Tandem inter [4+2]/intra [3+2] cycloadditions of nitroalkenes. Application to the synthesis of aminocarbasugars

Article abstract of DOI:10.1002/1522-2675(200211)85:11<3712::AID-HLCA3712>3.0.CO;2-5

The tandem inter [4+2]/intra [3+2] cycloaddition of nitroalkenes in the bridged mode was applied to the stereoselective synthesis of β-D-4-amino-2,4-dideoxycarbagulose, a representative aminocarbasugar. The synthesis required only five steps from known ma

Full text of DOI:10.1002/1522-2675(200211)85:11<3712::AID-HLCA3712>3.0.CO;2-5

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Helvetica Chimica Acta Vol. 85 (2002)
Tandem Inter [4 ‡ 2]/Intra [3 ‡ 2] Cycloadditions of Nitroalkenes.
Application to the Synthesis of Aminocarbasugars
by Scott E. Denmark* and Martin Juhl
Department of Chemistry, Roger Adams Laboratory, University of Illinois, 600 S. Mathews Avenue, Urbana,
Illinois 61801, U.S.A. (e-mail: denmark@scs.uiuc.edu)
Dedicated to Professor Dieter Seebach on the happy occasion of his 65th birthday
The tandem inter [4 ‡ 2]/intra [3 ‡ 2] cycloaddition of nitroalkenes in the bridged mode was applied to the
stereoselective synthesis of b-d-4-amino-2,4-dideoxycarbagulose, a representative aminocarbasugar. The
synthesis required only five steps from known materials and delivered the protected aminocarbasugar (À)-20
in excellent yield (see Scheme 9). The success of the synthetic sequence relies on 1) the ability to incorporate O-
substituents at the nitroalkene moiety, 2) the identification of a suitably modified chiral dienophile, and in
particular 3) the development of specific experimental conditions and protocols that allowfor the formation and
isolation of the highly sensitive nitroso acetals. The reduction of the C(1) carbonyl group of (‡)-19 gave
unexpected stereoselectivity, which could be rationalized by a conformational inversion of the substrate (see
Scheme 11).
1. Introduction. The Diels Alder reaction has proven to be one of the most useful
tools to create six-membered carbo- and heterocyclic ring systems with a high degree of
regio-, stereo-, and enantiocontrol, by incorporating a wide variety of dienes and
dienophiles [1]. Extensive studies from these laboratories beginning in 1986 have
demonstrated the utility of nitroalkenes as the heterodiene components in inverse-
electron-demand [4 ‡ 2] cycloadditions [2]. Nitroalkenes are effective as 4p-compo-
nents in Lewis acid promoted cycloadditions with cyclic and acyclic alkenes [3] as well
as vinyl ethers to form a diversity of nitronates [4]. Although cyclic nitronates are
stable intermediates that can be converted to a variety of useful derivatives, such as
alcohols, ketones, oximes, and amines [3b], their greatest potential lies in their ability
to undergo [3 ‡ 2] cycloadditions [5]. The 1,3-dipolar cycloaddition reaction of
nitronates was first reported by Tartakovskii and co-workers in 1964 [6] and has
subsequently been studied by Torssell [7], Carrie and co-workers [8], Seebach and co-
workers [9], and others [10].
The linking of these two pericyclic processes into a tandem sequence has been
extremely fruitful. The tandem [4 ‡ 2]/[3 ‡ 2] cycloaddition of nitroalkenes in various
combinations of inter- and intramolecular modes has been employed as a general
approach for the synthesis of a variety of cyclic, N-containing systems. The class of
tandem cycloaddition that has been most thoroughly investigated is the intermolecular
[4 ‡ 2]/intramolecular [3 ‡ 2] sequence. In the inter [4 ‡ 2]/intra [3 ‡ 2] sequence, a
wide variety of highly substituted nitroso acetals can be formed depending on the point
of attachment of the dipolarophile. We have investigated three distinct subclasses
(fused, spiro, and bridged) as illustrated in Scheme 1. The first subclass, termed the

Helvetica Chimica Acta Vol. 85 (2002)
3713
Scheme 1
fused mode, involves tethering of an olefin or dipolarophile at the b-position of the
nitroalkene. The intermediate nitronate, which results from an intermolecular [4 ‡ 2]
cycloaddition, possesses the pendant olefin at the C(4) position. Subsequent intra-
molecular [3 ‡ 2] cycloaddition affords a fused, tricyclic nitroso acetal [11]. In the spiro
mode, the dipolarophile is placed at the a-position of the nitroalkene, and tandem
cycloaddition nowaffords a nitroso acetal having a spiro-fused skeleton [12]. The third
subclass involves a construction entitled the bridged mode, in which the dipolarophile is
attached at either C(5) or C(6) of the nitronate and, thus, must originally be part of the
dienophile [13].
The bridged-mode process distinguishes itself from the fused- and spiro-mode
processes in that the products are carbocycles: cyclohexanes in the case of the a-tether
and cyclopentanes in the case of the b-tether. Although it might, at first glance, seem
inappropriate to employ a heterodiene cycloaddition to prepare a carbocycle, the
ability to install, in a stereo-defined manner, heteroatomic substituents in densely
functionalized rings provides ample justification for developing this sequence.
2. Background. Preliminary studies on the bridged-mode tandem [4 ‡ 2]/[3 ‡ 2]
cycloaddition employed [(1E)-2-nitroprop-1-enyl]benzene [14] (1) and 3,3-dimethyl-
penta-1,4-diene [15] (2) as the 4p- and 2p-components, respectively. As illustrated in
Scheme 2, the SnCl4-promoted [4 ‡ 2] cycloaddition provided the nitronate 3 as a single
diastereoisomer (68% yield), which then underwent a thermal [3 ‡ 2] cycloaddition to

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 2
Me
Me
Me Me
2
Me
Me
Me
Me
Me
O
OAc
O
O
O
AcO
N
SnCl4
toluene
N
1. H2, Raney-Ni
O
O
110 o
AcHN
Me
CH2Cl2
-15o
N
2. Ac2O / Py
57%
Me
Me
Ph
Ph
Ph
Ph
3
79%
4
1
5
68%
give nitroso acetal 4 in 79% yield [13a]. Hydrogenation of 4 and peracetylation gave
the highly functionalized cyclohexanemethanol triacetate 5. The entire configuration of
5 was determined by X-ray crystallographic analysis. The crystal structure revealed that
the [4 ‡ 2] cycloaddition proceeded with exo selectivity (Ph and AcO groups cis). The
facial selectivity in the thermal [3 ‡ 2] cycloaddition was set by the configuration at the
attachment point of the alkene tether, and the endo selectivity was due to the short
tether length.
The generality of the process was demonstrated with a variety of nitroalkenes,
dienophiles, and Lewis acids in the [4 ‡ 2] cycloaddition reaction. The most important
modification was to incorporate a stereocontrolling element in the reaction, so that the
enantiomerically enriched products could be obtained. Attachment of a chiral auxiliary
on the dienophile double bond showed very good stereocontrol through facial
selectivity in the [4 ‡ 2] cycloaddition. The SnCl4-promoted cycloaddition of nitro-
alkene 1 with enantiomerically pure vinyl ether (‡)-6 afforded an excellent yield of the
nitronate (‡)-7 (Scheme 3). The thermal intramolecular [3 ‡ 2] reaction of nitronate
( ‡ )-7 in refluxing anhydrous toluene gave 75% of the nitroso acetal (‡)-8. Selective
hydrogenolysis of the tricyclic nitroso acetal afforded (after subsequent acetylation)
the protected cyclohexanone (À)-9 in 86% yield and 99% ee [13a].
Scheme 3
OAc
O
O
Ph
OG*
N
OG*
Ph
O
O
O
toluene
O
SnCl4
N
1. H2,Raney-Ni
2. Ac2O / Py
86%
+
O
O
Me
-78o
98%
110 o
75%
N
Me
AcHN
Ph
Me
Me
1.2 equiv.
Ph
Ph
(+)-8
1
(+)-6
(+)-7
(–)-9
This sequence clearly demonstrated the potential of the bridged-mode tandem
cycloaddition to generate enantiomerically enriched and highly functionalized amino-
cyclohexanones. However, preliminary studies on the replacement of the phenyl group
with a latent hydroxyl functionality (which would allow for the synthesis of 4-amino-
2,4-dideoxycarbasugars) met with very limited success. Two problems were noted, 1)
poor diastereoselectivities with nitroalkenes bearing O-substituents at C(2) and 2) the
limited stability of nitronates bearing only a H-atom at C(3). Apparently, very subtle
changes in structure have a dramatic effect on the outcome of the reaction.

Helvetica Chimica Acta Vol. 85 (2002)
3715
The goal of the current study was to establish the structural and reaction conditions
necessary to permit successful application of the tandem, bridge-mode [4 ‡ 2]/[3 ‡ 2]
cycloaddition for the synthesis of aminocarbasugars. Carbasugars have attracted a great
deal of interest as synthetic analogs of sugars [16]. While retaining the basic shape of
the furanose or pyranose, they lack the anomeric linkage, and, therefore, may serve as
effective inhibitors of enzymes that process the natural substrates [17]. Several
aminocarbasugars occur in nature, e.g., validamine [18] and valienamine [19] (Fig. 1)
but most others are synthetic. Interestingly, among them, 4-amino-4-deoxy-5a-
carbahexoses are notably rare [20]. Finally, the rare and unusual 2,4-diamino-2,4,6-
trideoxygalactose (AAT) was recently found to be a component of a trisaccharide in
the capsule of Gram-positive bacteria [21]. The 5a-carba analog of AAT (Fig. 1) may
serve as a specific inhibitor of the cell-wall biosynthesis of these bacteria with obvious
implications for the development of selective antibiotics.
OH
OH
HO
Me
O
O
CO2H Me
OH
AcNH
NH2
OH
HO
HO
L-vancosamine
OH
5-N-acetylneuraminic acid
OH
HO
HO
HO
HO
OH
NH2
OH
NH2
validamine
valienamine
AcNH
HO
AcNH
AcNH
OH
OH
CH3
O
HO
HO
H2N
OH
OH
OH
Fig. 1. 4-Aminogalactose/carbagalactose derivatives
To accomplish this objective, a suitable nitroalkene would have to be identified
along with appropriate choice of chiral auxiliary and Lewis acid to influence the regio-
exo/endo- and facial stereocontrol [22]. As illustrated in the retrosynthetic analysis in
Scheme 4, the stereogenic center at C(1) is controlled by selective reduction of the C(1)
ketone, whereas the stereogenic center at C(3) arises from the configuration at C(4) of
the nitronate, which is established by the facial selectivity of the [4 ‡ 2] cycloaddition
(to iii or iv). Of course, the overall absolute stereocontrol depends on the configuration
of the auxiliary (G*) in combination with the choice of Lewis acid. We describe herein
the successful implementation of this approach to the stereocontrolled synthesis of an
aminocarbasugar.

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 4
H2N
OH
H2N
OH
G*O
O
1
OH(H)
N
3
OPG
O
O
H(OH)
OH
OH
4-aminogulose series
i
H2N
HO
OH
H2N
HO
OPG
G*O
OH
O
1
OH(H)
N
O
3
O
H(OH)
4-aminogalactose series
ii
_
OG*
G*O
+
O
O
O
N
exo
N
O
OPG
NO2
G*O
i
iii
OPG
+
_
O
OG*
+
N
OPG
G*O
O
OPG
O
N
endo
O
OPG
ii
iv
3. Results. 3.1. Preparation of Dienophiles. To begin the survey of oxygenated
nitroalkenes, we chose 1-(benzoyloxy)-2-nitroethene (10a) [23], which had served us
well in earlier total-synthesis endeavors. We also decided to survey two chiral-auxiliary-
modified dienes derived from trans-2-phenylcyclohexanol [13a] and trans-2-cumylcy-
clohexanol (ˆ2-(1-methyl-1-phenylethyl)cyclohexanol) [24], which we had employed
with good results previously. Both racemic and enantiomerically pure vinyl ether 13a
and enantiomerically pure vinyl ether (‡)-13b were prepared by allylcupration of the
corresponding alkoxyacetylenes 12a and (‡)-12b [25] in yields of 96 and 89%,
respectively (Scheme 5)1). The use of allylmagnesium chloride was found to be
necessary in the allylcupration; when the bromide was used in the reaction, the yield
dropped significantly [26]2).
3.2. [4 ‡ 2] Cycloaddition. In initial studies, Lewis acids were screened for
selectivity in the system involving 10a and vinyl ethers (Æ)-13a and (‡)-13b (Table 1).
Tin tetrachloride (SnCl4) was the only Lewis acid that gave rise to product 14
formation. With either titanium dichlorodiisopropoxide or MAD (methylaluminium
1
)
)
Enol ethers 13 are moisture sensitive and are prone to undergo isomerization to the corresponding penta-
1,3-diene and, thus, should be stored at À 258.
2
Allylmagnesium bromide was used because of the problems associated with the preparation of
allylmagnesium chloride in concentrations >0.3m [26].

Helvetica Chimica Acta Vol. 85 (2002)
3717
Scheme 5
Ph
MgCl
1. KH
2.Cl2C=CHCl
Ph
Ph
+CuBr
O
3. BuLi
4. H2O
HO
O
THF
-90o to -78o
(±)-13a
(±)-12a
(±)-11a
(= G*·OH)
Me
Me
Ph
MgCl
Me
Ph
Me
1. KH
2.Cl2C=CHCl
Me
Me
Ph
+CuBr
O
3. BuLi
4. H2O
O
THF
-90o to -78o
HO
(+)-13b
(+)-12b
(+)-11b
(= G*·OH)
bis[2,6-di(tert-butyl)phenolate]), no product could be isolated from the reaction3)4).
Attempts to thermally induce the [3 ‡ 2] cycloaddition afforded a crude product in
60% yield, but the nitroso acetal could be isolated only in very lowyield due to
instability towards purification by silica-gel chromatography, even with Et3N in the eluent.
Table 1. Survey of Lewis Acids for [4 ‡ 2] Cycloaddition with 10a
_
O
OG*
+
O
N
NO2
G*O
Lewis acid (2 equiv.)
+
toluene, -74 o
OBz
OBz
(±)-13a G* = (±)-11a (–OH)
(+)-13b G* = (+)-11b (–OH) 10a
14aa G* = (±)-11a (–OH)
14ba G* = (+)-11b (–OH)
Lewis acida)
Dienophileb)
Nitroalkene
Yield [%]
drc)
SnCl4
(Æ)-13a
(Æ)-13a
(Æ)-13a
(Æ)-13a
(‡)-13b
10a
10a
10a
10a
10a
78d)
0
0
0
44
1.2 : 1
TiCl2(OiPr)2
MADe)
MAPhf)
SnCl4
4.5 : 1
a) 2.0 equiv. b) 1.5 equiv.. c) Determined by 1H-NMR analysis. d) Contaminated with 11a. e) MAD ˆ methyl-
aluminium bis[2,6-di(tert-butyl)phenolate]. f) MAPh ˆ methylaluminium bis[2,6-diphenylphenolate].
Whereas previous investigations revealed the stabilizing influence of substituents at
C(3) of the nitronate [13a], this was not available to us in view of the target product
structures. Thus, we turned our attention to other nitroalkenes to evaluate the
1
3
4
)
)
With MAD, the isomerized dienophile was identified by H-NMR analysis of the crude product.
It was crucial to the isolation of the nitronates 14 that the reaction was quenched at À 748 with 1m
methanolic Et3N solution and that 1% of Et3N was present in the eluent for purification by silica-gel
chromatography.

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Helvetica Chimica Acta Vol. 85 (2002)
compatibility and stabilizing effect of different O-protecting groups. Trialkylsilyl
groups have been used with success in earlier studies involving tandem [4 ‡ 2]/[3 ‡ 2]
cycloadditions [27]. Nitro(silyloxy)alkenes 10b and 10c could be prepared by silylation
of the potassium enolate of nitroacetaldehyde, itself available from hydrolysis of N,N-
dimethyl-2-nitroethenamine (Scheme 6) [28]. The silylation was carried out with
triisopropylsilyl chloride (TIPS-Cl) and (tert-butyl)dimethylsilyl chloride (TBS-Cl),
with yields of 81% in both cases5).
Scheme 6
NO2
NO2
NO2
KOH, EtOH
SiR3Cl
CH2Cl2/CH3NO2, 1:1
-30o to r.t.
r.t., 1.5 h
94%
NMe2
OK
OSiR3
10b: R3Si = tBuMe2Si, 81%
10c: R3Si = iPr3Si, 81%
The results of [4 ‡ 2] cycloaddition of 10b and 10c with (Æ)-13a and (‡)-13b are
collected in Table 2. As was the case with 10a, only SnCl4 led to product formation with
both 10b and 10c. Cycloaddition with 10b (TBS) proceeded with exo selectivity (with
respect to OG*) as determined by X-ray crystallographic analysis of both the
cyclohexanone (Æ)-19 and the nitronate (À)-14ab (vide infra). The combination of 10b
and (Æ)-13a proved to be the most selective of those tried, giving a diastereoselectivity
of 19 :1. Surprisingly, the seemingly minor change in protective group from 10b (TBS)
to 10c (TIPS) had a significant impact on the selectivity. Although both nitroalkenes
reacted with exo preference, the selectivity of the reaction dropped from 19 :1 to 2 :1
for 10b and 10c, respectively. When the reaction was carried out with (‡)-13b, the
selectivity decreased even further to give a diastereomer ratio of 4.25 :4.25 :16).
3.3. [3 ‡ 2] Cycloaddition. The intramolecular [3 ‡ 2] cycloaddition in the a-
bridged mode with a nitronate 14 bearing only a H-atom at the C(3) position and a
OG* substituent at the C(6) position is unprecedented. The nitroso acetals 15 were
extremely acid sensitive and thus, to avoid decomposition, it was necessary to have an
insoluble base present in the reaction mixture [13]. Moreover, purification of the
nitroso acetals could not be performed with standard silica-gel column chromatog-
raphy, even with base (0.5 1% of Et3N) present in the eluent. The optimal purification
procedure involved column chromatography on basic alumina (act. III) along with ca.
20 mg of NaHCO3 present in all fraction tubes. In addition, 1H-NMR data was obtained
in (D8)toluene with NaHCO3 present. Only with these measures could reproducible
yields be obtained and the optimal reaction conditions be determined (Table 3). The
thermal [3 ‡ 2] reaction was much faster than expected (cf. Entry 1); 1H-NMR analysis
of an aliquot taken after 4 h showed that the nitronate 14ab was consumed and that
5
)
)
To obtain high yields of 10c, the product must be purified by both Schlenk filtration and high-vacuum
distillation to avoid decomposition.
Because none of the minor diastereoisomers was successfully taken on to aminocyclohexanones, it could
not be determined whether the minor isomers resulted from a loss of endo/exo selectivity or facial
selectivity.
6

Helvetica Chimica Acta Vol. 85 (2002)
3719
Table 2. Survey of Lewis Acids for [4 ‡ 2] Cycloaddition with 10b
c
_
OG*
NO2
+
O
O
Lewis acid
G*O
N
+
toluene, -74 o
OSiR3
OSiR3
(±)-13a G* = (±)-11a (–OH)
(+)-13b G* = (+)-11b (–OH)
10b R3Si = TBS
c R3Si = TIBS
14ab G* = (±)-11a (–OH), R3Si = TBS
14ac G* = (±)-11a (–OH), R3Si = TIPS
14bb G* = (+)-11b (–OH), R3Si = TBS
Lewis acida)
Dienophileb)
Nitroalkene
Yield [%]
drc)
SnCl4
SnCl4
TiCl2(OiPr)2
MAPhd)
SnCl4
(Æ)-13a
(Æ)-13a
(Æ)-13a
(Æ)-13a
(‡)-13b
10b
10c
10c
10c
10c
57
71
0
19 : 1
2 : 1
0e)
77
4.25 : 4.25 : 1
a) 2.0 equiv. b) 1.5 equiv. c) Determined by 1H-NMR analysis. d) MAPh ˆ methylaluminium bis[2,6-diphenyl-
phenolate]. e) 24% of isomerized 13a was isolated.
nitroso acetal 15ab was present with little contamination. Apparently, the lack of a
substituent at C(3) of the nitronate leads to faster [3 ‡ 2] cycloaddition7). The TIPS-
protected nitronate 14ac reacted more slowly, but nitroso acetal 15ac could be isolated
in good yield after 18 h at 1408
Table 3. Optimization of Conditions for [3 ‡ 2] Cycloaddition with 14
_
OG*
G*O
+
O
O
solvent, temp
7 equiv. base
N
O
N
O
OSiR3
OSiR3
14ab G* = (±)-11a (–OH), R3Si = TBS
14ac G* = (±)-11a (–OH), R3Si = TIPS
15ab G* = (±)-11a (–OH), R3Si = TBS
15ac G* = (±)-11a (–OH), R3Si = TIBS
Entry
Nitronate
R3Si
Solvent
Temp. [8]
Methoda)
Base
Time [h]
Yield [%]b)
1
2
3
4
14ab
14ac
14ac
14ac
TBS
toluene
toluene
xylenes
tBuC6H5
110
50
140
160
A
A
B
B
NaHCO3
K2CO3
NaHCO3
NaHCO3
4.5
60
18
69c)
TIPS
TIPS
TIPS
0 (20)d)
49c)
18
27c)
Method A: the reaction mixture was placed in a preheated oil bath. Method B: syringe-pump addition of
nitronate within 8 h into the refluxing reaction mixture, followed by stirring for an additional 10 h. b) Isolated
yield. c) Purified by alumina chromatography (act. III, basic). d) Yield by 1H-NMR analysis of the crude
mixture.
3.4. Hydrogenolysis. The nitroso acetal hydrogenolysis is a critical reaction whose
success relies upon a delicate balance of three parameters (H2 pressure, solvent, and
amount of catalyst). The use of 1 atm of H2 and MeOH as the solvent was dictated by
7
)
For example, the conversion of (‡)-7 to (‡)-8 (Scheme 3) required 26 h.

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Helvetica Chimica Acta Vol. 85 (2002)
previous experience with this type of tricyclic nitroso acetals [13a]. These foregoing
studies also revealed an important dependence of the rate of the nitroso acetal
hydrogenation on the Raney-Ni loading. High loadings (ca. 17 equiv.) of Raney-Ni were
required to obtain reasonable reaction times (1.3 4 h). The selective unmasking of
nitroso acetal 15ac to afford the corresponding ketone 16 could be achieved by stirring
a methanolic suspension of commercially available Raney-Ni (W2) and nitroso acetal
15ac under 1 atm of H2 at room temperature for 1.5 2 h (Scheme 7). The crude
product from the hydrogenation of nitroso acetal 15ac was acetylated to give amino
cyclohexanone 17 in 15% overall yield.
Scheme 7
O
O
Raney-Ni, H2 (1 atm)
MeOH, r.t., 80 min
OG*
Ac2O / Py
O
O
AcO
HO
OTIPS
OTIPS
N
0.002 M K CO
OTIPS
2
3
NHAc
NH2
2 steps 15%
16
17
15ac
The selective hydrogenation of nitroso acetal 15ab was carried out under conditions
similar to those described for 15ac, but all attempts to acetylate the crude product from
the hydrogenation failed8). It was discovered that the intermediate amino ketone (Æ)-
18 (Scheme 8) decomposed when the reaction mixture was concentrated in vacuo9).
Thus, we needed to employ a method for protecting the amine that would be
compatible with the use of MeOH as solvent. This was successfully accomplished by
adding ethyl trifluoroacetate (together with N,N-dimethylpyridin-4-amine (DMAP))
to the crude MeOH solution of the amino ketone after removal of the Ni catalyst. In
this way, protected cyclohexanone derivative (Æ)-19 could be obtained in 72% overall
yield (Scheme 8).
Scheme 8
O
G*O
H2N
CF3
NH
OH
OH
Raney-Ni, H2 (1 atm)
O
CF3CO2Et (3 equiv)
N
O
MeOH, K2CO3
r.t., 2 h
OTBS
DMAP (0.1 equiv)
MeOH, r.t., 2 h
O
O
OTBS
OTBS
(±)-15ab
(±)-19
72% overall
(±)-18
The structure of (Æ)-19 was confirmed by single-crystal X-ray analysis (Fig. 2)10).
1
Analysis of H-NMR coupling constants between HÀC(3) and HÀC(4) confirms that
these H-atoms also occupy equatorial positions in solution, (Fig. 3). Thus, the
8
)
)
)
The only compound isolated from the attempted hydrogenation/acetylation sequence of 15ac was a
partially reduced intermediate.
9
The decomposition is probably due to imine polymerization by concentrating the amino ketone containing
reaction mixture. It is also possible that this decomposition is catalyzed by Ni2‡
.
10
The crystallographic coordinates of (Æ)-19 have been deposited with the Cambridge Crystallographic Data
Centre, deposition No. CCDC-187303.

Helvetica Chimica Acta Vol. 85 (2002)
3721
Fig. 2. Chem-3D representation of X-ray crystal structure of (Æ)-19. Most H-atoms are omitted for clarity.
Red ˆ O, blue ˆ N, yellow ˆ F, light blue ˆ Si.
O
O
Jc
Me
O
CF3
OH
Me
HN
4
HN
4
O
H
H
H
H
3
Jb
H
3 H
O
Jb
O
O
Ja
Ja
O
TBS
TIPS
17
(±)-19
Ja = 4.7 Hz
Jb = 3.5 Hz
Jc = 7.9 Hz
Ja = 4.7 Hz
Jb = 3.5 Hz
1
Fig. 3. Selected H-NMR data of (Æ)-19 and 17
trifluoroacetamido and the TBSO groups at C(4) and C(3) must adopt axial positions
in solution as well as in the solid state. By analogy, small coupling constants for HÀC(3)
and HÀC(4) in the cyclohexanone 17 suggest that the acetamido and TIPSO groups
also occupy axial positions.
3.5. Cyclohexanone Reduction. The selective reduction of (Æ)-19 to the cyclo-
hexanediol (Æ)-20 was more challenging than expected. A variety of reagents and
conditions were surveyed (Table 4). Disappointingly, of all the reagents initially tried,
only the Meerwein-Ponndorf-Verley reduction (Entries 2 and 3) gave a favorable
equatorial/axial ratio of the OH group at C(5). This reaction gave moderate to good
selectivity, but longer reaction times and higher temperatures (conditions that should
favor the thermodynamically preferred product) led to extensive decomposition. The
use of Na in ammonia gave exclusively the unexpected axial product, although the
chemical yield was very poor (Entry 5). We next considered the reduction of (Æ)-19 to
the epimeric cyclohexanediol with an axial hydroxy group, using LS-Selectride [29].

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Helvetica Chimica Acta Vol. 85 (2002)
Here, again, the unexpected result was observed in the exclusive formation of the
equatorial alcohol product (Æ)-20. The reduction was also extremely slow (cf.
Entries 9 11; Table 4); complete consumption of the ketone at À 788 required
7.5 equiv. of LS-Selectride over 48 h, to afford a 77% yield of (Æ)-20. Raising the
temperature to À 308 and stirring the reaction mixture for 8 h gave (Æ)-20 in 55% yield,
with no starting material remaining.
Table 4. Optimization of Conditions for Reduction of (Æ)-19
O
O
CF3
NH
OH
CF3
NH
OH
reagent
1
OH
conditions
5
O
OTBS
OTBS
(±)-19
Conditions
(±)-20
Entry
Reagent
Equatorial/axial
Conversiona) [%]
1
2
3
4
5
6
7
8
9
NaBH4/CeCl3
Al(iPrO)3
MeOH, À 788, 12 h
1 : 1.17
4 : 1
10 : 1
86
iPrOH, 508, 1.5 h
100
Al(iPrO)3
iPrOH, 808, 3 d
iPrOH, 808, 3 d
100b)
dec.
La3(iPrO)9
Nac)/NH3/iPrOH
Nad)/NH3/iPrOH
Na
THF, À 788, 2 min
0 : 1
0 : 1
30
THF, À 788, 2 min
100e)
dec.
EtOH/Et2O, 08, 0.5 h
THF/H2O, 08, 0.5 h
SmI2
1 : 1.09
1 : 0
1 : 0
1 : 0
1 : 0
100 f)
29g) (61)h)
37g) (52)h)
77g)
LS-Selectride
LS-Selectride
LS-Selectride
LS-Selectride
3.2 equiv. THF, À 788, 2.5 h
3.5 equiv. THF, À 788, 12 h
7.5 equiv. THF, À 788, 48 h
8.0 equiv. THF, À 308, 8.0 h
10
11
12
55g)
b
a) Conversion based on 1H-NMR intergration. ) 1H-NMR analysis showed extensive decomposition.
c) 10 equiv. of Na used. d) 50 equiv. of Na added in three portions. e) Isolated 20% of axial product. f) Minor
by-products observed. g) Yield of isolated product. h) (Recovered starting material).
The assignment of the configuration at C(5) of (Æ)-20 was deduced from analysis of
1H-NMR coupling constants (Fig. 4). The large coupling constants between Ha and Hc
and He implied axial/axial coupling, which is possible only when the OHÀC(5) is in the
equatorial position. Additional structural evidence from chemical transformation was
secured by treatment of (Æ)-20 under Mitsunobu conditions (Fig. 4). None of the
expected benzoate was obtained but rather the bicyclic compound 21. This would be
most unlikely if OHÀC(5) were axial, because primary OH groups are know to react
faster than secondary OH groups under Mitsunobu conditions [30]11). Compound 21
could be formed by activation of the primary OH group followed by displacement of
the activated phosphonium group with the OHÀC(5) in a flipped chair conformation.
3.6. Enantioselective Synthesis of a 4-Amino-2,4-dideoxycarbasugar. On the basis of
the high degree of selectivity observed in the [4 ‡ 2] cycloaddition, the TBS-protected
nitroalkene 10b and the vinyl ether 13a were chosen to prepare an enantiomerically
11
)
For formation of a bicyclic tetrahydrofuran under Mitsunobu conditions, see [30c].

Helvetica Chimica Acta Vol. 85 (2002)
3723
O
CF3
NH
He
Hc
Hd
OHg
HO
5
Hf
H
b Ha
TBSO
(±)-20
CDCl3
d6-benzene
Jac = Jae = 9.4 Hz
Jab = Jad = Jag = 4.6 Hz
J
J
J
ac = Jae = 9.4 Hz
ab = 3.8 Hz
ad = 4.3 Hz
O
CF3
NH
OH
CF3
O
O
PPh3, DEAD, PhCO2H
OH
HN
THF
0 – 50 o
TBSO
TBSO
(±)-20
21
62%
Fig. 4. Structural assignment of reduction product 20
enriched aminocarbasugar. Given that a d-aminocarbasugar was desired, the correct
enantiomer of trans-2-phenylcyclohexanol had to be chosen. This was done on the basis
of the crystal structure of (Æ)-8 [13a] (Fig. 5). The relative configuration between the
chiral auxiliary and the nitroso acetal core can be determined by inspection. The
configuration of the chiral auxiliary depicted is (1S,2R)-trans-2-phenylcyclohexanol
((Æ)-11a), which would lead to the l-aminocarbasugar 22, derived from cyclohexanone
(À)-9 (Fig. 6). Thus, for the synthesis of d-aminocarbasugars, the (1R,2S)-trans-2-
phenylcyclohexanol ((À)-11a) is required.
Fig. 5. Chem-3D representation of the X-ray crystal structure of nitroso acetal (Æ)-8. Most H-atoms are omitted
for clarity. Red ˆ O, blue ˆ N.
The synthesis followed the optimal sequence established above and is outlined in
Scheme 9. Gratifyingly, all of the yields and selectivities were higher than in the

3724
Helvetica Chimica Acta Vol. 85 (2002)
OH
OH
CHO
AcO
C/O
H
H
H
Ph
Me
H
H
H
H
Ph
Me
H
H
H
H
OH
CH2
O
Ph
Me
H
RHN
RHN
RHN
HO
HO
ACHN
Me
Ph
RO
HO
22
L-aminocarbasugar
R=Ac
L-aminosugar
OH
H
OH
O
H
H
CHO
C/O
H
TBSO
H
H
H
H
H
TBSO
H
H
CF3
NH
OH
CH2
O
H
TBSO
H
OH
NHR
H
H
NHR
NHR
OH
OH
H
H
TBSO
OH
OH
D-aminosugar
(–)-20
D-aminocarbasugar
R=COCF3
Fig. 6. Fischer projections of aminocarbasugars 22 and (À)-20
orienting experiments. The SnCl4-promoted cycloaddition of nitroalkene 10b with
enantiomerically enriched dienophile (À)-13a produced the nitronate (À)-14ab in 85%
yield. The [3 ‡ 2] cycloaddition of nitronate (À)-14ab was carried out in refluxing
anhydrous toluene with 7 equiv. of NaHCO3 present to afford the nitroso acetal 15ab in
89% yield. The selective hydrogenolysis of the highly strained tricyclic nitroso acetal
proceeded under 1 atm of H2 with 17 equiv. of Raney-Ni in MeOH. After trifluoro-
acetylation of the crude amino ketone, the target cyclohexanone (‡)-19 was isolated
Scheme 9
(–)-G*O
_
O(–)-G*
(–)-G*O
+
N
NaHCO3 (7 equiv.)
SnCl4 (2 equiv.)
toluene, -78 o, 1.5 h
85%
O
O
NO2
O
N
O
+
OTBS
toluene
reflux, 1.25 h
(–)-13a
TBSO
OTBS
89%
(–)-14ab
Ph
10b
15ab
(–)-G* =
Raney-Ni, H2 (1 atm)
MeOH, K2CO3
r.t., 2 h
(–)-11a (–OH)
(–)-11a
O
O
LS-selectride
(8 equiv.)
H2N
OH
CF3CO2Et (3 equiv.)
CF3
CF3
NH
NH
OH
OH
1
DMAP (0.1 equiv.)
MeOH, r.t., 2 h
THF, 48 h, -70 ˚
OH
O
OTBS
O
TBSO
OTBS
70%
70%
(–)-20
(+)-19

Helvetica Chimica Acta Vol. 85 (2002)
3725
in 70% yield. Selective reduction of (‡)-19 was carried out with 8 equiv. of LS-
Selectride at À 708 in THF for 48 h, to give the b-d-4-amino-2,4-dideoxycarbagulose
((À)-20) in 70% yield after recrystallization.
4. Discussion. 4.1. [4 ‡ 2] Cycloaddition. There are two stereochemical issues to
consider in these inverse-electron-demand [4 ‡ 2] cycloadditions12). The first is the
relative stereochemistry that describes the pairwise relationship between the enantio-
topic faces of the diene and the diastereotopic faces of the dienophile. This is commonly
referred to as endo/exo selectivity, though we have recommended the use of the lk (like)
and ul (unlike) terms suggested by Seebach to more accurately describe the topical
relationship of the endo/exo transition states. The second type of selectivity, called
internal, becomes relevant when either the diene or the dienophile is chiral. In the case
at hand, we employed chirally modified vinyl ethers, and, thus, the internal selectivity is
defined as the pairwise relationship of the resident stereogenic center at the chiral unit
with respect to the face of the dienophile that is engaged in cycloaddition. This type of
selectivity is defined as (1,3-lk) and (1,3-ul). From computational analysis, it is known
that there are two limiting ground-state conformations in vinyl ethers, the s-cis and the
s-trans conformations around the GO*ÀC(2) bond. Which face of the vinyl ether is
accessible depends on whether the vinyl ether is in the s-cis or s-trans conformation.
There are four possible transition-state structures as shown in Fig. 7. Lewis acids
enhance the rates of these inverse-electron-demand cycloaddition reactions by
LA
O
N
O
LA
O
N
O
R3SiO
R3SiO
O
O
1´R
1´R
lk-(1,3-lk)
endo/s-cis
ul-(1,3-lk)
exo/s-cis
1´R
1´R
LA
O
O
O
N
O
O
LA
N
O
R3SiO
R3SiO
lk-(1,3-ul)
endo/s-trans
ul-(1,3-ul)
exo/s-trans
Fig. 7. Four limitingtransition-state structures for the [4 ‡ 2] cycloaddition
12
)
For a thorough discussion of the stereochemical features of these cycloadditions, see [22b].

3726
Helvetica Chimica Acta Vol. 85 (2002)
narrowing the FMO gap through the lowering of the LUMO(heterodiene) by complexation.
In addition, we have observed that the reaction selectivity has also been dramatically
affected [22][31]. With SnCl4, the [4 ‡ 2] reaction generally proceeds through a ul-type
transition structure (exo with respect to the OR group in the vinyl ether). This has been
proposed previously when groups capable of delocalizing electrons (e.g., a phenyl
group) are present in the b-position in the nitroalkene, (Fig. 8).
LA
O
N
O
LA
O
N
O
alkyl
R3SiO
d-
O
O
1´R
1´R
charge separation
exo (ul) favored
coulombic interaction
endo (lk) favored
Fig. 8. Electrostatic interactions in the lk and ul transition structures
Both Houk and co-workers [32] and Kahn and Hehre [33] have suggested that
coulombic interactions between the diene and dienophile in the transition structure
control the relative (exo/endo) selectivity in Diels Alder reactions. This model has
been used to explain previous results with nitroalkenes and simple vinyl ethers or b-
substituted vinyl ethers. Electrostatic interactions between the positively charged N-
atom and the electron-rich O-atom in the vinyl ether would lead to the l (endo-derived)
product. However, if an electron-delocalizing group, such as TBSO or TIPSO, were
placed in the b-position of nitroalkene, it could change the electronic environment of
the N-atom and delocalize the positive charge, thereby attenuating the coulombic
interactions. The less sterically demanding exo-type approach could then be the
controlling factor in the [4 ‡ 2] cycloaddition. The significantly higher exo selectivity
obtained with the TBSO-substituted nitroalkene 10b compared to the TIPSO-
substituted nitroalkene 10c is difficult to explain in the absence of accurate
transition-structure models. It is noteworthy that the exo-selective cycloaddition
affords the u product, which leads to the d-4-amino-2,4-dideoxycarbagulose series. To
access the d-4-amino-2,4-dideoxycarbagalactose series will require an endo cyclo-
addition promoted by a titanium- or aluminium-based Lewis acid.
To explain the origin of the internal selectivity imparted by the chiral auxiliary, we
must understand howthe phenyl group of the 2-phenylcyclohexyl unit shields the
diastereofaces of the vinyl ether. As shown in Figs. 7 and 8, the phenyl group of the
auxiliary blocks the Si face of the vinyl ether when it is in the s-cis conformation and
blocks the Re face of the vinyl when it is in the s-trans conformation. The X-ray crystal
structure of nitronate (À)-14ab (see below) unambiguously determined that the major
product in the [4 ‡ 2] cycloaddition was formed through an ul-(1,3-lk) (exo/s-cis type)
transition-state structure. This means that the vinyl ether attacked from the Re face at
C(2) to the Si face of the C(b) atom on the nitroalkene. There are no steric reasons for
the reaction to proceed through an s-cis conformation of the vinyl ether, and Houk and
co-workers have shown that simple vinyl ethers experience a conformational switch

Helvetica Chimica Acta Vol. 85 (2002)
3727
[34]. In the ground state, the s-trans conformation is disfavored due to unfavorable lone
pair/p-electron interactions. In the transition structure, on the other hand, the s-trans
conformation is more favorable because of lone-pair stabilization of the developing
positive charge. Indeed, earlier studies in this group have documented the conforma-
tional switch, but importantly also showed that it is Lewis acid dependent. For example,
with MAD and TiiPrO2Cl2, vinyl ethers react through s-trans conformations, while, with
SnCl4, they prefer to react through an s-cis conformation [22b]. The stereochemical
significance is reflected in the change in internal selectivity as a function of the Lewis
acid. In this study, observed facial selectivity of the cycloaddtion between (À)-13a and
10b indicates that the Houk conformational switch does not occur for these systems as
well in the presence of SnCl4.
4.2. [3 ‡ 2] Cycloaddition. The rate of the thermal dipolar cycloaddition is related in
part to the ease with which the nitronate can orient itself to a reactive conformation. It
has been shown previously that the ground-state conformation of the nitronate is a half
chair in which the alkoxy group (RO) at C(6) is placed in a pseudoaxial position to
maximize the anomeric effect [13a]. This places the pendant dipolarophile in a
pseudoequatorial position. This supposition has been confirmed in the solid state by the
X-ray crystal structure of (À)-14ab (Fig. 9)13).
Fig. 9. Chem-3D representation of the X-ray crystal structure of (À)-14ab. Most H-atoms are omitted for clarity.
Red ˆ O, blue ˆ N, yellow ˆ F, light blue ˆ Si.
For the dipolarophile to position itself in a reactive orientation, the nitronate ring
has to assume a high-energy, boat-like conformation wherein the dipolarophile is in a
pseudoaxial position, (Fig. 10). As observed in previous investigations, this conforma-
tional reorientation is particularly unfavorable in the trans-nitronate because of the
13
)
The crystallographic coordinates of (À)-14ab have been deposited with the Cambridge Crystallographic
Data Centre, deposition No. CCDC-187304.

3728
Helvetica Chimica Acta Vol. 85 (2002)
nonbonding interactions between the MeÀC(3) and PhÀC(4), when changing from a
dihedral angle (/MeÀCÀCÀPh) of ca. 458 to 08. This issue manifests itself in reaction
conditions necessary for the [3 ‡ 2] cycloaddition for the nitronate depicted in Fig. 10,
namely 24 h in refluxing xylenes for the trans-nitronate compared to 11 h in refluxing
benzene for the cis nitronate.
OR
N
OR
N
Ph
H
O
O
Me
Ph
Me
H
O
O
ul (trans)
dihedral angle ca. 45 o
lk (cis)
dihedral angle ca. 60 o
Ph
RO
H
RO
O
O
N
H
N
O
Ph
Me
O
Me
dihedral angle ca. 90 o
dihedral angle ca. 0 o
Fig. 10. Transition-state structure for [3 ‡ 2] cycloaddition
In the case of trans-nitronate (À)-14ab, the reaction time was only 4.25 h in
refluxing toluene to obtain complete conversion to 15ab. This significant rate increase
compared to the trans-nitronate in Fig. 10 most likely arises from the lack of a
substituent at C(3) in (À)-14ab. Two sterically related consequences of having a H-
atom at this position are: 1) reduced interactions between the dipole and the
dipolarophile in the transition structure and 2) reduced torsional interactions between
a H-atom and a TBSO group, compared to a Me and a Ph group (Fig. 11).
H
G*O
OG*
N
H
G*O
O
N
H
O
OTBS
O
O
H
OTBS
N
O
OTBS
O
trans
dihedral angle ca. 0 o
dihedral angle ca. 45 o
15ab
Fig. 11. Transition-state structure for the [3 ‡ 2] cycloaddition of (À)-14ab
4.3. Hydrogenation. The selective hydrogenation of 15ab to give cyclohexanone 18,
could be controlled by the amount of Raney-Ni used and the reaction time. The optimal
conditions were ca. 17 equiv. of Raney-Ni under 1 atm of H2 for 2 3 h. When 11 equiv.
of Raney-Ni were used for 4.5 h partially hydrogenated product 24 was isolated after
acetylation (Scheme 10). As in all previous studies, the isoxazolidine ring of the nitroso
acetal was cleaved first (to give 23), even when the other NÀO bond of the 1,2-oxazine
is longer.

Helvetica Chimica Acta Vol. 85 (2002)
3729
Scheme 10
(–)-G*O
O
AcN
OTBS
AcO
24
Ac2O/py
HO
O-(–)-G*
(–)-G*O
(–)-G*O
Raney-Ni, H2
O
Raney-Ni, H2
O
N
O
HO
HN
OTBS
MeOH
MeOH
OTBS
O
OTBS
HO
NH2
15ab
23
v
O
(–)-11a
Ac2O/Py
AcO
HO
X
OTBS
OTBS
decomposition
NH2
NHAc
18
CF3CO2Et
DMAP, MeOH
O
HO
F3C
OTBS
NH
O
(+)-19
The instability of aminocyclohexanones 16 and 18 stands in contrast to the
aminocyclohexanones from previous investigations (cf. Scheme 3). This increased
instability is probably due to oligomerization as a consequence of the less sterically
demanding environment around the amino group, which would be expected to
accelerate intermolecular imine formation.
4.4. Selective Ketone Reduction. The selective reduction of cylcohexanone (‡)-19 to
give alcohol (À)-20 bearing an equatorially oriented OH group was very surprising. The
bulky reducing agent LS-Selectride is well known to deliver hydride in an equatorial
direction to generate axial alcohols [29]. This unexpected result could only be
rationalized if the reactive conformation of the ketone (or ketone complex) were
significantly different from the ground state. Thus, to pursue this possibility, we
determined the ground-state conformation of 19 by a number of methods.
As described in Sect. 3.5, in both the solid (X-ray) and solution (1H-NMR) states,
the conformation of (Æ)-19 is that in which both the CF3CONH and TBSiO groups
occupy axial positions with the hydroxymethyl group at C(1) in an equatorial

3730
Helvetica Chimica Acta Vol. 85 (2002)
orientation (Fig. 2). Further, an MM2 conformational search with MacroModel 7.0
showed that the axial/axial conformation of the CF3CONH and silyloxy groups
(Me3SiO instead of TBSiO to minimize calculation time) in (Æ)-19 was 18.3 kJ/mol
lower in energy than the equatorial/equatorial conformation. The energy difference can
be explained by steric interactions between the two bulky substituents (CF3CONH and
the TBSiO group) when both are placed in the equatorial positions as well as dipole
interactions, which are minimized in the axial/axial conformation.
To rationalize the observed stereochemical outcome, we assume that LS-Selectride
attacks (‡)-19 only from an equatorial direction on the well-accepted basis of steric-
approach control. Direct reduction of (‡)-19 to give the expected axial alcohol (see vi
in Scheme 11) must be very slow. Thus, there must be a conformational switch in the
cyclohexanone ring prior to the hydride delivery to explain the equatorial OH group in
(À)-20. The observation that the starting material is consumed after 1.5 h based on TLC
analysis, but that prolonged exposure to H2O regenerates (‡)-19, gives an indication of
a complex formed from (‡)-19 and LS-Selectride. As shown in Scheme 11, one could
envision 2 equiv. of LS-Selectride reacting with the two most acidic protons in (‡)-19
thereby generating H2 gas and complex vii, which is in equilibrium with the other chair
conformation viii. This complexation must be faster than the delivery of hydride to the
ketone, which would again generate reduction product vi. To explain the observed
formation of the equatorial alcohol (À)-20, the reactive conformation must be viii. The
delivery of hydride in expected equatorial direction leads to ix. The slowreduction
(48 h), may in part be due to the lowequilibrium concentration of viii and the slowrate
of addition of hydride to a dianionic complex. Hydrolysis of ix then affords, after ring
flipping, (À)-20 in its more favorable conformation.
Scheme 11
We also note in passing that the dissolving metal reduction (Na/NH3) also gave rise
to an unexpected outcome in the preferential formation of the axial alcohol. This result

Helvetica Chimica Acta Vol. 85 (2002)
3731
appears contrary to the dogma that would predict the thermodynamically more
favorable alcohol to be formed. However, the generation of the axial alcohol could
‡
arise as a result of internal chelation of the Na cation between the ketyl radical anion
and the TBSO O-atom, thus affording the product of thermodynamic control at the
level of the ketyl radical [35]14).
5. Conclusions. The feasibility of a bridged-mode tandem [4 ‡ 2]/[3 ‡ 2] cyclo-
addition sequence to form b-d-4-amino-2,4-dideoxycarbagulose was demonstrated. An
appropriate combination of a nitro(silyloxy)alkene 10b and chiral vinyl ether (À)-13a
were found to give the tandem cycloaddition in high yield and with excellent
stereoselectivity. The success of the synthetic route was highly dependent on the
development of suitable experimental conditions due to the highly sensitive nature of
the compounds along the path. The sequence is short (5 steps) and provides for ample
structural modification. An unexpected reduction of the protected aminocyclohex-
anone provided the equatorial alcohol with LS-Selectride. Further investigations of
more-complex dienes and dienophiles in the [4 ‡ 2] cycloaddition is currently under
investigation to explore the synthesis of more-complex aminocarbasugars.
We are grateful to the National Institutes of Health for generous financial support (R01 GM30938). M. J.
thanks the Fulbright Foundation for a fellowship.
Experimental Part
General. Solvents for extraction and chromatography were technical grade and distilled from the indicated
drying agents: hexane and CH2Cl2 (CaCl2), AcOEt (K2CO3), Et2O and tBuOMe (CaSO4/FeSO4). All solvents
utilized in reactions were distilled from appropriate drying agents before use: THFand Et2O (Na/benzophenone
(ˆsodium oxidodiphenylmethyl), benzene (CaH2), and CH2Cl2 (CaH2 or P2O5). Butyllithium and allylmagne-
sium chloride were titrated according to the method of Gilman [36]. All reactions were conducted in flame-
dried glassware under N2. Brine refers to a sat. aq. NaCl soln. Bulb-to-bulb distillations were performed on a
B¸chi GKR-50-−Kugelrohr× apparatus, with air-bath temp. corresponding to boiling points. Anal. TLC: Merck-
60 glass-backed silica-gel plates with F-254 indicator; visualization with UV light, I2, ninhydrin, Ce(SO4)2/
Mo(NH4)3/H2SO4, and phosphoromolybdic acid. Column (flash) chromatography (FC): 32 63 mm silica gel or
alumina (neutral, act. IV, basic, act. III), ca. 150 mesh, 58 ä (Aldrich). All reaction temp. were measured as
internal temp. with Teflon-coated thermocouples. M.p.: Thomas Hoover capillary melting-point apparatus;
corrected. IR Spectra: Mattson Galaxy-FTIR-5000 spectrometer; CHCl3 solns; in cmÀ1; relative intensities: s
(67 100%), m (33 67%), or w (0 33%). 1H- and 13C-NMR Spectra: Varian Unity-400 (400 MHz 1H, 100 MHz
13C), À 500 (500 MHz 1H, 125.7 MHz 13C), and Varian Unity-Inova-500 (500 MHz 1H, 125.7 MHz 13C)
spectrometers; CDCl3, (D6)benzene, (D8)toluene, (D6)acetone, or CD3OD solns. with the deuterated solvent as
an internal reference; chemical shift d in ppm, coupling constants J in Hz; assignment of 13C resonances were
supported by HMQC and/or APT; in 13C-NMR spectra, all peaks for which coupling constants are reported are
q due to C,F-coupling. MS: Varian MAT-CH-5 spectrometer, fast atom bombardment (FAB) ionization
technique; in m/z. Combustion analyses were performed by the University of Illinois Microanalytical
Laboratory.
Preparations Accordingto the Literature . (1R,2S)-2-Phenylcyclohexanol ((À)-11a) [37], (1S,2R)-2-
cumylcyclohexanol ((‡)-11b) [24], {[(1R,2S)-2-phenylcyclohexyl]oxy}ethyne ((À)-12a) [22a], {[(1S,2R)-2-(1-
methyl-1-phenylethyl)cyclohexyl]oxy}ethyne ((‡)-12b) [13a], 2-{[(1R,2S)-2-phenylcyclohexyl]oxy}penta-1,4-
diene ((À)-13a) [13a], 2-{[(1S,2R)-2-(1-methyl-1-phenylethyl)cyclohexyl]oxy}penta-1,4-diene ((‡)-13b) [13a],
potassium nitroacetaldehyde [28], 2-(benzoyloxy)-1-nitroethene (10a) [23].
(1E)-1-{[(tert-Butyl)dimethylsilyl]oxy}-2-nitroethene (10b). To a cold (À268, internal temp.) suspension of
potassium 2-nitroethen-1-olate (3.76 g, 29.6 mmol) in CH2Cl2/MeNO2 1 :1 (300 ml) was added dropwise a soln.
14
)
This analysis finds compelling precedent in the work of Eschenmoser and co-workers [35].

3732
Helvetica Chimica Acta Vol. 85 (2002)
of (tert-butyl)dimethylsilyl chloride (4.46 g, 29.6 mmol) in CH2Cl2 (50 ml). The mixture was allowed to warm to
r.t. over 3 h, during which time the white-grey soln. turned slightly yellow. The salts were filtered off with a
Schlenk filtration apparatus, and the solvents were evaporated. The crude product was purified by distillation:
3.89 g (81%) of 10b [38]. Light yellowliquid, which turned solid at À 258 in the drybox freezer. B.p. 77 788/
0.15 Torr. 1H-NMR (500 MHz, CDCl3): 8.13 (d, J ˆ 10.5, 1 H); 7.03 (d, J ˆ 10.5, 1 H); 0.94 (s, tBuSi); 0.29
(s, Me2Si).
(1E)-1-Nitro-2-[(triisopropylsilyl)oxy]ethene (10c). To a cold (À 308) suspension of potassium 2-nitro-
ethen-1-olate (1.00 g, 7.87 mmol) in CH2Cl2/MeNO2 1:1 (100 ml) was added dropwise a soln. of triisopropylsilyl
chloride (1.73 ml, 8.06 mmol, 1.0 equiv.) in CH2Cl2 (40 ml). The mixture was allowed to warm to r.t. over 4 h.
The salts were filtered off, and the solvents were evaporated. The crude product was purified by −Kugelrohr×
distillation and subjected to high vacuum (0.3 0.4 Torr) for 12 h at r.t. to give 0.50 g (81%) of 10c. Light yellow
1
liquid. B.p. 120 1508 (air-bath temp.)/0.3 0.4 Torr. H-NMR (400 MHz, CDCl3): 8.20 (d, J ˆ 10.5, 1 H); 7.05
(d, J ˆ 10.5, 1 H); 1.2 1.3 (m, (Me2CH)3Si); 1.10 (d, J ˆ 7.1, ( Me2CH)3Si). 13C NMR (100 MHz, CDCl3): 158.30;
128.43; 17.55 (Me2CH)3Si); 11.84 ((Me2CH)3Si).
(4S,6R)-4-{[(tert-Butyl)dimethylsilyl]oxy}-5,6-dihydro-6-{[(1'R,2'S)-2'-phenylcyclohexyl]oxy}-6-(prop-2''-
enyl)-4H-1,2-oxazine 2-Oxide ((À)-14ab). SnCl4 (4.76 ml, 40.7 mmol, 2.0 equiv.) was added dropwise to a cold
(À 748) soln. of 10b (4.14 g, 20.4 mmol) in toluene (500 ml), and the mixture was stirred for 5 min. A cold
(À 748) soln. of (À)-13a (7.40 g, 30.5 mmol, 1.5 equiv.) in toluene (100 ml) was added via cannula. The yellow-
brown mixture was stirred for 1.5 h at À 748 and then quenched at À 748 with 1m Et3N in MeOH (173 ml,
173 mmol, 8.5 equiv.). The mixture was stirred for 15 min at À 748, then poured into Et2O (3 l) and sat. aq.
NaHCO3 soln. (400 ml). The org. phase was washed with sat. aq. NaHCO3 soln. (3 Â 400 ml), and the aq. phases
were back-extracted with Et2O (300 ml). The combined org. phase was washed with brine (400 ml), dried
(Na2SO4), and evaporated and the yellowoil purified by FC (silica, hexane/AcOEt/Et 3N 90 :9 :1): 8.37 g (92%)
of (À)-14ab. Recrystallization (hexane/AcOEt 5 :1) gave 7.73 g (85%) of a single stereoisomer of anal. pure (À)-
14ab. Colorless crystals. M.p. 114 1168 (hexane/AcOEt 5 :1). Rf (hexane/AcOEt/Et3N 4 :1 :0.05) 0.44. [a]D
ˆ
À156.68 (CDCl3, c ˆ 2.78). IR (CHCl3): 3008m, 2933s, 2859s, 1633s, 1492w, 1463w, 1450w, 1371w, 1253m, 1120s,
1
1078s, 1006s, 836s. H-NMR (500 MHz, CDCl3): 7.32 (t, J ˆ 7.35, 2 Ho); 7.24 7.18 (m, 2 Hm, Hp); 5.75 (ddt, J ˆ
17.09, 10.13, 7.08, HÀC(2'')); 5.18 (dd, J ˆ 10.13, 1.8, 1 HÀC(3'')); 5.15 (dd, J ˆ 17.09, 1.8, 1 HÀC(3'')); 5.04
(dd, J ˆ 2.31, 0.98, 1 HÀC(3)); 4.19 (dt, J ˆ 10.01, 4.28, HÀC(1')); 3.73 (ddd, J ˆ 10.25, 7.08, 2.32, HÀC(4));
2.64 2.54 (m, 2 HÀC(1'')); 2.54 2.48 (m, HÀC(2')); 2.26 (d, J ˆ 10.25, 1 HÀC(6')); 1.98 (ddd, J ˆ 13.18, 7.08,
1.1, 1 HÀC(5)); 1.85 (br. s, 1 HÀC(5')); 1.82 (br. s, 1 HÀC(3')); 1.75, (d, J ˆ 12.57, 1 HÀC(4')); 1.59 (dq, J ˆ
12.70, 4.15, 1 HÀC(3')); 1.51 1.37 (m, 1 HÀC(5), 1 HÀC(5'), 1 HÀC(6')); 1.31 (m, 1 HÀC(4')); 0.82
(s, tBuSi); 0.01 (s, 1 MeSi); 0.00 (s, 1 MeSi). 13C-NMR (125.7 MHz, CDCl3): 144.53 (Cipso); 131.42 (C(2''));
128.39 (Co)); 127.48 (Cm)); 126.24 (Cp); 119.80 (C(3'')); 113.79 (C(3)); 105.48 (C(6)); 75.19 (C(1')); 62.15 (C(4));
52.10 (C(2')); 42.69 (C(1'')); 35.74 (C(5)); 35.57 (C(6')); 34.60 (C(5')); 25.81 (C(4')); 25.55 (Me3CSi); 25.05
‡
(C(3')); 17.74 (Me3CSi); À4.65 (MeSi); À 4.83 (MeSi). FAB-MS (pos.): 446.2 ([M ‡ 1] ). Anal. Calc. for
C25H39NO4Si (445.63): C 67.38, H 8.82, N 3.14; found: C 67.42, H 9.09, N 3.30.
(1R,6S,7S,8S)-8-{[(tert-Butyl)dimethylsilyl]oxy}-1-{[(1'R,2'S)-2'-phenylcyclohexyl]oxy}-2,4-dioxa-3-aza-
tricyclo[4.3.1.03.7]decane (15ab). A soln. of nitronate (À)-14ab (1.5 g, 3.38 mmol, 1 equiv.) in toluene (350 ml)
was placed in a flask (1 l) containing vacuum-dried (0.1 Torr, 1 h) NaHCO3 (1.99 g, 23.6 mmol, 7 equiv.). The
flask was lowered into a 1188 oil bath, and the contents were stirred for 1 h under reflux. The solvent was
evaporated and the residue purified by FC (basic alumina (act. III), hexane/AcOEt 9 :1; the tubes for collecting
fractions contained ca. 50 mg of NaHCO3) to yield 1.33 g (89%) of 15ab. White foam. Rf (hexane/AcOEt 4 :1,
basic alumina) 0.76. IR (CHCl3): 3060w, 3060w, 2929s, 2886s, 2856s, 2273w, 1602w, 1492w, 1492m, 1450s, 1359s,
‡
1321s, 1257s. FAB-MS (pos.): 446.2 ([M ‡ 1] ). 1H-NMR (500 MHz, (D8)toluene): 7.27 (t, J ˆ 7.00, 2 Hm); 7.21
7.17 (m, 2 Ho, Hp)); 4.31 (ddd, J ˆ 9.28, 4.27, 1.95, HÀC(8)); 3.71 (m, CH2(5), HÀC(1')); 3.03 (t, J ˆ 4.03,
HÀC(7)); 2.62 (m, 1 HÀC(6')); 2.53 (ddd, J ˆ 3.66, 10.13, 12.82, HÀC(2')); 2.47 (m, HÀC(6)); 1.99 (dd, J ˆ
13.18, 9.77, 1 HÀC(10)); 1.86 (m, 1 HÀC(3')); 1.81 1.73 (m, 1 HÀC(5'), 1 HÀC(9)); 1.72 1.65
(m, 1 HÀC(10), 1 HÀC(4')); 1.64 1.54 (m, 1 HÀC(6'), HÀC(3')); 1.41 (qt, J ˆ 13.20, 3.5, 1 HÀC(5')); 1.24
(qt, J ˆ 12.8, 3.54, 1 HÀC(4')); 0.96 (s, tBuSi); 0.01 (s, 1 MeSi); 0.00 (s, 1 MeSi). 13C-NMR (125.7 MHz,
(D8)toluene): 144.85 (Cipso); 128.99 (Cm); 128.03 (Co); 126.54 (Cp); 96.66 (C(1)); 77.87, 76.65 (C(5), C(1')); 68.35
(C(8)); 63.75 (C(7)); 51.28 (C(6)); 41.06 (C(10)); 36.42 (C(6')); 34.50 (C(2')); 32.30 (C(3')); 26.20, 25.84 (C(5×),
C(9)); 25.80 (Me3CSi); 25.50 (C(4')); 18.00 (Me3CSi); À 4.60 (MeSi); À 4.80 (MeSi).
(3S,4S,5S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-5-(hydroxymethyl)-4-(2,2,2-trifluoroacetamido)cyclohexa-
none ((‡)-19). A soln. of 15ab (800 mg, 1.80 mmol, 1 equiv.) in MeOH (60 ml) was added to a flask (100 ml)
containing K2CO3 (16.6 mg, 0.12 mmol) and Raney-Ni (2.09 g, 30.5 mmol, 17 equiv.), which had been washed

Helvetica Chimica Acta Vol. 85 (2002)
3733
with anh. MeOH (5 Â 50 ml) prior to use. The mixture was vigorously stirred under H2 (1 atm) for 2.5 h. The
Raney-Ni was filtered off and washed with MeOH (10 Â 50 ml) and the combined org. phase concentrated to a
volume of 60 ml of MeOH at 08. The MeOH soln. of the amino ketone was then transferred to a 2-neck flask.
N,N-Dimethylpyridine-4-amine (12.7 mg, 0.104 mmol, 0.1 equiv.) and ethyl trifluoroacetate (0.37 ml,
3.12 mmol, 3 equiv.) were added. The resulting mixture was stirred for 2 h and then evaporated to leave a
slightly yellow-green oil. Purification of the oil by FC (hexane/AcOEt 70 :30) and subsequent recrystallization
from CH2Cl2 afforded 465 mg (70%) of anal. pure (‡)-19. M.p. 91 928 (CH2Cl2). Rf (hexane/AcOEt 2 :3) 0.47.
[a]D ˆ 5.3 (CHCl3, c ˆ 1.61). IR: 3615w, 3434m, 3357w, 3010w, 2954s, 2931s, 2886m, 2858m, 1722s, 1536m, 1471m,
1361m, 1338m, 1257s, 1230m, 1170s, 1112m, 1031m. 1H-NMR (500 MHz, CDCl3): 7.86 (br. s, NH); 4.69 (dt, J ˆ
4.7, 3.5, HÀC(3)); 4.12 (q, J ˆ 4.7, HÀC(4)); 3.97 (ddd, J ˆ 10.74, 3.76, 2.56, 1 H, CH2OH); 3.82 (ddd, J ˆ 10.74,
5.25, 3.78, 1 H, CH2OH); 2.75 (m, HÀC(5)); 2.62 (m, 1 HÀC(2), 1 HÀC(6)); 2.41 (m, 1 HÀC(2), 1 HÀC(6));
2.01 (t, J ˆ 3.78, OH); 0.89 (s, tBuSi); 0.14 (s, 1 MeSi); 0.12 (s, 1 MeSi). 13C-NMR (125.7 MHz, CDCl3): 207.66
(C(1)); 158.48 (q, J ˆ 37.28, CˆO); 115.95 (q, J ˆ 288.15, CF3); 69.17 (C(3)); 64.69 (CH2OH); 55.87 (C(4));
45.41 (C(6)); 39.83(C(2)); 35.46 (C(5)); 25.81 (Me3CSi); 18.04 (Me3CSi); À 4.70 (MeSi); À 4.84 (MeSi). FAB-
‡
MS (pos.): 370.1 ([M ‡ 1] ). Anal. calc. for C15H26F3NO4Si (369.45): C 48.76, H 7.09, N 3.80; found: C 48.88, H
7.31, N 3.93.
(1S,2S,3S,5R)-3-{[(tert-Butyl)dimethylsilyl]oxy}-5-hydroxy-2-(2,2,2-trifluoroacetamido)cyclohexanemeth-
anol ((À)-20). A cold (À 748) soln. of 1m LS-Selectride in THF (8.0 ml, 8 equiv.) in THF (15 ml) was transferred
via cannula into a cold (À 748) soln. of (‡)-19 in THF (30 ml), and the soln. was stirred for 48 h at À 748. The
reaction was quenched at À 748 with glycerol/buffer (pH 7) 1:1 (20 ml). Then the mixture was warmed to r.t.
and stirred for 2 h further. The mixture was poured into sat. aq. NaHCO3 soln. (120 ml) and extracted with
AcOEt (4 Â 80 ml). The combined org. phases were washed with brine (80 ml), dried (Na2SO4), and
evaporated. Purification of the residue by gradient column chromatography (silica gel, hexane/AcOEt 4 :1
(250 ml), 3 :2 (250 ml), 1:1 (250 ml), and 2 :3 (250 ml)) afforded 292 mg (79%) of a transparent oil that
crystallized upon cooling to À 788. Recrystallization from CHCl3 yielded 259 mg (70%) of (À)-20. Colorless
powder. M.p. 60 618 (CHCl3). Rf (hexane/AcOEt 2 :3) 0.20. [a]D ˆ À14.1 (MeOH, c ˆ 4.73). IR (CHCl3):
3627w, 3432w, 3342w, 3029w (br.), 2956m, 2931m, 2886w, 2859m, 2360w, 2341w, 1722s, 1542m, 1471w, 1257m,
1230m, 1176s, 1120m, 1097m. 1H-NMR (500 MHz, CDCl3): 7.01 (br. s, NH); 4.27 (m, HÀC(3)); 4.13 (tq, J ˆ
9.40, 4.64, HÀC(5)); 3.96 (m, HÀC(2)); 3.75 3.63 (m, CH2OH); 2.52 (br. s, CH2OH); 2.36 (m, HÀC(1));
1.93 1.80 (m, HeÀC(4), HeÀC(6), HOÀC(5)); 1.55 (ddd, J ˆ 12.82, 9.64, 2.44, HaÀC(6)); 1.44 (q, J ˆ 11.51,
HaÀC(4)); 0.91 (s, tBuSi); 0.14 (s, MeSi); 0.12 (s, MeSi). 13C-NMR (125.7 MHz, CDCl3): 158.19 (q, J ˆ 37.28,
COCF3); 116.00 (q, J ˆ 288.15, COCF3); 67.56 (C(3)); 65.35 (C(5)); 64.08 (CH2OH); 53.97 (C(2)); 38.30
(C(6)); 34.96 (C(1)); 33.06 (C(4)); 25.56 (Me3CSi); 17.76 (Me3CSi); À 5.00 (MeSi), À 5.15 (MeSi). FAB-MS
‡
(pos.): 372.1 ([M ‡ 1] ). Anal. calc. for C15H28F3NO4Si (371.47): C 48.50, H 7.60, N 3.77; found: C 48.21, H 7.63,
N 3.84.
(4S*,6R*)-5,6-Dihydro-6-{[(1'R*,2'S*)-2'-phenylcyclohexyl]oxy}-6-(prop-2''-enyl)-4-[(triisopropylsilyl)oxy]-
4H-1,2-oxazine 2-Oxide (14ac). SnCl4 (0.38 ml, 3.28 mmol, 2.0 equiv.) was added dropwise to a cold (À 748) soln.
of 10c (402 mg, 1.64 mmol) in toluene (40 ml), and the mixture was stirred for 5 min. A cold (À 748) soln. of (Æ)-
13a (583 mg, 2.41 mmol, 1.5 equiv.) in toluene (10 ml) was added via cannula. The yellow-brown mixture was
stirred for 1.5 h at À 748 and then quenched at À 748 with 1m Et3N in MeOH (16 ml, 16 mmol, 9.8 equiv.). The
mixture was stirred for 5 min and then poured into Et2O (350 ml) and sat. aq. NaHCO3 soln. (100 ml). The aq.
phase was back-extracted with Et2O (3 Â 75 ml). The combined org. phase was washed with brine (75 ml), dried
(Na2SO4), and evaporated and the residue purified by radial chromatography with a chromatotron (silica gel,
hexane/AcOEt/Et3N 90 :9 :1): 441 mg (55%) of one diastereoisomer of 14ac and 126 mg (16%) of another
diastereoisomer contaminated with impurities. Major diastereoisomer: Rf (hexane/AcOEt/Et3N 4 :1:0.05)0.49.
1H-NMR (500 MHz, CDCl3): 7.34 (t, J ˆ 6.99, 2 Hm); 7.29 7.21 (m, 2 Ho, Hp); 5.75 (ddt, J ˆ 17.00, 10.00, 7.50,
HÀC(8)); 5.18 (m, 2 HÀC(3''), HÀC(3)); 4.20 (dt, J ˆ 10.00, 4.00, HÀC(1')); 3.90 (ddd, J ˆ 9.50, 7.00, 2.50,
HÀC(4)); 2.64 (dd, J ˆ 14.50, 7.50, 1 HÀC(1'')); 2.55 (dd, J ˆ 9.00, 7.50, 1 HÀC(1'')); 2.54 2.42 (m, HÀC(2'));
2.26 (d, J ˆ 9.5, 1 HÀC(6')); 2.06 (dd, J ˆ 13.00, 6.50, 1 HÀC(5)); 1.85 (br. s, 1 HÀC(5')); 1.82 (br.
s, 1 HÀC(3')); 1.74 (d, J ˆ 12.50, 1 HÀC(4')); 1.62 1.35 (m, 1 HÀC(3'), 1 HÀC(5), 1 HÀC(5'), 1 HÀC(6'),
(Me2CH3Si); 1.31 (m, 1 HÀC(4')); 1.01 (d, 18 H, (Me2CH)3Si). 13C-NMR (125.7 MHz, CDCl3): 144.48; 131.51;
128.40; 127.38; 126.13; 119.72; 113.91; 105.47 (C(1)); 75.07 (C(1')); 62.24 (C(4)); 52.10 (C(2')); 42.65 (C(1''));
36.03 (C(5)); 35.55 (C(6')); 34.77 (C(5')); 25.82 (C(4')); 25.05 (C(3')); 17.91 (Me2CH)3Si); 17.86 (Me2CH)3Si);
11.96 ((Me2CH)3Si).
(1R*,6S*,7S*,8S*)-1-{[(1'R*,2'S*)-2'-Phenylcyclohexyl]oxy}-8-[(triisopropylsilyl)oxy]-2,4-dioxa-3-azatri-
cyclo[4.3.1.03.7]decane (15ac). A soln. of the major diastereoisomer of 14ac (220 mg, 0.45 mmol) in toluene

3734
Helvetica Chimica Acta Vol. 85 (2002)
(10 ml) was added dropwise via syringe pump within 8 h to a flask (100 ml) containing vacuum-dried (0.1 Torr,
1 h) NaHCO3 (265 mg, 3.16 mmol, 7 equiv.) in xylenes (40 ml) under reflux. After complete addition, the
mixture was stirred for an additional 10 h, then cooled to r.t., filtered through a cotton plug into a flask (250 ml)
containing NaHCO3 (50 mg), and then evaporated. The residue was purified by FC (basic alumina (act. III),
hexane/tBuOMe 4 :1; all fraction tubes contained ca. 50 mg of NaHCO3): 107 mg (49%) of 15ac. Colorless foam.
Rf (hexane/AcOEt 4 :1, basic alumina) 0.78. 1H-NMR (500 MHz, (D8)toluene): 7.30 7.10 (m, 5 arom. H); 4.45
(dd, J ˆ 9.00, 4.50, HÀC(8)); 3.75 (m, CH2(5), HÀC(1')); 3.19 (t, J ˆ 4.00, HÀC(8)); 2.68 (m, 1 HÀC(6'));
2.58 2.52 (m, HÀC(2'), HÀC(6)); 2.05 (dd, J ˆ 13.50, 9.50, 1 HÀC(10)); 1.86 (m, 1 HÀC(3')); 1.81 1.55
(m, 1 HÀC(9), 1 HÀC(3'), 1 HÀC(4'), 1 HÀC(5'), 1 HÀC(8), 1 HÀC(6')); 1.41 1.35 (m, 1 HÀC(5')); 1.26
1.22 (m, 1 HÀC(4'×)); 1.06 (d, J ˆ 7.00, (Me2CH)3Si); 0.98 (sept., J ˆ 7.00, (Me2CH)3Si).
(3R*,4R*,5R*)-5-[(Acetyloxy)methyl]-4-(2,2,2-trifluoroacetamido)-3-(triisopropylsilyloxy)cyclohexanone
(17). A soln. of 15ac (160 mg, 0.328 mmol, 1 equiv.) in MeOH (10 ml) was added to K2CO3 (5 mg, 0.036 mmol)
and Raney-Ni (327 mg, 5.58 mmol, 17 equiv.), which had been washed with anh. MeOH (3 Â 10 ml) prior to use.
The mixture was vigorously stirred under H2 (1 atm) for 80 min. The Raney-Ni was washed with MeOH (10 Â
50 ml) and the combined org. phase evaporated. The amino ketone 16 was then dissolved in Ac2O (10 ml) and
pyridine (15 ml), and the soln. was stirred at r.t. for 14 h. AcOEt (100 ml) was added, the mixture washed with
sat. aq. NaHCO3 soln. (4 Â 30 ml) and brine (30 ml), the org. phase dried (Na2SO4) and evaporated, and the
1
residue purified by FC (hexane/AcOEt 70 :30): 24 mg (15%) of 17. H-NMR (CDCl3, 500 MHz): 6.14 (d, J ˆ
7.93, NH); 4.45 (q, J ˆ 3.65, HÀC(3)); 4.33 (dt, J ˆ 7.93, 3.90, HÀ(4)); 4.09 (dd, J ˆ 7.29, 11.80, 1 H,
OCH2ÀC(5)); 3.99 (dd, J ˆ 11.15, 6.00, 1 H, OCH2ÀC(5)); 2.99 2.91 (m, HÀC(5)); 2.60 (dd, J ˆ 14.79, 3.22,
HeÀC(6)); 2.45 (d, J ˆ 14.79, HaÀC(6)); 2.39 (dd, J ˆ 15.01, 4.72, HeÀC(4)); 2.18 (dd, J ˆ 15.01, 13.29,
HaÀC(4)); 2.04 (s, 1 COMe)); 2.03 (s, 1 COMe); 1.08 1.02 (m, (Me2CH)3Si). 13C-NMR (125.7 MHz, CDCl3):
207.21 (C(1)); 170.86 (COMe); 170.35 (COMe); 70.80 (C(3)); 64.69 (OCH2ÀC(5)); 50.27 (C(4)); 45.21 (C(6));
39.45 (C(2)); 33.64 (C(5)); 23.33 (COMe); 20.76 (COMe); 17.88 ((Me2CH)3Si); 11.98 ((Me2CH)3Si).
(4S*,6R*)-4-(Benzoyloxy)-5,6-dihydro-6-{[(1'R*,2'S*)-2'-phenylcyclohexyl]oxy}-6-(prop-2''-enyl)-4H-1,2-
oxazine 2-Oxide (14aa). SnCl4 (0.19 ml, 1.6 mmol, 2.0 equiv.) was added dropwise to a cold (À 788) soln. of 10a
(154.6 mg, 0.80 mmol; dried at 0.1 Torr for 1.5 h) in toluene (20 ml), and the mixture was stirred for 5 min. A
cold (À 788) soln. of (Æ)-13a (291 mg, 1.20 mmol, 1.5 equiv.) in toluene (5 ml) was added via cannula. The
yellow-brown mixture was stirred for 25 min at À 788 and then quenched at À 788 with 1m Et3N in MeOH
(7.5 ml, 7.5 mmol, 9.4 equiv.). The mixture was stirred for 5 10 min and then poured into tBuOMe (200 ml) and
sat. aq. NaHCO3 soln. (50 ml). The aq. phase was extracted with tBuOMe (2 Â 75 ml). The combined org. phase
was washed with brine (2 Â 75 ml), dried (Na2SO4), filtered through a plug of Celite, and evaporated.
Purification of the residue by radial chromatography (silica gel, hexane/AcOEt/Et3N 90 :9 :1) afforded 203 mg
(58%) and 69.3 mg (20%) of two diastereomeric nitronates 14aa1 and 14aa2, resp., both contaminated with
chiral auxiliary (Æ)-11a.
Data of 14aa1: 1H-NMR (500 MHz, CDCl3): 7.96 (d, J ˆ 8.06, 2 Ho(Bz)); 7.59 (t, J ˆ 7.45, Hp(Ph)); 7.45
(t, J ˆ 8.06, 2 Hm(Bz)); 7.38 (t, J ˆ 7.45, 2 Hm(Ph)); 7.32 (d, J ˆ 6.96, 2 Ho(Ph)); 7.25 (t, J ˆ 7.32, Hp(Bz)); 5.79
(ddt, J ˆ 17.02, 10.25, 7.08, HÀC(2'')); 5.19 (dd, J ˆ 10.25, 1.01, 1 HÀC(3'')); 5.17 (dd, J ˆ 17.02, 1.01,
1 HÀC(3'')); 5.16 (d, J ˆ 2.56, HÀC(3)); 5.11 (ddd, J ˆ 10.13, 4.76, 2.56, HÀC(4)); 4.19 (dt, J ˆ 10.25, 4.00,
HÀC(1')); 2.70 2.57 (m, CH2(1''), HÀC(2')); 2.39 (dd, J ˆ 13.06, 7.32, 1 H); 2.28 (dd, J ˆ 12.21, 3.30, 1 H);
1.93 1.84 (m, 2 H); 1.82 1.75 (m, 1 H); 1.73 1.63 (m, 2 H); 1.60 1.28 (m, 3 H).
Data of 14aa2: 1H-NMR (500 MHz, CDCl3): 8.03 (dd, J ˆ 8.42, 1.34, 2 Ho(Bz)); 7.62 (dt, J ˆ 7.45, 1.34, 1 H);
7.47 (t, J ˆ 7.75, 2 H); 7.40 7.22 (m, 7 H); 6.51 (dd, J ˆ 2.81, 0.98, HÀC(3)); 5.96 (ddd, J ˆ 10.13, 7.32, 2.81,
HÀC(4)); 5.25 5.14 (m, HÀC(2'')); 4.95 (d, J ˆ 10.13, 1 HÀC(3'')); 4.73 (d, J ˆ 17.09, 1 HÀC(3'')); 3.87
(dt, J ˆ 10.01, 4.64, HÀC(1')); 2.72 1.31 (m, 12 H).
4-(Benzoyloxy)-5,6-dihydro-6-{[(1'S,2'R)-2'-(1-methyl-1-phenylethyl)cyclohexyl]oxy}-6-(prop-2''enyl)-
4H-1,2-oxazine 2-Oxide (14ba). SnCl4 (0.09 ml, 0.80 mmol, 2.0 equiv.) was added dropwise to a cold (À 748)
soln. of 10a (77.26 mg, 0.40 mmol, 1 equiv.) in toluene (10 ml), and the mixture was stirred for 5 min. A cold
(À 748) soln. of (‡)-13b (341 mg, 1.2 mmol, 3 equiv.) in toluene (2.5 ml) was added via cannula. The yellow-
brown mixture was stirred for 3 h at À 748 and then quenched at À 748 with 1m Et3N in MeOH (4 ml, 4 mmol,
10 equiv.). The mixture was stirred for 5 10 min and then poured into Et2O (200 ml) and sat. aq. NaHCO3
solution (50 ml). The aq. phase was extracted with Et2O (3 Â 75 ml), the combined org. phase washed with brine
(75 ml), dried (Na2SO4), filtered through a plug of Celite, and evaporated. 1H-NMR: diastereoisomer ratio 9 :2.
Purification of the residue by FC (silica gel, hexane/AcOEt/Et3N 83.3 :16 :0.6) afforded 45 mg (24%) of 14ba1
1
and 38 mg of another diastereoisomer 14ba2 contaminated with an unidentified by-product. 14ba1: H-NMR
(500 MHz, CDCl3): 8.01 (dd, J ˆ 8.30, 1.22, 2 Ho(Bz)); 7.61 (tt, J ˆ 7.57, 1.22, Hp(Bz)); 7.47 (t, J ˆ 7.81, 2 Hm(Bz));

Helvetica Chimica Acta Vol. 85 (2002)
3735
7.35 (dd, J ˆ 8.55, 1.46, 2 Hm(Ph)); 7.29 (t, J ˆ 8.30, 2 Ho(Ph)); 7.04 (t, J ˆ 7.08, Hp(Ph)); 6.43 (d, J ˆ 2.44,
HÀC(3)); 5.75 (dddd, J ˆ 16.80, 10.40, 9.20, 5.60, 1 HÀC(2'')); 5.21 (d, J ˆ 9.77, 1 HÀC(3'')); 5.17 (d, J ˆ 17.09,
1 HÀC(3'')); 5.03 (ddd, J ˆ 10.50, 7.81, 2.93, HÀC(4)); 3.88 (dt, J ˆ 9.28, 3.66, HÀC(1')); 2.78 (dd, J ˆ 14.16,
5.37, 1 H); 2.41 (dd, J ˆ 11.94, 3.42, 1 H); 2.18 (dd, J ˆ 14.16, 3.30, 1 H); 1.85 (d, J ˆ 10.01, 1 H); 1.83 (d, J ˆ
10.01, 1 H); 1.76 1.68 (m, 3 H); 1.38 (s, 1 Me); 1.36 1.14 (m, 7 H).
8-(Benzoyloxy)-1-{[(1'S,2'R)-2'-(1-methyl-1-phenylethyl)cyclohexyl]oxy}-2,4-dioxa-3-azatricyclo[4.3.1.03.7]-
decane (15ba1). A soln. of nitronate 14ba1 (45 mg, 0.094 mmol, 1 equiv.) in xylenes (5 ml) was added dropwise
via syringe pump within 1 h to NaHCO3 (55.4 mg, 0.66 mmol, 7 equiv.) and 40 ml of xylenes under reflux. After
complete addition, the mixture was stirred for an additional 1 h and then cooled to r.t. The mixture was filtered
through a cotton plug into a flask containing 50 mg of NaHCO3 and was evaporated. The residue was purified by
FC (basic alumina (act. III), hexane/tBuOMe 1:1; all fraction tubes contained ca. 50 mg of NaHCO3): 6.9 mg
1
(15%) of 15ba1. White foam. H-NMR (500 MHz, (D8)toluene): 7.99 (d, J ˆ 8.42, 2 Ho(Bz)); 7.31 (t, J ˆ 8.42,
1 Hp(Bz)); 7.20 7.16 (m, 2 Hm(Bz)); 7.12 7.01 (m, 5 H); 5.59 (br. d, J ˆ 11.60, HÀC(8)); 3.72 (dt, J ˆ 9.40, 3.91,
HÀC(1')); 3.59 (d, J ˆ 6.84, HÀC(5)); 3.54 (t, J ˆ 5.75, 1 HÀC(5)); 3.13 (t, J ˆ 3.91, HÀC(7)); 2.22 (ddd, J ˆ
13.67, 10.01, 3.54, 1 H); 2.16 (dt, J ˆ 9.64, 4.3, 1 H); 2.02 (br. d, J ˆ 13.18, 1 H); 1.92 (ddd, J ˆ 11.96, 8.67, 3.30,
1 H); 1.71 (dd, J ˆ 13.31, 9.89, 1 H); 1.52 (s, 1 Me); 1.45 1.30 (m, 4 H); 1.28 (s, 1 Me); 1.27 1.22 (m, 1 H);
1.06 0.86 (m, 2 H).
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Received June 10, 2002