Tandem [4 + 2]/[3 + 2] Cycloadditions with Nitroethylene

Article abstract of DOI:10.1021/jo972280f

The simplest nitroalkene, nitroethylene, undergoes Lewis acid-promoted [4 + 2] cycloaddition with chiral vinyl ethers to afford cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with electron deficient alkenes to effect a face selective [3 + 2] cycloaddition. The origin of stereocontrol in the [3 + 2] cycloaddition is due to the single ring substituent, a remote acetal center. The scope and limitations of the use of nitroethylene as a 4π component in Lewis acid-promoted cycloadditions are documented and discussed. Additionally, concise syntheses of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine are presented.

Full text of DOI:10.1021/jo972280f

J . Org. Chem. 1998, 63, 3045-3050
3045
Ta n d em [4 + 2]/[3 + 2] Cycloa d d ition s w ith Nitr oeth ylen e
Scott E. Denmark* and Alexander R. Hurd
Roger Adams Laboratory, Department of Chemistry, University of Illinois Urbana, Illinois 61801
Received December 16, 1997
The simplest nitroalkene, nitroethylene, undergoes Lewis acid-promoted [4 + 2] cycloaddition with
chiral vinyl ethers to afford cyclic nitronates with high diastereoselectivity. The resulting cyclic
nitronates react with electron deficient alkenes to effect a face selective [3 + 2] cycloaddition. The
origin of stereocontrol in the [3 + 2] cycloaddition is due to the single ring substituent, a remote
acetal center. The scope and limitations of the use of nitroethylene as a 4π component in Lewis
acid-promoted cycloadditions are documented and discussed. Additionally, concise syntheses of
the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine are presented.
Sch em e 1
In tr od u ction
The scope and sythetic utility of the asymmetric,
tandem [4 + 2]/[3 + 2] cycloaddition of nitroalkenes have
been extensively documented in reports from these
laboratories.1,2 While a variety of substituted nitroal-
kenes have been employed in this sequence (2-monosub-
stituted and 2,2-disubstituted 1-nitroalkenes, and 2-sub-
stituted 2-nitroalkenes),3-5 the very reactive nitroethyl-
ene6 had never been investigated. Since we have
envisioned the syntheses of several complex alkaloids
devoid of substitution at the nitroalkene carbons, we
chose to systematically investigate the utility of nitro-
ethylene in Lewis acid-promoted tandem cycloadditions.
but its use as a 4π component in cycloadditions has not
been documented. The closest analogy might be the
recently reported addition of silyl ketene acetals to
nitroethylene with an aluminum-based Lewis acid to
provide Michael addition products.9 We report, herein,
that nitroethylene engages in diastereoselective, Lewis
acid-promoted [4 + 2] cycloadditions with chiral vinyl
ethers and that the resulting nitronates undergo selective
[3 + 2] cycloadditions with electron deficient alkenes.
Lewis acid-promoted [4 + 2] cycloaddition between
nitroethylene and a chiral vinyl ether would create cyclic
nitronate A possessing a single stereogenic center at the
configurationally labile C(6) acetal carbon, Scheme 1.
Previous studies have shown that C(3)-unsubstituted
nitronates are both less stable and more reactive in [3 +
2] cycloadditions than the substituted analogues.1,7 Thus,
it was not clear whether compounds A would be isolable.
Moreover, the stereochemical course of the [3 + 2]
cycloaddition would be controlled by the remote substitu-
ent at C(6). From our studies in the spiro-mode tandem
cycloaddition5 we anticipated that a fair degree of selec-
tivity in the creation of three new stereocenters in nitroso
acetal B could be realized. Reduction would afford a
pyrrolidine-containing product in which the stereodirect-
ing acetal center had been removed.
Resu lts
To establish the potential for nitroethyleneas a 4π
component in tandem cycloadditions, it was necessary to
find reaction conditions suitable for [4 + 2] cycloaddition
with vinyl ethers which allowed for the isolation of the
(expectedly) reactive nitronates. The addition of a solu-
tion of nitroethylene10 (1 equiv) to a cold (-78 °C) solution
of MAPh11 (2 equiv) and chiral vinyl ether (1 equiv) in
toluene proved to afford the best results.12 The reactions
were effectively spontaneous at -78 °C, as judged by the
formation and rapid dissipation of the red, Lewis acid-
nitroalkene complex. The nitronates were surprisingly
stable and could be isolated after an aqueous workup,
Nitroethylene has been used as a 2π component in [4
+ 2] cycloadditions and as a powerful Michael acceptor,8
(1) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
(2) (a) Denmark, S. E.; Senanayake, C. B. W.; Ho, G.-D. Tetrahedron
1990, 46, 4857. (b) Denmark, S. E.; Schnute, M. E. J . Org. Chem. 1991,
56, 6738. (c) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J .
Org. Chem. 1993, 58, 1859. (d) Denmark, S. E.; Schnute, M. E.; Marcin,
L. R.; Thorarensen, A. J . Org. Chem. 1995, 60, 3205. (e) Denmark, S.
E.; Thorarensen, A. J . Org. Chem. 1996, 61, 6727.
(8) Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrotra, A. K.;
Iyengar, R. J . Org. Chem. 1980, 45, 1185-1189 and references therein.
(9) Tucker, J . A.; Clayton, T. L.; Mordas, D. M. J . Org. Chem. 1997,
62, 4370.
(10) Nitroethylene is easily prepared by the dehydration of nitro-
ethanol with phthallic anhydride (see ref 6), and despite reports
concerning its instability, it can be stored as a neat oil at -20 °C for
several months without loss in purity.
(11) Methylaluminum bis(2,6-diphenylphenoxide). Nonoshita, X.;
Banno, H.; Maruoka, K.; Yamomoto, H. J . Am. Chem. Soc. 1990, 112,
316.
(12) Trimethylaluminum also promoted the cycloaddition but was
not diastereoselective.
(3) Denmark, S. E.; Kesler, B. S.; Moon, Y.-C. J . Org. Chem. 1992,
57, 4912.
(4) (a) Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1993, 58, 3857.
(b) Denmark, S. E.; Schnute, M. E. J . Org. Chem. 1994, 59, 4576. (c)
Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1995, 60, 3221.
(5) Denmark, S. E.; Middleton, D. S J . Org. Chem. 1998, 63, 1604.
(6) Buckley, G. D.; Scaife, C. W. J . Chem. Soc. 1947, 1471.
(7) Chlenov, I. E.; Morozova, N. S.; Khudak, V. I.; Tartakovskii, V.
A. Izv. Akad. Nauk. SSSR, Ser. Chem. 1970, 2641 (English translation,
Bull. Acad. Sci., SSSR 1970, 2492).
S0022-3263(97)02280-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/17/1998

3046 J . Org. Chem., Vol. 63, No. 9, 1998
Denmark and Hurd
Sch em e 2
Sch em e 3
but could not withstand chromatographic purification
(silica gel or alumina).13
nitronate
no. of diastereomersa
3/4
6/1
6/1
8.3/1
7/1
yield, %
2a
2b
2c
2d
6
4
2
2
86
84
89
Several chiral vinyl ethers were surveyed to optimize
the diastereoselectivity of the [4 + 2] process. Cycload-
ditions with vinyl ethers 1a 2c and 1b2e provided nitro-
nates 2a and 2b as a 20/1 ratio of diastereomers at C(6)
in both cases, whereas vinyl ether 1c2d afforded the
a
Determined by 1H NMR analysis.
to the C(6) alkoxy substituent.16 Nitroso acetal 5 bears
an R C(2) carbomethoxy group and nitroso acetal 6 has
a â C(2) carbomethoxy group. These assignments were
confirmed by conversion to pyrrolizidine alkaloids of
known structure (vide infra). The facial preference of the
nitronate in the reaction with a trans disubstituted
alkene was determined on the assumption that all the
minor diastereomers arise from approach proximal to the
C(6) alkoxy substituent. Again, tandem cycloadditions
using nitronates 2a and 2b produced a number of
diastereomers. However, the facial selectivity is still 11/1
for nitronate 2a and 7/1 for nitronate 2b. The analysis
is clearer for reactions which employed nitronate 2c.
When the C(2) carbomethoxy substituent is oriented endo
(5c), the facial selectivity is 8/1. Likewise, when the C(2)
substituent is oriented exo (6c), the facial selectivity is
6/1.
Methyl acrylate also reacted with nitronate 2c to
provide nitroso acetal 7c in 81% yield with 7.5/1/1 ratio
of diastereomers, Scheme 5. The major product has been
assigned as arising from an exo, distal approach to the
C(6) alkoxy group and the two minor nitroso acetals as
endo, distal and exo, proximal.17 The endo, proximal
product is either not seen or obscured in the analysis.
Therefore, the facial selectivity for this monosubstituted
alkene is 8.5/1.
1
nitronate 2c as a single diastereomer, as judged by H
NMR analysis, Scheme 2. The major nitronates 2a -c
were assigned the R configuration at the acetal center
on the basis of previous studies using the (+)-(1S)
enantiomer of these vinyl ethers and MAPh.2
The crude nitronates were reactive 1,3-dipoles and
could be trapped with electron deficient dipolarophiles
(cis and trans disubstituted and monosubstituted acti-
vated alkenes). Reaction of 2 with dimethyl maleate at
room temperature afforded nitroso acetals 3 and 4 in good
yield as a mixture of diastereomers. The two major
diastereomers were both assigned as C(3)/C(3a) trans
isomers on the basis of the known exo preference for
dimethyl maleate in [3 + 2] cycloadditions with nitro-
nates Scheme 3.14 The major diastereomer 3 arises from
an approach distal the C(6) alkoxy substituent and the
minor diastereomer 4 proximal to the C(6) alkoxy sub-
stituent. The facial selectivity was approximately 6/1 for
nitroso acetals 3a and 3b and improved slightly to 8.3/1
for nitroso acetal 3c, Scheme 3. Dipolar cycloaddition
with 2c was more selective, as only two of eight possible
diastereomers were detected. This is a reflection of the
complete stereocontrol in the [4 + 2] cycloaddition with
vinyl ether 1c. Dipolar cycloaddition of 2a -d with
dimethyl maleate shows very little stereoselectivity
dependence on the size of alkoxy substituent. In fact,
the facial selectivty was 7/1 for nitroso acetal 3d , derived
from butyl vinyl ether, indicating that the size of the
alkoxy substituent has little influence in this process.
Dipolar cycloadditions with dimethyl fumarate were
next examined to ascertain the stereocontrol with trans
dipolarophiles, Scheme 4. The product analyses in these
reactions are complicated by the lack of exo/endo selectiv-
ity with dimethyl fumarate.15 Both major diastereomers
(5 and 6) were assigned as arising from approach distal
Hyd r ogen olysis of Nitr oso Aceta ls a n d Con ver -
sion to P yr r olizid in e Alk a loid s. Nitroso acetals 3c-
(16) The probable structures of the other four diastereomers are
shown below. All nitroso acetals have the same relative configuration
of the chiral auxiliary (OG*).
(13) Thermal [4 + 2] cycloaddition with nitroethylene is also
possible. Nitroethylene reacted with butyl vinyl ether at room tem-
perature with approximate reaction half-lives of 3 h in CDCl3 and 24
h in toluene-d8. However, the product nitronates are immediately
consumed by a [3 + 2] cycloaddition with unreacted nitroethylene and
the reactions stop at 50% conversion of vinyl ether. The undesired [3
+ 2] cycloaddition of nitronates was also problematic in the Lewis-
acid-promoted [4 + 2] cycloadditions. It was critical to use no more
than a single equivalent of nitroethylene, as upon quench (Me2NH/
MeOH or KOH/MeOH) excess nitroethylene would undergo [3 + 2]
cycloaddition prior to or at least competitive with its destruction.
(14) Denmark, S. E.; Thorarensen, A. J . Org. Chem. 1994, 60, 5672.
(15) In reactions with a nitronate system which is highly facially
selective, dimethyl fumarate was poorly endo/exo selective (1/1).
Denmark, S. E.; Herbert B.; Seierstad, M. J ., unpublished results.
(17) Methyl acrylate has been shown to react with exo selectivity.
See ref 15.
(18) The enantiomeric excess was determined by chiral-stationary-
phase, supercritical-fluid chromatography (SFC) (Chiralcel OD, 150
bar, 5% MeOH, 2 mL/min, 220 nm).
(19) The enantiomeric excess was determined by chiral-stationary-
phase, supercritical-fluid chromatography (SFC) (Chiralcel AD, 150
bar, 20% MeOH, 3 mL/min, 220 nm). The mother liquor contained a
mixture of (+)-10 and an unidentified hydroxy lactam, indicating that
the other nitroso acetal diastereomer present in (+)-6c was of a
different enantiomeric family.

Tandem [4 + 2]/[3 + 2] Cycloadditions with Nitroethylene
J . Org. Chem., Vol. 63, No. 9, 1998 3047
Sch em e 4
Sch em e 5
nitronate 5/6/diastereomersa products C(2) C(3) yieldb
Sch em e 6
2a
2b
2c
57/54/5/2/2/1
39/33/4/2/2/1
8/6/1/1
5a
6a
5b
6b
5c
6c
R
â
R
â
R
â
â
R
â
R
â
R
33%
35%
30%
24%
40%
34%
a
b
dr determined by crude 1H NMR analysis. Yield of isolated
material.
nitroso acetal yielda product C(2)
X
eeb
13
7c were reduced with H2 (180 psi) over Raney nickel in
modest yields (46-68%) and with high recovery of the
chiral alcohol 13 (94-98%), Scheme 6. Since the assign-
ment of the two fumarate-derived nitroso acetals (-)-5
and (+)-6 was not possible, a two-step conversion to
known pyrrolizidine alkaloids was required for structural
correlation. A single diastereomer of nitroso acetal (-)-
5c was reduced to afford hydroxy lactam (+)-9 in 53%
yield (>99% ee).18 Nitroso acetal (+)-6c (d.r. ) 6/1) was
reduced and after a single recrystallization afforded
hydroxy lactam (+)-10 in 55% yield (>99% ee).19
The hydroxy lactams (+)-9 and (+)-10 were converted
to the known pyrrolizidine alkaloids (+)-macronecine and
(+)-petasinecine, Scheme 7. Hydroxy lactam (+)-9 was
treated with LiAlH4 in THF for 3.5 h to afford, after silica
gel chromatography and recrystallization, (+)-macrone-
cine in 76% yield.21 Likewise, hydroxy lactam (+)-10 was
reduced with LiAlH4 to afford, after silica gel chroma-
tography and recrystallization, the unnatural, dextro-
rotatory enantiomer of petasinecine in 80% yield.22
3c
(-)-5c
(+)-6c
7c
46%
53%
55% (+)-10
58%
8
R
â
R
â
â-CO2Me
â-CO2Me 99% 96%
R-CO2Me 99% 94%
96%
(+)-9
1120
H
98%
a
b
Yield of isolated material. ee determined by CSP SFC.
an exo approach of the vinyl ether in MAPh-promoted
reactions with other nitroalkenes is preferred.2 Addition-
ally, it is well documented that (+)-(1S)-1c exposes the
re face of the vinyl ether for cycloaddition to produce
nitronates with the R configuration at the acetal center
C(6). The improved diastereoselectivity in exo-mode
cycloadditions using 1c versus 1a and 1b has been noted
previously.2d
Given the propensity for nucleophile-promoted polym-
erization of nitroethylene,6,8 and the documented Michael-
type transfer of trialkylaluminums to nitroalkenes,23 it
is noteworthy that the admixing of aluminum Lewis acids
(MAPh or trimethylaluminum), vinyl ethers, and nitro-
ethylene produces nitronates with high efficiency, as
judged by the conversion to nitroso acetals (yields typi-
cally 68-89%). Additionally, it is not surprising that the
compatibility of nitroethylene and Lewis acids has only
recently been demonstrated,9 because nitroethylene itself
is usually sufficiently reactive for most synthetic pur-
poses.
Th e [3 + 2] Cycloa d d ition . The facial selectivity in
the [3 + 2] cycloaddition with C(6) monosubstituted
nitronates (2) is dependent upon the configuration of the
C(6) substituent and the reactive conformation of the
cyclic nitronate. Since the configuration is assigned by
analogy with previous systems (vide supra), discussion
of the reactive conformation is relevant. The fact that
the size of the C(6) alkoxy substituent has no effect on
the selectivity in reactions producing nitroso acetals
3a -d suggests that in the transition structure the bulk
of the alkoxy group is oriented away from the nitronate
ring, but the mere presence of an alkoxy group in these
reactions with cis dipolarophiles is sufficient for selectiv-
ity. Nonbonded steric interactions should be expected
to become more severe when a trans dipolarophile is
employed and selectivities would be expected to increase.5
Yet, all dipolarophiles in this study whether monosub-
stituted, cis disubstituted, or trans disubstituted produce
nitroso acetals with a facial selectivity in the range of
Discu ssion
[4 + 2] Cycloa d d ition s w ith Nitr oeth ylen e. There
are two factors which influence the stereochemical out-
come of the [4 + 2] cycloaddition: (1) the endo/exo
approach of the dienophile and (2) the accessible face of
the vinyl ether. Although it is impossible to determine
if the nitronate derived from nitroethylene and (+)-1c
arises from an exo or endo approach of the vinyl ether,
(20) Hydroxy lactam 12 was isolated in 10% yield and is derived
from nitroso acetal 7c′ which is the endo addition product of methyl
acrylate to nitronate 2c.
(21) The physical and spectral properties of synthetic material
matched those reported for the natural (+)-macronecine: mp ) 128-
129 °C, [R]23 ) +42.7° (EtOH, c ) 0.96); lit. mp ) 129 °C, [R]23
)
D
D
+49.3° (EtOH, c ) 0.50). (a) Danilova, A.; Utkin, L.; Massagetov, P. J .
Gen. Chem. USSR. 1955, 25, 797. (b) Ito, H.; Ikeuchi, Y.; Taguchi, T.;
Hanazawa, Y.; Shiro, M. J . Am. Chem. Soc. 1994, 116, 5469.
(22) The physical and spectral properties of synthetic material
matched those reported for the natural (-)-petasinecine except for the
sign of the optical rotation: mp ) 133-134 °C, [R]23D ) +24.8° (EtOH,
c ) 0.25); lit. mp ) 132-134 °C, [R]23 ) -20.0° (EtOH, c ) 0.25). (a)
D
Yamada, K.; Tatematsu, H.; Unno, R.; Hirata, Y.; Hirono, I. Tetrahe-
dron Lett. 1978, 4543. (b) Mulzer, J .; Shanyoor, M. Tetrahedron Lett.
1993, 34, 6545.
(23) Pecunioso, A.; Menicagli, R. J . Org. Chem. 1988, 53, 45.

3048 J . Org. Chem., Vol. 63, No. 9, 1998
Denmark and Hurd
Sch em e 7
chemical efficiency and diastereoselectivity. Despite the
lack of proximate stereodirecting groups, nitroethylene-
derived cyclic nitronates undergo selective [3 + 2] cy-
cloadditions with external dipolarophiles. Natural prod-
uct syntheses using either a tethered dipolarophile26 or
a more complex external dipolarophile are currently
under consideration.
Exp er im en ta l Section
Gen er a l Exp er im en ta l. See Supporting Information for
details.
Gen er a l P r oced u r e I: Ta n d em [4 + 2]/[3 + 2] Cycloa d -
d ition s w ith Nitr oeth ylen e. (2S*,3a R*,3S*,6R*)-Hexa h y-
d r o-6-[(1S*)-2,2-d ip h en ylcyclop en t yloxy]isoxa zolo[2,3-
b][1,2]oxa zin e-2,3-d ica r boxylic Acid Dim eth yl Ester (3c).
Trimethylaluminum (4.00 mL, 8.00 mmol, 2 equiv) was added
rapidly to a solution of 2,6-diphenylphenol (3.94 g, 16.0 mmol,
4 equiv) in 80 mL of toluene at rt. The resulting clear, yellow
solution was allowed to stir for 30 min and then was added to
a solution of chiral ether 1c (1.05 g, 4.00 mmol) in 20 mL of
toluene at -78 °C (5 min). The resulting solution was stirred
at -78 °C for 10 min before a 0.83 M solution of nitroethylene
in toluene (4.90 mL, 4.07 mmol, 1.02 equiv) was added
dropwise (10 min). During the addition a brown complex
developed and rapidly faded. After the addition was com-
pleted, the mixture was stirred at -78 °C for 10 min and then
was quenched with H2O (10 mL) and allowed to warm to room
temperature. The resulting mixture was partitioned between
CH2Cl2 (200 mL) and H2O (200 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 200 mL), the combined organic
extracts were washed with brine (100 mL), and the brine wash
was back extracted with CH2Cl2 (100 mL). The combined
organic extracts were dried (Na2SO4), filtered, and concen-
trated to approximately 50 mL. The solution was diluted with
toluene (50 mL) and concentrated again to approximately 50
mL. An aliquot was removed and concentrated under high
vacuum to afford a crude oil which was shown by 1H NMR
analysis to be a 20/1 mixture of diastereomeric nitronates.
Dimethyl maleate (1.00 mL, 8.00 mmol, 2.0 equiv) was added
neat, and the solution was stirred at rt for 17 h. Concentration
of the solution under vaccum afforded a pale-yellow oil, which
was purified by silica gel chromatography (hexane/EtOAc; 6/1,
4/1, 2/1) to afford 3.93 g of 2,6-diphenylphenol, 0.510 g of
dimethyl maleate, and 1.708 g (89%) of nitroso acetal 3c as a
8.25/1 mixture of diastereomers. Recrystallization from MeOH
afforded 1.465 g (77%) of 3c as a 10/1 mixture of diastereomers.
Data for 3c: mp 139-140 °C (MeOH); 1H NMR (500 MHz,
CDCl3) δ 7.08-7.28 (m, 10 H), 5.19 (d, J ) 10.1, 1 H), 4.75 (t,
J ) 4.4, 1H), 4.50 (br s, 1 H), 3.91-3.96 (m, 1 H), 3.72-3.77
(m, 1 H), 3.74 (s, 3 H), 3.69 (s, 3 H), 2.59 (dt, J ) 12.3, 9.1,
1H), 2.32-2.42 (m, 1 H), 2.16-2.30 (m, 3 H), 1.76-1.90 (m, 1
H), 1.62-1.70 (m, 1 H), 1.36-1.48 (m, 2 H), 1.09-1.16 (m, 1
H); 13C NMR (125.6 MHz, CDCl3) δ 170.15, 168.73, 146.83,
145.60, 128.62, 128.13, 127.51, 127.09, 125.84, 125.49, 101.85,
85.07, 82.02, 69.92, 59.99, 52.58, 52.55, 49.06, 35.24, 31.20,
22.39, 20.49, 18.79; IR (KBr) 1762 (s), 1730 (s); MS (CI, CH4)
482 (M+ + 1); TLC, Rf ) 0.37 (hexane/EtOAc, 2/1). Anal.
Calcd for C27H31NO7 (481.54): C, 67.35; H, 6.49; N, 2.91.
Found: C, 67.14; H, 6.52: N, 2.77.
F igu r e 1. Preferred approach of dipolarophile to nitronate
2.
6-8/1. The directing ability of any alkoxy group and the
insensitivity to steric constraints is suggestive of an
electronic controlling element.
There are two likely reactive conformations of the
nitronate in the [3 + 2] cycloaddition: a twist-chair with
an axially disposed alkoxy group (A) and with an equa-
torially alkoxy group (B), Figure 1. The R-face approach
to nitronate A would lead directly to a favorable chair
conformation of the major product C. Additionally, this
pathway may also benefit from a kinetic anomeric
effect.24 The minor diastereomer D may arise from either
an â-face approach to nitronate A, which must then
undergo a ring flip to D,25 or react directly through
nitronate conformer B.
In addition to confirming structural assignments, the
enantioselective, four-step syntheses of (+)-macronecine
and (+)-petasinecine in 16% and 15% yields, respectively,
represent the shortest synthesis of these compounds on
record.
(2R,3a R,3S,6R)-Hexa h yd r o-6-[(1S*)-2,2-d ip h en ylcyclo-
p en t yloxy]isoxa zolo[2,3-b][1,2]oxa zin e-2,3-d ica r b oxyl-
ic Acid Dim eth yl Ester ((-)-5c) a n d (2S,3a R,3R,6R)-
H exa h yd r o-6-[(1S*)-2,2-d ip h en ylcyclop en t yloxy]isox-
a zolo[2,3-b][1,2]oxa zin e-2,3-d ica r boxylic Acid Dim eth yl
Ester ((+)-6c). Following General Procedure I with the
following quantity of reagents and reaction times: MAPh
(15.00 mmol, 2.5 equiv), (+)-1c (1.59 g, 6.00 mmol), nitroeth-
ylene (438 mg, 6.00 mmol, 1.0 equiv) at -78 °C for 15 min,
Con clu sion
Nitroethylene readily engages in Lewis acid-promoted
[4 + 2] cycloadditions with chiral vinyl ethers with high
(24) A kinetic anomeric effect has been used to rationalize stereo-
selective [3 + 2] cycloadditions of nitrones (Vasella, A. Helv. Chim.
Acta 1977, 60, 1273. Petrizilka, M.; Felix, D.; Eschenmoser, A. Helv.
Chim. Acta 1973, 56, 2950) and nitronates (Denmark, S. E.; Dappen,
M. S.; Cramer, C. J . J . Am. Chem. Soc. 1986, 108, 1306. Denmark, S.
E.; Cramer, C. J .; Sternberg, J . A. Helv. Chim. Acta 1986, 69, 1971).
(25) The ground state conformation of the minor diastereomers in
all tandem cycloadditions has an equatorially disposed C(6) alkoxy
substituent, as determined by NMR analysis.
(26) (a) Denmark, S. E.; Stolle, A.; Dixon, J . A.; Guagnano, V. J .
Am. Chem. Soc. 1995, 117, 2100. (b) Denmark, S. E.; Guagnano, V.;
Dixon, J . A.; Stolle, A. J . Org. Chem. 1997, 62, 4610. (c) Denmark, S.
E.; Dixon, J . A. J . Org. Chem. 1997, 62, 7086.

Tandem [4 + 2]/[3 + 2] Cycloadditions with Nitroethylene
J . Org. Chem., Vol. 63, No. 9, 1998 3049
dimethyl fumarate (1.08 g, 7.50 mmol, 1.25 equiv) at rt for 16
h. The crude product was purified by silica gel chromatogra-
phy (hexane/EtOAc; 6/1, 4/1, 2/1) to afford 6.44 g of 2,6-
diphenylphenol, 1.160 g (40%) of nitroso acetal (-)-5c as a
white foam (single diastereomer), and 0.980 g (34%) of nitroso
acetal (+)-6c as a white foam (6c/6c′ ) 6/1). Data for (-)-5c:
1H NMR (500 MHz, CDCl3) δ 7.08-7.24 (m, 10 H), 5.21 (d, J
) 6.1, 1 H), 4.80 (dd, J ) 5.6, 2.7, 1H), 4.47 (m, 1 H), 3.93 (dd,
J ) 10.0, 6.1, 1 H), 3.86 (s, 3 H), 3.80 (s, 3 H), 3.70 (m, 1 H),
2.64 (td, J ) 12.3, 9.2, 1H), 2.41 (tt, J ) 13.6, 4.9, 1 H), 2.17-
2.32 (m, 3 H), 1.78-1.92 (m, 2 H), 1.42-1.55 (m, 2 H), 1.03-
1.06 (m, 1 H); 13C NMR (125.6 MHz, CDCl3) δ 171.52, 170.84,
146.88, 145.54, 128.66, 128.11, 127.51, 127.15, 125.84, 125.52,
101.64, 84.84, 83.44, 71.26, 59.98, 52.91, 52.82, 47.82, 35.35,
31.33, 21.95, 20.43, 18.49; IR (KBr) 1739 (s); MS (CI, CH4) 482
(s); MS (CI, CH4) 200 (M+ + 1); TLC Rf ) 0.28 (CH2Cl2/MeOH,
19/1). Anal. Calcd for C9H13NO4 (199.21): C, 54.26; H, 6.58;
N, 7.03. Found: C, 54.30; H, 6.68; N, 6.96.
[1R,2R,7a R]-Hexa h yd r o-2-h yd r oxy-3-oxo-1H-p yr r oliz-
in e-1-ca r boxylic Acid Meth yl Ester ((+)-9). Following
General Procedure II with the following quantity of reagents
and reaction times: nitroso acetal (-)-5c (1.00 g, 2.08 mmol)
in 80 mL of MeOH, 48 h, 180 psi H2. The crude product was
purified by silica gel chromatography (hexane/ EtOAc; 4/1;
CH2Cl2/MeOH; 19/1) to afford 466 mg (94%) of white, crystal-
line 2,2-diphenylcyclopentanol (13) and hydroxy lactam (+)-
9, which was recrystallized (EtOAc) to afford 219 mg (53%) of
(+)-9 as a white, crystalline solid. Hydroxy lactam (+)-9 was
determined to be greater than 99% ee by chiral stationary
phase supercritical fluid chromatography (Chiralcel OD, 150
bar, 5% MeOH, 2 mL/min, 220 nm). Data for (+)-9: mp 191-
(M+ + 1); [R]23 ) -21.1° (EtOH, c ) 1.00), TLC Rf ) 0.32
D
(hexane/EtOAc, 2/1). Anal. Calcd for C27H31NO7 (481.54): C,
67.35; H, 6.49; N, 2.91. Found: C, 67.12; H, 6.49: N, 2.81.
Data for (+)-6c: 1H NMR (500 MHz, CDCl3) δ 7.08-7.29 (m,
10 H), 5.62 (d, J ) 6.8, 1 H), 4.79 (dd, J ) 5.9, 2.2, 1H), 4.57
(t, J ) 4.6, 1 H), 3.97 (td, J ) 10.3, 5.9, 1 H), 3.84 (s, 3 H),
3.78 (s, 3 H), 3.56 (dd, J ) 10.4, 7.0, 1 H), 2.64 (td, J ) 12.5,
9.2, 1H), 2.09-2.33 (m, 4 H), 1.83-1.91 (m, 1 H), 1.67-1.74
(m, 1 H), 1.39-1.48 (m, 1 H), 1.07-1.19 (m, 2 H); 13C NMR
(125.6 MHz, CDCl3) δ 170.63, 169.54, 146.70, 145.59, 128.5,
128.14, 127.53, 127.06, 125.85, 125.46, 101.68, 85.40, 81.92,
68.80, 60.06, 52.83, 52.61, 49.62, 35.21, 31.46, 23.49, 20.47,
18.80; IR (KBr) 1747 (s), 1722 (s), 1711 (s); MS (CI, CH4) 482
1
192 °C (EtOAc); H NMR (500 MHz, CDCl3) δ 4.65 (dd, J )
6.2, 3.8, 1 H), 4.45 (ddd, J ) 9.8, 7.8, 5.9, 1 H), 4.00 (d, J )
3.7, 1 H), 3.83 (s, 3 H), 3.53 (dt, J ) 12.0, 8.3, 1 H), 3.23 (ddd,
J ) 12.2, 9.0, 3.4, 1 H), 2.97 (dd, J ) 7.7, 6.2, 1 H), 2.15-2.29
(m, 3 H), 1.36-1.75 (m, 1 H); 13C NMR (125.6 MHz, CDCl3) δ
70.72, 169.65, 76.83, 61.56, 52.32, 52.20, 40.72, 31.04, 27.04;
IR (KBr) 1741 (s), 1731 (s), 1713 (s); MS (CI, CH4) 200 (M+
+
1); [R]23 ) +120.0° (EtOH, c ) 1.00); TLC Rf ) 0.20 (CH2Cl2/
D
MeOH, 19/1). Anal. Calcd for C9H13NO4 (199.21):C, 54.26; H,
6.58; N, 7.03. Found: C, 54.38; H, 6.67; N, 7.04.
[1S,2S,7a R]-Hexa h yd r o-2-h yd r oxy-3-oxo-1H-p yr r oliz-
in e-1-ca r b oxylic Acid Met h yl E st er ((+)-10). Following
General Procedure II with the following quantity of reagents
and reaction times: nitroso acetal (+)-6c (880 mg, 1.84 mmol)
(d.r. ) 6/1) in 80 mL of MeOH, 48 h, 180 psi H2. The crude
product was purified by silica gel chromatography (hexane/
EtOAc; 4/1, 0/1; CH2Cl2/ MeOH; 19/1) to afford 420 mg (96%)
of white, crystalline 2,2-diphenylcyclopentanol (13) and 237
mg of hydroxy lactam (+)-10, which was recrystallized (EtOAc)
to afford 201 mg (55%) of (+)-10 as a white, crystalline solid.
An analytical sample of hydroxy lactam (+)-10, obtained by
sublimation (100 °C, 0.1 mmHg), which was determined to be
greater than 99% ee by chiral stationary phase supercritical
fluid chromatography (Chiralcel AD, 150 bar, 20% MeOH, 3
mL/min, 220 nM). Data for (+)-10: sublimation point 100 °C
(0.1 mmHg); 1H NMR (500 MHz, CDCl3) δ 4.80 (br d, J ) 6.6,
1 H), 4.08 (dt, J ) 8.8, 6.4, 1 H), 3.76 (s, 3 H), 3.70 (t, J ) 6.4,
1 H), 3.65 (dt, J ) 11.2, 7.1, 1 H), 3.15-3.19 (m, 2 H), 2.01-
2.14 (m, 3 H), 1.51-1.59 (m, 1 H); 13C NMR (125.6 MHz,
CDCl3) δ 172.52, 170.21, 73.97, 57.82, 51.82, 51.43, 41.99,
27.00, 25.67; IR (KBr) 1734 (s), 1684 (s); MS (CI, CH4) 200
(M+ + 1); [R]23 ) +68.6° (CH2Cl2, c ) 0.95), TLC Rf ) 0.31
D
(hexane/EtOAc, 2/1). Anal. Calcd for C27H31NO7 (481.54): C,
67.35; H, 6.49; N, 2.91. Found: C, 67.22; H, 6.52: N, 2.81.
(2S*,3a R*,6R*)-Hexa h yd r o-6-[(1S*)-2,2-d ip h en ylcyclo-
p en tyloxy]isoxa zolo[2,3-b][1,2]oxa zin e-2-ca r boxylic Acid
Meth yl Ester (7c). Following the General Procedure I with
the following quantity of reagents and reaction times: MAPh
(8.00 mmol, 2.0 equiv), 1c (1.06 g, 4.00 mmol), nitroethylene
(295 mg, 4.01 mmol, 1.0 equiv) at -78 °C for 10 min, methyl
acrylate (0.720 mL, 8.00 mmol, 2.0 equiv) at rt for 20 h. The
crude product was purified by silica gel chromatography
(hexane/EtOAc; 8/1, 6/1, 4/1, 2/1) to afford 3.92 g of 2,6-
diphenylphenol and 1.371 g (81%) of nitroso acetal 7c as a 7.5/
1/1 mixture of diastereomers. Data for 7c: 1H NMR (500 MHz,
CDCl3) δ 7.03-7.15 (m, 10 H), 5.00 (dd, J ) 10.5, 3.5 1 H),
4.75 (t, J ) 4.4, 1H), 4.48 (m, 1 H), 3.76 (s, 3 H), 3.66 (m, 1 H),
2.59 (td, J ) 12.3, 9.0, 1H), 2.50 (td, J ) 11.3, 10.8, 1H), 2.30-
2.37 (m, 1 H), 2.19-2.28 (m, 4 H), 1.81-1.87 (m, 1 H), 1.53-
1.59 (m, 1 H), 1.38-1.46 (m, 2 H), 1.07-1.12 (m, 1 H); 13C NMR
(125.6 MHz, CDCl3) δ 171.06, 146.94, 145.70, 128.66, 128.11,
127.48, 127.12, 125.81, 125.43, 101.84, 84.93, 80.79, 66.65,
59.99, 52.49, 35.29, 31.84, 31.29, 22.41, 20.49, 19.35; IR (KBr)
1758 (s); MS (CI, CH4) 424 (M+ + 1); TLC, Rf ) 0.32 (hexane/
EtOAc, 2/1). Anal. Calcd for C25H29NO5 (423.51): C, 70.90;
H, 6.90; N, 3.31. Found: C, 71.10; H, 7.17; N, 3.32.
(M+ + 1); [R]23 ) +50.0° (EtOH, c ) 0.95); TLC Rf ) 0.27
D
(CH2Cl2/MeOH, 19/1). Anal. Calcd for C9H13NO4 (199.21): C,
54.26; H, 6.58; N, 7.03. Found: C, 54.12; H, 6.61; N, 6.95.
[2S *,7a R *]-H e xa h yd r o-2-h yd r oxy-3H -p yr r olizin -3-
on e (11) a n d [2R*,7a R*]-Hexa h yd r o-2-h yd r oxy-3H-p yr -
r olizin -3-on e (12). Following General Procedure II with the
following quantity of reagents and reaction times: nitroso
acetal 7c (630 mg, 1.49 mmol, d.r. ) 7.5/1/1) in 72 mL of
MeOH, 48 h, 180 psi H2. The crude product was purified by
silica gel chromatography (hexane/EtOAc; 4/1; CH2Cl2/ MeOH;
19/1) to afford 348 mg (98%) of white, crystalline 2,2-diphen-
ylcyclopentanol (13) and 146 mg (70%) of a mixture of 11/12
(6/1). The diastereomeric hydroxy lactams were separated on
preparative HPLC (silica gel, EtOAc, 10 mL/min) to afford 123
mg (58%) of hydroxy lactam 11 as a white solid and 21.3 mg
(10%) of hydroxy lactam 12 as a 9/1 mixture of 12/11. Data
Gen er a l P r oced u r e II: H yd r ogen olysis of Nit r oso
Aceta ls. [1S*,2S*,7a R*]-Hexa h yd r o-2-h yd r oxy-3-oxo-1H-
p yr r olizin e-1-ca r boxylic Acid Meth yl Ester (8). A sus-
pension of a catalytic amount of Raney nickel W-2 (washed 5
× 75 mL MeOH) and nitroso acetal 3c (730 mg, 1.45 mmol) in
72 mL of MeOH was pressurized with H2 to 180 psi in a steel
autoclave. The mixture was stirred at rt for 45 h. The reaction
vessel was carefully vented, and the suspension was filtered
through Celite (4 cm pad). The Celite pad was rinsed with
500 mL of MeOH, and the filtrate was concentrated. The
resulting pale yellow oil was purified by silica gel chromatog-
raphy (hexane/EtOAc; 4/1; CH2Cl2/ MeOH; 19/1) to afford 334
mg (98%) of white, crystalline 2,2-diphenylcyclopentanol (13)
and crude hydroxy lactam 8, which was recrystallized (EtOAc/
hexane) to provide 133 mg (46%) of 8 as a white crystalline
1
for 11: mp 111-112 °C (EtOAc/hexane); H NMR (500 MHz,
CDCl3) δ 4.59 (t, J ) 9.0, 1 H), 3.71 (tt, J ) 9.0, 5.9, 1 H), 3.60
(dt, J ) 11.5, 7.8, 1 H), 3.10 (ddd, J ) 11.7, 9.3, 3.0, 1 H), 2.82
(br s, 1 H), 2.79 (ddd, J ) 12.1, 7.6, 5.9, 1 H), 1.99-2.16 (m, 3
H), 1.63 (ddd, J ) 12.1, 10.6, 9.0, 1 H), 1.40 (m, 1 H); 13C NMR
(125.6 MHz, CDCl3) δ 174.80, 73.57, 57.04, 41.15, 38.23, 32.16,
26.03; IR (KBr) 1672 (s); MS (CI, CH4) 142 (M+ + 1); TLC Rf
) 0.31 (CH2Cl2/MeOH, 19/1). Anal. Calcd for C7H11NO2
(141.17): C, 59.56; H, 7.85; N, 9.92. Found: C, 59.58; H,
7.90: N, 9.97. Data for 12: mp 109-113 °C (EtOAc/hexane);
1H NMR (500 MHz, CDCl3) δ 4.43 (dd, J ) 7.2, 1.8, 1 H), 4.04
1
solid. Data for 8: mp 136-137 °C (EtOAc/hexane); H NMR
(500 MHz, CDCl3) δ 4.88 (d, J ) 9.8, 1 H), 4.25 (br s, 1 H),
3.90 (td, J ) 9.7, 6.0, 1 H,), 3.81 (s, 3 H), 3.62 (dt, J ) 11.5,
8.1, 1 H), 3.15 (m, 1 H), 2.91 (dd, J ) 9.8, 8.3), 2.20-2.30 (m,
1 H), 2.11-2.20 (m, 1 H), 2.00-2.11 (m, 1 H), 1.51-1.59 (m, 1
H); 13C NMR (125.6 MHz, CDCl3) δ 172.32, 171.60, 75.70,
59.23, 56.03, 52.52, 41.59, 31.48, 25.86; IR (KBr) 1726 (s), 1686

3050 J . Org. Chem., Vol. 63, No. 9, 1998
Denmark and Hurd
(m, 1 H), 3.51 (dt, J ) 11.7, 8.0, 1 H), 3.15 (ddd, J ) 12.3, 9.3,
3.7, 1 H), 2.53 (br s, 1 H), 2.27 (ddd, J ) 13.9, 6.6, 2.0, 1 H),
2.02-2.20 (m, 3 H), 1.93-2.00 (m, 1 H), 1.21-1.28 (m, 1 H);
13C NMR (125.6 MHz, CDCl3) δ 174.19, 75.61, 60.63, 40.65,
35.44, 31.89, 26.97; IR (KBr) 1692 (s); MS (CI, CH4) 142 (M+
+ 1); TLC Rf ) 0.22 (CH2Cl2/MeOH, 19/1). Anal. Calcd for
C7H11NO2 (141.17): C, 59.56; H, 7.85; N, 9.92. Found: C,
59.72; H, 7.69; N, 9.87.
solution was cooled to rt, the reaction was quenched with H2O
(0.175 mL), 10% NaOH (0.175 mL), and H2O (0.35 mL) and
was stirred for 1 h. The light gray suspension was filtered
through a sintered glass filter, the filter cake was rinsed with
50 mL of MeOH, and the filtrate was concentrated to a white
solid. The crude product was purified by silica gel chroma-
tography on a column which had a 10 mm × 40 mm plug of
Celite under the silica gel (MeOH/CH2Cl2/NH4OH; 5/10/1).
Recrystallization from acetone afforded 88.6 mg (80%) of (+)-
petasinecine as white needles. Data for (+)-15: mp 132-133
°C (acetone), lit.22a mp ) 132-134 °C; 1H NMR (500 MHz, CD3-
OD) δ; 13C NMR (125.6 MHz, CD3OD) δ 4.30 (dt, J ) 4.4, 1.25,
1 H), 3.92 (dd, J ) 10.8, 7.3, 1 H), 3.76 (dd, J ) 10.8, 7.3, 1 H),
3.59 (m, 1 H), 3.21 (ddd, J ) 9.5, 7.0, 2.5, 1 H), 3.13 (dd, J )
12.7, 3.9, 1 H), 2.91 (dt, J ) 9.9, 5.7, 1 H), 2.83 (dd, J ) 12.7,
1.2, 1 H), 2.31 (m, 1 H,), 1.96-2.04 (m, 2 H), 1.67-1.79 (m, 2
H); 13C NMR (125.6 MHz, CD3OD) δ 74.54, 67.83, 63.47 59.80,
57.81, 49.73, 28.65, 27.90; IR (KBr) 3289 (br s); MS (70 ev)
[1S,2R,7a R]-H exa h yd r o-2-h yd r oxy-1H -p yr r olizin e-1-
m eth a n ol, (+)-m a cr on ecin e ((+)-14). A suspension of hy-
droxy lactam (+)-9 (116 mg, 0.582 mmol) in 8 mL of THF was
added dropwise to a cold (0 °C) suspension of LiAlH4 (145 mg,
3.63 mmol, 6.2 equiv) in 3 mL of THF. The gray suspension
was then heated to reflux for 3.5 h. After the solution was
cooled to rt, the reaction was quenched with H2O (0.15 mL),
10% NaOH (0.15 mL), and H2O (0.30 mL) and was stirred for
1 h. The light gray suspension was filtered through a sintered
glass filter, and the filter cake was rinsed with 50 mL of
MeOH. The filtrate was concentrated to a white solid, which
was purified by silica gel chromatography on a column which
had a 10 mm × 40 mm plug of Celite under the silica gel
(MeOH/CH2Cl2/NH4OH; 5/10/1). Recrystallization from ac-
etone afforded 69.8 mg (76%) of (+)-macronecine as a highly
crystalline, white solid. Data for (+)-14: mp 128-129 °C
157 (M+); [R]23 ) +24.8° (EtOH, c ) 0.25), lit.22a [R]23
)
D
D
-20.0° (EtOH, c ) 0.25); TLC Rf ) 0.13 (CH2Cl2/MeOH/NH4-
OH, 10/5/1). Anal. Calcd for C8H15NO2 (157.21): C, 61.16;
H, 6.62; N, 8.91. Found: C, 60.93; H, 9.39; N, 8.88.
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-30938) for financial support.
We thank Dr. J ohn A. Tucker (Pharmacia and Upjohn)
for helpful discussions and Mr. Robert A. Stavenger for
the SFC data. A.R.H. thanks the University of Illinois
for a Graduate Fellowship.
1
(acetone), lit.21a mp ) 129 °C; H NMR (500 MHz, CDCl3) δ
4.49 (t, J ) 3.7,1 H), 4.03 (br s, 2 H), 3.82-3.88 (m, 2 H), 3.51-
3.57 (m, 1 H), 3.17 (d, J ) 11.0, 1 H), 2.95 (td, J ) 10.6, 6.5,
1 H), 2.67 (dd, J ) 11.0, 3.4, 1 H), 257 (m, 1 H), 1.95 (dq, J )
12.2, 7.2, 1 H), 1.76-1.86 (m, 3 H), 1.52 (dq, J ) 12.2, 6.0, 1
H); 13C NMR (125.6 MHz, CDCl3) δ 75.33, 64.00, 62.94, 60.56,
54.97, 52.51, 31.20 25.40; IR (KBr) 3322 (s), 2951 (s); MS (70
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal, a full list of IR absorbances, MS fragments, 1H NMR, and
13C NMR listings with assignments for compounds 3c, 5c-
7c, 8-12, 14 and 15, and full experimental details and
characterization data for compounds 3a , 5a , 6a , 3b, 5b, and
6b (19 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
ev) 157 (M+); [R]23 ) +42.7° (EtOH, c ) 0.96), lit.21a [R]23
)
D
D
+49.3° (EtOH, c ) 0.50); TLC Rf ) 0.13 (CH2Cl2/MeOH/NH4-
OH, 10/5/1). Anal. Calcd for C8H15NO2 (157.21): C, 61.16;
H, 6.62; N, 8.91. Found: C, 60.93; H, 9.39; N, 8.88.
[1R,2S,7a R]-H exa h yd r o-2-h yd r oxy-1H -p yr r olizin e-1-
m eth a n ol, (+)-P eta sin ecin e ((+)-15). A suspension of hy-
droxy lactam (+)-10 (140 mg, 0.703 mmol) in 8 mL of THF
was added dropwise to a cold (0 °C) suspension of LiAlH4 (175
mg, 4.38 mmol, 6.2 equiv) in 3 mL of THF. The gray
suspension was then heated to reflux for 3.5 h. After the
J O972280F