Lewis acid mediated diastereoselective keto-ene cyclization on chiral perhydro-1,3-benzoxazines: synthesis of enantiopure cis-3,4-disubstituted 3-hydroxypyrrolidines

Article abstract of DOI:10.1016/j.tet.2009.09.091

Chiral 2-acyl-3-allyl-perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol were easily cyclized in the presence of Lewis acids at 0 °C. The diastereoselectivity of the cyclization was dependent on the nature of the Lewis acid. The cyclization compoun

Full text of DOI:10.1016/j.tet.2009.09.091

Tetrahedron 65 (2009) 9728–9736
Contents lists available at ScienceDirect
Tetrahedron
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Lewis acid mediated diastereoselective keto-ene cyclization on chiral
perhydro-1,3-benzoxazines: synthesis of enantiopure cis-3,4-disubstituted
3-hydroxypyrrolidines
*
*
´
´
´
Celia Andres , Israel Gonzalez, Javier Nieto , Carlos D. Roson
´
Centro de Innovacio´n en Qu´ımica y Materiales Avanzados (CINQUIMA) and Departamento de Qu´ımica Organica, Facultad de Ciencias,
Universidad de Valladolid, Dr. Mergelina s/n, 47011 Valladolid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral 2-acyl-3-allyl-perhydro-1,3-benzoxazines derived from (ꢀ)-8-aminomenthol were easily cyclized
in the presence of Lewis acids at 0 ꢁC. The diastereoselectivity of the cyclization was dependent on the
nature of the Lewis acid. The cyclization compounds can be transformed into enantiopure cis-3,4-di-
substituted 3-hydroxypyrrolidines by ring opening of the N,O-acetal moiety and subsequent elimination
of the menthol appendage.
Received 18 May 2009
Received in revised form
22 September 2009
Accepted 23 September 2009
Available online 26 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor Josep Font on the
occasion of his 70th birthday
Keywords:
Carbonyl-ene cyclization
Chiral 3-hydroxypyrrolidines
Perhydro-1,3-benzoxazines
Diastereoselective synthesis
Lewis acids
1. Introduction
a modest degree of stereoselection. Ketones are less reactive than
aldehydes due to both steric and electronic effects. However, it is
The 3-hydroxypyrrolidine subunit is found in a wide range of
naturally occurring alkaloids1 and optically active 3-pyrrolidinols
are constituents of several bioactive compounds or they can be
used as intermediates for the synthesis of other interesting
biologically active molecules.2 Consequently, several approaches to
the stereoselective synthesis of 3-hydroxypyrrolidine and its
derivatives have appeared.3,4 Nevertheless, general and effective
methods for the synthesis of enantioselective cis-4-substituted
3-hydroxypyrrolidines are noticeably rare.5
known that ene adducts can be isolated in smooth conditions in the
intramolecular ene reaction of unsaturated ketones in the presence
of Lewis acids.8 Herein, we report on a versatile diastereoselective
synthesis of enantiopure cis-4-substituted 3-hydroxypyrrolidines
by Lewis acid induced intramolecular keto-ene9,10 reactions on
2-acyl-3-allyl-substituted 1,3-perhydrobenzoxazines.
2. Results and discussion
We have recently reported the utility of chiral perhydro-1,3-
benzoxazines derived from (ꢀ)-8-aminomenthol in the synthesis of
cis-3,4-disubstituted pyrrolidines by olefin-ene6 and carbonyl-ene7
intramolecular cyclizations. The thermally induced intramolecular
carbonyl-ene cyclization of chiral 2-acyl-3-allyl-1,3-perhy-
drobenzoxazines took place in smooth conditions and total dia-
stereoselectivity with formyl derivatives, but the cyclization of keto
derivatives required high temperatures and the reaction showed
The starting chiral perhydro-1,3-benzoxazines were synthesized
as summarized in Scheme 1. Compounds 3b–e were prepared as
single diastereomers in good to excellent yields by condensation of
(ꢀ)-8-aminomenthol11 with freshly prepared substituted aryl
glyoxals12 and subsequent alkylation with prenyl bromide of the
resulting N-unsubstituted perhydrobenzoxazines. Compound 3f
was prepared by condensation of phenylglyoxal with the amino
alcohol 2, which was obtained by condensation of (ꢀ)-8-amino-
menthol with trans-b
-methylcinnamaldehyde13 and reduction of
the resulting perhydrobenzoxazine with aluminum hydride in THF.
The isopropylketone 3h was obtained by treatment of the Weinreb
* Corresponding authors. Tel.: þ34 983 423564; fax: þ34 983 423013.
E-mail address: javiernr@qo.uva.es (J. Nieto).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.091

C. Andre´s et al. / Tetrahedron 65 (2009) 9728–9736
9729
Table 1
amide 5h with isopropylmagnesium chloride, which was obtained
Keto-ene reaction of 3a–h in the presence of different Lewis acids
by reaction of the ester 4h with N,O-dimethylhydroxylamine
hydrochloride and isopropylmagnesium chloride in THF. The ester
4h was prepared by condensation of the amino alcohol 2 with ethyl
glyoxylate. The synthesis of the perhydrobenzoxazines 3a and 3g
has been previously described.7
Entry
Ketone
Lewis acid (equiv)
Yielda (%)
Productsb (ratio)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
MgBr2 (2.0)c
ZnCl2 (2.0)c
90
91
34
70
93
94
81
92
83
93
76
93
85
90
81
95
90
92
84
93
88
6a (77), 7a (23)
6a (79), 7a (21)
6a (81), 7a (19)
6a (90), 7a (10)
6a (96), 7a (4)
6a (96), 7a (4)
6a (18), 7a (82)
6b (91), 7b (9)
6b (20), 7b (80)
6c (>97)
6c (10), 7c (90)
6d (90), 7d (10)
6d (85), 7d (25)
6e (87), 7e (13)
6e (56), 7e (44)
6f (96), 7f (4)
BF3$OEt2 (2.0)c
EtAlCl2 (2.0)d
Et2AlCl (1.5)d
Me2AlCl (1.5)d
SnCl4 (1.5)d
R1
NH2
N
Me2AlCl (1.5)d
SnCl4 (1.5)d
i, ii
O
OH
9
O
10
11
12
13
14
15
16
17
18
19
20
21
Et2AlCl (1.5)d
SnCl4 (1.5)d
3b, R1 = p-CH3-C6H4
3c, R1 = p-OCH3-C6H4
3d, R1 = p-NO2-C6H4
3e, R1 = m-NO2-C6H4,
1
Me2AlCl (1.5)d
SnCl4 (1.5)d
Me2AlCl (1.5)d
SnCl4 (1.5)d
Et2AlCl (1.5)d
SnCl4 (1.5)d
3f
6f (21), 7f (79)
6g (85), 7g (15)
6g (30), 7g (70)
6h (83), 7h (17)
6h (14), 7h (86)
3g
3g
3h
3h
Me2AlCl (1.5)d
SnCl4 (1.5)d
C6H5
NH2
OH
H
N
Et2AlCl (1.5)d
SnCl4 (1.5)d
iii, iv
OH
a
Chemical yields refer to pure compounds after column chromatography.
Determined by 1H NMR on the reaction mixtures.
Et2O was used as solvent.
b
c
1
2
d
CH2Cl2 was used as solvent.
v
C6H5
Different Lewis acids were initially explored using the phenyl-
C6H5
O
N
R1
N
ketone 3a. In the presence of 2 equiv of MgBr2 or ZnCl2 in Et2O, 3a
gave only two of the four possible ene adducts with an excellent
yield and moderate stereoselectivity (entries 1 and 2 in Table 1). In
contrast, in the presence of BF3$OEt2 stereoselectivity was similar
but the chemical yield was poor (entry 3). In these conditions sig-
nificant amounts (30%) of oxetane 8 (Fig. 1) were isolated. This
compound was presumably formed via a stepwise cyclization
(Fig. 1).14
NCH3-OCH3
vi
O
O
O
3f, R1 = C6H5
4h, R1 = OEt
5h
vii
C6H5
The use of aluminum derivatives as Lewis acids in the keto-ene
cyclization improved the diastereomeric ratios (entries 4, 5, and 6).
The best results were obtained when 1.5 equiv of Me2AlCl or Et2AlCl
in CH2Cl2 were used instead of the stronger Lewis acid EtAlCl2
(compare entries 5 and 6 vs 4). In these conditions unsaturated
aromatic ketones 3a–f (entries 5, 6, 8, 10, 12, 14, and 16) and ali-
phatic ketones 3g, h (entries 18 and 20) reacted with high dia-
stereoselectivity leading to a mixture of two hydroxypyrrolidine
derivatives 6a–h and 7a–h in excellent yields. Electron-with-
drawing nitro groups (entries 12 and 14) and electron-donor
methoxy groups attached at the phenyl group of the aromatic ke-
tones were tolerated (entry 10). The diastereoselectivity in cycli-
zation of isopropyl ketones 3g and 3h (entries 18 and 20) was
slightly lower than that observed for aromatic ketones 3a–f.
Interestingly, when the cyclization was carried out in CH2Cl2 at
0 ꢁC in the presence of SnCl4 and larger reaction times, the ster-
eoselection was reversed and the diastereoisomers 7a–c,f–h were
obtained as majority products (entries 7, 9, 11, 17, 19, and 21). The
chemical yields and diastereoselectivity were lower when reaction
was carried out using SnCl4 than in the presence of Me2AlCl or
Et2AlCl. An exception to this behavior was the cyclization of ketones
N
O
O
3h
Scheme 1. Reagents and conditions: (i) ArCOCHO, CH2Cl2, rt. (ii) Prenyl bromide, K2CO3,
acetonitrile, rt, 3b (82%), 3c (87%), 3d (66%), 3e (68%). (iii) trans-3-methyl-
cinnamaldehyde, CH2Cl2, rt. (iv) LiAlH4, AlCl3, THF, 0 ꢁC, 88%. (v) PhCOCHO or EtO2C-
CHO, toluene, Dean–Stark, reflux, 3f (52%), 4h (60%). (vi) MeNHOMe$HCl, i-PrMgCl,
THF, ꢀ20 ꢁC to room temperature. (vii) i-PrMgCl, THF, rt, 61% from 4h.
Keto-ene cyclization of ketones 3a–h was tested under the in-
fluence of some Lewis acids of different hardness and the results are
summarized in Scheme 2 and Table 1.
R2
R1
R1
OH
R2
H
N
N
N
O
OH
1H
Lewis acid
0 ºC
R
O
+
O
R2
6a-h
O
7a-h
3a, R1 = C6H5, R2 = CH3
3b, R1 = p-CH3-C6H4, R2 = CH3
3c, R1 = p-OCH3-C6H4, R2 = CH3
3d, R1 = p-NO2-C6H4, R2 = CH3
3e, R1 = m-NO2-C6H4, R2 = CH3
3f, R1 = C6H5, R2 = C6H5
H
Ph
N
H
O
O
3g, R1 = iPr, R2 = CH3
8
3h, R1 = iPr, R2 = C6H5
Scheme 2. Diastereoselective keto-ene cyclization of compounds 3a–h.
Figure 1.

9730
C. Andre´s et al. / Tetrahedron 65 (2009) 9728–9736
3d and 3e bearing a nitro group in the aromatic ring (entries 13 and
15). However, the 3-hydroxypyrrolidine derivatives 7d and 7e can
be obtained as majority products in a thermally induced keto-ene
cyclization. In this way, the heating of 3d or 3e in refluxing aceto-
nitrile for 1.5 h, led to 6d and 7d in a ratio of 23:77 (92% yield) and
6e and 7e in a ratio of 25:75 (86% yield), respectively.
the vinyl group in adducts 7 resonates downfield of the same proton
in diastereomers 6 (ca. 0.6 ppm in adducts derived from aromatic
ketones and 0.20–0.35 ppm in adducts derived from isopropyl ke-
tones). The resonance for the hydrogen H-9a attached to the N,O-
acetalic carbon is shifted upfield (ca. 0.15 ppm) in adducts 7 with
respect tothe same protonin compounds 6, except foradducts 6gand
7g, which have the same chemical shift. This general trend allowed
the assignation of the stereochemistry for all these compounds.
The transformation of some ene adducts into the final cis-3,4-
disubstituted-3-hydroxypyrrolidines was carried out in two steps
as depicted in Scheme 4.
It is known that the nature of the Lewis acid can affect the
reactivity and simple diastereoselectivity in
a carbonyl-ene
reaction.15 In our case, it is noteworthy that the carbonyl-ene
cyclization of 3a–h showed complete simple diastereoselectivity
for the formation of the cis-3,4-disubstituted products. However,
the induced diastereoselectivity is dramatically affected by the
nature of the Lewis acid.
R2
H
Probably, the difference in the induced diastereoselectivity
observed by changing the Lewis acid from tin(IV) chloride to alu-
minum reagents is due to their acid–base nature. Me2AlCl is
a strong Lewis acid but it is also a Bronsted base due to the basic
alkyl groups.16 The alcohol/Me2AlCl complex intermediate formed
in the cyclization reaction decomposes rapidly to give methane and
an aluminum alkoxide making the cyclization irreversible. On the
other hand, SnCl4 behaves only as Lewis acid and in the reaction
conditions, cyclization is reversible. An 1H NMR study of the cy-
clization course of 3a in the presence of SnCl4 shows that at 60 min
of reaction (ca. 85% conversion) a mixture 36:64 of products 6a:7a
was formed. After 3 h (100% of conversion) the ratio of the reaction
products 6a:7a changed to 23:77 and to 18:82 after 8 h of reaction
time. This behavior is not observed in the reaction of 3a in the
presence of Me2AlCl. The ratio of the products 6a:7a remains in-
variable with the reaction time. On the other hand, the isolated
diastereomer 6a was transformed into a mixture of 6a:7a in a ratio
of 34:65 by stirring in CH2Cl2 at 0 ꢁC for 6 h in the presence of
1.5 equiv of SnCl4, whereas the diastereomer 7a remained un-
changed in the same conditions. Neither 6a nor 7a was inter-
converted when Me2AlCl was used.
From the experimental results, it suggested that the energy
potential of this cyclization reaction can be described as Scheme 3.
The product 6a is kinetic product due to lower activation energy,
while product 7a is thermodynamic product with higher stability.
For the aluminum complex, it is not only a Lewis acid but also
a strong Bronsted base. The kinetic product 6a rapidly decomposed
to methane and aluminum alkoxide. This makes the pathway I ir-
reversible. So the product 6a is major product with aluminum as
Lewis acid. And tin complex acts only as Lewis acid, the pathway I is
reversible. So the thermodynamic product 7a was obtained as
major product at the end while increasing the experimental time.
Diastereoisomers formed in each reactionwere separated by flash
chromatography and their stereochemistry was assigned on the basis
of NOESY experiments for compounds 6b–d, 6h, and 7b–d. On the
other hand, the hydrogen (H-2) attached to the carbon that supports
R2
R1
H
i
N
iii, iv, v
iii, iv, v
OH
6b,c,f
R1
OH
OH
TsN
9b,c,f
11b,c,f
R2
H
R2
OH
H
ii
N
7c,h
R1
OH
R1
TsN
12c,h
OH
10c,h
Scheme 4. Reagents and conditions: (i) LiAlH4, AlCl3, THF, ꢀ10 ꢁC, 9b (92%), 9c (95%), 9f
(90%). (ii) NaBH3CN, MeOH, HCl 0.1 M (pHw4), 60 ꢁC, 10c (86%), 10h (85%). (iii) PCC,
CH2Cl2, 4 Å molecular sieves, rt. (iv) KOH, H2O/MeOH/THF, rt. (v) TsCl, i-Pr2NEt, AcOEt,
rt, 11b (54%), 11c (46%), 11f (50%), 12c (52%), 12h (46%).
Treatment of adducts 6b,c,f with aluminum hydride in THF at
ꢀ10 ꢁC for 10 min led to amino alcohols 9b,c,f in good yields. In the
same conditions, adducts 7c,h provided alcohols 10c,h, in poor
chemical yields. Better yields were obtained when the reductive
ring opening of the N,O-acetal moiety was carried out by treatment
with sodium cyanoborohydride in acidic media.17 The elimination
of the menthol appendage was carried out by oxidation with PCC of
the amino alcohols to the aminomenthone derivatives, followed by
elimination with a solution of KOH in THF/MeOH/H2O18 leading to
the final enantiopure 3-hydroxypyrrolidines in moderate yields.
These compounds were isolated and characterized as N-tosyl de-
rivatives 11b,c,f and 12c,h by treatment with tosyl chloride and
diisopropylethylamine in ethyl acetate. The absolute stereochem-
istry of compound 11f was established by X-ray diffraction
analysis,19 corroborating the absolute configuration of the ene-
cyclization product 6f. As expected, the 3-hydroxypyrrolidines 11c
and 12c were enantiomers.
pathway II
pathway I
R1
H
N
Lewis Acid
OH
OH
O
R2
3a
R2
N
SnCl4
6a
1H
kinetic product
R
O
R1
R1
H
H
7a
N
N
thermodynamic product
OH
O
O
O
+
CH4
R2
AlMeCl
R2
AlMe2Cl
Scheme 3.

C. Andre´s et al. / Tetrahedron 65 (2009) 9728–9736
9731
3. Conclusion
was stirred at room temperature for 120–150 h. The reaction mix-
ture was diluted with ethyl acetate and the solid was separated by
filtration and washed with hot ethyl acetate (3ꢂ25 mL). The sol-
vents were evaporated under vacuum and the residue was purified
by flash chromatography on silica gel, using a mixture of hexane/
EtOAc 25:1 as eluent.
In summary, this paper describes an efficient access to enan-
tiopure cis-3,4-disubstituted 3-hydroxypyrrolidines through Lewis
acid induced intramolecular carbonyl-ene cyclization reaction of
2-acyl-3-allyl-perhydro-1,3-benzoxazine derivatives.
A dramatic changeover in the diastereoselectivity of the cycli-
zation was observed by changing the Lewis acid from aluminum
reagents to tin(IV) chloride, which permits us to obtain both en-
antiomers of the final product by the judicious choice of the Lewis
acid employed starting from the same perhydrobenzoxazine.
4.3.1. (2S,4aS,7R,8aR)-[3-(3-Methylbut-2-enyl)-4,4,7-trimethylocta-
hydro-2H-benzo[e][1,3]oxazin-2-yl]-p-tolyl ketone (3b). Yield: 82%.
25
Colorless oil. [
a
]
þ4.3 (c 2.4, CHCl3). 1H NMR
d: 0.86–1.11 (m, 2H);
D
0.94 (d, 3H, J¼6.4 Hz); 1.18 (s, 3H); 1.23 (m, 1H); 1.30 (s, 3H); 1.36 (s,
3H); 1.40 (s, 3H); 1.43–1.58 (m, 2H); 1.63 (m, 1H); 1.72 (m, 1H); 2.03
(m, 1H); 2.37 (s, 3H); 3.18 (dd, 1H, J1¼16.6 Hz, J2¼6.1 Hz); 3.31 (dd,
1H, J1¼16.6 Hz, J2¼6.1 Hz); 3.56 (td, 1H, J1¼10.5 Hz, J2¼4.0 Hz); 4.75
(t, 1H, J¼6.1 Hz); 5.64 (s, 1H); 7.24 (d, 2H, J¼8.1 Hz); 8.10 (d, 2H,
4. Experimental
4.1. General
J¼8.1 Hz). 13C NMR
d: 17.5 (CH3); 19.9 (CH3); 21.5 (CH3); 22.1 (CH3);
All reactions were carried out in anhydrous solvents under an
argon atmosphere and in oven-dried glassware. 1H NMR (300 MHz)
and 13C NMR (75 MHz) were registered in CDCl3 as solvent and
chemical shifts are given relative to TMS as an internal reference.
Specific rotations were determined on a digital polarimeter using
a Na lamp and concentration is given in g per 100 mL. Melting
points were determined in open capillary tubes and are un-
corrected. Solvents were dried by standard methods. TLC was
performed on glass-backed plates coated with silica gel 60 with
F254 indicator; the chromatograms were visualized under UV light
and/or by staining with a Ce/Mo reagent. Flash chromatography
was carried out on silica gel 60 (230–240 mesh).
24.9 (CH2); 25.3 (CH3); 26.7 (CH3); 31.2 (CH); 34.8 (CH2); 41.2 (CH2);
42.3 (CH2); 46.1 (CH); 57.4 (C); 76.1 (CH); 88.5 (CH); 126.2 (CH);
128.4 (2 CH); 129.2 (2 CH); 130.4 (C); 132.9 (C); 143.2 (C); 194.1(C).
IR (Neat): 2925, 2870, 1700, 1610, 755, 735, 665 cmꢀ1. HRMS: calcd
for C24H35NO2Na [MþNa]þ 392.2565, found 392.2552.
4.3.2. (2S,4aS,7R,8aR)-[3-(3-Methylbut-2-enyl)-4,4,7-trimethy-
loctahydro-2H-benzo[e][1,3]oxazin-2-yl]-(4-methoxyphenyl) ketone
25
(3c). Yield: 87%. Colorless solid. Mp: 113–114 ꢁC (from EtOH). [
a]
D
þ16.6 (c 0.5, CHCl3). 1H NMR
d: 0.90–1.05 (m, 2H); 0.94 (d, 3H,
J¼6.4 Hz); 1.19 (s, 3H); 1.22 (m, 1H) 1.32 (s, 3H); 1.35 (s, 3H); 1.40
(s, 3H); 1.47–1.60 (m, 2H); 1.67 (m, 1H); 1.71 (m, 1H); 2.02 (m, 1H);
3.18 (dd, 1H, J1¼16.6 Hz, J2¼5.8 Hz); 3.25 (dd, 1H, J1¼16.6 Hz,
J2¼5.8 Hz); 3.56 (td, 1H, J1¼10.5 Hz, J2¼4.0 Hz); 3.85 (s, 3H); 4.78
(t, 1H, J¼5.8 Hz); 5.61 (s, 1H); 6.87 (d, 2H, J¼8.8 Hz); 8.22 (d, 2H,
Compounds 3a, 3g, 6a, 6g, 7a, and 7g have been previously
described.7
4.2. (1R,2S,5R)-5-Methyl-2-[1-[(E)-3-phenylbut-2-
enylamino]-1-methylethyl]-cyclohexanol (2)
J¼8.8 Hz). 13C NMR
d: 17.5 (CH3); 19.6 (CH3); 22.1 (CH3); 24.9
(CH2); 25.3 (CH3); 26.6 (CH3); 31.2 (CH); 34.8 (CH2); 41.2 (CH2);
42.3 (CH2); 46.1 (CH); 55.2 (CH3); 57.4 (C); 76.0 (CH); 88.7 (CH);
112.9 (2 CH); 126.2 (CH); 128.4 (C); 130.3 (C); 131.5 (2 CH); 163.0
(C); 193.2 (C). IR (Nujol dispersion): 1690, 1595, 855, 660,
615 cmꢀ1. HRMS: calcd for C24H35NO3Na [MþNa]þ 408.2515,
found 408.2503.
Dry AlCl3 (2.0 g, 15.0 mmol) was added, in portions, to a suspen-
sion of LiAlH4 (1.71 g, 45.0 mmol) in anhydrous THF (40 mL) cooled
to ꢀ10 ꢁC. The mixture was stirred for 15 min at ꢀ10 ꢁC and a solu-
tion of the benzoxazine obtained by condensation of (ꢀ)-8-amino-
menthol and trans-b
-methylcinnamaldehyde13 (4.5 g,15.0 mmol) in
dry THF (25 mL) was slowly added. The reaction mixture was stirred
for 10 min at 0 ꢁC and quenched by the addition of a 10% aqueous
solution of NaOH (4.0 mL). The resulting mixture was filtered, the
solid was washed with hot EtOAc, and the organic layer was dried
over anhydrous MgSO4. The solvent was eliminated under reduced
pressure and the residue was chromatographed on silica gel using
4.3.3. (2S,4aS,7R,8aR)-[3-(3-Methylbut-2-enyl)-4,4,7-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2-yl]-(4-nitrophenyl) ketone (3d). Yield:
25
66%. Yellow solid. Mp: 105–106 ꢁC (from EtOH). [
a]
D
ꢀ1.4 (c 0.8,
CHCl3). 1H NMR
d
: 0.92–1.07 (m, 2H); 0.94 (d, 3H, J¼6.4 Hz); 1.17
(s, 3H); 1.20 (m, 1H); 1.23 (s, 3H); 1.30 (s, 3H); 1.37 (s, 3H); 1.43–1.60
(m, 2H); 1.69–1.75 (m, 2H); 2.01 (m, 1H); 3.09 (dd, 1H, J1¼16.0 Hz,
J2¼6.4 Hz); 3.32 (dd, 1H, J1¼16.0, Hz, J2¼6.4 Hz); 3.58 (td, 1H,
J1¼10.5 Hz, J2¼4.0 Hz); 4.61 (t,1H, J¼6.4 Hz); 5.44 (s, 1H); 8.24 (dd, 2H,
a mixture of hexane/EtOAc 3:1 as eluent. Yield: 88%. Colorless solid.
25
Mp: 106–107 ꢁC (from hexane). [
a
]
ꢀ26.8 (c 1.0, CHCl3). 1H NMR
d:
D
0.88–1.9 (m, 5H); 0.91 (d, 3H, J¼6.5 Hz); 1.15 (s, 3H); 1.17 (s, 3H); 1.30
(m, 1H); 1.42 (m, 1H); 1.61–1.69 (m, 2H); 1.95 (m, 1H); 2.05 (s, 3H);
3.37 (dd, 1H, J1¼12.8, Hz, J2¼6.8 Hz); 3.43 (dd, 1H, J1¼12.8, Hz,
J2¼6.8 Hz); 3.63 (td, 1H, J1¼10.4 Hz, J2¼4.0 Hz); 5.79 (t, 1H,
J1¼7.1 Hz, J2¼1.6 Hz); 8.43 (dd, 2H, J1¼7.1 Hz, J2¼1.6 Hz). 13C NMR
d:
17.5 (CH3); 17.8 (CH3); 22.0 (CH3); 24.8 (CH2); 25.2 (CH3); 26.7 (CH3);
31.1 (CH); 34.6 (CH2); 41.1 (CH2); 42.0 (CH2); 47.1 (CH); 57.6 (C); 76.0
(CH); 89.8 (CH); 122.8 (2 CH); 125.6 (CH); 130.3 (2 CH); 132.6 (C);
139.8 (C); 149.6 (C); 192.8 (C). IR (Nujol dispersion): 3080, 3110, 3055,
1705, 1600, 720, 690 cmꢀ1. HRMS: calcd for C23H33N2O4 [MþH]þ
401.2440, found 401.2438.
J¼6.8 Hz); 7.19–7.38 (m, 5H). 13C NMR
d: 15.8 (CH3); 21.4 (CH3); 22.0
(CH3); 25.6 (CH2); 26.1 (CH3); 30.9 (CH); 34.9 (CH2); 39.3 (CH2); 44.3
(CH2); 49.6 (CH); 56.6 (C); 72.4 (CH); 125.3 (CH); 125.5 (2 CH); 126.9
(CH); 128.0 (2 CH); 137.1 (C); 142.8 (C). IR (Nujol dispersion): 3260
(broad), 3040, 1595, 750, 700 cmꢀ1. HRMS: calcd for C20H32NO
[MþH]þ 302.2484, found 302.2467.
4.3.4. (2S,4aS,7R,8aR)-[3-(3-Methylbut-2-enyl)-4,4,7-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2-yl]-(3-nitrophenyl) ketone (3e). Yield:
68%. Yellow solid. Mp: 113–114 ꢁC (from EtOH). 1H NMR
d: 0.86–1.08
4.3. Synthesis of ketones 3b, 3c, 3d, and 3e
(m, 2H); 0.94 (d, 3H, J¼6.4 Hz); 1.16 (s, 3H); 1.21 (m, 1H); 1.24 (s, 3H);
1.33 (s, 3H); 1.36 (s, 3H); 1.43–1.67 (m, 2H); 1.70–1.79 (m, 2H); 2.01
(m, 1H); 3.09 (dd, 1H, J1¼16.1 Hz, J2¼6.5 Hz); 3.33 (dd, 1H, J1¼16.1 Hz,
J2¼6.5 Hz); 3.58 (td, 1H, J1¼10.6 Hz, J2¼4.1 Hz); 4.60 (t, 1H, J¼6.5 Hz);
5.46 (s, 1H); 7.60 (t, 1H, J¼8.0 Hz); 8.35 (m, 1H); 8.52 (m, 1H); 9.25
A mixture of (ꢀ)-8-aminomenthol (2.5 g, 15 mmol) and the
appropriate arylglioxal derivative (15 mmol) in dichloromethane
(60 mL) was stirred for 24 h at room temperature. The solvent was
removed under vacuum and the residue was dissolved in dry
acetonitrile (8 mL). Potassium carbonate (4.3 g, 31.0 mmol) and
prenyl bromide (2.5 mL, 21.2 mmol) were added and the mixture
(t, 1H, J¼1.9 Hz). 13C NMR
d: 17.5 (CH3); 17.9 (CH3); 22.1 (CH3); 25.0
(CH2); 25.2 (CH3); 26.8 (CH3); 31.2 (CH); 34.7 (CH2); 41.1 (CH2); 42.1
(CH2); 47.2 (CH); 57.6 (C); 76.1 (CH); 89.8 (CH); 124.8 (CH); 125.6 (CH);

9732
C. Andre´s et al. / Tetrahedron 65 (2009) 9728–9736
126.8 (CH); 128.8 (CH); 132.6 (C); 134.7(CH); 136.5 (C); 147.6 (C); 192.4
(br s, 3H); 3.38–3.57 (m, 2H); 3.65–3.83 (m, 4H); 5.53 (m, 1H); 5.81
(m, 1H); 7.13–7.39 (m, 5H). 13C NMR
: 15.7 (CH3); 21.1 (CH3); 22.1
(C). IR (Nujol dispersion): 3120, 1700, 1603, 1526, 710, 685 cmꢀ1
.
d
HRMS: calcd for C23H32N2O4Na [MþNa]þ 423.2260, found 423.2253.
(CH3); 24.8 (CH2); 26.8 (CH3); 31.3 (CH); 32.3 (CH3); 34.8 (CH2); 41.0
(CH2); 42.6 (CH2); 45.0 (CH); 57.5 (C); 61.6 (CH3); 76.6 (CH); 82.8
(CH); 125.4 (2 CH); 126.3 (CH); 128.0 (2 CH); 130.6 (CH); 132.4 (C);
143.6 (C); 170.0 (C). IR (Neat): 2975, 2920, 2865, 1685, 1680, 760,
730, 700 cmꢀ1. HRMS: calcd for C24H36N2O3Na [MþNa]þ 423.2624,
found 423.2621.
4.4. Synthesis of oxazines 3f and 4h
A mixture of alcohol 2 (2.4 g, 8.0 mmol), phenyglyoxal (1.3 g,
9.7 mmol) or ethyl glyoxalate (1.9 mL of a commercial 50% solution
in toluene, 9.7 mmol), and toluene (60 mL) was heated at reflux
with a Dean–Stark trap for 38 h. The solvent was evaporated under
vacuum and the residue was chromatographed on silica gel using
a mixture of hexane/EtOAc 15:1 as eluent.
4.5.2. (2S,4aS,7R,8aR)-2-Methyl-1-[3-[(E)-3-phenylbut-2-enyl]-
4,4,7-trimethyloctahydro-2H-benzo[e][1,3]oxazin-2-yl]propan-1-one
25
(3h). Yield: 61% from 4h. Colorless oil. [
NMR
a]
ꢀ79.3 (c 1.1, CHCl3). 1H
D
d
: 0.85–1.05 (m, 2H); 0.94 (d, 3H, J¼6.4 Hz); 1.00 (d, 3H,
4.4.1. (2S,4aS,7R,8aR)-Phenyl-[3-[(E)-3-phenylbut-2-enyl]-4,4,7-tri-
methyloctahydro-2H-benzo[e][1,3]oxazin-2-yl] ketone (3f). Yield:
J¼6.9 Hz); 1.10 (d, 3H, J¼6.9 Hz); 1.17 (s, 3H); 1.26 (m, 1H); 1.29
(s, 3H); 1.48–1.61 (m, 2H); 1.66 (m, 1H); 1.73 (m, 1H); 1.93 (s, 3H);
2.04 (m, 1H); 3.12 (sep, 1H, J¼6.9 Hz); 3.21 (dd, 1H, J1¼17.7, Hz,
J2¼5.5 Hz); 3.48–3.56 (m, 2H); 5.21 (s, 1H); 5.79 (t, 1H, J¼5.5 Hz);
25
52%. Colorless solid. Mp: 110–111 ꢁC (from EtOH). [
a
]
ꢀ25.2 (c 0.9,
D
CHCl3). 1H NMR
d
: 0.90–1.08 (m, 2H); 1.02 (d, 3H, J¼6.4 Hz); 1.22 (s,
3H); 1.29 (m, 1H); 1.41 (s, 3H); 1.42–1.79 (m, 4H); 1.82 (s, 3H); 2.06
(m, 1H); 3.39 (dd, 1H, J1¼17.5 Hz, J2¼6.1 Hz); 3.52 (dd, 1H,
J1¼17.5 Hz, J2¼6.1 Hz); 3.61 (td, 1H, J1¼10.5 Hz, J2¼4.1 Hz); 5.32
(t, 1H, J¼6.1 Hz); 5.74 (s, 1H); 6.80–6.83 (m, 2H); 7.09–7.11 (m, 3H);
7.18–7.40 (m, 5H). 13C NMR
d: 15.9 (CH3); 17.4 (CH3); 19.5 (CH3); 21.6
(CH3); 22.2 (CH3); 24.9 (CH2); 26.6 (CH3); 31.4 (CH); 35.0 (CH2);
36.3 (CH); 41.1 (CH2); 44.1 (CH2); 44.8 (CH); 57.3 (C); 76.4 (CH); 88.5
(CH); 125.5 (2 CH); 126.6 (CH); 128.1 (2 CH); 130.7 (CH); 132.7 (C);
143.3 (C); 210.8 (C). IR (Neat): 2975, 2930, 2870, 1725, 1600, 735,
700 cmꢀ1. HRMS: calcd for C25H38NO2 [MþH]þ 384.2903, found
384.2899.
7.33–7.39 (m, 2H); 7.49 (m, 1H); 8.18–8.22 (m, 2H). 13C NMR
d: 15.6
(CH3); 20.0 (CH3); 22.2 (CH3); 25.0 (CH2); 26.9 (CH3); 31.3 (CH);
34.9 (CH2); 41.2 (CH2); 42.9 (CH2); 46.2 (CH); 57.7 (C); 76.2 (CH);
88.5 (CH); 125.3 (2 CH); 126.3 (CH); 127.7 (2 CH); 128.0
(2 CH); 129.4 (2 CH); 130.0 (CH); 132.9 (CH); 133.1 (C); 135.2 (C);
143.3 (C); 194.7(C). IR (Nujol dispersion): 1700, 1600, 1575, 775,
755, 735, 700, 685 cmꢀ1. HRMS: calcd for C28H35NO2Na [MþNa]þ
440.2565, found 440.2564.
4.6. General procedure for keto-ene cyclization of 3a–3h in
the presence of Me2AlCl, Et2AlCl or SnCl4
A commercial solution of Me2AlCl or Et2AlCl in hexanes or SnCl4
in CH2Cl2 (5.25 mL, solution 1 M) was slowly added to a solution of
ketone 3a–h (3.5 mmol) in anhydrous CH2Cl2 (70 mL) cooled to
0 ꢁC. The mixture was stirred at this temperature for 1.5 h for the
reactions in the presence of aluminum derivatives and 15 h for
reactions in the presence of SnCl4. Then the reaction was quenched
by addition of a saturated aqueous solution NH4Cl (40 mL). The
organic layer was decanted and the aqueous layer was extracted
with CH2Cl2 (3ꢂ20 mL). The combined organic fractions were
washed with brine, dried over anhydrous MgSO4, filtered, and the
solvent was eliminated under reduced pressure. The residue was
purified by flash chromatography on silica gel using a mixture of
hexane/EtOAc as eluent.
4.4.2. (2S,4aS,7R,8aR)-2-(Ethoxycarbonyl)-3-[(E)-3-phenylbut-2-
enyl]-4,4,7-trimethyloctahydro-2H-benzo[e][1,3]oxazine (4h). Yield:
25
60%. Colorless solid. Mp: 105–106 ꢁC (from EtOH). [
a
]
D
ꢀ27.3 (c 1.1,
CHCl3). 1H NMR
d
: 0.90–1.04 (m, 2H); 0.94 (d, 3H, J¼6.5 Hz); 1.15
(m, 1H); 1.17 (t, 3H, J¼6.1 Hz); 1.19 (s, 3H); 1.23 (s, 3H); 1.42–1.74
(m, 4H); 1.98 (s, 3H); 2.01 (m, 1H); 3.40–3.59 (m, 3H); 4.01–4.20 (m,
2H); 5.10 (s, 1H); 5.86 (t, 1H, J¼5.6 Hz); 7.18 (m, 1H); 7.25–7.30 (m,
2H); 7.36–7.39 (m, 2H). 13C NMR
d: 13.9 (CH3); 15.6 (CH3); 19.7
(CH3); 22.1 (CH3); 24.8 (CH2); 26.5 (CH3); 31.2 (CH); 34.7 (CH2); 40.9
(CH2); 43.5 (CH2); 45.8 (CH); 57.1 (C); 61.2 (CH2); 76.0 (CH); 85.7
(CH); 125.3 (2 CH); 126.4 (CH); 127.9 (2 CH); 130.1 (CH); 132.6 (C);
143.0 (C); 168.9 (C). IR (Nujol dispersion): 1750, 770, 765, 700 cmꢀ1
.
HRMS: calcd for C24H36NO3 [MþH]þ 386.2695, found 386.2695.
4.6.1. (1R,2S,4aS,7R,8aR,9aS)-2-Isopropenyl-4,4,7-trimethyl-1-(p-
tolyl)-decahydro-9-oxa-3a-azacyclopenta[b]naphthalen-1-ol
25
4.5. Synthesis of oxazine 3h
(6b). Colorless solid. Mp: 114–115 ꢁC (from EtOH). [
a
]
ꢀ24.0
D
(c 1.0, CHCl3). 1H NMR
d
: 0.83–1.01 (m, 2H); 0.91 (d, 3H, J¼6.5 Hz);
A solution of i-PrMgCl in diethyl ether (13.7 mL, 2 M) was slowly
added (1 h) to a slurry of the ester 4h (3.0 g, 7.8 mmol) and
Me(MeO)NH$HCl (1.1 g, 11.7 mmol) in THF (35 mL), cooled to
ꢀ20 ꢁC. The mixture was stirred for 10 min at ꢀ20 ꢁC and then for
15 min at room temperature. The reaction was quenched with
a saturated solution of NH4Cl, and the product was extracted with
diethyl ether (4ꢂ20 mL). The organic layer was dried over MgSO4
and concentrated under vacuum to give an oily residue, which was
purified by flash chromatography on silica gel with hexanes/ethyl
acetate as eluent to yield 1.6 g of amide 5h and 0.71 g of ketone 3h.
A solution of i-PrMgCl (2.8 mL, 2 M) was slowly added at ꢀ40 ꢁC
to a solution of amide 5h in THF (10 mL). The reaction mixture was
stirred for 30 min and the mixture was treated as above to obtain
1.1 g of ketone 3h.
1.09 (m, 1H); 1.14 (s, 3H); 1.19 (s, 3H); 1.35–1.54 (m, 2H); 1.59
(s, 3H); 1.61 (m, 1H); 1.70 (m, 1H); 1.90 (m, 1H); 2.32 (s, 3H); 2.93
(dd, 1H, J1¼9.0 Hz, J2¼7.6 Hz); 3.08 (dd, 1H, J1¼8.1 Hz, J2¼7.6 Hz);
3.35 (dd, 1H, J1¼9.0 Hz, J2¼8.1 Hz); 3.43 (td, 1H, J1¼10.5 Hz,
J2¼4.1 Hz); 3.69 (s, 1H); 4.58 (s, 1H); 4.69 (s, 1H); 4.86 (s, 1H); 7.12
(d, 2H, J¼8.0 Hz); 7.54 (d, 2H, J¼8.0 Hz). 13C NMR
d: 20.0 (CH3); 21.0
(CH3); 22.2 (CH3); 23.5 (CH3); 24.7 (CH2); 26.9 (CH3); 31.1 (CH); 34.9
(CH2); 41.1 (CH2); 44.5 (CH); 46.9 (CH2); 53.3 (C); 56.6 (CH); 74.9
(CH); 79.7 (C); 91.9 (CH); 111.1 (CH2); 124.5 (2 CH); 128.4 (2 CH);
135.6 (C); 143.6 (C); 144.9 (C). IR (Nujol dispersion): 3545, 3080,
1645, 1510, 730, 700 cmꢀ1. HRMS: calcd for C24H36NO2 [MþH]þ
370.2746, found 370.2749.
4.6.2. (1R,2S,4aS,7R,8aR,9aS)-2-Isopropenyl-4,4,7-trimethyl-1-(4-
methoxyphenyl)decahydro-9-oxa-3a-azacyclopenta[b]naphthalen-1-
25
4.5.1. (2S,4aS,7R,8aR)-N-Methoxy-3-[(E)-3-phenylbut-2-enyl]-
ol (6c). Colorless oil. [
a]
ꢀ6.9 (c 0.9, CHCl3). 1H NMR
d: 0.89–
D
N,4,4,7-tetramethyloctahydro-2H-benzo[e][1,3]oxazine-2-carbox-
0.99 (m, 2H); 0.91 (d, 3H, J¼6.4 Hz); 1.07 (m, 1H); 1.14 (s, 3H);
1.19 (s, 3H); 1.34–1.57 (m, 2H); 1.61 (s, 3H); 1.62 (m, 1H); 1.70 (m,
1H); 1.90 (m, 1H); 2.91 (dd, 1H, J1¼8.9 Hz, J2¼8.2 Hz); 3.08 (dd,
1H, J1¼8.2 Hz, J2¼7.8 Hz); 3.34 (dd, 1H, J1¼8.9 Hz, J2¼7.8 Hz); 3.44
25
amide (5h). Colorless oil. [
d
a
]
D
ꢀ37.7 (c 1.3, CHCl3). 1H NMR (333 K)
: 0.86–1.07 (m, 2H); 0.93 (d, 3H, J¼6.4 Hz); 1.19 (s, 3H); 1.20 (m,
1H); 1.29 (s, 3H); 1.38–1.78 (m, 4H); 1.97 (s, 3H); 2.03 (m, 1H); 3.09

C. Andre´s et al. / Tetrahedron 65 (2009) 9728–9736
9733
(td, 1H, J1¼10.4 Hz, J2¼4.1 Hz); 3.68 (s, 1H); 3.79 (s, 3H); 4.58 (s,
1H); 4.69 (s, 1H); 4.86 (s, 1H); 6.85 (d, 2H, J¼8.4 Hz); 7.57 (d, 2H,
53.2 (C); 74.9 (CH); 81.8 (C); 87.1 (CH); 116.1 (CH2); 126.8 (CH);
126.9 (2 CH); 128.0 (2 CH); 144.7 (C); 148.7 (C). IR (Nujol disper-
sion): 3515, 3080, 3050, 2935, 775, 700 cmꢀ1. HRMS: calcd for
C25H38NO2 [MþH]þ 384.2903, found 384.2897.
J¼8.4 Hz). 13C NMR
d: 19.8 (CH3); 22.1 (CH3); 23.3 (CH3); 24.6
(CH2); 26.8 (CH3); 31.0 (CH); 34.8 (CH2); 40.9 (CH2); 44.3 (CH);
46.8 (CH2); 53.2 (C); 54.8 (CH3); 56.4 (CH); 74.8 (CH); 79.4 (C);
91.7 (CH); 111.0 (CH2); 112.9 (2 CH); 125.6 (2 CH), 139.8 (C); 143.4
(C); 157.9 (C). IR (Neat): 3525, 3080, 2975, 2930, 2860, 1645, 1610,
4.6.7. (1S,2R,4aS,7R,8aR,9aS)-2-Isopropenyl-4,4,7-trimethyl-1-
(p-tolyl)decahydro-9-oxa-3a-azacyclopenta[b]naphthalen-1-ol
25
1580, 835, 735 cmꢀ1
386.2695, found 386.2686.
.
HRMS: calcd for C24H36NO3 [MþH]þ
(7b). Colorless oil. [
a
]
ꢀ91.4 (c 1.5, CHCl3). 1H NMR
d: 0.86–
D
1.10 (m, 3H); 0.89 (d, 3H, J¼6.5 Hz); 1.16 (s, 3H); 1.17 (s, 3H);
1.35 (m, 1H); 1.47–1.61 (m, 2H); 1.49 (s, 3H); 1.70 (m, 1H); 1.81
(m, 1H); 2.32 (s, 3H); 2.85 (s, 1H); 3.08 (dd, 1H, J1¼9.0 Hz,
J2¼6.4 Hz); 3.27 (td, 1H, J1¼10.4 Hz, J2¼4.0 Hz); 3.38 (dd, 1H,
J1¼9.9 Hz, J2¼9.0 Hz); 3.53 (dd, 1H, J1¼9.9 Hz, J2¼6.4 Hz); 4.43
(s, 1H); 4.85 (s, 1H); 4.88 (s, 1H); 7.12 (d, 2H, J¼8.1 Hz); 7.56 (d,
4.6.3. (1R,2S,4aS,7R,8aR,9aS)-2-Isopropenyl-4,4,7-trimethyl-1-(4-
nitrophenyl)decahydro-9-oxa-3a-azacyclopenta[b]naphthalen-1-ol
25
(6d). Colorless solid. Mp: 100–101 ꢁC (from EtOH). [
a
]
ꢀ12.2
D
(c 0.9, CHCl3). 1H NMR
d
: 0.88–1.04 (m, 2H); 0.93 (d, 3H, J¼6.5 Hz);
1.11 (m, 1H); 1.18 (s, 3H); 1.23 (s, 3H); 1.41–1.81 (m, 4H); 1.59 (s,
3H); 1.91 (m, 1H); 2.90 (dd, 1H, J1¼9.0 Hz, J2¼8.0 Hz); 3.14 (dd, 1H,
J1¼8.0 Hz, J2¼7.7 Hz); 3.41 (dd, 1H, J1¼9.0 Hz, J2¼7.7 Hz); 3.49 (td,
1H, J1¼10.4 Hz, J2¼4.1 Hz); 3.83 (s, 1H); 4.61 (s, 1H); 4.70 (s, 1H);
2H, J¼8.1 Hz). 13C NMR
d: 21.0 (CH3); 22.1 (CH3); 22.3 (CH3);
23.9 (CH3); 24.8 (CH2); 26.2 (CH3); 31.2 (CH); 35.1 (CH2); 41.2
(CH2); 43.0 (CH); 46.6 (CH2); 51.3 (CH); 53.3 (C); 74.5 (CH); 81.4
(C); 93.3 (CH); 112.5 (CH2); 127.0 (2 CH); 128.0 (2 CH); 136.2
(C); 136.7 (C); 143.1 (C). IR (Neat): 3505, 3080, 2925, 2870,
1640, 1515, 820, 735 cmꢀ1. HRMS: calcd for C24H36NO2 [MþH]þ
370.2746, found 370.2755.
4.89 (s, 1H); 7.87 (d, 2H, J¼8.8 Hz); 8.17 (d, 2H, J¼8.8 Hz). 13C NMR
d:
20.4 (CH3); 22.1 (CH3); 23.3 (CH3); 24.7 (CH2); 26.9 (CH3); 31.1 (CH);
34.8 (CH2); 41.0 (CH2); 44.1 (CH); 47.1 (CH2); 53.5 (C); 57.1(CH); 75.2
(CH); 80.0 (C); 91.1 (CH); 112.0 (CH2); 123.1 (2 CH); 125.6 (2 CH),
142.6 (C); 146.5 (C); 155.5 (C). IR (Nujol dispersion): 3500, 3065,
1645, 1595, 1510, 760, 720, 710 cmꢀ1. HRMS: calcd for C23H33N2O4
[MþH]þ 401.2440, found 401.2437.
4.6.8. (1S,2R,4aS,7R,8aR,9aS)-2-Isopropenyl-4,4,7-trimethyl-1-
(4-methoxyphenyl)decahydro-9-oxa-3a-azacyclopenta[b]naph-
25
thalen-1-ol (7c). Colorless oil. [
a]
ꢀ105.5 (c 1.5, CHCl3). 1H NMR
d:
D
0.83–0.95 (m, 2H); 0.90 (d, 3H, J¼6.5 Hz); 1.04 (m, 1H); 1.16 (s, 3H);
1.17 (s, 3H); 1.28–1.51 (m, 2H); 1.49 (s, 3H); 1.56 (m, 1H); 1.70
(m, 1H); 1.82 (m, 1H); 2.85 (s, 1H); 3.07 (dd, 1H, J1¼9.0 Hz,
J2¼6.3 Hz); 3.29 (td, 1H, J1¼10.5 Hz, J2¼4.0 Hz); 3.37 (dd, 1H,
J1¼9.9 Hz, J2¼9.1 Hz); 3.50 (dd, 1H, J1¼9.9 Hz, J2¼6.3 Hz); 3.70 (s,
3H); 4.43 (s, 1H); 4.84 (s, 1H); 4.89 (s, 1H); 6.85 (d, 2H, J¼8.8 Hz);
4.6.4. (1R,2S,4aS,7R,8aR,9aS)-2-Isopropenyl-4,4,7-trimethyl-1-(3-ni-
trophenyl)decahydro-9-oxa-3a-azacyclopenta[b]naphthalen-1-ol
25
(6e). Yellow oil. [
a
]
D
ꢀ41.6 (c 1.0, CHCl3). 1H NMR
d: 0.85–1.01 (m,
2H); 0.94 (d, 3H, J¼6.5 Hz); 1.13 (m, 1H); 1.19 (s, 3H); 1.23 (s, 3H);
1.38–1.68 (m, 3H); 1.61 (s, 3H); 1.73 (m, 1H); 1.93 (m, 1H); 2.90 (dd,
1H, J1¼9.0 Hz, J2¼7.7 Hz); 3.15 (dd, 1H, J1¼8.1 Hz, J2¼7.7 Hz); 3.40
(dd, 1H, J1¼9.0 Hz, J2¼8.1 Hz); 3.49 (td, 1H, J1¼10.5 Hz, J2¼4.1 Hz);
3.81 (s, 1H); 4.60 (s, 1H); 4.71 (s, 1H); 4.89 (s, 1H); 7.50 (t, 1H,
7.59 (d, 2H, J¼8.8 Hz). 13C NMR
d: 22.0 (CH3); 22.2 (CH3); 23.8 (CH3);
24.7 (CH2); 26.1 (CH3); 31.1 (CH); 35.1 (CH2); 41.2 (CH2); 42.9 (CH);
46.5 (CH2); 51.3 (CH); 53.2 (C); 54.9 (CH3); 74.4 (CH); 81.2 (C); 93.2
(CH); 112.5 (CH2þ2 CH); 128.2 (2 CH), 131.8 (C); 142.9 (C); 158.3 (C).
IR (Neat): 3505, 3080, 2930,1640,1610,1585, 830, 740 cmꢀ1. HRMS:
calcd for C24H36NO3 [MþH]þ 386.2695, found 386.2684.
J¼7.9 Hz); 8.02–8.11 (m, 2H); 8.58 (t, 1H, J¼1.9 Hz). 13C NMR
d: 20.3
(CH3); 22.1 (CH3); 23.3 (CH3); 24.7 (CH2); 26.8 (CH3); 31.1 (CH); 34.8
(CH2); 41.0 (CH2); 44.1 (CH); 47.0 (CH2); 53.5 (C); 56.8 (CH); 75.2
(CH); 79.7 (C); 91.2 (CH); 112.0 (CH2); 120.0 (CH); 121.4 (CH); 128.7
(CH); 130.9 (CH); 142.6 (C); 148.0 (C); 150.2 (C). IR (Neat): 3515,
3085, 2925, 2870, 1650, 1530, 730, 700, 685 cmꢀ1. HRMS: calcd for
C23H33N2O4 [MþH]þ 401.2440, found 401.2422.
4.6.9. (1S,2R,4aS,7R,8aR,9aS)-2-Isopropenyl-4,4,7-trimethyl-1-
(4-nitrophenyl)decahydro-9-oxa-3a-azacyclopenta[b]naph-
25
thalen-1-ol (7d). Colorless oil. [
NMR
a
]
ꢀ96.8 (c 0.6, CHCl3). 1H
D
d
: 0.88–1.10 (m, 3H); 0.89 (d, 3H, J¼6.5 Hz); 1.16 (s, 3H);
4.6.5. (1R,2S,4aS,7R,8aR,9aS)-1-Phenyl-2-(1-phenylvinyl)-4,4,7-tri-
methyldecahydro-9-oxa-3a-azacyclopenta[b]naphthalen-1-ol
1.20 (s, 3H); 1.33–1.66 (m, 3H); 1.47 (s, 3H); 1.68–1.82 (m, 2H);
3.01 (s, 1H); 3.11 (dd, 1H, J1¼9.1 Hz, J2¼6.2 Hz); 3.38 (td, 1H,
J1¼10.5 Hz, J2¼4.0 Hz); 3.42 (dd, 1H, J1¼9.7 Hz, J2¼9.1 Hz); 3.52
(dd, 1H, J1¼9.7 Hz, J2¼6.2 Hz); 4.46 (s, 1H); 4.82 (s, 1H); 4.89 (s,
25
(6f). Colorless oil. [
a]
ꢀ9.4 (c 0.9, CHCl3). 1H NMR (CDCl3)
d: 0.90–
D
1.09 (m, 2H); 0.99 (d, 3H, J¼6.5 Hz); 1.19 (m,1H); 1.25 (s, 3H); 1.28 (s,
3H); 1.51 (m, 1H); 1.60–1.75 (m, 2H); 1.80 (m,1H); 1.99 (m,1H); 3.38
(t,1H, J¼7.8 Hz); 3.47–3.65 (m, 3H); 3.79 (s,1H); 4.75 (s,1H); 5.31 (s,
1H); 5.50 (s,1H); 7.06–7.16 (m, 5H); 7.18–7.29 (m, 3H); 7.54–7.59 (m,
1H); 7.90 (d, 2H, J¼9.1 Hz); 8.15 (d, 2H, J¼9.1 Hz). 13C NMR
d:
21.3 (CH3); 22.1 (CH3); 23.5 (CH3); 24.6 (CH2); 26.1 (CH3); 31.0
(CH); 34.9 (CH2); 41.0 (CH2); 43.2 (CH); 46.2 (CH2); 52.2 (CH);
53.4 (C); 74.6 (CH); 81.3 (C); 93.1 (CH); 113.1 (CH2); 122.1 (2
CH); 128.1 (2 CH), 141.9 (C); 146.6 (C); 147.9 (C). IR (Neat):
3515, 3085, 2965, 1640, 1600, 730, 700 cmꢀ1. HRMS: calcd for
C23H33N2O4 [MþH]þ 401.2440, found 401.2435.
2H). 13C NMR
d: 20.5 (CH3); 22.2 (CH3); 24.7 (CH2); 26.9 (CH3); 31.1
(CH); 34.9 (CH2); 41.1 (CH2); 44.2 (CH); 49.6 (CH2); 53.4 (C); 54.6
(CH); 75.0 (CH); 79.6 (C); 91.7 (CH); 114.4 (CH2); 124.6 (2 CH); 126.1
(CH); 126.5 (2 CH); 126.6 (CH); 127.5 (4 CH); 142.7 (C); 147.2 (2 C). IR
(Neat): 3520, 3050, 2975, 2925, 2870, 1605, 765, 700 cmꢀ1. HRMS:
calcd for C28H36NO2 [MþH]þ 418.2746, found 418.2742.
4.6.10. (1S,2R,4aS,7R,8aR,9aS)-2-Isopropenyl-4,4,7-trimethyl-1-
(3-nitrophenyl)decahydro-9-oxa-3a-azacyclopenta[b]naph-
4.6.6. (1S,2S,4aS,7R,8aR,9aS)-1-Isopropyl-2-(1-phenylvinyl)-4,4,7-
trimethyldecahydro-9-oxa-3a-azacyclopenta[b]naphthalen-1-ol
thalen-1-ol (7e). Yellow solid. Mp: 154–155 ꢁC (from MeOH).
25
[
a
]
ꢀ86.3 (c 0.9, CHCl3). 1H NMR (CDCl3)
d: 0.83–1.15 (m, 3H);
D
25
(6h). Colorless solid. Mp: 73–74 ꢁC (from EtOH). [
a
]
D
þ13.9 (c 0.9,
0.90 (d, 3H, J¼6.5 Hz); 1.16 (s, 3H); 1.19 (s, 3H); 1.43 (m, 1H); 1.50
(s, 3H); 1.51–1.68 (m, 2H); 1.70–1.85 (m, 2H); 2.95 (s, 1H); 3.10
(dd, 1H, J1¼8.9 Hz, J2¼6.1 Hz); 3.29 (td, 1H, J1¼10.4 Hz,
J2¼4.0 Hz); 3.43 (dd, 1H, J1¼9.7 Hz, J2¼8.9 Hz); 3.51 (dd, 1H,
J1¼9.7 Hz, J2¼6.1 Hz); 4.45 (s, 1H); 4.82 (s, 1H); 4.90 (s, 1H); 7.46
(t, 1H, J¼8.0 Hz); 8.01–8.08 (m, 1H); 8.09–8.12 (m, 1H); 8.62 (t,
CHCl3). 1H NMR
d
: 0.72 (d, 3H, J¼6.8 Hz); 0.80 (d, 3H, J¼6.8 Hz);
0.87–1.04 (m, 2H); 0.93 (d, 3H, J¼6.5 Hz); 1.10 (m, 1H); 1.10 (s, 3H);
1.13 (s, 3H); 1.44–1.54 (m, 2H); 1.55–1.76 (m, 3H); 1.96 (m, 1H); 3.21
(s, 3H); 3.23 (s,1H); 3.50 (td,1H, J1¼10.5 Hz, J2¼4.0 Hz); 4.56 (s,1H);
5.30 (s, 1H); 5.40 (s, 1H); 7.19–7.37 (m, 5H). 13C NMR
d: 17.4 (CH3);
17.8 (CH3); 20.6 (CH3); 22.3 (CH3); 24.9 (CH2); 26.6 (CH3); 31.3 (CH);
35.1 (CH2); 35.9 (CH); 41.4 (CH2); 43.9 (CH); 47.3 (CH); 51.8 (CH2);
1H, J¼1.9 Hz). 13C NMR
d: 21.6 (CH3); 22.2 (CH3); 23.7 (CH3); 24.7
(CH2); 26.2 (CH3); 31.2 (CH); 35.0 (CH2); 41.0 (CH2); 43.2 (CH);

9734
C. Andre´s et al. / Tetrahedron 65 (2009) 9728–9736
46.5 (CH2); 52.1 (CH); 53.5 (C); 74.7 (CH); 81.1 (C); 93.1 (CH);
113.4 (CH2); 121.8 (CH); 122.6 (CH), 127.9 (CH); 133.5 (CH);
142.0 (C); 142.6 (C); 147.7 (C). IR (Nujol dispersion): 3480, 3085,
1635, 1580, 720, 700 cmꢀ1. HRMS: calcd for C23H33N2O4 [MþH]þ
401.2440, found 401.2432.
(s, 3H); 1.24–1.50 (m, 2H); 1.33 (s, 3H); 1.52–1.70 (m, 2H); 1.94 (m,
1H); 2.29 (s, 3H); 2.50 (br s, 1H); 2.98–3.19 (m, 4H); 3.33 (m, 1H);
3.65 (td, 1H, J1¼10.4 Hz, J2¼4.0 Hz); 4.83 (s, 1H); 4.95 (s, 1H); 7.10
(d, 2H, J¼8.1 Hz); 7.36 (d, 2H, J¼8.1 Hz); 8.41 (br s, 1H). 13C NMR
(333 K) d: 17.0 (CH3); 20.6 (CH3); 21.3 (CH3); 21.8 (CH3); 24.0 (CH3);
25.5 (CH2); 30.8 (CH); 35.0 (CH2); 44.2 (CH2); 48.4 (CH2); 48.7 (CH);
56.0 (CH); 59.3 (C); 62.2 (CH2); 72.7 (CH); 79.1 (C); 113.4 (CH2);
124.9 (2 CH); 128.6 (2 CH); 136.0 (C); 141.2 (C); 141.3 (C). IR (Neat):
3530, 3260, 3085, 2920, 1640, 1510, 730, 645 cmꢀ1. HRMS: calcd for
C24H38NO2 [MþH]þ 372.2903, found 372.2890.
4.6.11. (1S,2R,4aS,7R,8aR,9aS)-1-Phenyl-2-(1-phenylvinyl)-4,4,7-tri-
methyldecahydro-9-oxa-3a-azacyclopenta[b]naphthalen-1-ol
25
(7f). Colorless solid. Mp: 98–99 ꢁC (from EtOH). [
a
]
D
ꢀ26.5 (c 0.9,
CHCl3). 1H NMR
d
: 0.86–1.01 (m, 3H); 0.89 (d, 3H, J¼6.5 Hz); 1.12
(s, 3H); 1.16 (s, 3H); 1.39 (m, 1H); 1.48–1.63 (m, 2H); 1.71 (m, 1H);
1.81 (m, 1H); 2.94 (dd, 1H, J1¼9.2 Hz, J2¼7.3 Hz); 3.04 (s, 1H); 3.30
(td, 1H, J1¼10.4 Hz, J2¼4.0 Hz); 3.52 (dd, 1H, J1¼9.9 Hz, J2¼9.2 Hz);
4.12 (dd, 1H, J1¼9.9 Hz, J2¼7.3 Hz); 4.54 (s, 1H); 5.29 (s, 1H); 5.37 (s,
4.7.2. (3R,4S)-4-Isopropenyl-1-(8-mentholyl)-3-(4-methoxy-
phenyl)pyrrolidin-3-ol (9c). Yield: 95%. Colorless oil. 1H NMR
(333 K)
d
: 0.86–1.14 (m, 3H); 0.89 (d, 3H, J¼6.5 Hz); 1.03 (s, 3H);
1H); 7.10–7.22 (m, 8H); 7.56–7.60 (m, 2H). 13C NMR
d
: 21.7 (CH3);
1.21 (s, 3H); 1.23–1.50 (m, 2H); 1.35 (s, 3H); 1.56–1.67 (m, 2H); 1.93
(m, 1H); 2.34 (br s, 1H); 3.00–3.16 (m, 4H); 3.31 (m, 1H); 3.66 (td,
1H, J1¼10.3 Hz, J2¼4.0 Hz); 3.77 (s, 3H); 4.85 (s, 1H); 4.98 (s, 1H);
6.84 (d, 2H, J¼8.8 Hz); 7.35 (br s, 1H); 7.40 (d, 2H, J¼8.8 Hz). 13C
22.2 (CH3); 24.7 (CH2); 26.2 (CH3); 31.2 (CH); 35.0 (CH2); 41.2 (CH2);
43.3 (CH); 48.4 (CH); 48.9 (CH2); 53.3 (C); 74.5 (CH); 81.5 (C); 93.6
(CH); 115.7 (CH2); 126.6 (CH); 126.7 (2 CH); 126.8 (CH); 127.1 (4
CH); 127.8 (2 CH); 139.4 (C); 143.1 (C); 146.1 (C). IR (Nujol disper-
NMR (333 K) d: 17.1 (CH3); 21.4 (CH3); 21.9 (CH3); 24.2 (CH3); 25.6
sion): 3488, 2927, 2860, 1605, 699 cmꢀ1
.
HRMS: calcd for
(CH2); 31.0 (CH); 35.1 (CH2); 44.3 (CH2); 48.5 (CH2); 48.9 (CH);
55.1 (CH3); 56.1 (CH); 59.5 (C); 62.3 (CH2); 72.9 (CH); 79.1 (C);
113.6 (2 CH); 113.7 (CH2); 126.2 (2 CH); 136.3 (C); 141.5 (C); 158.7
(C). HRMS: calcd for C24H38NO3 [MþH]þ 388.2852, found
388.2851.
C28H35NO2Na [MþNa]þ 440.2565, found 440.2548.
4.6.12. (1R,2R,4aS,7R,8aR,9aS)-1-Isopropyl-2-(1-phenylvinyl)-4,4,7-
trimethyldecahydro-9-oxa-3a-azacyclopenta[b]naphthalen-1-ol
25
(7h). Colorless oil. [
a]
ꢀ6.2 (c 1.3, CHCl3). 1H NMR
d: 0.71 (d, 3H,
D
J¼6.8 Hz); 0.83–1.00 (m, 2H); 0.88 (d, 3H, J¼6.8 Hz); 0.92 (d, 3H,
J¼6.5 Hz); 1.05 (m, 1H); 1.10 (s, 3H); 1.18 (s, 3H); 1.40–1.53 (m, 2H);
1.59 (m, 1H); 1.72 (m, 1H); 1.81–1.94 (m, 2H); 2.27 (s, 1H); 2.89 (dd,
1H, J1¼8.6 Hz, J2¼5.6 Hz); 3.35 (td, 1H, J1¼10.4 Hz, J2¼4.0 Hz); 3.43
(dd, 1H, J1¼10.0 Hz, J2¼5.6 Hz); 3.56 (dd, 1H, J1¼10.0 Hz, J2¼8.6 Hz);
4.7.3. (3R,4S)-1-(8-Mentholyl)-3-phenyl-4-(1-phenylvinyl)pyrrolidin-
25
3-ol (9f). Yield: 90%. Colorless oil. [
a
]
þ8.2 (c 1.1, CHCl3). 1H NMR
D
(333 K)
d
: 0.71–1.00 (m, 3H); 0.81 (d, 3H, J¼6.5 Hz); 0.98 (s, 3H); 1.15
(s, 3H); 1.32 (m, 1H); 1.46–1.62 (m, 2H); 1.72 (m, 1H); 1.87 (m, 1H);
2.50 (br s, 1H); 3.02–3.21 (m, 2H); 3.34 (m, 1H); 3.51–3.68 (m, 3H);
5.21 (s, 1H); 5.26 (s,1H); 6.79–6.81 (m, 2H); 6.87–7.02 (m, 6H); 7.17–
4.55 (s, 1H); 5.39 (s, 1H); 5.55 (s, 1H); 7.20–7.39 (m, 5H). 13C NMR
d:
17.6 (CH3); 18.4 (CH3); 22.3 (2 CH3); 24.8 (CH2); 26.3 (CH3); 31.3
(CH); 32.1 (CH); 35.1 (CH2); 41.5 (CH2); 42.9 (CH); 47.0 (CH); 53.1
(C); 53.4 (CH2); 74.5 (CH); 83.9 (C); 92.7 (CH); 115.9 (CH2); 126.6 (2
CH); 127.0 (CH); 128.1 (2 CH); 144.3 (C); 149.2 (C). IR (Neat): 3530,
3085, 3060, 3025, 2925, 1610, 775, 700 cmꢀ1. HRMS: calcd for
C25H38NO2 [MþH]þ 384.2903, found 384.2893.
7.20 (m, 3H). 13C NMR (333 K)
d: 17.1(CH3); 21.4(CH3); 21.9(CH3);
25.6(CH2); 31.0(CH); 35.1(CH2); 44.3(CH2); 48.8 (CH); 49.9 (CH2);
54.3 (CH); 59.5 (C); 62.3 (CH2); 72.8 (CH); 79.7 (C); 116.4 (CH2);
125.0 (2 CH); 126.4 (CH); 126.5 (2 CH); 126.9 (CH); 127.7 (4 CH);
142.1 (C); 143.6 (C); 145.6 (C). IR (Neat): 3275, 3050, 3025, 2945,
1605, 760, 730, 700 cmꢀ1. HRMS: calcd for C28H38NO2 [MþH]þ
420.2903, found 420.2896.
4.6.13. Oxetane (8). Yellow oil. 1H NMR
d: 0.84–1.00 (m, 2H); 0.87
(d, 3H, J¼6.3 Hz); 0.94 (s, 3H); 1.18 (m, 1H); 1.25 (s, 3H); 1.28 (s, 3H);
1.30 (m, 1H); 1.45 (m, 1H); 1.53 (s, 3H); 1.61–1.72 (m, 2H); 1.85 (m,
1H); 2.59 (d, 1H, J¼6.1 Hz); 2.77 (dd, 1H, J1¼10.1 Hz, J2¼6.1 Hz); 3.18
(d, 1H, J¼10.1 Hz); 3.23 (td, 1H, J1¼10.4 Hz, J2¼4.2 Hz); 3.98 (s, 1H);
4.8. Synthesis of amino alcohols 10c and 10h
NaBH3CN (0.52 g, 8.3 mmol) was added to a solution of 7c or
7h (3 mmol) in methanol (50 mL) cooled to 0 ꢁC and acidified to
pHw4 by an aqueous solution of HCl 0.1 M. The mixture was
heated at 60 ꢁC and the pH maintained at 4 by periodic addition of
0.1 M HCl until the reaction was completed (TLC). The solvents
were eliminated under reduced pressure, the residue dissolved in
CH2Cl2 (40 mL), and an aqueous solution of KOH 2.5 M (25 mL)
was added. The mixture was stirred for 30 min, the organic layer
was decanted, and the aqueous layer was extracted with CH2Cl2
(3ꢂ20 mL). The combined organic fractions were washed with
brine, dried over anhydrous MgSO4, filtered, and the solvent was
eliminated under reduced pressure. The residue was purified by
flash chromatography on silica gel using a mixture of hexane/
EtOAc 3:1 as eluent.
7.21–7.48 (m, 5H). 13C NMR
d: 10.7 (CH3); 22.0 (2 CH3); 24.5 (CH2);
26.5 (CH3); 30.6 (CH3); 31.3 (CH); 34.7 (CH2); 41.0 (CH2); 41.8 (CH2);
48.1 (CH); 49.4 (CH); 54.6 (C); 76.5 (CH); 81.8 (C); 85.1 (C); 93.1
(CH); 125.0 (2 CH); 126.7 (CH); 127.8 (2 CH); 143.4 (C). IR (Neat):
2950, 1600, 1450, 1380, 990, 750, 690 cmꢀ1. HRMS: calcd for
C23H34NO2 [MþH]þ 356.2590, found 356.2572.
4.7. Synthesis of amino alcohols 9b, 9c, and 9f
Dry AlCl3 (0.67 g, 5 mmol) was added, in portions, to a suspen-
sion of LiAlH4 (0.57 g, 15 mmol) in anhydrous THF (40 mL) cooled to
ꢀ10 ꢁC. The mixture was stirred for 10 min and a solution of the
corresponding adduct (3 mmol) in dry THF (20 mL) was slowly
added. The reaction mixture was stirred for 8 min at ꢀ10 ꢁC and
quenched by addition of H2O (4 mL). The resulting mixture was
filtered, the solid was washed with EtOAc, and the organic layer
was dried (MgSO4). The solvent was eliminated under reduced
pressure and the residue was chromatographed on silica gel with
hexane/EtOAc 3:1 as eluent.
4.8.1. (3S,4R)-4-Isopropenyl-1-(8-mentholyl)-3-(4-methoxy-
phenyl)pyrrolidin-3-ol (10c). Yield: 86%. Colorless solid. Mp: 138–
25
139 ꢁC (from Hexane). [
a]
ꢀ65.8 (c 0.4, CHCl3). 1H NMR (333 K)
d:
D
0.78–1.11 (m, 3H); 0.84 (d, 3H, J¼6.5 Hz); 0.96 (s, 3H); 1.08 (s, 3H);
1.29 (s, 3H); 1.35–1.66 (m, 4H); 1.92 (m, 1H); 2.25 (br s, 1H); 2.90
(dd, 1H, J1¼10.8 Hz, J2¼7.8 Hz); 2.93–3.21 (m, 4H); 3.61 (td, 1H,
J1¼10.6 Hz, J2¼4.1 Hz); 3.70 (s, 3H); 4.74 (s, 1H); 4.92 (s, 1H); 6.76 (d,
2H, J¼8.8 Hz); 7.31 (d, 2H, J¼8.8 Hz); 8.12 (br s, 1H). 13C NMR
4.7.1. (3R,4S)-4-Isopropenyl-1-(8-mentholyl)-3-p-tolylpyrrolidin-3-
25
ol (9b). Yield: 92%. Colorless oil. [
(333 K)
a]
þ5.4 (c 0.7, CHCl3). 1H NMR
(333 K) d: 17.7 (CH3); 21.0 (CH3); 22.0 (CH3); 24.1 (CH3); 25.9 (CH2);
D
d
: 0.79–1.11 (m, 3H); 0.89 (d, 3H, J¼6.5 Hz); 1.04 (s, 3H); 1.21
31.1 (CH); 35.2 (CH2); 44.4 (CH2); 48.2 (CH2); 48.7 (CH); 55.2 (CH3);

C. Andre´s et al. / Tetrahedron 65 (2009) 9728–9736
9735
56.8 (CH); 59.3 (C); 63.1 (CH2); 72.9 (CH); 78.6 (C); 113.7 (2 CH);
113.8 (CH2); 125.9 (2 CH); 137.6 (C); 141.8 (C); 158.6 (C). IR (Nujol
143.5 (C). 158.8 (C). IR (Neat): 3505, 3065, 2955, 1640, 1610, 1515,
830, 755, 660 cmꢀ1. HRMS: calcd for C21H25NO4NaS [MþNa]þ
410.1402, found 410.1398.
dispersion): 3340, 3080, 1640, 1610, 1580, 770, 755, 685 cmꢀ1
.
HRMS: calcd for C24H38NO3 [MþH]þ 388.2852, found 388.2845.
4.9.3. (3R,4S)-3-Phenyl-4-(1-phenylvinyl)-1-tosylpyrrolidin-3-ol
(11f). Yield: 50%. Colorless solid. Mp: 103–104 ꢁC (from Hexane).
4.8.2. (3R,4R)-3-Isopropyl-1-(8-mentholyl)-4-(1-phenyl-
25
25
vinyl)pyrrolidin-3-ol (10h). Yield: 85%. Colorless oil. [
a
]
ꢀ63.5
[a
]
þ15.15 (c 0.5 CHCl3). 1H NMR
d: 2.27 (br s, 1H); 2.45 (s, 3H);
D
D
(c 1.1, CHCl3). 1H NMR (333 K)
d
: 0.72 (d, 3H, J¼6.8 Hz); 0.77
3.51 (dd, 1H, J1¼11.5 Hz, J2¼9.2 Hz); 3.62 (d, 1H, J¼11.3 Hz); 3.70
(dd, 1H, J1¼11.5 Hz, J2¼7.2 Hz); 3.75 (d, 1H, J¼11.3 Hz); 3.90 (dd, 1H,
J1¼9.2 Hz, J2¼7.2 Hz); 5.13 (s, 1H); 5.30 (s, 1H); 6.82–6.85 (m, 2H);
6.99–7.15 (m, 8H); 7.35 (d, 2H, J¼8.2 Hz); 7.78 (d, 2H, J¼8.2 Hz). 13C
(d, 3H, J¼6.8 Hz); 0.87–1.11 (m, 3H); 0.92 (d, 3H, J¼6.5 Hz); 1.01
(s, 3H); 1.18 (s, 3H); 1.31–1.52 (m, 2H); 1.55–1.73 (m, 3H); 1.96
(m, 1H); 2.71 (d, 1H, J¼10.4 Hz); 2.91 (m, 1H); 3.02 (d, 1H,
J¼10.4 Hz); 3,23–3.31 (m, 2H); 3.65 (td, 1H, J1¼10.0 Hz,
J2¼4.0 Hz); 5.29 (s, 1H); 5.42 (s, 1H); 7.23–7.33 (m, 5H); 8.07 (br s,
NMR d: 21.5 (CH3); 51.2 (CH2); 53.3 (CH); 62.6 (CH2); 80.2 (C); 117.1
(CH2); 124.9 (2 CH); 126.4 (2 CH); 127.1 (CH); 127.2 (CH); 127.5 (2
CH); 127.8 (2 CH); 127.9 (2 CH); 129.6 (2 CH); 133.7 (C); 140.6 (C);
141.4 (C); 143.5 (C); 143.7 (C). IR (Nujol dispersion): 3510, 3060,
3030, 2955, 2890, 1620, 1600, 760, 705, 670 cmꢀ1. HRMS: calcd for
C25H25NO3NaS [MþNa]þ 442.1453, found 442.1447.
1H). 13C NMR (333 K)
d: 17.4 (CH3); 17.5 (CH3); 18.0 (CH3); 21.1
(CH3); 22.0 (CH3); 25.9 (CH2); 31.1 (CH); 35.2 (CH2); 35.6 (CH);
44.5 (CH2); 48.4 (CH); 48.5 (CH); 50.6 (CH2); 54.6 (CH2); 59.2 (C);
72.8 (CH); 81.2 (C); 117.0 (CH2); 126.8 (2 CH); 127.5 (CH); 128.3 (2
CH); 143.4 (C); 146.9 (C). IR (Neat): 3400, 3055, 2950, 2875, 1625,
1600, 775, 735, 700 cmꢀ1. HRMS: calcd for C25H40NO2 [MþH]þ
386.3059, found 386.3053.
4.9.4. (3S,4R)-4-Isopropenyl-3-(4-methoxyphenyl)-1-tosylpyrroli-
25
din-3-ol (12c). Yield: 52%. Colorless oil. [
a
]
D
ꢀ14.2 (c 1.1, CHCl3). 1H
NMR, 13C NMR and IR data are coincident with those reported for
11c. HRMS: calcd for C21H25NO4NaS [MþNa]þ 410.1402, found
410.1387.
4.9. Elimination of the menthol appendage
A
solution of amino derivatives 9b, 9c, 19f, 10c or 10h
(1.0 mmol) and PCC (1.3 g, 6 mmol) in CH2Cl2 (40 mL) and 4 Å
molecular sieves (2 g) was stirred at room temperature until the
oxidation was finished (TCL, 3–6 h). The solvent was eliminated
under reduced pressure, the residue was dissolved in a 15%
aqueous solution of NaOH (25 mL), and the resulting solution was
extracted with EtOAc. The organic phase was washed with brine
and dried over anhydrous magnesium sulfate. The solvents were
eliminated under vacuum, the residue was taken up in a 2.5 M
solution (16 mL) of KOH in THF/MeOH/H2O (2:1:1), and the solu-
tion was stirred at room temperature for 5–6 h. After elimination
of the solvents under reduced pressure, the residue was dissolved
in 50 mL of CH2Cl2 and washed with H2O. The organic layer was
dried over MgSO4 and filtered and the solvent was eliminated
under vacuum to give an oily residue that was treated with an
excess of tosyl chloride in diisopropylethylamine in ethyl acetate
for 72 h. After elimination of the solvents, the residues were pu-
rified by flash chromatography on silica gel using a mixture of
hexane/EtOAc 15:1 as eluent.
4.9.5. (3R,4R)-3-Isopropyl-4-(1-phenylvinyl)-1-tosylpyrrolidin-3-ol
25
(12h). Yield: 46%. Colorless oil. [
a]
ꢀ40.2 (c 1.3, CHCl3). 1H NMR
d:
D
0.53 (d, 3H, J¼6.8 Hz); 0.78 (d, 3H, J¼6.8 Hz); 1.27 (m, 1H); 1.51
(s, 1H); 2.45 (s, 3H); 3.23 (d, 1H, J¼11.0 Hz); 3.26 (dd, 1H, J1¼11.5 Hz,
J2¼6.9 Hz); 3.38 (dd, 1H, J1¼11.5 Hz, J2¼8.9 Hz); 3.46 (d, 1H,
J¼11.0 Hz); 3.78 (dd, 1H, J1¼8.9 Hz, J2¼6.9 Hz); 5.19 (s, 1H); 5.41
(s, 1H); 7.20–7.33 (m, 5H); 7.35 (d, 2H, J¼8.2 Hz); 7.78 (d, 2H,
J¼8.2 Hz). 13C NMR
d: 17.5 (CH3); 17.8 (CH3); 21.6 (CH3); 34.4 (CH);
48.1 (CH); 52.1 (CH2); 55.2 (CH2); 82.5 (C); 117.4 (CH2); 126.5
(2 CH); 127.5 (2 CH); 127.8 (CH); 128.5 (2 CH); 129.6 (2 CH); 133.9
(C); 142.6 (C); 143.4 (C); 144.3 (C). IR (Neat): 3515, 3060, 2960,
2880, 1620, 1600, 1495, 780, 735, 710, 665 cmꢀ1. HRMS: calcd for
C22H27NO3NaS [MþNa]þ 408.1609, found 408.1608.
Acknowledgements
We acknowledge financial support by the Spanish Ministerio de
´
Ciencia e Innovacion (project CTQ2008-03960/BQU) and Junta de
´
Castilla y Leon (GR168).
4.9.1. (3R,4S)-4-Isopropenyl-3-(p-tolyl)-1-tosylpyrrolidin-3-ol
25
(11b). Yield: 54%. Colorless oil. [
a]
þ8.5 (c 1.5, CHCl3). 1H NMR
d:
D
Supplementary data
1.23 (s, 3H); 2.12 (br s, 1H); 2.31 (s, 3H); 2.44 (s, 3H); 3.11 (dd, 1H,
J1¼11.5 Hz, J2¼7.3 Hz); 3.46 (dd, 1H, J1¼11.5 Hz, J2¼9.4 Hz); 3.59
(d, 1H, J¼11.3 Hz); 3.67 (d, 1H, J¼11.3 Hz); 3.74 (dd, 1H, J1¼9.4 Hz,
J2¼7.3 Hz); 4.73 (s, 1H); 4.96 (s, 1H); 7.12 (d, 2H, J¼8.2 Hz); 7.23
(d, 2H, J¼8.2 Hz); 7.34 (d, 2H, J¼8.2 Hz); 7.76 (d, 2H, J¼8.2 Hz). 13C
Copies of 1H NMR and 13C NMR spectra for compounds 3b–f, 3h,
6b–f, 6h, 7b–f, 7h, 9b–c, 9f, 10c, 10h, 11b–c, 11f, 12c, 12h and copies
of NOESY experiments for 6b–d, 6h, 7b–d. Supplementary data
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2009.09.091.
NMR d: 20.9 (CH3); 21.6 (CH3); 24.3 (CH3); 50.1 (CH2); 55.5 (CH);
62.7 (CH2); 79.7 (C); 114.6 (CH2); 124.8 (2 CH); 127.6 (2 CH); 129.0
(2 CH); 129.6 (2 CH); 133.9 (C); 137.2(C); 138.4 (C); 139.7 (C); 143.5
References and notes
(C). IR (Neat): 3505, 3025, 2950, 2925, 1640, 1595, 735, 660 cmꢀ1
.
HRMS: calcd for C21H25NO3NaS [MþNa]þ 394.1453, found 394.1457.
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25
din-3-ol (11c). Yield: 46%. Colorless oil. [
NMR
a]
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D
d
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