolecular oxo-Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(02)01711-2

Preparation of densely functionalized pyrrolidinone templates, is a challenge for synthetic chemists. These templates are important building blocks for novel conformationally constrained natural products or for library generation of highly functionalized

Full text of DOI:10.1016/S0040-4039(02)01711-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7389–7392
Synthesis of densely functionalized pyrrolidinone templates by an
intramolecular oxo-Diels–Alder reaction
William V. Murray,* Pranab K. Mishra, Sengen Sun and Amy Maden
Johnson & Johnson Pharmaceutical Research and Development LLC, 1000 Route 202, Raritan, NJ 08869, USA
Received 16 July 2002; revised 14 August 2002; accepted 15 August 2002
Abstract—Preparation of densely functionalized pyrrolidinone templates, is a challenge for synthetic chemists. These templates are
important building blocks for novel conformationally constrained natural products or for library generation of highly functional-
ized bi or polycyclic compounds. We discovered that trienes 6a–j undergo facile stereoselective intramolecular Diels–Alder
reactions to generate densely functionalized cis fused pyrrolidinone templates 1a–j. These reactions allow for directed remote
hydroxylation with complete control of stereochemistry. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Densely functionalized pyrrolidinone templates are a
challenge for the synthetic chemist. These templates are
important building blocks for library generation of
peptidomimetic compounds.1 An efficient way to
address this challenge is the intra-molecular Diels–
Alder (IMDA) reaction using appropriately designed
trienes.2 The IMDA reaction is often superior to the
intermolecular Diels–Alder reaction with regard to
reactivity and selectivity.1 The tether connecting the
diene and dienophile reactive partners could vary sub-
stantially.2a–d Herein we report the short, efficient entry
Trienes 6a–j were prepared in five steps from NH-Boc
protected
L-amino acids using a modification of our
amino acid derived triene preparation protocol.4 The
corresponding Weinreb amides 2a–e from the acids
were prepared in 87–92% yield via a mixed anhydride
using NMM, isobutyl chloroformate and N-methyl-N-
methoxy hydroxyl amine hydrochloride. The amides
2a–e then were reduced to the desired aldehydes 3a–e
by LAH at −78°C.5 The desired aldehydes were the
only isolated products in 80–85% yields. These alde-
hydes did not undergo racemization when stored briefly
at 4°C. On treatment of 3a–e with triethyl phospho-
noacetate in presence of potassium t-butoxide in THF
the unsaturated ester 4a–e were produced in 70–75%
yields without any detected racemization.6 The corre-
sponding amine derivatives were prepared by treatment
with 50% TFA, which were then benzylated using
CsCO3/BnBr in dry methylene chloride to afford the
products 5a–e in 76–82% yields. The triene precursors
6a–j were prepared by coupling of the requisite keto
acid to the N-benzyl protected unsaturated esters.
Compounds 5a–e in 80–84% yields. The intramolecular
Diels–Alder reactions of 6a–j were carried out at reflux
in dry toluene. Unprotected (NH) containing trienes 6
did not produce any cycloaddition products after reflux
in toluene for 72 h and slowly decomposed when
refluxed over a longer period of time. Although there
are four possible isomers only the cis fused isomers 1a–j
were isolated. It appears that the intramolecular Diels–
Alder reaction of these trienes proceeds with exo-selec-
tivity to give the cis-fused pyrrolidinone templates.
into
a class of complex pyrrolidinone templates
(Scheme 1).
Recently we have utilized electrocyclic reactions of
amino acid derived trienes to produce densely function-
alized octahydroquinolines and hexahydroisoindoles.2a,b
The chemistry is also adaptable to solid support and
has been used to generate libraries of considerable
complexity. These Diels–Alder reactions are carried out
in solution or on solid support and allow for the
control of facial selectivity, endo versus exo selectivity
and stereochemical selectivity at most of the ring posi-
tions. Based on this work we began to examine oxo-
Diels–Alder
reactions
to
generate
remotely
hydroxylated pyrrolidinone analogs.3
Keywords: intramolecular hetero Diels–Alder reaction; remote
hydroxylation; pyrrolidinone.
* Corresponding author. E-mail: wmurray@prdus.jnj.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01711-2

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W. V. Murray et al. / Tetrahedron Letters 43 (2002) 7389–7392
Scheme 1. Reagents and conditions: (a) IBCF, NMM, Me–N(OMe)H·HCl, CH2Cl2; (b) LAH, THF, −78°C; (c) KtBuO−, triethyl
phosphonoacetate, THF; (d) 50% TFA, rt; (e) CsCO3, BnBr, CH2Cl2; (f) 3-acetyl acrylic acid or 3-benzyl acrylic acid, HOAT,
EDCI, 0°C.
Compounds 1a–j slowly undergo hydrolysis at room
temperature in wet toluene to produce the hydroxy-
acetic acid, ethyl ester derivative of pyrrolidinones 7a–j.
Stereochemical assignments at the pyrrolidinone rings
1a–f at the alkyl and ester branched centers were made
based on two-dimensional NMR experiments.
C-4 and C-5 is 2.5 Hz, which is consistent with the
orientation shown. Based on this data we believe that
the ring junction is cis with the protons at C-3 and C-4
coming out of the plane of the page. We also believe
that both the amino acid R group and the ester are on
the same face of the molecule as the ring protons. Since
a single diastereomer is produced by this approach we
have been unable to compare the products produced
with the other possible isomers.8 Work is continuing to
establish conditions for other isomeric products.
Initially, COSY experiments were used to locate the
position of the different protons. The protons at the 5-
and 6-positions overlapped with each other in deuter-
ated chloroform, but they were resolved in acetonitrile.7
A series of NOESY experiments followed by HMBC
and HMQC were then carried out. These experiments
helped determine the relative stereochemistry of each
ring positions.
We believe our synthetic protocol will give versatile
access to a wide range of pyrrolidinone analogs, allow-
ing the synthesis of a novel class of conformationally
restricted polycyclic compounds both on and off the
solid support.
We observed
a strong transfer of magnetization
between protons at the 4- and 3-positions (Fig. 1,
structure 1). The proton at the 4- and 3-positions also
had strong transfer of magnetization with the benzylic
protons of the amino acid moiety. No transfer of
magnetization was observed between the proton at the
5-position and the proton at the 3-position. No NOE
was also observed between the protons at the 4-position
and the benzylic protons of the benzyl group attached
to the nitrogen. In each case the coupling constant
between the protons at C-3 and C-4 is 8.0 Hz which is
consistent with cis ring juncture. The coupling constant
between the protons at C-4 and C-6 is 8.6 Hz and is
consistent with the ester group in the orientation
shown. The coupling constant between the proton on
Preparation of 1a: The triene (0.181 g, 0.44 mmol) was
dissolved in dry toluene (8 mL). The reaction mixture
was refluxed for 16 h. The residual toluene was then
removed in vacuo. After chromatography 1a (0.164g,
0.40 mmol, 91%) was isolated by eluting the desired
compound with 10–20% EtOAc/CH2Cl2. 1H NMR
(CDCl3, 300 MHz) l: 1.20 (t, J=7.14, 3H), 1.85 (s,
3H), 2.48 (ddd, J=3.41, 8.6 Hz, 1H), 2.65 (m, J=
13.82, 3.41, 1H), 2.85 (m, 1H), 3.05 (dd, J=13.82, 4.27,
1H), 3.52 (m, 2H), 3.95 (q, J=7.16, 2H), 4.01 (d,
J=14.82, 1H), 4.85 (d, J=4.27, 1H), 5.15 (d, J=14.82,
1H), 7.01–7.42 ( m, 10H). 13C NMR (CDCl3, 75 MHz),
d: 14.3, 20.1, 37.5, 37.8, 38.7, 44.9, 58.2, 61.8, 73.8,
94.4, 127.5, 128.2, 128.6, 129.2, 129.3, 129.6, 136.3,

W. V. Murray et al. / Tetrahedron Letters 43 (2002) 7389–7392
7391
Figure 1. IMDA products from the triene precursors.
136.6, 152.3, 169.6, 174.1 The LC/MS calculated: 405.2
found (M+H)+=406.2, found (M+Na)+=428.2,
HRFABMS (M+H)+ calculated=405.2011, found
405.2018; [h]2D0 +58 (c 0.10, CHCl3).
Y.; Green, M. A.; Bergstrom, D. E. J. Comb. Chem. 2000,
2, 297 and references 2–9 therein; (d) Polyak, F.; Lubell,
W. D. J. Org. Chem. 2001, 66, 1171; (e) Feng, Z.; Lubell,
W. D. J. Org. Chem. 2001, 66, 1181.
2. For synthesis of other hydroisoquinone and hydroisoin-
dole derivatives via Diels–Alder reactions, see: (a) Guitier-
rez, A. J.; Shea, K. J.; Svoboda, J. J. J. Org. Chem. 1989,
54, 4335; (b) Moriwake, T.; Hmano, S.; Saito, S.; Torii, S.;
J. Org. Chem. 1989, 54, 4114; (c) Martin, S.; Williamson,
S. A.; Gist, R. P.; Smith, K. M. J. Org. Chem. 1983, 48,
5170; (d) Guy, A.; Lemaire, M.; Negre, M.; Guette, J. P.
Tetrahedron Lett. 1985, 26, 3575; (e) Takeuchi, H.; Fuji-
moto, T.; Hshino, K.; Motoyoshia, J.; Kakehi, A.;
Yamamoto, I. J. Org. Chem. 1998, 63, 7172.
3. For synthesis of 6,5 fused systems via oxo Diels–Alder
reactions, see: Tietze, L. F.; Beifuss, U.; Ruthe, M.;
Ruhlmann, A.; Antel, J.; Sheldrick, G. M. Angew. Chem.,
Int. Ed. 1988, 27, 1186–1187; Tietze, L. F.; Bachmann, J.;
Scul, W. Angew. Chem., Int. Ed. 1988. 27, 971–973.
4. (a) Murray, W. V.; Sun, S.; Turchi, I. J.; Brown, F. K.;
Gauthier, A. D. J. Org. Chem. 1999, 64, 5930; (b) Sun, S.;
Turchi, I. J.; Murray, W. V. J. Org. Chem. 2000, 65, 2555;
(c) Sun, S.; Murray, W. V. J. Org. Chem. 1999, 64, 5941.
5. Synthesis of amino aldehydes and their stability, see: (a)
Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.;
Lanman, B. A.; Kwon, S. Tetrahedron Lett. 2000, 41,
1359–1362; (b) Myers, A. G.; Kung, D. W.; Zhong, B. J.
Am. Chem. Soc. 2000, 122, 3226. J. Chem. Soc., Chem.
Preparation of 7a: The cycloaddition product 1a (0.11g,
27 mmol) was dissolved in toluene (5 mL) and water
(0.5 mL). The reaction mixture was stirred for 16 h.
The residual toluene/H2O was then removed in vacuo.
After chromatography 7a (0.089 g, 0.21 mmol, 78%)
was isolated by eluting the desired compound with 20%
1
EtOAc/CH2Cl2. H NMR (CDCl3, 300 MHz) l 1.21 (t,
J=7.12, 3H), 1.75–1.85 (m, J=13.70, J=3.31, 1H),
1.98 (s, 3H), 2.30 (m, 1H), 2.55 (dd, J=13.75, J=3.41,
1H), 2.70–2.98 (m, 2H), 3.31 (bs, OH), 3.60 (m, 2H),
3.90 (m, 1H), 4.10 (m, 2H), 4.15 (d, J=14.90, 1H),
5.00–5.10 (d, J=14.90, 1H). 6.85–7.50 (m, 10H). 13C
NMR (CDCl3, 75 MHz) l: 22.7, 29.3, 30.0, 37.5, 38.6,
43.8, 44.8, 59.1, 62.1, 71.1, 126.7, 127.0, 127.5, 127.7,
128.0, 128.5, 128.7, 129.1, 129.9, 135.9, 136.3, 138.6,
173.1, 175.0, 207.3. LC/MS calculated: 423.2, found
423.2, and (M+Na)+=446.2. [h]D20 +78 (c 0.32, CHCl3).
References
1. (a) Boger, D. L. Tetrahedron 1983, 39, 2869; (b) Dessi-
moni, G.; Tacconi, G. Chem. Rev. 1975, 75, 651; (c) Guan,

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by chiral HPLC.
Commun. 1993, 18 1463–1464 and Chem. Lett. 1990, 11,
7. While protons on C-5 and C-6 were resolved they were too
close to accurately observe NOEs between them.
8. By chiral HPLC.
2043–2046.
6. Compounds 4a–c were compared to identical compounds
from racemic aldehyde and no racemization was detected