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

Article abstract of DOI:10.1021/jo9802168

A new variation of the tandem inter [4 + 2]/intra [3 + 2] cycloaddition of nitroalkenes has been developed. This method involves the Lewis acid-promoted [4 + 2] cycloaddition of nitro olefins 12 with 1-alkoxy-1,4-dienes 3. The resulting nitronates 13, bearing a C(5) tethered dipolarophile, undergo thermal, intramolecular [3 + 2] cycloaddition to afford stable tricyclic nitroso acetals 14, which can be subsequently reduced to unveil a new carbocycle 16, Thus, in three steps, highly functionalized aminocyclopentanes can be stereoselectively constructed in high yield.

Full text of DOI:10.1021/jo9802168

J . Org. Chem. 1998, 63, 6167-6177
6167
Ta n d em In ter [4 + 2]/In tr a [3 + 2] Cycloa d d ition s of Nitr oa lk en es.
Th e Br id ged Mod e (â-Teth er )†
Scott E. Denmark* and J ulie A. Dixon
Roger Adams Laboratory, Department of Chemistry, University of Illinois Urbana, Illinois 61801
Received February 6, 1998
A new variation of the tandem inter [4 + 2]/intra [3 + 2] cycloaddition of nitroalkenes has been
developed. This method involves the Lewis acid-promoted [4 + 2] cycloaddition of nitro olefins 12
with 1-alkoxy-1,4-dienes 3. The resulting nitronates 13, bearing a C(5) tethered dipolarophile,
undergo thermal, intramolecular [3 + 2] cycloaddition to afford stable tricyclic nitroso acetals 14,
which can be subsequently reduced to unveil a new carbocycle 16. Thus, in three steps, highly
functionalized aminocyclopentanes can be stereoselectively constructed in high yield.
In tr od u ction
subclass involves a relatively new construction entitled
the bridged mode.4 The fundamental difference in this
class is that the dipolarophile is attached to the vinyl
ether or dienophile, as opposed to the nitroalkene. In
the R-tether bridged mode, the intermediate nitronate
bears a C(6) olefin which undergoes an intramolecular
[3 + 2] cycloaddition to afford the bridged nitroso acetal.
Importantly, the utility of the tandem process has been
illustrated for all three subclasses by the reduction of the
polycyclic nitroso acetals into hydroxy lactams and ami-
nocyclohexanes.
The hetero-Diels-Alder reaction constitutes a powerful
method for the construction of a diverse array of hetero-
cyclic compounds.1 This process allows for the rapid and
predictable formation of complex ring systems with
remarkably high regio-, diastereo-, and enantiocontrol.
The utility of this method can be further enhanced if the
resulting cycloadduct is poised to undergo a second
reaction in tandem. Tandem pericyclic reactions are
extremely valuable for the expedient and efficient con-
struction of highly functionalized polycyclic compounds.2
In these laboratories, the tandem [4 + 2]/[3 + 2] cycload-
dition of nitroalkenes and nitronates has been developed
as a general approach for the synthesis of a variety of
cyclic, nitrogen-containing systems.3 In this sequence,
the Lewis acid-promoted [4 + 2] cycloaddition provides
nitronic esters which undergo [3 + 2] cycloaddition with
appropriate dipolarophiles to afford polycyclic nitroso
acetals. Depending on the choice of the dienophile and
dipolarophile, a wide variety of highly substituted nitroso
acetals can be formed. In the realm of inter [4 + 2]/intra
[3 + 2] nitroalkene tandem cycloadditions, threedistinct
subclasses have evolved. The first two subclasses, termed
the fused and spiro modes, employ substrates in which
the dipolarophile is tethered at the â- and R-positions of
the nitroalkene, respectively, Scheme 1. The third
A recent communication from these laboratories dis-
closed the development of a new variant of the bridged-
mode tandem sequence in which the dipolarophile is
attached to the â-position of the vinyl ether, Scheme 2.5
Thus, intermolecular [4 + 2] cycloaddition affords a
nitronate with the dipolarophile tethered to the C(5)
position. Subsequent dipolar cycloaddition provides a
novel bridged nitroso acetal which upon reduction reveals
a highly substituted aminocyclopentane.6
Since these products have a structural motif that is
common to a variety of known glycosidase inhibitors,7 a
general and stereoselective method for the synthesis of
these compounds would be useful. This full report details
our efforts on the â-tethered bridged-mode process
([4 + 2]/[3 + 2]/cleavage) with achiral vinyl ethers and
simple nitro olefins.
† Tandem [4 + 2]/[3 + 2] Cycloadditions of Nitroalkenes. 19.
(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) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) 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. (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131. (d) Cascade Reactions; Grigg, R., Ed.; Tetrahedron
Symposium in Print No. 62, 1996; Vol. 52 (35).
Resu lts
Syn th esis of 1-Alk oxy-1,4-p en ta d ien es. To explore
the scope and limitation of the â-bridged-mode tandem
(4) (a) Denmark, S. E.; Stolle, A.; Dixon, J . A.; Guagnano, V. J . Am.
Chem. Soc. 1995, 117, 2100. (b) Denmark, S. E.; Guagnano, V.; Dixon,
J . A.; Stolle, A. J . Org. Chem. 1997, 62, 4610.
(5) Denmark, S. E.; Dixon, J . A. J . Org. Chem. 1997, 62, 7086.
(6) For a review of a 1,3-dipolar cycloaddition approach to substitued
aminocyclopentanols see: Padwa, A.; Schoffstall, A. M. In Advances
in Cycloadditions; Curran, D. P., Ed.; J AI Press: Greenwich 1990; Vol.
2, pp 1-89.
(7) (a) Ledford, B. E.; Carreira, E. M. J . Am. Chem. Soc. 1995, 117,
11811. (b) Goering, B. K.; Li, J .; Ganem, B. Tetradron Lett. 1995, 36,
8905. (c) Chiara, J . K.; Marco-Contelles, J .; Khiar, N.; Gallego, P.;
Destabel, C.; Bernabe´, M. J . Org. Chem. 1995, 60, 6010. (d) Knapp,
S.; Purandare, A.; Rupitz, K, Withers, S. G. J . Am. Chem. Soc. 1994,
116, 7461. (e) Shiozaki, M.; Arai, M.; Kobayashi, Y.; Kasuya, A.;
Miyamoto, S. J . Org. Chem. 1994, 59, 4450. (f) King, S. B.; Ganem, B.
J . Am. Chem. Soc. 1994, 116, 562. (g) Trost, B. M.; Van Vranken, D.
L. J . Am. Chem. Soc. 1993, 115, 444.
(3) (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
(b) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J . Org. Chem.
1993, 58, 1859. (c) Denmark, S. E.; Thorarensen, A. J . Am. Chem. Soc.
1997, 119, 127. (d) Denmark, S. E.; Hurd, A. R.; Sacha, H. J . J . Org.
Chem. 1997, 62, 1668. (e) Denmark, S. E.; Marcin, L. R. J . Org. Chem.
1997, 62, 1675.
S0022-3263(98)00216-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/21/1998

6168 J . Org. Chem., Vol. 63, No. 18, 1998
Denmark and Dixon
Sch em e 1
Sch em e 2
Sch em e 4
Sch em e 3
Preparation of the disubstituted vinyl ether 6 was
accomplished in two steps starting from cyclohexanol (4).
The potassium alkoxide of 4 was combined with trichlo-
roethylene and n-butyllithium, to afford, after quenching
with saturated aqueous ammonium chloride solution, the
acetylenic ether 5 in 74% yield, Scheme 4. Methyl-
cupration of alkynyl ether 5 followed by trapping the
vinyl cuprate with allyl bromide provided the disubsti-
tuted vinyl ether 6 in 77% yield.10
The silyl-substituted vinyl ethers 7 and 11 were
prepared as outlined in Scheme 5. The simple vinyl ether
7 was accessed through metalation of n-butyl vinyl ether
followed by quenching with trimethylsilyl chloride.11
Synthesis of the R-silyl-â-allyl vinyl ether 11 was ac-
complished as reported by Ito from a novel silastannation
procedure.12 Palladium-mediated reaction of silylstan-
nane 9 with ethoxy acetylene (8) provided the vinylstan-
nane 10, which was subsequently coupled with allyl
bromide to afford the desired silyl-substituted pentadiene
11 in moderate yield.
process, a variety of dienophile/dipolarophile components
were prepared. In all cases, the dienophile (enol ether)
was â-substituted with a simple allyl group (dipolaro-
phile) in a trans configuration. In the inital survey, a
simple butyl ether was employed, while in a subsequent
investigation a chiral auxiliary was appended. For most
studies, a disubstituted dienophile (R2 ) H) was used,
though a brief examination of substitutent effects (R2 )
Me, Me3Si) will be mentioned.
Cycloa d d ition s of Nitr oa lk en e 12 a n d Vin yl Eth er
3. (E)-2-Methyl-2-nitrostyrene (12)13 was chosen as the
test nitro olefin for orienting experiments with the vinyl
ether 3. A variety of Lewis acids were found to be useful
in promoting the [4 + 2] cycloaddition, Table 1. Titanium
Following the method of Greene,8 the potassium alkox-
ide of 1 was treated sequentially with trichloroethylene
and n-butyllithium, to afford, after quenching with allyl
bromide, the acetylenic ether 2 in 40% yield, Scheme 3.
Lithium aluminum hydride reduction of 2 provided
exclusively the trans-vinyl ether 3 in 70% yield.9
(10) Wijkens, P.; Vermeer, P. J . Organomet. Chem. 1986, 301, 247.
(11) Soderquist, J . A.; Hsu, G, J .-H. Organometallics 1982, 1, 830.
(12) Murakami, M.; Amii, H.; Takizawa, N.; Ito, Y. Organometallics
1993, 12, 4223.
(13) Denmark, S. E.; Kesler, B. S.; Moon, Y.-C. J . Org. Chem. 1992,
57, 4912.
(8) Moyano, A.; Charbonnier, F.; Greene, A. E. J . Org. Chem. 1987,
52, 2919-2922.
(9) Sola, L.; Castro, J .; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron Lett. 1992, 33, 2863-2866.

Tandem Inter/Intra Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 63, No. 18, 1998 6169
Sch em e 5
F igu r e 1. 1H NMR chemical shift data for HC(4) of nitronates
13a -d .
Ta ble 1. [4 + 2] Cycloa d d ition s of Nitr oa lk en e 12 w ith
relation. The assignment of the trans C(4)/C(5) config-
uration for 13a and 13b was made on the basis of the
following: (1) both 13a and 13b were subsequently
converted to the same aminocyclopentane 16, (2) the
diagnostic resonance at HC(4) in nitronates 13a and 13b
displays a significant upfield chemical shift (0.5-1.1 ppm)
with respect to the same proton in nitronates 13c and
13d , Figure 1, and (3) Ti(O-i-Pr)2Cl2-promoted cycload-
ditions of very similar partners have been shown to
proceed via an endo-(alkoxy) [4 + 2] transition struc-
ture.15 Thus, it is reasonable to conclude that nitronates
13a and 13b, which were formed with high selectivity
in a Ti(O-i-Pr)2Cl2-promoted reaction (Table 1), arose
from an endo-(alkoxy) mode process and must contain a
trans C(4)/C(5) relationship. By default, the minor
product of this reaction 13c must have a cis C(4)/C(5)
relationship and be designated as resulting from an exo-
(alkoxy) mode cycloaddition.16 The suggestion that it
bore a trans C(5)/C(6) relationship was supported by its
formation from an MAD-promoted reaction. Aluminum-
based Lewis acids have never been observed to cause
epimerization of the products in nitroalkene cycloaddi-
tions. Only two diastereomers, 13a and 13c, were
produced from the MAD-promoted reaction, and they are
assigned to be the unepimerized C(4)/C(5) trans and C(4)/
C(5) cis nitronates, respectively. Significantly, the major
diastereomer was found to be identical to 13a formed in
the “Ti”-promoted reaction, thereby allowing the assign-
ment of 13b as the C(4)/C(5) trans, C(5)/C(6) cis isomer.
Finally, diastereomer 13d , which was produced as a
minor product from a SnCl4-promoted [4 + 2] reaction,
must possess a C(4)/C(5) cis, C(5)/C(6) cis relationship,
i.e., exo-mode cycloaddition, affording 13c, followed by
epimerization of the anomeric center.
Vin yl Eth er 3
endo/exo
yield,
%
13a /13b/-
13c/13d a
(13a + 13b/-
Lewis acid (equiv) T, °C
Ti(O-i-Pr)2Cl2 (6) -30
13c + 13d )a
97
91
94
14/98/1/0
1/4.9/11.5/1.3
3.9/0/1/0
112/1
1/2.2
3.9/1
SnCl4 (2)
MAD (3)
-78
-20
a
Determined by isolation and by 1H NMR integration.
diisopropoxide dichloride (Ti(O-i-Pr)2Cl2) effected a highly
selective cycloaddition affording in 97% yield a mixture
of three diastereomeric nitronates 13a , 13b, and 13c in
a ratio of 14/98/1 (13a /13b/13c). An interesting switch
in diastereoselectivity was observed when tin(IV) chloride
(SnCl4) was used as the Lewis acid promoter. In this case
a diastereomeric mixture of four nitronates (1/4.9/11.5/
1.3, 13a /13b/13c/13d ) was obtained in 91% yield. Ad-
ditionally, an aluminum-based Lewis acid, methylalu-
minum bis(2,6-di-(tert-butyl)-4-methylphenyloxide) (MAD),
provided a 3.9/1 mixture of only two diastereomeric
nitronates 13a and 13c in 94% yield.
The Lewis acid-promoted [4 + 2] cycloaddition of
nitroalkene 12 with enol ether 3 should only produce
twodiastereomeric nitronates 13a and 13c, which result
from endo- and exo-mode approaches of the vinyl ether
to the nitroalkene, respectively. The other two diaster-
eomers 13b and 13d are believed to have arisen from
epimerization of the anomeric center (C(6)) under the
reaction conditions.14 The stereostructural assignments
of 13a -d draw on ample precedent and chemical cor-
As was the case in the R-tethered bridged-mode cy-
cloadditions,4 thermal activation was required to effect
the intramolecular [3 + 2] cycloaddition. Thus, the
desired nitroso acetal 14a was obtained in good yield
(79%) by heating a dilute solution (0.01 M) of 13a in
(15) (a) Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1993, 58, 3857.
(b) Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1995, 60, 3221.
(16) This was subsequently confirmed by correlation of the end
product 17 to an identical material derived from a nitroso acetal related
to 14c whose structure was established by X-ray crystallography, see
accompanying paper in this issue and Denmark, S. E.; Swiss, K. A.;
Dixon, J . D. Acta Crystallogr. C 1996, C52, 2561.
(14) The nitroalkene and vinyl ether are presumed to retain their
stereochemical integrity under the reaction condition.

6170 J . Org. Chem., Vol. 63, No. 18, 1998
Denmark and Dixon
Sch em e 6
Sch em e 8
Sch em e 7
sought a new reagent combination that would intercept
the aldehyde before imine formation could occur. Con-
sequently, we were delighted to find that the addition of
sodium borohydride to a solution of the nitroso acetal
14a and Raney nickel, under an atmosphere of hydrogen
in ethanol at room temperature, provided the desired
aminocyclopentane 16a in moderate yield (50% after
acylation), Scheme 8. Similarly, the diastereomeric
nitroso acetal 14b was reduced to the same amino-
cyclopentane triacetate 16a in 53% yield over the two
steps. Finally, nitroso acetal 14c was hydrogenated in
the presence of Raney nickel and sodium borohydride to
provide, after acylation, the epimeric aminocyclopentane
triacetate 16b in 51% yield.
Cycloa d d it ion s of Nit r oa lk en e 12 w it h Vin yl
Eth er s 6, 7, a n d 11. An alternative strategy to avoid
the formation of bicyclic amine in the hydrogenolysis
entailed the use of a disubstituted enol ether as the
dienophile/dipolarophile component in the tandem pro-
cess. It was speculated that during the hydrogenolysis
the intermediate amino ketone would be less prone to
undergo intramolecular imine formation as readily as an
intermediate amino aldehyde. The Ti(O-i-Pr)2Cl2-pro-
moted [4 + 2] cycloaddition of nitroalkene 12 with enol
ether 6 provided a 5/1 mixture of diastereomeric nitron-
ates 17a and 17b in moderate yield, Scheme 9.19 The
major diastereomer, which arose from an endo(alkoxy)-
mode cycloaddition, was heated in toluene at reflux for
12 h to afford the desired nitroso acetal 18 in 72% yield.
Unfortunately, hydrogenation of nitroso acetal 18 using
Raney nickel and hydrogen provided, after acylation, a
complex mixture of bicyclic amines 19 and desired
aminocyclopentane derivatives 20 in low yield. Addition-
ally, a stable bicyclic imine could be isolated from these
reactions in varying amounts. While this alternate
strategy provided small quantities of the desired ami-
nocyclopentanes, the formation of unwanted bicyclic
amine still predominated in the hydrogenolysis.
toluene at reflux for 3 h in the presence of sodium
bicarbonate,17 Scheme 6. The sodium bicarbonate serves
to neutralize acid resulting from the slow decomposition
of nitronates and/or nitroso acetals. In a similar fashion,
nitronates 13b and 13c smoothly underwent [3 + 2]
cycloaddition to afford their corresponding diastereomeric
nitroso acetals 14b and 14c in good to excellent yield.
Red u ction of Nitr oso Aceta ls 14a -c. After dem-
onstrating the feasibility of the â-bridged-mode tandem
process, our attention was focused on the unmasking of
the nitroso acetals. Initial efforts at hydrogenolytic
cleavage of a mixture of nitroso acetals 14b and 14a
using the standard Raney nickel protocol (W-2 Ra-Ni/1
atm of hydrogen) failed to provide the desired aminocy-
clopentanedimethanol, Scheme 7. Unexpectedly, the
interesting bicyclic amine 15 was obtained in good yield.
Furthermore, bicyclic amines were obtained as the major
products from the reduction of pure nitroso acetals 14a ,
14b , and 14c. Several experimental variations of the
reduction were employed to circumvent the formation of
amine 15, including the use of higher hydrogen pressures,
more activated Raney nickel, and additives such as
chloroplatinic acid. Unfortunately, none of the modifica-
tions prevented intramolecular reductive amination which
lead to the construction of bicyclic amine 15.18
Since bicyclic amine 15 must arise from condensation
and reduction of an intermediate amino aldehyde, we
In a similar vein, we evaluated the use of silyl-
substituted vinyl ethers as a means to achieve our goal
(17) The presence of an insoluble base such as NaHCO3 in [3 + 2]
cycloadditions was critical for the success of these reactions, since the
resulting nitroso acetals are acid labile.
(18) Additionally, the use of lithium aluminum hydride as a reducing
agent was explored but the starting nitroso acetal remained unchanged
even in a refluxing solution of THF.
(19) The stereochemical assignment of the nitronates was based on
previous results that Ti(O-i-Pr)2Cl2 promotes endo selective [4 + 2]
cycloadditions and the relative chemical shift of the C(4) proton in the
nitronate as discussed above.

Tandem Inter/Intra Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 63, No. 18, 1998 6171
Sch em e 9
Sch em e 10
Discu ssion
Ep im er iza tion . The tendency for epimerization at
C(6) when Ti(O-i-Pr)2Cl2 or SnCl4 was used as the Lewis
acid promoter is believed to result from trace amounts
of acid that are generated from hydrolysis of these Lewis
acids by adventitious moisture or enol ether decomposi-
tion.21 The driving force for the epimerization of 13a to
13b is clearly due to the formation of a thermodynami-
cally more stable nitronate. If the preferred conformation
of 13a is a half-chair with the oxygen substituent in an
axial position for anomeric stabilization, then epimer-
ization of 13a places the phenyl and allyl substituents
equatorially, relieving serious 1,3-diaxial interaction and
leading to a more stable nitronate, 13b, Figure 2. The
driving force for epimerization of 13c to 13d is not so
obvious; however, this isomerization may be attributed
to the relief of A1,2 strain in 13c.22
Sch em e 11
[4 + 2] Cycloa d d ition : En d o/Exo Selectivity. The
stereochemical course of the [4 + 2] cycloaddition is
governed by the orientation of the vinyl ether (exo or
endo) in its approach to the nitroalkene. Importantly,
the Lewis acid employed in the cycloaddition has an
enormous influence on endo/exo selectivity. Previous
investigations from these laboratories have documented
that Ti(O-i-Pr)2Cl2 promotes endo selective [4 + 2]
cycloadditions.3b,23 This phenomenon has been attributed
to a favorable Coulombic interaction between the electron-
rich oxygen atom of the vinyl ether and the electron-
of accessing aminocyclopentanes. It was envisioned that
during the reduction of a silyl-substituted nitroso acetal,
formed via a tandem [4 + 2]/[3 + 2] cycloaddition, the
intermediate acyl silane would be too sterically encum-
bered to undergo intramolecular condensation, Scheme
10. Furthermore, it was hoped that the acyl silane
moiety would provide a convenient handle for further
functional group manipulations.
Curiously, the SnCl4-promoted [4 + 2] cycloaddition of
nitroalkene 12 with vinyl ether 7 did not provide the
expected nitronate, Scheme 11. Instead, an 85% yield
of the substituted oxime 21 was obtained.20 Similarly,
the [4 + 2] cycloaddition of nitroalkene 12 with tert-
butyldimethylsilyl-substituted pentadiene 11 afforded a
product that is believed to be the silylated oxime 22.
Interestingly, other Lewis acids such as Ti(O-i-Pr)2Cl2
and MAD failed to promote this reaction.
(21) It should be noted that alkylaluminum-derived Lewis acids can
also serve as Bronsted bases. Snider, B. B. Acc. Chem. Res. 1980, 13,
426.
(22) Since this epimerization is only observed when SnCl4 is used
as the Lewis acid and only a small quantity of product is formed,
generation of nitronate 13d may not be due to a simple epimerization.
Perhaps, under the SnCl4-promoted [4 + 2] cycloaddition conditions,
isomerization of a small amount of the trans-vinyl ether 3 to a cis-
vinyl ether followed by and an exo mode cycloaddition could give rise
to nitronate 13d . In the presence of MAD and Ti(O-i-Pr)2Cl2, the
stereochemical integrity of the vinyl ether is maintained; however, the
stereochemical integrity of the vinyl ether in the presence of SnCl4
has never been addressed.
(23) (a) Denmark, S. E.; Senanayake, C. B. W. J . Org. Chem. 1993,
58, 8, 1853. (b) Denmark, S. E.; Thorarensen, A. J . Org. Chem. 1994,
59, 5672. (c) Denmark, S. E.; Schnute, M. E.; Marcin, L. R.; Thora-
rensen, A. J . Org. Chem. 1995, 60, 3205.
(20) The identity of 21 was secured by 1-D and 2-D NMR spectros-
copy as well as other analytical techniques.

6172 J . Org. Chem., Vol. 63, No. 18, 1998
Denmark and Dixon
F igu r e 2. Proposed stable conformations of nitronates 13a -d
(the C(2)-methyl group is omitted for clarity).
F igu r e 4. Proposed mechanism for the hydrogenolysis.
tramolecular [3 + 2] cycloaddition of nitronates 13a -c
and 17a is an energetically costly processes since it
involves the reaction of an unactivated, monosubstituted
dipolarophile. The difference in rates of cycloaddition of
trans C(4)/C(5) nitronates (13a /b) and cis C(4)/C(5)
nitronate 13c was noted previously, in the related
bridged-mode (R-tether) cycloadditions.4b While the effect
observed herein is much less dramatic, we again suspect
that the avoidance of A1,2 strain between the methyl and
phenyl substitutents allows for more facile access to the
reactive conformers in 13a /b.
F igu r e 3. Preferred endo approach of the vinyl ether to the
nitroalkene-Lewis acid complex.
deficient nitroalkene, Figure 3. Alternatively, an asso-
ciation of the vinyl ether oxygen with the coordinatively
unsaturated titanium Lewis acid may be considered.
Interestingly, the MAD-promoted [4 + 2] cycloaddition
of 12 with 3 favored an endo transition structure. While
the ability of MAD to promote selective endo-mode
cycloadditions has precedence,4 the nature of this selec-
tivity is intriguing when considering the significant steric
bulk of this Lewis acid. The predominance for exo
selectivity in the cycloaddition of 12 with 3 when pro-
moted by SnCl4 is also consistent with other results from
these laboratories.4,24 The origin of this selectivity might
be a conformational change of the vinyl ether (s-trans/
s-cis) in the presence of SnCl4 or from the formation of
bulky hexacoordinate tin complexes. In any case, this
interesting reversal in selectivity is the subject of more
detailed investigations that will be reported in the
accompanying paper in this issue.
[3 + 2] Cycloa d d ition . The nitroso acetals arose from
a single stereochemical pathway which was dictated by
the geometrical constraints on the dipolarophile. Specif-
ically, the allyl group approached the nitronate moiety
in an endo, syn-cofacial fashion with the methylene
terminus attached to the oxygen of the dipole. No other
arrangement is geometrically feasible. The activation
energy required for the [3 + 2] cycloaddition is dependent
on the reactivity of the dipolarophile and the accessibility
of a reactive conformation of the nitronate. The effects
of dipolarophile geometry and substitution on the rate
of the intramolecular [3 + 2] cycloaddition of cyclic
nitronates has been studied in detail.25 This investiga-
tion revealed that the rate of cycloaddition with unacti-
vated, monosubstituted dipolarophiles is much slower
than with disubstituted dipolarophiles. Thus, the in-
The generation and stability of the unique skeleton of
the nitroso acetals are quite remarkable since the tricyclic
core appears to be a very strained framework. Addition-
ally, the nitroso acetals are thermally stable and less acid
labile than the corresponding tricyclic nitroso acetals
derived from the bridged mode (R-tether).4 The confor-
mation (chair or boat) of the oxazine ring in the various
nitroso acetals has not been unambiguously determined
and has been drawn with the oxygen axial in all cases.26
The factors that are believed to influence the preferred
conformation of the oxazine ring include anomeric sta-
bilization and 1,3-diaxial interactions. The optimum
conformation would be one in which the oxygen substitu-
ent would be placed axial in order to enjoy anomeric
stabilization, while not experiencing interactions with a
neighboring axially standing substituent. In many of the
nitroso acetals, the benefit of the anomeric stabilization
cannot be experienced without the adverse 1,3-diaxial
interactions. Thus, the conformation of the oxazine ring
in these cases cannot be predicted.
Hyd r ogen olysis. A suggested mechanism for the
formation of the bicyclic amine and aminocyclopentane
derivative from the Raney nickel reduction of the nitroso
acetal is outlined in Figure 4. Double N-O bond cleav-
age of the nitroso acetal affords, after breakdown of the
(24) Denmark, S. E.; Schnute, M. E. J . Org. Chem. 1994, 59, 4576.
(25) Denmark, S. E.; Senanayake, C. B. W. Tetrahedron 1996, 35,
11579.
(26) X-ray crystal structure analysis of several chiral nitroso acetals
from the â-tether tandem process indicate that the oxygen substituent
prefers to be axial so that anomeric stabilization is gained, cf. ref 16.

Tandem Inter/Intra Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 63, No. 18, 1998 6173
1,4-dicarbonyl compounds that are not easily generated
by other methods.
Con clu sion
The feasibility of the bridged (â-tether) mode tandem
inter [4 + 2]/intra [3 + 2] cycloaddition process has been
demonstrated. Simple 1-alkoxy-1,4-pentadienes as well
as 1-alkoxy-1-alkyl-1,4-pentadiene function effectively as
the dienophile/dipolarophile component in the tandem
sequence. Good to excellent selectivities and yields were
obtained in the [4 + 2] cycloaddition when promoted by
a variety of Lewis acids. The intramolecular [3 + 2]
cycloadditions proceeded with good yields affording stable,
bridged nitroso acetals. Hydrogenolytic unmasking of the
nitroso acetals was successfully accomplished using a
combination of Raney nickel and sodium borohydride to
provide the target aminocyclopentanes. Further studies
on the application of this tandem sequence for the
asymmetric preparation of aminocyclopentane deriva-
tives will be addressed in the following report.
F igu r e 5. Proposed mechanism for the formation of oximes.
intermediate hemiacetal, an amino aldehyde which is
capable of reacting through two different pathways. The
first involves the reduction of the aldehyde with a hydride
source to provide the desired aminocyclopentane. The
second pathway entails the intramolecular condensation
of the amino aldehyde followed by reduction of the imine
to afford the bicyclic amine. The intramolecular conden-
sation of intermediate amino aldehydes, generated from
the reduction of a variety of nitroso acetals and nitr-
onates, is a very important event in the formation of a
variety of polycyclic nitrogen-containing compounds and
pyrrolidines.3,15,23-25 In the reduction of the tricyclic
nitroso acetals, it was initially thought that the intramo-
lecular condensation would be energetically disfavored
since a strained bicyclic system would be produced.
However, by looking at a low-energy conformation of the
five-membered ring (structure a) it can be seen that the
aldehyde and the amine are placed pseudoaxially and are
poised to undergo a facile intramolecular imine forma-
tion.
The combined use of Raney nickel and sodium boro-
hydride in the hydrogenolysis was successful in the
generation of our desired aminocyclopentane derivatives.
The presence of sodium borohydride in the reaction
mixture serves to reduce the intermediate aldehyde
before an intramolecular condensation can occur. Ad-
ditionally, the combination of sodium borohydride and
Raney nickel may be creating a new nickel species that
serves as the reducing agent which cleaves the N-O
bonds of the nitroso acetal. It is well established that
adding sodium borohydride to nickel acetate or nickel
chloride generates nickel boride which is a powerful
reducing agent.27
Exp er im en ta l Section
Gen er a l. See Supporting Information.
Ma ter ia ls. See Supporting Information.
1-Bu tyloxyp en t-4-en e-1-yn e (2). To a room temperature
suspension of prewashed (5 × 20 mL hexanes) potassium
hydride (3.5 g, 87.3 mmol, 2 equiv) in THF (90 mL) was added
a solution of n-butanol 1 (4.04 mL, 43.63 mmol) in THF (90
mL) via cannula. The suspension was stirred at room tem-
perature for 1 h and then cooled to -60 °C. A solution of
trichloroethylene (5.2 mL, 43.63 mmol, 1 equiv) in THF (50
mL) was then added via cannula to the cold reaction mixture.
After the addition, the reaction was allowed to warm to room
temperature and stir for 2 h. The resulting dark brown
mixture was recooled to -78 °C, and n-butyllithium (67 mL,
104.7 mmol, 2.4 equiv) was added via cannula. The reaction
was allowed to warm to -10 °C over a 2 h period and was
then recooled to -78 °C. A solution of allyl bromide (19 mL,
218.2 mmol, 5 equiv) in hexamethylphosphoramide (HMPA)
(10 mL) was added to the cold reaction via cannula, and the
reaction was allowed to warm to room temperature and stir
for 4 h. Reaction mixture was quenched with aqueous NH4Cl
(20 mL), diluted with pentane (150 mL), and washed with
water (3 × 150 mL). The aqueous phase was back extracted
with pentane (2 × 100 mL), and the combined organic layer
was washed with brine (100 mL), dried (Na2SO4), filtered, and
concentrated to provide a dark brown oil. The crude organic
concentrate was purified by basic alumina (activity III) chro-
matography (pentane) and then by silica gel (pretreated with
Et3N (2 mL/300 mL of hexane)) column chromatography
(hexane). Residual solvent was removed at 25 °C with an 80
mbar vacuum to provide 2.4 g (40%) of alkynyl ether 2 as a
light yellow liquid: 1H NMR (400 MHz, CDCl3) δ 5.83 (ddt, J
) 16.8, 10.0, 5.0, 1 H), 5.29 (dq, J ) 16.9, 2.0, 1 H), 5.06 (dq,
J ) 10.0, 1.8, 1 H), 4.00 (t, J ) 6.2, 2 H), 2.90 (dt, J ) 5.2, 2.0,
2 H), 1.74-1.67 (m, 2 H), 1.45-1.36 (m, 2 H), 0.94 (t, J ) 7.4,
3 H); 13C NMR (100.6 MHz, CDCl3) δ 134.29, 114.94, 91.82,
78.15, 33.59, 30.73, 21.63, 18.57, 13.61; IR (neat) 2962, 2937,
2275, 1237, 1212, 937, 914; TLC Rf 0.30 (hexane).
Oxim e F or m a tion . The unexpected generation of
oxime 22 from the SnCl4-promoted [4 + 2] cycloaddition
of nitro olefin 12 with silyl-substituted vinyl ether 7 is
rationalized as outlined in Figure 5. Intermediate i is
ideally set up for a silyl-Kornblum-type28 fragmentation
to produce the ester oxime 21. Presumably, the immedi-
ate product is the silyl oxime as was seen for 22 which
was generated from nitroalkene 12 and silyl-substituted
pentadiene 11 in a similar fashion. However, the tert-
butyldimethylsilyl group is maintained in the final
product 22, due to the robust nature of this silyl group
under acidic conditions. The product oximes are versatile
1-Bu tyloxy-1,4-p en ta d ien e (3). Lithium aluminum hy-
dride (98 mg, 25.87 mmol, 4 equiv) was added to a solution of
the acetylenic ether (-)-2 (89 mg, 6.47 mmol) in THF (64 mL).
The suspension was heated to reflux for 45 min. After the
solution was cooled to room temperature, the excess hydride
was quenched with water (0.98 mL), 15% NaOH/H2O (0.98
mL), and finally water (1.86 mL). The suspension was stirred
at room temperature approximately 30 min, and the white
salts were removed by filtration, washing with EtOAc (100
mL). Concentration afforded a light yellow oil. The crude
(27) For review on nickel boride see: Ganem, B.; Osby, J . O. Chem.
Rev. 1986, 86, 763.
(28) Kornblum, N.; Brown, R. A. J . Am. Chem. Soc. 1964, 86, 2681.

6174 J . Org. Chem., Vol. 63, No. 18, 1998
Denmark and Dixon
organic concentrate was purified by basic alumina (activity
III) chromatography (pentane), and the residual solvent was
removed at 25 °C with a 60 mbar vacuum to provide 635 mg
(70%) of vinyl ether 3 as a clear liquid: 1H NMR (400 MHz,
CDCl3) δ 6.25 (d, J ) 12.7, 1 H), 5.87-5.77 (m, 1 H), 5.07-
5.01 (m, 1 H), 4.98-4.94 (m, 1 H), 4.75 (dt, J ) 12.7, 7.1, 1 H),
3.65 (t, J ) 6.6, 2 H), 2.68-2.64 (m, 2 H), 1.65-1.58 (m, 2 H),
1.44-1.35 (m, 2 H), 0.93 (t, J ) 7.5, 3 H); 13C NMR (100.6
MHz, CDCl3) δ 147.13, 138.17, 114.36, 101.19, 68.86, 31.94,
31.33, 19.16, 13.82; IR (neat) 2960, 2935, 2874, 1655, 1175;
MS (70 eV) 141 (M+ + 1, 7), 83 (100); TLC Rf 0.36 (hexane).
(1-Bu toxyvin yl)tr im eth ylsila n e (7). To a -78 °C solu-
tion of butyl vinyl ether (4.14 mL, 32 mmol, 1.6 equiv) in THF
(12 mL) was slowly added tert-butyllithium (20.0 mL, 26 mmol,
1.3 equiv) over a period of 1.5 h. The resulting, bright-yellow,
heterogeneous mixture was allowed to warm to 0 °C over a 3
h period and was then recooled to -78 °C. Trimethylsilyl
chloride (2.54 mL, 20 mmol) was added dropwise via syringe,
and the reaction was allowed to warm to room temperature
and stir for 3 h. The reaction mixture was quenched with
saturated aqueous NH4Cl (20 mL), diluted with pentane (75
mL), and washed with saturated aqueous NH4Cl (3 × 100 mL).
The aqueous phase was back-extracted with pentane (2 × 50
mL) and the combined organic layers were washed with brine
(50 mL) and then were dried (K2CO3), filtered, and concen-
trated. The crude organic concentrate was purified by bulb-
to-bulb distillation to afford 2.36 g (68%) of analytically pure
7 as a clear thin oil: bp 55 °C (5.0 Torr); 1H NMR (499.7 MHz,
CDCl3) δ 4.55 (d, J ) 1.7 1 H), 4.26 (d, J ) 1.7 1 H), 3.63 (t, J
) 6.3, 2 H), 1.68-1.62 (m, 2 H), 1.46-1.38 (m, 2 H), 0.94 (t, J
) 7.4, 3 H), 0.11 (s, 9 H); 13C NMR (125.6 MHz, CDCl3) δ
170.15, 93.21, 66.13, 31.09, 19.42, 13.86, -2.38; IR (neat) 2960,
2936, 1584, 1249, 1216; MS (CI) 173 (M+ + 1, 8), 57 (100).
Anal. Calcd for C9H20OSi (172.34): C, 62.72; H, 11.70.
Found: C, 62.62; H, 11.86.
r el-(4R,5S,6S)-6-Bu tyloxy-3-m eth yl-4-p h en yl-5-(2-p r o-
p en yl)-5,6-d ih yd r o-4H-[1,2]-oxa zin e 2-Oxid e (13a ). Tri-
methylaluminum (2.0 M in toluene, 2.19 mL, 4.38 mmol, 3.0
equiv) was added dropwise to a solution of 2,6-di-tert-butyl-
4-methylphenol (1.93 g, 8.76 mmol, 6.0 equiv) in toluene (8
mL) at room temperature. Gas evolution (CH4) was observed,
and the resulting clear solution was stirred at room temper-
ature for 45 min. The Lewis acid solution (MAD) was
transferred, via cannula, to a second reaction vessel containing
a -78 °C solution of nitroalkene 12 (238 mg, 1.46 mmol) and
vinyl ether 3 (410 mg, 2.92 mmol, 2 equiv) in toluene (3 mL).
The resulting dark green solution was allowed to warm slowly
to -35 °C and was left to stir for 12 h (the color faded to a
light yellow), after which time the reaction was quenched with
H2O (8 mL). The mixture was diluted with CH2Cl2 (150 mL)
and was washed with water (3 × 150 mL). The aquous layers
were back-extracted with CH2Cl2 (3 × 75 mL), and the
combined organic phases were washed with brine (100 mL)
and then were dried (Na2SO4), filtered, and concentrated in
vacuo. The crude material was purified by silica gel column
chromatography (hexane/EtOAc, 4/1) to afford 256 mg of
nitronate 13a , 80 mg of a 20/1 (13a / 13c) mixture of 13a and
13c, and 82 mg of nitronate 13c. The overall yield of the
reaction was 418 mg (94%) with an overall selectivity of 3.9/1
(13a /13c) (selectivity reflects the endo/exo ratio). An analytical
sample of 13a was obtained by recrystallization (pentane).
Nitronate 13c was found to be identical by 1H NMR to
nitronate 13c obtained from the Ti(O-i-Pr)2Cl2- and SnCl4-
promoted [4 + 2] cycloadditions. Data for 13a : mp 36-37.5
°C (pentane); 1H NMR (400 MHz, C6D6) δ 7.05-6.96 (m, 3 H),
6.89-6.86 (m, 2 H), 5.51-5.41 (m, 1 H), 4.95-4.86 (m, 2 H),
4.83 (d, J ) 4.6, 1 H), 4.08 (dt, J ) 9.5, 6.5, 1 H), 3.36 (dt, J )
9.5, 6.6, 1 H), 3.07 (dd, J ) 7.3, 1.6, 1 H), 2.16-2.10 (m, 1 H),
2.04-1.97 (m, 1 H), 1.90-1.82 (m, 1 H), 1.68 (d, J ) 1.7, 3 H),
1.51-1.44 (m, 2 H), 1.34-1.20 (m, 2 H), 0.81 (t, J ) 7.3, 3 H);
13C NMR (100.6 MHz, C6D6) δ 140.09, 134.65, 129.11, 128.94,
127.47, 120.88, 118.03, 105.62, 69.65, 47.80, 45.87, 35.14,
31.75, 19.45, 16.84, 13.91; IR (CCl4) 2961, 2935, 1613, 1273,
1116, 922, 894; MS (CI) 304 (M+ + 1, 100); TLC Rf 0.17
(hexane/EtOAc, 2/1). Anal. Calcd for C18H25NO3 (303.405):
C, 71.26; H, 8.31; N, 4.62. Found: C, 71.41; H, 8.20; N, 4.77.
r el-(4R,5S,6R)-6-Bu tyloxy-3-m eth yl-4-p h en yl-5-(2-p r o-
p en yl)-5,6-d ih yd r o-4H-[1,2]-oxa zin e 2-Oxid e (13b). Tita-
nium(IV) chloride (0.503 mL, 4.59 mmol, 3.0 equiv) was added
to a solution of titanium(IV) isopropoxide (1.37 mL, 4.59 mmol,
3.0 equiv) in CH2Cl2 (7 mL) at room temperature. The
resulting solution was allowed to stir for 30 min and was then
added via cannula to a -50 °C solution of nitroalkene 12 (250
mg, 1.53 mmol) and 3 (429 mg, 3.06 mmol, 2.0 equiv) in
CH2Cl2 (2.0 mL). The resulting dark brown reaction mixture
was allowed to warm slowly to -35 °C, was left to stir for 16
1-Cycloh exyloxya cetylen e (5). To a room temperature
suspension of prewashed (5 × 20 mL of hexanes) potassium
hydride (2.0 g, 49.9 mmol, 2 equiv) in THF (45 mL) was added
a solution of cyclohexanol 4 (2.6 mL, 24.9 mmol) in THF (45
mL) via cannula. The suspension was stirred at room tem-
perature for 1.5 h and then cooled to -60 °C. A solution of
trichloroethylene (2.98 mL, 24.9 mmol, 1 equiv) in THF (27
mL) was then added via cannula to the cold reaction mixture.
After the addition, the reaction was allowed to warm to room
temperature and stir for 2 h. The resulting dark brown
mixture was recooled to -78 °C, and n-butyllithium (40 mL,
62.3 mmol, 2.5 equiv) was added via cannula. The reaction
was allowed to warm to -10 °C over a 2 h period and was
then quenched with ammonium chloride (30 mL). The reaction
mixture was diluted with pentane (100 mL) and washed with
water (3 × 100 mL). The aqueous phase was back extracted
with pentane (2 × 100 mL), and the combined organic layer
was washed with brine (100 mL), dried (Na2SO4), filtered, and
concentrated to provide a dark brown oil. The crude organic
concentrate was purified by basic alumina (activity III) chro-
matography (pentane). Residual solvent was removed at 25
°C with a 60 mbar vacuum to provide 2.28 g (74%) of alkynyl
ether 5 as a light brown liquid: 1H NMR (499.7 MHz, CDCl3)
δ 4.11-4.06 (m, 1 H), 1.99-1.96 (m, 2 H), 1.79-1.73 (m, 2 H),
1.65-1.58 (m, 2 H), 1.53-1.48 (m, 2 H), 1.37-1.25 (m, 3 H);
13C NMR (125.6 MHz, CDCl3) δ 89.89, 86.49, 30.74, 27.03,
25.04, 23.09; IR (neat) 3320, 2942, 2938, 2862, 2143; MS (CI)
125 (M+ + 1, 0.2), 83 (100); TLC Rf 0.33 (hexane); HRMS
(FAB) calcd for C8H11O 123.08079, found 123.08099.
1-Cycloh exyloxy-1-m eth yl-1,4-p en ta d ien e (6). Lithium
bromide (547 mg, 6.3 mmol, 1.26 equiv) was placed under
vacuum and flame dried until the internal temperature was
approximately 150 °C. Copper bromide (904 mg, 6.3 mmol,
1.26 equiv) was then added, and the solids were placed under
vacuum for 20 min. Tetrahydrofuran (23 mL) was added, the
suspension was cooled to -90 °C, and a solution of methyl-
magnesium bromide (2.0 mL, 6.0 mmol, 1.2 equiv) in THF (5
mL) was added dropwise via cannula. After 15 min, a solution
of acetylenic ether 5 (620 mg, 5.0 mmol) in THF (1 mL) was
added dropwise and the reaction was allowed to warm to -78
°C. After 1 h, a solution of allyl bromide (0.93 mL, 10.0 mmol,
2 equiv) in THF (1 mL) was slowly added dropwise and the
mixture was allowed to warm to 0 °C over a 2 h period. The
reaction was allowed to stir for an additional 1 h between 0
°C and room temperature and was then quenched with
saturated aqueous NH4Cl (20 mL). The mixture was diluted
with pentane (100 mL) and was washed with water (3 × 100
mL). The aqueous phase was back extracted with pentane (3
× 50 mL), and the combined organic layers were washed with
brine (75 mL), dried (Na2SO4), filtered, and concentrated with
care (compound is volatile). The crude organic concentrate was
purified by basic alumina (activity III) chromatography (pen-
tane). Residual solvent was removed at 25 °C with a 60 mbar
vacuum to provide 698 mg (77%) of vinyl ether 6 as a clear
liquid: 1H NMR (499.7 MHz, CDCl3) δ 5.86-5.78 (m, 1 H),
5.02 (dd, J ) 17.0, 1.6, 1 H), 4.94 (dd, J ) 10.0, 1.5, 1 H), 4.43
(t, J ) 7.5, 1 H), 3.94-3.89 (m, 1 H), 2.72 (dd, J ) 7.0, 6.6, 2
H), 1.93-1.90 (m, 2 H), 1.74-1.72 (m, 5 H), 1.55-1.53 (m, 1
H), 1.40-1.22 (m, 5 H); 13C NMR (125.6 MHz, CDCl3) δ 151.35,
138.23, 113.69, 95.92, 73.21, 31.75, 31.25, 25.77, 24.01, 16.39;
IR (neat) 2933; MS (CI) 181 (M+ + 1, 0.6), 83 (100); TLC Rf
0.33 (hexane); HRMS (FAB) calcd for C12H21O 181.15863,
found 181.15924.

Tandem Inter/Intra Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 63, No. 18, 1998 6175
h, and was then warmed further to -25 °C for 8 h. The
reaction mixture was quenched (at -25 °C) with a methanolic
sodium hydroxide solution (1 N, 8 mL) and then was diluted
with CH2Cl2 (150 mL) and washed with water (3 × 150 mL).
The aqueous layers were back-extracted with CH2Cl2 (3 × 70
mL), and the combined organic phases were washed with brine
(100 mL) and then were dried (Na2SO4), filtered, and concen-
trated to afford a yellow oil. The crude material was purified
twice by silica gel column chromatography (hexane/EtOAc, 4/1
(500 mL), 3/1 (400 mL), 2/1) to afford 256 mg of nitronate 13b,
180 mg of a 2.2/1 (13b/13a ) mixture of 13b and 13a , 13 mg of
a 10/1 (13b/13c) mixture of 13b and 13c, and 3 mg of nitronate
13c. The overall yield of the reaction was 452 mg (97%) with
an overall selectivity of 98/14/1 (13b/13a /13c) and an endo/
exo ratio of 112/1 (13a + 13b/13c). An analytical sample of
13b was obtained by recrystallization (pentane). Nitronates
13a and 13c were found to be identical by 1H NMR to
nitronates 13a and 13c obtained from the MAD- and SnCl4-
promoted [4 + 2] cycloadditions. Data for 13b: mp 39-40.5
°C (pentane); 1H NMR (400 MHz, C6D6) δ 6.99-6.96 (m, 3 H),
6.70-6.78 (m, 2 H), 5.28-5.17 (m, 1 H), 5.02 (d, J ) 1.7, 1 H),
4.89-4.81 (m, 2 H), 4.00 (dt, J ) 9.8, 6.3, 1 H), 3.37 (dt, J )
9.8, 6.3, 1 H), 3.18-3.16 (m, 1 H), 2.00-1.90 (m, 3 H), 1.69 (d,
J ) 1.7, 3 H), 1.54-1.40 (m, 2 H), 1.38-1.20 (m, 2 H), 0.84 (t,
J ) 7.3, 3 H); 13C NMR (100.6 MHz, C6D6) δ 140.19, 134.87,
129.13, 128.80, 127.63, 119.05, 117.54, 102.16, 69.08, 47.37,
42.90, 33.69, 31.78, 19.51, 17.57, 13.89; IR (CCl4) 2961, 2935,
1618, 1277, 1272, 1238, 921, 897; MS (CI) 304 (M+ + 1, 100);
TLC Rf 0.22 (hexane/EtOAc, 2/1). Anal. Calcd for C18H25NO3
(303.405): C, 71.26; H, 8.31; N, 4.62. Found: C, 71.52; H, 8.43;
N, 4.88.
2.54-2.47 (m, 1 H), 2.04-1.97 (m, 1 H), 1.87 (d, J ) 1.2, 3 H),
1.66-1.51 (m, 3 H), 1.38-1.24 (m, 2 H), 0.89 (t, J ) 7.3, 3 H);
TLC Rf 0.11 (hexane/EtOAc, 2/1).
r el-(1R,6S,7S,8R,9S)-6-Bu t yloxy-9-m et h yl-8-p h en yl-4-
a za -3,5-d ioxa tr icyclo[5.2.1.04,9]d eca n e (14a ). A solution of
nitronate 13a (162 mg, 0.53 mmol) in toluene (10 mL) was
added to a suspension of sodium bicarbonate (314 mg, 3.73
mmol, 7 equiv) in toluene (43 mL), and the mixture was heated
to reflux for 3.5 h. After the solution was cooled to room
temperature, the reaction mixture was concentrated (until only
ca. 10 mL remained) and then was filtered through a cotton
pipet plug, eluting with TBME (20 mL). The crude organic
concentrate was purified by column chromatography on basic
(III) alumina (hexane/TBME 7/1) to provide 173 mg (79%) of
analytically pure nitroso acetal 14a as a white solid: mp 85-
86 °C (hexane/TBME); 1H NMR (400 MHz, C6D6) δ 7.68-7.66
(m, 2 H), 7.26-7.22 (m, 2 H), 7.13-7.09 (m, 1 H), 4.69 (d, J )
1.0, 1 H), 4.05 (t, J ) 8.3, 1 H), 3.79 (dd, J ) 8.0, 3.7, 1 H),
3.72 (dt, J ) 9.3, 6.5, 1 H), 3.06 (dt, J ) 9.3, 6.4, 1 H), 2.70 (d,
J ) 4.5, 1 H), 2.33 (t, J ) 5.2, 1 H), 1.95-1.90 (m, 1 H), 1.48
(ddd, J ) 13.2, 10.3, 6.0, 1 H), 1.22-1.14 (m, 5 H), 1.03-0.93
(m, 3 H), 0.71 (t, J ) 7.5, 3 H); 13C NMR (100.6 MHz, C6D6) δ
138.43, 130.94, 128.48, 126.35, 106.32, 81.07, 77.68, 68.06,
51.50, 49.16, 45.66, 35.45, 32.09, 22.59, 19.55, 14.17; IR (CCl4)
2959, 2935, 2872; MS (CI) 304 (M+ + 1, 100); TLC Rf 0.45
(hexane/EtOAc, 2/1). Anal. Calcd for C18H25NO3 (303.405):
C, 71.26; H, 8.31; N, 4.62. Found: C, 71.35; H, 8.31; N, 4.74.
r el-(1R,6R,7S,8R,9S)-6-Bu tyloxy-9-m eth yl-8-p h en yl-4-
a za -3,5-d ioxa tr icyclo[5.2.1.04,9]d eca n e (14b). A solution of
nitronate 13b (230 mg, 0.79 mmol) in toluene (10 mL) was
added to a suspension of sodium bicarbonate (466 mg, 5.3
mmol, 7 equiv) in toluene (70 mL) and the mixture was heated
to reflux for 3 h. After the solution was cooled to room
temperature, the reaction mixture was concentrated (until only
ca. 10 mL remained) and then was filtered through a cotton
pipet plug, eluting with TBME (20 mL). The brown organic
concentrate was purified by column chromatography on basic
(III) alumina (hexane/TBME 7/1) to provide 173 mg (75%) of
nitroso acetal 14b as a white solid. An analytical sample of
14b was obtained by recrystallization (pentane): mp 63-65
r el-(4S,5S,6S)-6-Bu tyloxy-3-m eth yl-4-p h en yl-5-(2-p r o-
p en yl)-5,6-d ih yd r o-4H-[1,2]-oxa zin e 2-Oxid e (13c) a n d
r el-(4S,5S,6R)-6-Bu tyloxy-3-m eth yl-4-p h en yl-5-(2-p r op e-
n yl)-5,6-d ih yd r o-4H-[1,2]-oxa zin e 2-Oxid e (13d ). Tin(IV)
chloride (0.29 mL, 2.44 mmol, 2 equiv) was added to a -78 °C
solution of nitroalkene 12 (200 mg, 1.22 mmol) in CH2Cl2 (10
mL), and the resulting bright yellow complex was left to stir
for 15 min. A solution of vinyl ether 3 (342 mg, 2.44 mmol,
2.0 equiv) in CH2Cl2 (2 mL) was added slowly over a 20 min
period to the cold reaction mixture via syringe. The reaction
was left to stir at -78 °C for an additional 15 min and was
then quenched with a methanolic sodium hydroxide solution
(1 N, 4 mL). The mixture was diluted with CH2Cl2 (150 mL)
and washed with water (3 × 150 mL). The aqueous phase
was back-extracted with CH2Cl2 (3 × 50 mL), and the
combined organic layers were washed with brine (100 mL) and
then were dried (Na2SO4) and concentrated to afford a cloudy
oil. The crude organic concentrate was purified by silica gel
column chromatography (hexane/EtOAc, 4/1) to afford 199 mg
of nitronate 13c, 77 mg of a 7.5/1 (13b/13c) mixture of 13b
and 13c, 38 mg of a 1.1/1 (13a /13b) mixture of 13a and 13b,
and 24 mg of nitronate 13d . The overall yield of the reaction
was 338 mg (91%) with an overall selectivity of 1/5/11.5/1.3
(13a /13b/13c/13d ) and an endo/exo ratio of 2.2/1 (13c + 13d /
13a + 13b). An analytical sample of 13c was obtained by
recrystallization (pentane/TBME). Nitronates 13a and 13b
1
°C (pentane); H NMR (400 MHz, C6D6) δ 7.67 (d, J ) 7.6, 2
H) 7.24-7.20 (m, 2 H), 7.12-7.08 (m, 1 H), 4.67 (d, J ) 5.4, 1
H), 4.10 (d, J ) 6.8, 2 H), 3.76 (dt, J ) 9.5, 6.6, 1 H), 3.00 (dt,
J ) 9.5, 6.4, 1 H), 2.77 (d, J ) 4.2, 1 H), 2.33 (q, J ) 4.9, 1 H),
2.13-2.08 (m, 1 H), 1.98 (d, J ) 12.7, 1 H), 1.42-1.30 (m, 3
H), 1.25-1.15 (m, 2 H), 0.77 (t, J ) 7.3, 3 H); 13C NMR (100.6
MHz, C6D6) δ 137.00, 130.46, 128.44, 126.78, 101.40, 79.85,
77.27, 68.28, 53.27, 49.86, 45.79, 32.06, 30.43, 22.06, 19.66,
13.95; IR (CCl4) 2960, 2935, 2875, 1090; MS (CI) 304 (M+ + 1,
100); TLC Rf 0.59 (hexane/EtOAc, 2/1). Anal. Calcd for
C
18H25NO3 (303.405): C, 71.26; H, 8.31; N, 4.62. Found: C,
71.38; H, 8.41; N, 4.78.
r el-(1R,6S,7S,8S,9S)-6-Bu t yloxy-9-m et h yl-8-p h en yl-4-
a za -3,5-d ioxa tr icyclo[5.2.1.04,9]d eca n e (14c). A solution of
nitronate 13c (136 mg, 0.45 mmol) in toluene (10 mL) was
added to a suspension of sodium bicarbonate (264 mg, 3.14
mmol, 7 equiv) in toluene (35 mL), and the mixture was heated
to reflux for 18 h. After the solution was cooled to room
temperature, the reaction was concentrated (until only ca. 10
mL remained) and the reaction mixture was filtered through
a cotton pipet plug, eluting with TBME (20 mL). The crude
organic concentrate was purified by column chromatography
on basic (III) alumina (hexane/TBME 7/1) to provide 127 mg
(93%) of analytically pure nitroso acetal 14c as a white solid:
mp 58-60 °C (pentane); 1H NMR (400 MHz, C6D6) δ 7.12-
7.02 (m, 5 H), 4.67 (d, J ) 2.4, 1 H), 4.26-4.24 (m, 2 H), 4.11
(t, J ) 7.8, 1 H), 4.04 (dt, J ) 9.6, 6.7, 1 H), 3.39 (dt, J ) 9.5,
6.6, 1 H), 2.14-2.07 (m, 3 H), 1.62-1.55 (m, 2 H), 1.43-1.24
(m, 3 H), 1.04 (s, 3 H), 0.86 (t, J ) 7.3, 3 H); 13C NMR (100.6
MHz, C6D6) δ 140.90, 129.06, 128.77, 126.86, 106.08, 87.92,
79.63, 67.70, 47.70, 46.04, 44.66, 36.08, 32.14, 20.01, 19.77,
14.09; IR (CCl4) 2959, 2938, 2875, 1096, 1078; MS (CI) 304
(M+ + 1, 89), 230 (100); TLC Rf 0.50 (hexane/EtOAc, 2/1).
1
were found to be identical by H NMR to nitronates 13a and
13b obtained from the MAD- and Ti(O-i-Pr)2Cl2-promoted [4
+ 2] cycloadditions. Data for 13c: mp 82-83 °C (pentane);
1H NMR (400 MHz, CDCl3) δ 7.36-7.26 (m, 3 H), 7.11-7.08
(m, 2 H), 5.54-5.43 (m, 1 H), 5.19 (d, J ) 2.0, 1 H), 5.04-4.99
(m, 2 H), 4.17 (d, J ) 6.6, 1 H), 4.01 (dt, J ) 9.5, 6.6, 1 H),
3.64 (dt, J ) 9.5, 6.3, 1 H), 2.11-1.97 (m, 2 H), 1.92 (d, J )
1.6, 3 H), 1.72-1.56 (m, 3 H), 1.37 (sept, J ) 7.3, 2 H), 0.92 (t,
J ) 7.4, 3 H); 13C NMR (100.6 MHz, CDCl3) δ 136.42, 134.79,
129.31, 128.71, 127.51, 122.55, 118.22, 103.23, 69.10, 44.75,
38.87, 32.11, 31.42, 19.12, 18.23, 13.74; IR (CCl4) 3004, 2962,
2935, 1613, 881; MS (CI) 304 (M+ + 1, 100); TLC Rf 0.31
(hexane/EtOAc, 2/1). Anal. Calcd for C18H25NO3 (303.405):
C, 71.26; H, 8.31; N, 4.62. Found: C, 71.13; H, 8.39; N, 4.92.
Data for 13d : 1H NMR (400 MHz, CDCl3) δ 7.31-7.25 (m, 5
H), 5.73-5.63 (m, 1 H), 5.17 (d, J ) 2.9, 1 H), 5.04 (d, J )
10.0, 1 H), 4.95 (dd, J ) 17.1, 12, 1 H), 4.06 (dt, J ) 9.3, 6.4,
1 H), 3.70 (dd, J ) 8.8, 1.2, 1 H), 3.47 (dt, J ) 9.3, 6.7, 1 H),

6176 J . Org. Chem., Vol. 63, No. 18, 1998
Denmark and Dixon
Anal. Calcd for C18H25NO3 (303.405): C, 71.26; H, 8.31; N,
4.62. Found: C, 71.26; H, 8.31; N, 4.84.
(EtOAc/hexane, 1/1) to afford 80 mg (53% over two steps) of
aminocyclopentane triacetate 16a : 1H NMR (400 MHz, CDCl3)
δ 7.34-7.30 (m, 2 H), 7.28-7.24 (m, 1 H), 7.21-7.19 (m, 2 H),
5.73 (s, 1 H), 4.40 (dd, J ) 11.3, 6.1, 1 H), 4.23 (dd, J ) 11.5,
7.5, 1 H), 3.79 (d, J ) 6.4, 2 H), 3.35 (d, J ) 9.0, 1 H), 2.81-
2.70 (m, 1 H), 2.49-2.41 (m, 1 H), 2.19-1.12 (m, 1 H), 2.10 (s,
3 H), 1.98 (s, 3 H), 1.79 (s, 3 H), 1.71 (s, 3 H), 1.71-1.64 (m, 1
H); 13C NMR (100.6 MHz, CDCl3) δ 170.80, 170.34, 169.34,
136.69, 129.91, 128.37, 127.11, 65.10, 64.64, 63.73, 60.21,
49.11, 39.36, 31.97, 28.10, 24.24, 20.90, 20.82; IR (CCl4) 1745,
1235; MS (FAB) 362 (M+ + 1, 67), 302 (100); TLC Rf 0.23
(EtOAc/hexanes, 2/1); HRMS (FAB) calcd for C20H28N5O
362.19675, found 362.19710.
r el-(1R,2S,4R,7S)-2-Hyd r oxym et h yl-1-m et h yl-7-p h en -
yl-6-a za -bicyclo[2.2.1]h exa n e (15). A mixture 6/1 (13b/13a )
of nitroso acetals 13a and 13b (110 mg, 0.363 mmol) was added
to a suspension of prewashed (5 × 5 mL MeOH) Raney nickel
(amount that would fit on a tip of a spatula) in MeOH (8 mL).
The reaction was placed under 1 atm of H2 at room temper-
ature for 24 h. The Raney nickel was removed by filtering
the reaction mixture through a cotton pipet plug, washing with
copious amounts of MeOH, and concentrating. The crude
organic concentrate was purified by column chromatography
on neutral (III) alumina (CHCl3/MeOH, 32/1) to provide 56 mg
(71%) of bicyclic amine 15 as a clear viscous oil: 1H NMR (400
MHz, CDCl3) δ 7.34-7.30 (m, 2 H), 7.25-7.21 (m, 3 H), 4.43
(s, 1 H), 4.18 (dd, J ) 11.6, 2.3, 1 H), 3.71 (dd, J ) 11.6, 2.9,
1 H), 3.41 (dt, J ) 10.3, 3.4, 1 H), 2.89 (d, J ) 10.5, 1 H), 2.81
(s, 1 H), 2.66 (t, J ) 3.9, 1 H), 2.04-1.96 (m, 1 H), 1.89-1.83
(m, 1 H), 1.78 (dd, J ) 11.5, 5.1, 1 H), 1.35 (s, 3 H); 13C NMR
(100.6 MHz, CDCl3) δ 137.78, 128.59, 128.26, 126.41, 69.24,
62.25, 57.97, 51.54, 46.37, 42.05, 31.67, 16.59; IR (CCl4) 3689,
3583, 3011, 2997, 2966, 2896, 1453, 1102, 980, 830; TLC Rf
0.22 (CHCl3/MeOH, 32/1) [alumina plate].
[(1S,3R,4S,5S)-4-(Acetyla m in o)-4-m eth yl-5-p h en yl]-1,3-
cyclop en ta n ed im eth a n ol Dia ceta te (16b). Nitroso acetal
14c (200 mg, 0.66 mmol) was added to a suspension of
prewashed (5 × 10 mL MeOH) Raney nickel (amount that
would fit on a tip of a spatula) in EtOH (35 mL). Sodium
borohydride (99 mg, 2.64 mmol, 4 equiv) was directly added
to the reaction mixture and was then immediately placed
under 1 atm of H2. After approximately 1 h, a solution of
sodium borohydride (99 mg, 2.64 mmol, 4 equiv) in EtOH (1
mL) was added to the reaction while it was under 1 atm of
H2. The reaction was allowed to stir 2 h further. The Raney
nickel was removed by filtering the reaction mixture through
a cotton pipet plug, washing with copious amounts of MeOH,
and concentrating. The crude material was dissolved in
pyridine (8 mL) and acetic anhydride (8 mL) and was left to
stir at room temperature for 18 h. The excess pyridine and
acetic anhydride were removed in vacuo, using an external
trap, providing a brown oil. The crude organic concentrate
was purified by silica gel column chromatography (EtOAc/
hexane, 1/1) to afford 122 mg (51% over two steps) of ami-
nocyclopentane triacetate 16b along with 28 mg of an uni-
dentified byproduct: 1H NMR (400 MHz, CDCl3) δ 7.35-7.31
(m, 2 H), 7.28-7.24 (m, 1 H), 7.17-7.14 (m, 2 H), 5.43 (s, 1
[(1S,3R,4S,5R)-4-(Acetyla m in o)-4-m eth yl-5-p h en yl]-1,3-
cyclop en ta n ed im eth a n ol Dia ceta te (16a ). Nitroso acetal
14a (107 mg, 0.355 mmol) was added to a suspension of
prewashed (5 × 15 mL MeOH) Raney nickel (amount that
would fit on a tip of a spatula) in EtOH (35 mL). Sodium
borohydride (54 mg, 1.42 mmol, 4 equiv) was directly added
to the reaction mixture and was then immediately placed
under 1 atm of H2. After 1.5 h, a solution of sodium borohy-
dride (54 mg, 1.42 mmol, 4 equiv) in EtOH (1 mL) was added
to the reaction while it was under 1 atm of H2. After an
additional 2 h, a solution of sodium borohydride (54 mg, 1.42
mmol, 4 equiv) in EtOH (1 mL) was again added and the
reaction was allowed to stir 2.5 h further. The Raney nickel
was removed by filtering the reaction mixture through a cotton
pipet plug, washing with copious amounts of MeOH, and
concentrating. The crude material was dissolved in pyridine
(3 mL), and acetic anhydride (3 mL) and was left to stir at
room temperature for 8 h. The excess pyridine and acetic
anhydride were removed in vacuo, using an external trap,
providing a brown oil. The crude organic concentrate was
purified by silica gel column chromatography (EtOAc/hexane,
1/1) to afford 62 mg (49% over two steps) of aminocyclopentane
H), 4.16 (ABX, J ab ) 11.0, J ax ) 5.6, 1 H), 4.16 (ABX, J bx
)
7.4, 1 H), 4.07 (ABX, J ab ) 10.2, J ax ) 3.5, 1 H), 3.91 (ABX, J bx
) 6.3, 1 H), 3.42 (d, J ) 11.2, 1 H), 2.73-2.63 (m, 1 H), 2.58-
2.51 (m, 1 H), 2.23-2.15 (m, 1 H), 2.07 (s, 3 H), 1.92 (s, 3 H),
1.82 (s, 3 H), 1.70-1.62 (m, 1 H), 1.06 (s, 3 H); 13C NMR (100.6
MHz, CDCl3) δ 171.03, 171.00, 169.90, 138.11, 128.95, 128.50,
127.19, 66.95, 65.43, 63.86, 54.52, 46.59, 39.56, 30.20, 24.22,
23.47, 21.04, 20.60; IR (CCl4) 1742, 1686, 1683, 1366, 1233;
MS (FAB) 362 (M+ + 1, 78), 302 (100); TLC Rf 0.31 (EtOAc/
hexanes, 2/1); HRMS (FAB) calcd for C20H28N5O 362.19675,
found 362.19710
1
triacetate 16a , which was found to be identical by H NMR to
the triacetate derived from the reduction and acylation of
nitroso acetal 14b: 1H NMR (400 MHz, CDCl3) δ 77.34-7.30
(m, 2 H), 7.28-7.24 (m, 1 H), 7.21-7.19 (m, 2 H), 5.73 (s, 1
H), 4.40 (dd, J ) 11.3, 6.1, 1 H), 4.23 (dd, J ) 11.5, 7.5, 1 H),
3.79 (d, J ) 6.4, 2 H), 3.35 (d, J ) 9.0, 1 H), 2.81-2.70 (m, 1
H), 2.49-2.41 (m, 1 H), 2.19-1.12 (m, 1 H), 2.10 (s, 3 H), 1.98
(s, 3 H), 1.79 (s, 3 H), 1.71 (s, 3 H), 1.71-1.64 (m, 1 H); TLC
Rf 0.23 (EtOAc/hexanes, 2/1).
r el-(4R,5S,6S)-6-Cycloh exyloxy-3,6-d im eth yl-4-p h en yl-
5-(2-pr open yl)-5,6-dih yd r o-4H-[1,2]-oxa zin e 2-Oxid e (17a )
a n d r el-(4R,5R,6R)-6-Cycloh exyloxy-3,6-dim eth yl-4-p h en -
yl-5-(2-p r op en yl)-5,6-d ih yd r o-4H -[1,2]-oxa zin e 2-Oxid e
(17b). Titanium(IV) chloride (0.329 mL, 3.00 mmol, 3.0 equiv)
was added to a solution of titanium(IV) isopropoxide (0.892
mL, 3.00 mmol, 3.0 equiv) in CH2Cl2 (9 mL) at room temper-
ature. The resulting solution was allowed to stir for 30 min
and was then added via cannula to a -78 °C solution of
nitroalkene 12 (163 mg, 1.00 mmol) and 6 (325 mg, 1.80 mmol,
1.8 equiv) in CH2Cl2 (3.0 mL). The resulting dark reaction
mixture was left to stir at -78 °C for 2 h and was then warmed
to -50 °C for 5 h. The reaction mixture was quenched with a
methanolic sodium hydroxide solution (1 N, 8 mL) and then
was diluted with CH2Cl2 (150 mL) and washed with water (3
× 100 mL). The aqueous layers were back-extracted with CH2-
Cl2 (3 × 50 mL), and the combined organic phases were washed
with brine (75 mL), dried (Na2SO4), filtered, and concentrated
to afford a yellow oil. The crude material was purified by silica
gel column chromatography (hexane/EtOAc, 5/1 (600 mL), 4/1)
to afford 39 mg of analytically pure nitronate 17b and 197
mg of analytically pure 17a to give a combined yield of 236
mg (69%) and an overall endo/exo ratio of 5/1 (17a /18b). Data
for 17a : 1H NMR (499.7 MHz, CDCl3) δ 7.35-7.28 (m, 3 H),
7.20-7.18 (m, 2 H), 5.72-5.63 (m, 1 H), 4.94-4.90 (m, 2 H),
4.06-4.01 (m, 1 H), 3.47 (d, J ) 10.2, 1 H), 2.25-2.12 (m, 3
H), 1.83-1.68 (m, 7 H), 1.58-1.19 (m, 9 H); 13C NMR (125.7
MHz, CDCl3) δ 139.47, 136.07, 129.04, 128.99, 127.73, 124.48,
[(1S,3R,4S,5R)-4-(Acetyla m in o)-4-m eth yl-5-p h en yl]-1,3-
cyclop en ta n ed im eth a n ol Dia ceta te (16a ). Nitroso acetal
14b (129 mg, 0.42 mmol) was added to a suspension of
prewashed (5 × 10 mL MeOH) Raney nickel (amount that
would fit on a tip of a spatula) in EtOH (35 mL). Sodium
borohydride (65 mg, 1.70 mmol, 4 equiv) was directly added
to the reaction mixture and was then immediately placed
under 1 atm of H2. After approximately 1 h, a solution of
sodium borohydride (65 mg, 1.70 mmol, 4 equiv) in EtOH (1
mL) was added to the reaction while it was under 1 atm of
H2. After an additional hour, a solution of sodium borohydride
(65 mg, 1.70 mmol, 4 equiv) in EtOH (1 mL) was again added
and the reaction was allowed to stir 4 h further. The Raney
nickel was removed by filtering the reaction mixture through
a cotton pipet plug, washing with copious amounts of MeOH,
and concentrating. The crude material was dissolved in
pyridine (5 mL) and acetic anhydride (5 mL) and was left to
stir at room temperature for 18 h. The excess pyridine and
acetic anhydride were removed in vacuo, using an external
trap, providing a brown oil. The crude organic concentrate
was purified twice by silica gel column chromatography

Tandem Inter/Intra Cycloadditions of Nitroalkenes
J . Org. Chem., Vol. 63, No. 18, 1998 6177
116.69, 106.89, 70.87, 48.25, 47.69, 33.89, 33.57, 32.80, 25.51,
24.03, 20.96, 17.24; IR (CCl4) 2934, 1621, 1271, 1237; MS (FAB)
344 (M+ + 1, 100); TLC Rf 0.23 (hexane/EtOAc, 2/1). Anal.
Calcd for C21H29NO3 (343.47): C, 73.44; H, 8.51; N, 4.08.
Found: C, 73.58; H, 8.63; N, 4.16. Data for 17b: 1H NMR
(499.7 MHz, CDCl3) δ 7.34-7.31 (m, 2 H), 7.28-7.26 (m, 1 H),
7.13-7.12 (m, 2 H), 5.30-5.22 (m, 1 H), 4.75-4.70 (m, 2 H),
4.42 (d, J ) 6.0, 1 H), 4.07-4.02 (m, 1 H), 2.11-2.00 (m, 3 H),
1.95 (d, J ) 1.3, 3 H), 1.79-1.67 (m, 4 H), 1.53-1.49 (m, 4 H),
1.41-1.15 (m, 5 H); 13C NMR (125.7 MHz, CDCl3) δ 137.25,
137.05, 129.70, 128.67, 127.33, 123.29, 115.58, 107.37, 70.66,
46.27, 44.54, 34.31, 33.64, 30.68, 25.42, 24.30, 24.24, 20.49,
18.24; IR (Neat) 2934; MS (FAB) 344 (M+ + 1, 100); TLC Rf
0.34 (hexane/EtOAc, 2/1). Anal. Calcd for C21H29NO3
(343.47): C, 73.44; H, 8.51; N, 4.08. Found: C, 73.29; H, 8.59;
N, 4.94.
r el-(1R,6S,7S,8R,9S)-6-Cycloh exyloxy-6,9-d im et h yl-8-
p h en yl-4-a za -3,5-d ioxa tr icyclo[5.3.1.04,9]d eca n e (18). So-
dium bicarbonate (262 mg, 3.12 mmol, 7 equiv) was added to
a solution of nitronate 17a (153 mg, 0.445 mmol) in toluene
(45 mL), and the suspension was heated to reflux for 12 h.
After being cooled to room temperature, the concentrated
reaction mixture was redissolved in benzene (10 mL), filtered
through a cotton pipet plug, followed by washing the plug with
excess benzene and reconcentrating. The crude material was
purified by basic alumina (activity III) chromatography (hex-
ane/EtOAc, 8/1) to afford 110 mg (72%) of analytically pure
nitroso acetal 18 as a white crystalline solid: mp 150-157 °C
(hexane/EtOAc); 1H NMR (499.7 MHz, C6D6) δ 7.61 (bs, 2 H),
7.21-7.18 (m, 2 H), 7.08-7.05 (m, 1 H), 4.28 (dd, J ) 6.8, 3.5,
1 H), 4.09 (dd, J ) 9.1, 6.8, 1 H), 3.86-3.80 (m, 1 H), 2.82 (d,
J ) 4.0, 1 H), 2.33-2.17 (m, 4 H), 1.66-1.42 (m, 4 H), 1.35-
1.24 (m, 6 H), 1.19-1.03 (m, 3 H), 0.79 (s, 3 H); 13C NMR (125.7
MHz, C6D6) δ 139.66, 130.81, 128.31, 126.57, 102.86, 78.36,
77.48, 70.59, 54.26, 51.85, 50.98, 35.07, 33.92, 31.26, 25.98,
25.88, 24.85, 24.68, 21.97; IR (neat) 2937; MS (FAB) 344 (M+
+ 1, 68), 171 (100); TLC Rf 0.56 (hexane/EtOAc, 2/1). Anal.
Calcd for C21H29NO3 (343.47): C, 73.44; H, 8.51; N, 4.08.
Found: C, 73.22; H, 8.60; N, 3.91.
r el-(1R,2S,4R,5R,7S)-2-Hyd r oxym eth yl-1,5-d im eth yl-7-
ph en yl-6-azabicyclo[2.2.1]h exan e an d r el-(1R,2S,4S,5S,7S)-
2-H yd r oxym et h yl-1,5-d im et h yl-7-p h en yl-6-a za -b icyclo-
[2.2.1]h exa n e (19) a n d r el-[(1S,3R,4R,5R,6R)-4-(Acet yl-
a m in o)-4,6-d im eth yl-5-p h en yl]-1,3-cyclop en ta n ed im eth -
an ol Diacetate an d r el-[(1S,3R,4S,5R,6S)-4-(Acetylam in o)-
4,6-d im eth yl-5-p h en yl]-1,3-cyclop en ta n ed im eth a n ol Di-
a ceta te (20). Nitroso acetal 18 (91 mg, 0.26 mmol) was added
to a suspension of prewashed (4 × 10 mL of MeOH) Raney
nickel (amount that would fit on a tip of a spatula) in MeOH
(10 mL). The reaction was placed under 1 atm of H2 at room
temperature for 24 h. The Raney nickel was removed by
filtering the reaction mixture through a cotton pipet plug,
washing with copious amounts of MeOH, and concentrating.
The crude material was dissolved in pyridine (3 mL) and acetic
anhydride (3 mL) and was left to stir at room temperature for
4.5 h. The excess pyridine and acetic anhydride were removed
in vacuo to provide a brown oil. The crude organic concentrate
was purified by silica gel column chromatography (EtOAc/
hexane, 2/1) to provide a complex mixture of four compounds.
Separation of the two main components was accomplished
using MPLC (silica gel; hexane/i-PrOH, 85:15) which afforded
10 mg of a 1.4/1 mixture of diastereomeric bicyclic amines 19
at C(5) and 10 mg of a 7.3/1 mixture of diastereomeric
triacetates 20 at C(6). The combined yield of the reaction over
two steps was 20 mg (21%). Data for 19: 1H NMR (499.7 MHz,
C6D6) δ 7.14-7.04 (m, 5 H), 4.51 (dd, J ) 11.2, 6.6, 0.59 H),
4.31-4.21 (m, 1.41 H), 3.96 (dd, J ) 11.2, 9.2, 0.41 H), 3.44-
3.41 (m, 0.59 H), 2.46 (s, 0.59 H), 2.40 (s, 0.41 H), 2.09-2.03
(m, 0.59 H), 1.97 (s, 1.23 H), 1.95-1.88 (m, 2.18 H), 1.78 (s,
1.77 H), 1.72 (s, 1.77 H), 1.64-1.57 (m, 1.82 H), 1.49-1.31 (m,
2 H), 1.26 (d, J ) , 1.77 H), 1.10 (dd, J ) 13.3, 4.8, 0.41 H),
0.79 (d, J ) 6.2, 1.23 H); MS (FAB) 316 (M+ + 1, 100); TLC Rf
0.32 (EtOAc/hexane). Data for 21: 1H NMR (499.7 MHz, C6D6)
δ 7.12-7.02 (m, 5 H), 5.74 (s, 0.12 H), 5.25 (s, 0.88 H), 4.91 (t,
J ) 6.6, 0.12 H), 4.54 (dd, J ) 11.5, 6.0, 0.012 H), 4.47-4.41
(m, 1.76 H), 4.29 (dd, J ) 11.3, 7.3, 0.88 H), 4.25 (dd, J ) 11.3,
7.5, 0.12 H), 3.34 (d, J ) 7.9, 0.88 H), 2.92 (d, J ) 9.5, 0.12 H),
2.32-2.24 (m, 1.76 H), 2.15-2.08 (m, 0.24 H), 1.89 (s, 0.36
H), 1.79 (s, 2.64 H), 1.72 (s, 2.64 H), 1.64-1.54 (m, 1.36 H),
1.51 (s, 2.64 H), 1.46-1.35 (m, 0.9 H), 1.26 (s, 2.64 H), 1.02 (d,
J ) 6.0, 2.64 H), 0.95 (d, J ) 6.2, 0.36 H), 0.91-0.86 (m, 0.88
H); MS (FAB) 376 (M+ + 1, 42), 316 (100); TLC Rf 0.32 (EtOAc/
hexane, 2/1)
4-Hyd r oxyim in o-3-p h en ylp en ta n oic Acid Bu tyl Ester
(21). To a -78 °C solution of nitroalkene 12 (100 mg, 0.613
mmol) in CH2Cl2 (4 mL) was added SnCl4 (0.143 mL, 1.23
mmol, 2.0 equiv). The resulting, bright-yellow complex was
allowed to stir for 15 min, and then a solution of silane 7 (317
mg, 1.84 mmol, 3 equiv) in CH2Cl2 (1 mL) was slowly added
dropwise via syringe. The reaction was left to stir at -78 °C
for 30 min and subsequently quenched with 1 N NaOH/CH3-
OH(4 mL). The cold reaction mixture was diluted with CH2-
Cl2 (150 mL) and was washed with water (3 × 100 mL). The
aqueous phase was back-extracted with CH2Cl2 (3 × 50 mL),
and the combined organic layers were washed with brine (100
mL), dried (Na2SO4), filtered, and concentrated to afford a light
yellow oil. The crude organic concentrate was purified by silica
gel column chromatography (hexane/EtOAc 7/1, 6/1) to provide
137 mg (85%) of oxime 21 as white solid: mp 64-65 °C
(hexane/EtOAc); 1H NMR (499.7 MHz, CDCl3) δ 7.33-7.30 (m,
3 H), 7.27-7.23 (m, 2 H), 4.07-3.96 (M, 3 H), 3.04 (dd, J )
15.9, 8.6, 1 H), 2.65 (dd, J ) 15.9, 6.9, 1 H), 1.76 (s, 3 H), 1.56-
1.50 (m, 2 H), 1.33-1.25 (m, 2 H), 0.88 (t, J ) 7.5, 3 H); 13C
NMR (125.7 MHz, CDCl3) δ 172.06, 158.37, 139.83, 128.77,
128.06, 127.32, 64.37, 48.02, 38.09, 30.55, 18.99, 13.63, 13.53;
IR (CHCl3) 3504, 3475, 3420, 3401, 3361; MS (FAB) 264 (M+
+ 1, 100); TLC Rf 0.22 (hexane/EtOAc, 4/1). Anal. Calcd for
C
15H21NO3 (263.33): C, 68.42; H, 8.04; N, 5.32. Found: C,
68.43; H, 7.91; N, 5.38.
4-[Dim et h yl-(1,1-d im et h ylet h yl)]-silyloxyim in o-2-(3-
p r op en yl)-3-p h en ylp en ta n oic Acid Eth yl Ester (22). To
a -78 °C solution of nitroalkene 12 (24 mg, 0.146 mmol) in
CH2Cl2 (2 mL) was added tin tetrachloride (43 µL, 0.291 mmol,
2.0 equiv). The resulting, bright-yellow complex was allowed
to stir for 15 min, and then a solution of vinyl silane 11 (66
mg, 0.291 mmol, 2.0 equiv) in CH2Cl2 (1 mL) was slowly added
dropwise via syringe. The reaction was stirred at -78 °C for
15 min and subsequently quenched with a 1 N NaOH/CH3OH
solution (3 mL). The cold reaction mixture was diluted with
CH2Cl2 (100 mL) and washed with water (3 × 100 mL). The
aqueous phase was back-extracted with CH2Cl2 (3 × 50 mL),
and the combined organic layers were washed with brine (100
mL), dried (Na2SO4), filtered, and concentrated to afford a light
yellow oil. The crude product was purified by silica gel column
chromatography (hexane/EtOAc 50/1) to provide 42.4 mg (75%)
of a 7/1 mixture of oxime 22 and an unidentified compound as
a clear oil: 1H NMR (499.7 MHz, CDCl3) δ 7.27-7.20 (m, 5
H), 5.81-5.73 (m, 1 H), 5.05 (dd, J ) 17.0, 1.5, 1 H), 5.00 (dd,
J ) 11.2, 0.9, 1 H), 3.81-3.75 (m, 2 H), 3.61 (d, J ) 11.5, 1 H),
3.32-3.27 (m, 1 H), 2.59-2.55 (m, 1 H), 3.39-3.33 (m, 1 H),
1.72 (s, 3 H), 0.96 (s, 9 H), 0.87 (t, J ) 7.1, 3 H) 0.19 (s, 3 H),
1.72 (s, 3 H); 13C NMR (125.7 MHz, CDCl3) δ 173.98, 160,01,
138.79, 135.19, 128.68, 128.30, 127.19, 116.74, 59.91, 54.21,
48.41, 35.65, 26.17, 18.11, 14.13, 13.86, -5.07; IR (neat) 1737,
876, 839; MS (FAB) 390 (M+ + 1, 100); TLC Rf 0.15 (hexane/
EtOAc, 40/1); HRMS (FAB) calcd for C22H36NO3Si 390.24645,
found 390.24630.
Ack n ow led gm en t. We are grateful to the National
Institute of Health (GM-30938) for generous financial
support.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal and materials as well as complete H NMR, 13C NMR, IR,
and MS data for all characterized compounds (22 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
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J O9802168