An intramolecular oxo Diels-Alder approach to 1-oxo-1,2,3,3a,4,7a- hexahydro-pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl esters

Article abstract of DOI:10.1016/j.tet.2003.04.007

The diastereoselective synthesis of a series of 1-oxo-1,2,3,3a,4,7a- hexahydro-pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl esters via an oxo Diels-Alder reaction is described. Ab initio calculations predicted the products of the exo cycloaddition to be the thermodynamic products while the products resulting from the endo cycloaddition were predicted to be the kinetic products. The calculations were born out by experimental data.

Full text of DOI:10.1016/j.tet.2003.04.007

Tetrahedron 59 (2003) 8955–8961
An intramolecular oxo Diels–Alder approach to
1-oxo-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-carboxylic
acid ethyl esters
*
William V. Murray, Pranab K. Mishra, Ignatius J. Turchi, Dorota Sawicka, Amy Maden
and Sengen Sun
Johnson & Johnson Pharmaceutical Research & Development LLC, 1000 Route 202, Box 300, Raritan, NJ 08869, USA
Received 14 March 2003; accepted 2 April 2003
Abstract—The diastereoselective synthesis of a series of 1-oxo-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl esters
via an oxo Diels–Alder reaction is described. Ab initio calculations predicted the products of the exo cycloaddition to be the thermodynamic
products while the products resulting from the endo cycloaddition were predicted to be the kinetic products. The calculations were born out
by experimental data.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
While experimentally we observed that the intramolecular
Diels–Alder reaction of these trienes proceeded with
complete exo-selectivity to give the cis-fused pyrrolidinone
templates, calculations5 at the B3LYP/6-31G(d)//B3LYP/
6-31G(d) level of theory6 suggested that the trans isomers 2
and 3 are the kinetic products of the reaction and the cis
isomer 4 can be formed via an isomerization of the trans
isomers. The activation energies leading to the trans
isomers 2 and 3 are 24.3 and 24.9 kcal/mol, respectively,
while those for the cis isomers 4 and 5 are both 28.4 kcal/
mol. The calculated heats of reaction leading to 2 and 3 are
29.3 and 29.1 kcal/mol, respectively, while those for 4
and 5 are 217.4 and 214.7 kcal/mol (Fig. 1). While the
calculations agree with our observations and predict that the
observed cis product 4 is the thermodynamic product, we
felt it would be reasonable to try to isolate a kinetic product.
The synthesis of functionalized pyrrolidine templates is a
good entry point to the synthesis of peptidomimetic
libraries.1 We recently communicated the synthesis of a
series densely functionalized pyrrolidines 1 using the
intramolecular oxo Diels–Alder reaction.2,3 These Diels–
Alder reactions allowed for the control of facial selectivity,
and complete exo selectivity affording the cis fused 5,6
system 1. Our previous work on analogous carbon Diels–
Alder reactions afforded endo selective reactions which
yielded a trans ring junction in our 5,6 systems. As in all
previous studies the oxo case proceeded with complete
facial selectivity.4 The selectivity is derived from the R
group on the carbon alpha to the amino group initially
originating from the alpha amino acid precursor. The
complete exo selectivity of this reaction was intriguing and
led us to further examine this system. We initially decided to
carry out ab initio calculations on this Diels–Alder reaction.
The intermediate triene 7 was synthesized as described
previously (Scheme 1).2 We then carried out the intra-
molecular Diels–Alder reactions of 7a-j at reflux in
benzene. Previously reflux of 7a-j in toluene produced
only 9a-j with the cis ring juncture shown. The compounds
resulting from (7a-j) reflux in benzene 8a-j, had the trans
fused ring juncture (Fig. 2). Both reactions proceed with
complete facial selectivity. The phenylalanine derivatives 8
proceeded smoothly to the trans fused products but
decomposed at room temperature over time depending on
the substitution pattern. As 8a-j are predicted to be the
kinetic products, we attempted to convert the isolated trans
products 8a-j to the proposed thermodynamic products 9a-j
by refluxing them in toluene. We were not able to directly
convert 8 to 9 in the cases attempted. Once isolated the
Keywords: Diels–Alder; pyrrolidine templates; diastereoselective
synthesis.
*
Corresponding author. Tel.: þ1-908-704-4375; fax: þ1-908-722-3420;
e-mail: wmurray@prdus.jnj.com
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.04.007

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W. V. Murray et al. / Tetrahedron 59 (2003) 8955–8961
Figure 1.
compounds are relatively labile to an undetermined
oxidative decomposition mechanism which bleeds off
product. These compounds 8a-j, however, could be stored
in benzene under argon at 2208C.
case. With 2 ring juncture isomers of each template in hand,
structural assignments were made based on two-dimen-
sional NMR experiments. COSY experiments were used to
locate the position of different protons as previously
described.2 The resolution in deuterated chloroform was
not satisfactory in all cases so the NMR studies were carried
out in deuterated acetonitrile or toluene to further resolve
NOE, HMBC, HMQC and HETCOR experiments were
utilized to prove the stereochemistry of the isomers in each

W. V. Murray et al. / Tetrahedron 59 (2003) 8955–8961
8957
Scheme 1.
H5. This again is consistent with the relative stereochem-
istry shown in structure 9d. With this data in hand the rest of
the compounds could be assigned by comparison of
coupling constants.
We believe that we have demonstrated that the trans fused
products of the oxo Diels–Alder reaction in question are the
kinetic products of the reaction. While the products
themselves are interesting it is clear that any analogs of
these compounds will be more difficult to handle than the cis
fused products. This may limit the utility of the trans fused
compounds as inputs for library generation.
2. Experimental
2.1. General methods
All reactions were carried out in an atmosphere of dry
nitrogen at room temperature unless otherwise stated.
Reaction temperatures other than room temperature were
1
recorded as bath temperature unless otherwise stated. H
NMR and 13C NMR were recorded on 300, 400 MHz
spectrometers (300 or 400 MHz 1H NMR, respectively, and
75 or 100 MHz 13C NMR, respectively) in deuteriochloro-
1
form (CDCl3) with chloroform (d 7.26 ppm H, d 77 ppm
13C) as the internal standard unless otherwise stated.
All non-aqueous reactions were carried out in an atmo-
sphere of dry nitrogen at room temperature unless otherwise
stated. All solvents were purchased from commercial
sources and were used without further purification. TLC
were performed on glass baked plates coated with silica gel
60 with an F 254 indicator. The chromatograms were
visualized under UV light and/or by staining with
phosphomolybdic acid (20% solution in ethanol). Flash
column chromatography was performed with 40–60 mm
silica gel (Merck).
Figure 2.
adjacent peaks. A series of NOESY experiments followed
by HMBC and HMQC were then performed.
The NOE studies are best exemplified by comparing 8d to
9d (Fig. 3). In 8d there is a strong NOE between H6 to H3
indicating they are on the same face of the molecule.
There is no observable NOE between H4 and H3. There is a
NOE between H3 and H5 again indicating they are on the
same face and finally there is no observable NOE between
H4 and H5. This data is consistent with the relative
stereochemistry shown in structure 1.7 We irradiated
structure 9d and found a strong NOE between H4 and H3
indicating they are on the same face of the molecule. We
were unable to resolve H5 and H3 enough to irradiate either
peak. Finally we observed a strong NOE between H6 and
2.2. Procedure for chiral HPLC
The enantiomeric purity of the compounds 6a-e checked by
comparing with corresponding racemic compounds via
chiral HPLC separation techniques using the following
conditions: Instrument: Agilent Technologies 1100 series.
Solvent system: 0.1% TEA/MeOH, column: Chiralcel AD-
RH, flow rate of 1 mL/min. Retention time for racemic

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W. V. Murray et al. / Tetrahedron 59 (2003) 8955–8961
O
O
6
6
H
H
O
O
O
O
4
H
4
5
H
8
8
10
10
9
9
5
11
11
2
3
H
N
3
H
N
12
12
O
O
8d
9d
Figure 3.
compound: 4.056 and 4.421 min. The retention time for the
L-amino acid derived compound 4.413 min. Back pressure:
22 bar.
(3.5 g, 10.9 mmol) was added 25 mL of TFA in CH2Cl2
(1:1) at 08C and stirred at room temperature for 30 min. The
excess methylene chloride and TFA was evaporated by
solvent exchange with chloroform (4 iterations). The
compound was then dissolved in dry methylene chloride
again (50 mL) and cooled to 08C. BnBr (2.8 g, 16.4 mmol)
and CsCO3 (10.7 g, 32.91 mmol) was added. The solution
was stirred for 12 h while slowly warming to room
temperature. The reaction mixture was then again cooled
to 08C and ice-cold water (150 mL) was added. The reaction
mixture was then extracted with methylene chloride
(3£50 mL). The combined organic layers were washed
with brine, dried over NaSO4 and filtered. The solvent was
then removed. Flash chromatography using a gradient of
10–20% EtOAc/hexane gave the desired compound (2.7 g,
81%) as an oily liquid. 1H NMR d: 1.26 (t, J¼7.2 Hz, 3H),
2.79 (ABX, J¼5.7, 12 Hz, 2H), 3.47 (m, J¼6.3 Hz, 1H),
3.56 (AB, J¼13.8 Hz, 2H), 4.18 (m, J¼7.2 Hz, 2H), 5.90
(d, J¼15 Hz, 1H), 6.86 (dd, J¼15.6, 7.5 Hz, 1H), 7.27
(m, 10H).
2.3. LC/MS conditions
The LC/MS data were collected by using the following
conditions: solvents are A: H2Oþ0.5% TFA, B:
CH3CNþ0.5% TFA, The gradient method was 5–100% B
over 3.7 min, hold at 100% B for 0.5 min. Return to 5% B
over 0.4 min. The total runtime is 4.6 min. The flow rate is
0.450 mL/min. Column: Zorabax Bonus-RP 5 mm
2.1£50 mm. Instrument: Agilent technologies: 1100
LC/MSD using ESI.
2.4. General procedure for preparation of amino acid
derived N-Bn protected unsaturated esters: 4-benzyl
amino-5 phenyl-pent-2-enoic acid ethyl ester 6a
To a solution of the Boc-protected phenylalanine ester

W. V. Murray et al. / Tetrahedron 59 (2003) 8955–8961
8959
13C NMR, (75 MHz, CDCl3) d: 21.4, 42, 51.7, 60.1, 60.7,
122.5, 127.3, 128.3, 128.7, 128.9, 129.7, 140.3, 150.5,
166.7. LC/MS calculated for C20H23NO2 (MHþ): 310,
found 310.
2.5.4. 4[Benzyl-(4-oxo-4-phenyl-but-2-enoyl)amino]-5-
methylhex-2-enoic acid ethyl ester 7d. The title compound
was isolated in 72% yield as a yellow oil. 1H NMR: 0.82 (d,
3H, J¼7.3 Hz), 0.90 (d, 3H, J¼7.25 Hz), 1.30 (t, 3H,
J¼7.25 Hz), 1.98–2.15 (m, 1H, J¼7.1 Hz), 2.45 (dd, 1H,
J¼10.2, 2.5 Hz), 3.05 (dd, 1H, J¼2.8, 12.6 Hz), 3.45 (dd,
1H, J¼2.24, 9.6 Hz), 3.95 (d, 1H, J¼15.5 Hz), 4.15–4.38
(m, 2H), 4.70 (d, J¼10.9 Hz), 5.30 (d, 1H, J¼15.43 Hz),
6.05 (d, J¼2.9 Hz), 7.05–7.65 (m, 10H). 13C NMR: 17.3,
27.1, 40.6, 42.6, 44.5, 61.6, 63.8, 79.4, 96.5, 124.7, 127.5,
127.7, 128.2, 128.5, 134.4, 136.4, 151.7, 169.7, 172.9.
HRMS calculated for: C26H29NO4 (MHþ) 420.2175, found
420.2183.
2.5. General procedure for the preparation of amino
acid derived trienes
2.5.1. 4-[Benzyl-(4-oxo-pent-2-enoyl)-amino]-5-phenyl-
pent-2-enoic acid ethyl ester 7a. To a stirred solution of
the N-benzyl protected unsaturated ester (0.167 g,.54 mmol)
in dry DMF (15 mL), was added at 08C (.31 g, 1.63 mmol)
EDCI, followed by HOAT (.22 g, 1.63 mmol), and 3-acetyl
acrylic acid (.185 g, 1.63 mmol). The reaction mixture was
stirred overnight (14 h) slowly warming from 08C to room
temperature. The reaction mixture was then quenched with
ice-cold water (100 mL) and was extracted with diethyl
ether (3£50 mL). The combined ether layer was washed
with water (3£20 mL) and saturated brine solution
(1£20 mL). The organic layer was then dried over NaSO4
and concentrated under vacuum to give a yellow liquid. On
chromatography using 20–40% EtOAc/hexane a pure
compound was isolated (.182 g) in 82% yield as a yellow
foam.
2.5.5. (3S,3aR,4S,7aR) 2,3-Dibenzyl-6-methyl-1-oxo-
1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-car-
boxylic acid ethyl ester 9a. The triene (0.181 g,
0.45 mmol) was dissolved in dry toluene (8 mL). The
reaction mixture was refluxed for 16 h. The residual toluene
was then removed in vacuo. The title compound was
isolated by eluting with 10–20% EtOAc/CH2Cl2. to afford a
1
yellow foam (0.164 g, 0.40 mmol), yield 91%. H NMR
(CDCl3, 300 MHz) d: 1.20 (t, J¼7.14 Hz, 3H), 1.85 (s, 3H),
2.48 (ddd, J¼3.41, 8.6 Hz, 1H), 2.65 (m, J¼13.82, 3.41 Hz,
1H), 2.85 (m, 1H), 3.05 (dd, J¼13.82, 4.27 Hz, 1H), 3.52
(m, 2H), 3.95 (q, J¼7.16 Hz, 2H), 4.01 (d, J¼14.82 Hz,
1H), 4.85 (d, J¼4.27 Hz, 1H), 5.15 (d, J¼14.82 Hz, 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, 136.6, 152.3,
169.6, 174.1. HRMS calculated for: C25H27NO4 (MH)þ
406.2018, found 406.2018; [a]2D0¼þ58 (c 0.10, CHCl3).
1H NMR d: 1.12 (t, J¼7.24 Hz, 3H), 2.21 (s, 3H), 2.85–3.25
(m, 2H), 4.05 (q, J¼7.24 Hz), 4.10–4.50 (AB, J¼18.6 Hz),
4.85 (m, 1H), 5.65 (d, J¼14.26 Hz, 1H), 6.53–7.35 (m,
12H). 13C NMR d: (CDCl3): 21.4, 29.3, 38.1, 50.9, 59.8,
60.7, 61.1, 123.6, 123.8, 127, 127.2, 127.6, 127.9, 128.3,
128.8, 129.0, 129.4, 132.2, 136.7, 138.5, 144.9, 165.6,
166.9, 197.7. LC/MS calculated for: C25H27NO4 (MHþ)
406.2018, found 406.2027.
2.5.6. (3S,3aR,4S,7aS) 2,3-Dibenzyl-6-methyl-1-oxo-
1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-car-
boxylic acid ethyl ester 8a. The triene (0.158 g,
0.39 mmol) was dissolved in dry benzene (8 mL). The
reaction mixture was refluxed for 7 h. The residual benzene
was then removed in vacuo. The title compound was
isolated by eluting with 10–20% EtOAc/CH2Cl2 to afford a
yellow oil (0.137 g, 0.34 mm) yield 87%. 1H NMR (CDCl3,
300 MHz) d: 1.25 (t, J¼7.10 Hz, 3H), 1.68 (s, 3H), 2.10 (m,
J¼3.41, 10.58 Hz, 1H), 2.65 (m, J¼13.82, 3.41 Hz, 1H),
2.85 (m, 1H), 3.05 (dd, J¼10.82, 4.27 Hz, 1H), 3.52 (m,
2H), 3.00–3.25 (m, 2H), 3.90 (d, J¼13.90 Hz, 1H), 4.05 (m,
2H), 4.25 (m, 1H), 5.05 (d, J¼13.9 Hz, 1H), 5.75 (d,
J¼10.57 Hz, 1H), 6.56–8.51 (m, 10H, J¼7.16 , 2H), 4.01
(d, J¼14.82 Hz, 1H), 4.85 (d, J¼4.27 Hz, 1H), 5.15 (d,
J¼14.82 Hz, 1H), 7.01–7.42 (m, 10H). HRMS calculated
for: C25H27NO4 (MH)þ 406.2018, found 406.2006.
2.5.2. 4[Benzyl-(4-oxo-4-phenyl-but-2amino]-5-phenyl-
pent-2-enoic acid ethyl ester 7b. To the chilled solution
(08C) of N-benzyl ester (0.247 g, 0.79 mmol) dissolved in
dry DMF (20 mL) was added EDCI (0.53 g, 2.79 mmol),
followed by HOAT (0.37 g, 2.79 mmol), and 3-benzyl
acrylic acid (0.49 g, 2.79 mmol). The reaction mixture was
stirred at room temperature for 19 h. Then the reaction
mixture was again cooled down to 08C and 100 mL water
was added. The crude reaction mixture was then extracted
with diethyl ether (3£25 mL). The combined organic layer
was further washed with water again followed by brine. It
was dried over NaSO4 and solvent was removed in vacuo.
The crude compound was then used immediately in next
step to carry out the cyclization. LC–MS calculated for:
C30H29NO4 (MHþ) 468, found 468.
2.5.3. 4[Benzyl-(4-oxo-4-phenyl-pent-2-enoyl)-amino]-5-
methylhex-2-enoic acid ethyl ester 7c. The title compound
was prepared as described for 7b and was isolated in 81%
2.5.7. (3S,3aR,4S,7aR) 2,3-Dibenzyl-1-oxo-6-phenyl-
1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-car-
boxylic acid ethyl ester 9b. The crude compound was
dissolved in toluene and was refluxed for 16 h to isolate the
desired compound after chromatography using 30% EtOAc/
hexane, in 85% yield as an off white foam. 1H NMR
(CDCl3, 300 MHz) d: 1.21 (t, J¼7.12 Hz, 3H), 2.65 (ddd,
J¼14.82, 3.41 Hz, 1H), 3.05 (dd, J¼7.95, 3.41 Hz, 1H),
3.35 (m, J¼14.82, 3.62 Hz, 1H), 3.65 (J¼7.95, 3.62 Hz,
1H), 3.75 (m, 1H), 4.05–4.30 (m, 3H), 5.11 (d, J¼14.94 Hz,
1H), 5.55 (d, J¼4.32 Hz, 1H), 7.05–7.70 (m, 15H). 13C
NMR (CDCl3, 75 MHz), d: 27.6, 37.8, 42.5, 45.6, 53.0,
1
yield as a yellow oil. H NMR: 0.80 (d, 3H, J¼5.07 Hz),
0.85 (d, 3H, J¼5.21 Hz), 1.15 (t, 3H, J¼7.15 Hz), 1.97 (s,
3H), 2.01 (m, 1H), 2.55 (dd, 1H, J¼8.55, 2.11 Hz), 3.11 (m,
1H), 3.25 (m, 1H), 3.80 (d, 1H, J¼9.56 Hz), 3.86 (d,
J¼14.82 Hz), 4.25 (m, 2H, J¼7.15 Hz), 4.99 (d, 1H,
J¼4.39 Hz), 5.11 (d, 1H, J¼14.81 Hz), 7.15–7.41 (m,
5H). 13C NMR: 16.1, 18.7, 20.0, 28.5, 33.1, 39.1, 44.6, 61.7,
61.8, 75.4, 95.0, 128.0, 128.6, 129.1, 130.2, 136.3, 152.4,
169.9, 174.1. HRMS calculated for: C21H27NO4 (MHþ)
358.2018, found 358. 1999.

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W. V. Murray et al. / Tetrahedron 59 (2003) 8955–8961
59.5, 67.9, 69.3, 95.8, 124.0, 125.3, 125.6,125.7, 126.2,
126.8, 126.9, 127.2, 127.5, 132.2, 133.2, 133.5, 152.2,
166.7, 171.7. HRMS calculated for: C30H29NO4 467.2097
(Mþ), found 467.2096; [a]D20¼235 (c 0.25, CHCl3).
2.5.12. (3S,3aR,4S,7aR) 2-Benzyl-3-isopropyl-1-oxo-6-
phenyl-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-
carboxylic acid ethyl ester 9d. The title compound was
prepared as described for 1b and was isolated as a yellow oil
1
in 77% yield. H NMR: 0.87 (dd, J¼7.10, 6.93 Hz, 6H),
2.5.8. (3S,3aR,4S,7aS) 2,3-Dibenzyl-1-oxo-6-phenyl-
1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-car-
boxylic acid ethyl ester 8b. The title compound was
prepared as before and was isolated in as a yellow oil in 78%
yield. 1H NMR: 1.25 (t, J¼7.25 Hz, 3H), 2.35 (dd, J¼8.64,
2.35 Hz, 1H), 2.85 (dd, J¼8.67, 2.41 Hz, 1H), 3.15 (m,
J¼10.42 Hz, 2H), 4.00 (m, 1H), 4.05 (d, J¼14.41 Hz, 1H),
4.15–4.45 (m, J¼7.21 Hz, 2H), 4.90 (d, J¼10.52 Hz, 1H),
5.13 (d, J¼14.41 Hz, 1H), 5.95 (m, 1H), 6.85–7.75 (m,
15H). HRMS calculated for: C30H29NO4 468.2175 (MHþ),
found 468.2166.
1.18 (t, J¼7.14 Hz, 3H), 2.11 (m, 1H), 2.70 (dd, J¼2.70,
8.43, 1 Hz), 3.31 (m, 2H), 3.85 (d, J¼14.81 Hz, 1H), 4.00
(d, J¼8.76 Hz, 1H), 4.15 (q, J¼7.12 Hz, H), 5.11 (d,
J¼14.88 Hz, 1H), 5.81 (d, J¼4.47 Hz, 1H), 7.18–7.64 (m,
5H). 13C NMR: 15.6, 18.4, 28.1, 33.4, 39.4, 44.3, 61.3, 61.6,
75.5, 96.0, 125.0, 127.7, 128.1, 128.2, 128.7, 134.2, 135.8,
152.4, 169.4, 173.3. HRMS calculated for: C26H29NO4
(MH)þ 420.2175, found: 420.2174.
2.5.13. (3S,3aR,4S,7aS) 2-Benzyl-3-(1-benzyl-1H-indol-
3-ylmethyl)-6-methyl-1-oxo-1,2,3,3a,4,7a-hexahydro-
pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl ester 8e.
The title compound was isolated as a yellow gum in 66%
yield. 1H NMR: 0.99 (t, J¼7.24 Hz, 3H), 2.42 (AB, J¼5.45,
10.55 Hz, 1H), 3.05 (ABX, J¼14.6 Hz, 1H), 3.98 (q, J¼
7.24 Hz, 2H), 4.65 (d, J¼15.82 Hz, 1H), 4.92 (d, J¼
15.82 Hz, 1H), 7.02–7.65 (m, 14H). HRMS calculated for:
C34H34NO4 (MH)þ 535.2597, found: 535.2566.
2.5.9. (3S,3aR,4S,7aS) 2-Benzyl-3-isopropyl-6-methyl-1-
oxo-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-
carboxylic acid ethyl ester 8c. The title compound was
prepared as described for 1b and was isolated in 81% yield
as a beige foam. 1H NMR: 0.81 (d, J¼7.19 Hz, 3H), 0.91–
0.95 (d, J¼7.16 Hz, 3H), 1.31 (t, J¼7.16 Hz, 3H), 1.81 (s,
3H), 1.92 (m, J¼5.60, 7.16 Hz, 1H), 2.31–3.42 (m,
J¼10.24, 12.45 Hz, 1H), 2.87 (m, J¼12.48 Hz, 1H), 3.35
(d, J¼9.87 Hz), 1H), 3.89 (d, J¼15.03 Hz, 1H), 4.05–4.35
(m, 2H), 4.58 (d, J¼10.59 Hz), 5.16 (s, 1H), 5.18 (d,
J¼15.06 Hz, 1H), 6.99–7.35 (m, 5H). 13C NMR: 15.2, 18.0,
19.2, 20.7, 28.6, 41.8, 43.7, 45.9, 62.8, 64.5, 80.3, 96.0,
128.7, 129.9, 129.2, 130.0, 130.2, 137.7, 152.6, 171.2.
HRMS calculated for: C21H27NO4 (MH)þ 358.2018, found
358.2022.
2.5.14. (3S,3aR,4S,7aR) 2-Benzyl-3-(1-benzyl-1H-indol-
3-ylmethyl)-6-methyl-1-oxo-1,2,3,3a,4,7a-hexahydro-
pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl ester 9e.
The title compound was isolated as a yellow foam in 72%
yield. 1H NMR: 0.99 (t, J¼7.24 Hz, 3H), 1;.82 (s, 3H), 2.42
(AB, J¼5.45, 10.55 Hz, 1H), 3.75 (ABX, J¼14.6 Hz, 1H),
3.99 (q, J¼7.24 Hz, 2H), 4.75 (d, J¼15.82 Hz, 1H), 4.97 (d,
J¼15.82 Hz, 1H), 5.20 (s, 2H), 7.02–7.65 (m, 14H). HRMS
calculated for: C34H34NO4 (MH)þ 535.2597, found:
535.2606.
2.5.10. (3S,3aR,4S,7aR) 2-Benzyl-3-isopropyl-6-methyl-
1-oxo-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-
carboxylic acid ethyl ester 9c. The title compound was
prepared as described for 1b and was isolated in 87% yield
2.5.15. (3S,3aR,4S,7aS) 2-Benzyl-3-benzyloxycarbonyl-
methyl-1-oxo-6-phenyl-1,2,3,3a,4,7a-hexahydro-
pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl ester 8f.
The title compound was isolated as a yellow oil in 49%
1
as an off white foam. H NMR: 0.80 (d, 3H, J¼7.20 Hz,
3H), 0.85 (d, J¼7.20 Hz, 3H), 1.15 (t, J¼7.15 Hz, 3H), 1.97
(s, 3H), 2.02 (m, 1H), 2.55 (dd, J¼8.42, 2.0 Hz, 1H), 3.11
(m, 1H), 3.25 (m, 1H), 3.80 (d, J¼8.45 Hz, 1H), 3.86 (d,
J¼15.5 Hz, 1H), 4.25 (m, 2H), 4.99 (d, 1H, J¼2.9 Hz, 1H),
5.11 (d, J¼15.50 Hz, 1H), 7.15–7.41 (m, 5H). 13C NMR:
16.1, 18.7, 20.0, 28.5, 33.1, 39.1, 44.6, 61.7, 61.8, 75.4,
95.0, 128.0, 128.6, 129.1, 130.2, 136.3, 152.4, 169.9, 174.1.
HRMS calculated for C21H27NO4: (MH)þ 358.2018, found
358.2005.
1
yields. H NMR: 1.32 (m, J¼7.21 Hz, 3H), 2.30–2.55 (m,
2H), 3.05–3.25 (m, J¼12.76 Hz, 1H), 3.85 (m, J¼12.65 Hz,
1H), 4.00–4.25 (m, 2H), 4.70–5.00 (m, 2H), 5.85 (m, 1H),
5.89 (m, 1H), 6.99–7.68 (m, 10H). HRMS calculated for:
C32H31NO6 (MH)þ 526.2229, found 526.2220.
2.5.16. (3S,3aR,4S,7aR) 2-Benzyl-3-benzyloxycarbonyl-
methyl-1-oxo-6-phenyl-1,2,3,3a,4,7a-hexahydro-
pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl ester 9f.
The title compound was isolated as a yellow foam in 48%
2.5.11. (3S,3aR,4S,7aS) 2-Benzyl-3-isopropyl-1-oxo-6-
phenyl-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-
carboxylic acid ethyl ester 8d. The title compound was
prepared as described for 1b and was isolated as an off
1
yields. H NMR: 1.52 (m, J¼7.20 Hz, 3H), 2.52 (dd, 1H,
J¼4.45 Hz, 1H), 2.81 (dd, J¼4.10 Hz, 1H), 2.85 (m, 1H),
3.35 (m, 1H), 3.85 (m, 1H), 3.99 (d, J¼15.2 Hz, 1H), 4.25
(m, 2H), 4.95 (d, J¼15.2 Hz, 1H), 5.05 (s, 2H), 5.75
(d, J¼4.21 Hz, 1H), 7.02–7.75 (m, 15H). 13C NMR: 37.0,
38.1, 38.6, 44.5, 54.3, 61.7, 66.9, 73.7, 95.3, 117.0, 122.9,
125.1, 127.8, 127.9, 128.2, 128.5, 128.6, 128.8, 130.5,
133.4, 134.2, 135.2, 135.7, 152.6, 169.3, 169.9. HRMS
calculated for: C32H31NO6 (MH)þ 526.2229, found
526.2231.
1
white foam in 70% yield. H NMR: 0.82 (d, J¼7.20 Hz,
3H), 0.90 (d, J¼7.25 Hz, 3H), 1.98–2.15 (m, J¼2.0,
7.12 Hz, 1H), 2.45 (dd, J¼10.2, 2.01 Hz, 1H), 3.05 (dd,
J¼2.8, 12.6 Hz, 1H), 3.45 (dd, J¼2.2, 9.6 Hz, 1H), 3.95 (d,
J¼15.5 Hz, 1H), 4.15–4.38 (m, 2H), 4.70 (d, J¼10.90 Hz,
1H), 5.30 (d, J¼15.3 Hz, 1H), 6.05 (d, J¼2.9 Hz, 1H),
7.05–7.65 (m, 10H). 13C NMR: 17.3, 27.1, 40.6, 42.6, 44.5,
61.6, 63.8, 79.4, 96.5, 124.7, 127.5, 127.7, 128.2, 128.5,
128.7, 128.8, 134.3, 136.4, 151.7, 169.7, 172.9. HRMS
calculated for: C26H29NO4 (MH)þ 420.2175, found:
420.2191.
2.5.17. (3S,3aR,4S,7aR) 2-Benzyl-3-methyl-1-oxo-6-
phenyl-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-
carboxylic acid ethyl ester 9g. The title compound was

W. V. Murray et al. / Tetrahedron 59 (2003) 8955–8961
8961
isolated as a pale yellow oil in 82% yield. 1H NMR: 0.98 (m,
2H), 1.20 (m, 3H), 2.00 (s, 3H), 2.65 (m, 1H), 3.25 (m, 1H),
3.35 (m, 1H), 3.85 (m, 1H), 3.95–4.25 (m, 2H), 4.32 (m,
1H), 4.89 (d, J¼14.89 Hz, 1H), 5.65 (d, J¼3.85 Hz), 7.05–
7.65 (m, 5H). 13C NMR: 18.1, 22.7, 29.3, 38.1, 41.1, 44.0,
53.0, 61.7, 72.6, 95.3, 125.3, 127.5, 127.7, 134.6, 136.0,
152.3, 169.7, 173.1; HRMS calculated for C24H25NO4
(MH)þ 392.1862, found 392.1857.
(s, 3H), 2.42 (AB, J¼5.45, 10.55 Hz, 1H), 3.75 (ABX,
J¼14.6 Hz, 1H), 3.99 (q, J¼7.24 Hz, 2H), 4.75 (d, J¼
15.82 Hz, 1H), 4.97 (d, J¼15.82 Hz, 1H), 5.20 (s, 2H),
7.02–7.65 (m, 14H). HRMS calculated for; C34H34NO4
(MH)þ 535.2597, found: 535.2606.
References
2.5.18. (3S,3aR,4S,7aS) 2-Benzyl-3-methyl-1-oxo-6-
phenyl-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-
carboxylic acid ethyl ester 8g. The title compound was
1. (a) Boger, D. L. Tetrahedron 1983, 39, 2869. Dessimoni, G.;
Tacconi, G. Chem. Rev. 1975, 75, 651. (b) Guan, Y.; Green,
M. A.; Bergstrom, D. E. J. Comb. Chem. 2000, 2, 297. and Refs.
2–9 therein. (c) Polyak, F.; Lubell, W. D. J. Org. Chem. 2001,
66, 1171. (d) Feng, Z.; Lubell, W. D. J. Org. Chem. 2001, 66,
1181.
1
isolated as a yellow oil in 78% yield. H NMR: 0.98 (m,
2H), 1.20 (m, 3H), 2.00 (s, 3H), 2.55 (m, 1H), 3.25 (m, 1H),
3.35 (m, 1H), 3.85 (m, 1H), 3.95–4.25 (m, 2H), 4.32 (m,
1H), 4.89 (d, J¼14.89 Hz, 1H), 5.65 (d, J¼3.85 Hz), 7.05–
7.65 (m, 5H). 13C NMR: 19.3, 30.0, 38.6, 43.5, 44.6, 53.3,
62.07, 72.6, 95.4, 128.0, 128.6, 129.1, 134.9, 137.0, 152.0,
169.8, 171.5. HRMS calculated for C24H25NO4 (MH)þ
392.1862, found 392.1885.
2. Murray, W. V.; Mishra, P. K.; Sun, S.; Maden, A. Tetrahedron
Lett. 2002, 43(41), 7389–7392.
3. For synthesis of 6,5 fused systems via oxo Diels Alder reactions
see: Tietz, L. F.; Beifus, U.; Ruthe, M.; Ruhlman, A.; Antel, J.;
Sheldrick, G. M. Angew. Chem. Int. Ed. 1988, 27, 1186–1187.
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. For synthesis of
other hydroisoquinone and hydroisoindole derivatives via
Diels–Alder reactios, see: (c) Guitierrez, A. J.; Shea, K. J.;
Svoboda, J. J. J. Org. Chem. 1989, 54, 4335. (d) Moriwake, T.;
Hmano, S.; Saito, S.; Torii, S. J. Org. Chem. 1989, 54, 4114.
(e) Martin, S.; Williamson, S. A.; Gist, R. P.; Smith, K. M.
J. Org. Chem. 1983, 48, 5170. (f) Guy, A.; Lemaire, M.; Negre,
M.; Guette, J. P. Tetrahedron Lett. 1985, 26, 3575. (g) Takeuchi,
H.; Fujimoto, T.; Hshino, K.; Motoyoshia, J.; Kakehi, A.;
Yamamoto, I. J. Org. Chem. 1998, 63, 7172.
2.5.19. (3S,3aR,4S,7aS) 2-Benzyl-3-(1-benzyl-1H-indol-
3-ylmethyl)-6-methyl-1-oxo-1,2,3,3a,4,7a-hexahydro-
pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl ester 8h.
The title compound was prepared directly from 6e without
intermediate isolation of 7 h and was isolated in 66% yield
1
as a yellow gum. H NMR: 0.99 (t, J¼7.24 Hz, 3H), 2.42
(AB, J¼5.45, 10.55 Hz, 1H), 3.05 (ABX, J¼14.6 Hz, 1H),
3.98 (q, J¼7.24 Hz, 2H), 4.65 (d, J¼15.82 Hz, 1H), 4.92 (d,
J¼15.82 Hz, 1H), 7.02–7.65 (m, 14H). HRMS calculated
for: C34H34NO4 (MH)þ 535.2597, found: 535.2566.
2.5.20. (3S,3aR,4S,7aR) 2-Benzyl-3-(1-benzyl-1H-indol-
3-ylmethyl)-6-methyl-1-oxo-1,2,3,3a,4,7a-hexahydro-
pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl ester 9h.
The title compound was prepared directly from 6e without
intermediate isolation of 7 h and was isolated in 72% yield
as a yellow foam. 1H NMR: 0.99 (t, J¼7.24 Hz, 3H), 1;.82
5. Jaguar; Schrodinger, Inc. 121 SW Morrison, Suite 1212,
Portland, OR 97204.
6. Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
7. Fujimoto, H.; Hshino, T.; Motoyoshia, K.; Kakehi, J.;
Yamamoto, I. J. Org. Chem. 1998, 63, 7172.