Cycloaddition Reactions of Chiral 2-Amino-1,3-butadienes with Nitroalkenes: Synthesis of Enantiomerically Pure 4-Nitrocyclohexanones

Article abstract of DOI:10.1021/jo970237m

2-Amino-1,3-butadienes bearing commercially available S-(+)-2-(methoxymethyl)pyrrolidine as chiral auxiliary undergo a [4 + 2] cycloaddition reaction with nitroalkenes to furnish 4-nitrocyclohexanones upon hydrolysis of the resulting enamine. The cycloadd

Full text of DOI:10.1021/jo970237m

6746
J . Org. Chem. 1997, 62, 6746-6753
Cycloa d d ition Rea ction s of Ch ir a l 2-Am in o-1,3-bu ta d ien es w ith
Nitr oa lk en es: Syn th esis of En a n tiom er ica lly P u r e
4-Nitr ocycloh exa n on es1
J ose´ Barluenga,* Fernando Aznar, Cristina Ribas, and Carlos Valde´s
Instituto de Quı´mica Organometa´lica “Enrique Moles” (Unidad Asociada al CSIC),
Universidad de Oviedo, Oviedo 33071, Spain
Received February 10, 1997X
2-Amino-1,3-butadienes bearing commercially available S-(+)-2-(methoxymethyl)pyrrolidine as
chiral auxiliary undergo a [4 + 2] cycloaddition reaction with nitroalkenes to furnish 4-nitrocy-
clohexanones upon hydrolysis of the resulting enamine. The cycloadducts are obtained with good
yields and very high enantiomeric excesses. The reaction has been performed with aromatic and
aliphatic conjugated nitroalkenes. Moreover, a 2-amino diene which features a (Z) double bond
undergoes a Michael addition reaction with nitroalkenes, which gives rise to open chain compounds
with high enantioselectivity. After acidic hydrolysis, the open chain compounds cyclize to form
chiral substituted furans.
In tr od u ction
Enantioselective [4 + 2] cycloadditions constitute an
excellent strategy for the preparation of functionalized
optically active 6-membered rings. During the process,
up to four new stereogenic centers can be created in a
single synthetic operation. Asymmetric induction in
these processes has been achieved by employing chiral
catalysts (catalytic approach),2 chirally modified dieno-
philes,3 and chirally modified dienes4 (stoichiometric
approaches). While the usefulness of the first two
methodsschiral catalysts and chiral dienophilesshas
been widely demonstrated, optically active dienes have
been employed less frequently in [4 + 2] cycloadditions.
Most of the examples described in the literature rely on
F igu r e 1. Asymmetric synthesis with chiral 2-amino dienes.
the use of dienes which carry the chiral information
attached to the C-1 position of the diene.5 However, these
dienes are far from ideal; they usually present limitations
in accessibility of the enantiomerically pure diene, poor
reactivity, low stereoselectivity of the cycloaddition pro-
cess, or cleavage of the chiral auxiliary.
Comparatively, few examples are known to date of the
use of dienes with a chiral auxiliary linked to C-2 of the
diene.6 Recently our group, simultaneously with Enders
et al., introduced a new class of optically active 2-amino-
1,3-butadienes I;7 a type of diene that fulfills most of the
requirements for an ideal chiral reagent: they are easily
accessible by a variety of methods8 in optically pure form,
and the chiral auxiliary can be readily cleaved once the
reaction has been carried out (Figure 1). In fact, chiral
2-amino dienes have been successfully employed in highly
stereoselective [4 + 2] homo-9 and hetero-Diels-Alder
reactions,10 and also in [4 + 3] cyclization processes
X Abstract published in Advance ACS Abstracts, August 15, 1997.
(1) A communication containing preliminary results on this work
has been previously published: Barluenga, J .; Aznar, F.; Valde´s, C.;
Mart´ın, A.; Garc´ıa-Granda, S.; Mart´ın, E. J . Am. Chem. Soc. 1993,
115, 4403-4404.
(2) For recent reviews on catalytic asymmetric Diels-Alder reac-
tions, see: (a) Kagan, B. H.; Riant, O. Chem. Rev. 1992, 92, 1007. (b)
Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 497.
(c) Seyden-Penne, J . Chiral Auxiliares and Ligands in Asymmetric
Synthesis; J ohn Wiley & Sons: New York, 1995; pp 537-553. For some
leading articles, see: (d) Evans, D. A.; Murry, J . A.; von Matt, P.;
Norcross, R. D.; Miller, S. J . Angew. Chem., Int. Ed. Engl. 1995, 34,
798. (e) Ishihara, K.; Kurihara, H.; Yamamoto, H. J . Am. Chem. Soc.
1996, 118, 3049. (f) Hayashi, Y.; Rohde, J . J .; Corey, E. J . J . Am. Chem.
Soc. 1996, 118, 5502 and references cited therein.
(3) For leading references on the use of chiral dienophiles in
asymmetric Diels-Alder reactions, see: (a) Corey, E. J .; Ensley, H. E.
J . Am. Chem. Soc. 1975, 97, 6908. (b) Evans, D. A.; Chapman, K. T.;
Bisasha, J . J . Am. Chem. Soc. 1988, 110, 1238. (c) Oppolzer, W.
Camphor derivatives as Chiral Auxiliares in Asymmetric Synthesis.
Tetrahedron 1987, 43, 1969. (d) Oppolzer, W.; Willis, M.; Kelly, M. J .;
Signer, M.; Blagg, J . Tetrahedron Lett. 1990, 31, 5015.
(4) For review on chiral dienes, see: (a) Mulzer, J .; Altenbach, H.
J .; Braun, M.; Krohn, K.; Reissig, H. U. In Organic Synthesis
Highlights; VCH Verlagsgesellschaft: Weinheim, 1991; pp 60-61. (b)
Seyden-Penne, J . Chiral Auxiliares and Ligands in Asymmetric
Synthesis; J ohn Wiley & Sons: New York, 1995; pp 586-593.
(5) For some leading references on C1-substituted chiral dienes,
see: (a) Trost, B. M.; O’Krongly, D.; Belletire, J . L. J . Am. Chem. Soc.
1980, 102, 7595-7596. (b) Larsen, D. S.; Stoodley, R. J . J . Chem. Soc.,
Perkin Trans. 1 1990, 1339-1352. (c) Gree, R.; Kessabi, L.; Mosset,
P.; Martelli, J .; Carrie, R. Tetrahedron Lett. 1984, 25, 3697. (d) Fisher,
M. J .; Hehre, W. J .; Kahn, S. D.; Overman, L. E. J . Am. Chem. Soc.
1988, 110, 4625-4633. (e) Datta, S. C.; Franck, R. W.; Tripathy, R.;
Quigley, G. J .; Huang, L.; Chen, S.; Sihaed, A. J . Am. Chem. Soc. 1990,
112, 8472-8478. (f) Tripathy, R.; Carroll, P. J .; Thornton, E. R. J . Am.
Chem. Soc. 1991, 113, 7630-7640. (g) Arce, F.; Carren˜o, M. C.; Cid,
M. B.; Garc´ıa-Ruano, J . L. J . Org. Chem. 1994, 59, 3421 and references
cited therein.
(6) (a) Suryaawanshi, S. N.; Dhami, T. S.; Bhakuni, D. S. Tetrahe-
dron Lett. 1991, 32, 1519. (b) Hatakeyama, S.; Sugawara, K.; Takano,
S. J . Chem. Soc., Chem. Commun. 1992, 953-955. (c) Adams, H.;
J ones, D. N.; Aversa, M. C.; Bonaccorsi, P.; Giannetto, P. Tetrahedron
Lett. 1993, 34, 6481-6484. (d) Barluenga, J .; Toma´s, M.; Sua´rez-
Sobrino, A. L.; Lo´pez, L. A. J . Chem. Soc., Chem. Commun. 1995,
1785-1786.
(7) For
a very recent review on the chemistry of 2-amino-1,3-
butadienes, see: Enders, D.; Meyer, O. Liebigs Ann. 1996, 1023-1035.
(8) (a) Barluenga, J .; Aznar, F.; Valde´s, C.; Cabal, M. P. J . Org.
Chem. 1991, 56, 6166-6171. (b) Barluenga, J .; Merino, I.; Palacios, F.
Tetrahedron Lett. 1990, 31, 6713-6716. (c) Enders, D.; Meyer, O.;
Raabe, G. Synthesis 1992, 1242-1244. (d) Enders, D.; Hecker, P.;
Meyer, O. Tetrahedron 1996, 52, 2909.
(9) (a) Barluenga, J .; Aznar, F.; Mart´ın, A.; Barluenga, S.; Garc´ıa-
Granda, S.; Paneque-Quevedo, A. A. J . Chem. Soc., Chem. Commun.
1994, 843-844. (b) Barluenga, J .; Canteli, R. M.; Flo´rez, J .; Garc´ıa-
Granda, S.; Gutie´rrez-Rodr´ıguez, A. J . Am. Chem. Soc. 1994, 116,
6949-6950.
(10) (a) Enders, D.; Meyer, O.; Raabe, G.; Runsik, J . Synthesis 1994,
66-72. (b) Barluenga, J .; Aznar, F.; Ribas, C.; Valde´s, C.; Ferna´ndez,
M.; Cabal, M. P.; Trujillo, J . Chem. Eur. J . 1996, 2, 805-811.
S0022-3263(97)00237-5 CCC: $14.00 © 1997 American Chemical Society

Chiral 2-Amino-1,3-butadiene-Nitroalkene Cycloaddition
J . Org. Chem., Vol. 62, No. 20, 1997 6747
involving R,â-unsaturated Fischer carbene complexes.11
On the other hand, conjugated nitroalkenes have been
shown to be very potent dienophiles in [4 + 2] cycload-
ditions;12 in particular, their reactivity toward 2-amino
dienes is well-known.13 It has been previously demon-
strated that depending on the nature of the diene used,
open chain 4-nitro ketones II (arising from a Michael type
addition of the enamine moiety to the nitroolefin), or
4-nitrocyclohexanones III (formal [4 + 2] cycloaddition)
can be obtained (Figure 2).14 The chiral version of this
reaction has received much less attention. As far as we
know, only one contribution by the Enders’ group re-
stricted to the use of aromatic nitroolefins,8c apart from
our previous communication, has been described.
Recently, we have been interested in the synthesis of
enantiomerically pure compounds by using chiral 2-amino-
1,3-butadienes bearing (S)-2-(methoxymethyl)pyrrolidine
as chiral auxiliary. In our first communication in this
field we introduced the reaction between chiral 2-amino
dienes 1 and nitroolefins,1 a process that afforded 4-ni-
trocyclohexanones in which four new stereocenters were
created in good yields and high ee (82-90%). Encouraged
by these promising results, as well as by the potential
synthetic interest of these functionalized nitro deriva-
tives, we set out to investigate the scope of this reaction
with the purpose of developing a more general method
for the preparation of substituted 4-nitrocyclohexanones.
In this paper we describe the reaction of substituted
chiral 2-amino dienes with a variety of nitroalkenes with
aromatic, heteroaromatic, and aliphatic substituents. The
effect of the substituents on both the diene and dienophile
on the enantiomeric excess has been studied. Addition-
ally an enantioselective synthesis of substituted furans
is reported.
F igu r e 2. Reactivity of 2-amino dienes toward conjugated
nitroalkenes.
reactions were carried out in MeOH as solvent at -80
°C for 12 h and then warmed to room temperature over
10 h. The initially formed enamines 3 were not isolated
due to their moisture sensitivity but hydrolyzed with an
acidic aqueous buffer (HOAc/NaOAc, pH ) 4.6) to release
the chiral auxiliary, yielding 4-nitrocyclohexanones 4
(Scheme 1). Both the cycloaddition process and the
hydrolysis of the enamine moiety are highly diastereo-
selective, and in most of the cases a single diastereoiso-
mer of all the possible combinations was isolated (83-
1
99% de),15 as deduced from the H NMR spectra analysis
of the crude reactions. Only for compound 4i was a
notable decrease in the selectivity observed (3:1 mixture
of diastereoisomers). The facial diastereoselectivity of the
cycloaddition is very high in most of the cases, ranging
the enantiomeric excesses of compounds 4 from good to
excellent. Enantiomeric excesses were determined by
HPLC (unless otherwise indicated).16 The racemic mix-
tures of compounds 4, needed for the determination of
the ee, were synthesized by following the same methodol-
ogy, but using 2-morpholino-1,3-butadienes instead of
chiral dienes 1.17 General results are summarized in
Table 1.
Resu lts a n d Discu ssion
As we are interested in the development of a method
of synthesis of functionalized 4-nitrocyclohexanones, we
decided to use 2-amino dienes 1, which incorporate
additional functionality as a protected hydroxymethyl
substituent in position 4 of the diene (Scheme 1). The
commercial precursor of these dienes is available in the
form of both E and Z isomers. It turned out that the
stereochemistry of the trisubstituted double bond of the
diene is crucial for the outcome of the reaction; therefore
we will discuss first the behavior of the dienes with an
(E) double bond “(E)-dienes”, and later the results
obtained with “(Z)-dienes”.
Rea ction s betw een (E)-Dien es a n d Nitr oolefin s:
Syn th esis of 4-Nitr ocycloh exa n on es. The reactivity
of dienes 1 was investigated toward a collection of
nitroolefins, which were substituted with both aromatic
and aliphatic groups. In a first run all cycloaddition
From the data in Table 1 it can be observed that the
substituents on both the diene and the nitroolefin exert
some influence in the diastereoselectivity of the cycload-
dition. It is interesting to discuss the effect of R3 on the
enantiomeric excesses of cycloadducts 4. Electron rich
aromatic rings (4c-e) provided lower enantiomeric ex-
cesses than the phenyl group itself (4a ) or electron
deficient aromatics (4b , 4f). Very good ee’s (92-95%)
were obtained with all the aliphatic nitroalkenes tested,
regardless of the substitution pattern on the olefin: R-
and â-monosubstituted and R,â-disubstituted nitro-
(11) Barluenga, J .; Aznar, F.; Mart´ın, A.; Va´zquez, J . T. J . Am.
Chem. Soc. 1995, 117, 9419-9426.
(15) Only compound 4i was obtained with lower selectivity (3:1
mixture of diastereoisomers). Unfortunately, the structure of this minor
diastereoisomer could not be unequivocally determined by NOESY
experiments, as both the C2-epimer and the C4-epimer of 4i match
the observations. Additionally, compound 4k was obtained along with
a cyclic product [3-(((tert-butyldimethylsilyl)oxy)methyl)-2,4-dimethyl-
4-nitro-6-(2-nitropropyl)-1-cyclohexanone, 4:1 mixture, 8% yield from
1H NMR], derived from the reaction of the chiral diene with two
molecules of 2-nitro-1-propene.
(16) The enantiomeric excesses of compounds 4l and 4m were
determined by 1H NMR of the Mosher’s esters obtained by reduction
of the carbonyl group, followed by esterification with (R)-(+)-MPTA
chloride. Experimental details and spectrocopic data are available in
the supplementary material of ref 1.
(12) For a review on the synthetic applications of nitroalkenes as
dienophiles, see: (a) Barrett, A. G. M.; Graboski, G. G.; Chem. Rev.
1986, 86, 751. For some recent leading references, see: (b) Node, M.;
Nishide, K.; Imazato, H.; Kurosaki, R.; Inoue, T.; Ikariya, T. J . Chem.
Soc., Chem. Commun. 1996, 2559-2560. (c) Clive, D. L. J ., Bo, Y. B.;
Tao, Y.; Daigneault, S.; Wu, Y.-J .; Meignan, G. J . Am. Chem. Soc. 1996,
118, 4904. (d) Clive, D. J .; Selvakumar, N. J . Chem. Soc., Chem.
Commun. 1996, 2543.
(13) (a) Pitacco, G.; Risaliti, A.; Trevisan, M. L.; Valentin, E.
Tetrahedron 1977, 33, 3145-3148. (b) Benedetti, F.; Pitacco, G.;
Valentin, E. Tetrahedron 1979, 35, 2293-2299. (c) Mezzetti, A.; Nitti,
P.; Pitacco, G; Valentin, E. Tetrahedron 1985, 41, 1415-1422.
(14) Barluenga, J .; Aznar, F.; Cabal, M. P.; Valde´s, C. J . Chem. Soc.
Perkin Trans 1 1990, 633-638.
(17) For the synthesis of nonchiral 2-morpholino-1,3-butadienes, see
ref 8a.

6748 J . Org. Chem., Vol. 62, No. 20, 1997
Barluenga et al.
Sch em e 1
Ta ble 1. 4-Nitr o-1-cycloh exa n on es 4 P r ep a r ed
Accor d in g to Sch em e 1
Ta ble 2: Solven t In flu en ce on th e Syn th esis of 4a
a n d 4p
R1
R2
R3
compd yield, % ee % (recryst)
compd
solvent
yield, %a
ee %b (recryst)
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS Me
Me
Me
Me
Me
MOM
H
H
H
H
H
H
H
H
H
Ph
o-ClC6H4
2-furyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
63a
68a
88a
53a
49a
54a
48a
56a
38c
70a
32c
70a
76a
42a
48a
70a
94b (>99)
4a
4a
4p
4p
4p
MeOH
Et2O
MeOH
Et2O
Tol
63
31
63
50
42
94 (>99)
99
56
88 (>99)
84 (>99)
98b (>99)
64b
3-furyl
89b (99)
83b (>99)
94b (>99)
95b
p-MeOC6H4
p-NO2C6H4
Me
a
Yield of the major diastereoisomer isolated after SiO2 column
chromatography. ee determined by HPLC.
b
iPr
92b
BnOCH2
94b
-(CH2)4-
94b (>99)
94b
H
Ph
o-ClC6H4
2-furyl
H
H
H
82d
90d
70b
-(CH2)4-
2-furyl
>99b
H
56b
a
Yield of the major diastereoisomer isolated after SiO2 column
chromatography. ee determined by HPLC. c Yield of the major
b
cycloadduct deduced from integration of the 1H NMR spectra of
the chromatographed mixture. ee determined by 1H NMR (see
d
ref 16).
F igu r e 3. Some selected NOEs for compounds 4g, 4l, 4k , and
4j.
ethenes. However no reaction was observed for a â,â-
disubstituted nitroolefin, probably due to sterical rea-
sons.18
methanol. The data summarized in Table 2 indicate that
the yield of the major diastereoisomer increases with the
polarity of the solvent, while less polar solvents provide
a higher ee.20 The remarkable decrease in the chemical
yield obtained when Et2O and toluene are employed is
due to the lower selectivity of the process. Upon hy-
drolysis, along with compound 4, the C-3 epimer of 4 and
Z/ E open chain products 6 (see following section) are
The influence of the substituent R1 at the diene is not
easy to rationalize. The methyl group provided better
ee’s than TBDMS and MOM with an electron rich
aromatic substituted nitroalkene (R3 ) 2-furyl; 4n , 4c,
4p ) and also with an aliphatic substituted nitroolefin (R2,
R3 ) -(CH2)4-; 4o, 4j). However, TBDMS gave better
results in reactions with â-nitrostyrene (4a , 4l) and
electron deficient aromatic nitroalkenes (4b, 4m ). From
a synthetical point of view, we find the TBDMS ether a
very interesting protecting group for this reaction. First,
it can be easily cleaved to afford hydroxymethyl-substi-
tuted cyclohexanones; second, in most of the cases
TBDMS-protected compounds 4 are crystalline solids that
can be enantiomerically enriched up to ee >99% by
crystallization.
It has been previously established with nonchiral
dienes that the polarity of the solvent plays an important
role in the course of this type of cycloaddition.19 A similar
behavior has been observed in this case. We studied the
influence of the solvent for compounds 4a (R1 ) TBDMS,
R3 ) Ph) and 4p (R1 ) MOM, R3 ) 2-furyl) for a series of
solvents with increasing polarity: toluene, diethyl ether,
1
formed as detected by H NMR of the crude.
The relative configurations of the major cycloadducts
4 as depicted in Figure 3 were deduced from 1H NMR
data analysis. For instance, for compound 4l the equato-
rial disposition of phenyl and nitro groups is indicated
by the large axial-axial coupling constant between H4
and H5 (J H4,H5 ) 12.4 Hz) and the axial arrangement of
CH2OCH3 group by the small equatorial-axial coupling
constant between H3 and H4 (J H3,H4 ) 4.6 Hz); moreover,
the positive NOE effect found between H2 and H4
indicated the axial orientation of H2 and therefore the
equatorial disposition of the methyl group. This particu-
lar structure was further confirmed by an X-ray structure
determination.21 The same relative configuration was
deduced for 4a -f (cycloadducts derived from aromatic
nitroalkenes) and 4g-i (cycloadducts derived from ali-
phatic nitroalkenes) in light of the values of the coupling
constants, similar to those found for 4l; NOE experiments
carried out on 4g also support the proposed structure
(Figure 3). In compound 4k , the methyl group at C4
(18) When 2-amino diene
1
(R1 ) TBDMS) was reacted with
2-methyl-1-nitro-1-propene under the standard conditions, no reaction
product was observed and the starting materials were recovered.
(19) In our previous paper dedicated to the reaction of nonchiral
2-amino dienes with â-nitrostyrene (see ref 14), we observed that very
polar solvents such as MeOH favor the cyclization process, giving rise
to a single diastereoisomer. However, less polar solvents like THF or
chloroform lead to a mixture of three compounds: two diastereoisomers
of nitrocyclohexanone and the open chain compound derived from the
Michael type addition of the enamine to the electrophilic double bond.
(20) Similar observations have been reported by Enders et al. (ref
8c).
(21) Absolute configurations of 4l and 4m have been determined
by X-ray using the anomalous dispersion technique and are available
in the supplementary material of ref 1.

Chiral 2-Amino-1,3-butadiene-Nitroalkene Cycloaddition
Sch em e 2
J . Org. Chem., Vol. 62, No. 20, 1997 6749
Ta ble 3. Solven t a n d Su bstr a te In flu en ce in th e
Syn th esis of Com p ou n d s 6 a n d 7
racemates of these compounds, which was achieved again
starting from the corresponding 2-morpholino dienes. The
enantiomeric excess of compound 7c could not be ob-
tained by HPLC, and it was determined by 19F NMR
following Mosher’s procedure.23 With that purpose the
nitro group of furan 7c was reduced24 to give amine 8 in
71% yield (Scheme 3). Reaction of 8 with MPTA chloride
yielded amide 9 as a 7.1:1 mixture of diastereoisomers,
which corresponds to 75% ee of compound 7c.
R3
solvent
compd
yield, %a
% ee
Ph
Ph
Ph
Et2O
MeOH
Et2O
Et2O
Et2O
6a
7a
7a
7b
7c
58
65
69
71
56
86b
78b
85b
88b
75c
o-ClC6H4
Me
a
b
Chemical yield of chromatographed compound. Determined
by HPLC. c Determined by NMR.
To establish the absolute configuration of the stereo-
genic center of compounds 6 and 7, compound 7c was
transformed into pyrrolidinone 12, a previously described
compound with known absolute configuration and optical
rotation value25 (Scheme 3). With this purpose, the
amino group of 8 was Boc-protected by treatment with
(Boc)2O in CH2Cl2. Then the furan ring was converted
into a carboxylic ester by ozonolysis in the presence of
hydrogen peroxide, followed by esterification with diaz-
omethane, to obtain ester 11. Cleavage of the carbamate
with TFA and subsequent basic aqueous workup afforded
pyrrolidinone 12. The measurement of the optical rota-
tion and comparison with the literature value indicates
the S configuration for the stereogenic center and con-
firms the ee value determined with the Mosher’s ester
method.
It is noteworthy that the same spatial arrangement of
the substituents of this stereogenic center is obtained for
both open chain nitroketones 6 and cycloadducts 4. From
this observation it can be postulated that both linear and
cyclic compounds arise from a similar type of approxima-
tion of the nitroolefin to the enamine in the transition
state. In fact, the model described by Seebach26 et al.
for the reactions of enamines and nitroalkenes takes
account of the absolute configuration of this stereogenic
center obtained in our reactions.
showed positive NOE with H2, which points to an axial
arrangement of both; a positive NOE between methyl
group at C4 and H3 was also observed, consistent with
an equatorial disposition of H3. The determination of the
stereochemistry of 4j required COSY90 and HMQC
experiments in order to assign the different protons in
the 1H NMR spectrum (400 MHz, CDCl3). A phase
sensitive NOESY experiment (with time proportional
phase incrementation) showed NOE between H3 and H6,
indicating that the methyl group at C3 and the nitro
substituent are in a syn equatorial arrangement.
A
coupling constant of 6.7 Hz between axial H3 and H4
pointed to an equatorial disposition of H4. All other NOE
signals observed were in agreement with the stereochem-
istry shown in Figure 3. Finally, the absolute configu-
ration indicated in Scheme 1 for compounds 4 is based
on X-ray determinations carried out for 4l and 4m .21
In flu en ce of th e Su bstitu en ts on th e Dien e: Re-
a ction s w ith (Z)-Dien es. In our previous contribution
dedicated to the reaction of nonchiral amino dienes
toward nitroalkenes, we observed that the stereochem-
istry of the non-enaminic double bond on the 2-amino
diene is decisive for the outcome of the reaction. Usually
dienes with a Z double bond are unable to participate in
cycloaddition processes; instead, open chain compounds
are isolated. This is also the case here. When diene 5
was reacted with nitroolefins 2 followed by hydrolysis of
the intermediate enamine under the same conditions
(buffer HOAc/NaOAc, pH ) 4.6) no cyclic compounds
were detected, instead open chain compounds 6 were
afforded (Scheme 2). Moreover, when stronger acidic
conditions were employed (3 N HCl/THF) in the hydro-
lytic step, chiral 2-substituted furans 7 were obtained in
good yields (Table 3). For these reactions, diethyl ether
resulted in a more advantageous solvent than methanol,
as it provided both better chemical yields and ee’s.
Formation of furans 7 can be easily explained as a
result of desilylation of compound 6 under the strong
acidic conditions, followed by the formation of a cyclic
hemiketal and subsequent aromatization through dehy-
dration. This mechanism is supported by the fact that
desilylation of pure 6a under the same conditions affords
7a in quantitative yield. The determination of the
enantiomeric excesses22 required the synthesis of the
Two different mechanisms can be proposed for the [4
+ 2] cycloaddition reaction between 2-amino-1,3-buta-
dienes and nitroolefins: a concerted Diels-Alder process
or a polar stepwise pathway which involves a Michael
type 1,4-addition of the enamine to the nitroalkene,
followed by an intramolecular vinylogous Mannich reac-
tion. The strong dependence of chemical yields, products
formed, rate of reaction,14 and enantiomeric excesses
upon the polarity of the solvent indicate that the polar
stepwise reaction pathway is more likely. This mecha-
(22) Enantiomeric excesses were determined from furans 7 and not
from open chain compounds 6 due to the unstability of the latter. Upon
standing, compounds 6 undergo isomerization of the Z double bond.
(23) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(24) Osby, J . O.; Ganem, B. Tetrahedron Lett. 1985, 26, 6413-6416.
(25) Baggiolini, E.; Berscheid, H. G.; Bozzato, G.; Cavalieri, E.;
Schaffner, K.; J eger, O. Helv. Chim. Acta 1971, 54, 429-449.
(26) (a) Seebach, D.; Golinski, J .; Helv. Chim. Acta 1981, 64, 1413-
1423. (b) Blarer, S. J .; Schweizer, W. B.; Seebach, D. Helv. Chim. Acta
1982, 65, 1637-1654.

6750 J . Org. Chem., Vol. 62, No. 20, 1997
Barluenga et al.
Sch em e 3
CDCl3) δ 151.0 (broad), 136.3, 128.2, 80.7 (broad), 73.5, 61.3,
59.0, 57.2, 48.7, 28.8, 26.0, 24.3, 23.3, 18.4, -5.2 ppm.
Nitroolefins 2 were purchased from Aldrich [â-nitrostyrene,
2-chloro-ω-nitrostyrene, 1-(2-furyl)-2-nitroethylene, 4-nitro-ω-
nitrostyrene, and 1-nitro-1-cyclohexene] or were prepared
according to previously reported procedures: 3-(benzyloxy)-1-
nitro-1-propene,29 2-nitro-1-propene;30 1-(3-furyl)-2-nitroeth-
ylene and 1-(p-methoxyphenyl)-2-nitroethylene analogously to
â-nitrostyrene;31 1-nitro-1-propene was synthesized by follow-
ing the same methodology employed for 3-methyl-1-nitro-1-
butene.32
nism is consistent with the well-known strong enaminic
character of 2-amino dienes27 and also with the fact that
similar results are obtained in terms of yields, stereose-
lectivity, and face selectivity both when the [4 + 2]
cycloadducts are formed (from E-dienes) and when open
chain compounds are isolated (from Z-dienes). However
a [4 + 2] concerted mechanism in which the nitroalkene
would approach in an endo fashion (relative to the nitro
group) to the diene12b also explains the relative stereo-
chemistry of the final cycloadducts and therefore cannot
be neglected in the absence of more rigorous mechanis-
tical and theoretical studies.
Gen er a l P r oced u r e for th e Syn th esis of En a n tioen -
r ich ed 4-Nitr o-1-cycloh exa n on es 4. A solution of the
corresponding nitroalkene 2 (1 mmol) in dry MeOH (10 mL)
was cooled down to -80 °C. Pure chiral diene 1 (0.92 mmol)
was added dropwise via syringe, and the stirred reaction
mixture was kept at this temperature overnight with the aid
of a cryocool apparatus (immersion cooler). The cooling
equipment was then switched off, and the reaction mixture
was permitted to reach rt slowly (10 h). Methanol was
removed under vacuum (0.1 Torr), and the resulting oil was
redissolved in THF (5 mL). The reaction was quenched with
an aqueous AcOH/NaOAc solution (pH ) 4.6, 5 mL), and after
10 min of stirring the aqueous layer was extracted with EtOAc
(3 × 5 mL); the combined organic layers were washed with
brine (5 mL), dried, and evaporated to dryness. The resulting
crude product was purified by SiO2 column chromatography.
(2R,3S,4R,5R)-3-(((ter t-Bu tyldim eth ylsilyl)oxy)m eth yl)-
2-m eth yl-4-n itr o-5-p h en yl-1-cycloh exa n on e (4a ). Chiral
diene 1 (R1 ) TBDMS, 0.30 g) and â-nitrostyrene (0.15 g) were
employed. Compound 4a was isolated as a white crystalline
solid in 63% yield (220 mg): Rf ) 0.43 (SiO2, hexane/EtOAc
4:1); ee ) 94% (determined by HPLC at 220 nm, hexane/EtOH
6:1, F ) 0.8 mL/min; tRmajor ) 7.4 min, tRminor ) 10.1 min);
recrystallized from CH2Cl2/MeOH, ee >99%, mp 154-155 °C;
Con clu sion
We have described a highly enantioselective synthesis
of 4-nitrocyclohexanones through an asymmetric [4 + 2]
cycloaddition process between chiral 2-amino dienes and
nitroalkenes. Moreover, if (Z)-dienes are employed, open
chain compounds can be synthesized with good levels of
stereocontrol, which upon hydrolysis lead to 2-substituted
chiral furans. The compounds described herein are
potentially interesting synthetic intermediates due to
their high functionalization. The study of some of their
applications in this direction is currently underway.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under N2 employ-
ing solvents dried following standard procedures.28 For isola-
tion, organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
Column chromatography was carried out using 230-400 mesh
silica gel (SiO2). TLC analyses were performed on aluminum-
backed silica gel 60 F254 plates, and compounds were visualized
with UV light and by spraying with an acidic Mo7O24(NH4)6‚
4H2O/Ce(SO4)2 solution. Chiral HPLC analyses were carried
out by employing a CHIRALCEL OD-H column (25 cm × 0.46
cm i.d., Daicel Chemical Industries) at rt with a Shimadzu
photo diode array UV-vis detector (D2 lamp, 200-300 nm);
racemic compounds were used to choose the operating condi-
tions [flow rate (F), solvent mixture] for the resolution of both
enantiomer peaks, and ee’s were determined at the wavelength
of maximum absorbance. Semipreparative HPLC separations
were performed on a Nucleosil 120-10 column (250 mm × 16
mm i.d.). Optical rotations were measured in CH2Cl2 or CHCl3
at rt. All melting points are uncorrected. 1H NMR spectra
were recorded at 200 or 300 MHz at rt by employing CDCl3
as solvent. Chemical shifts are reported in parts per million
(ppm) relative to residual CHCl3 peak; J values are given in
hertz. 13C NMR spectra were performed at 50 or 75 MHz.
Elemental analyses were obtained on a Perkin-Elmer 240B
microanalyzer. HRMS were determined on a Finnigan Mat-
95 mass spectrometer. Chiral dienes 1 were synthesized as
reported previously.10b Diene 5, which had not been previously
described, was prepared by following the same procedure:
[R]20 ) +26.5 (c 1.3, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ
589
7.35-7.23 (m, 5H), 5.39 (dd, J ) 12.5, 4.1, 1H), 4.44 (td, J )
12.5, 6.0, 1H), 3.83 (dd, J ) 11.6, 2.2, 1H), 3.72 (d, J ) 11.6,
1H), 2.75-2.68 (m, 3H), 2.44 (dd, J ) 15.7, 13.1, 1H), 1.25 (d,
J ) 6.5, 3H), 0.95 (s, 9H), 0.16 (s, 3H), 0.09 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 205.0, 140.0, 128.7, 127.3, 126.6, 90.8, 57.9,
46.1, 46.0, 43.8, 42.5, 25.3, 17.8, 11.3, -6.3, -6.4. Anal. Calcd
for C20H31NO4Si (377.56): C, 63.63; H, 8.28; N, 3.71. Found:
C, 64.02; H, 8.34; N, 3.64.
(2R,3S,4R,5R)-3-(((ter t-Bu tyldim eth ylsilyl)oxy)m eth yl)-
5-(o-ch lor oph en yl)-2-m eth yl-4-n itr o-1-cycloh exan on e (4b).
Chiral diene 1 (R1 ) TBDMS, 0.30 g) and 2-chloro-ω-nitrosty-
rene (0.18 g) were employed. Compound 4b was isolated as a
white crystalline solid in 68% yield (260 mg): Rf ) 0.36 (SiO2,
hexane/EtOAc 4:1); ee ) 98% (determined by HPLC at 215
nm, hexane/EtOH 6:1, F ) 0.8 mL/min; tRmajor ) 7.8 min, tRminor
) 10.7 min); recrystallized in CH2Cl2/MeOH, ee >99%, mp
190-192 °C; [R]20
) +13.9 (c 1.1, CH2Cl2); 1H NMR (200
589
MHz, CDCl3) δ 7.42-7.16 (m, 4H), 5.63-5.42 (s, br, 1H), 5.16-
4.91 (s, br, 1H), 3.85 (dd, J ) 11.5, 3.3, 1H), 3.72 (dd, J ) 11.5,
1.0, 1H), 2.90-2.66 (m, 3H), 2.30-2.06 (s, br, 1H), 1.28 (d, J
) 6.7, 3H), 0.94 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H); 13C NMR
(50 MHz, CDCl3) δ 204.6, 137.9, 133.8, 130.2, 128.4, 127.5,
yield 40%, [R]20 ) +46.8 (c 2.9, CH2Cl2); 13C NMR (75 MHz,
589
(29) Chandler, M.; Conroy, R.; Cooper, A. W. J .; Lamont, R. B.;
Scicinski, J . J .; Smart, J . E.; Storer, R.; Weir, N. G.; Wilson, R. D.;
Wyatt, P. G. J . Chem. Soc., Perkin Trans. 1 1995, 1189-1197.
(30) Buckley, G. D.; Scaife, C. W. J . Chem. Soc. 1947, 1471-1472.
(31) Worrall, D. E. In Organic Syntheses, Collect. Vol. I, 2nd ed.;
Blatt, A. H., Ed.; J ohn Wiley and Sons: New York, 1948; pp 413-415.
(32) Kumaran, G.; Kulkarni, G. H. Synthesis 1995, 1545-1548.
(27) (a) Ahmed, Md. G.; Ahmed, S. A.; Hickmott, P. W. J . Chem.
Soc., Perkin Trans. 1 1980, 2823. (b) Barluenga, J .; Aznar, F.; Valde´s,
C.; Lo´pez-Ortiz, F. Tetrahedron Lett. 1990, 31, 5237-5240.
(28) Perrin, D. D.; Armarego, W. L. F. In Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988.

Chiral 2-Amino-1,3-butadiene-Nitroalkene Cycloaddition
J . Org. Chem., Vol. 62, No. 20, 1997 6751
124.9, 89.5, 57.9, 46.2, 44.8, 44.2, 37.9, 25.6, 18.1, 11.5, -4.7,
-4.8. Anal. Calcd for C20H31ClNO4Si (412.01): C, 58.30; H,
7.34; N, 3.40. Found: C, 58.70; H, 7.34; N, 3.31.
1 (R1 ) TBDMS, 0.30 g) and 1-nitro-1-propene (90 mg) were
employed. Compound 4g was isolated as a colorless oil in 48%
yield (140 mg): Rf ) 0.37 (SiO2, hexane/EtOAc 4:1); ee ) 95%
(determined by HPLC at 215 nm, hexane/EtOH 6:1, F ) 0.8
mL/min; tRmajor ) 6.9 min, tRminor ) 8.0 min); mp 49-50 °C;
(2R,3S,4R,5S)-3-(((ter t-Bu tyldim eth ylsilyl)oxy)m eth yl)-
5-(2-fu r yl)-2-m eth yl-4-n itr o-1-cycloh exa n on e (4c). Chiral
diene 1 (R1 ) TBDMS, 0.30 g) and 1-(2-furyl)-2-nitroethylene
(0.14 g) were employed. Compound 4c was isolated as a white
crystalline solid in 88% yield (300 mg): mp 81-83 °C; Rf )
0.22 (SiO2, hexane/EtOAc 8:1); ee ) 64% (determined by HPLC
at 230 nm, hexane/EtOH 6:1, F ) 0.8 mL/min; tRmajor ) 7.2
min, tRminor ) 9.4 min); [R]20589 ) +28.4 (c 1.0, CH2Cl2); 1H NMR
(200 MHz, CDCl3) δ 7.30 (m, 1H), 6.27 (dd J ) 3.1, 1.9, 1H),
6.11 (d, J ) 3.1, 1H), 5.32 (dd, J ) 12.1, 4.1, 1H), 4.55 (td, J
) 12.1, 6.7, 1H), 3.79 (dd, J ) 11.7, 2.0, 1H), 3.67 (dd, J )
11.7, 1.0, 1H), 2.78-2.53 (m, 4H), 1.21 (d, J ) 6.0, 3H), 0.89
(s, 9H), 0.10 (s, 3H), 0.05 (s, 3H); 13C NMR (50 MHz, CDCl3)
δ 204.7, 152.4, 141.9, 110.2, 106.7, 89.1, 58.0, 46.0, 43.9, 42.9,
36.7, 25.5, 18.0, 11.5, -4.6, -4.7. Anal. Calcd for C18H29NO5Si
(367.52): C, 58.83; H, 7.95; N, 3.81. Found: C, 58.52; H, 8.15;
N, 3.76.
[R]20 ) +14.7 (c 0.1, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ
589
4.71 (dd, J ) 12.0, 4.5, 1H), 3.77 (dd, J ) 11.5, 3.0, 1H), 3.58
(dd, J ) 11.5, 1.1, 1H), 3.21 (ddd, J ) 12.1, 6.5, 5.9, 1H), 2.63-
2.45 (m, 3H), 1.98 (ddd, J ) 16.0, 12.2, 1.0, 1H), 1.17 (d, J )
6.5, 3H), 1.03 (d, J ) 6.5, 3H), 0.85 (s, 9H), 0.05 (s, 3H), 0.01
(s, 3H); 13C NMR (50 MHz, CDCl3) δ 205.8, 93.2, 57.8, 46.4,
45.6, 44.0, 31.5, 25.4, 19.6, 17.9, 11.4, -4.6, -4.7. Anal. Calcd
for C15H29NO4Si (315.49): C, 57.11; H, 9.27; N, 4.44. Found:
C, 57.19; H, 9.33; N, 4.41.
(2R,3S,4R,5R)-3-(((ter t-Bu tyldim eth ylsilyl)oxy)m eth yl)-
2-m eth yl-4-n itr o-5-isopr opyl-1-cycloh exan on e (4h ). Chiral
diene 1 (R1 ) TBDMS, 0.30 g) and 3-methyl-1-nitro-1-butene
(0.12 g) were employed. Compound 4h was isolated as a
colorless oil in 56% yield (180 mg): Rf ) 0.45 (SiO2, hexane/
EtOAc 8:1); ee ) 92% (determined by HPLC at 210 nm,
hexane/EtOH 20:1, F ) 0.8 mL/min; tRmajor ) 7.5 min, tRminor
) 8.9 min); [R]20589 ) +18.0 (c 2.1, CH2Cl2); 1H NMR (200 MHz,
CDCl3) δ 4.94 (dd, J ) 12.2, 4.2, 1H), 3.66 (m, 2H), 3.16 (tdd,
J ) 12.5, 6.1, 3.1, 1H), 2.55-2.33 (m, 3H), 1.98 (dd, J ) 15.6,
12.8, 1H), 1.76 (m, J ) 7.0, 3.1, 1H), 1.12 (d, J ) 6.4, 3H),
0.84 (d, J ) 7.0, 3H), 0.81 (s, 9H), 0.79 (d, J ) 7.0, 3H), 0.01
(s, 3H), -0.03 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 206.6, 89.7,
57.9, 46.2, 44.1, 40.4, 36.5, 27.1, 25.4, 20.2, 17.9, 14.3, 11.4,
-6.2, -6.3; HRMS (FAB) calcd for C17H34NO4Si: 344.2257,
found 344.2253.
(2R,3S,4R,5R)-3-(((ter t-Bu tyldim eth ylsilyl)oxy)m eth yl)-
5-(3-fu r yl)-2-m eth yl-4-n itr o-1-cycloh exa n on e (4d ). Chiral
diene 1 (R1 ) TBDMS, 0.30 g) and 1-(3-furyl)-2-nitroethylene
(0.14 g) were employed. Compound 4d was isolated as a white
crystalline solid in 53% yield (180 mg): Rf ) 0.24 (SiO2,
hexane/EtOAc 8:1); ee ) 89% (determined by HPLC at 215
nm, hexane/EtOH 6:1, F ) 0.8 mL/min; tRmajor ) 7.8 min, tRminor
) 9.9 min); recrystallized in Et2O, ee ) 99%, mp 105-106 °C;
[R]20 ) +29.3 (c 0.8, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ
589
7.36-7.34 (m, 1H), 7.29 (s, 1H), 6.29-6.28 (m, 1H), 5.09 (dd,
J ) 12.4, 3.9, 1H), 4.38 (td, J ) 12.4, 5.8, 1H), 3.78 (dd, J )
11.4, 2.1, 1H), 3.69 (dd, J ) 11.4, 1.0, 1H), 2.76-2.57 (m, 3H),
2.40 (dd, J ) 15.9, 12.4, 1H), 1.21 (d, J ) 6.0, 3H), 0.89 (s,
9H), 0.09 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
204.9, 143.3, 139.4, 124.3, 108.1, 91.5, 57.9, 45.9, 44.7, 43.9,
33.6, 25.3, 17.9, 11.4, -6.3, -6.4. Anal. Calcd for C18H29NO5Si
(367.52): C, 58.83; H, 7.95; N, 3.81. Found: C, 59.15; H, 8.04;
N, 3.72.
(2R,3S,4R,5S)-5-((Ben zyloxy)m et h yl)-3-(((ter t-b u t yl-
d im eth ylsilyl)oxy)m eth yl)-2-m eth yl-4-n itr o-1-cycloh ex-
a n on e (4i). Chiral diene 1 (R1 ) TBDMS, 0.30 g) and
1-((benzyloxy)methyl)-2-nitroethylene (0.19 g) were employed.
A mixture of compound 4i and a diastereoisomer (3:1 by 1H
NMR) was isolated as a colorless oil in 52% yield (200 mg).
Cycloadduct 4i was separated by semipreparative HPLC
(hexane/THF 20:1, F ) 8 mL/min; tR ) 23.5 min): Rf ) 0.24
(SiO2, hexane/EtOAc 8:1); ee ) 94% (determined by HPLC at
210 nm, hexane/EtOH 110:1, F ) 0.9 mL/min; tRmajor ) 16.0
(2R,3S,4R,5R)-3-(((ter t-Bu tyldim eth ylsilyl)oxy)m eth yl)-
5-(p -m e t h o x y p h e n y l)-2-m e t h y l-4-n it r o -1-c y c lo h e x a -
n on e (4e). Chiral diene 1 (R1 ) TBDMS, 0.30 g) and 1-(p-
methoxyphenyl)-2-nitroethylene (0.18 g) were employed. Com-
pound 4e was isolated as a white crystalline solid in 49% yield
(180 mg): Rf ) 0.28 (SiO2, hexane/EtOAc 4:1); ee ) 83%
(determined by HPLC at 215 nm, hexane/EtOH 6:1, F ) 0.8
mL/min; tRmajor ) 8.6 min, tRminor ) 10.7 min); recrystallized in
min, tRminor ) 17.1 min); [R]20 ) +15.7 (c 0.2, CH2Cl2); 1H
589
NMR (300 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 5.25 (dd, J )
11.8, 4.5, 1H), 4.49 (d, J ) 12.0, 1H), 4.44 (d, J ) 12.0, 1H),
3.76 (dd, J ) 11.8, 3.0, 1H), 3.60 (dd, J ) 11.6, 0.9, 1H), 3.53
(dd, J ) 9.7, 3.2, 1H), 3.42-3.29 (m, 2H), 2.67-2.43 (m, 4H),
1.19 (d, J ) 6.9, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H);
13C NMR (50 MHz, CDCl3) δ 206.6, 137.6, 128.3, 127.7, 127.5,
86.7, 73.1, 69.1, 58.0, 46.3, 43.9, 40.8, 36.9, 25.5, 18.0, 11.5,
-6.2, -6.3; HRMS (FAB) calcd for C22H36NO5Si 422.2363,
found, 422.2366.
EtOH, ee >99%, mp 132-136 °C; [R]20
) +22.4 (c 0.6,
589
1
CH2Cl2); H NMR (200 MHz, CDCl3) δ 7.14 (d, J ) 8.6, 2H),
6.86 (d, J ) 8.6, 2H), 5.30 (dd, J ) 12.5, 3.9, 1H), 4.38 (td, J
) 12.5, 6.0, 1H), 3.85-3.69 (m, 2H), 3.78 (s, 3H), 2.75-2.64
(m, 3H), 2.41 (dd, J ) 15.9, 12.7, 1H), 1.24 (d, J ) 6.4, 3H),
0.94 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H); 13C NMR (50 MHz,
CDCl3) δ 205.3, 158.7, 132.0, 127.9, 114.2, 91.6, 58.1, 55.0, 46.4,
46.2, 44.2, 41.9, 25.5 , 18.0, 11.5, -6.2, -6.3. Anal. Calcd for
C21H33NO5Si (407.59): C, 61.88; H, 8.16; N, 3.44. Found: C,
62.06; H, 8.21; N, 3.40.
(3R,4S,5R,10S)-4-(((ter t-Bu tyldim eth ylsilyl)oxy)m eth yl)-
3-m eth yl-5-n itr o-2-d eca lon e (4j). Chiral diene 1 (R1
)
TBDMS, 0.30 g) and 1-nitro-1-cyclohexene (113 µL, 1 mmol)
were employed. Compound 4j was isolated as a white crystal-
line solid in 70% yield (230 mg): Rf ) 0.48 (SiO2, hexane/EtOAc
4:1); ee ) 94% (determined by HPLC at 210 nm, hexane/EtOH
6:1, F ) 0.8 mL/min; tRmajor ) 6.6 min, tRminor ) 8.3 min);
recrystallized in EtOH, ee >99%, mp 77-79 °C; [R]20589 ) +3.3
(c 1.1, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ 3.63 (dd, J )
11.8, 3.5, 1H), 3.48 (m, 1H), 3.22 (d, J ) 11.8 , 1H), 2.59
(quintet, J ) 6.4, 1H), 2.45-2.11 (m, 5H), 1.88-1.65 (m, 2H),
1.48-1.14 (m, 4H), 1.06 (d, J ) 6.7, 3H), 0.76 (s, 9H), -0.07
(s, 3H), -0.09 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 207.4, 95.3,
59.5, 52.5, 42.1, 41.8, 34.2, 30.6, 26.4, 25.4, 22.3, 18.7, 17.9,
11.6, -3.5, -3.6. Anal. Calcd for C18H33NO4Si (355.55): C,
60.81; H, 9.35; N, 3.94. Found: C, 60.47; H, 9.73; N, 3.94.
(2R,3S,4R)-3-(((ter t-Bu t yld im et h ylsilyl)oxy)m et h yl)-
2,4-d im eth yl-4-n itr o-1-cycloh exa n on e (4k ). Chiral diene
1 (R1 ) TBDMS, 0.30 g) and 2-nitro-1-propene (87 mg) were
employed. A mixture of compound 4k and a product of
addition of two molecules of nitroalkene (4:1 by 1H NMR) was
isolated as a colorless oil in 39% yield (120 mg). Cycloadduct
4k was separated by semipreparative HPLC (hexane/THF
10:1, F ) 8 mL/min; tR ) 20.8 min): Rf ) 0.39 (SiO2, hexane/
EtOAc 4:1); ee ) 94% (determined by HPLC at 210 nm,
hexane/iPrOH 100:1, F ) 0.9 mL/min; tRmajor ) 17.6 min, tRminor
(2R,3S,4R,5R)-3-(((ter t-Bu tyldim eth ylsilyl)oxy)m eth yl)-
2-m eth yl-4-n itr o-5-(p-n itr op h en yl)-1-cycloh exa n on e (4f).
Chiral diene 1 (R1 ) TBDMS, 0.30 g) and 1-(p-nitrophenyl)-
2-nitroethylene (0.19 g) were employed. Compound 4f was
isolated as a white crystalline solid in 54% yield (210 mg): Rf
) 0.47 (SiO2, hexane/EtOAc 2:1); ee ) 94% (determined by
HPLC at 264 nm, hexane/EtOH 6:1, F ) 0.8 mL/min; tRmajor
)
14.4 min, tRminor ) 18.2 min); recrystallized in CH2Cl2/EtOH,
ee >99%, mp 224-226 °C dec; [R]20589 ) +13.1 (c 1.0, CH2Cl2);
1H NMR (200 MHz, CDCl3) δ 8.22 (d, J ) 8.9, 2H), 7.42 (d, J
) 8.9, 2H), 5.39 (dd, J ) 12.4, 4.3, 1H), 4.64 (td, J ) 12.4, 5.9,
1H), 3.85 (dd, J ) 11.5, 2.4, 1H), 3.68 (dd, J ) 11.5, 1.0, 1H),
2.83-2.66 (m, 3H), 2.41 (dd, J ) 15.9, 12.4, 1H), 1.26 (d, J )
6.4, 3H), 0.94 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 204.0, 147.4, 147.2, 127.9, 124.2, 90.4, 58.0,
46.3, 45.6, 44.2, 42.4, 25.5, 18.0, 11.5, -6.2, -6.3. Anal. Calcd
for C20H30N2O6Si (422.56): C, 56.85; H, 7.16; N, 6.63. Found:
C, 57.11; H, 7.10; N, 6.49.
(2R,3S,4R,5S)-3-(((ter t-Bu tyldim eth ylsilyl)oxy)m eth yl)-
2,5-d im eth yl-4-n itr o-1-cycloh exa n on e (4g). Chiral diene

6752 J . Org. Chem., Vol. 62, No. 20, 1997
) 14.7 min); [R]20 ) +32.3 (c 0.7, CH2Cl2); 1H NMR (200
MHz, CDCl3) δ 3.70 (dd, J ) 11.7, 3.7, 1H), 3.30 (dd, J ) 11.7,
1.0, 1H), 3.13-2.97 (m, 1H), 2.60 (quintet, J ) 6.7, 1H), 2.54-
2.42 (m, 2H), 2.34-2.23 (m, 1H), 2.17-2.04 (m, 1H), 1.85 (s,
3H), 1.12 (d, J ) 6.7, 3H), 0.78 (s, 9H), -0.05 (s, 3H), -0.06
(s, 3H); 13C NMR (50 MHz, CDCl3) δ 206.9, 90.0, 59.3, 50.9,
41.3, 36.8, 30.5, 25.4, 25.3, 17.9, 11.9, -3.5, -3.6; HRMS (FAB)
calcd for C15H30NO4Si 316.1944, found 316.1945.
Barluenga et al.
6.9, 3H); 13C NMR (75 MHz, CDCl3) δ 205.0, 152.2, 141.8,
110.2, 106.6, 96.3, 88.6, 62.2, 55.6, 44.4, 43.9, 42.8, 36.9, 11.2.
Anal. Calcd for C14H19NO6 (297.31): C, 56.56; H, 6.44; N, 4.71.
Found: C, 56.49; H, 6.50; N, 4.70.
589
Gen er a l P r oced u r e for th e Syn th esis of En a n tiom er i-
ca lly En r ich ed Nitr op r op yl Vin yl Keton es 6 a n d (Nitr o-
p r op yl)fu r a n s 7. These reactions were carried out as de-
scribed above for cycloadducts 4, but employing dry Et2O as
solvent. After the 22 h period, the reaction mixture was
concentrated under reduced pressure and redissolved in dry
THF (5 mL). Hydrolysis with 5 mL of a AcOH/NaOAc buffer
solution (8 min stirring), usual extractive workup, followed by
SiO2 column chromatography afforded compound 6a (R3 ) Ph).
Alternatively, quenching with aqueous HCl (3 N, 5 mL, 10 min
stirring) and exhaustive extractive workup afforded com-
pounds 7, which were purified by column chromatography.
(Z)-(6R)-1-((ter t-Bu tyld im eth ylsilyl)oxy)-3-m eth yl-7-n i-
tr o-6-p h en yl-2-h ep ten -4-on e (6a ). Chiral diene 5 (0.30 g)
and â-nitrostyrene (0.15 g) were employed. Hydrolysis was
accomplished with the acidic buffer solution. Compound 6a
was isolated after SiO2 column chromatography as a yellow
oil in 58% yield (200 mg): Rf ) 0.34 (SiO2, hexane/EtOAc 8:1);
ee ) 86% (determined by HPLC at 212 nm, hexane/EtOH 20:
(2R,3S,4R,5R)-3-(Meth oxym eth yl)-2-m eth yl-4-n itr o-5-
p h en yl-1-cycloh exa n on e (4l). Chiral diene 1 (R1 ) Me, 0.23
g) and â-nitrostyrene (0.15 g) were employed. Compound 4l
was isolated as a white crystalline solid in 70% yield (180
mg): Rf ) 0.37 (SiO2, hexane/EtOAc 3:1); ee ) 82% (deter-
mined by 1H NMR over a Mosher derivative); mp 142 °C;
1
[R]20 ) +19.0 (c 0.3, CHCl3); H NMR (300 MHz, CDCl3) δ
578
7.3-7.1 (m, 5H), 5.3 (dd, J ) 12.4, 4.6, 1H), 4.2 (td, J ) 12.4,
6.0, 1H), 3.4 (t, 2H), 3.1 (s, 3H), 2.96 (m, 3H), 2.3 (dd, 1H), 1.1
(d, J ) 7.0, 3H); 13C NMR (75 MHz, CDCl3) δ 203.1, 134.9,
127.9, 126.5, 126.1, 89.7, 66.3, 58.0, 45.4, 44.5, 43.4, 42.0, 10.5.
Anal. Calcd for C15H19NO4 (277.32): C, 64.96; H, 6.91; N, 5.05.
Found: C, 64.72; H, 6.80; N, 5.12.
(2R,3S,4R,5R)-5-(o-Ch lor op h en yl)-3-(m eth oxym eth yl)-
2-m eth yl-4-n itr o-1-cycloh exa n on e (4m ). Chiral diene 1 (R1
) Me, 0.23 g) and 2-chloro-ω-nitrostyrene (0.18 g) were
employed. Compound 4m was isolated as a white crystalline
solid in 76% yield (220 mg): Rf ) 0.28 (SiO2, hexane/EtOAc
3:1); ee ) 90% (determined by 1H NMR over a Mosher
derivative); mp 154 °C; [R]20578 ) -3.6 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.4-7.1 (m, 4H), 5.45 (m, 1H), 3.5-3.3
(m, 3H), 3.23 (s, 3H), 2.5-2.3 (m, 3H), 2.2 (m, 1H), 1.13 (d,
3H); 13C NMR (75 MHz, CDCl3) δ 205.3, 137.4, 133.6, 130.9,
128.2, 127.5, 125.4, 88.9, 68.1, 59.8, 46.0, 45.5, 45.3, 37.9, 11.4.
Anal. Calcd for C15H18NO4Cl (311.77): C, 57.79; H, 5.82; N,
4.49. Found: C, 57.99; H, 5.62; N, 4.30.
1, F ) 0.8 mL/min; tRmajor ) 13.5 min, tRminor ) 15.4 min); [R]20
589
1
) -12.6 (c 0.8, CH2Cl2); H NMR (300 MHz, CDCl3) δ 7.36-
7.22 (m, 5H), 5.97-5.94 (m, 1H), 4.74 (dd, J ) 12.4, 6.8, 1H),
4.61 (dd, J ) 12.4, 7.8, 1H), 4.49-4.32 (m, 2H), 4.07 (quintet,
J ) 6.9, 1H), 3.03 (dd, J ) 18.1, 6.5, 1H), 2.96 (dd, J ) 18.1,
7.3, 1H), 1.96 (q, J ) 1.7, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 199.9, 145.2, 139.0, 131.9, 128.9,
127.7, 127.3, 79.4, 62.2, 43.7, 38.8, 25.8, 19.8, 18.1, -5.4;
HRMS (EI) calcd for C20H31NO4Si 377.2022, found 377.2025.
3-Met h yl-2-[(2R)-3-n it r o-2-p h en ylp r op yl]fu r a n (7a ).
Chiral diene 5 (0.30 g) and â-nitrostyrene (0.15 g) were
employed. Hydrolysis was accomplished with a 3 N HCl
aqueous solution. Compound 7a was isolated after SiO2
column chromatography as a yellow oil in 69% yield (160
mg): Rf ) 0.41 (SiO2, hexane/EtOAc 8:1); ee ) 85% (deter-
mined by HPLC at 215 nm, hexane/EtOH 20:1, F ) 0.8 mL/
(2R,3S,4R,5S)-5-(2-Fu r yl)-3-(m eth oxym eth yl)-2-m eth yl-
4-n itr o-1-cycloh exa n on e (4n ). Chiral diene 1 (R1 ) Me, 0.23
g) and 1-(2-furyl)-2-nitroethylene (0.14 g) were employed.
Compound 4n was isolated as a yellow oil in 42% yield (100
mg): Rf ) 0.18 (SiO2, hexane/EtOAc 4:1); ee ) 70% (deter-
mined by HPLC at 215 nm, hexane/EtOH 6:1, F ) 0.9 mL/
min; tRmajor ) 11.9 min, tRminor ) 14.4 min); [R]20 ) -8.4 (c
589
2.6, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ 7.33-7.15 (m, 6H),
6.15 (d, J ) 1.5, 1H), 4.68 (d, J ) 7.3, 2H), 3.90 (quintet, J )
7.3, 1H), 2.97 (d, J ) 7.3, 2H), 1.77 (s, 3H); 13C NMR (50 MHz,
CDCl3) δ 146.5, 140.4, 138.8, 128.4, 127.3, 126.9, 116.2, 112.5,
78.7, 43.2, 30.0, 9.1; HRMS (EI) calcd for C14H15NO3 245.1052,
found: 245.1054.
min; tRmajor ) 9.9 min, tRminor ) 13.0 min); [R]20 ) +29.6 (c
589
0.3, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.29-7.28 (m, 1H),
6.26-6.25 (m, 1H), 6.14-6.13 (m, 1H), 5.31 (dd, J ) 12.0, 4.3,
1H), 4.40 (td, J ) 12.0, 6.0, 1H), 3.49-3.40 (m, 2H), 3.24 (s,
3H), 2.76-2.53 (m, 4H), 1.18 (d, J ) 6.9, 3H); 13C NMR (75
MHz, CDCl3) δ 205.1, 152.3, 141.8, 110.3, 106.8, 88.8, 66.9,
59.0, 44.9, 44.2, 42.9, 36.8, 11.4; HRMS (FAB) calcd for
C13H17NO5 267.1107, found 267.1102.
2-[(2R)-2-(o-Ch lor op h en yl)-3-n itr op r op yl]-3-m eth ylfu -
r a n (7b). Chiral diene 5 (0.30 g) and o-chloro-ω-nitrostyrene
(0.18 g) were employed. Hydrolysis was accomplished with a
3 N HCl solution. Compound 7b was isolated after SiO2
column chromatography as a yellow oil in 69% yield (180
mg): Rf ) 0.33 (SiO2, hexane/EtOAc 8:1); ee ) 88% (deter-
mined by HPLC at 215 nm, hexane/EtOH 100:1, F ) 0.9 mL/
(3R,4S,5R,10S)-4-(Meth oxym eth yl)-3-m eth yl-5-n itr o-2-
d eca lon e (4o). Chiral diene 1 (R1 ) Me, 0.23 g) and 1-nitro-
1-cyclohexene (113 µL, 1 mmol) were employed. Compound
4o was isolated as a white crystalline solid in 48% yield (110
mg): Rf ) 0.25 (SiO2, hexane/EtOAc 4:1); ee > 99% [deter-
mined by HPLC at 210 nm, hexane/EtOH 6:1, F ) 0.9 mL/
min; tRmajor ) 9.2 min, (tRminor ) 11.2 min)]; mp 141-142 °C;
min; tRmajor ) 16.6 min, tRminor ) 19.5 min); [R]20 ) +11.0 (c
589
1.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ 7.44-7.08 (m, 5H),
6.15 (d, J ) 1.8, 1H), 4.81 (dd, J ) 13.1, 8.5, 1H), 4.72 (dd, J
) 13.1, 6.2, 1H), 4.44 (dq, J ) 8.5, 6.7, 1H), 3.02 (d, J ) 7.0,
2H), 1.77 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 146.3, 140.7,
136.1, 133.8, 129.9, 128.6, 127.5, 127.0, 116.7, 112.7, 77.1, 39.6,
28.5, 9.3; HRMS (EI) calcd for C14H14ClNO3 279.0662, found
279.0658.
[R]20 ) +12.2 (c 0.8, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ
589
3.53-3.40 (m, 1H), 3.40 (dd, J ) 11.1, 3.8, 1H), 3.14 (s, 3H),
3.05 (dd, J ) 11.1, 1.5, 1H), 2.66 (m, J ) 6.7, 1H), 2.52-2.16
(m, 5H), 1.95-1.71 (m, 2H), 1.53-1.22 (m, 4H), 1.12 (d, J )
6.7, 3H); 13C NMR (50 MHz, CDCl3) δ 207.8, 94.8, 68.4, 58.6,
51.4, 41.90, 41.85, 34.2, 30.3, 26.3, 22.1, 18.4, 11.4. Anal. Calcd
for C13H21NO4 (255.32): C, 61.16; H, 8.29; N, 5.49. Found:
C, 61.53; H, 8.09; N, 5.21.
3-Met h yl-2-[(2S)-2-m et h yl-3-n it r op r op yl]fu r a n (7c).
Chiral diene 5 (0.30 g) and 1-nitro-1-propene (87 mg) were
employed. Hydrolysis was accomplished with a 3 N HCl
solution. Compound 7c was isolated after SiO2 column chro-
matography as a yellow oil in 66% yield (110 mg): Rf ) 0.49
(SiO2, hexane/EtOAc 8:1); ee ) 75% (determined over Mosher
(2R,3S,4R,5S)-5-(2-Fu r yl)-3-((m eth oxym eth oxy)m eth yl)-
2-m eth yl-4-n itr o-1-cycloh exa n on e (4p ). Chiral diene 1 (R1
) MOM, 0.26 g) and 1-(2-furyl)-2-nitroethylene (0.14 g) were
employed. Compound 4p was isolated as a white crystalline
solid in 70% yield (190 mg): Rf ) 0.35 (SiO2, hexane/EtOAc
2:1); ee ) 56% (determined by HPLC at 215 nm, hexane/EtOH
6:1, F ) 0.8 mL/min; tRmajor ) 13.5 min, tRminor ) 16.3 min);
derivative 9); [R]20
) -3.4 (c 1.0, CH2Cl2); 1H NMR (200
589
MHz, CDCl3) δ 7.25 (d, J ) 1.8, 1H), 6.18 (d, J ) 1.8, 1H),
4.36 (dd, J ) 11.9, 5.5, 1H), 4.19 (dd, J ) 11.9, 7.2, 1H), 2.79-
2.61 (m, 3H), 1.96 (s, 3H), 1.04 (d, J ) 6.1, 3H); 13C NMR (50
MHz, CDCl3) δ 147.3, 140.4, 115.9, 112.6, 80.3, 32.4, 29.7, 16.9,
9.6; HRMS (EI) calcd for C9H13NO3 183.0895, found 183.0890.
Deter m in a tion of ee of F u r a n 7c. Red u ction of th e
Nitr o Gr ou p of Com p ou n d 7c: Syn th esis of 2-[(2S)-3-
Am in o-2-m eth ylp r op yl]-3-m eth ylfu r a n (8). The reaction
recrystallized in EtOH, ee > 99%, mp 96-97 °C; [R]20
)
589
+54.6 (c 0.3, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.32-7.31
(m, 1H), 6.29-6.27 (m, 1H), 6.16-6.15 (m, 1H), 5.36 (dd, J )
12.0, 4.7, 1H), 4.55 (d, J ) 6.9, 1H), 4.50 (d, J ) 6.9, 1H), 4.46
(td, J ) 12.0, 6.2, 1H), 3.71 (dd, J ) 11.2, 3.4, 1H), 3.54 (dd, J
) 11.2, 1.3, 1H), 3.38 (s, 3H), 2.87-2.59 (m, 4H), 1.21 (d, J )

Chiral 2-Amino-1,3-butadiene-Nitroalkene Cycloaddition
J . Org. Chem., Vol. 62, No. 20, 1997 6753
was carried out as described in ref 24 employing furan 7c (100
mg, 0.55 mmol), except that the reaction mixture was stirred
overnight. Methanol was evaporated at reduced pressure, and
the resulting black solid was dissolved in H2O (10 mL) and
EtOAc (10 mL). The aqueous layer was extracted with EtOAc
(2 × 10 mL), and the combined organic layers were washed
with brine (5 mL), dried, and concentrated. Amine 8 was
isolated after flash column chromatography as a colorless oil
in 71% yield (60 mg): Rf ) 0.21 (SiO2, CH2Cl2/MeOH/NEt3 9:1:
and cooled to -78 °C. Then a stream of O3/O2 (300 L/h, 2.5 g
of O3) was bubbled through the solution using a gas diffusion
tube. The ozone stream was mantained until complete dis-
sapearance of the starting material was observed by TLC. The
ozonizer was turned off, and oxygen was bubbled for 15 min.
The mixture was stirred at room temperature for one ad-
ditional hour, and the reaction was quenched with the aqueous
buffer HOAc/NaOAc (pH ) 4.6). After addition of 20 mL of
CH2Cl2, the layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were dried over Na2SO4, and the solvent was evaporated
under reduced pressure. The crude acid obtained was dis-
solved in 15 mL of Et2O, and a freshly prepared solution of
diazomethane (1 mmol) in ether (5 mL) was added. After 15
min at room temperature 0.3 mL of AcOH and 10 mL of water
were added succesively. The layers were separated, and the
aqueous layer was extracted with ethyl acetate (2 × 15 mL).
The organic layers were combined and dried with Na2SO4 and
the solvent evaporated to afford a colorless oil that was purified
by column chromatography (SiO2, hexane:ethyl acetate, 2:1)
to afford ester 11 in 65% yield (60 mg): Rf ) 0.33 (hexane/
EtOAc 1:1); ee ) 75%; [R]20589 ) -1.3 (c 0.4, CH2Cl2); 1H NMR
δ (300 MHz, CDCl3) 4.79 (m, 1H), 3.62 (s, 3H), 2.99 (m, 1H),
2.3-2.0 (m, 3H), 1.38 (s, 9H), 0.90 (d, 3H); 13C NMR (75 MHz,
CDCl3) δ 173.1, 155.9, 78.9, 51.3, 45.7, 38.6, 31.0, 28.2, 17.5;
0.01); ee ) 75% (determined over Mosher derivative 9); [R]20
589
) -4.44 (c 1.1, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ 7.20 (d,
J ) 1.5, 1H), 6.14 (d, J ) 1.5, 1H), 4.64 (s br, 1H), 2.81 (dd, J
) 12.4, 5.7, 1H), 2.68-2.57 (m, 2H), 2.50 (dd, J ) 15.0, 7.0,
1H), 2.07 (sextet, J ) 6.7, 1H), 1.94 (s, 3H), 0.97 (d, J ) 6.7,
3H); 13C NMR (75 MHz, CDCl3) δ 148.8, 140.1, 115.2, 112.6,
46.3, 34.2, 30.4, 17.3, 9.9; HRMS (EI) calcd for C9H15NO
153.1154, found 153.1152.
F or m a tion of Mosh er ’s Am id e fr om Am in e 8: Syn th e-
sis of N-[2-Meth yl-3-(3-m eth yl-2-fu r yl)pr opyl]-(R)-r-m eth -
oxy-r-p h en yl-r-(tr iflu or om eth yl)a ceta m id e (9). The re-
action was carried out as described in ref 23 employing amine
8 (40 mg, 0.26 mmol). Amide 9 was obtained quantitatively
as a 7.1:1 mixture of diastereoisomers. NMR data of the major
diastereoisomer were obtained from the mixture: 1H NMR
(200 MHz, CDCl3) δ 7.23-7.08 (m, 6H), 6.03 (d, J ) 1.8, 1H),
3.20 (q, J ) 1.5, 3H), 3.06 (td, J ) 6.7, 0.9, 2H), 2.39 (dd, J )
14.7, 6.4, 1H), 2.23 (dd, J ) 14.7, 7.3, 1H), 1.96-1.80 (m, 1H),
1.77 (s, 3H), 0.73 (d, J ) 6.7, 3H); 13C NMR (75 MHz, CDCl3)
δ 166.6, 150.2, 141.0, 134.4, 130.1, 129.0, 128.7, 116.0, 113.7,
85.3, 60.4, 55.5, 45.4, 34.6, 31.4, 18.2, 10.5.
P r ot ect ion of t h e Am in o Gr ou p of Am in ofu r a n 8.
Syn th esis of 2-[(2S)-3-((ter t-Bu toxyca r bon yl)a m in o)-2-
m eth ylp r op yl]-3-m eth ylfu r a n (10). A solution of (tBoc)2O
(152 mg, 0.7 mMol) in 5 mL of CH2Cl2 was added dropwise to
a solution of aminofuran 8 (100 mg, 0.66 mMol) in 15 mL of
CH2Cl2 at room temperature. After 4 h of stirring the reaction
was quenched with 10 mL of 0.1 N aqueous HCl. The layers
were separated, and the aqueous layer was extracted with
CH2Cl2. The organic layers were combined, washed with 0.1
N HCl, and brine, and dried over Na2SO4. The solvents were
evaporated under reduced pressure to afford a colorless oil
which was purified by column chromatography in 84% yield
t
HRMS (EI) calcd for C7H12NO4 (M+ - Bu) 174.0766, found
174.0771.
Syn th esis of (4S)-4-Meth yl-2-p yr r olid in on e (12). Ester
11 (60 mg, 0.26 mmol) was dissolved in 3 mL of trifluoroacetic
acid. After 30 min the trifluoroacetic acid was removed under
reduced pressure and the residue treated with 5 mL of a 2 N
NaOH aqueos solution and stirred for 5 min. Finally the
organic compound was extracted with ethyl acetate (3 × 15
mL), and the combined organic layers were dried with Na2SO4.
Removal of the solvents under reduced pressure afforded
lactone 12 in 99% yield (25 mg): [R]20589 ) -15 (c 0.2, CHCl3);
1H NMR δ (300 MHz, CDCl3) 5.95 (broad, 1H), 3.54 (dd, 1H),
2.95 (dd, 1H), 3.2-2.8 (m, 2H), 1.98 (dd, 1H), 1.06 (d, 3H); 13
C
NMR (75 MHz, CDCl3) δ 178.7, 49.5, 38.4, 29.3, 19.5; HRMS
(EI) calcd for C5H9NO 99.0684, found 99.0682.
Ack n ow led gm en t. Financial support of this work
by Direccio´n General de Investigacio´n Cient´ıfica y
Te´cnica (DGICYT) PB-1005. A FICYT predoctoral fel-
lowship to C.R. is gratefully acknowledged.
(140 mg): Rf ) 0.49 (hexane/EtOAc 5:1); ee ) 75%; [R]20
)
589
-2.5 (c 0.7, EtOH); 1H NMR δ (300 MHz, CDCl3) 7.20 (s, 1H),
6.15 (s, 1H), 4.66 (broad, 1H), 3.00 (dd, J ) 7.3, 6.2, 1H), 2.53
(dd, J ) 15.0, 6.2, 1H), 2.42 (dd, J ) 15.0, 7.3, 1H), 1.95 (m,
1H), 1.93 (s, 3H), 1.43 (s, 9H), 0.88 (d, J ) 6.9, 3H); 13C NMR
δ (75 MHz, CDCl3) 155.9, 149.3, 139.8, 114.9, 112.6, 78.9, 45.8,
33.8, 30.3, 20.3, 17.4, 9.8; HRMS (EI) calcd for C14H23NO3
253.1678, found 253.1677.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
compounds 4h -i, 4n , 6a , 7a -c, 8, 10, 11, and 12 (12 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
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Ozon olysis of th e F u r a n Rin g. Syn th esis of Meth yl
(3S )-4-((t er t -Bu t oxyca r b on yl)a m in o)-3-m e t h ylb u t a n -
oa te (11). Furan 10 (100 mg, 0.4 mmol) was dissolved in a
mixture of 15 mL of CH2Cl2, 5 mL of ethanol, 1.25 mL of H2O2,
and 120 mg of NaOH. The solution was stirred for 10 min
J O970237M