Highly diastereoselective synthesis of 2-azabicyclo[2.2.1]hept-5-ene derivatives: Bronsted acid catalyzed aza-Diels-Alder reaction between cyclopentadiene and imino-acetates with two chiral auxiliaries

Article abstract of DOI:10.1016/j.tet.2011.06.097

The cycloaddition between protonated glyoxylate imines possessing two chiral auxiliaries, N-(S)- or N-(R)-1-phenylethyl and (-)-8-phenylmenthyl or (+)-8-phenylneomenthyl, and cyclopentadiene is described. The absolute configuration of all adducts formed was unequivocally assigned through NMR, specific optical rotation, and X-ray data of appropriated derivatives. Experimental results confirm the highly exo-selectivity for these aza-Diels-Alder reactions, single adducts being obtained from combinations of (8PM)-(R-PEA) and (8PNM)-(S-PEA).

Full text of DOI:10.1016/j.tet.2011.06.097

Tetrahedron 67 (2011) 7162e7172
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Tetrahedron
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Highly diastereoselective synthesis of 2-azabicyclo[2.2.1]hept-5-ene derivatives:
Bronsted acid catalyzed aza-DielseAlder reaction between cyclopentadiene and
imino-acetates with two chiral auxiliaries
,
b
,
b
c
Xerardo García-Mera a , Jose E. Rodríguez-Borges , M. Luísa C. Vale , Maria J. Alves
*
*
ꢀ
a
ꢀ
Departamento de Química Organica, Facultade de Farmacia, Uˇ niversidade de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
b CIQ-Departamento de Química e Bioquímica, Faculdade de Ciencias, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal
c Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The cycloaddition between protonated glyoxylate imines possessing two chiral auxiliaries, N-(S)- or
N-(R)-1-phenylethyl and (ꢀ)-8-phenylmenthyl or (þ)-8-phenylneomenthyl, and cyclopentadiene is de-
scribed. The absolute configuration of all adducts formed was unequivocally assigned through NMR,
specific optical rotation, and X-ray data of appropriated derivatives. Experimental results confirm the
highly exo-selectivity for these aza-DielseAlder reactions, single adducts being obtained from combi-
nations of (8PM)-(R-PEA) and (8PNM)-(S-PEA).
Received 28 April 2011
Received in revised form 14 June 2011
Accepted 27 June 2011
Available online 2 July 2011
Keywords:
Asymetric synthesis
Cycloadditions
Ó 2011 Elsevier Ltd. All rights reserved.
Aza-DielseAlder reaction
Induction
Chiral auxiliaries
1. Introduction
The products obtained, 2-azabicyclo[2.2.1]hept-5-enes,3 can be
used as precursors of a large variety of compounds of chemical,
The great versatility of cycloadditions, their high stereochemical
control, and the fair predictability of their regiochemistry allied to
the rapid accumulation of polyfunctionality in a relatively small
molecular framework, have contributed to the popularity of these
reactions.1 Within the diverse transformations comprising cyclo-
additions, aza-DielseAlder reactions of imine derivatives and di-
enes leading to six-membered aza-heterocycles, monocyclic and
bicyclic molecules, have attracted much interest, especially those
employing cyclopentadiene as starting material.2,3 The imines,
used as aza-dienophiles, generally require activation by an
electron-withdrawing group and a Lewis acid (LA) and/or Bronsted
acid (BA) to participate in these [4þ2] cycloaddition reactions.3 It
has been shown that the electronic nature of the substituents at the
diene/dienophile pair may strongly influence the reaction path-
ways and determine either a concerted mechanism (synchronous
or asynchronous) or a stepwise one.4 In addition, experimentalists
have always employed catalysts to change the kinetics of this class
of reactions. In particular, a wide range of homogeneous and het-
erogeneous Lewis acids have been used to improve the rate and
exo/endo selectivities of these cycloadditions.2,3
biological, and pharmaceutical interest.5,6 The products obtained in
these reactions contain a highly functionalized bridged [2.2.1] ring
system that may undergo further transformations (Scheme 1).
Oxidation of the double bond, ring opening of the vicinal-diol, re-
duction or hydrolysis of the ester functionality would lead to a great
number of chiral nonnatural amino alcohols and
a-amino acids
(pyrrolidine derivatives). Many of these ‘glycomimetics’, also called
azasugars, may show useful activity as glycosidase inhibitors7 with
application as antiviral,8 included potential nonnucleosidic in-
hibitors of HIV replication,9 antineoplastic,10 and antidiabetic
agents.8a,11 On the other hand, the sequence based on Bar-
biereWieland degradation and the cleavage of the NeC3 bond,
would lead to chiral bicyclic lactams, useful as precursors of GABA
analogs,12 and chiral amino alcohols, derived from cyclopentene
and cyclopentane, useful for the synthesis of carbocyclic nucleo-
sides with antiviral and antineoplastic properties.13
Bailey and co-workers14 investigated cycloadditions of (ꢀ)-8-
phenylmenthyl (R)- and (S)-N-1-phenylethylimino glyoxylates
with cyclopentadiene. The reaction showed high diaster-
eoselectivity when the R-1-phenylethyl group was incorporated in
the imine (>95%), and poor selectivity when the S-1-phenylethyl
group was incorporated in the imine (<49%). The absolute config-
uration of the stereoisomers obtained was not determined, but the
* Corresponding authors. E-mail addresses: xerardo.garcia@usc.es (X. García-Mera),
jrborges@fc.up.pt (J.E. Rodríguez-Borges).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.097

X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
7163
Scheme 1. 2-Azabicyclo[2.2.1]hept-5-enes as precursors of a large variety of compounds.
stereochemistry of the single product (bicycle) obtained in the case
of the imine with the R-1-phenylethyl group was assumed to be
(3S,exo), according to results obtained before by Stella and co-
workers3e with racemic methyl 1-phenylethylimine glyoxylate.
Obviously, the reaction outcomes cannot be compared, as in one
case (Bailey) 8-phenylmenthyl glyoxylate and in the other case
(Stella) methyl glyoxylate was used. In fact, and as can be confirmed
further in this paper, using 8-phenylneomenthyl glyoxylate and (R)-
1-phenylethylamine (R-PEA) three diastereoisomers were obtained.
Our reasons to re-visit these reactions were first, to confirm the
stereochemistry of these reactions for which no conclusive evi-
dences had been apported before; and second, to enlarge the scope
of these cycloadditions incorporating another menthyl chiral aux-
iliary, (þ)-8-phenylneomenthyl, instead of the virtually in-
accessible (þ)-8-phenylmenthol (w500 euro/g), providing an
alternative route to the obtention of the reverse adducts.
In a previous work on cycloadditions between chiral iminodie-
nophiles of glyoxylates of 8-phenylmenthols and cyclopentadiene,
we showed these reactions to be highly accelerated by the addition
of an LA, due to the formation of an iminium cation complex that
rapidly undergoes cycloaddition under mild conditions to give
products with high stereo exo-selectivity.3c,d,6b Herein we describe
the most efficient synthesis of all the adducts formed in the cy-
cloaddition of N-(S)- or N-(R)-1-phenylethylimines of (ꢀ)-8-
phenylmenthyl or (þ)-8-phenylneomenthyl glyoxylates, and
cyclopentadiene. The assignment of the absolute configuration of
all the adducts formed was achieved through NMR, specific optical
rotation, and X-ray data of the appropriated derivatives.
Treatment of the exo-cycloadducts 5a, 5b and the endo-cyclo-
3iek
adduct 6a with LiAlH4
afforded the corresponding amino alco-
hols 7, while allowing quantitative recovery of the chiral auxiliaries
(1a and 1b, respectively)16 with retention of configuration in all
cases. Attempts to reduce endo-cycloadduct 6b with LiAlH4 were
not successful.
The results of the aza-DielseAlder reactions are presented in
Table 1.
As can be seen, on reaction with cyclopentadiene (ꢀ)-8-
phenylmenthyl (R)-N-phenylethylimino glyoxylate (entry 1) gave
the single product 5a1 (1S,3exo) in 79% yield; (ꢀ)-8-phenylmenthyl
(S)-N-phenylethylimino glyoxylate (entry 2) gave a mixture of
products: 5a2 (1S,3exo), 25% yield; 5a3 (1R,3exo), 35% yield; 6a
(1R,3endo), 15% yield; (þ)-8-phenylneomenthyl (S)-N-phenyl-
ethylimino glyoxylate (entry 3) gave the single product 5b1
(1R,3exo) in 76% yield; (þ)-8-phenylneomenthyl (R)-N-phenyl-
ethylimino glyoxylate derivative (entry 4) gave a mixture of
cycloadducts: 5b2 (1R,3exo), 26% yield; 5b3 (1S,3exo) in 37% yield;
6b (1R,3endo) in 10% yield. Resuming, reactions of cyclopentadiene
with 3a and (R)-PEA and with 3b and (S)-PEA yielded only one
optically pure adduct (reverse adduct families (1S,3exo)- and
(1R,3exo)-2-azabicyclo[2.2.1]hept-5-enes, respectively). The other
combinations of these two reagents (3a/(S)-PEA and 3b/(R)-PEA)
led to a mixture of three diastereomeric adducts.
In an attempt to explain this outcome we present in Scheme 3
a model for the approach of diene and dienophile. Taking into ac-
count, simultaneously, polar effects (hydrogen bonding) and re-
pulsive interactions in the different conformations, the geometry
corresponding to a synesynesyn alignment3d is the one which best
explains the obtention of the single adduct (1S,3exo) with the chiral
auxiliaries 8-phenylmenthol/R-phenylethyl (attack on the si-face)
and the obtention of other single adduct (1R,3exo) with the chiral
auxiliaries 8-phenylneomenthol/S-phenylethyl (attack on the re-
face). The high exo-selectivity observed in these cases may be
explained considering that:
2. Results and discussion
(ꢀ)-8-Phenylmenthol (1a),15a and (þ)-8-phenylneomenthol
(1b),15b,c were obtained before in our laboratory in good yields,
from inexpensive (þ)-(R)-pulegone, andaretherefore non-expensive
chiral auxiliaries. Conversion of the alcohols into the corresponding
glyoxylates (3a and 3b) was achieved by reaction with acryloyl
chloride in the presence of Et3N and DMAP, followed by treatment of
the resulting acrylates (2a and 2b) with either ozone (with Me2S
quenching) or OsO4 and NaIO4.3c,15d,e Treatment of the glyoxylate (3a
or 3b) with equimolar amounts of 1-phenylethylamine (R-PEA or S-
PEA), trifluoroacetic acid (TFA), and BF3$OEt2 in DCM generated the
corresponding iminium salt (protonated imine) (4), which reacted in
situ with excess cyclopentadiene at ꢀ78 ꢁC to give the corresponding
adducts (5/6) (Scheme 2). The reaction was monitored by TLC (ali-
quots treated with NaHCO3), and the total consumption of the imine
was observed after 5 h.
* the iminium ion, which acts as dienophile in the reaction, should
have an E configuration, more stable for stereochemical (bulky
groups far apart) and polar (hydrogen bonding C]O/NꢂH)
reasons.
* in the close vicinity of the C]N bond, the 1-phenylethyl group
exerts a larger steric hindrance than the ester group.
Consequently, in order to minimize stereochemical in-
teractions (in the transition state) between the methylene group
of the diene and the bulky substituents of the dienophile, the

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X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
Scheme 2. Synthesis of 2-azabicyclo[2.2.1]hept-5-ene derivatives via cycloadducts 5 and 6. Reagents and conditions: (a) acryloyl chloride, DCM, Et3N, DMAP, 0 ꢁC; (b) (1) O3, DCM,
ꢀ78 ꢁC; (2) SMe2; (c) OsO4, NaIO4, dioxane/H2O; (d) (1) R-PEA or S-PEA, DCM, 0 ꢁC, 1 h; (2) TFA, BF3$OEt2, ꢀ78 ꢁC; (e) (1) cyclopentadiene, ꢀ78 ꢁC, 5 h; (2) NaHCO3/H2O; (f) (1)
LiAlH4, Et2O, 12 h; (2) H2O; (g) 3,5-dinitrobenzoyl chloride, DMAP, DCM; (h) OsO4, NMO, tert-butanol/THF/H2O; (i) TFA, Et2O.
approach dieneedienophile must occur in an exo manner. The
stereochemical factors are more important than the secondary
nitrogen atom in the final adduct is irrelevant, since it exists as
a tertiary amine, after work up (HCO3ꢀ), capable of undergoing
inversion of the lone pair of electrons to achieve the most stable
conformation.
orbital interactions between the
p systems of cyclopentadiene
and the ester group in the dienophile. The configuration of the

X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
7165
Table 1
The results for the aza-DielseAlder reaction between cyclopentadiene and in situ generated N-phenylethyliminoacetates of (ꢀ)-8-phenylmenthol and (þ)-8-
phenylneomenthol (ꢀ78 ꢁC, 5 h)
Entry
Glyoxylate
Phenylethylamine
Products-yielda (%)
Ph
O
O
NH2
O
H
N
O
1
Ph
P
h
O
P
h
(R)-PEA
5a1
a
3
(1S,3exo)
79
%
Ph
P
h
Ph
N
O
N
H
O
NH2
O
O
O
H
P
h
O
O
Ph
O
H
N
2
H
P
h
O
P
h
Ph
(S)-PEA
5a2
25%
5a3
35%
6a
15%
3a
Ph
O
N
O
NH2
Ph
H
O
O
3
P
h
O
P
h
(S)-PEA
5b1
3b
(1R,3exo)
76%
4
a
After chromatographic purification.
In what concerns the preference observed in the approach of the
diene to the diastereotopic faces of the dienophile, it is more dif-
ficult to suggest a hypothesis. The presence of two chiral auxiliaries
and in particular the stereochemistry of the phenylethyl group
must play an important role in the obtention of the single adducts,
since the need for coplanarity of the benzene rings and for maxi-
mum distance of bulky substituents turns one of the diastereotopic
faces much less hindered than the other. In the case of R-phenyl-
ethylamine, coplanarity of the benzene ring and maximum dis-
tance of this substituent from the phenylmenthyl group places the
methyl group of the phenylethylamine backwards to the re-face
and favors therefore highly attack from the less hindered si-face. In
the case of S-phenylethylamine a similar rationalizing explains the
preference for the re-face.
For the determination of the absolute configurations of ad-
ducts 5 and 6, the transformations outlined in Scheme 4 were
performed. Reduction with LiAlH4 of the exo-cycloadducts 5a,b
gave the four alcohols (þ)-7A, (ꢀ)-7A, (þ)-7B, (ꢀ)-7B, whose
optical rotations were determined. The absolute configuration of
adduct 5a3 (1R,3exo) was unequivocally determined from
Scheme 3. Model for the approach of diene (cyclopentadiene) and iminium cations of
corresponding imino-acetates to afford single adducts 5a1 and 5b1.

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X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
Scheme 4. Determination of the absolute configuration of adducts 5 and 6: transformations performed. aSee Scheme 2.
crystallographic data of X-ray diffraction of the corresponding
aminoalcohol (þ)-7A (1R,3exo) (Fig. 1).17 Amino alcohols 7A and
7B were transformed into the corresponding 3,5-dinitro-
benzoates (8) by reaction with 3,5-dinitrobenzoyl chloride. The
absolute configuration of adduct 5a2 (1S,3exo) was unequivocally
determined from crystallographic data of X-ray diffraction of the
corresponding 3,5-dinitrobenzoyl derivative (ꢀ)-8B (Fig. 1)18
prepared from the corresponding aminoalcohol (ꢀ)-7B
(1S,3exo). The absolute configurations of the remaining adducts,
5b1 (1R,3exo), 5b2 (1R,3exo), and 5b3 (1S,3exo), were determined
by comparison of NMR spectroscopic data (1H and 13C) and
specific rotation data of the corresponding aminoalcohol de-
rivatives, (þ)-7A, (þ)-7B, and (ꢀ)-7A, respectively, with the
values obtained for their enantiomers (configuration determined
by X-ray). Dihydroxylation of endo-cycloadduct 6a with OsO4 in
the presence of N-methylmorpholine-N-oxide yielded diol 9 as
crystals suitable for X-ray analysis (Fig. 1).19 In the case of endo-
adduct 6b (1S,3endo), the absolute configuration was un-
equivocally determined from crystallographic data of X-ray dif-
fraction of the corresponding ammonium trifluoroacetate 10
(1S,3endo) (Fig. 1).20
3. Conclusions
The results obtained illustrate the utility of (ꢀ)-8-phenylmenthol
and (þ)-8-phenylneomenthol (used instead of virtually inaccessible
(þ)-8-phenylmenthol) as easily recoverable stereo controlling
auxiliaries, affording optically pure 3-functionalized 2-azabicyclo
[2.2.1]hept-5-enes from aza-DielseAlder reaction between cyclo-
pentadiene and chiral protonated phenylethylimines, formed from
the corresponding (R)- or (S)-phenylethylamine and the glyoxylates of
these alcohols. For the combination of the auxiliaries N-(S)-phenyl-
ethyl/8-phenylmenthyl and N-(R)-phenylethyl/8-phenylneomenthyl,
the reaction yielded three diastereomers, (1R,3exo)-5a3, (1S,3exo)-
5a2, (1R,3endo)-6a (2.3:1.7:1) and (1S,3exo)-5b3, (1S,3exo)-5b2,
(1S,3endo)-6b (3.7:2.6:1), respectively. However, when N-(R)-phe-
nylethyl/8-phenylmenthyl and N-(S)-phenylethyl/8-phenylneo-
menthyl were used in combination, only a single diastereomeric ad-
duct was obtained, (1S,3exo)-5a1 (79%) and (1R,3exo)-5b1 (76%), re-
spectively. We have unambiguously the absolute configuration of all
the adducts assigned, using NMR, specific optical rotation and X-ray
data of the appropriated derivatives (amino alcohols 7, 3,5-
dinitrobenzoates 8, diol 9, and ammonium trifluoroacetate 10).

X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
7167
Fig. 1. X-ray single crystal structures of compounds (þ)-7A,17 (ꢀ)-8B,18 (ꢀ)-9,19 and (þ)-10.20
4. Experimental
26 mmol), and DMAP (227 mg, 1.81 mmol) in dry DCM (60 mL) at
0 ꢁC. The mixture was stirred for 2 h at rt and was then treated with
saturated NaHCO3 solution (125 mL) and extracted with DCM
(3ꢄ100 mL). The pooled organic layers were washed with saturated
NaHCO3 solution (2ꢄ100 mL) and brine (100 mL), and were then
dried with Na2SO4. The solvent was removed in a rotary evaporator,
and purification of the resulting residue on a short column of silica
gel using Et2O/EtOAc 9:1 as eluent afforded the corresponding ac-
rylate as a yellow oil.
4.1. General methods
All reactions were carried out under anhydrous conditions.
Solvents were dried according to standard procedures and distilled
prior to use. All reagents were commercially available and used
without further purification, unless otherwise stated. Flash column
ꢁ
chromatography was performed on silica gel (60 A, 230e240 mesh)
and analytical thin-layer chromatography (TLC) on pre-coated silica
gel 60 F254 plates using iodine vapor and/or UV light (254 nm) for
visualization. Melting points were determined on an electrother-
mal melting point apparatus and are uncorrected. Infrared spectra
were recorded on FT/IR spectrophotometers and main bands are
given in cmꢀ1. The 1H NMR (300 MHz or 400 MHz) and 13C NMR
(75.47 MHz) spectra were recorded using CDCl3 as solvent and are
reported in parts per million downfield from TMS. Optical rotations
were measured on a conventional thermostated polarimeter using
4.2.1. (ꢀ)-(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclo-
hexyl acrylate (2a)15e. Yield: 97%. ½a 2D5
ꢃ
ꢀ9.5 (c 1, CHCl3). 1H NMR
(300 MHz, CDCl3):
d
¼0.89 (d, 3H, J 6.6 Hz, 50-CH3), 0.80e1.2 (m, 3H,
menthyl), 1.25 (s, 3H, 80-CH3), 1.34 (s, 3H, 80-CH3), 1.38e1.59 (m, 1H,
menthyl), 1.60e1.74 (m, 2H, menthyl), 1.76e1.96 (m, 2H, menthyl),
1.97e2.35 (m, 2H, menthyl), 4.90 (dt, 1H, Jt 10.7 Hz, Jd 4.3 Hz, H10),
5.55e5.65 (m, 2H, H2þH3a), 6.02e6.11 (dd, 1H, J 13.9, 5.0 Hz, H3b),
7.10e7.14 (m, 1H, Ph), 7.23e7.30 (m, 4H, Ph). 13C NMR (CDCl3):
a t
a sodium lamp and are reported as follows: ½ ꢃD (c in g per 100 mL,
d
¼22.2 (50-CH3), 25.8 (80-CH3), 27.0 (C40), 28.0 (80-CH3), 31.7 (C50),
0
solvent). Elementary analyses were obtained on a microanalyser
apparatus.
35.0 (C30), 40.1 (C8q ), 42.0 (C60), 50.9 (C20), 75.0 (C10), 125.4 (C4Ph),
126.4 (C3PhþC5Ph), 128.4 (C2PhþC6Ph), 129.3 (C2), 130.3 (C3), 152.0
(C1Ph), 165.8 (C(O)O). IR (NaCl):
n
¼2954, 2924, 1740, 1719, 1634,
4.2. General procedure for the synthesis of acrylates
(2a,b)3c,15d,e
1457, 1405, 1371, 1270, 1181, 1131, 1048, 984, 809, 700 cmꢀ1. Anal.
Calcd for C19H26O2: C, 79.67; H, 9.15; found: C, 79.53; H, 9.41.
A solution of acryloyl chloride (2.10 mL, 25.8 mmol) in dry DCM
(40 mL) was added dropwise under argon to a solution of 8-
phenylmenthol (1a or 1b) (3.00 g, 12.9 mmol), Et3N (3.6 mL;
4.2.2. (þ)-(1S,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclo-
hexyl acrylate (2b). Yield: 95%. ½a D25
ꢃ
þ53.1 (c 1, CHCl3). 1H NMR
(300 MHz, CDCl3):
d
¼0.82 (d, 3H, J 6.6 Hz, 50-CH3), 0.85e1.10 (m, 2H,

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X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
neomenthyl),1.33 [s, 6H, 80-(CH3)2],1.46e1.67 (m, 4H, neomenthyl),
1.67e1.80 (m, 1H, neomenthyl), 1.86e1.99 (m, 1H, neomenthyl),
5.15 (br s, 1H, H10), 5.80 (dd, 1H, Jcis 10.4 Hz, Jgem 1.6 Hz, H3E), 6.07
(dd, 1H, Jtrans 17.3 Hz, Jcis 10.4 Hz, H2), 6.34 (dd, 1H, Jtrans 17.3 Hz, Jgem
1.6 Hz, H3Z), 7.10e7.22 (m, 1H, Ph), 7.25e7.30 (m, 4H, Ph). 13C NMR
1.50e1.93 (m, 6H, phenylneomenthyl), 4.85e5.15 (m, 1H, H10),
7.14e7.19 (m, 1H, Ph), 7.24e7.28 (m, 4H, Ph), 9.17 (s, 1H, CHO). 13C
NMR (CDCl3):
d
¼22.4 (50-CH3), 22.7 (C40), 26.3 (C50), 27.1 (80-CH3),
27.7 (80-CH3), 35.6 (C30), 40.3 (C60), 40.4 (C80), 51.6 (C20), 74.6 (C10),
126.2(C4Ph), 126.37 (C2PhþC6Ph), 128.61 (C3PhþC5Ph), 148.78 (C1Ph),
(CDCl3):
d
¼22.4 (50-CH3), 22.8 (C40), 26.5, 27.0 and 27.3 (80-CH3,
159.19 (C(O)O),184.53 (HC]O). IR (NaCl):
n
¼3445, 2948,1733,1601,
C50), 35.7 (C30), 40.2 (C60), 40.4 (C8q ), 51.7 (C20), 71.9 (C10), 126.0
1496, 1456, 1404, 1371, 1219, 1096, 918, 836, 760, 700 cmꢀ1. Anal.
Calcd for C18H24O3: C, 74.97; H, 8.39; found: C, 75.15; H, 8.21.
Compound (3a or 3b) was converted into the corresponding 2,4-
dinitrophenylhydrazone derivative, by the usual procedure.21
A solution of 2,4-dinitrophenylhydrazine (82 mg, 0.42 mmol)
and H2SO4 (0.2 mL) in absolute MeOH was added to a solution of
the glyoxylate and its hydrate (100 mg, approx. 0.3467 mmol) in the
minimum quantity of MeOH, at rt. The solid obtained was isolated
by filtration and recrystallized from absolute MeOH, yielding
a yellow solid (0.145 g), which was identified as the corresponding
2,4-dinitrophenylhydrazone.
0
(C4Ph), 126.4 (C2PhþC6Ph), 128.4 (C3PhþC5Ph), 129.8 (C2), 130.5 (C3),
149.9 (C1Ph), 165.6 (C(O)O). IR (NaCl):
n
¼2948, 1718, 1636, 1496,
1456, 1404, 1369, 1270, 1197, 1147, 1047, 984, 810, 760, 700 cmꢀ1
.
Anal. Calcd for C19H26O2: C, 79.67; H, 9.15; found: C, 79.85; H, 9.23.
4.3. General procedure for the synthesis of glyoxylates
(3a,b)3c,15d,e
Method A. A vigorously stirred solution of acrylate (2a or 2b)
(3.20 g, 11.1 mmol) in 140 mL of MeOH/DCM 4:1 at ꢀ78 ꢁC was
bubbled for 20 min with ozone at a rate of 6 g/h in a 60 L/h current
of O2 (as specified by manufactures of the Fischer Mod. 503 ozone
apparatus). Me2S (2 mL), was added and stirring was continued
under argon for a further 12 h, time after which the solvent was
evaporated and the residue extracted with DCM (3ꢄ100 mL). The
pooled organic layers were washed with water (100 mL) and brine
(100 mL) and dried over Na2SO4. Removal of the solvent in a rotary
evaporator afforded a yellow oil, which was purified on a short
column of silica gel using hexane/EtOAc 3:1 as eluent yielding the
corresponding glyoxylate as a mixture of the glyoxylate and its
hydrate, which was used without further purification.
4.3.3. 2,4-Dinitrophenylhydrazone of (ꢀ)-8-phenylmenthyl glyoxy-
late (3a-2,4-DNP)21. Yield 89%. Mp 159e162 ꢁC (MeOH). ½a 2D5
ꢀ17.5
ꢃ
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼0.91 (d, 3H, J 6.5 Hz, 50-
CH3), 0.95e1.17 (m, 2H, phenylmenthyl), 1.12 (s, 3H, 80-CH3), 1.32 (s,
3H, 80-CH3), 1.49e1.60 (m, 2H, phenylmenthyl), 1.70e1.78 (m, 1H,
phenylmenthyl), 1.91e1.97 (m, 2H, phenylmenthyl), 2.18 (td, 1H, Jt
11.4 Hz, Jd 3.4 Hz, phenylmenthyl), 5.03 (td, 1H, Jt 10.7 Hz, Jd 4.4 Hz,
H10), 6.07 (s, 1H, CH]N), 7.06e7.11 (m, 1H, Ph), 7.19e7.29 (m, 4H,
Ph), 8.04 (d, 1H, J 9.5 Hz, H6DNP), 8.38 (dd, 1H, J 9.5, 2.6 Hz, H5DNP),
9.15 (d, 1H, J 2.6 Hz, H3DNP), 14.08 (s, 1H, NH). IR (KBr):
n
¼3272,
Method B. A mixture of acrylate (2a or 2b) (2.35 g, 8.205 mmol),
OsO4 (20.8 mg, 10 mequiv), water (9 mL), and dioxane (30 mL) was
stirred at rt for 5 min, time during which the mixture became dark
brown. Then NaIO4 (3.51 g, 2 equiv) was added in portions over
30 min, and the mixture (now pale brown) was stirred at rt for
another 2 h and then extracted thoroughly with Et2O. The com-
bined organic extracts were dried (Na2SO4) and concentrated,
affording a yellow oil that upon filtration through a short column of
silica gel using hexane/EtOAc 3:1 as eluent afforded corresponding
glyoxylate as a mixture of the glyoxylate and its hydrate, which was
used without further purification. After heating a small sample for
2965, 1687, 1618, 1596, 1570, 1423, 1336, 1310, 1215, 1139, 1085,
1052, 920, 871, 834, 763, 742, 700 cmꢀ1. Anal. Calcd for C24H28N4O6:
C, 61.53; H, 6.02; N, 11.96; found: C, 61.46; H, 6.18; N, 12.02.
4.3.4. 2,4-Dinitrophenylhydrazone of (þ)-8-phenylneomenthyl
glyoxylate (3b-2,4-DNP)3c. Yield 90%. Mp 105e108 ꢁC (MeOH).
½
a 2D5
ꢃ
þ35 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3):
¼0.84 (d, 3H, J
d
6.5 Hz, 5-CH3), 0.90e1.28 (m, 2H, phenylneomenthyl), 1.39 (s, 6H,
80-(CH3)2), 1.55e1.85 (m, 5H, phenylneomenthyl),1.90e2.05 (m, 1H,
phenylneomenthyl), 5.10 (br s, 1H, H10), 6.87 (s, 1H, CH]N),
7.10e7.23 (m, 1H, Ph), 7.26e7.30 (m, 4H, Ph), 8.12 (d, 1H, J 9.5 Hz,
H6DNP), 8.44 (dd, 1H, J 9.5, 2.6 Hz, H5DNP), 9.15 (d, 1H, J 2.6 Hz,
2 h at 50 ꢁC under reduced pressure (10ꢀ3 mmHg), the 1H and 13
C
NMR spectra showed it to be essentially (>85%) the anhydrous
form of the corresponding glyoxylate.
H3DNP), 14.40 (s, 1H, NH). 13C NMR (300 MHz, CDCl3):
d
¼22.3 (50-
CH3), 22.7 (C40), 26.5 (C50), 27.3 (80-CH3), 27.7 (80-CH3), 35.6 (C30),
40.0 (C60), 40.4 (C80), 51.6 (C20), 74.0 (C10), 118.1 (C6DNP), 123.4
(C3DNP), 126.0 (C4Ph), 126.3 (C2PhþC6Ph), 126.4 (C5DNP), 128.5
(C3PhþC5Ph),131.6 (C2DNP),137.3 (C4DNP),140.6 (C1DNP),144.4 (CH]
4.3.1. (ꢀ)-(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclo-
hexyl glyoxylate (3a). Yield: 97% (method A). Yield: 98% (method B).
An analytical sample of the mono-hydrate was obtained by re-
crystallization from hexane.
N), 149.3 (C1Ph), 161.8 (C(O)O). IR (KBr):
n¼3292, 3106, 2949, 1718,
1654, 1619, 1583, 1506, 1424, 1324, 1269, 1212, 1138, 1097, 918, 834,
758, 742, 701 cmꢀ1. Anal. Calcd for C24H28N4O6: C, 61.53; H, 6.02; N,
11.96; found: C, 61.37; H, 6.18; N, 12.17.
4.3.1.1. (ꢀ)-(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cy-
clohexyl glyoxylate hydrate. Mp 146e148 ꢁC (hexane). 1H NMR
(300 MHz, CDCl3):
d
¼0.85 (d, 3H, J 6.4 Hz, 50-CH3), 0.97e1.18 (m, 2H,
4.4. General procedure for aza-DielseAlder reaction
phenylmenthyl), 1.30 (s, 3H, 80-CH3), 1.38 (s, 3H, 80-CH3), 1.40e1.70
(m, 5H, phenylmenthyl), 1.81e2.21 (m, 3H, phenyl-
menthylþC(OH)2), 4.87 (dt, 1H, Jt 10.7 Hz, Jd 4.4 Hz, H10), 7.10e7.15
4.4.1. (ꢀ)-(1R,2S,5R)-8-Phenylmenthyl (1S,3S,4R)-2-[(1R)-1-
phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (5a1)6. A
solution of (R)-1-phenylethylamine (1.86 mL, 1.70 g, 14.0 mmol) in
dry DCM (10 mL) was added dropwise under argon to a stirred
suspension of (ꢀ)-8-phenylmenthyl glyoxylate (3a) (4.04 g, ca.
(m, 1H, Ph), 7.23e7.29 (m, 4H, Ph). 13C NMR (CDCl3):
d¼22.1, 25.4,
28.1, 29.2, 31.7, 34.8, 40.6, 41.6 (C80), 50.9 (C20), 77.5 (C1PM), 125.8
(C4Ph), 126.1 (C2PhþC6Ph), 128.4 (C3PhþC5Ph), 150.6 (C1Ph), 159.9
ꢁ
(CH(OH)2), 162.9 [C(O)O]. IR (NaCl):
n
¼3464, 2955, 2924, 2870,
14.0 mmol) and 3 A molecular sieves (10 g) in dry DCM (50 mL) at
1732, 1497, 1389, 1370, 1289, 1227, 1094, 980, 766, 702 cmꢀ1. Anal.
Calcd for C18H26O4: C, 70.56; H, 8.55; found: C, 70.79; H, 8.33.
0
ꢁC. The reaction mixture was stirred for 1 h and then cooled to
ꢀ78 ꢁC and treated successively with TFA (1.08 mL, 1.60 g,
14.0 mmol), BF3$OEt2 (1.77 mL, 1.99 g, 14.0 mmol), and freshly
distilled cyclopentadiene (2.3 mL, ca. 28 mmol). After 5 h a mixture
of saturated aqueous NaHCO3 solution (28 mL) and then solid
NaHCO3 (3.3 g) were added. The reaction mixture was allowed to
reach rt and filtered through a pad of Celite. The two layers were
separated and the aqueous layer was extracted with DCM
4.3.2. (þ)-(1S,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclo-
hexyl glyoxylate (3b) (mixture of glyoxylate/hydrate). Yield: 96%
(method A). Yield: 98% (method B). ½a D25
ꢃ
þ36 (c 1, CHCl3). 1H NMR
(300 MHz, CDCl3):
d
¼0.82 (d, 3H, J 6.4 Hz, 50-CH3), 0.88e1.27 (m,
2H, phenylneomenthyl), 1.34 (s, 3H, 80-CH3), 1.35 (s, 3H, 80-CH3),

X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
7169
0
0
(3ꢄ100 mL). The aqueous layer was extracted with DCM
(3ꢄ100 mL). The pooled organic layers were washed with saturated
NaHCO3 solution (3ꢄ100 mL) and brine (100 mL) and dried
(Na2SO4). Removal of the solvent on a rotavap yielded an orange oil,
which was purified by column chromatography (silica gel) using
hexane/AcOEt 3:1 as eluent. Fractions 7e10 (Rf 0.6.) afforded
a colorless oil (5.09 g) identified as the pure single adduct (1R,3exo)
3H, 80-CH3), 1.45e1.70 (m, 3H, H3b þH4b þH50), 1.61 (d, 1H, J 8.4 Hz,
H7syn), 2.01 (s, 1H, H3endo), 1.90e2.15 (m, 2H, H20þH6b ), 2.86 (s, 1H,
0
H4), 2.95 (q, 1H, J 6.5 Hz, CHCH3Ph), 3.48 (d, 1H, J 1.3 Hz, H1), 4.85
(dt,1H, J 10.6, 4.3 Hz, H10), 5.98 (dd,1H, J 5.54, 1.82 Hz, H6), 6.28 (dd,
1H, J 5.54, 2.31 Hz, H5), 7.17e7.41 (m, 10H, Ph). 13C NMR (CDCl3):
d
¼22.3 (50-CH3), 24.6 (CH3CHPh), 26.9 (80-CH3), 27.29 (C40), 27.31
(80-CH3), 31.7 (C50), 35.1 (C30), 40.4 (C80), 41.95 (C60), 46.2 (C7), 49.7
(C4), 50.7 (C20), 63.7 (CHPh), 64.0 (C1), 64.9 (C3), 75.4 (C10), 125.6,
125.9, 127.4, 128.1, 128.4 and 128.7 (CHPh), 134.1 (C6), 136.2 (C5),
0
(5a1). Yield 79%. ½a D25
ꢃ
ꢀ66.5 (c 1, CHCl3). 1H NMR (300 MHz, CDCl3):
0
0
0
d
¼0.67 (s, 3H, 80-CH3), 0.65e0.90 (m, 3H, H3a þH6a þH4a ), 0.81 (0d,
3H, J 6.3 Hz, 50-CH3), 0.89 (s, 3H, 80-CH3), 1.11e1.27 (m, 1H, H3b ),
1.37 (d, 3H, J 6.5 Hz, CHCH3Ph), 1.28e1.37 (m, 2H, H7antiþH50),
1.38e1.51 (m, 1H, H40b), 1.70e1.79 (m, 1H, H20), 1.80e1.93 (m, 2H,
145.6 (C1PheC8 ), 152.0 (C1PheCH), 173.7 [C(O)O]. IR (NaCl):
n¼3059,
2954, 1742, 1600, 1495, 1454, 1371, 1323, 1285, 1243, 1171, 1109,
1094, 1052, 1007, 918, 839, 765, 730, 700 cmꢀ1. Anal. Calcd for
C31H39NO2: C, 81.36; H, 8.59; N, 3.06; found: C, 81.27; H, 8.65;
N, 3.09.
0
H7synþH6b ), 1.99 (s, 1H, H3endo), 2.80 (br s, 1H, H4), 3.03 (q, 1H, J
6.5 Hz, CHCH3Ph), 4.29 (br s, 1H, H1), 4.50 (dt, 1H, J 10.6, 4.2 Hz,
H10), 6.28 (dd, 1H, J 5.6, 1.4 Hz, H6), 6.35 (dd, 1H, J 5.6, 2.9 Hz, H5),
7.00 (d, 2H, J 7.4 Hz, H2PhþH6Ph), 7.01e7.38 (m, 6H, Ph), 7.37 (d, 2H, J
(1R,3exo) (5a3): Rf 0.25; 4.82 g (35%). ½a D25
ꢃ
þ85.3 (c 1, CHCl3). 1H
0
NMR (300 MHz, CDCl3):
d
¼0.55e0.75 0(m, 1H, H3a ), 0.78 (d, 3H, J
7.2 Hz, H2PhCHþH6PhCH). 13C NMR (CDCl3):
d
¼22.2 (50-CH3), 23.8
6.2 Hz, 50-CH3), 0.81e0.99 (m, 2H, H4a þH6a ), 1.14 (s, 3H, 80-CH3),
0
(CH3CHPh), 24.8 (80-CH3), 27.3 (C30), 28.4 (80-CH3), 31.5 (C50), 35.0
(C40), 40.1 (C80), 41.6 (C60), 45.7 (C7), 49.9 (C4), 50.9 (C20), 63.6
(CHPh), 64.4 (C1), 65.6 (C3), 75.1 (C10), 125.2, 125.8, 127.5, 128.1,
1.25 (s, 3H, 80-CH3), 1.35 (d, 3H, J 6.5 Hz, CHCH3Ph), 1.20e1.44 (m,
4H, H4b þH7synþH50þH3b ), 1.45e1.55 (m, 1H, H20), 1.65e1.80 (m,
0
0
0
1H, H6b ), 1.82 (s, 1H, H3endo), 2.12 (d, 1H, J 8.3 Hz, H7syn), 2.69 (s, 1H,
0
128.3 and 128.7 (CHPh), 133.9 (C6), 136.4 (C5), 145.4 (C1PheC8 ), 151.9
H4), 2.91 (q, 1H, J 6.5 Hz, CH(CH3)Ph), 4.25 (br s, 1H, H1), 4.47 (dt,
(C1PheCH), 172.9 [C(O)O]. IR (NaCl): 3086, 3059, 2954, 2870, 1741
(CO), 1600,1564, 1494, 1454, 1371, 1347,1325,1289,1244,1219,1191,
1169, 1108, 1078, 1059, 1032, 1009, 982 cmꢀ1. Anal. Calcd for
C31H39NO2: C, 81.36; H, 8.59; N, 3.06; found: C, 81.15; H, 8.62;
N, 2.99.
1H, J 10.6, 4.1 Hz, H10), 6.23 (dd, 1H, J 5.5, 1.5 Hz, H6), 6.32 (dd, 1H, J
5.6, 2.9 Hz, H5), 7.12e7.29 (m, 10H, Ph). 13C NMR (CDCl3):
d
¼22.1
(50-CH3), 23.0 (CH3CHPh), 26.6 (80-CH3), 27.2 (C40), 27.9 (80-CH3),
31.4 (C30), 34.9 (C50), 40.3 (C80), 41.40 (C60), 45.53 (C7), 48.7 (C4),
50.0 (C20), 63.0 (CH3CHPh), 64.3 (C1), 65.2 (C3), 75.3 (C10), 125.4,
125.9, 127.5, 128.3, 128.4 and 128.7 (CHPh), 133.6 (C6), 136.6 (C5),
0
4.4.2. (þ)-(1S,2S,5R)-8-Phenylmenthyl (1R,3R,4S)-2-[(1S)-1-
phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate
(5b1). Following the same procedure as above, using (S)-1-
phenylethylamine (1.88 g, 15.5 mmol) and (þ)-8-pheny-
lneomenthyl glyoxylate (3b) (4.47 g, ca. 15.5 mmol). Flash chro-
matography of the crude product (hexane/EtOAc 1:1) afforded
a colorless oil (5.39 g) identified as pure single adduct (1S,3exo)
145.6 (C1PheC8 ), 151.8 (C1PheCH), 173.8 [C(O)O]. IR (NaCl):
n
¼3058,
2955,1739,1600,1493,1453,1371,1323,1290,1247,1167,1107,1055,
1031, 1009, 917, 838, 763, 699 cmꢀ1. Anal. Calcd for C31H39NO2: C,
81.36; H, 8.59; N, 3.06; found: C, 81.29; H, 8.64; N, 3.10.
(1R,3endo) (6a): Rf 0.4; 2.07 g (15%). ½a D25
ꢃ
ꢀ50.5 (c 1, CHCl3). 1H
NMR (300 MHz, CDCl3):0d¼0.87 (d, 3H, J 6.5 Hz, 50-CH3), 0.75e0.99
0
0
0
(m, 3H, H3a þH3a þH4a ), 1.00e1.26 (m, 1H, H6a ), 1.23 (s, 3H, 80-
CH3), 1,28 (d, 1H, J 8.3 Hz, H7anti), 1.34 (d, 3H, J 6.5 Hz, CHCH3Ph),
1.35 (s, 3H, 80-CH3), 1.54 (d, 1H, J 8.3 Hz, H7syn), 1.51e1.52 (m, 2H,
(5b1). Yield 76%; Rf 0.7. ½a D23
ꢃ
þ53.2 (c 1, CHCl3). 1H NMR (400 MHz,
CDCl3):
d
¼0.77 (s, 3H, 80-CH3), 0.80 (d, 3H, J 6.5 Hz, 50-CH3), 0.90 (s,
3H, 80-CH3), 0.70e0.98 (m, 2H, H4a þH6a ), 1.13e1.19 (m, 1H, H500),
H4b þH50), 1.88e1.99 (m, 1H, H20), 2.05e2.13 (m, 1H, H6b ), 2.90 (br
s, 1H, H4), 3.36e3.52 (m, 3H, H3exoþH1þCHCH3Ph), 4.70 (dt, 1H, Jt
10.54 Hz, Jd 4.2 Hz, H10), 5.96 (dd, 1H, J 5.52, 2.58 Hz, H5), 6.28 (dd,
1H, J 5.52, 2.91 Hz, H6), 7.17e7.42 (m, 10H, Ph). 13C NMR (CDCl3):
0
0
0
0
1.42 (d, 3H, J 6.5 Hz, CHCH3Ph),1.25e1.49 (m, 3H, H7antiþH20þH4b ),
1.50e1.71 (m, 2H, H30), 1.75e1.86 (m, 1H, H6b ), 2.0 (d, 1H, J 8.4 Hz,
0
H7syn), 2.34 (br s, 1H, H3endo), 2.93 (br s, 1H, H4), 3.10 (q, J 6.5 Hz,1H,
CHCH3Ph), 4.36 (br s, 1H, H1), 4.98 (br s, 1H, H10), 6.35 (dd, 1H, J 5.6,
1.7 Hz, H5), 6.47e6.51 (m, 1H, H6), 7.12e7.41 (m, 10H, Ph). 13C NMR
d
¼22.3 (50-CH3), 24.9 (CHCH3Ph), 25.7 (80-CH3), 27.0 (C40), 28.3 (80-
CH3), 31.6 (C50), 35.1 (C30), 40.1 (C80), 41.9 (C60), 44.70 (C7), 48.4
(C4), 50.8 (C20), 64.1 (CHPh), 64.8 (C1), 65.2 (C3), 75.0 (C10), 125.3,
125.8, 127.3, 127.9, 128.4 and 128.8 (CHPh), 134.9 (C5), 139.2 (C6),
(CDCl3):
d
¼22.0 (C40), 22.1 (50-CH3), 23.2 (C50), 23.9 (CH3CHPh), 27.0
(80-CH3), 27.1 (80-CH3), 35.3 (C30), 39.6 (two, C80þC60), 45.4 (C7),
49.6 (C4), 50.9 (C20), 63.1 (C1), 64.1 (CHPh), 65.5 (C3), 70.7 (C10),
125.3,126.0,127.2,127.8 (double) and 128.4 (CHPh),133.6 (C6),135.9
0
146.7 (C1PheC8 ), 152.60 (C1PheCH), 172.78 [C(O)O]. IR (NaCl):
n
¼3059, 2953, 1734, 1600, 1495, 1455, 1370, 1323, 1244, 1172, 1094,
(C5), 145.0 (C1PheC8 ), 150.5 (C1PheCH), 172.5 [C(O)O]. IR (NaCl):
1052, 1007, 910, 839, 765, 730, 700 cmꢀ1. Anal. Calcd for C31H39NO2:
C, 81.36; H, 8.59; N, 3.06; found: C, 81.40; H, 8.63; N, 3.11.
0
2949, 1737 (CO), 1493, 1450, 1379, 1323, 1245, 1219, 1191, 1168, 1148,
1109, 1079, 1061, 1033, 1009, 918, 833 cmꢀ1. Anal. Calcd for
C31H39NO2: C, 81.36; H, 8.59; N, 3.06; found: C, 81.18; H, 8.61; N,
3.04.
4.4.4. (þ)-(1S,2S,5R)-8-Phenylneomenthyl (1R,3R,4S)-2-[(1R)-1-
phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate
(5b2),
(ꢀ)-(1S,2S,5R)-8-phenylneomenthyl (1S,3S,4R)-2-[(1R)-1-
phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (5b3), and
(þ)-(1S,2S,5R)-8-phenylneomenthyl (1S,3R,4R)-2-[(1R)-1-
phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate
(6b). Following the same procedure as above, using (R)-1-
phenylethylamine (3.67 g, 30.3 mmol) and (ꢀ)-8-phenylne-
omenthyl glyoxylate (3b) (8.74 g, ca. 30.3 mmol). Flash chroma-
tography of the crude product (hexane/EtOAc 8:1) afforded three
pure compounds (73% global).
4.4.3. (ꢀ)-(1R,2S,5R)-8-Phenylmenthyl (1S,3S,4R)-2-[(1S)-1-
phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate
(5a2),
(þ)-(1R,2S,5R)-8-phenylmenthyl (1R,3R,4S)-2-[(1S)-1-phenylethyl]-
2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (5a3), and (ꢀ)-(1R,2S,-
5R)-8-phenylmenthyl (1R,3S,4S)-2-[(1S)-1-phenylethyl]-2-azabicyclo
[2.2.1]hept-5-ene-3-carboxylate (6a). Following the same pro-
cedure as above, using (S)-1-phenylethylamine (3.65 g, 30.1 mmol)
and (ꢀ)-8-phenylmenthyl glyoxylate (3a) (8.69 g, ca. 30.1 mmol).
Flash chromatography of the crude product (hexane/EtOAc 10:1)
afforded three pure compounds (75% global).
(1R,3exo) (5b2): Rf 0.5; 3.60 g (26%). ½a D23
ꢃ
þ35.2 (c 1, CHCl3). 1H
NMR (400 MHz, CDCl3):
d
¼0.89 (d, 3H, J 6.4 Hz, 50-CH3), 0.85e0.99
(1S,3exo) (5a2): Rf 0.6; 3.44 g (25%). ½a D25
ꢃ
ꢀ100.7 (c 1, CHCl3). 1H
(m, 1H, H3a ), 1.00e1.15 (m, 1H, H6a ), 1.25 (d, 1H, J 8.0 Hz, H7anti),
1.29 (d, 3H, 6.4 Hz, CHCH3Ph), 1.38 (s, 3H, 80-CH3)0, 1.39 (s, 3H, 80-
CH3), 1.27e1.43 (m, 1H, H50), 1.48e1.58 (m, 1H, H4a ), 1.59e1.87 (m,
0
0
NMR (300 MHz, CDCl3):
d
¼0.88 (d, 3H, J 6.4 Hz, 50-CH3), 0.83e0.93
0
0
0
(m, 1H, H3a ), 0.94e1.12 (m, 2H, H6a þH4a ), 1.13 (d, 1H, J 8.4 Hz,
0
0
H7anti), 1.23 (d, 3H, J 6.5 Hz, CHCH3Ph), 1.26 (s, 3H, 80-CH3), 1.38 (s,
3H, H20þH4b þH3b ), 1.90 (d, 1H, J 8.0 Hz, H7syn), 1.92e2.05 (m, 1H,

7170
X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
0
H6b ), 2.48 (br s, 1H, H3endo), 3.10 (q, 1H, J 6.4 Hz, CH(CH3)Ph), 3.13
(br s, 1H, H4), 3.57 (br s, 1H, H1), 5.13 (br s, 1H, H10), 6.07 (dd, 1H, J
5.6, 2.0 Hz, H5), 6.46 (dd, 1H, J 4.4, 3.2 Hz, H6), 7.18e7.40 (m, 10H,
1H, H5), 6.43 (br s, 1H, H6), 7.15e7.70 (m, 10H, Ph), 9.36 (br s, 1H,
NH). 13C NMR (DMSO-d6):
d
¼18.3 (CH3CHPh), 21.7 (C40), 21.8 (50-
CH3), 24.7 (80-CH3), 26.7 (C50), 27.8 (80-CH3), 34.4 (C30), 38.7 (C60),
38.79e40.15 (DMSO, C80), 45.0 (C7), 47.2 (C4), 49.4 (C20), 65.7
(CHPh), 66.2 (C3), 69.9 (C1), 74.5 (C10), 125.4 (CF3COO), 125.66,
125.73, 125.80, 126.54, 126.68, 128.06, 128.42, 128.46, 128.74 and
Ph). 13C NMR (CDCl3):
d
¼22.1 (50-CH3), 22.5 (C40), 24.3 (CH3CHPh),
26.2 (80-CH3), 26.3 (80-CH3), 27.0 (C50), 35.4 (C30), 39.9 (C60), 40.0
(C80), 45.9 (C7), 49.3 (C4), 51.2 (C20), 63.4 (C1), 63.5 (CHPh), 65.0
(C3), 71.7 (C10), 125.6, 125.9, 127.0, 127.5, 128.0 and 128.3 (CHPh),
0
129.07 (CHPh), 135.5 (C1PheC8 ), 136.2 (C6), 139.7 (C5), 136.2 (C6),
0
133.8 (C6), 135.9 (C5), 145.3 (C1PheC8 ), 149.8 (C1PheCH), 173.6 [C(O)
149.6 (C1PheCH), 169.6 [C(O)O], 184.4 [CF3C(O)O].
O]. IR (NaCl): 2924, 2869, 1738, 1716, 1662, 1600, 1449, 1370, 1276,
1245, 1218, 1169, 1147, 1109, 1080, 1032, 1005, 973, 919, 809 cmꢀ1
.
4.5. General procedure for reduction of cycloadducts
Anal. Calcd for C31H39NO2: C, 81.36; H, 8.59; N, 3.06; found: C,
81.42; H, 8.66; N, 3.10.
4.5.1. (ꢀ)-(1S,3S,4R)-2-[(1R)-1-Phenylethyl]-2-azabicyclo[2.2.1]
hept-5-en-3-yl]methanol [(ꢀ)-7A] from 5a16. A solution of 5a1
(1.70 g; 3.71 mmol) in dry Et2O (10 mL) was added dropwise under
argon to a suspension of LiAlH4 (ca. 6 equiv; 0.85 g; 22.3 mmol) in
dry Et2O (10 mL) at 0 ꢁC. The reaction mixture was stirred for 12 h at
rt, and then MeOH (20 mL) and H2O (100 mL) were added dropwise
at 0 ꢁC. The resulting mixture was extracted with AcOEt (4ꢄ100 mL)
and the pooled organic layers were washed with brine (100 mL)
and dried with Na2SO4. Removal of the solvent in a rotary evapo-
rator left a yellow oil that when chromatographed on silica gel with
hexane/EtOAc 3:1 as eluent afforded the chiral auxiliary, (ꢀ)-8-
phenylmenthol (Rf 0.4; 0.84 g; 97%),16 in the early fractions and
compound 7A (Rf 0.1; 0.82 g; 96%), as white solid, in the latter ones.
(1S,3exo) (5b3): Rf 0.3; 5.13 g (37%). ½a D23
ꢃ
ꢀ15.6 (c 1, CHCl3). 1H
NMR (400 MHz, CDCl3):
d
¼0.66 (d, 3H, J 5.6 Hz, 50-CH3), 0.67e0.71
(m, 1H, H3a ), 0.71e0.77 (m, 1H, H6a ), 1.27 (s, 6H, 80-CH3), 1.29 (s,
0
0
6H, 80-CH3), 1.22e1.35 (m, 3H, H4a þH50þH6b )0, 1.41 (d, 3H, J 6.4 Hz,
0
0
CHCH3Ph), 1.36e1.48 (m, 3H, H7antiþH20þH4b ), 1.49e1.57 (m, 1H,
0
H3b ), 2.12 (d,1H, J 8.4 Hz, H7syn), 2.28 (br s,1H, H3endo), 3.06 (q,1H, J
6.4 Hz, CHCH3Ph), 3.09 (br s, 1H, H4), 4.35 (br s, 1H, H1), 4.86 (br s,
1H, H10), 6.35 (dd, 1H, J 5.6, 1.6 Hz, H6), 6.45e6.51 (m, 1H, H5),
7.14e7.35 (m,10H, Ph). 13C NMR (CDCl3):
d
¼22.0 (C40), 22.3 (50-CH3),
22.9 (CH3CHPh), 25.7 (80-CH3), 26.0 (C50), 26.5 (80-CH3), 35.2 (C30),
39.4 (C60), 39.9 (C80), 45.0 (C7), 48.6 (C4), 51.0 (C20), 62.7 (C1), 64.0
(CHPh), 65.0 (C3), 71.3 (C10), 125.5, 125.8, 127.1, 127.8, 127.93 and
127.94 (CHPh), 133.6 (C6), 135.8 (C5), 144.9 (C1PheC8 ), 149.9
Mp 110e113 ꢁC (hexane/Et2O). ½a 2D5
ꢃ
ꢀ41.81 (c 1, CHCl3). 1H NMR
0
(C1PheCH), 172.9 [C(O)O]. IR (NaCl): 2948, 1737, 1601, 1494, 1453,
1368, 1324, 1246, 1222, 1190, 1166, 1146, 1108, 1078, 1057, 1032,
1006, 964, 922, 853, 830, 810, 757cmꢀ1. Anal. Calcd for C31H39NO2:
C, 81.36; H, 8.59; N, 3.06; found: C, 81.32; H, 8.51; N, 3.12.
(300 MHz, CDCl3): 1.35 (d, 1H, J 8.5 Hz, H7anti), 1.39 (d, 3H, J 6.5 Hz,
CH3CH), 1.80 (d, 1H, J 8.5 Hz, H7syn), 1.74e1.82 (br s, 1H, H3endo),
2.70e2.77 (m, 2H, CHHOHþH4), 3.05 (q, 1H, J 6.5 Hz, CHMe),
2.99e3.08 (m, 1H, CHHOH), 4.15 (d, 1H, J 1.4 Hz, H1), 4.73 (br s, 1H,
D2O exch, OH), 6.20 (dd, J 5.6, 1.7 Hz, 1H, H6), 6.46 (m, 1H, H5),
7.19e7.31 (m, 5H, Ph). 13C NMR (CDCl3): 22.5 (CHMe), 45.3 (C7), 47.5
(C4), 63.3 (C1), 63.9 (CHMe), 64.3 (C3), 65.3 (CH2OH), 127.8, 128.2
and 128.8 (CHPh), 132.1 (C6), 138.1 (C5), 146.2 (C1PheCH). IR (KBr):
3272, 3214 (OH), 2988, 2863, 1454, 1375, 1323, 1181, 1034, 1011,
806 cmꢀ1. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11;
found: C, 78.49; H, 8.41; N, 6.02.
(1S,3endo) (6b): Rf 0.4; 1.39 g (10%). ½a D23
ꢃ
þ45.1 (c 1, CHCl3). 1H
NMR (400 MHz, CDCl3):
d
¼0.85 (d, 3H, J 6.6 Hz, 50-CH3), 0.88e0.94
0
0
(m, 1H, H3a ), 0.95e1.05 (m, 1H, H6a ), 1.39 (s, 3H, 80-CH3), 1.40 (s,
3H, 80-CH3), 1.42 (d, 3H, J 6.7 Hz, CHCH3Ph), 1.43e1.47 (m, 1H,
H7anti), 1.53e1.65 (m, 3H, H4a þH20þH50), 1.67e1.77 (m, 1H, H4b ),
0
0
0
0
1.73e1.81 (m, 2H, H3b þH7syn), 1.92e2.01 (m, 1H, H6b ), 3.46 (br s,
2H, H4þH3exo), 3.56 (br s, 1H, H1), 3.60 (q, 1H, J 6.7 Hz, CHCH3Ph),
4.93 (br s, 1H, H10), 6.08 (d, 1H, J 5.3 Hz, H5), 6.42 (dd, 1H, J 5.6,
3.0 Hz, H6), 7.17e7.45 (m, 10H, Ph). 13C NMR (CDCl3):
d
¼22.1 (50-
4.5.2. (þ)-(1R,3R,4S)-2-[(1S)-1-Phenylethyl]-2-azabicyclo[2.2.1]
hept-5-en-3-yl]methanol [(þ)-7A] from 5a3. Following the same
procedure as above, using adduct 5a3 (2.05 g, 4.48 mmol). Flash
chromatography of the crude product (hexane/EtOAc 3:1) afforded
the auxiliary, (ꢀ)-8-phenylmenthol (Rf 0.4; 1.02 g; 98%),16 in the
early fractions and compound (þ)-7A (Rf 0.1; 0.98 g; 95%), as white
CH3), 22.6 (C40), 24.7 (CH3CHPh), 26.2 (80-CH3), 26.6 (80-CH3), 27.1
(C50), 35.3 (C30), 39.6 (C60), 40.0 (C80), 44.6 (C7), 48.4 (C4), 51.1 (C20),
64.2 (C3), 64.5 (C1), 64.8 (CHPh), 71.7 (C10), 125.5, 125.6, 126.0,
126.2, 126.9, 127.4, 127.9, 128.0, 128.2 and 128.4 (CHPh), 134.5 (C5),
0
139.2 (C6), 146.2 (C1PheC8 ), 149.7 (C1PheCH), 172.4 [C(O)O]. IR
(NaCl): 2926, 1738, 1658, 1599, 1578, 1494, 1447, 1370, 1317, 1276,
1175, 1148, 1115, 1073, 1029, 1000, 941, 919, 810, 762 cmꢀ1. Anal.
Calcd for C31H39NO2: C, 81.36; H, 8.59; N, 3.06; found: C, 81.42; H,
8.64; N, 3.13.
solid, in the latter ones. Mp 110e113 ꢁC (hexane/Et2O). ½a 2D5
þ41.80
ꢃ
(c 1, CHCl3). The NMR (1H, 13C) spectra are identical to those of
compound (ꢀ)-7A. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N,
6.11; found: C, 78.51; H, 8.39; N, 6.05. Suitable crystals of
(þ)-(1R,3exo)-7A were obtained from hexane/Et2O and the struc-
ture was confirmed by the X-ray crystallographic analysis.6b,17
4.4.5. (þ)-(1S,3R,4R)-2-[(1R)-1-Phenylethyl]-3-[(1S,2S,5R)-8-
phenylneomenthyl-oxycarbonyl]-2-azabicyclo[2.2.1]hept-5-ene-2-
ammonium trifluoroacetate (10). Compound 6b was converted into
the corresponding ammonium trifluoroacetate derivative (10), by
4.5.3. (þ)-(1R,3R,4S)-2-[(1S)-1-Phenylethyl]-2-azabicyclo[2.2.1]
hept-5-en-3-yl]methanol [(þ)-7A] from 5b1. Following the same
procedure as above, using adduct 5b1 (2.00 g, 4.37 mmol). Flash
chromatography of the crude product (hexane/EtOAc 3:1) afforded
the auxiliary, (þ)-8-phenylneomenthol (Rf 0.6; 0.99 g; 98%),16 in the
early fractions and compound (þ)-7A (Rf 0.1; 0.96 g; 96%), as white
the usual procedure: A 1 M solution of TFA in dry Et2O (200 mL,
0.20 mmol) was added to a solution of amine 6b (100 mg,
0.19 mmol) in dry Et2O (10 mL), at ambient temperature. Upon slow
evaporation of the solvent a white crystalline solid precipitated.
The solid was isolated by filtration (931 mg, 85%) and identified as
the corresponding ammonium trifluoroacetate (10). Suitable crystals
of (þ)-10 were obtained and the structure was confirmed by X-ray
solid, in the latter ones. Mp 110e113 ꢁC (hexane/Et2O). ½a 2D5
þ41.82
ꢃ
(c 1, CHCl3). The NMR (1H, 13C) spectra are identical to those of
compound (ꢀ)-7A. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N,
6.11; found: C, 78.50; H, 8.38; N, 6.07.
crystallographic analysis.20 Mp 91e93 ꢁC. ½a D23
þ10.2 (c 1, DMSO).
ꢃ
1H NMR (400 MHz, DMSO-d6):
d
¼0.84 (d, 3H, J 6.5 Hz, 50-CH3),
0
0
0.83e0.89 (m, 1H, H4a ), 0.90e1.01 (m, 1H, H3a ), 1.02e1.10 (m, 1H,
4.5.4. (ꢀ)-(1S,3S,4R)-2-[(1R)-1-Phenylethyl]-2-azabicyclo[2.2.1]
hept-5-en-3-yl]methanol [(ꢀ)-7A] from 5b3. Following the same
procedure as above, using adduct 5b3 (1.02 g, 2.23 mmol). Flash
chromatography of the crude product (hexane/EtOAc 3:1) afforded
the auxiliary, (þ)-8-phenylneomenthol (Rf 0.6; 0.49 g; 95%),16 in the
H6a0), 1.28 (s, 3H, 80-CH3), 1.30 (s, 3H, 80-CH3), 1.50e1.70 (m, 6H,
0
H4b þH6b þH50þCH3CHPh), 1.71e1.83 (m, 3H, H7antiþH3b þH20),
2.29 (br s, 1H, H7syn), 3.75 (br s, 1H, H4), 4.09 (br s, 1H, H1), 4.61 (br
s, 1H, H10), 4.75 (br s, 1H, CH3CHPh), 5.08 (br s, 1H, H3exo), 6.40 (br s,
0
0

X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
7171
early fractions and compound (ꢀ)-7A (Rf 0.1; 0.49 g; 96%), as white
organic layer was dried (Na2SO4), and removal of the solvent left
a yellow oil. Flash chromatography of the crude product (hexane/
EtOAc 9:1) afforded a white solid (Rf 0.7; 1.21 g, 92%) identified as the
solid, in the later fractions. Mp 110e113 ꢁC (hexane/Et2O). ½a 2D5
ꢃ
ꢀ41.81 (c 1, CHCl3). The NMR (1H, 13C) spectra are identical to those
of compound (ꢀ)-7A. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N,
6.11; found: C, 78.52; H, 8.37; N, 6.09.
pure 3,5-dinitrobenzoate (ꢀ)-8B. Mp 127e130 ꢁC. ½a D25
ꢀ43.47 (c 1,
ꢃ
CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼1.32 (d, 1H, J 8.6 Hz, H7anti),
1.36 (d, 3H, J 6.5 Hz, CH3), 1.72 (d, 1H, J 8.5 Hz, H7syn), 2.25 (dd, 1H, J
10.0, 3.8 Hz, H3endo), 2.99 (s, 1H, H4), 3.16 (q, 1H, J 6.5 Hz, CHCH3),
3.44e3.51 (m, 1H, H1), 4.24e4.31 (t, 1H, J 11.1 Hz, CHHO), 4.86 (dd,
1H, J 11.1, 3.8 Hz, CHHO), 6.07 (dd, 1H, J 5.6,1.8 Hz, H6), 6.38 (dd,1H, J
5.0, 3.4 Hz, H5), 7.23e7.36 (m, 5H, Ph), 9.20 (d, 2H, J 2.1 Hz,
H2orthoþH6ortho), 9.24 (t, 1H, J 2.1 Hz, H4para). 13C NMR (CDCl3):
4.5.5. (ꢀ)-(1S,3S,4R)-2-[(1S)-1-Phenylethyl]-2-azabicyclo[2.2.1]
hept-5-en-3-yl]methanol [(ꢀ)-7B] from 5a2. Following the same
procedure as above, using adduct 5a2 (2.40 g, 5.24 mmol). Flash
chromatography of the crude product (hexane/EtOAc 3:1) afforded
the auxiliary, (ꢀ)-8-phenylmenthol (Rf 0.4; 1.16 g; 95%),16 in the
early fractions and compound (ꢀ)-7B (Rf 0.1; 1.13 g; 94%), as yellow
d
¼25.0 (CH3), 45.0 (C7), 46.6 (C4), 60.1 (C3), 63.4 (C1), 63.8 (CHCH3),
oil, in the latter ones. ½a D25
ꢃ
ꢀ97.50 (c 1, CHCl3). 1H NMR (300 MHz,
71.2 (CH2O), 122.8 (C4Ph), 127.4, 127.7 and 128.9 (CHPh), 129.9 (dou-
ble) (C2DNPþC6DNP), 134.2 (C5), 134.4 (C1Ph), 136.0 (C6), 145.7
CDCl3):
d
¼1.22 (d, 1H, J 8.5 Hz, H7anti),1.28 (d, 3H, J 6.5 Hz, CH3), 1.76
(d, 1H, J 8.5 Hz, H7syn), 2.04e2.07 (m, 1H, H3endo), 2.88 (br s, 1H, H4),
2.80e2.90 (br s, 1H, D2O exch, OH), 3.14 (q, 1H, J 6.5 Hz, CHCH3),
3.44 (d, 1H, J 1.2 Hz, H1), 3.69 (dd, 1H, J 10.6, 7.2 Hz, CHHOH), 3.78
(dd, 1H, J 10.6, 3.2 Hz, CHHOH), 6.04 (dd, 1H, J 5.6, 1.9 Hz, H6), 6.42
(C1DNP), 149.1 (C3DNPþC5DNP), 162.9 [C(O)O]. IR (KBr): ¼2974, 1723,
n
1684, 1653, 1629, 1541, 1457, 1343, 1280, 1169, 1136, 1074, 964, 913,
770, 729, 702 cmꢀ1. Anal. Calcd for C22H21N3O6: C, 62.41; H, 5.00; N,
9.92; found: C, 62.39; H, 4.95; N, 9.89. Suitable crystals of
(ꢀ)-(1S,3exo)-8B were obtained from hexane/Et2O and the structure
was confirmed by the X-ray crystallographic analysis.18
(m, 1H, H5), 7.22e7.36 (m, 5H, Ph). 13C NMR (CDCl3):
d¼24.6 (CH3),
45.6 (C7), 48.8 (C4), 62.7 (C1), 63.7 (CHCH3), 64.0 (C3), 66.2
(CH2OH), 127.5, 127.7 and 128.9 (CHPh), 133.5 (C6), 138.1 (C5), 145.1
(C1PheCH). IR (NaCl):
n
¼3382, 3060, 2971, 2873, 1659, 1601, 1493,
4.6.2. (þ)-(1R,3R,4S)-2-[(1S)-1-Phenylethyl]-2-azabicyclo[2.2.1]
1453, 1371, 1324, 1283, 1246, 1210, 1187, 1080, 1020, 912, 893, 831,
762, 702 cmꢀ1. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11;
found: C, 78.51; H, 8.39; N, 6.13.
hept-5-en-3-yl]methyl
3,5-dinitrobenzoate
[(þ)-8A]
from
(þ)-7A. Following the same procedure as above, using the alcohol
(þ)-7A (80 mg, 0.35 mmol). Flash chromatography of the crude
product (hexane/EtOAc 9:1) afforded compound (þ)-8A (Rf 0.7;
4.5.6. (þ)-(1R,3R,4S)-2-[(1R)-1-Phenylethyl]-2-azabicyclo[2.2.1]
hept-5-en-3-yl]methanol [(þ)-7B] from 5b2. Following the same
procedure as above, using adduct 5b2 (1.07 g, 2.34 mmol). Flash
chromatography of the crude product (hexane/EtOAc 3:1) afforded
the auxiliary, (þ)-8-phenylneomenthol (Rf 0.6; 0.52 g; 95%),16 in the
early fractions and compound (þ)-7B (Rf 0.1; 0.52 g; 96%), as yellow
135 mg; 91%), as white solid. Mp 95e98 ꢁC (pentane). ½a D25
þ3.02 (c
ꢃ
1, CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼1.40 (d, 3H, J 6.5 Hz, CH3),
1.48 (d,1H, J 8.4 Hz, 7Hanti),1.76 (d,1H, J 8.4 Hz, 7Hsyn), 2.08 (dd,1H, J
9.6, 4.1 Hz, H3endo), 2.84 (d, 1H, J 1.2 Hz, H4), 3.11 (q, 1H, J 6.5 Hz,
CHCH3), 3.72 (dd, 1H, J 11.0, 4.2 Hz, CHHO), 3.92 (dd, 1H, J 11.0,
9.9 Hz, CHHO), 4.24 (d, 1H, J 1.2 Hz, H1), 6.27 (dd, 1H, J 5.7, 1.7 Hz,
H6), 6.45 (dd, 1H, J 4.8, 3.3 Hz, H5), 7.18e7.35 (m, 5H, Ph), 9.00 (d,
2H, J 2.0 Hz, H2orthoþH6ortho), 9.18 (t, 1H, J 4.2 Hz, Jd 2.0 Hz, H4para).
oil, in the latter ones. ½a D25
ꢃ
ꢀ97.51 (c 1, CHCl3). The NMR (1H, 13C)
spectra are identical to those of compound (ꢀ)-7B. Anal. Calcd for
C15H19NO: C, 78.56; H, 8.35; N, 6.11; found: C, 78.52; H, 8.38;
N, 6.12.
13C NMR (CDCl3):
d
¼22.7 (CH3), 45.0 (C7), 45.9 (C4), 61.8 (C3), 63.5
(C1), 63.8 (CHCH3), 70.0 (CH2O), 122.6 (C4Ph), 127.8, 128.3 and 128.9
(CHPh), 129.8 (double) (C2DNPþC6DNP), 133.0 (C6), 134.4 (C1Ph),
136.6 (C5), 146.1 (C1DNP), 149.0 (double) (C3DNPþC5DNP), 162.4 [C(O)
4.5.7. (ꢀ)-(1R,3S,4S)-2-[(1S)-1-Phenylethyl]-2-azabicyclo[2.2.1]
hept-5-en-3-yl]methanol [(ꢀ)-7C] from endo-6a. Following the
same procedure as above, using adduct 6a (2.02 g, 4.41 mmol).
Flash chromatography of the crude product (hexane/EtOAc 3:1)
afforded the auxiliary, (ꢀ)-8-phenylmenthol (Rf 0.4; 0.97 g; 95%),16
in the early fractions and compound (ꢀ)-7C (Rf 0.1; 0.93 g; 92%), as
O]. IR (KBr):
n
¼2968, 1726, 1653, 1629, 1547, 1457, 1344, 1284, 1172,
1072, 968, 919, 756, 720, 704 cmꢀ1. Anal. Calcd for C22H21N3O6: C,
62.41; H, 5.00; N, 9.92; found: C, 62.37; H, 4.93; N, 9.87.
4.6.3. (ꢀ)-(1S,3S,4R)-2-[(1R)-1-Phenylethyl]-2-azabicyclo[2.2.1]
yellow oil, in the later fractions. ½a D25
ꢃ
ꢀ46.16 (c 1, CHCl3). 1H NMR
hept-5-en-3-yl]methyl
3,5-dinitrobenzoate
[(ꢀ)-8A]
from
(300 MHz, CDCl3):
d
¼1.34 (d, 3H, J 6.5 Hz, CH3), 2.12e2.21 (m, 1H,
(ꢀ)-7A. Following the same procedure as above, using the alcohol
(ꢀ)-7A (90 mg, 0.39 mmol). Flash chromatography of the crude
product (hexane/EtOAc 9:1) afforded compound (ꢀ)-8A (Rf 0.7;
7Hanti), 2.56e2.71 (m, 2H, H7synþH3exo), 3.22 (q, 1H, J 6.5 Hz,
CHCH3), 3.15e3.25 (m, 1H, H4), 3.72e3.82 (m, 2H, CH2OH), 4.72 (br
s, 1H, D2O exch, OH), 5.05 (d, 1H, J 7.1 Hz, H1), 5.65 (dd, 1H, J 5.6,
2.2 Hz, H5), 5.96 (m, 1H, H6), 7.22e7.33 (m, 5H, Ph). 13C NMR
149 mg; 90%), as white solid. Mp 95e98 ꢁC (pentane). ½a D25
ꢀ3.01 (c
ꢃ
1, CHCl3). The NMR (1H, 13C) spectra are identical to those of com-
pound (þ)-8A. Anal. Calcd for C22H21N3O6: C, 62.41; H, 5.00; N,
9.92; found: C, 62.39; H, 4.96; N, 9.90.
(CDCl3):
69.4 (CH2OH), 89.2 (C3), 127.1, 127.5 and 128.8 (CHPh), 130.2 (C5),
136.3 (C6), 146.1 (C1PheCH). IR (NaCl):
d
¼24.6 (CH3), 33.0 (C7), 42.0 (C4), 57.4 (C1), 58.7 (CHCH3),
n
¼3310, 3059, 2962, 2851,
1676, 1492, 1450, 1357, 1208, 1134, 1041, 990, 929, 861, 762,
701 cmꢀ1. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11;
found: C, 78.55; H, 8.34; N, 6.10.
4.6.4. (ꢀ)-(1R,2S,5R)-8-Phenylmenthyl (1R,3S,4S,5R,6S)-5,6-
dihydroxy-2-[(1S)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-
carboxylate (ꢀ)-9 from (ꢀ)-6a. A solution of adduct (ꢀ)-6a (0.60 g,
1.3 mmol), NMO (0.21 g, 1.01 equiv), and OsO4 (1,5 mL, 0.0039 M sol
in water, 0.45 mol %) in tert-butanol/THF/water 9:15:1 (7 mL) was
stirred at ambient temperature under argon for 1 h. The reaction
mixture was then filtered through a Celite pad and washed with
THF. Removal of the solvent on a rotavapor yielded a bordeaux
residue, which was purified by column chromatography (silica gel)
using hexane/EtOAc 3:2 as eluent. Fractions 3e9 (Rf 0.35) afforded
a light pink oil (0.50 g), which solidified on standing and which was
identified as the dihydroxylated adduct (ꢀ)-9. Yield 79%. Suitable
white crystals of (ꢀ)-9 were obtained from hexane/EtOAc and the
structure was confirmed by X-ray crystallographic analysis.19 Mp
4.6. General procedure for preparation of 3,5-
dinitrobenzoates15a
4.6.1. (ꢀ)-(1S,3S,4R)-2-[(1S)-1-Phenylethyl]-2-azabicyclo[2.2.1]hept-
5-en-3-yl]methyl3,5-dinitrobenzoate[(ꢀ)-8B]from(ꢀ)-7B. A mixture
of alcohol (ꢀ)-7B (71 mg, 0.31 mmol), 3,5-dinitrobenzoyl chloride
(144 mg, 0.62 mmol; freshly crystallized from CCl4), and DMAP
(76.3 mg, 0.62 mmol) in dry DCM (10 mL) was stirred under argon for
48 h at rt. The mixture was washed with 0.5 M NaOH solution
(3ꢄ60 mL), 0.5 M HCl solution (3ꢄ80 mL), and brine (80 mL). The

7172
X. García-Mera et al. / Tetrahedron 67 (2011) 7162e7172
202e204 ꢁC (hexane). ½a 2D3
ꢃ
ꢀ15.1 (c 1, CHCl3). 1H NMR (400 MHz,
4. (a) Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558; (b) Badorrey, R.;
Cativiela, C.; Díaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron 1999, 55, 7601.
ꢀ
CDCl3): d0¼0.91 (d, 3H, J 6.4 Hz, 50-CH3), 0.92e1.07 (m, 2H,
5. (a) Alonso, D. A.; Guijarro, D.; Pinho, P.; Temme, O.; Andersson, P. G. J. Org.
Chem. 1998, 63, 2749; (b) Sodergren, M. J.; Bertilsson, S. K.; Andersson, P. G. J.
Am. Chem. Soc. 2000, 122, 6610; (c) Brandt, P.; Andersson, P. G. Synlett 2000,
1092; (d) Murata, K.; Ikariya, T.; Noyori, R. J. Org. Chem. 1999, 64, 2186; (e)
O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439; (f) de Sousa, S. E.; O’Brien, P.;
Steffens, H. C. Tetrahedron Lett. 1999, 40, 8423; (g) Pinho, P.; Andersson, P. G.
Tetrahedron 1998, 54, 7897; (h) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org.
Chem. 1998, 63, 2530.
6. (a) Alves, M. J.; García-Mera, X.; Vale, M. L. C.; Santos, T. P.; Aguiar, F. R.; Ro-
driguez-Borges, J. E. Tetrahedron Lett. 2006, 47, 7595; (b) Rodriguez-Borges, J. E.;
Vale, M. L. C.; Aguiar, F. R.; Alves, M. J.; García-Mera, X. Synthesis 2008, 971 and
references cited therein; (c) Maison, W. Eur. J. Org. Chem. 2007, 2276 and ref-
erences cited therein.
7. (a) Johns, B. A.; Pan, Y. T.; Elbein, A. D.; Johnson, C. R. J. Am. Chem. Soc. 1997, 119,
4856; (b) Robinson, K. M.; Rhinehart, B. L.; Ducep, J. B.; Danzin, C. Drugs Future
1992, 17, 705.
8. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645; (b) Dwek, R. A.; Butters, T. D.; Platt, F. M.; Zitzmann, N. Nat. Rev.
Drug Discovery 2002, 1, 65.
0
0
H4a þH6a ), 1.08e1.19 (m, 1H, H3a ), 1.21 (d, 3H, J 6.4 Hz, CHCH3Ph),
1.23 (s, 3H, 80-CH3), 1.27 (d, 1H, J 10.8 Hz, H7syn), 1.34 (s, 3H, 80-CH3),
1.45e1.57 (m, 1H, H50), 1.58 (d, 1H, J 10.8 Hz, H7anti), 1.62e1.79 (m,
0
0
0
2H, H4b þH3b ), 1.99e2.08 (m, 1H, H6b ), 2.09e2.15 (m, 1H, H20),
2.16 (d, 1H, J 2.0 Hz, H4), 2.45 (br s, 1H, exch D2O, OH), 2.69 (d, 1H, J
4.0 Hz, H3exo), 2.76 (br s, 1H, exch D2O, OH), 2.82 (br s, 1H, H1), 3.46
(q, 1H, J 6.4 Hz, CHCH3Ph), 3.68 (br s, 1H, H5), 3.84 (br s, 1H, H6),
4.74 (dt, 1H, Jt 10.8 Hz, Jd 6.4 Hz, H10), 7.15e7.43 (m, 10H, Ph). 13C
NMR (CDCl3):
d
¼21.8 (50-CH3), 22.5 (CH3CHPh), 24.9 (80-CH3), 26.5
(C30), 28.0 (80-CH3), 29.0 (C7), 31.3 (C50), 34.6 (C40), 39.6 (C80), 41.29
(C60), 47.6 (C4), 50.1 (C20), 63.2 (CHPh), 64.0 (C1), 65.0 (C3), 69.9
(C5), 73.3 (C6), 75.3 (C10), 124.9, 125.3, 127.0, 127.2, 127.9 and 128.4
0
(CHPh), 145.8 (C1PheC8 ), 152.0 (C1PheCH), 172.0 [C(O)O]. IR (neat):
3435, 2952, 1725, 1493, 1454, 1373, 1134, 1074, 1026, 980, 910, 842,
781, 764, 729 cmꢀ1. Anal. Calcd for C31H41NO4: C, 75.73; H, 8.41; N,
2.85; found: C, 75.81; H, 8.50; N, 2.78.
9. (a) Greimel, P.; Spreitz, J.; Stutz, A. E.; Wrodniggm, T. M. Curr. Top. Med. Chem.
2003, 3, 513; (b) Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.;
Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.; Son, J. C.; Wilson,
F. X.; Witty, D. R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett. 1988, 237, 128.
10. (a) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546; (b) Pearson, W. H.;
Guo, L. Tetrahedron Lett. 2001, 42, 8267; (c) Fleet, G. W. J.; Nash, R. J.; Fellows, L.
E.; Parekh, R. J.; Rademacher, T. W. Chem. Lett. 1986, 1051.
Acknowledgements
ˇ
~
Thanks are due to Fundac¸ ao para a Ciencia e Tecnologia (FCT) for
ˇ
11. Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phyto-
chemistry 2001, 56, 265.
12. Ashby, C. R.; Paul, M.; Gardner, E. L.; Gerasimov, M. R.; Dewey, S. L.; Lennon, I.
C.; Taylor, S. J. C. Synapse 2002, 44, 61.
13. (a) Zhu, X.-F. Nucleosides, Nucleotides Nucleic Acids 2000, 19, 651; (b) Rodríguez,
J. B.; Comin, M. J. Mini-Rev. Med. Chem. 2003, 3, 95; (c) Mehellou, Y.; De Clercq,
E. J. Med. Chem. 2010, 53, 521; (d) Nucleoside Analogs in Cancer Therapy; Cheson,
B. D., Keating, M. J., Plunkett, W., Eds.; Marcel Dekker: New York, NY, 1997; (e)
Ena, J.; Pasquau, F. Clin. Infect. Dis. 2003, 36, 1186.
financial support given to Faculdade de Ciencias do Porto (project
PTDC/QUI/67407/2006) and for financial support through the re-
equipment program REDE/1517/RMN/2005.
Supplementary data
14. (a) Bailey, P. D.; Londesbrough, D. J.; Hancox, T. C.; Heffernan, J. D.; Holmes, A. B.
J. Chem. Soc., Chem. Commun. 1994, 2543; (b) Bailey, P. D.; Wilson, R. D.; Brown,
G. R. J. Chem. Soc., Perkin Trans. 1 1991, 1337; (c) Bailey, P. D.; Brown, G. R.;
Korber, F.; Reed, A.; Wilson, R. D. Tetrahedron: Asymmetry 1991, 12, 1263.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.06.097.
ꢀ
15. (a) Fernandez, F.; García-Mera, X.; Lopez, C.; Rodríguez, G.; Rodríguez-Borges, J.
~
ꢀ
References and notes
E. Tetrahedron: Asymmetry 2000, 41, 4805; (b) Caamano, O.; Fernandez, F.;
García-Mera, X.; Rodríguez-Borges, J. E. Tetrahedron Lett. 2000, 41, 4123; (c)
Halterman, R. L.; Vollhard, K. P. C. Organometallics 1988, 7, 883; (d) Whitesell, J.
K.; Liu, C.-L.; Buchanan, C. M.; Chen, H.-H.; Minton, M. A. J. Org. Chem. 1986, 51,
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2, 47.
16. The recovered alcohols were identified as (ꢀ)-8-phenylmenthol [½a D25
ꢀ25.2 (c
ꢃ
2. (a) Kleemann, A.; Engel, J.; Kutscher, B.; Reischert, D. Pharmaceutical Substances:
0.5, CHCl3)] and (þ)-8-phenylneomenthol [½a D23
þ34.0 (c 1.0, CHCl3)] by com-
ꢃ
€
Synthesis, Patents, Applications, 3rd ed.; Thieme: Wurtsburg, Germany, 1999; (b)
parison of its spectroscopic and specific rotation data with those reported in
literature.15a
Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1; (c) Buonora, P.; Olsen, J.-
C.; Oh, T. Tetrahedron 2001, 57, 6099; (d) Heintzelman, G. R.; Meigh, I. R.; Ma-
hajan, Y. R.; Weinreb, S. M. Org. React. 2005, 65, 141; (e) Weinreb, S. M. In
Comprehensive Organic Synthesis; Paquette, L. A., Ed.; Pergamon: Oxford, 1991,
Chapter 4.2.
17. The crystallographic data for the structure (þ)-7A6b have been deposited at the
Cambridge Crystallographic Data Center as supplementary publication number
CCDC 240700. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge, CB2, 1EZ, UK.
ꢀ
3. (a) Timen, A. S.; Somfai, P. J. Org. Chem. 2003, 68, 9958; (b) Rodríguez-Borges, J.
18. The crystallographic data for the structure (ꢀ)-8B have been deposited at the
Cambridge Crystallographic Data Center as supplementary publication number
CCDC 240701. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge, CB2, 1EZ, UK.
19. The crystallographic data for the structure (ꢀ)-9 have been deposited at the
Cambridge Crystallographic Data Center as supplementary publication number
CCDC 240702. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge, CB2, 1EZ, UK.
ꢀ
~
E.; García-Mera, X.; Fernandez, F.; Lopes, V. H. C.; Magalhaes, A. L.; Cordeiro, M.
ꢀ
N. D. S. Tetrahedron 2005, 61, 10951; (c) Fernandez, F.; García-Mera, X.; Vale, M.
L. C.; Rodriguez-Borges, J. E. Synlett 2005, 319; (d) Vale, M. L. C.; Rodriguez-
~
ꢀ
Borges, J. E.; Caamano, O.; Fernandez, F.; García-Mera, X. Tetrahedron 2006, 62,
9475; (e) Stella, L.; Feneau-Dupont, j.; Tinant, B.; Declercq, J. P. Tetrahedron Lett.
1990, 31, 2306; (f) Ekegren, J. K.; Modin, S. A.; Alonso, D. A.; Andersson, P. G.
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1992, 48, 9707; (h) Szymanski, S.; Chapuis, C.; Jurczak, J. Tetrahedron: Asym-
metry 2001, 12, 1939; (i) Alves, C. N.; da Silva, A. B. F.; Marti, S.; Moliner, V.;
20. The crystallographic data for the structure (þ)-10 have been deposited at the
Cambridge Crystallographic Data Center as supplementary publication number
CCDC 801195. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge, CB2, 1EZ, UK.
ꢀ
Oliva, M.; Andres, J.; Domingo, L. R. Tetrahedron 2002, 58, 2695; (j) García, J. I.;
Martinez-Merino, V.; Mayoral, J. A.; Salvatelha, L. J. Am. Chem. Soc. 1998, 120,
ꢀ
2415; (k) Fernandez, F.; García-Mera, X.; Rodríguez-Borges, J. E.; Vale, M. L. C.
~
ꢀ
ꢀ
21. Blanco, J. M.; Caamano, O.; Fernandez, F.; García-Mera, X.; Lopez, C.; Rodríguez-
ꢀ
Tetrahedron Lett. 2003, 44, 431; (l) Domingo, L. R.; Oliva, M.; Andres, J. J. Org.
Borges, J. E. Synthesis 1998, 1590.
Chem. 2001, 66, 6151.