Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions of Nitroalkenes. 15. The Bridged Mode (α-Tether)

Article abstract of DOI:10.1021/jo970686m

A new variant of the tandem inter [4 + 2]/intra [3 + 2] cycloaddition of nitroalkenes is described in detail. The scope and limitations of the bridged mode tandem cycloaddition in which the diene and dienophile are part of the same molecule are documented

Full text of DOI:10.1021/jo970686m

4610
J . Org. Chem. 1997, 62, 4610-4628
Ta n d em In ter [4 + 2]/In tr a [3 + 2] Cycloa d d ition s of Nitr oa lk en es.
15. Th e Br id ged Mod e (r-Teth er )
Scott E. Denmark,* Vito Guagnano, J ulie A. Dixon, and Andreas Stolle
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801
Received April 16, 1997X
A new variant of the tandem inter [4 + 2]/intra [3 + 2] cycloaddition of nitroalkenes is described
in detail. The scope and limitations of the bridged mode tandem cycloaddition in which the diene
and dienophile are part of the same molecule are documented. Simple 1,4-pentadienes as well as
2-alkoxy-1,4-pentadienes can function effectively as dienophile and dipolarophile combinations with
excellent chemical selectivity and regio- and diastereoselectivities. Hydrogenation of the bridged
nitroso acetals produces aminocyclohexanemethanol derivatives in high diastereo- and enantio-
selectivities. Further, insights into the mechanistic aspects of the Raney nickel promoted
hydrogenation are reported. An intriguing influence of the nitro olefin R-substituent on the
diastereoselectivity in the [4 + 2] cycloaddition has been documented. The reactivity of the R-chloro-
substituted nitroalkene 26 as the heterodiene in the Diels-Alder reaction is assayed, and the use
of the chlorine atom as a hydrogen surrogate is described.
In tr od u ction
mented: the fused mode (â tether) and the spiro mode
(R tether) constructions, Scheme 1. Each mode is re-
sponsible for the formation of a particular class of
polycyclic nitroso acetals which can be unmasked by a
simple hydrogenation reaction to reveal interesting tri-
cyclic structures.2 In both cases, the use of chiral
dienophiles derived from optically active alcohols G*OH
led to the production of enantiomerically enriched R-hy-
droxy lactams.
The hetero Diels-Alder reaction represents one of the
most important tools for the stereoselective construction
of highly functionalized heterocyclic systems.1 Further-
more, the heteroatomic [4 + 2] cycloaddition allows for
the simultaneous formation of carbon-carbon and carbon-
heteroatom bonds, as well as the creation of stereogenic
centers in a predictable fashion. In recent years, we have
extensively investigated the asymmetric tandem inter [4
+ 2]/intra [3 + 2] cycloaddition sequence using chiral
vinyl ethers as the dienophiles and nitroalkenes with
pendant dipolarophiles as the heterodienes.2 The Lewis
acid promoted [4 + 2] cycloadditions result in the highly
stereoselective formation of nitronates which can either
be cleaved by hydrogenolysis to afford substituted pyr-
rolidines3 or, owing to their dipolar nature, undergo [3
+ 2] cycloadditions to afford the corresponding nitroso
acetals.2 Depending on the point of attachment of the
dipolarophile to the nitroalkene, two subclasses of inter
[4 + 2]/intra [3 + 2] cycloadditions have been docu-
A recent report from our laboratories disclosed a new
construction named the bridged mode, which arises from
the attachment of the dipolarophile to the R position of
the dienophile, Scheme 2.4 Thus, a Lewis acid promoted
cycloaddition affords nitronates bearing a tethered olefin
at the C(6) position. Subsequent intramolecular [3 + 2]
cycloaddition leads to bridged tricyclic nitroso acetals
which can be converted by hydrogenolysis into highly
substituted aminocyclohexanes. Since these compounds
occur as subunits in clinically useful therapeutic agents,5
a general route to their preparation would be desirable.
Our initial studies sought to demonstrate the feasibility
of the overall construction ([4 + 2]/[3 + 2]/cleavage) with
the use of simple 1,4-pentadienes. Furthermore, the use
of 2-alkoxy-1,4-pentadienes as the 2π component in the
tandem sequence was of considerable interest since
ultimately optically active 2-alkoxy-1,4-pentadienes could
be employed to access the aminocyclohexane derivatives
in enantiomerically enriched form. The following report
provides a detailed account of our studies directed toward
defining the scope and limitation of the bridged (R-tether)
construction.
X Abstract published in Advance ACS Abstracts, J une 15, 1997.
(1) (a) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: New York, 1987. (b) Carruthers,
W. Cycloaddition Reactions in Organic Synthesis; Pergamon: New
York, 1990. (c) Boger, D. L. In Comprehensive Organic Chemistry,
Combining C-C π-Bonds, Vol. 5; Paquette, L. A., Ed.; Pergamon
Press: Oxford, 1991; pp 451-512. (d) Ho, T.-L. Tandem Organic
Reactions; Wiley: New York, 1992. (e) Ziegler, F. E. In Comprehensive
Organic Synthesis, Combining C-C π-Bonds; Paquette, L. A., Ed.;
Pergamon Press: Oxford, 1991; Vol. 5, Chapter 7.3. (f) Tietze, L. F.;
Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
(2) (a) Denmark, S. E.; Moon, Y. C.; Senanayake, C. B. W. J . Am.
Chem. Soc. 1990, 112, 311 and reference cited. (b) Denmark, S. E.;
Senanayake, C. B. W.; Ho, G. D. Tetrahedron 1990, 46, 4857. (c)
Denmark, S. E.; Schnute, M. E. J . Org. Chem. 1991, 56, 6738. (d)
Denmark, S. E.; Senanayake, C. B. W.; Schnute, M. E.; Moon, Y. C.;
Ho, G. D.; Middleton, D. S. Proceedings of the Fifth International Kyoto
Conference on New Aspects of Organic Chemistry; VCH Verlagsgesell-
schaft and Kodansha Ltd.: Weinhein, 1992. (e) Denmark, S. E.;
Senanayake, C. B. W. J . Org. Chem. 1993, 58, 1853. (f) Denmark, S.
E.; Schnute, M. E.; Senanayake, C. B. W. J . Org. Chem. 1993, 58, 1859.
(g) Denmark, S. E.; Schnute, M. E.; Thorarensen, A.; Middleton, D.
S.; Stolle, A. Pure Appl. Chem. 1994, 66, 2041. (h) Denmark, S. E.;
Schnute, M. E.; Marcin, L. R.; Thorarensen, A. J . Org. Chem. 1995,
60, 3205. (i) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J . Org.
Chem. 1995, 60, 3574. (j) Denmark, S. E.; Thorarensen J . Org. Chem.
1994, 59, 5672.
Resu lts
P r ep a r a t ion of 2-Alk oxy-1,4-p en t a d ien es 1 a n d
4a -c. The substrates for our initial survey, 1,4-penta-
(4) Denmark, S. E.; Stolle, A.; Dixon, J . A.; Guagnano, V. J . Am.
Chem. Soc. 1995, 117, 2100.
(5) (a) Rinehart, K. L.; Shield, L. S., Eds.; Aminocyclitol Antibiotics;
ACS Symposium Series 125; ACS: American Chemical Society: Wash-
ington, DC, 1980. (b) Suami, T.; Ogawa S. Advances in Carbohydrate
Chemistry and Biochemistry 1990, 48, 21. (c) Hudlicky, T.; Olivo, H.
F.; McKibben, B. J . Am. Chem. Soc. 1994, 116, 5108.
(3) (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.
S0022-3263(97)00686-5 CCC: $14.00 © 1997 American Chemical Society

Tandem Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 62, No. 14, 1997 4611
Sch em e 1
Sch em e 2
Sch em e 4
diene and 3,3-dimethyl-1,4-pentadiene, were readily
available either commercially or by literature proce-
dures.6 In addition, the functionalized substrate 2-bu-
toxy-1,4-pentadiene (1) could be prepared in one step by
modification of a known procedure.7 Treatment of n-
butyl vinyl ether with tert-butyllithium (t-BuLi) followed
by copper cyanide and subsequent reaction of the corre-
sponding cyanocuprate with allyl bromide afforded the
desired product in 60% yield after fractional distillation,
Scheme 3.
that enol ethers 4a -c are moisture sensitive and are
prone to undergo isomerization to the corresponding 1,3-
pentadiene. Finally, despite the extensive use of allyl-
copper reagents in the 1,4-conjugated addition to R,â-
unsaturated ketones10 and despite the known regio- and
stereoselective reactions of ethoxyacetylene with alkyl-,
1-alkenyl-, and arylcopper(I) compounds,11 no example
of allylcupration of alkoxyacetylenes has been previously
reported.
Sch em e 3
Cycloa d d ition s w ith 1,4-P en ta d ien es. In orienting
experiments, (E)-(2-nitro-1-propenyl)benzene (5a )12 was
selected as the test nitroalkene and 3,3-dimethyl-1,4-
pentadiene6 as the dienophile. The choice of dienophile
was guided by the initial concern that the Lewis acid
could promote isomerization to a conjugated 1,3-penta-
diene. In no previous study on tandem cycloaddditions
has a simple vinyl group been successfully employed as
a dienophile, although examples of substituted olefinic
dienophiles2a,13 and unactivated vinyl dipolarophiles are
on record.14 A brief survey of Lewis acids15 indicated that
SnCl4 was the promoter of choice for the [4 + 2]
cycloaddition. According to the preferred protocol, the
cycloaddition was carried out in CH2Cl2 at -15 °C for
Unfortunately, this procedure could not be applied to
the synthesis of chiral 2-alkoxy-1,4-pentadienes because
of the inability of t-BuLi to metallate vinyl ethers of
secondary alcohols. An alternative strategy for the
preparation of these compounds involves the allylboration
of the corresponding alkoxyacetylenes.8 However, the
difficult accessibility of allylboranes and the limitation
associated with the use of unfunctionalized allyl chains
prompted us to explore a different synthetic route, based
on the use of a more versatile and functional-group-
tolerant organometallic reagent. Thus, vinyl ethers 4a -c
were prepared by allylcupration of alkoxyacetylenes 3a -
c. The alkynyl ethers 3a -c were synthesized from the
corresponding chiral alcohols 2a -c according to a modi-
fied literature procedure, Scheme 4.9 It should be noted
(9) (a) So¨rensen, H.; Greene, A. E. Tetrahedron Lett. 1990, 31, 7597.
(b) Porter, N. A.; Dussault, P.; Breyer, R. A.; Kaplan, J .; Morelli, J .
Chem. Res. Toxicol. 1990, 3, 236.
(10) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Smith, R. A.
J . J . Am. Chem. Soc. 1990, 112, 4404.
(11) Wijkens, P.; Vermeer, P. J . Organomet. Chem. 1986, 301, 247.
(12) Denmark, S. E.; Kesler, B. S.; Moon, Y.-C. J . Org. Chem. 1992,
57, 4912.
(13) (a) Denmark, S. E.; Cramer, C. J .; Sternberg, J . A. Helv. Chim.
Acta. 1986, 69, 1971. (b) Denmark, S. E.; Moon, Y.-C.; Cramer, C. J .;
Dappen, M. S.; Senanayake, C. B. W. Tetrahedron 1990, 46, 7373.
(14) Denmark, S. E.; Senanayake, C. B. W. Tetrahedron 1996, 35,
11579.
(6) Eilbracht, P.; Acker, M.; Totzauer, W. Chem. Ber. 1983, 116, 238.
(7) Santiago, R.; Soderquist, J . A. J . Org. Chem. 1992, 57, 5844.
(8) Bubnov, Y. N.; Grigorian, M. S.; Tsyban, A. V.; Mikhailov, B. M.
Synthesis 1980, 902.
(15) Other Lewis acids examined were BF3‚OEt2, TiCl4, and AlCl3.

4612 J . Org. Chem., Vol. 62, No. 14, 1997
Denmark et al.
Ta ble 1. Yield s of P r od u cts in Ta n d em [4 + 2]/[3 + 2]
Sch em e 5
Cycloa d d ition sa
entry
5 (R)
9 (yield, %) 10 (yield, %) 11 (yield, %)
36-48 h, using a ratio of 1.0/2.0/1.7 for 5a /pentadiene/
SnCl4, Scheme 5. The stable, crystalline nitronate 6a
was obtained in 68% yield as a single stereoisomer. The
regiochemical course of the [4 + 2] cycloaddition was
revealed by the appearance of a low-field methine hy-
drogen at 4.08 ppm (dd, J ) 11.8, 1.6 Hz) corresponding
to HC(6). The trans stereochemistry depicted for the
nitronate (arising form an exo-mode cycloaddition) was
subsequently assigned by X-ray analysis of the final
product.
1
2
3
5a (Ph)
5b (c-Hex)
5c (n-Pent)
9a (91)b
9b (62)b
9c (55)b
10a (84)
10b (100)
10c (100)
11a (78)
11b (74)
11c (67)
a
b
Yields of analytically pure material. Chromatographically
homogenous, nondistillable oil.
The isolation and stability of nitronate 6a supports the
notion that the intramolecular [3 + 2] cycloaddition in
the bridged mode series is not a facile process. This is
not unexpected as the dipolarophile is unactivated14 and
the nitronate must adopt a conformation with an axial
C(6) substituent for the cycloaddition to take place. Thus,
heating nitronate 6a in toluene at 110 °C induced a [3 +
2] cycloaddition to afford nitroso acetal 7a in 79% yield.
The bridged tricyclic structure of 7a (an unprecedented
ring system) was easily confirmed by 2D NMR spectros-
copy. This rather strained nitroso acetal was unstable
to silica gel chromatography but could be purified by
crystallization. Hydrogenolysis of the nitroso acetal in
the presence of Raney nickel, followed by acetylation,
afforded the highly functionalized cyclohexanemethanol
triacetate 8a as a single stereoisomer in 59% yield.
F igu r e 1. Chem 3D representation of the X-ray structure of
11a .
The reactivity of the simplest dienophile/dipolarophile
was next examined. 1,4-Pentadiene was not plagued by
the expected isomerization to 1,3-pentadiene and was
found to be a superior partner in the Diels-Alder
reaction, Table 1, entry 1. The SnCl4-promoted cyclo-
addition of 5a with 1,4-pentadiene afforded nitronate 9a
as a single diastereomer in 91% yield. The intramolecu-
lar [3 + 2] cycloaddition of 9a and subsequent hydro-
genolysis/acetylation produced the triacetate 11a in 66%
yield. The stereostructure of triacetate 11a was estab-
lished by X-ray analysis which in turn provided confir-
mation of the basic structures of 9a and 10a , Figure 1.
Moreover, the determination of the structure of 11a
demonstrated that this compound arose from a preferred
exo-mode cycloaddition, as expected on the basis of the
results of a previous investigation.13 The exo selectivity
in the analogous reaction of nitroalkene 5a and 3,3-
dimethyl-1,4-pentadiene was established by 1H NMR
correlation between nitronates 6a and 9a , Figure 2.
F igu r e 2. 1H NMR correlation between nitronates 6a and 9a .
to be general. The SnCl4-promoted cycloadditions of
nitroalkenes 5b12 and 5c12 with 1,4-pentadiene provided
nitronates 9b and 9c in 62% and 55% yield and nitroso
acetals 10b and 10c in quantitative yield, respectively,
Table 1, entries 2-3. Furthermore, the hydrogenolyses
To evaluate the scope of the tandem process, secondary
and primary â-alkyl substituted nitroalkenes were em-
ployed as the heterodienes in the [4 + 2] cycloaddition.
Gratifyingly, the tandem [4 + 2]/[3 + 2] sequence proved

Tandem Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 62, No. 14, 1997 4613
Sch em e 6
Sch em e 7
Ta ble 2. Selected 1H NMR Da ta for Tr ia ceta tes 11a -c
11
R
Ha ppm (J , Hz)
Hb ppm (J , Hz)
11a
11b
11c
Ph
c-Hex
n-Pent
4.57 (dd, 11.5, 3.9)
4.51 (dd, 11.6, 3.8)
4.53 (dd, 11.5, 3.9)
3.95 (ddd, 11.5, 8.6)
3.87 (ddd, 11.5, 8.3)
3.91 (ddd, 11.5, 8.5)
a 4.6/1 (12b/12a ) mixture in 62% yield, Scheme 6. The
minor diastereomer 12a was found to be identical by H
of these nitroso acetals proceeded as expected to afford
good yields of the functionalized aminocyclohexanemeth-
anols as their triacetates, 11b and 11c (Table 2).
1
NMR spectroscopy to the major nitronate obtained from
the analogous cycloaddition promoted by SnCl4. Inter-
estingly, partial isomerization of 1 to the corresponding
4-butoxy-1,3-pentadiene occurred when the cycloaddition
was carried out at temperatures higher than -30 °C. The
MAD-induced isomerization of pentadiene 1 was estab-
Cycloa d d ition s of Nitr oa lk en e 5a w ith 2-Bu toxy-
1,4-p en ta d ien e (1). The development of an asymmetric
variant of the highly stereoselective tandem sequence
required the introduction of a stereocontrolling element
in one of the three participants (heterodiene, dienophile,
and Lewis acid) in the [4 + 2] cycloaddition. Taking into
account the successful use of chiral vinyl ethers as the
carriers of the chiral modifier group in both fused and
spiro mode cycloadditions,2b,c,d,f,g a chiral dienophile in the
form of a 2-alkoxy-1,4-pentadiene appeared to be the best
candidate. The 2-alkoxy group would serve to enhance
the reactivity of the dienophile (due to the inverse
electron demand nature of the cycloaddition) and also
would assure the proper regiocontrol in the [4 + 2]
process to place the dipolarophile at C(6) of the nitronate.
Thus, 2-butoxy-1,4-pentadiene (1) was first tested as the
dienophile/dipolarophile in the tandem cycloaddition
process. The SnCl4-promoted cycloaddition of nitroalkene
5a and enol ether 1 proceeded in a highly selective
manner, producing nitronate 12a as the major diastere-
omer in 89% yield, Scheme 6. The assignment of ste-
reostructure could not be assured until completion of the
synthetic sequence as described below. In agreement
with previous observations,2f the Lewis acid played a
crucial role in determining the diastereoselectivity in the
reaction. Nitronate 12b now became the major compo-
nent of the diastereomeric mixture when methylalumi-
num bis(2,6-di-tert-4-methylphenoxide) (MAD)16 was used
as the Lewis acid promoter, Scheme 6. However, it was
found that careful control of reaction parameters was
essential for reproducibility. A solution of MAD in
toluene was added over a 10 h period to a solution of
nitroalkene 5a and vinyl ether 1 in toluene at -35 °C.
After the mixture was stirred for an additional 10 h
period, the reaction provided nitronates 12b and 12a as
1
lished by the H NMR detection of a nitronate deriving
from the cycloaddition of nitro olefin 5a and the isomer-
ized pentadiene.
Both nitronates 12a and 12b underwent thermal [3 +
2] cycloaddition, though optimization of addition rate,
time, and temperature was necessary, Scheme 7. The
rates of cycloaddition for the two diastereomers were
quite different; 12b was consumed within 11 h in
refluxing benzene, while 12a required 24 h in refluxing
xylene. The resulting nitroso acetals 13a and 13b are
extremely acid sensitive, and it was critical to have solid
NaHCO3 present in the reaction vessel as well as for any
manipulation of the isolated nitroso acetals. Other bases
(CaCO3, CsHCO3, Cs2CO3, 2,6-lutidine) were found to be
less satisfactory in the [3 + 2] cycloaddition. Nitroso
acetal 13a was obtained in 82% yield after chromatog-
raphy on basic alumina. However, its congener 13b was
not isolated and was carried on directly in the next step.
Thus, the crude nitroso acetal 13b was immediately
hydrogenated in the presence of Raney nickel to afford,
after acetylation, a diastereomeric mixture of triacetates
11a /16a (11a /16a , 1/1.8) in 68% overall yield (from 13a ),
Scheme 7. Similarly, the hydrogenation/acetylation se-
quence performed on nitroso acetal 13a produced the
triacetates 14a /15a (14a /15a , 1/1.6) in 78% overall yield.
The triacetates in each diastereomeric pair (11a /16a and
14a /15a ) were found to be epimeric at the C(5) position,
as a result of the unselective reduction of the ketone (vide
infra).
While the unselective (and unwanted) reduction of the
ketone function provided a temporary inconvenience it
did allow for an unambiguous assignment of the stereo-
structures of 14a /15a and 11a /16a . The minor (less
(16) Maruoka, K.; Itoh, T.; Yamamoto, H. J . Am. Chem. Soc. 1985,
107, 4573.

4614 J . Org. Chem., Vol. 62, No. 14, 1997
Denmark et al.
Ta ble 3. In flu en ce of th e Lew is Acid on Cycloa d d ition s
w ith (()-4a
entry
Lewis acid (equiv)
T (°C)
17a /18a
yield (%)a
F igu r e 3. Coupling patterns of Ha with Hb-e in 14a and 15a .
1
2
3
SnCl4 (2)
-74
-67
-74
1/0
89
MAD (1.3)b
1/40.7/3.8c
8.8/0/1c
55(48)d
52e
Ti(Oi-Pr)2Cl2 (2.4)
polar) triacetate formed by hydrogenation of 13b was
found to be identical in all respects to 11a , the product
triacetate from the cycloaddition of 1,4-pentadiene. Since
the stereostructure of 11a was established by X-ray
analysis, the structures of nitronate 12b and nitroso
acetal 13b can be easily deduced. Thus, the cis relation-
ship of acetoxymethyl and phenyl substituents must arise
from a trans relationship of allyl and phenyl substituents
in 12b. This series therefore arises from an endo (butoxy)
[4 + 2] cycloaddition. Furthermore, 12a must arise from
an exo (butoxy) cycloaddition which confirms the full
structure of 13a . It therefore remained to establish the
configuration of the acetoxy group in 14a /15a which was
deduced by analyzing the coupling patterns of the tri-
acetates, Figure 3. The axial hydrogen Ha in triacetate
14a appears in the 1H NMR spectrum as a triplet of
triplets by virtue of its coupling with the four vicinal
hydrogens (Hb-e), of which two are axial (J ac ) J ad ) 12.0
Hz) and two are equatorial (J ab ) J ae ) 5.0 Hz).
Alternatively, the coupling constants of the corresponding
equatorial hydrogen (Ha) in triacetate 15a with the
adjacent hydrogens Hb-e are virtually identical (J ) 3.3
Hz); thus the multiplicity of the Ha 1H NMR signal is a
quintet, Figure 3.
Cycloa d d ition of Nitr oa lk en e 7a a n d Alk oxyp en -
ta d ien e (()-4a . The ability to control the absolute
stereochemical course of the bridged mode tandem cy-
cloadditions could be achieved through the use of a chiral
nonracemic 2-alkoxy-1,4-pentadiene. Previous reports
from our laboratories have illustrated the successful use
of chiral vinyl or propenyl ethers as the 2π components
in [4 + 2] cycloadditions, although no R-substituted enol
ether had yet been examined.2f,3c From previous experi-
ence, trans-2-phenylcyclohexanol (3a ) represented the
logical first choice due to availability and ease of prepa-
ration.17 The enantiofacial discrimination of the selected
dienophile/dipolarophile (()-4a was tested in the SnCl4-
promoted cycloaddition with nitroalkene 5a , Table 3,
entry 1. The reaction resulted in the completely stereo-
selective formation of a single cycloadduct (17a ) which
was isolated in 89% yield. It is noteworthy that as little
as 1.2 equiv of (()-4a could be used for the complete
consumption of 5a . On the basis of the stereochemical
outcome of the analogous reaction of vinyl ether 1,
nitronate 17a is expected to be the product of an exo
(butoxy) [4 + 2] pathway. In agreement with the results
reported in the previous section, the use of MAD as the
Lewis acid promoter afforded a different nitronate (which
is assumed to arise from an endo mode cycloaddition in
analogy to the MAD-promoted cycloaddition of 5a and
a
b
Isolated as a mixture of diastereomers. Reaction carried out
in toluene. c Unassigned diastereomer. Yield of the analytically
d
pure major diastereomer. e 79% Conversion of 5a as determined
by 1H NMR analysis of crude reaction mixture.
Sch em e 8
1) as the major component of a diastereomeric mixture,
Table 3, entry 2. The modest yield of the nitronate is
the consequence of the chemical incompatibility between
4a and MAD. When Ti(O-i-Pr)2Cl2 was employed, the
cycloaddition was moderately exo selective (the major
component of the diastereomeric mixture of nitronates
showed H NMR identical to that of 17a , obtained from
the SnCl4-promoted cycloaddition). The complete conver-
sion of the nitroalkene 5a was not achieved since the H
NMR spectrum of the crude reaction mixture revealed
the presence of unreacted 5a (21%), Table 3, entry 3.
The [3 + 2] dipolar cycloaddition of the nitronate (()-
17a was performed under the optimized conditions
employed for the analogous reaction of nitronate 12a .
After slow addition (12 h) of a solution of nitronate 17a
in xylene to a suspension of sodium bicarbonate in
refluxing xylene, additional (12 h) heating of the reaction
mixture, and purification by column chromatography,
nitroso acetal 19a was isolated in 47% yield, Scheme 8.
Reasoning that the prolonged heating could be respon-
sible for a thermal decomposition of the starting nitronate
and/or of the product, several experiments were per-
formed to improve the yield in the preparation of the
nitroso acetal. The highest yield (80%) of 19a was
achieved when a solution of the nitronate in toluene was
heated at reflux for 30 h in the presence of 7 equiv of
NaHCO3. Other combinations of base (K2CO3, NaHCO3)
and equivalents of base (0.1 to 10) provided the nitroso
acetal 19a in comparable yields at similar reaction times
in refluxing toluene.
1
1
(17) Schwartz, A.; Madan, P.; Whitesell, J . K.; Lawrence, R. M. Org.
Synth. 1990, 69, 1.
A descriptive preparation of nitroso acetal (()-19a was

Tandem Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 62, No. 14, 1997 4615
Sch em e 9
F igu r e 4. Chem 3D representation of the X-ray crystal
structure of (()-19a . All hydrogens (except hydrogens on C(8),
C(1′′), C(2′′)) are removed for clarity.
carried out under the optimized experimental conditions,
and the desired compound was obtained in analytically
pure form in 76% yield, Scheme 8. The full stereostruc-
ture of (()-19a , obtained by X-ray crystallographic
analysis, Figure 4, confirmed the original assignment of
(()-17a as having arisen from an exo (alkoxy) [4 + 2]
cycloaddition and also established the sense of asym-
metric induction from the chiral auxiliary. Hydrogenoly-
sis of (()-19a followed by acetylation of the resulting
crude amino diol afforded a mixture of triacetates 14a /
15a (14a /15a , 1.8/1) in 86% yield along with an 85%
recovery of trans-2-phenylcyclohexyl acetate, Scheme 8.
Syn th esis of Op tica lly Active Am in o Cycloh ex-
a n on e 20. The assessment of the enantiomeric excess
of the triacetates 14a /15a , obtained as a mixture of
epimers, would require the oxidation of the epimeric
alcohols to a single ketone. The introduction of additional
steps in the tandem sequence would reduce the efficiency
of this new construction and overshadow its intrinsic
utility. Therefore, the ability to isolate the ketone before
unselective reduction could occur in the hydrogenation
of nitroso acetal 19a became the next challenge.
Sch em e 10
The nitroso acetal hydrogenolysis is a critical reaction
whose success relies upon the suitable choice of three
parameters (hydrogen pressure, solvent, and amount of
the promoter). Considering that our goal was to avoid
the reduction of a carbonyl group to the corresponding
hydroxyl functionality, it seemed logical to carry out the
hydrogenation of 19a under 1 atm of hydrogen. Fur-
thermore, the choice of methanol as the reaction solvent
was dictated by the results of previous observations.
Thus, the influence of the amount of the Raney nickel
on the course of the hydrogenolysis of 19a was examined.
A strict dependence of the rate of the nitroso acetal
hydrogenation on the Raney nickel loading was observed.
The selective unmasking of the nitroso acetal to afford
the corresponding ketone could be achieved by stirring
a methanolic suspension of commercially available Raney
Ni (W2) (Ra-Ni) and nitroso acetal 19a (Ra-Ni/19a , 1.5/
1, w/w) under 1 atm of H2 at room temperature for 55
min, Scheme 9. The crude product, obtained after
removal of the nickel catalyst by filtration, was acetylated
to give aminocyclohexanone 20 in 83% yield. Interest-
ingly, during the optimization, it was found that the
hydrogenation of 19a proceeds through a partially re-
duced intermediate, which could be detected by thin-layer
chromotographic (TLC) analysis. This new compound,
whose bicyclic structure was confirmed by spectroscopic
and analytical data, was obtained as a diacetate deriva-
tive, according to the following protocol. The hydrogena-
tion of the nitroso acetal 19a was performed in methanol,
under 1 atm of H2, for 100 min, using a Ra-Ni/19a ratio
of 0.82/1, w/w, Scheme 9. The complete conversion of 19a
could not be achieved since TLC analysis of the reaction
mixture showed the concomitant slower formation of
ketone 20. The crude product underwent acetylation to
afford 55% of the diacetate derivative 21.
The assignment of the structure of 21 presented a
challenge. It should be noted that two distinct bicyclic
compounds (22 and 23) can be obtained depending on
which N-O bond is cleaved first, Scheme 10. Although
the analytical data confirmed that 21 is the product of a
single N-O bond cleavage, these data did not allow for
a definitive assignment of its structure. However, under
the reaction conditions hemiacetal 23 is expected to be a
nonisolable species that would immediately collapse to
the corresponding ketone 24. Both the 13C NMR or the
IR spectra of the diacetate did not indicate the presence
of a carbonyl functionality. Furthermore, the spectro-
scopic data revealed that the intermediate still retained
the chiral auxiliary. A characteristic feature that dis-
tinguishes the bridged derivative 21 from the fused
structure 24 is the existence, in the former, of a correla-
tion (3J CH) between the alkoxy methylenic hydrogens Ha
and Hb and the sp2 carbon of the acetoxy group, Scheme

4616 J . Org. Chem., Vol. 62, No. 14, 1997
Ta ble 4. Cycloa d d ition s of Nitr oa lk en es 5b-e w ith (()-4a
Denmark et al.
4a
(equiv)
SnCl4
(equiv)
time
(h)
diastereomeric
ratioa
25
entry
5 (R) (R1)
T (°C)
(yield, %)b
1
2
3
4
5b (Me) (c-Hex)
5b (Me) (c-Hex)
5c (Me) (n-Pent)
5c (Me) (n-Pent)
5d (H) (Ph)
1.2
3
3
1.3
1.5
1.5
2
1
2
2
2
2
-74 f 0
-65
1.5
20
0.75
0.75
0.25
3
25ba (0)
25ba (0)
25ca (70.7)
25ca (54.7)
25d a (84)
25ea (92)d
-74
9.7/1.1/1.0
-74
5
-74
14.0/6.0/1.0
1.4/1.0
6c
5e (H) (OBz)
-74
Determined by 1H NMR. Isolated as a mixture of diastereomers. c The reaction was carried out in toluene. Contaminated by
a
b
d
2-phenylcyclohexanol.
Ta ble 5. Cycloa d d ition s of Nitr oa lk en es 5c-e w ith
Dien op h iles (()-4b,c
Sch em e 11
(()-4
time diastereomeric
ratioa
25
entry
5 (R) (R1)
(equiv) (h)
(yield, %)b
1
2
3
4
5
6
5c (Me) (n-Pent) 4b (3.0) 0.75 17.1/3.0/1.6/1.0 25cb (71)
5c (Me) (n-Pent) 4c (3.0) 0.75 7.1/1.0/1.0
25cc (85)c
25cb (83)
25d c (84)
25eb (100)
25ec (37)d
5d (H) (Ph)
5d (H) (Ph)
5e (H) (OBz)
5e (H) (OBz)
4b (1.3) 0.25 1.1/1.0
4c (1.5) 0.25 1.9/1.0
4b (2.0) 3.00 2.4/2.1/1.0
4c (3.0) 3.00 16.8/1.4/1.0
10. This correlation was established by performing a
HMBC experiment which helped to unambiguously de-
termine the structure of diacetate 21.
With reproducible conditions for the selective hydro-
genation of the nitroso acetal in hand, the synthesis of
optically active aminocyclohexanone 20 was undertaken.
The SnCl4-promoted cycloaddition of nitroalkene 5a with
1.2 equiv of vinyl ether (+)-4a provided nitronate (+)-
17a as a single diastereomer, in 98% yield, Scheme 11.
The thermal, intramolecular [3 + 2] cycloaddition was
carried out by refluxing a solution of nitronate (+)-17a
in anhydrous toluene, in the presence of an insoluble base
(K2CO3). After workup and purification, the nitroso
acetal (+)-19a was isolated in 75% yield. The hydro-
genolysis of 19a was accomplished under the usual
protocol (H2/Ra-Ni) in a 0.002 N methanolic solution of
K2CO3. After acetylation, aminocyclohexanone 20 was
isolated in 86% yield and 99% ee as determined by chiral
HPLC, Scheme 11. The acetylated chiral alcohol was
recovered in 83% yield.
Cycloa d d ition s of Nitr oa lk en es 5b-e a n d Dien o-
p h iles (()-4a -c. The generality of this remarkably
stereoselective sequence was examined by performing
SnCl4-promoted [4 + 2] cycloadditions of selected ni-
troalkenes with 2-alkoxy-1,4-pentadiene (()-4a . The
results of this study, shown in Table 4, underline the poor
reactivity of the secondary alkyl â-substituted nitro-
alkene 5b, Table 4, entry 1, and a general decrease of
the selectivity in the cycloadditions of nitroalkenes 5c-
e. The erosion in the diastereoselectivity of the cyclo-
addition becomes dramatic in the nitroalkenes 5d 12 and
a
b
Determined by 1H NMR. Isolated as a mixture of diastere-
omers. c Contaminated by trans-2-(1-methyl-1-phenylethyl)cyclo-
hexanol (4c). Partially decomposed.
d
5e2j bearing no R-substituent. A low exo/endo selectivity
(exo/endo, 2.4/1, Table 4, entry 5) was observed in the
SnCl4-promoted cycloaddition of nitrostyrene (5d ) with
(()-4a , whereas the analogous reaction of 5a displayed
exclusive exo selectivity.
No improvement in the diastereoselectivity was ob-
served when dienophiles derived from 2,2-diphen-
ylcyclopentanol,2h (()-4b, or 2-(1-methyl-1-phenylethyl)-
cyclohexanol,18 (()-4c (whose application to the fused
mode tandem cycloadditions has provided remarkable
results2f,19 ), were employed, Table 5. In all cases, SnCl4-
promoted [4 + 2] cycloaddition of nitroalkenes 5c-e with
vinyl ethers 4b,c afforded mixtures of diastereomeric
nitronates in varying yields and selectivity.
It should be noted that the nitronates derived from
nitroalkenes 5d and 5e proved to be more thermally
labile and acid-sensitive than the methyl-substituted
nitronate 17a . The chemical behavior of these delicate
nitronates in the [3 + 2] cycloaddition was nonetheless
assayed. The two diastereomeric nitronates 25d c could
be separated by column chromatography, but only the
(18) Comins, D. L.; Salvador J . M. Tetrahedron Lett. 1993, 34, 801.
(19) Denmark, S. E.; Thorarensen J . Org. Chem. 1996, 61, 6727.

Tandem Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 62, No. 14, 1997 4617
Ta ble 6. Op tim iza tion of [3 + 2] Cycloa d d ition s w ith
(()-27
Sch em e 12
minor one was recovered in analytically pure form. The
minor diastereomer was then subjected to a refluxing
suspension of potassium carbonate in toluene. Unfortu-
nately, no [3 + 2] cycloadduct could be isolated, even
when the reaction was carried out at lower temperatures.
Cycloa d d ition of Nitr oa lk en e 26 a n d (()-4a . The
low selectivities observed in the cycloadditions of 5c and
5d directed our attention to the use of heterodienes which
incorporate a “hydrogen surrogate”. According to this
strategy, a group attached to C(1) of the nitroalkene
would act as stereochemical director to achieve high
selectivity in the [4 + 2] cycloaddition. The group would
then be replaced by a hydrogen atom. This strategy has
been used previously to control the exo/endo selectivity
in intramolecular [4 + 2] cycloadditions20 with groups
such as Me3Si, PhSO2, and PhS. Unfortunately, the
nitroalkenes which incorporate these moieties proved to
be either difficult to prepare or unreactive toward cy-
cloaddition.
K2CO3
entry (equiv)
T
additive
(equiv)
time yield
solvent
(°C)a
(h)
(%)
1
2
3
4
1
1
1
2
nitromethane 82
41
1
40
0
acetonitrile
acetonitrile
acetonitrile
reflux LiClO4 (100)
reflux
22
79
30
60
73b
a
b
Temperature of the oil bath. Internal temperature.
owing to its high polarity and low donor number. How-
ever, the partial polymerization of CH3NO2, favored by
the presence of K2CO3, occurred and the nitroso acetal
28 was isolated only in modest yield, Table 6, entry 1.
Finally, higher and more reproducible yields of 28 could
be obtained by heating a mixture of the nitronate 27 and
K2CO3 (2 equiv) in acetonitrile at 72-73 °C (internal
temperature) for 79 h, Table 6, entry 4. Under these
conditions, the nitroso acetal was isolated in 60% yield.
The hydrogenolysis of nitroso acetal 28, carried out in
methanol under H2 (1 atm) at room temperature and in
the presence of NaOH (3 equiv), afforded after acetylation
a diastereoisomeric mixture of the aminocyclohexanones
29/30 (29/30, 1/1) in 63% yield, Scheme 13. Separation
by radial chromatography and spectroscopic analysis of
each stereoisomer revealed that the two compounds were
epimers at the C(2) (amino-bearing) carbon.
The assignment of the relative configuration of the two
epimeric aminocyclohexanones 29/30 was accomplished
by analysis of the coupling patterns between HC(2) and
the adjacent hydrogens HC(1) and HC(3), respectively,
Figure 5. The less polar epimer 29 exhibits an axial-
equatorial coupling between Ha and Hb (J b ) 5.0 Hz) and
a coupling between the two equatorial hydrogens Ha and
Hc (J a ) 10.4 Hz). In diacetate 30, there exists a diaxial
coupling between Ha and Hb (J b ) 10.0 Hz) and an axial-
equatorial coupling Ha and Hc (J a ) 3.8 Hz).
(2-Chloro-2-nitroethenyl)arenes are heterodienes which
contain a potential hydrogen surrogate. This novel class
of compounds has been extensively explored by Dauzonne
et al. in conjugate addition reactions.21 To assess the
potential of the chlorine atom as a hydrogen surrogate
in the tandem sequence, the reactivity of nitroalkene
2621b in the [4 + 2] cycloadditions was investigated. We
were pleased to find that the SnCl4-promoted [4 + 2]
cycloaddition of 26 with vinyl ether (()-4a afforded the
corresponding nitronate 27 as a single diastereomer in
78% yield after recrystallization, Scheme 12. Interest-
ingly, the nitronate displayed improved crystallinity and
relative stability. This may be attributed to the presence
of a chlorine substituent. On the basis of the stereo-
chemical outcome of the cycloaddition of nitroalkene 5a
and the dienophile (()-4a , the nitronate is assumed to
arise from an exo-mode cycloaddition. This assumption
1
We next directed our efforts toward the selective
cleavage of only the C-Cl bond in 28 as a solution to the
formation of epimeric products. The following reagents,
which have been previously employed in the reduction
of the C-X bond in tertiary bridged halides, were tried:
Pd/C (10%),23 Zn(BH4)2,24 Bu3SnH/AIBN (thermally and
photochemically initiated),25 Na(Hg),26 Al(Hg),27 LiAlH4/
is supported by H NMR data (vide infra). The [3 + 2]
cycloaddition of nitronate 27 was carried out according
to the usual protocol in refluxing toluene and in the
presence of K2CO3. Under these conditions, extensive
decomposition occurred and no product could be isolated.
Performing the reaction at lower temperatures resulted
in a slower but complete destruction of the nitronate.
A summary of the optimization experiments for the
synthesis of the nitroso acetal 28 is shown in Table 6.
The use of polar solvents and mild temperatures seemed
to be crucial, although in solvents with high donor
number,22 the starting nitronate decomposed. The for-
mation of many byproducts was observed with additives
such as LiBr and LiClO4. Nitromethane, despite its
thermal instability, appeared to be a promising solvent,
(22) Donor number (or donicity) has been defined as the negative
∆H values for 1/1 adduct formation between antimony pentachloride
and electron pair donor solvents in dilute solution in the noncoordi-
nating solvent 1,2-dichloroethane (Reichardt, C. Solvents and Solvents
Effects in Organic Chemistry; VCH Verlagsgesellschaft mbH: Wein-
hein, 1988).
(23) Imamoto, T. In Comprehensive Organic Synthesis, Vol. 8,
Reduction; Paquette, L. A., Ed.; Pergamon Press: Oxford, 1991;
Chapter 4.1
(24) Kim, S.; Hong, C. Y.; Yang, S. Angew. Chem., Int. Ed. Engl.
1983, 22, 562.
(20) (a) J acobs, R. T. Unpublished observations in these laboratories.
(b) Wilde, R. G. Unpublished observations in these laboratories.
(21) Dauzonne, D.; Demerseman, P. J . Heterocycl. Chem. 1990, 27,
1581. (b) Dauzonne, D.; Demerseman, P. Synthesis 1990, 66. (c)
Dauzonne, D.; J osien, H; Demerseman, P. Synthesis 1992, 309.
(25) (a) Della, E. W.; Patney, H. K. Synthesis 1976, 251. (b) Fort, R.
C., J r.; Hiti, J . J . Org. Chem. 1977, 42, 3968. (c) Duri, Z. H.; Fraga, B.
M.; Hanson, J . R. J . Chem. Soc., Perkin Trans. 1 1981, 161.
(26) Austin, E.; Alonso, R. A.; Rossi, R. A. J . Chem. Res., Synop.
1990, 190.

4618 J . Org. Chem., Vol. 62, No. 14, 1997
Ta ble 7. Selected 1H NMR Da ta for Nitr on a tes 17a , 27, a n d 32
Denmark et al.
nitronate
R1
R2
HC(2′) ppm (J , Hz)
HC(1′′) ppm (J , Hz)
17a
27
32
Me
Cl
Br
Ph
5.78 (ddt, 17.2, 10.4, 7.1)
5.76 (ddt, 17.0, 10.2, 7.2)
5.69 (ddt, 17.2, 10.4, 7.1)
4.16 (dt, 4.0, 10.0)
4.15 (dt, 4.0, 10.0)
4.07 (dt, 4.3, 9.8)
4-MeOC6H4
Ph
Sch em e 14
the distinction between the trans (exo approach) and the
cis (endo approach) nitronates. Nitronate 17a was
established to have arisen from an exo approach of the
vinyl ether 4a to the nitro olefin 5a by correlation to
nitroso acetal 19a whose stereostructure was unambigu-
ously determined by X-ray analysis, Figure 4.
F igu r e 5. Coupling patterns of HC(2) in 29 and 30.
Sch em e 13
Discu ssion
[4 + 2] Cycloa d d ition : Exo/En d o Selectivity a n d
Asym m etr ic In d u ction . The stereochemical course of
the [4 + 2] cycloaddition is governed by two factors: (1)
the exo or endo approach of the dienophile to the
nitroalkene (with respect to the alkoxy group) and (2) the
facial selectivity of the dienophile (with respect to the
chiral auxiliary). It has also been demonstrated that both
the rate of the [4 + 2] cycloaddition and its stereochemical
outcome are profoundly affected by the Lewis acid.1 The
first effect can be rationalized in terms of frontier
molecular orbital theory and has been discussed previ-
ously.31 The influence of the Lewis acid on the stereo-
chemical outcome of the reaction is more complex and
not completely understood. It has been shown that the
Lewis acid influences not only the exo/endo selectivity
of the [4 + 2] cycloaddition but also which conformation
of the dienophile (vinyl ether) is the most reactive, which,
in turn, dictates the sense of the asymmetric induction.2f
The exo preference in SnCl4-promoted cycloadditions of
substituted olefinic dienophiles is not unusual, and it has
been documented in previous studies.3b,12 High exo
selectivity was observed in the cycloadditions of nitroalk-
enes 5a with 1,4-pentadienes, 3,3-dimethyl-1,4-pentadi-
ene, and the 2-alkoxy-1,4-pentadienes 1 and 4a . Fur-
thermore, (2-chloro-2-nitroethenyl)benzene (26) underwent
exclusively an exo-mode cycloaddition with vinyl ether
4a in the presence of SnCl4. The exo selectivity in the
cycloadditions of nitroalkene 5a and simple pentadienes
is easily understood in terms of the avoidance of steric
interactions between the allyl chain of the dienophile and
the heterodiene in the transition structure leading to
trans nitronate. The exo (alkoxy) preference observed
NiCl2(cat),28 and SmI2/HMPA.29 In all cases, either an
intractable mixture of products was obtained or decom-
position of the nitroso acetal 28 occurred.
To facilitate the selective cleavage of the halogen
surrogate, a bromine substituent was introduced at C(1).
Thus, the [4 + 2] cycloaddition of (2-bromo-2-nitroeth-
enyl)benzene30 (31) and vinyl ether (()-4a was performed,
Scheme 14. The resulting nitronate 32 was isolated in
high yield (93%), although the selectivity (exo/endo,
19/1) was slightly lower than that observed in the
analogous reaction of 27. The [3 + 2] cycloaddition of
32, performed using the same conditions employed for
nitronate 27, resulted in the poor mass recovery of a
mixture of products.
The exo selectivity in the cycloadditions of the chloro-
and bromo-substituted nitroalkenes 27 and 31 can be
inferred by comparison of 1H NMR data of the nitronates
27, 32, and 17a , Table 7. The chemical shifts and the
coupling patterns of the olefinic hydrogen H(2′) and the
hydrogen H(1′′) on the chiral auxiliary are diagnostic for
(27) Hudlicky, T.; Olivo, H. F. Tetrahedron Lett. 1991, 32, 6077.
(28) (a) Ashby, E. C.; Lin, J . J . J . Org. Chem. 1978, 43, 1263. (b)
Ganem, B.; Osby, J . O. Chem. Rev. 1986, 86, 763.
(29) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485.
(30) (a) Devlin, C. J .; Walker, B. J . J . Chem. Soc., Perkin Trans. 1
1973, 1428. (b) Parham, W. E.; Bleasdale, J . L. J . Am. Chem. Soc. 1951,
73, 4664.
(31) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
J ohn Wiley and Sons: New York, 1976.

Tandem Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 62, No. 14, 1997 4619
F igu r e 6. Preferred exo approach of a vinyl ether to the
nitroalkene 5a -Lewis acid complex.
F igu r e 7. MOPAC (PM3) calculated s-cis and s-trans confor-
mations of 4a .
in the reactions with the alkoxypentadienes 1 and 4a is
more intriguing and deserves a more detailed discussion.
Coulombic interactions between diene and dienophile in
the transition state have been invoked by Houk32 and
Hehre33 to rationalize the exo/endo selectivity in Diels-
Alder reactions. This model has allowed for an inter-
pretation of the selectivity observed in the Lewis acid
promoted cycloadditions of nitroalkenes with simple or
â-substituted vinyl ethers.2f,3b In this context it has been
pointed out that the nature of the substituent on the
â-position on the nitroalkene can influence the exo/endo
selectivity of the cycloaddition. Thus, attractive electro-
static interactions between the electron poor nitrogen of
the diene and the partially electron rich oxygen of the
dienophile would be responsible for the selective forma-
tion of the endo cycloadduct, Figure 6. However, the
presence of an extended π-conjugation in aryl-substituted
nitroalkenes could modify the electronic environment of
the nitrogen and allow for a delocalization of the positive
charge into the aryl ring. A consequent weakening of
the attractive interaction would be expected, such that
the less sterically demanding exo approach would be
preferred, Figure 6.3b
Obviously, the application of this model to the cycload-
ditions of the R-substituted vinyl ethers 1 and 4a with
nitroalkene 5a provides a convenient rationalization for
the high exo selectivity observed in these reactions.
However, this simplistic view does not take into account
both the nature of the nitroalkene-Lewis acid complex34
and the reactive conformation of the dienophile. In
addition, it fails to explain the complementary selectivi-
ties observed in the reactions promoted by SnCl4 and
MAD of 5a and the 2-alkoxy-1,4-pentadienes 1 and 4a .
The predominance of the endo selectivity in the [4 +
2] cycloadditions promoted by the bulky aluminum-based
Lewis acid MAD is surprising since one would expect the
exo approach of the vinyl ether to the nitroalkene-MAD
complex to be preferred on steric grounds. It could be
argued that, depending on the reactive conformation of
the enol ether, steric interactions between the methylenic
hydrogens in the allyl chain and the Lewis acid could
develop such that the endo approach is favored. How-
ever, this hypothesis is not convincing since the nonsyn-
chronous nature of the [4 + 2] cycloaddition process
attenuates the significance of such nonbonded inter-
actions.13a
The interpretation of the influence of the R-substituent
on the nitro olefin on the selectivity of the [4 + 2]
cycloaddition is even more problematic and difficult to
rationalize. The low selectivities observed in the cycload-
ditions of R-hydrogen substituted nitroalkenes (Tables 4
and 5) indicate that the R-substituent affects the orienta-
tion of the â-substituent which in turn might determine
the conformation of the dienophile in the transition
structure. An exclusive exo approach of the dienophile
4a occurs in the SnCl4-promoted cycloadditions of methyl-
and chloro-substituted nitroalkenes 5a and 26. Further-
more, the analogous reaction of the bromo-substituted
heterodiene 31 shows a slight decrease in selectivity (exo/
endo, 19/1).
The exo/endo selectivity is only one of the two compo-
nents that dictate the stereochemical outcome of the [4
+ 2] cycloaddition with chiral vinyl ethers. The second
contribution is given by the dienophile face selectivity,
i.e., the stereodifferentiation provided by the auxiliary.
This stereodifferentiation arises from the interaction of
the dienophile with the Lewis acid-substrate complex
and also the structure of the chiral auxiliary. Enol ethers
have been shown to exist in two limiting conformations,
s-cis and s-trans.35 The semiempirical calculated ground
state structure (PM3) for the s-cis and s-trans conforma-
tions of 2-alkoxy-1,4-pentadiene 4a show that a different
face of the enol ether is shielded in each conformation,
Figure 7.
The reactive conformation of the vinyl ether 4a in the
[4 + 2] cycloaddition with 5a can be inferred by the X-ray
crystal structure of nitroso acetal (()-19a , which in turn
reveals the sense of the asymmetric induction provided
by the chiral auxiliary. The crystallographically deter-
mined cis relationship between the phenyl (C(4)) and the
allyl group (C(6)) in nitronate 17a is uniquely established
by an exo-mode orientation of the vinyl ether with respect
to the heterodiene in the [4 + 2] cycloaddition. Moreover,
since the relative configuration of the auxiliary (1S*,2R*)-
2-phenylcyclohexanol is known, the relative configura-
tions of C(4) and C(6) in 17a can both be assigned as S*.
To obtain the 4S* configuration, the 2-alkoxy-1,4-penta-
diene 4a must approach the si face of nitroalkene 5a ,
whereas the C(6) configuration implies the approach of
5a to the re face of the vinyl ether. The high selectivity
observed in the [4 + 2] cycloaddition is a consequence of
the very efficient shielding provided by the chiral aux-
iliary to the si face of the vinyl ether. As shown in Figure
(32) (a) Loncharich, R. J .; Schwartz, T. R.; Houk, K. N. J . Am. Chem.
Soc. 1987, 109, 14. (b) Birney, D. M.; Houk, K. N. J . Am. Chem. Soc.
1990, 112, 4127.
(33) Kahn, S. D.; Hehre, W. J . J . Am. Chem. Soc. 1987, 109, 663.
(34) Early studies employing variable-temperature NMR experi-
ments suggested that the tin tetrachloride complex with 1-nitrocyclo-
hexene has a 1/1 stochiometry; however, the complex was still dynamic
at -120 °C (Cramer, C. J . Ph.D. Thesis; University of Illinois, Urbana,
IL, 1988).
(35) (a) Bond, D.; Schleyer, P. v. R. J . Org. Chem. 1990, 55, 1003.
(b) For a review, see: Fischer, P. Enol Ethers-Structure, Synthesis,
and Reaction. In The Chemistry of Ethers, Crown Ethers, Hydroxyl
Groups, and their Sulphur Analogs; Patai, S., Ed.; Wiley: New York,
1980; Part 2, p 761.

4620 J . Org. Chem., Vol. 62, No. 14, 1997
Denmark et al.
F igu r e 9. Proposed ground state and reactive conformations
for exo and endo nitronates.
F igu r e 8. Facial selectivity and reactive s-cis conformation
of alkoxypentadiene 4a .
8, only the s-cis conformation of 4a exposes the reactive
face of the alkoxypentadiene in the cycloaddition. There-
fore, the dienophile reacts in a cisoid conformation,
exposing its re face and approaching the si face of 5a ,
Figure 8. It is noteworthy that these R-substituted enol
ethers react in an s-cis conformation while simple vinyl
ethers or â-substituted enol ethers prefer an s-trans
conformation.2f However, we have recently discovered
that this behavior is actually a consequence of the Lewis
acid employed in the cycloaddition.36 The preference for
a s-cis reactive conformation appears to be characteristic
for SnCl4-promoted reactions (except for (Z)-â-substituted
enol ethers where the s-cis orientation is sterically
inaccessible).
[3 + 2] Cycloa d d ition . The activation energy re-
quired for the [3 + 2] dipolar cycloaddition is influenced
by the reactivity of the dipolarophile and the accessibility
of a suitable reactive conformation of the nitronate. A
previous study has documented the significant effects of
dipolarophile geometry and substitution on the rate of
the intramolecular [3 + 2] cycloadditions of cyclic
nitronates bearing a pendant dipolarophile on the C(4).14
The rate of the cycloaddition with unactivated dipolaro-
philes is considerably slower than that with activated
dipolarophiles. Furthermore, the order of the cycload-
dition rates has been found to be trans disubstituted >
monosubstituted > trisubstituted > cis disubstituted (a
similar trend has also been observed with activated
dipolarophiles). Thus, the intramolecular cycloadditions
of nitronates 9a -c, 12a ,b, and 17a are energetically
disfavored processes since they involve the reaction of a
nitronate dipole with an unactivated, monosubstituted
olefin as the dipolarophile. Both the trans and cis
nitronates are believed to adopt a half-chair conformation
in the ground state in which the phenyl group is placed
in a pseudoequatorial (trans nitronate) or in a pseudo-
axial position (cis nitronate), while the alkoxy group is
pseudoaxially oriented, by virtue of the anomeric effect,
Figure 9. A suitable approach of the dipolarophile to the
dipole can be accommodated only in a higher energy boat-
like conformation, which is particularly unfavorable in
the trans nitronate due to the nonbonded interactions
between the methyl and phenyl groups (Figure 9). The
F igu r e 10. Proposed mechanism for formation of 33.
difference in the experimental conditions (temperature
and reaction time), under which the [3 + 2] cycloadditions
of 12a and 12b (Scheme 6) are carried out, bears out the
difference in energies for reaction of the two nitronates.
The use of an insoluble base (NaHCO3 or K2CO3) in
the [3 + 2] cycloadditions of the nitronates derived from
2-alkoxy-1,4-pentadienes was essential for the success of
the reactions. Presumably, the base neutralizes acidic
products generated by the thermal destruction of the
nitronate, which in turn could accelerate the decomposi-
tion of both the nitroso acetal and nitronate. Interest-
ingly, the dipolar cycloaddition of nitronate (()-17a ,
conducted either in the absence of the base or in the
presence of a soluble and non-nucleophilic base (2,6-
lutidine), afforded a new compound which was identified
as the 1,2-oxazine 33. As shown in Figure 10, compound
33 could arise from the acid-catalyzed opening of the five-
membered ring of the tricyclic nitroso acetal 19a to give
intermediate i. Subsequent deprotonation and concomi-
tant bridge opening would lead to the observed product.
Hyd r ogen olysis. The studies on the selective hydro-
genolysis of nitroso acetal 19a to afford cyclohexanone
20 revealed an important insight into the mechanism of
the process. As shown in Scheme 9, the rate of the
Raney-nickel-promoted hydrogenation of 19a could be
modulated by a judicious choice of the catalyst loading
and the reaction time. The isolation of the diacetate 21
demonstrated that the two nitrogen-oxygen bonds in the
nitroso acetal are cleaved at different rates. Although
the isolation of 21 implies 22 as an intermediate, it does
not necessarily exclude the operation of the alternative
oxazine N-O bond cleavage pathway. Inspection of the
X-ray crystallographic structure of 19a revealed that the
(36) Dixon, J . A. Unpublished observations in these laboratories.

Tandem Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 62, No. 14, 1997 4621
with excellent asymmetric induction. The range of useful
nitroalkene components is currently limited to those
containing R-substituents. The hydrogenolytic unmask-
ing of the unusual tricyclic nitroso acetals proceeds
cleanly under mild conditions to afford highly substituted
aminocyclohexanemethanols as single stereoisomers. Ap-
plication of this method to the synthesis of aminocyclitols
is under investigation.
Exp er im en ta l Section
Gen er a l. See Supporting Information.
Ma ter ia ls. See Supporting Information.
2-Bu toxy-1,4-p en ta d ien e (1). To a cold (-70 °C) solution
of n-butyl vinyl ether (13.0 g, 16.8 mL, 130 mmol, 2.0 equiv)
in THF (84 mL) was added tert-butyllithium (1.43 M in
heptane, 70 mL, 100 mmol, 2.0 equiv), via an addition funnel.
The resulting bright yellow mixture was allowed to warm to
0 °C over a 3 h period. The almost colorless mixture was cooled
to -78 °C and transferred via cannula to a mechanically
stirred suspension of CuCN (4.48 g, 50.0 mmol, 1.0 equiv) in
THF (45 mL). The resulting tan suspension was allowed to
warm to -50 °C over a 2 h period and subsequently recooled
to -78 °C. Allyl bromide (6.10 g, 4.30 mL, 50 mmol) was added
dropwise over a 25 min period. The resulting orange-red
suspension was stirred for 1.5 h at -78 °C, allowed to warm
to rt, and quenched with aqueous NH4OH solution (pH ) 8,
100 mL). The mixture was diluted with diethyl ether (500
mL), and the organic phase was successively washed with an
aqueous NH4OH solution (pH ) 8, 3 × 100 mL), water (6 ×
100 mL), and brine (100 mL), then was dried (K2CO3), filtered,
and concentrated in vacuo. Fractional distillation of the
residue afforded 4.20 g (60%) of 3 as a clear, colorless liquid:
bp 72 °C (40 Torr); 1H NMR (400 MHz) δ 5.88 (ddt, J d ) 17.1,
10.3, J t ) 6.8, 1 H), 5.12-5.03 (m, 2 H), 3.87-3.85 (m, 2 H),
3.66 (t, J ) 6.6, 2 H), 2.84 (d, J ) 6.8, 2 H), 1.69-1.62 (m, 2
H), 1.46-1.37 (m, 2 H), 0.94 (t, J ) 7.3, 3 H); 13C NMR (100
MHz) δ 161.95, 134.87, 116.30, 80.98, 67.03, 39.52, 30.99,
19.34, 13.85; IR (neat) 2960, 2936, 1656, 1645, 1303, 1229,
1079, 1035; MS (70 eV) 140 (M+ + 1, 7), 42 (100). Anal. Calcd
for C9H16O (140.23): C, 77.09; H, 11.50. Found: C, 77.11; H,
11.60.
F igu r e 11. Mechanism of nitroso acetal 19a hydrogenolysis.
Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of
Ch ir a l 2-Alk oxy-1,4-p en ta d ien es 4a -c (Rep r esen ta tive
P r oced u r e I). The preparation of (+)-4a will serve to
illustrate the general procedure utilized.
F igu r e 12. Proposed mechanism for nitroso acetal 28 hydro-
genolysis.
2-[(1S,2R)-tr a n s-(2-P h en ylcycloh exyl)oxy]-1,4-p en ta d i-
en e ((+)-4a ). Rep r esen ta tive P r oced u r e I. A cold (-90
°C) solution of allylmagnesium chloride (2 M in THF, 8 mL,
15.90 mmol, 1.20 equiv) in THF (35 mL) was transferred via
a precooled cannula into a 3-neck, 250 mL, round-bottom flask
containing a cold (-90 °C) yellow-green solution of LiBr (1.45
g, 16.70 mmol, 1.26 equiv) and CuBr (2.40 g, 16.7 mmol, 1.26
equiv) in THF (35 mL). A solution of (+)-3a 9 (2.50 g, 13.30
mmol) in THF (3.5 mL) was added to the orange solution of
the allylcopper reagent (-90 °C). The dark brown reaction
mixture was warmed to -78 °C and stirred for 90 min. The
reaction was quenched by the addition of a NH4Cl solution
containing ammonium hydroxide (NH4Cl/NH4OH, pH ) 8, 80
mL). After warming to room temperature, the dark green
mixture was poured into pentane (800 mL) and washed with
the NH4Cl/NH4OH solution (4 × 100 mL). The aqueous layer
was back-extracted with pentane (3 x 100 mL). The combined
organic extracts were washed with brine (3 × 150 mL), dried
(Na2SO4), filtered, and concentrated in vacuo to afford a black
oil. The crude product was purified by column chromatogra-
phy on Activity IV neutral alumina (hexane) to give 2.67 g
(83%) of (+)-4a as a colorless oil: 1H NMR (400 MHz) δ 7.40-
7.10 (m, 5 H), 5.45 (ddt, J d ) 17.2, 10.4, J t ) 6.4, 1 H), 4.88-
4.76 (m, 2 H), 4.04 (dt, J d ) 4.0, J t )10.0, 1 H), 3.84 (d, J )
1.6, 1 H), 3.77 (d, J ) 1.6, 1 H), 2.70 (ddd, J ) 12.4, 10.2, 3.9,
1 H), 2.54 (d, J ) 6.4, 2 H), 2.39-2.31 (m, 1 H), 1.98-1.90 (m,
1 H), 1.89-1.83 (m, 1 H), 1.81-1.73 (m, 1 H), 1.60-1.22 (m, 4
H); 13C NMR (100 MHz) δ 160.50, 144.04, 134.83, 128.03,
127.51, 125.97, 115.64, 81.03, 78.62, 50.27, 39.72, 34.10, 31.02,
N-O bond in the oxazine ring is 0.051 Å longer than the
one in the five-membered ring. The longer and weaker
N-O bond would be expected to undergo reductive
cleavage more easily to afford, after acylation, the fused
bicyclic compound 24, Scheme 10. However, since only
diacetate 21 was isolated as an intermediate, one can
rationalize that 22 is the kinetic product and that the
cleavage of the N-O bond in the six-membered ring is
the slow step of the reaction, Figure 11.
The formation of the epimeric mixture of ketones 29/
30, upon hydrogenolysis of (()-28, can be explained on
the basis of the unselective reduction of the intermediate
imine iii which originates from the extrusion of the
chlorine atom after cleavage of the N-O bonds, Figure
12.
Con clu sion
The feasibility of the bridged (R-tether) mode of the
tandem inter [4 + 2]/intra [3 + 2] cycloaddition has been
demonstrated. Simple 1,4-pentadienes as well as 2-alkoxy-
1,4-pentadienes can function effectively as dienophile and
dipolarophile combinations with excellent chemical se-
lectivity and, regio- and diastereoselectivities. Chiral
2-alkoxy-1,4-pentadienes undergo the tandem process

4622 J . Org. Chem., Vol. 62, No. 14, 1997
Denmark et al.
26.08, 24.76; IR (CCl4) 3085, 2934, 2857, 1660, 1603, 1451,
28.01, 27.33, 25.40, 24.59, 24.22; IR (CCl4) 3329, 2967, 2941,
2934, 2861, 2143, 1496, 1118, 1088, 1014; MS (CI, CH4) 243
(M+ + 1, 2), 201 (100); TLC Rf 0.79 (hexane/TBME, 24/1).
Anal. Calcd for C17H22O (242.36): C, 84.25; H, 9.15. Found:
C, 84.46; H, 9.32.
1293, 1226, 1070, 1060; MS (CI, CH4) 243 (M+ + 1, 6), 159
(100); [R]22D +14.2° (CHCl3, c ) 1.45). Anal. Calcd for C17H22
(242.36): C, 84.25; H, 9.15. Found: C, 84.01; H, 9.34.
O
Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of
Ch ir a l Alk oxy Alk yn es 3b,c (Rep r esen ta tive P r oced u r e
II). The preparation of (()-3b will serve to illustrate the
general procedure utilized.
2-[(1R*,2S*)-tr a n s-(2-(1-Met h yl-1-p h en ylet h yl)cyclo-
h exyl)oxy]-1,4-p en ta d ien e ((()-4c). Following representa-
tive procedure I, from allylmagnesium chloride (2 M in THF,
4.9 mL, 9.71 mmol, 1.20 equiv) in THF (30 mL), LiBr (0.890
g, 10.23 mmol, 1.26 equiv), CuBr (1.47 g, 10.23 mmol, 1.26
equiv) in THF (30 mL), and (()-3c (1.97 g, 8.12 mmol, 1.0
equiv) in THF (4 mL) was obtained 2.01 g (87%) of (()-4c, as
a clear, colorless oil after column chromatography on Activity
IV neutral alumina (hexane): 1H NMR (400 MHz) δ 7.38-
7.06 (m, 5 H), 5.74 (ddt, J d ) 15.2, 10.0, J t ) 6.8, 1 H), 5.04-
4.96 (m, 2 H), 3.86-3.79 (m, 3 H), 2.51 (d, J ) 7.2, 2 H), 2.22-
2.12 (m, 1 H), 1.97 (ddd, J ) 12.2, 10.0, 3.4, 1 H), 1.70-1.63
(m, 1 H), 1.62-1.54 (m, 1 H), 1.52-1.43 (m, 1 H), 1.37 (s, 3
H), 1.25 (s, 3 H), 1.18-1.08 (m, 3 H), 0.98-0.86 (m, 1 H); 13C
NMR (100 MHz) δ 159.22, 151.41, 134.97, 127.71, 125.68,
124.88, 116.24, 80.37, 76.66 , 51.67, 40.31, 39.69, 31.01, 27.93,
27.51, 26.22, 25.77, 24.68; IR (CCl4) 2966, 2934, 2857, 1654,
1644, 1599, 1496, 1446, 1330, 1292, 1210, 1062, 1050, 1040;
(()-[(2,2-Diph en ylcyclopen tyl)oxy]eth yn e ((()-3b). Rep-
r esen ta tive P r oced u r e II. A 3-neck, 250-mL, round-bottom
flask equipped with magnetic stir bar was charged with a
suspension of potassium hydride (KH) in mineral oil. The KH
was washed with hexane (2 × 20 mL), and the residual solvent
was removed under high vacuum (0.1 Torr). (()-2,2-Diphen-
ylcyclopentanol2h ((()-2b) (4.45 g, 18.70 mmol) dissolved in 20
mL of THF was added dropwise to the cold (0 °C) suspension
of KH (1.50 g, 37.4 mmol, 2.0 equiv) in THF (20 mL). The
reaction mixture was stirred for 16 h at room temperature and
then was cooled to -74 °C. A solution of trichloroethylene (2.0
mL, 22.40 mmol, 1.0 equiv) in THF (6.0 mL) was slowly added,
maintaining the internal temperature below -70 °C. The
reaction mixture was warmed to room temperature, stirred
for 1 h, and cooled to -74 °C. n-Butyllithium (1.6 M in hexane,
35.3 mL, 56.1 mmol, 3.0 equiv) was added dropwise to the
resulting dark brown mixture. The reaction mixture was
stirred for 1 h at -74 °C, warmed to 0 °C, quenched with water
(25 mL), and then poured into a mixture of brine (50 mL) and
pentane (200 mL). The aqueous layer was back-extracted with
pentane (3 × 50 mL). The combined organic extracts were
washed with brine (50 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The resulting black oil was purified
by vacuum filtration through a plug of Activity III basic
alumina (hexane) to give 4.12 g (84%) of analytically pure (()-
3b as a light yellow solid, which could be stored at -25 °C
(3b decomposes at room temperature): 1H NMR (400 MHz) δ
7.40-7.05 (m, 10 H), 5.29-5.25 (m, 1 H), 2.65-2.57 (m, 1 H),
2.54-2.43 (m, 1 H), 2.36-2.25 (m, 1 H), 2.07-1.87 (m, 2 H),
1.73-1.59 (m, 1 H), 1.54 (s, 1 H); 13C NMR (100 MHz) δ 144.48,
143.99, 128.50, 128.05, 127.84, 126.32, 126.24, 126,01, 95.08,
89.93, 59.54, 33.64, 28.44, 27.84, 19.90; IR (CCl4) 3330, 2975,
2148, 1494, 1124, 1107; MS (FAB) 263 (M+ + 1, 9), 117 (100);
MS (CI, CH4) 284 (M+, 2), 119 (100). Anal. Calcd for C20H28
(284.44): C, 84.45; H, 9.92. Found: C, 84.29; H, 10.12.
O
Rep r esen ta tive P r oced u r e for th e [4 + 2] Cycloa d d i-
tion s of Nitr oa lk en es 5a -c a n d 3,3-Dim eth yl-1,4-p en ta -
d ien e a n d 1,4-P en ta d ien e. Rep r esen ta tive P r oced u r e
III. The preparation of (()-6a will serve to illustrate the
general procedure utilized.
(4R*,6R*)-3-Meth yl-6-(2-m eth yl-3-bu ten -2-yl)-4-p h en yl-
5,6-d ih yd r o-4H-[1,2]oxa zin e N-Oxid e ((()-6a ). Rep r e-
sen ta tive P r oced u r e III. To a cold (-78 °C) solution of
nitroalkene 5a 12 (0.489 g, 2.99 mmol) and 3,3-dimethyl-1,4-
pentadiene (0.565 g, 5.87 mmol, 2.0 equiv) in CH2Cl2 (4.0 mL)
was added dropwise SnCl4 (1.36 g, 0.60 mL, 5.20 mmol, 1.74
equiv). The yellow mixture was stirred at -78 °C for 20 min
and was then allowed to stand at -15 °C for 40 h. The reaction
was quenched with saturated aqueous NaHCO3 solution (6
mL), stirred for 5 min, allowed to warm to rt, and diluted with
CH2Cl2 (100 mL). The organic layer was washed with a
saturated aqueous NaHCO3 solution (2 × 50 mL) and brine
(50 mL). The combined aqueous layers were back-extracted
with CH2Cl2 (2 × 50 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. Purification by
column chromatography on neutral alumina (hexane/EtOAc,
2/1) afforded 0.526 g (68%) of nitronate (()-6a as a light yellow
solid. An analytical sample was obtained after recrystalliza-
tion (TBME) of a portion to afford (()-6a as a crystalline
solid: mp 115-116 °C (TBME): 1H NMR (400 MHz) δ 7.39-
7.26 (m, 3 H), 7.16-7.14 (m, 2 H), 5.73 (dd, J ) 17.3, 10.8, 1
H), 5.01 (dd, J ) 10.9, 1.0, 1 H), 4.97 (dd, J ) 17.5, 1.0, 1 H),
4.08 (dd, J ) 11.8, 1.6, 1 H), 3.80 (d, J ) 6.8, 1 H), 2.11 (ddd,
TLC Rf 0.69 (hexane/TBME, 24/1). Anal. Calcd for C19H18
O
(262.35): C, 86.99; H, 6.92. Found: C, 87.05; H, 7.05.
2-[(()-(2,2-Dip h en ylcyclop en t yl)oxy]-1,4-p en t a d ien e
((()-4b). Following representative procedure I, from allyl-
magnesium chloride (2 M in THF, 4.6 mL, 9.15 mmol, 1.20
equiv) in THF (25 mL), LiBr (0.834 g, 9.60 mmol, 1.26 equiv),
CuBr (1.38 g, 9.60 mmol, 1.26 equiv) in THF (25 mL), and (()-
3b (2.00 g, 7.62 mmol, 1 equiv) in THF (4 mL) was obtained
2.08 g (90%) of (()-4b as a clear, colorless oil after column
chromatography on Activity IV neutral alumina (hexane): 1H
NMR (400 MHz) δ 7.35-7.15 (m, 10 H), 5.55 (ddt, J d ) 17.2,
10.0, J t ) 6.8, 1 H), 5.03-4.98 (m, 1 H), 4.96-4.85 (m, 2 H),
3.96-3.92 (m, 2 H), 2.66-2.42 (m, 4 H), 2.05-1.76 (m, 3 H),
1.70-1.58 (m, 1 H); 13C NMR (100 MHz) δ 160.24, 146.36,
145.41, 134.80, 128.30, 128.23, 127.56, 126.70, 125.88, 125.38,
115.95, 82.18, 81.78, 59.29, 39.78, 34.65, 28.47, 20.49; IR (CCl4)
2972, 1654, 1598, 1495, 1447, 1303, 1292, 1267, 1227, 1074,
1034; MS (CI, CH4) 305 (M+ + 1, 1), 221 (100). Anal. Calcd
for C22H24O (304.44): C, 86.80; H, 7.95. Found: C, 86.74; H,
8.01.
J ) 13.7, 11.7, 7.1, 1 H), 1.98 (d, J ) 1.0, 3 H), 1.82 (dt, J d
)
13.7, J t ) 1.5, 1 H), 1.09 (s, 3 H), 1.02 (s, 3 H); 13C NMR (100
MHz) δ 142.67, 141.48, 129.04, 127.80, 127.42, 120.74, 113.56,
82.81, 42.76, 39.51, 29.17, 23.43, 22.12, 18.67; IR (KBr) 3065,
2974, 1606, 1275, 1238, 1014; MS (CI, CH4) 260 (M+ + 1, 41),
230 (100); TLC Rf 0.15 (hexane/EtOAc, 2/1). Anal. Calcd for
C16H21NO2 (259.35): C, 74.10; H, 8.16; N, 5.40. Found: C,
73.96; H, 8.15; N, 5.31.
Rep r esen ta tive P r oced u r e for th e [3 + 2] Cycloa d d i-
tion s of Nitr on a tes 6a a n d 9a -c. Rep r esen ta tive P r o-
ced u r e IV. The preparation of (()-7a will serve to illustrate
the general procedure utilized.
(1R*,2S*)-tr a n s-[(2-(1-Meth yl-1-ph en yleth yl)cycloh exyl)-
oxy]eth yn e ((()-3c). Following representative procedure II,
from (()-2c18 (2.26 g, 10.35 mmol) in THF (20 mL), KH (0.830
g, 20.70 mmol, 2.0 equiv) in THF (20 mL), trichloroethylene
(1.12 mL, 12.42 mmol, 1.2 equiv) in THF (4.0 mL), and
n-butyllithium (1.6 M, in hexane, 20 mL, 31.10 mmol, 3 equiv)
was obtained 2.36 g (94%) of (()-3c as a yellow oil after
vacuum filtration through a compressed pad of Activity III
basic alumina (hexane): 1H NMR (400 MHz) δ 7.40-7.10 (m,
5 H), 3.92 (dt, J d ) 4.4, J t ) 10.8, 1 H), 2.34-2.26 (m, 1 H),
1.89 (ddd, J ) 11.8, 10.1, 3.6, 1 H), 1.80-1.70 (m, 1 H), 1.60-
(1R*,6R*,7S*,8R*)-3-Aza -7,10,10-tr im eth yl-2,4-d ioxa -8-
p h en yl-tr icyclo[4.3.1.03,7]d eca n e ((()-7a ). Rep r esen ta -
tive P r oced u r e IV. A solution of nitronate (()-6a (0.384 g,
1.62 mmol) in toluene (23 mL) was allowed to stir at 110 °C
(oil bath) for 3 h. After being cooled to rt, the mixture was
concentrated in vacuo and the residue recrystallized (TBME)
to afford 0.305 g (79%) of nitroso acetal (()-7a as a white
solid: mp 164-165 °C (TBME): 1H NMR (400 MHz) δ 7.46-
7.39 (bs, 1 H), 7.33-7.29 (m, 2 H), 7.25-7.21 (m, 2 H), 4.06
(d, J ) 8.1, 1 H), 3.95 (dd, J ) 8.1, 5.1, 1 H,), 3.53 (t, J ) 2.7,
1 H), 3.30 (dd, J ) 11.5, 7.8, 1 H), 2.36 (ddd, J ) 11.9, 11.8,
1.48 (m, 3 H), 1.45 (s, 3 H), 1.42-1.34 (m, 4 H), 1.15 (qt, J q
)
12.8, J t ) 3.6, 1 H,), 1.03 (qt, J q ) 12.8, J t ) 3.6, 1 H), 0.83
(ddd, J ) 25.8, 12.6, 3.6, 1 H); 13C NMR (100 MHz) δ 149.76,
127.91, 125.86, 125.38, 89.70, 89.34, 51.08, 40.50, 31.80, 29.38,

Tandem Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 62, No. 14, 1997 4623
2.1, 1 H), 2.09 (d, J ) 5.1, 1 H), 2.00-1.91 (m, 1 H), 1.19 (s, 3
H, CH3), 1.13 (s, 3 H, CH3), 0.82 (s, 3 H); 13C NMR (100 MHz)
δ 143.59, 129.56, 128.75, 126.98, 76.09, 70.39, 70.13, 51.96,
41.86, 36.71, 33.94, 28.81, 25.91, 21.46; IR (KBr) 2938, 2874,
1493, 1456, 1388, 1230; MS (10 eV) 259 (M+, 2), 69 (100). Anal.
Calcd for C16H21NO2 (259.35): C, 74.10; H, 8.16; N, 5.40.
Found: C, 74.00; H, 8.16; N, 5.43.
Rep r esen ta tive P r oced u r e for th e Hyd r ogen a tion /
Acetyla tion of Nitr oso Aceta ls 7a a n d 10a -c. Rep r esen -
ta tive P r oced u r e V. The preparation of (()-8a will serve to
illustrate the general procedure utilized.
NO2 (231.29): C, 72.70; H, 7.41; N, 6.06. Found: C, 72.59; H,
7.40; N, 6.07.
[(1R*,2S*,3R*,5R*)-5-Acetoxy-2-(a cetyla m in o)-2-m eth -
yl-3-p h en ylcycloh exylm eth yl Aceta te ((()-11a ). Follow-
ing representative procedure V, from nitroso acetal (()-10a
(0.096 g, 0.41 mmol) was obtained 0.117 g (78%) of (()-11a as
a white, crystalline solid: mp 205-206 °C (hexane/EtOAc, 20/
1); 1H NMR (400 MHz) δ 7.33-7.24 (m, 3 H), 7.14-7.12 (m, 2
H), 5.28 (bs, 1 H), 4.92-4.84 (m, 1 H), 4.57 (dd, J ) 11.5, 3.9,
1 H), 3.95 (dd, J ) 11.5, 8.6, 1 H), 2.66 (dd, J ) 12.6, 4.5, 1 H),
2.14-2.08 (m, 1 H), 2.17-2.00 (m, 2 H), 2.05 (s, 3 H), 2.04 (s,
3 H), 1.97-1.86 (m, 1 H), 1.93 (s, 3 H), 1.62 (dd, J ) 24.8,
12.4, 1 H) 1.48 (s, 3 H); 13C NMR (100.6 MHz) δ 170.88, 170.27,
169.57, 139.30, 128.83, 128.19, 127.39, 71.08, 65.47, 56.37,
52.58, 46.38, 32.88, 30.76, 24.86, 23.22, 21.30, 21.02; IR (KBr)
3352, 2953, 1726, 1649, 1545, 1383, 1250, 1032; MS (70 eV)
301 (M+ - CH3CO2, 6), 43 (100); TLC Rf 0.12 (hexane/EtOAc,
1/1). Anal. Calcd for C20H27NO5 (361.44): C, 66.46; H, 7.53;
N, 3.88. Found: C, 66.46; H, 7.51; N, 3.91.
[(1R*,2S*,3R*,5R*)-5-Acetoxy-2-(a cetyla m in o)-2,6,6-tr i-
m eth yl-3-ph en ylcycloh exyl]m eth yl Acetate ((()-8a). Rep-
r esen ta tive P r oced u r e V. To a suspension of a small
amount of Raney nickel (washed with methanol (4 × 5 mL))
in methanol (6 mL) was added nitroso acetal (()-7a (0.061 g,
0.24 mmol). The suspension was stirred for 23 h under 1 atm
of hydrogen at rt. The cloudy suspension was filtered through
a cotton plug, washing with copious amounts of methanol. The
filtrate was concentrated in vacuo to afford a white solid (0.069
g). The crude product was dissolved in pyridine (2 mL), and
a catalytic amount of DMAP was added followed by acetic
anhydride (2 mL). The mixture was allowed to stir for 46 h
at rt and concentrated in vacuo. The residue was dissolved
in 100 mL of CH2Cl2 and washed successively with a saturated
aqueous NaHCO3 solution (2 × 30 mL), brine (30 mL), 2 M
HCl (2 × 30 mL), and brine (30 mL). The organic phase was
then dried (MgSO4) and concentrated in vacuo. The crude
organic concentrate was purified by silica gel column chroma-
tography (EtOAc/hexane, 2/1) to afford 0.054 g (59%) of
analytically pure (()-8a as a white solid: mp 171 °C (hexane/
EtOAc): 1H NMR (400 MHz) δ 7.34-7.24 (m, 3 H), 7.16-7.12
(m, 2 H), 5.26 (bs, 1 H), 4.74 (dd, J ) 11.5, 4.4, 1 H), 4.71 (dd,
J ) 12.5, 4.2, 1 H), 4.36 (dd, J ) 12.5, 3.7, 1 H), 2.77 (dd, J )
13.7, 3.2, 1 H), 2.23-2.00 (m, 1 H), 2.07 (s, 3 H), 2.04 (s, 3 H),
1.92 (dt, J d ) 13.4, J t ) 3.6, 1 H), 1.86 (s, 3 H), 1.61 (dd, J )
3.9, 3.7, 1 H), 1.53 (s, 3 H), 1.09 (s, 3 H), 1.02 (s, 3 H); 13C
NMR (100 MHz) δ 170.66, 170.48, 169.44, 139.33, 128.84,
128.22, 127.40, 78.53, 63.00, 59.04, 55.81, 52.42, 38.42, 28.55,
27.39, 24.97, 24.32, 21.18, 21.07, 16.50; IR (KBr) 3427, 3400,
2980, 1738, 1664, 1531, 1369, 1248, 1022; MS (70 eV) 389 (M+,
2), 43 (100); TLC Rf 0.18 (hexane/EtOAc, 1/1). Anal. Calcd
for C22H31NO5 (389.49): C, 67.84; H, 8.02; N, 3.60. Found:
C, 67.83; H, 8.01; N, 3.58.
(4R*,6S*)-4-Cycloh exyl-3-m eth yl-6-(2-p r op en yl)-5,6-d i-
h yd r o-4H-[1,2]oxa zin e N-Oxid e ((()-9b). Following rep-
resentative procedure III, from nitroalkene 5b12 (0.173 g, 1.02
mmol) in CH2Cl2 (1 mL), 1,4-pentadiene (0.197 g, 0.30 mL,
2.89 mmol, 2.3 equiv) in toluene (0.3 mL), and SnCl4 (0.565 g,
0.25 mL, 2.17 mmol, 2.1 equiv) was obtained a yellow oil
1
(mixture of diastereomers, 91/9 by H NMR). Purification by
column chromatography on neutral alumina (hexane/EtOAc,
2/1) afforded 0.149 g (62%) of nitronate (()-9b as a thick,
colorless oil: 1H NMR (400 MHz) δ 5.85-5.75 (m, 1 H), 5.17-
5.12 (m, 2 H), 4.35-4.29 (m, 1 H), 2.53-2.46 (m, 1 H), 2.36-
2.28 (m, 2 H), 2.06 (d, J ) 1.0, 3 H), 1.92 (ddd, J ) 14.4, 3.4,
3.2, 1 H), 1.81-1.62 (m, 5 H), 1.57-1.50 (m, 2 H), 1.35-1.20
(m, 4 H), 1.00-0.84 (m, 1 H); 13C NMR (100 MHz) δ 131.91,
123.58, 118.50, 78.40, 40.72, 40.03, 37.39, 31.01, 28.53, 26.70,
26.13, 25.83, 25.37, 17.50; IR (neat) 2930, 2851, 1601, 1448,
1252, 998; MS (CI, CH4) 238 (M+ + 1, 100); TLC Rf 0.17
(hexane/EtOAc, 1/1), 0.11 (hexane/EtOAc, 2/1).
(1R *,6R *,7S *,8R *)-3-Aza -8-cycloh e xyl-7-m e t h yl-2,4-
d ioxa tr icyclo[4.3.1.03.7]d eca n e ((()-10b). Following rep-
resentative procedure IV, from nitronate (()-9b (0.342 g, 1.44
mmol) in toluene (21 mL) was obtained 0.342 g (100%) of
analytically pure nitroso acetal (()-10b as a white solid: mp
1
149-150 °C (toluene); H NMR (400 MHz, C6D6) δ 3.81 (t, J
) 6.0, 1 H), 3.64-3.39 (m, 1 H), 3.47 (d, J ) 7.1, 1 H), 2.25 (d,
J ) 12.9, 1 H), 1.78-1.65 (m, 2 H), 1.64-1.48 (m, 4 H), 1.34-
1.26 (m, 2 H), 1.25-0.85 (m, 8 H), 0.84 (s, 3 H); 13C NMR (100
MHz, C6D6) δ 79.19, 68.31, 63.47, 41.35, 38.58, 38.31, 35.89,
31.36, 28.76, 27.33, 26.78, 26.43, 25.96, 19.78; IR (KBr) 2993,
2920, 2847, 1448, 930; MS (70 eV) 237 (M+, 8), 55 (100). Anal.
Calcd for C14H23NO2 (237.34): C, 70.85; H, 9.77; N, 5.90.
Found: C, 70.80; H, 9.78; N, 5.88.
(4R*,6S*)-3-Meth yl-4-ph en yl-6-(2-pr open yl)-5,6-dih ydr o-
4H-[1,2]oxa zin e N-Oxid e ((()-9a ). Following representative
procedure III, to a cold (-78 °C) solution of nitroalkene 5a 12
(0.098 g, 0.58 mmol) and 1,4-pentadiene (0.198 g, 0.30 mL,
2.90 mmol, 5.0 equiv) in CH2Cl2 (1.7 mL) was added dropwise
SnCl4 (0.249 g, 0.11 mL, 0.950 mmol, 1.7 equiv). Usual
workup, followed by column chromatography purification on
basic alumina (hexane/EtOAc, 1/1), afforded 0.125 g (91%) of
nitronate (()-9a as a thick, red oil: 1H NMR (400 MHz) δ
7.40-7.28 (m, 3 H), 7.18-7.15 (m, 2 H), 5.80-5.69 (m, 1 H),
5.11-5.05 (m, 2 H), 4.45-4.42 (m, 1 H), 3.80 (d, J ) 3.8, 1 H),
2.49-2.41 (m, 1 H), 2.38-2.28 (m, 1 H), 2.18 (ddd, J ) 13.8,
[(1R*,2S*,3R*,5R*)-5-Acetoxy-2-(a cetyla m in o)-3-cyclo-
h exyl-2-m eth ylcycloh exyl]m eth yl Aceta te ((()-11b). Fol-
lowing representative procedure V, from nitroso acetal (()-
10b (0.087 g, 0.37 mmol) was obtained a white solid, which
was washed with hexane/EtOAc and filtered to give 0.100 g
(74%) of (()-11b. An analytical sample was obtained after
recrystallization (ethanol) of a portion to afford (()-11b as a
10.9, 7.1, 1 H), 1.98 (d, J ) 1.0, 3 H), 1.88 (dt, J d ) 13.9, J t
)
2.0, 1 H); 13C NMR (100 MHz) δ 141.33, 131.63, 129.03, 127.71,
127.43, 120.76, 118.70, 76.29, 42.53, 37.41, 32.90, 18.50; IR
(Neat) 3065, 3026, 2926, 1730, 1606, 1495, 1284, 1240, 993,
918; MS (CI, CH4) 232 (M+ + 1, 100); TLC Rf 0.28 (hexane/
EtOAc, 2/1).
1
crystalline solid: mp 216 °C (ethanol); H NMR (400 MHz) δ
5.12 (bs, 1 H), 4.76-4.68 (m, 1 H), 4.51 (dd, J ) 11.6, 3.8, 1
H), 3.87 (dd, J ) 11.5, 8.3, 1 H), 2.06 (s, 3 H), 2.04 (s, 3 H),
2.03-1.89 (m, 2 H), 1.95 (s, 3 H), 1.71-1.31 (m, 6 H), 1.71 (s,
3 H), 1.22-0.96 (m, 9 H); 13C NMR (100 MHz) δ 170.86, 170.34,
169.52, 71.80, 65.32, 57.04, 51.75, 46.67, 36.37, 34.57, 30.72,
29.37, 28.35, 26.94, 26.65, 26.27, 25.08, 22.07, 21.31, 20.99;
IR (KBr) 3350, 2924, 1743, 1724, 1653, 1537, 1369, 1248, 1034;
MS (70 eV) 367 (M+, 3), 43 (100); TLC Rf 0.12 (hexane/EtOAc,
1/1), 0.26 (hexane/EtOAc, 1/2). Anal. Calcd for C20H33NO5
(367.48): C, 65.37; H, 9.06; N, 3.81. Found: C, 65.24; H, 9.17;
N, 3.80.
(1 R *,6 R *,7 S *,8 R *)-3 -Az a -7 -m e t h y l -2 ,4 -d i o x a -8 -
p h en yltr icyclo[4.3.1.03,7]d eca n e ((()-10a ). Following rep-
resentative procedure IV, from a solution of nitronate (()-9a
(0.327 g) in toluene (23 mL) was obtained 0.283 g (84%) of
nitroso acetal (()-10a as a white solid after recrystallization
(TBME): mp 161-162 °C (TBME); 1H NMR (400 MHz) δ
7.48-7.36 (bs, 1 H), 7.35-7.28 (m, 2 H), 7.26-7.20 (m, 2 H),
4.27 (ddd, J ) 8.1, 5.4, 1.0, 1 H), 4.15-4.10 (m, 1 H), 3.93 (d,
J ) 7.1, 1 H), 3.29 (dd, J ) 11.0, 7.6, 1 H), 2.56 (dd, J ) 9.3,
5.2, 1 H), 2.25 (dd, J ) 13.6, 9.6, 1 H), 2.15-2.03 (m, 3 H),
0.90 (s, 3 H); 13C NMR (100 MHz) δ 143.00, 129.00, 128.35,
126.56, 77.51, 68.38, 64.23, 41.61, 40.02, 37.66, 35.77, 20.88;
IR (KBr) 2951, 2914, 1495, 1454, 1252, 1093, 1074, 1028, 987;
(4S*,6S*)-3-Meth yl-4-pen tyl-6-(2-pr open yl)-5,6-dih ydr o-
4H-[1,2]oxa zin e N-Oxid e ((()-9c). Following representative
procedure III, to a cold (-78 °C) solution of nitroalkene 5c12
(0.154 g, 0.92 mmol) in CH2Cl2 (1 mL) was added a solution of
1,4-pentadiene (0.197 g, 0.30 mL, 2.89 mmol, 2.3 equiv) in
toluene (0.30 mL) followed by SnCl4 (0542 g, 0.24 mL, 2.08
MS (70 eV) 231 (M+, 11), 104 (100). Anal. Calcd for C14H17
-

4624 J . Org. Chem., Vol. 62, No. 14, 1997
Denmark et al.
mmol, 2.1 equiv). After being stirred at -78 °C for 5 min, the
deep yellow reaction mixture was allowed to stand at -15 °C
for 14 h. After usual workup, a crude yellow oil (mixture of
diastereomers, 94/6 by 1H NMR) was obtained. Purification
by column chromatography on neutral alumina (hexane/
EtOAc, 2/1, 1/1) afforded 0.120 g (55%) of nitronate (()-9c as
a thick, colorless oil: 1H NMR (400 MHz) δ 5.86-5.76 (m, 1
H), 5.18-5.13 (m, 2 H), 4.37-4.31 (m, 1 H), 2.53-2.47 (m, 1
H), 2.39-2.32 (m, 2 H), 2.05 (d, J ) 1.0, 3 H), 1.82-1.60 (m,
3 H), 1.41-1.24 (m, 7 H), 0.89 (t, J ) 6.9, 3 H); 13C NMR (100
MHz) δ 131.78, 123.45, 118.59, 76.89, 37.49, 35.92, 32.47,
31.32, 27.76, 26.48, 22.26, 17.72, 3.77; IR (neat) 2961, 2933,
2846, 1605, 1460, 1273, 997; MS (CI, CH4) 226 (M+ + 1, 100);
TLC Rf 0.17 (hexane/EtOAc, 1/1), 0.11 (hexane/EtOAc, 2/1).
(1R*,6R*,7S*,8S*)-3-Aza -9-m et h yl-2,4-d ioxa -8-p en t yl-
tr icyclo-[4.3.1.03.7]d eca n e ((()10c). Following representa-
tive procedure IV, from nitronate (()-9c (0.200 g, 0.89 mmol)
in toluene (13 mL) was obtained 0.200 g (100%) of analytically
pure nitroso acetal (()-10c as a white solid: mp 69 °C
10.5, J t ) 7.3, 1 H), 5.14-5.09 (m, 2 H), 3.86-3.78 (m, 2 H),
3.65 (dt, J d ) 9.0, J t ) 5.9, 1 H), 2.72-2.66 (m, 1 H), 2.48 (dd,
J ) 14.7, 7.6, 1 H), 2.28 (dd, J ) 13.9, 7.7, 1 H), 1.85 (dd, J )
13.9, 11.7, 1 H), 1.82 (d, J ) 1.5, 3 H), 1.63-1.46 (m, 2 H),
1.41-1.31 (m, 2 H), 0.91 (t, J ) 7.3, 3 H); 13C NMR (100 MHz)
δ 140.02, 130.28, 129.02, 127.86, 127.46, 122.99, 119.86,
104.45, 61.59, 41.86, 38.46, 37.78, 31.61, 19.10, 17.22, 13.70;
IR (CCl4) 3050, 2960, 1615, 1455, 1280, 1240, 1086; MS (CI,
CH4) 304 (M+ + 1, 100); TLC Rf 0.50 (hexane/EtOAc, 2/1). Anal.
Calcd for C18H25NO3 (303.405): C, 71.26; H, 8.31; N, 4.62.
Found: C, 71.27; H, 8.30; N, 4.62.
Rep r esen ta tive P r oced u r e for th e MAD-P r om oted [4
+ 2] Cycloa d d ition s of Nitr oa lk en e 5a a n d 2-Alk oxy-1,4-
p en t a d ien es 1 a n d (()-4a . R ep r esen t a t ive P r oced u r e
VII. The preparation of (()-12b will serve to illustrate the
general procedure utilized.
(4R*,6S*)-6-Bu toxy-3-m eth yl-4-p h en yl-6-(2-p r op en yl)-
5,6-d ih yd r o-4H-[1,2]oxa zin e N-Oxid e ((()-12b). Rep r e-
sen ta tive P r oced u r e VII. To a solution of BHT (1.46 g, 8.00
mmol, 4.0 equiv) in toluene (8 mL) was added dropwise a
solution of trimethylaluminum (2.0 M in toluene, 2.0 mL, 4.00
mmol, 2.0 equiv). Gas evolution was observed as the solution
was stirred at rt for 1 h. The resulting clear solution was
added over a 10 h period, via syringe pump, to a cold (-35
°C), stirred solution of nitroalkene 5a 12 (0.328 g, 2.00 mmol, 1
equiv) and vinyl ether 1 (1.12 g, 8.00 mmol, 4.0 equiv) in
toluene. The resulting pale-yellow reaction mixture was
stirred an additional 10 h at -35 °C and then was quenched
with water (5 mL) and poured into CH2Cl2 (200 mL). The
organic layer was washed with water (3 × 150 mL), and the
combined aqueous layer was back extracted with CH2Cl2 (3 ×
100 mL). The combined organic phase was washed with brine
(100 mL), dried (Na2SO4/NaHCO3, 1/1), filtered, and concen-
trated in vacuo to afford a yellow oil. The crude residue was
purified by silica gel column chromatography (hexane/EtOAc,
4/1) to afford a 4.6/1 (12b/12a ) ratio of diastereomers as
1
(toluene); H NMR (400 MHz, C6D6) δ 3.89 (t, J ) 6.4, 1 H),
3.95-3.61 (m, 1 H), 3.53 (d, J ) 7.1, 1 H), 1.68-1.00 (m, 14
H), 0.90 (t, J ) 7.2, 3 H), 0.87 (s, 3 H); 13C NMR (100 MHz,
C6D6) δ 77.30, 68.33, 63.23, 40.24, 35.99, 34.27, 33.81, 32.26,
32.24, 26.57, 23.03, 20.82, 14.33; IR (KBr) 2955, 2912, 2858,
1462, 1340, 1230, 1095; MS (10 eV) 225 (M+, 7), 69 (100). Anal.
Calcd for C13H23NO2 (225.33): C, 69.30; H, 10.29; N, 6.22.
Found: C, 69.26; H, 10.34; N, 6.20.
[(1R*,2S*,3S*,5R*)-5-Acetoxy-2-(a cetyla m in o)-2-m eth -
yl-3-p en tylcycloh exyl]m eth yl Aceta te ((()-11c). Follow-
ing representative procedure V, from nitroso acetal (()-10c
(0.117 g, 0.52 mmol) was obtained 0.124 g (67%) of (()-11c as
a white solid after column chromatography on silica gel
(EtOAc/hexane, 3/1). An analytical sample was obtained after
recrystallization (hexane/EtOAc) to afford (()-11c as a crystal-
line solid: mp 100-102 °C (hexane/EtOAc): 1H NMR (400
MHz) δ 5.00 (bs, 1 H), 4.76-4.62 (m, 1 H), 4.53 (dd, J ) 11.5,
3.9, 1 H), 3.91 (dd, J ) 11.5, 8.5, 1 H), 2.10-2.00 (m, 2 H),
2.04 (s, 3 H), 2.02 (s, 3 H), 1.97 (s, 3 H), 1.80-1.65 (m, 2 H),
1.65 (s, 3 H), 1.40-1.05 (m, 9 H), 0.98-0.93 (m, 1 H), 0.87 (t,
J ) 7.1, 3 H); 13C NMR (100 MHz) δ 170.77, 170.25, 169.85,
70.96, 65.33, 56.28, 46.62, 46.19, 32.30, 31.80, 30.51, 29.47,
27.62, 24.71, 22.47, 21.75, 21.20, 20.92, 13.92; IR (KBr) 3348,
2934, 1740, 1656, 1543, 1367, 1248, 1030; MS (70 eV) 355 (M+,
1), 43 (100); TLC Rf 0.14 (hexane/EtOAc, 1/1). Anal. Calcd
for C19H33NO5 (355.48): C, 64.20; H, 9.36; N, 3.94. Found:
C, 64.19; H, 9.35; N, 3.96.
1
determined by H NMR integration. After a second silica gel
column chromatography (hexane/EtOAc, 5/1), 0.042 g of nitr-
onate 12a , 0.087 g of a mixture of nitronates 12a and 12b,
and 0.243 g of analytically pure nitronate 12b were obtained
1
to give a combined yield of 0.377 g (62%). The H NMR data
for the less polar nitronate were consistent with those previ-
ously reported for 12a obtained through a tin(IV) chloride
promoted cycloaddition of nitroalkene 5a 12 and vinyl ether 1.
(()-12b: 1H NMR (400 MHz) δ 7.34-7.23 (m, 5 H), 5.70 (ddt,
J d ) 17.1, 9.8, J t ) 7.1, 1 H), 5.19-5.14 (m, 2 H), 3.88 (dt J d
) 9.0, J t ) 6.4, 1 H), 3.75-3.72 (m, 1 H), 3.59 (dt, J d ) 8.8, J t
) 6.8, 1 H), 2.70 (ddt, J d ) 14.7, 6.8, J t ) 1.2, 1 H), 2.52 (dd,
J ) 14.9, 7.6, 1 H), 2.43 (dd, J ) 13.9, 8.8, 1 H), 2.12 (dd, J )
13.9, 4.6, 1 H), 1.91 (d, J ) 1.5, 3 H), 1.61-1.49 (m, 2 H), 1.36-
Rep r esen ta tive P r oced u r e for th e Sn Cl4-P r om oted [4
+ 2] Cycloa d d ition s of Nitr oa lk en es a n d 2-Alk oxy-1,4-
p en ta d ien es 1 a n d 4a . Rep r esen ta tive P r oced u r e VI.
The preparation of (()-12a will serve to illustrate the general
procedure utilized.
1.26 (m, 2 H), 0.90 (t, J ) 7.3, 3 H);
13C NMR (100 MHz) δ
140.58, 130.77, 128.75, 128.58, 127.23, 123.74, 119.78, 105.59,
62.38, 41.92, 38.79, 37.23, 31.72, 19.22, 17.37, 13.90; IR (CCl4)
3050, 2960, 2874, 1613, 1495, 1281, 1250, 1217, 1079, 1005;
MS (CI, CH4) 304 (M+ + 1, 100); TLC Rf 0.35 (hexane/EtOAc,
2/1). Anal. Calcd for C18H25NO3 (303.405): C, 71.26; H, 8.31;
N, 4.62. Found: C, 71.26; H, 8.31; N, 4.63.
(4S*,6S*)-6-Bu toxy-3-m eth yl-4-p h en yl-6-(2-p r op en yl)-
5,6-d ih yd r o-4H-[1,2]oxa zin e N-Oxid e ((()-12a ). Rep r e-
sen ta tive P r oced u r e VI. To a cold (-78 °C) solution of
nitroalkene 5a 12 (0.250 g, 1.50 mmol) in CH2Cl2 (10 mL) was
added SnCl4 (0.780 g, 0.35 mL, 3.00 mmol, 2.0 equiv), and a
bright yellow solution resulted. After the solution was stirred
for 15 min at -78 °C, a solution of vinyl ether 1 (0.840 g, 6.00
mmol, 4.0 equiv) in CH2Cl2 (2 mL) was added over a 30 min
period. The mixture was allowed to stir for an additional 15
min and then was quenched with a solution of Et3N (0.5 mL)
in methanol (10 mL). The cold reaction mixture was diluted
with CH2Cl2 (200 mL), and the organic phase was washed with
water (3 × 200 mL). The combined aqueous layers were back-
extracted with CH2Cl2 (3 × 100 mL), and the combined organic
phase was washed with brine (100 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. The cloudy, yellow oil was
purified by silica gel column chromatography (hexane/EtOAc,
5/1) to afford 0.388 g of (()-12a as a white solid and 0.016 g of
(()-12b as a clear oil, for a combined yield of 0.404 g (89%)
and a diastereomeric ratio of 24/1 (12a /12b). The 1H NMR
spectral data for the more polar nitronate were consistent with
those reported for (()-12b obtained through an MAD-promoted
cycloaddition of nitroalkene 5a 12 with vinyl ether 1 (see next
preparation): mp 49-50.5 °C (hexane): 1H NMR (400 MHz)
δ 7.34-7.24 (m, 3 H), 7.17-7.14 (m, 2 H), 5.69 (ddt, J d ) 16.9,
(1R*,6R*,7S*,8S*)-3-Aza -1-bu t oxy-7-m et h yl-2,4-d ioxa -
8-p h en yltr icyclo[4.3.1.03,7]d eca n e ((()-13a ). A solution of
nitronate (()-12a (0.285 g, 0.94 mmol) in xylenes (10 mL), was
added over an 8 h period, via syringe pump, to a stirred
suspension of NaHCO3 (0.552 g, 6.57 mmol, 7.0 equiv) in
refluxing xylenes (84 mL). After the addition was complete,
the resulting mixture was heated at reflux for an additional
24 h. The suspension was cooled to rt, and the solvent was
removed in vacuo (0.5 Torr) to afford a brown solid. The crude
organic concentrate was dissolved in benzene (20 mL) and
filtered through a cotton plug into a round-bottom flask
charged with NaHCO3 (100 mg). After concentration in vacuo
(0.5 Torr), the crude residue was purified by column chroma-
tography on Activity III basic alumina (hexane/TBME, 5/1),
and fractions were collected in 13 × 100 mm tubes charged
with NaHCO3 (∼0.05 g). The fractions containing the product
were concentrated in vacuo (0.5 Torr) and filtered through a
cotton plug into a preweighed round-bottom flask containing
NaHCO3 (0.05 g). The solvent was removed in vacuo (0.5 Torr)

Tandem Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 62, No. 14, 1997 4625
to afford 0.234 g (82%) of nitroso acetal (()-13a as a white
solid in the presence of NaHCO3: 1H NMR (400 MHz, C6D6) δ
7.15-7.06 (m, 3 H), 6.96 (d, J ) 7.8, 2 H), 3.76-3.73 (m, 1 H),
3.65 (d, J ) 6.8, 1 H), 3.58 (dt, J t ) 6.6, J d ) 1.7, 2 H), 3.35
(dd, J ) 12.0, 6.1, 1 H), 2.40 (dt, J t ) 12.5, J d ) 3.4, 1 H),
2.08-1.96 (m, 2 H), 1.87 (dd, J ) 12.9, 3.4, 1 H), 1.54-1.46
(m, 3 H), 1.35-1.26 (m, 2 H), 0.79 (t, J ) 7.3, 3 H), 0.64 (s, 3
H); 13C NMR (100 MHz, C6D6) δ 142.85, 128.97, 128.91, 127.11,
96.13, 79.09, 69.31, 62.44, 44.21, 40.57, 40.02, 38.81, 32.55,
20.23, 19.54, 14.05.
(1R*,2S*,3R*,5S*)-5-Acetoxy-2-(a cetyla m in o)-2-m eth yl-3-
p h en ylcycloh exyl]m eth yl Aceta te ((()-16a ). Following
representative procedure V as described for the preparation
of 14a /15a , from a suspension of nitroso acetal (()-13b (0.66
mmol) and ca. 1.0 g of Raney nickel in methanol (16 mL) was
obtained, after acetylation, a light brown oil which was purified
by silica gel column chromatography (hexane/EtOAc, 1/1) to
afford 0.038 g of 11a , 0.028 g of a mixture of triacetates 16a
and 11a , and 0.094 g of analytically pure 16a , for a combined
yield of 0.160 g (68%) and an overall diastereomeric ratio of
1
1.8:1 (16a /11a ). The H NMR spectral data for the less polar
[(1R*,2S*,3S*,5S*)-5-Acetoxy-2-(a cetyla m in o)-2-m eth -
yl-3-p h en ylcycloh exyl]m et h yl Acet a t e ((()-14a ) a n d
[(1R*,2S*,3S*,5R*)-5-Acetoxy-2-(a cetyla m in o)-2-m eth yl-
3-p h en ylcycloh exyl]m eth yl Aceta te ((()-15a ). Following
representative procedure V, a suspension of nitroso acetal (()-
13a (0.210 g, 0.69 mmol), NaHCO3 (0.05 g), and Raney nickel
(2.00 g), in methanol (60 mL) was stirred for 40 h under 1
atm of hydrogen at rt. The cloudy suspension was filtered
through a Bu¨chner funnel lined with Whatman no. 1 filter
paper, washed with methanol (30 mL), and concentrated in
vacuo. The residue was treated with pyridine (8 mL) and
acetic anhydride (8 mL) at rt for 32 h. After usual workup,
the resulting crude oil was purified by silica gel column
chromatography (hexane/EtOAc, 1/1) to afford 0.195 g (78%)
of a mixture of triacetates (()-14a and (()-15a as a 1/1.6 (14a /
triacetate were consistent with those previously reported for
(()-11a obtained through the hydrogenolysis of nitroso acetal
(()-10a . (()-16a : 1H NMR (400 MHz) δ 7.32-7.21 (m, 3 H),
7.15-7.14 (m, 2 H), 5.28 (s, 1 H), 5.23 (bt, J ) 2.7, 1 H), 4.53
(dd, J ) 11.5, 4.1, 1 H), 3.93 (dd, J ) 11.5, 8.1, 1 H), 2.95 (dd,
J ) 13.9, 3.4, 1 H), 2.25 (dt, J d ) 14.7, J t ) 2.7, 1 H), 2.20-
2.13 (m, 1 H), 2.08-1.96 (m, 7 H), 1.90-1.80 (m, 5 H), 1.48 (s,
3 H); 13C NMR (100 MHz) δ 170.94, 170.34, 169.86, 139.73,
129.05, 128.09, 127.23, 68.49, 65.75, 57.17, 48.41, 42.15, 31.35,
29.47, 24.80, 24.13, 21.40, 21.01; IR (CCl4) 3400, 2920, 1741,
1698, 1366, 1238, 1033; MS (70 eV) 361 (M+, 2), 150 (100),
142 (100); TLC Rf 0.30 (EtOAc/hexane, 2/1). Anal. Calcd for
C20H27NO5 (361.44): C, 66.46; H, 7.53; N, 3.88. Found: C,
66.27; H, 7.68; N, 3.82.
1
15a ) ratio of diastereomers (determined by H NMR integra-
(4S,6S)-3-Met h yl-4-p h en yl-6-[(1S,2R)-(2-p h en ylcyclo-
h exyl)oxy]-6-(2-p r op en yl)-5,6-d ih yd r o-4H-[1,2]oxa zin e N-
Oxid e ((+)-17a ). Following representative procedure VI, a
mixture of nitroalkene 5a 12 (0.490 g, 3.00 mmol), SnCl4 (0.70
mL, 6.00 mmol, 2.0 equiv), and (+)-4a (0.870 g, 3.60 mmol,
1.2 equiv) in CH2Cl2 (23 mL) was stirred for 10 min at -74 °C
and then quenched by the addition of a methanolic solution of
triethylamine (52 mL, 0.5 M). The clear, cold (-75 °C) mixture
was poured into a separatory funnel containing H2O (50 mL)
and CH2Cl2 (250 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 200 mL). The combined organic extracts were
dried (Na2SO4), filtered through a compressed pad of Celite,
and concentrated in vacuo. The resulting crude product was
purified by silica gel column chromatography (hexane/EtOAc,
4/1) to give 1.19 g (98%) of (+)-17a as white crystals. Analyti-
cally pure (+)-17a (1.13 g, 93%) was obtained after recrystal-
lization from hexane/CH2Cl2: mp 137-138 °C (hexane/CH2-
Cl2); 1H NMR (400 MHz) δ 7.40-7.10 (m, 8 H), 6.90-6.84 (m,
2 H), 5.78 (ddt, J d ) 17.2, 10.4, J t )7.1, 1 H), 5.13-5.02 (m, 2
H), 4.16 (dt, J d ) 4.0, J t )10.0, 1 H), 2.74-2.67 (m, 1 H), 2.66-
2.57 (m, 3 H), 2.46-2.38 (m, 1 H), 1.92 (dd, J ) 13.6, 6.4, 1
H), 1.88-1.70 (m, 3 H), 1.68-1.42 (m, 4 H), 1.40-1.28 (m, 4
H); 13C NMR (100 MHz) δ 145.01, 139.73, 131.72, 128.83,
128.37, 128.07, 127.71, 127.34, 126.19, 122.30, 119.50, 104.10,
75.84, 51.71, 43.55, 39.75, 36.85, 35.16, 34.25, 25.74, 24.82,
17.94; IR (CCl4) 3029, 2934, 2859, 1613, 1494, 1455, 1278,
1238, 1130, 1078; MS (CI, CH4) 406 (M+ + 1, 12), 159 (100);
tion). A small amount of the triacetate mixture was separated
using MPLC (hexane/EtOAc, 3/2) to provide diastereomerically
pure samples of 14a (first eluted) and 15a (second eluted).
Compound 14a was recrystallized being dissolved in EtOAc
(1 mL) and then precipitated with hexane (3 mL) to afford an
analytically pure white crystalline solid. Diastereomer 15a
was further purified by silica gel column chromatography
(hexane/EtOAc, 1/1). (()-14a : mp 166-168°C (hexane/
EtOAc); 1H NMR (400 MHz) δ 7.40-7.30 (m, 3 H), 7.19-7.16
(m, 2 H), 5.37 (s, 1 H), 5.02 (tt, J ) 12.0, 5.5, 1 H), 4.30 (dd, J
) 11.2, 9.5, 1 H), 4.16 (dd, J ) 11.1, 4.8, 1 H), 3.31 (dtd, J d
)
10.0, 3.0, J t ) 5.0, 1 H), 2.90 (dd, J ) 12.5, 3.9, 1 H), 2.21-
2.16 (m, 1 H), 2.13-2.01 (m, 8 H) 1.83-1.75 (m, 4 H), 1.53 (s,
3 H); 13C NMR (100 MHz) δ 171.39, 170.35, 169.69, 138.95,
128.98, 128.93, 127.92, 68.67, 63.44, 56.98, 46.18, 40.06, 33.31,
28.90, 24.30, 21.29, 21.09, 18.98; IR (CHCl3) 3421, 2994, 2256,
1732, 1678, 1504, 1368, 1256, 1034; MS (FAB) 362 (M+ + H,
96), 302 (100); TLC Rf 0.22 (EtOAc/hexane, 2/1). Anal. Calcd
for C20H27NO5 (361.44): C, 66.46; H, 7.53; N, 3.88. Found:
C, 66.51 H, 7.61 N, 4.05. (()-15a : 1H NMR (400 MHz) δ 7.41-
7.34 (m, 3 H), 7.35-7.31 (m, 2 H), 5.44 (s, 1 H), 5.16 (q, J )
3.3, 1 H), 4.51 (t, J ) 10.4, 1 H), 4.13 (dd, J ) 10.5, 5.6, 1 H),
3.21 (dd, J ) 12.8, 3.3, 1 H), 3.15 (dtd, J d ) 10.0, 3.0, J t ) 5.0,
1 H), 2.30-2.20 (m, 2 H), 2.06 (s, 3 H) 2.01 (s, 3 H) 1.96-1.89
(m, 1 H,), 1.85 (dt, J d ) 15.8, J t ) 4.4, 1 H), 1.78 (s, 3 H), 1.47
(s, 3 H); 13C NMR (100 MHz) δ 171.43, 170.20, 169.64, 139.42,
129.15, 128.94, 127.80, 69.09, 65.03, 57.07, 42.11, 38.68, 32.52,
26.74, 24.31, 21.40, 20.96, 18.84; IR (CHCl3) 3421, 2957, 2258,
2250, 1732, 1678, 1504, 1380, 1369, 1263, 1034; MS (FAB) 362
(M+ + H, 27), 119 (100); TLC Rf 0.22 (EtOAc/hexane, 2/1); exact
mass calcd for C20H27NO5 + H 362.1967, found 362.1961
(FAB).
TLC Rf 0.30 (hexane/EtOAc, 2/1); [R]22 +284.5° (CHCl3, c )
D
1.10). Anal. Calcd for C26H31NO3 (405.54): C, 77.01; H, 7.71;
N, 3.46. Found: C, 77.01; H, 7.79; N, 3.29.
(4R*,6S*)-3-Met h yl-4-p h en yl-6-[(1S*,2R*)-(2-p h en yl-
cycloh e xyl)oxy]-6-(2-p r op e n yl)-5,6-d ih yd r o-4H -[1,2]-
oxa zin e N-Oxid e ((()-18a ). Following representative pro-
cedure VII, a solution of MAD (1.04 mmol, 1.3 equiv) in toluene
(3.5 mL) was added over a 20 h period, via syringe pump, to
a cold (-67 °C), stirred solution of nitroalkene 5a 12 (0.131 g,
0.80 mmol, 1.0 equiv) and vinyl ether (()-4a (0.252 g, 1.04
mmol, 1.3 equiv) in toluene. The resulting yellow-green
reaction mixture was stirred for an additional hour at -67 °C
and then was quenched with methanol (5 mL) and poured into
a mixture of CH2Cl2 (400 mL) and H2O (100 mL). The aqueous
layer was extracted with washed with CH2Cl2 (2 × 200 mL).
The combined organic phase was dried over Na2SO4, filtered
through a compressed pad of Celite, and concentrated in vacuo
to afford a yellow oil. The crude residue was purified by silica
gel column chromatography (hexane/EtOAc, 4/1) to afford a
diastereomeric mixture (17a /18a /18a ′, 1/40.7/3.8, as deter-
(1R*,6R*,7S*,8R*)-3-Aza -1-bu toxy-7-m eth yl-2,4-d ioxa -
8-p h en yltr icyclo[4.3.1.03,7]d eca n e ((()-13b). A solution of
nitronate (()-12b (0.200 g, 0.66 mmol) dissolved in benzene
(10 mL) was added to a suspension of NaHCO3 (0.388 g, 4.61
mmol, 7.0 equiv) in benzene (56 mL). The resulting reaction
mixture was heated to reflux for 11 h. After being cooled to
rt, the mixture was concentrated in vacuo (0.5 Torr) to afford
nitroso acetal (()-13b as a white solid: 1H NMR (400 MHz,
C6D6) δ 7.20-7.15 (m, 3 H), 7.08-7.04 (m, 2 H), 3.88-3.85
(m, 1 H), 3.66 (dt, J d ) 9.0, J t ) 6.6, 1 H), 3.64 (d, J ) 7.1, 1
H), 3.49 (dt, J d ) 9.0, J t ) 6.6, 1 H), 2.89 (dd, J ) 11.5, 6.8, 1
H), 2.13-2.07 (m, 1 H), 1.93-1.80 (m, 4 H), 1.54-1.47 (m, 2
H), 1.36-1.27 (m, 2 H), 0.81 (t, J ) 7.6, 3 H), 0.64 (s, 3 H); 13
C
NMR (100.6 MHz, C6D6) δ 143.85, 129.46, 128.74, 126.99,
96.66, 77.29, 68.98, 62.49, 43.56, 41.94, 41.20, 40.08, 32.50,
20.27, 19.53, 14.05.
1
mined by H NMR integration) of nitronates 17a /18a /18a ′ in
1
55% yield. The H NMR spectrum of nitronate (()-17a were
[(1R*,2S*,3R*,5R*)-5-Acetoxy-2-(a cetyla m in o)-2-m eth -
yl-3-p h en yl-cycloh exyl]m et h yl Acet a t e ((()-11a ) a n d
consistent with those previously reported for (+)-17a (obtained
through a tin(IV) chloride promoted cycloaddition of nitroalk-

4626 J . Org. Chem., Vol. 62, No. 14, 1997
Denmark et al.
ene 5a and vinyl ether (+)-4a . Recrystallization of the
diastereomeric mixture (hexane/CH2Cl2/Et2O) afforded nitr-
onate (()-18a in analytically pure form and in 48% yield: mp
124-125 °C (hexane/CH2Cl2/Et2O); 1H NMR (400 MHz) δ
7.46-7.22 (m, 5 H), 7.12-7.05 (m, 3 H), 6.68-6.60 (m, 2 H),
5.10-4.89 (m, 1 H), 4.81 (d, J ) 8.8, 1 H), 4.72 (d, J ) 16.8, 1
H), 3.76-3.64 (m, 2 H), 2.60-2.50 (m, 1 H), 2.28 (dd, J ) 14.8,
6.4, 1 H), 2.24-2.15 (m, 1 H), 2.10 (dd, J ) 14.0, 8.8, 1 H),
2.04 (s, 3 H), 1.94-1.58 (m, 5 H), 1.54-1.22 (m, 4 H); 13C NMR
(100 MHz) δ 143.73, 141.64, 131.38, 128.87, 128.23, 127.57,
126.80, 125.98, 122.02, 118.82, 105.72, 76.97, 50.30, 41.44,
38.59, 35.64, 34.69, 31.42, 25.75, 25.08, 18.38; IR (CCl4) 3082,
2933, 1615, 1494, 1451, 1289, 1253, 1137, 1074, 1004; MS (CI,
CH4) 406 (M+ + 1, 15), 159 (100); TLC Rf hexane/EtOAc, 2/1).
Anal. Calcd for C26H31NO3 (405.54): C, 77.01; H, 7.71; N, 3.46.
Found: C, 76.77; H, 7.64; N, 3.46.
[4 + 2] Cycloa d d ition of 7a a n d (()-6a P r om oted by
Ti(O-i-P r )2Cl2. (4S*,6S*)-3-Meth yl-4-p h en yl-6-[(1S*,2R*)-
(2-p h en ylcycloh exyl)oxy]-6-(2-p r op en yl)-5,6-d ih yd r o-4H-
[1,2]oxa zin e N-Oxid e ((()-17a ). A freshly prepared solution
of Ti(O-i-Pr)2Cl2 (0.48 mmol, 2.4 equiv) in CH2Cl2 (0.3 mL) was
slowly added to a cold (-74 °C) solution of 5a 12 (0.033 g, 0.2
mmol, 1 equiv) in CH2Cl2 (1 mL), and the resulting solution
was allowed to stir for 15 min. Subsequently, (()-4a (0.063
g, 0.26 mmol, 1.3 equiv) in CH2Cl2 (0.5 mL) was added. The
reaction mixture was stirred for 30 min at -74 °C and then
quenched by addition of a methanolic solution of triethylamine
(0.5 M, 3 mL). The mixture was diluted with CH2Cl2 (250 mL),
washed with H2O (50 mL), dried over Na2SO4, filtered through
a compressed pad of celite, and concentrated in vacuo. 1H
NMR of the crude product revealed the presence of unreacted
nitroalkene 5a (20%). Purification of the crude mixture by
silica gel column chromatography (hexane/EtOAc, 4/1) afforded
0.042 g (52%) of a diastereomeric mixture of nitronates 17a /
18a ′ (17a /18a ′, 8.8/1). The 1H NMR data for the major
diastereomer were consistent with those reported for (+)-17a
obtained through the SnCl4-promoted cycloaddition of 5a and
(+)-4a .
and subsequentely cooled to room temperature, and the
reaction mixture was filtered through a glass-sintered (me-
dium frit) funnel and concentrated in vacuo, in the presence
of a small amount of fresh NaHCO3. The crude product was
purified by column chromatography on basic alumina Activity
III (hexane/EtOAc, 1/2) to give 0.298 g (76%) of (()-19a as a
white solid. A suitable crystal for X-ray analysis was obtained
by diffusion crystallization in EtOAc/pentane: mp 138-139
°C; 1H NMR (400 MHz) δ 7.19-6.88 (m, 8 H), 6.81-6.76 (m, 2
H), 3.79 (dt, J d ) 4.3, J t ) 10.2, 1 H), 3.68-3.57 (m, 2 H), 3.20
(dd, J ) 12.0, 6.0, 1 H), 2.70-2.62 (m, 1 H), 2.58-2.50 (m, 1
H), 2.10 (dt, J d ) 3.5, J t ) 12.8, 1 H), 1.97 (dd, J ) 13.8, 10.2,
1 H), 1.82-1.70 (m, 3 H), 1.66-1.55 (m, 2 H), 1.52-1.36 (m, 2
H), 1.30-1.16 (m, 1 H), 1.14-1.04 (m, 1 H), 0.61 (s, 3 H), 0.49
(dd, J ) 13.2, 6.0, 1 H); 13C NMR (100 MHz) δ 144.86, 142.74,
128.77, 128.68, 128.64, 128.00, 126.91, 126.24, 96.68, 78.94,
76.51, 69.26, 51.44, 44.21, 43.31, 38.62, 37.61, 36.27, 32.89,
26.12, 25.39, 20.31; IR (KBr) 3028, 2977, 2926, 2856, 1494,
1459, 1383, 1344, 1326, 1321, 1256, 1168, 1122, 1094, 1019,
796, 754; MS (FAB) 406 (M+ + 1, 19), 154 (100); TLC Rf 0.40
(hexane/EtOAc, 2/1). Anal. Calcd for C26H31NO3 (405.54): C,
77.01; H, 7.71; N, 3.46. Found: C, 76.93; H, 7.48; N, 3.64.
Hyd r ogen a tion /Acetyla tion of Nitr oso Aceta l (()-19a .
[(1R*,2S*,3S*,5S*)-5-Acet oxy-2-(a cet yla m in o)-2-m et h yl-
3-p h en ylcycloh exyl]m et h yl Acet a t e ((()-14a ) a n d
[(1R*,2S*,3S*,5R*)-5-Acetoxy-2-(a cetyla m in o)-2-m eth yl-
3-p h en ylcycloh exyl]m eth yl Aceta te ((()-15a ). Following
representative procedure V, from a suspension of nitroso acetal
(()-19a (0.390 g, 0.96 mmol) and ca. 1.2 g of Raney nickel in
methanol (33 mL) was obtained, after acetylation, a yellow oil
which was purified by silica gel column chromatography
(hexane/EtOAc, 1/2) to afford 0.298 g (86%) of a mixture of
triacetates (()-14a and (()-15a as a 1.8/1 (14a /15a ) ratio of
diastereomers (determined by 1H NMR integration) along with
0.212 g (61%) of acetylated chiral auxyliary. The 1H NMR data
for the triacetates were consistent with those reported for (()-
14a and (()-15a obtained through the analogous reaction
sequence from nitroso acetal (()-13a .
(1R ,6R ,7S ,8S )-3-Aza -7-m e t h yl-2,4-d ioxa -8-p h e n yl-1-
[(1S ,2R )-(2-p h e n ylcycloh e xyl)oxy]t r icyclo[4.3.1.03,7]-
d eca n e ((+)-19a ). A 250-mL, round-bottom flask equipped
with magnetic stir bar and a condenser was charged with K2-
CO3 (1.28 g, 9.10 mmol, 7.0 equiv). Potassium carbonate was
dried in the reaction apparatus in vacuo (200 °C, 0.1 Torr, 10
min). The apparatus was allowed to cool to room temperature,
and K2CO3 was suspended in 90 mL of toluene. A solution of
the nitronate (+)-17a (0.527 g, 1.30 mmol, 1.0 equiv) in toluene
(40 mL) was then added, and the resulting mixture was
refluxed for 26 h. The grey-blue reaction mixture was cooled
to room temperature, filtered through a glass-sintered (me-
dium frit) funnel, and concentrated in the presence of a small
amount of fresh K2CO3. The crude product was purified by
column chromatography on Activity III basic alumina (hexane/
TBME, 2/1) to give 0.395 g (75%) of (+)-19a as a white solid:
[(1R,2S,3S)-2-(Acetyla m in o)-2-m eth yl-5-oxo-3-p h en yl-
cycloh exyl]m eth yl Aceta te ((-)-20). A solution of nitroso
acetal (+)-19a (0.434 g, 1.07 mmol) in a 0.002 M methanolic
solution of K2CO3 (48 mL) was added to a suspension of 0.675
g of Raney nickel (prewashed with methanol and dried under
stream of nitrogen, rt, 1 atm). The reaction mixture was
stirred for 40 min under 1 atm of hydrogen at room temper-
ature and then filtered through a compressed pad of Celite.
The catalyst was washed with methanol. The solvent was
removed in vacuo, and the residue was dissolved in pyridine
(14 mL) and treated with acetic anhydride (14 mL). The
resulting reaction mixture was stirred for 6 h at room
temperature. Pyridine and acetic anhydride were removed by
bulb-to-bulb distillation (40 °C, 0.1 Torr), and the residual
yellow oil was purified by silica gel column chromatography
(hexane/EtOAc, 1/1) to give 0.292 g (86%) of ketone (-)-20 in
99% enantiomeric excess (by chiral HPLC): 1H NMR (400
MHz) δ 7.42-7.25 (m, 3 H), 7.20-7.15 (m, 2 H), 5.71 (bs, 1
H), 4.31 (dd, J ) 11.4, 4.2, 1 H), 4.07 (dd, J ) 11.4, 6.2, 1 H),
3.99 (dd, J ) 11.4, 4.6, 1 H), 2.97 (dd, J ) 16.0, 8.8, 1 H), 2.90-
2.83 (m, 1 H), 2.79 (dd, J ) 16.6, 11.8, 1 H), 2.66-2.54 (m, 2
H), 2.05 (s, 3 H), 1.95 (s, 3 H), 1.40 (s, 3 H); 13C NMR (100
MHz) δ 209.47, 170.54, 170.18, 138.55, 128.92, 128.55, 127.60,
64.09, 57.12, 44.80, 42.33, 40.42, 40.09, 24.23, 21.57, 20.74;
IR (CCl4) 3425, 3032, 1736, 1719, 1510, 1369, 1232; MS (CI,
CH4) 318 (M+ + 1, 22), 258 (100); TLC Rf 0.19 (hexane/EtOAc,
1
mp 142-144 °C; H NMR (400 MHz, C6D6) δ 7.20-6.70 (m,
10 H), 3.79 (dt, J d ) 4.3, J t ) 10.1, 1 H), 3.68-3.57 (m, 2 H),
3.20 (dd, J ) 12.0, 6.0, 1 H), 2.70-2.62 (m, 1 H), 2.54 (ddd, J
) 13.0, 9.8, 3.4, 1 H), 2.10 (dt, J d ) 3.5, J t ) 12.4, 1 H), 1.96
(dd, J ) 13.6, 10.4, 1 H), 1.82-1.70 (m, 3 H), 1.66-1.55 (m, 2
H), 1.52-1.36 (m, 2 H), 1.30-1.16 (m, 1 H), 1.14-1.04 (m, 1
H), 0.61 (s, 3 H), 0.48 (dd, J ) 12.8, 6.0, 1 H); 13C NMR (100
MHz, C6D6) δ 144.86, 142.73, 128.78, 128.69, 128.64, 128.00,
126.93, 126.25, 96.69, 78.94, 76.51, 69.27, 51.44, 44.20, 43.30,
38.62, 37.59, 36.27, 32.88, 26.12, 25.39, 20.31; IR (CCl4) 3031,
2934, 2858, 1496, 1450, 1351, 1176, 1122, 1093, 1040, 1026;
MS (FAB) 406 (M+ + 1, 12), 154 (100); TLC Rf 0.40 (hexane/
1/2); [R]23D -48.66° (CHCl3, c ) 1.695). Anal. Calcd for C18H23
-
NO4 (317.38): C, 68.12; H, 7.30; N, 4.41. Found: C, 67.97; H,
7.41; N, 4.27.
EtOAc, 2/1); [R]23 +103.7° (CH3OH, c ) 1.010). Anal. Calcd
D
for C26H31NO3 (405.54): C, 77.01; H, 7.71; N, 3.46. Found:
C, 77.09; H, 7.90; N, 3.41.
(1R*,4S*,5S*,8R*)-8-(Acetoxym eth yl)-N-a cetyl-3-a za -2-
oxa -5-p h e n yl-1-[(1R *,2S *)-(2-p h e n ylcycloh e xyl)oxy]-
bicyclo[2.2.2]octa n e ((()-21). A solution of nitroso acetal
(()-19a (0.171 g, 0.42 mmol) in methanol (16 mL) was added
to a suspension of 0.166 g of Raney nickel (prewashed with
methanol and dried under stream of nitrogen, rt, 1 atm). The
reaction mixture was stirred for 100 min under 1 atm of
hydrogen at room temperature and then filtered through a
plug of Celite. The catalyst was washed with methanol (5 ×
(1R*,6R*,7S*,8S*)-3-Aza -7-m et h yl-2,4-d ioxa -8-p h en yl-
1-[(1S,2R)-(2-p h en ylcycloh exyl)oxy]t r icyclo[4.3.1.03,7]-
d eca n e ((()-19a ). A 1-neck, 250-mL, round-bottom flask
equipped with magnetic stir bar and a condenser was charged
with NaHCO3 (0.76 g, 9.1 mmol, 7 equiv), 90 mL of toluene,
and a solution of the nitronate 17a (0.53 g, 1.3 mmol) in
toluene (40 mL). The resulting mixture was refluxed for 30 h

Tandem Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 62, No. 14, 1997 4627
20 mL). The solvent was removed in vacuo. The crude product
was dissolved in pyridine (5.5 mL) and treated with acetic
anhydride (5.5 mL). The resulting reaction mixture was
stirred for 6 h at room temperature. Pyridine and acetic
anhydride were removed by bulb-to-bulb distillation (30 °C,
0.1 Torr), and the residual yellow oil was purified by column
chromatography on Activity III neutral alumina (hexane/
EtOAc, 3/1) to afford 0.114 g (55%) of (()-21, as a white solid.
Diacetate (()-21 (0.108 g, 42%) was obtained in analytically
pure form after two recrystallizations from hexane/CH2Cl2: mp
172-173 °C (hexane/CH2Cl2); 1H NMR (400 MHz) δ 7.30-7.20
(m, 7 H), 7.15-7.10 (m, 1 H), 6.96-6.90 (m, 2 H), 4.15 (dd, J
CH2Cl2 to afford 0.457 g (78%) of (()-27 as a pale yellow
solid: mp 140 °C (hexane/CH2Cl2); 1H NMR (400 MHz) δ 7.40-
7.17 (m, 5 H), 6.85-6.78 (m, 4 H), 5.76 (ddt, J d ) 17.0, 10.2,
J t ) 7.2, 1 H), 5.16-5.04 (m, 2 H), 4.15 (dt, J d ) 4.0, J t
)
10.0, 1 H), 3.77 (s, 3 H), 2.93 (dd, J ) 12.4, 6.0, 1 H), 2.68-
2.57 (m, 3 H), 2.44-2.36 (m, 1 H), 2.05 (dd, J ) 13.8, 6.2, 1
H), 1.92-1.71 (m, 4 H), 1.70-1.24 (m, 4 H); 13C NMR (100
MHz) δ 159.01, 144.30, 131.21, 130.27, 129.16, 128.70, 127.29,
126.57, 120.11, 119.96, 114.05, 105.23, 76.42, 55.18, 51.54,
42.89, 41.35, 38.68, 34.88, 34.02, 25.61, 24.73; IR (CCl4) 3020,
2936, 1597, 1514, 1252, 1177, 1034, 1004; MS (CI, CH4) 456
(M+ + 1, 10), 159 (100); TLC Rf 0.65 (hexane/EtOAc, 2/1).
Anal. Calcd for C26H30ClNO4 (455.98): C, 68.49; H, 6.63; N,
3.07; Cl, 7.78. Found: C, 68.64; H, 6.69; N, 2.93; Cl, 7.49.
[(1R*,6S*,7R*,8S*)-3-Aza-7-ch lor o-8-(4-m eth oxyph en yl)-
2,4-d ioxa -1-[(1R*,2S*)-(2-p h en ylcycloh exyl)oxy]tr icyclo-
[4.3.1.03,7]d eca n e ((()-28). A suspension of (()-27 (0.474 g,
1.04 mmol) and K2CO3 (0.288 g, 2.08 mmol, 2.0 equiv) in CH3-
CN (120 mL) was stirred for 79 h at 72-73 °C. The reaction
mixture was cooled to room temperature, filtered through a
glass-sintered (medium frit) funnel, and concentrated in vacuo
in the presence of a small amount of fresh K2CO3. The crude
product was purified by column chromatography on Activity
II basic alumina (pentane/Et2O, 1/1) to give 0.284 g (60%) of
(()-28 as a white solid: mp 107-108 °C; 1H NMR (400 MHz)
δ 7.30-7.05 (m, 5 H), 7.02-6.95 (m, 2 H), 6.88-6.80 (m, 2 H),
4.31 (dd, J ) 6.4, 3.6, 1 H), 4.02 (d, J ) 6.4, 1 H), 3.80 (s, 3 H),
3.69 (dt, J d ) 4.3, J t ) 10.3, 1 H), 3.60 (dd, J ) 12.0, 6.0, 1 H),
2.78 (dd, J ) 10.0, 4.0, 1 H), 2.54-2.44 (m, 1 H), 2.32-2.15
(m, 3 H), 2.00-1.56 (m, 5 H), 1.52-1.22 (m, 3 H), 0.60 (dd, J
) 13.0, 5.8, 1 H); 13C NMR (100 MHz) δ 158.82, 143.91, 131.53,
129.89, 128.20, 127.76, 126.22, 113.67, 96.29, 95.07, 78.51,
77.38, 55.16, 50.64, 43.55, 42.86, 41.38, 37.33, 35.44, 31.92,
25.64, 25.01; IR (CCl4) 3024, 2937, 2859, 1515, 1353, 1250,
1231, 1173; MS (FAB) 456 (M+ + 1, 6), 154 (100); TLC Rf 0.30
(hexane/EtOAc, 3/1). Anal. Calcd for C26H30ClNO4 (455.98):
C, 68.49; H, 6.63; N, 3.07; Cl, 7.78. Found: C, 68.40; H, 6.67;
N, 3.18; Cl, 7.82.
) 10.8, 4.8, 1 H), 4.00 (dd, J ) 10.6, 9.4, 1 H), 3.69 (dt, J d
)
4.4, J t ) 10.4, 1 H), 3.53 (dd, J ) 11.2, 3.6, 1 H), 2.57 (ddd, J
) 12.4, 10.2, 3.4, 1 H), 2.25-2.16 (m, 1 H), 2.06 (s, 3 H), 1.97
(s, 3 H), 2.02-1.64 (m, 8 H), 1.50 (s, 3 H), 1.58-1.46 (m, 1 H),
1.44-1.24 (m, 2 H), 0.69 (dd, J ) 14.4, 3.6, 1 H); 13C NMR
(100 MHz) δ 173.73, 170.82, 143.62, 138.52, 128.48, 128.36,
128.05, 127.86, 126.93, 126.40, 104.96, 77.42, 65.95, 61.93,
50.51, 46.52, 37.72, 35.63, 35.44, 32.12 31.38, 25.58, 25.17,
22.96, 22.59, 20.78; IR (CHCl3) 3030, 3009, 1736, 1732, 1656,
1450, 1384, 1234; MS (FAB) 493 (M+ + 2, 29), 492 (86), 154
(100); TLC Rf 0.69 (hexane/EtOAc, 2/1). Anal. Calcd for
C30H37NO5 (491.63): C, 73.29; H, 7.59; N, 2.85. Found: C,
73.55; H, 7.61; N, 2.93.
6-[(1R*,2S*)-(2-(1-Met h yl-1-p h en ylet h yl)cycloh exyl)-
o x y ]-4-p h e n y l-6-(2-p r o p e n y l)-5,6-d ih y d r o -4H -[1,2]-
oxa zin e N-Oxid e (25d c). Following representative procedure
VI, a mixture of 5d 12 (0.191 g, 1.28 mmol), SnCl4 (0.30 mL,
2.56 mmol, 2.0 equiv), and (()-4c (0.555 g, 1.92 mmol, 1.5
equiv) in toluene (11 mL) was stirred for 15 min at -74 °C
and then quenched by the addition of a methanolic solution of
triethylamine (20 mL, 0.5 M). The cold (-74 °C) mixture was
poured into a mixture of H2O (150 mL) and TBME (500 mL).
The aqueous layer was back-extracted with TBME (3 × 150
mL). The combined organic phase was dried (Na2SO4), filtered
through a compressed pad of Celite, and concentrated in vacuo.
Purification of the crude product by silica gel column chroma-
tography (hexane/EtOAc, 9/1) afforded 0.308 g (55.5%) of
nitronate 25d ca as a pale yellow foam and 0.159 g (28.7%) of
analytically pure nitronate 25d cb as a white foam. 25d ca :
1H NMR (400 MHz, C6D6) δ 7.75-7.68 (m, 2 H), 7.38-6.88
(m, 6 H), 6.72-6.64 (m, 2 H), 5.93 (d, J ) 2.4, 1 H), 5.55 (ddt,
J d ) 16.8, 10.0, J t ) 7.2, 1 H), 4.91 (dd, J ) 10.0, 1.6, 1 H),
4.81 (dd, J ) 17.2, 1.6, 1 H), 4.36-4.28 (m, 1 H), 3.73 (ddd, J
) 12.2, 6.9, 2.8, 1 H), 2.40-2.33 (m, 1 H), 2.32-2.16 (m, 2 H),
1.88 (ddd, J ) 13.2, 6.9, 0.7, 1 H), 1.78-1.38 (m, 15 H); 13C
NMR (100 MHz, C6D6) δ 150.48, 140.61, 131.58, 129.03, 128.35,
127.86, 127.45, 127.07, 125.82, 119.44, 111.86, 104.64, 69.74,
48.71, 41.11, 39.79, 37.76, 36.76, 29.76, 28.45, 28.09, 23.13,
22.61, 20.21; IR (CCl4) 3088, 2936, 2933, 2866, 1625, 1497,
1454, 1319, 1234, 1106, 1002; MS (CI, CH4) 434 (M+ + 1, 6),
105 (100); TLC Rf 0.72 (hexane/EtOAc, 3/1); exact mass calcd
for C28 H35 NO3 + H 434.2692, found 434.2695. 25d cb: 1H
NMR (400 MHz, C6D6) δ 7.30-6.80 (m, 10 H), 5.99 (d, J )
2.9, 1 H), 5.80-5.66 (m, 1 H), 5.04-4.90 (m, 2 H), 3.77 (dt, J d
) 4.0, J t ) 9.2, 1 H), 3.29 (ddd, J ) 12.0, 6.8, 3.1, 1 H), 2.86-
2.75 (m, 1 H), 2.67 (dd, J ) 14.2, 5.8, 1 H), 2.10-1.94 (m, 2
H), 1.74-1.44 (m, 5 H), 1.41-1.09 (m, 9 H), 0.98-0.88 (m, 1
H); 13C NMR (100 MHz, C6D6) δ 152.74, 141.15, 132.25, 129.01,
128.10, 127.93, 127.37, 125.68, 125.33, 119.40, 111.53, 105.35,
75.00, 51.63, 40.01, 39.36, 37.28, 36.35, 34.04, 29.77, 27.08,
25.98, 24.68, 24.53; IR (CCl4) 3087, 2930, 1626, 1496, 1454,
1235, 1111, 1096, 1006; MS (FAB) 434 (M+ + 1, 19), 105 (100);
TLC Rf 0.54 (hexane/EtOAc, 3/1). Anal. Calcd for C28H35NO3
(433.60): C, 77.56; H, 8.14 N, 3.23. Found: C, 77.54; H, 8.42
N, 2.98.
[(1R*,2R*,3S*)-2-(Acetyla m in o)-3-(4-m eth oxyp h en yl)-
5-oxocycloh exyl]m et h yl Acet a t e ((()-29) a n d [(1R*,-
2S*,3S*)-2-(Acetyla m in o)-3-(4-m eth oxyp h en yl)-5-oxocy-
cloh exyl]m eth yl Aceta te ((()-30). A solution of nitroso
acetal (()-28 (0.249 g, 0.54 mmol) in a 0.03 M methanolic
solution of NaOH (55 mL) was added to a suspension of 0.822
g of Raney nickel (prewashed with methanol and dried under
stream of nitrogen, rt, 1 atm). The reaction mixture was
stirred for 45 min under 1 atm of hydrogen at room temper-
ature, filtered through a plug of Celite, and concentrated.
Acetylation of the crude residue by treatment with pyridine
(10 mL) and acetic anhydride (10 mL) afforded a yellow oil
which was purified by silica gel column chromatography
(hexane/EtOAc, 1/1, 1/2, 1/3, 1/4). A second silica gel column
chromatography (CHCl3/MeOH, 15/1) provided 0.115 g (63%)
of a diastereomeric mixture of ketones 29/30 (29/30, 1.1/1) in
analytically pure form. Anal. Calcd for C18H23NO5 (333.38):
C, 64.85; H, 6.95; N, 4.20; Found: C, 64.84; H, 7.13; N, 4.20.
The two diastereomeric products were separated by radial
chromatography (CHCl3/MeOH, 99/1) and characterized by
spectroscopic methods. Ketone 29 was recrystallized from
hexane/CH2Cl2/Et2O. (()-29: mp 122-124 °C (hexane/CH2-
Cl2/Et2O); 1H NMR (400 MHz) δ 6.96 (d, J ) 8.4, 2 H), 6.86 (d,
J ) 8.4, 2 H), 5.14 (d, J ) 8.8, 1 H), 4.50 (dt, J d ) 4.7, J t
)
10.2, 1 H), 4.00-3.88 (m, 2 H), 3.72 (m, 3 H), 3.52-3.47 (m, 1
H), 2.82 (dd, J ) 16.0, 6.8, 1 H), 2.68-2.56 (m, 2 H), 2.45 (dd,
J ) 15.2, 12.0, 1 H), 2.15-2.02 (m, 1 H), 1.98 (s, 3 H), 1.88 (s,
3 H); 13C NMR (100 MHz) δ 209.25, 170.75, 169.61, 158.85,
130.92, 129.88, 114.01, 64.69, 55.22, 49.50, 44.51, 43.12, 42.96,
36.04, 23.28, 20.77; IR (CHCl3) 3427, 3026, 2937, 1738, 1715,
1673, 1514, 1254; MS (CI, CH4) 334 (M+ + 1, 100); TLC Rf
0.40 (CHCl3/MeOH, 15/1). (()-30: 1H NMR (400 MHz) δ 7.05
(d, J ) 8.4, 2 H), 6.79 (d, J ) 8.4, 2 H), 6.07 (d, J ) 7.6, 1 H),
4.64-4.52 (m, 1 H), 4.15 (dd, J ) 11.4, 4.2, 1 H), 3.97 (dd, J )
11.2, 5.6, 1 H), 3.72 (s, 3 H), 3.20-3.10 (m, 1 H), 2.72-2.62
(m, 2 H), 2.61-2.54 (m, 2 H), 2.52-2.41 (m, 1 H), 1.97 (s, 3 H),
1.77 (s, 3 H); 13C NMR (100 MHz) δ 208.22, 171.00, 170.03,
158.66, 132.57, 128.08, 114.24, 63.66, 55.17, 51.92, 46.74,
(4S*,6S*)-3-Ch lor o-4-(4-m et h oxyp h en yl)-6-[(1R*,2S*)-
(2-p h en yl-cycloh exyl)oxy]-6-(2-p r op en yl)-5,6-d ih yd r o-
4H-[1,2]oxa zin e N-Oxid e ((()-27). Following representative
procedure V as described for the preparation of 25d c, from a
mixture of nitroalkene 2621b (0.253 g, 1.28 mmol), SnCl4 (0.30
mL, 2.56 mmol, 2.0 equiv), and (()-4a (0.419 g, 1.73 mmol,
1.35 equiv) in toluene (14 mL) was obtained a yellow solid
which was purified by silica gel column chromatography
(hexane/EtOAc, 4/1) followed by recrystallization from hexane/

4628 J . Org. Chem., Vol. 62, No. 14, 1997
Denmark et al.
43.98, 41.60, 36.48, 23.06, 20.80; IR (CHCl3) 3436, 3026, 2961,
1736, 1731, 1720, 1673, 1514, 1372, 1252, 1036; MS (CI, CH4)
334 (M+ + 1, 56), 274 (100); TLC Rf 0.35 (CHCl3/MeOH, 15/1).
(4S*,6S*)-3-Br om o-4-p h en yl-6-[(1R*,2S*)-(2-p h en ylcy-
c lo h e x y l)o x y ]-6-(2-p r o p e n y l)-5,6-d ih y d r o -4H -[1,2]-
oxa zin e N-Oxid e ((()-32). Following representative proce-
dure V as described for the preparation of 25d c, from a
mixture of nitroalkene 3130 (0.390 g, 1.71 mmol), SnCl4 (0.40
mL, 3.42 mmol, 2.0 equiv), and (()-4a (0.829 g, 3.42 mmol,
2.0 equiv), in toluene (15 mL) was obtained a pale yellow solid
which was purified by column chromatography (hexane/EtOAc,
9/1) to afford 0.750 g (93%) of analytically pure (()-32 as a
mixture of diastereomers (32a /32b, 19/1): mp 132 °C (hexane/
EtOAc). Anal. Calcd for C25H28BrNO3 (470.41): C, 63.83; H,
6.00; N, 2.98; Br, 16.99. Found: C, 63.89; H, 6.17; N, 2.89;
Br, 16.97. (()-32a : 1H NMR (400 MHz) δ 7.40-7.05 (m, 8
H), 6.90-6.75 (m, 2 H), 5.69 (ddt, J d ) 17.2, 10.4, J t ) 7.1, 1
H), 5.10-4.97 (m, 2 H), 4.07 (dt, J d ) 4.3, J t ) 9.8, 1 H), 2.94
(dd, J ) 12.0, 6.0, 1 H), 2.61-2.52 (m, 3 H), 2.36-2.29 (m, 1
H), 1.98 (dd, J ) 14.0, 6.0, 1 H), 1.84-1.74 (m, 3 H), 1.72-
1.64 (m, 1 H), 1.62-1.20 (m, 4 H); 13C NMR (100 MHz) δ
144.29, 139.79, 131.22, 128.75, 128.64, 128.17, 127.70, 127.34,
126.60, 119.91, 111.07, 105.34, 76.45, 51.37, 43.72, 42.92,
38.74, 34.72, 33.83, 25.54, 24.63; IR (CHCl3) 3019, 2936, 1595,
1584, 1494, 1455, 1234, 1120, 1078, 1004; MS (CI, CH4) 472
(M+ + 2, 3), 471 (1), 159 (100); TLC Rf 0.38 (hexane/EtOAc,
4/1).
Ack n ow led gm en t. We are grateful to the National
Institute of Health (RO1 GM-30938) for generous fi-
nancial support. A.S. also thanks Alexander von Hum-
boldt Foundation for a Feodor Lynen Stipendium. We
are grateful to Prof. D. Dauzonne for a gift of 26.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal as well as complete 1H NMR, 13C NMR, IR, MS, and
microanalytical data for all characterized compounds, spec-
troscopic data for (()-33 and 25, and a tabular listing of the
fractional coordinates and thermal parameters for 11a and (()-
19a (66 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 ACS; see any
current masthead page for ordering information.
J O970686M