Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions of Nitroalkenes. A Versatile Asymmetric Synthesis of Highly Functionalized Aminocyclopentanes

Full text of DOI:10.1021/jo9713215

7086
J . Org. Chem. 1997, 62, 7086-7087
Sch em e 1
Ta n d em In ter [4 + 2]/In tr a [3 + 2]
Cycloa d d ition s of Nitr oa lk en es. A
Ver sa tile Asym m etr ic Syn th esis of High ly
F u n ction a lized Am in ocyclop en ta n es†
Scott E. Denmark* and J ulie A. Dixon
Roger Adams Laboratory, Department of Chemistry,
University of Illinois, Urbana, Illinois 61801
Received J uly 21, 1997
Tandem pericyclic reactions have become extremely
useful for the rapid and efficient construction of highly
functionalized compounds.1 In these laboratories, the
tandem [4 + 2]/[3 + 2] cycloaddition of nitroalkenes and
nitronates has been developed as a general approach for
the synthesis of a diverse array of cyclic, nitrogen-
containing structures.2 Recently, we reported a novel
subclass of the inter [4 + 2]/intra [3 + 2] cycloaddition
sequence called the bridged-mode (R-tether).3 This pro-
cess involves the Lewis acid promoted [4 + 2] cycload-
dition of nitro olefins with vinyl ethers bearing an
R-tethered dipolarophile, Scheme 1. The resulting ni-
tronates undergo thermal intramolecular [3 + 2] cycload-
dition to afford bridged nitroso acetals which, upon
reduction, provide aminocyclohexanemethanols. This
success encouraged us to pursue a second variant of the
bridged-mode tandem cycloaddition that would be ap-
plicable to the synthesis of aminocyclopentanes. If the
dipolarophile were attached to the â-carbon of the vinyl
ether, then the [4 + 2] cycloaddition would generate a
cyclic nitronate now bearing a C(5)-tethered olefin,
Scheme 1. Intramolecular [3 + 2] cycloaddition would
subsequently provide a bridged tricyclic nitroso acetal
that could be converted into a highly-functionalized
aminocyclopentane.4 In this communication, we report
the successful realization of the bridged mode (â-tether)
construction with an enantiomerically pure 1-alkoxy-1,4-
diene. We also describe the remarkable effect of the
Lewis acid on the diastereofacial selectivity of the [4 +
2] cycloaddition process.
Sch em e 2
Sch em e 3
Preparation of a chiral dienophile for use in the
â-bridged-mode tandem process was accomplished in two
steps from trans-(1R,2S)-phenylcyclohexanol ((-)-1). Thus,
the potassium alkoxide of (-)-1 (>99% ee) was combined
sequentially with trichloroethylene and n-butyllithium,
to afford, after quenching with allyl iodide, the acetylenic
ether (-)-2 in 83% yield, Scheme 2. Lithium aluminum
hydride reduction of (-)-2 provided exclusively the trans-
vinyl ether (-)-3 in 85% yield.5
For the initial investigations of the tandem process,
we chose (E)-2-methyl-2-nitrostyrene (4a ) as the test
substrate. The [4 + 2] cycloaddition of nitroalkene 4a
with (-)-3 was efficiently promoted by SnCl4 to afford a
mixture of diastereomeric nitronates 5a , 5a ', and 5a '' (32/
2/1) in 93% yield, Scheme 3. Diastereomers 5a and 5a '
possess a cis relationship between the phenyl and allyl
substituents and retain the trans relationship in the vinyl
ether. Thus, they must arise from an exo(alkoxy)-mode
cycloaddition while trans (C(4)/C(5)) nitronate 5a '' results
from an endo(alkoxy)-mode reaction.6 The nitronic ester
subunits of 5a and 5a ' are enantiomorphic and arise from
exo-mode cycloadditions with the diastereotopic faces of
the chiral vinyl ether. Therefore, the overall exo/endo
selectivity of the cycloaddition is >30/1 (5a +5a '/5a ''),
while the diastereofacial selectivity in the exo series is
15/1 (5a /5a '). Intramolecular [3 + 2] cycloaddition of
pure 5a in refluxing benzene provided the tricyclic nitroso
acetal 6a as a crystalline solid in quantitative yield. The
full stereostructure of 6a was secured through single
† This paper is dedicated to Professor Dieter Seebach with admira-
tion and best wishes on the occasion of his 60th birthday.
(1) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(c) Ziegler, F. E. In Comprehensive Organic Synthesis, Combining C-C
p-Bonds; Paquette, L. A., Ed.; Pergamon Press: Oxford, 1991; Vol. 5,
Chapter 7.3. (d) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131. (e) Cascade Reactions; Grigg, R., Ed.; Tetrahedron
Symposium in Print No. 62, 1996; Vol. 52 (35).
(2) (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.
(3) (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.
(4) For a review of a 1,3-dipolar cycloaddition approach to substi-
tuted aminocyclopentanols see: Padwa, A.; Schoffstall, A. M. In
Advances in Cycloaddition; Curran, D. P., Ed.; J AI Press: Greenwich,
1990; Vol. 2, pp 1-89.
(5) (a) Moyano, A.; Charbonnier, F.; Greene, A. E. J . Org. Chem.
1987, 52, 2919. (b) Sola, L.; Castro, J .; Moyano, A.; Pericas, M. A.;
Riera, A. Tetrahedron Lett. 1992, 33, 2863.
(6) The stereostructural assignment of the endo(alkoxy)-derived
product 5a ′′ was established by X-ray crystal structure analysis.
S0022-3263(97)01321-2 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 21, 1997 7087
Ta ble 1. Th e Ta n d em [4 + 2]/[3 + 2] Cycloa d d ition a n d
Sch em e 4
Red u ction Sequ en ce
series
6 yield, %
(ratio of) 7 yield, %
(-)-8 yield, %
(R1, R2)
5 yield,a
%
(ee, %)d
crystal X-ray analysis of (()-6a that was obtained from
a SnCl4-promoted tandem cycloaddition of nitroalkene 4
with enol ether (()-3.7 Nickel boride8 reduction of the
nitroso acetal afforded an amino diol (-)-7a in 82% yield
along with 94% of the recovered alcohol (-)-1. To
facilitate purification and determine the extent of enan-
tiomeric enrichment, the amino diol was peracylated to
provide the triacetate (+)-8a in 83% yield and >99% ee.9
In view of our previous observations on the influence
of Lewis acids on the stereochemical course of the
[4 + 2] cycloaddition,2c we next examined the reaction of
4a with (-)-3 promoted by MAPh.10 The same three
diastereomeric nitronates (5a , 5a ', and 5a '') were formed
in excellent yield (95%), however, this time in a ratio of
1/15/1.8 (Scheme 4). Thus, the reaction was again highly
exo-selective (exo/endo, >8.8/1 (5a +5a '/5a ''), but remark-
ably, the major diastereomer from the MAPh-promoted
cycloaddition corresponded to the minor exo diastereomer
obtained in the SnCl4-promoted cycloaddition. The 15/1
mixture of nitronates 5a ' and 5a was heated in benzene
to afford a 25/1 mixture of nitroso acetals 6a ' and 6a in
96% yield. Unmasking of the nitroso acetals with nickel
boride provided a single amino diol (+)-7a in 72% yield
(94% of (-)-1 was recovered). The triacetate (-)-8a ,
obtained by acetylation of (+)-7a , was found to be of 93%
ee9 but was levorotatory and thus belonged to the
opposite enantiomeric series as the triacetate derived
from the SnCl4-promoted tandem process. Therefore,
from a single, chiral, nonracemic auxiliary, either enan-
tiomer of the final amino diol can be obtained by ap-
propriate selection of the Lewis acid in the tandem
sequence. A number of Lewis acid dependent switches
in enantioselectivity have been observed.11 However, in
these cases the change is presumably due to different
coordination modes of the Lewis acid. In our system,
both products derive from exo transition structures, so
the change in stereochemical course is not likely due to
different modes of coordination, but rather, due to a
remarkable change in the reactive conformation of the
vinyl ether (s-cis with SnCl4 and s-trans with MAPh).
The generality of the new, bridged-mode tandem
[4 + 2]/[3 + 2] reaction was demonstrated by applying
b (Me, c-Hex)
c (H, Ph)
d (H, OBz)
90
92
68
91 (6.7/1)
87 (25/1)
- (nd)
96
73 (>95)
59b (95)
68 (>98)
82b
61c
a
b
Isolated as
a mixture of diastereomers. Isolated as 3/1
mixture of epimeric amino diols at C(1). c Yield over two steps.
d
Determined by chiral HPLC.
the reaction sequence to a variety of substrates which
incorporated branched alkyl, aromatic, and heteroatom
substituents. Thus, nitroalkenes 4b-d underwent MAPh
promoted [4 + 2] cycloaddition with (-)-3 to afford nitro-
nates 5b-d in good to excellent yields (68-92%), Table
1. In all cases, the major diastereomer is believed to have
arisen from an exo(alkoxy)-mode cycloaddition. Unfortu-
nately, the exact diastereomeric ratios could not be deter-
mined at this stage due to the propensity of the nitro-
nates to slowly undergo [3 + 2] cycloaddition at ambient
temperature. Consequently, intramolecular [3 + 2] cyclo-
additions of 5b and 5c proceeded smoothly in refluxing
benzene to provide the tricyclic nitroso acetals 6b (6.7/1
ratio of facial diastereomers) and 6c (25/1 ratio of facial
diastereomers) in 87 and 91% yield, respectively. Nickel
boride reduction of a diastereomerically enriched sample
of 6b (>25/1 mixture) afforded amino diol 7b in 96% yield
along with recovered (-)-1 (98%). Acetylation of 7b pro-
vided the corresponding triacetate (-)-8b in 73% yield and
>95% ee.9 The reduction of nitroso acetal 6c afforded
the desired amino diol 7c as a 3/1 mixture of epimers at
C(1) in 82% yield.12 After acylation, the ee of 8c was
established to be 95%.9 Intramolecular [3 + 2] cycload-
dition of nitronate 5d and subsequent reduction of the
unstable nitroso acetal 6d 13 with nickel boride provided
the amino diol 7d in 61% over two steps. Acetylation of
7d afforded the triacetate 8d in 68% yield and >98% ee.9
In summary, we have developed a novel variant of the
tandem cycloaddition of nitroalkenes which is useful for
the asymmetric synthesis of highly substituted aminocy-
clopentanes. Moreover, by changing the Lewis acid from
SnCl4 to MAPh in the tandem sequence, enantiomeric
amino diols can be obtained using a single enantiomer
of the chiral vinyl ether. Further studies on the applica-
tion of this process to the synthesis of aminocyclopen-
tanoid natural products are in progress.
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-30938) for financial support.
(7) Dixon, J . A.; Swiss, K. A.; Denmark, S. E. Acta. Crystallogr. C
1996, 52, 2561.
(8) For review on nickel boride see: Ganem, B.; Osby, J . O. Chem.
Rev. 1986, 86, 763.
(9) Determined by chiral stationary phase HPLC, see Supporting
Information for details.
Su p p or tin g In for m a tion Ava ila ble: General and experi-
mental procedures along with complete spectroscopic and
analytical data for all characterized compounds (35 pages).
(10) Methylaluminum bis(2,6-diphenylphenoxide). Maruoka, K.;
Yamamoto, H. Tetrahedron 1988, 44, 5001.
J O9713215
(11) (a) Tietze, L. F.; Schneider, C.; Grote, A. Chem. Eur. J . 1996,
58, 139. (b) Poll, T.; Helmchen, G.; Bauer, B. Tetrahedron Lett. 1984,
25, 2191. (b) Waldmann, H. J . Org. Chem. 1988, 53, 6133. (c) Suzuki,
H.; Mochizuki, K.; Hattori, T.; Takahashi, N.; Tajima, O.; Takiquchi,
T. Bull Chem. Soc. J pn. 1988, 61, 1999. (d) Amoroso, R.; Cardillo, G.;
Sabatino, P.; Tomasini, C.; Trere`, A. J . Org. Chem. 1993, 58, 5615. (e)
Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J . Am.
Chem. Soc. 1993, 115, 2613.
(12) Epimeric ratios ranging from 3-20/1 have been obtained for
this reaction. The epimerization of C(1) in 7c may proceed via an
enamine from a dehydrogenation/reduction sequence due to the ben-
zylic nature of the hydrogen at the C(9) position of the nitroso acetal.
(13) Nitroso acetal 6d was unstable to alumina and silica gel
chromatography and was used in the subsequent reaction without
purification.