Stereoselective total synthesis of (-)-β-conhydrine and (+)-α-conhydrine

Article abstract of DOI:10.1055/s-0030-1258390

We have carried out the stereoselective synthesis of (-)-β- conhydrine and (+)-α-conhydrine, two bioactive α-hydroxyalkyl-substituted piperidines, using the commercially available and inexpensive amino alcohol (S,S)-(+)-pseudoephedrine as chiral auxiliary. The key step of this synthesis relies on new methodology previously developed in our group, consisting of the chemo- and diastereoselective addition of Grignard reagents across the C=N bond of α-iminoglyoxylamides derived from (S,S)-(+)-pseudoephedrine followed by the selective monoaddition of organolithium reagents to the carbamoyl group, leading to the formation of enantioenriched -amino ketones. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258390

PAPER
443
Stereoselective Total Synthesis of (–)-b-Conhydrine and (+)-a-Conhydrine
Efraim Reyes, Nerea Ruiz, Jose L. Vicario,* Dolores Badía,* Luisa Carrillo
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko Unibertsitatea,
P. O. Box 644, 48080 Bilbao, Spain
Fax +34(94)6012748; E-mail: dolores.badia@ehu.es; E-mail: joseluis.vicario@ehu.es
Received 28 September 2010; revised 2 November 2010
developed methodology for the stereoselective modular
synthesis of a-amino ketones.5 In this transformation, we
have set up an efficient protocol for carrying out the addi-
tion of Grignard reagents to the azomethine moiety of an
Abstract: We have carried out the stereoselective synthesis of (–)-
b-conhydrine and (+)-a-conhydrine, two bioactive a-hydroxyalkyl-
substituted piperidines, using the commercially available and inex-
pensive amino alcohol (S,S)-(+)-pseudoephedrine as chiral auxilia-
ry. The key step of this synthesis relies on new methodology a-imino glyoxylamide derived from (+)-(S,S)-pseudo-
ephedrine.6 Access to enantioenriched a-amino ketones
previously developed in our group, consisting of the chemo- and
diastereoselective addition of Grignard reagents across the C=N
bond of a-iminoglyoxylamides derived from (S,S)-(+)-pseudoephe-
epimerization-free 1,2-addition of organolithium reagents
drine followed by the selective monoaddition of organolithium
reagents to the carbamoyl group, leading to the formation of enan-
was subsequently achieved by selective and almost
across the amide C=O bond (Scheme 1).
tioenriched a-amino ketones.
O
O
Key words: asymmetric synthesis, chiral auxiliaries, piperidines,
total synthesis, conhydrine
R1
Bn
Ph
R1MgCl
H
Ph
N
N
Me
Me
THF, –78 °C
NH
OH
N
OH
Bn
19–89%
dr 94:6 to >99:5
Conhydrine belongs to the family of 2-(1-hydroxy-
alkyl)piperidines, which have attracted considerable in-
terest from synthetic organic chemists due to the potent
antiviral and antitumor activity displayed by these com-
pounds.1 In the particular case of conhydrine, two differ-
ent diastereomers, namely a-conhydrine and b-
conhydrine (Figure 1), have been isolated from the seeds
and leaves of the poisonous plant Conium maculatum L.
Since its first isolation in 1856,2 several
nonstereoselective3 and stereocontrolled4 syntheses have
been reported. However, in contrast to the wide number of
reports describing the asymmetric synthesis of the a-iso-
mer of conhydrine, the examples related to the asymmet-
ric synthesis of b-conhydrine are scarce. In fact, to the
best of our knowledge, there are only three literature pre-
cedents related to the synthesis of (+)-b-conhydrine4c,j,s
and another few papers have reported the preparation of
the enantiomer, (–)-b-conhydrine.4b,e,i,n,r
O
R1
Bn
R2
R2Li
NH
THF, –78 °C to r.t.
27–83%
78 to >99% ee
Scheme 1
Therefore, the synthesis of conhydrine was planned ac-
cording to the retrosynthetic approach shown in
Scheme 2, according to which the target compound
should be obtained from a 6-acylpiperidin-2-one precur-
sor through several consecutive reductions, the diastereo-
selective reduction of the ketone moiety being a critical
step of the synthesis. The construction of the piperidinone
skeleton was proposed to be carried out by ring-closing
metathesis (RCM) from a conveniently functionalized a-
amino ketone, which in turn should be accessible in an
enantioenriched form by applying the already mentioned
protocol set up by our research group.
NH
NH
NH
NH
OH
OH
OH
OH
O
O
(+)-β-conhydrine (–)-β-conhydrine (+)-α-conhydrine (–)-α-conhydrine
NH
Bn
O
Bn
O
N
N
Figure 1 The four different stereoisomers of conhydrine
OH
With these precedents in mind, we became interested in
carrying out the synthesis of (–)-b-conhydrine as a test
molecule for us to check the applicability of our recently
Bn
H
Bn
N
OH
NH
Me
N
Ph
SYNTHESIS 2011, No. 3, pp 0443–0450
Advanced online publication: 05.01.2011
DOI: 10.1055/s-0030-1258390; Art ID: T19910SS
x
x
.
x
x
.2
0
1
1
O
O
Scheme 2
© Georg Thieme Verlag Stuttgart · New York

444
E. Reyes et al.
PAPER
The synthesis commenced with the preparation of the similar diastereoselective reductions of N-Boc-protected
enantioenriched chiral a-amino ketone 4, starting from the a-amino ketones when using borohydride reagents.9 The
corresponding (+)-(S,S)-pseudoephedrine a-imino glyox- synthesis was completed by lithium aluminum hydride
ylamide 2, according to the procedure previously de- promoted reduction of the lactam moiety followed by de-
scribed by us (Scheme 3).5 Imino amide 2, which is benzylation under hydrogenolytic conditions, which led
actually present in the reaction medium as a mixture of us to the target compound 9.
tautomeric cyclic 2¢ and acyclic 2 forms, was prepared by
condensation of morpholinone 1 and benzylamine. Dia-
O
O
Grubbs II cat.
(4 mol%)
H2C=CHCOCl
Et3N
stereoselective addition of allylmagnesium chloride to this
compound followed, with the open-chain tautomer readily
undergoing the diastereoselective 1,2-addition reaction
with the azomethine moiety. Subsequently, the enantioen-
riched a-amino ketone 4 was obtained by selective
monoaddition of ethyllithium across the C=O bond of the
amide moiety, leading to the target compound in moderate
yield and 78% ee. As has been shown in other examples,
the pseudoephedrine amino alcohol moiety plays a crucial
role in this reaction by stabilizing the tetrahedral interme-
diate formed during this step and avoiding the competitive
overaddition reaction, with similar efficiency as that of
morpholine or Weinreb amides.7
Bn
O
Bn
O
N
N
4
Et
Et
CH2Cl2, reflux
75%
THF, r.t.
80%
5
6
H2, Pd/C
MeOH, r.t.
99%
O
O
1. LAH, THF,
reflux
Bn
Bn
N
NH
LiBH4
N
Et
2. H2, Pd/C
MeOH, r.t.
Et THF, –78 °C
Et
53%
OH
dr >95:5
OH
O
9
92%
8
7
Scheme 4
Ph
Ph
Bn
BnNH2
Disappointingly, when we compared the [a]D20 value ob-
tained for our synthesized sample of (–)-b-conhydrine (9)
{[a]D20 –3.82 (c 0.40 in CHCl3)} with the one reported in
the literature for the same isomer {[a]D20 –34.10 (c 0.40 in
CHCl3)},4r we found a significant difference between the
two values; this seemed to indicate that the stereoisomeric
purity of the obtained compound was not as high as ex-
pected. As the NMR spectrum of 9 indicated the presence
of a single diastereomer, this should indicate that a certain
degree of racemization had occurred during the synthetic
route depicted in Scheme 4. After analyzing the per-
formed steps and all the compounds obtained, we hypo-
thesized that the racemization side reaction probably
occurs in the metathesis step, due to the high temperature
and rather long reaction time needed for the conversion of
a-amino ketone 5 into piperidinone 6 and also given the
known ability of these kinds of compounds to racemize,
because of the rather high acidity of the a-hydrogen
present at the stereogenic center.
N
OH
anhyd Na2SO4
O
Me
N
O
MeN
H
Ph
MeN
Et2O, r.t.
OH
NHBn
73%
O
O
O
1
2
2'
H2C=CHCH2MgCl
THF, –78 °C
79%
dr 92:8
Bn
Bn
NH
NH
OH
1. EtLi, –78 to 0 °C
Me
N
Ph
2. NH4Cl, r.t.
42%, 78% ee
O
O
4
3
Scheme 3
We next proceeded with the N-acylation of a-amino ke-
tone 4 under standard conditions, isolating the corre-
sponding keto amide 5 in good yield (Scheme 4) and then,
after refluxing a solution of 5 in anhydrous dichlo-
romethane for 48 hours in the presence of 4 mol% of
benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidin-
ylidene]dichloro(tricyclohexylphosphine)ruthenium (sec-
ond generation Grubbs catalyst),8 we were able to isolate
the expected dihydropyridinone 6 in 75% yield. Catalytic
hydrogenation with palladium on carbon furnished deriv-
ative 7 with no presence of any byproduct arising from de-
benzylation processes, which could possibly occur under
the reaction conditions employed. The diastereoselective
reduction of the ketone moiety was achieved by using lith-
ium borohydride as the reducing agent and working at low
temperature, which allowed us to isolate piperidinone 8 in
moderate yield, but as a single diastereomer, as its 1H- and
13C NMR spectra indicated. The syn relative configuration
was tentatively assigned according to literature data for
We therefore modified the synthetic route according to the
retrosynthetic approach shown in Scheme 5. In this sec-
ond approach, we still maintained the metathesis reaction
as the key step regarding the formation of the piperidine
ring, but we decided to carry out the reduction of the ke-
tone moiety before the metathesis step, therefore avoiding
the possibility of racemization at this stage. We also mod-
ified the approach by introducing an allyl group as the N-
substituent of the starting (+)-(S,S)-pseudoephedrine gly-
oxylimine, which would reduce the number of synthetic
steps by avoiding the reduction of the lactam moiety. This
modification would also help in the metathesis reaction
due to the higher reactivity of the allyl group compared to
the acryloyl group towards the metathesis reaction.10
Synthesis 2011, No. 3, 443–450 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of (–)-b-Conhydrine and (+)-a-Conhydrine
445
it in low yield. This compound was converted into the cor-
responding cyclic carbamate 15 after basic treatment.
Alternatively, we were able to directly obtain 15 from 13
by modifying the conditions of the diastereoselective re-
duction step and, therefore, when we subjected N-Cbz-
protected a-amino ketone 13 to reaction with lithium
borohydride at 0 °C followed by stirring for 16 hours at
room temperature, cyclic carbamate 15 was isolated in ex-
cellent yield and also as a single diastereomer, as 1H NMR
analysis of the crude reaction mixture indicated. We next
carried out the ring-closing metathesis reaction, obtaining
bicyclic derivative 16 in good yield, and, finally, complet-
ed the synthesis with a catalytic hydrogenation reaction
followed by base hydrolysis. Both steps proceeded with
satisfactory yield, allowing the isolation of (–)-b-conhy-
drine (9), which showed a specific rotation value [a]D20 of
–28.5 (c = 0.40, CHCl3), which is in agreement with the
expected ee (80% ee) based on the dr of 11. In addition,
NOE experiments carried out on compounds 16 and 17
also indicated a trans relative stereochemistry between
the two stereogenic centers, which was also in agreement
with the syn relative arrangement previously proposed for
b-amino alcohol 14.
NH
NH
NH
OH
OH
O
N
OH
NH
OH
Me
N
Me
N
H
Ph
Ph
O
O
Scheme 5
We prepared the starting chiral N-allyl-a-imino amide 10
derived from pseudoephedrine (Scheme 6), starting from
morpholinone 1 and allylamine and following the same
procedure employed for the preparation of imino amide 2.
It was also observed that, as in the case of 2, a-imino
amide 10 was obtained mainly as its cyclic morpholine
tautomer 10¢, as its NMR spectra indicated. Next, we car-
ried out the addition of allylmagnesium chloride to the
equilibrating mixture of 10 and 10¢ under our optimized
conditions, which furnished the expected a-amino amide
adduct 11. The adduct was obtained in moderate yield, but
with a diastereoselectivity comparable to the one ob-
tained in the addition of allylmagnesium bromide to 2 (cf.
Scheme 3). Subsequently, we prepared the enantioen-
riched a-amino ketone 12 by addition of ethyllithium to
the pseudoephedrine amide moiety; this gave N-allyl-a-
amino ketone 12 in moderate yield. We were not able to
determine the optical purity of 12 at this stage, because it
was not possible for us to find the appropriate conditions
to resolve the corresponding racemic mixture either by
chiral HPLC or GC.
Cbz
Cbz
N
LiBH4
N
Cbz2O, NaOH
12
Et
THF, –78 °C
Et
dioxane–H2O, r.t.
99%
35%
dr >95:5
OH
O
14
13
LiBH4, THF
0 °C to r.t.
4 M KOH
CH2Cl2, r.t.
98%
80%
dr 84:16
O
O
Grubbs II cat.
(1 mol%)
N
N
O
O
Ph
CH2Cl2, reflux
83%
H2C=CHCH2NH2
anhyd Na2SO4
N
OH
Et
O
Et
H2, Pd/C
EtOH, r.t.
Me
N
90%
O
16
15
1
MeN
Et2O, r.t.
60%
H
Ph
N
H
O
O
NH
10
10'
LiOH
N
O
H2C=CHCH2MgCl
THF, –78 °C
THF–H2O–EtOH
reflux
66%
dr 90:10
OH
45%
Et
17
9
1. EtLi, THF
–78 to 0 °C
(–)-β−conhydrine
NH
O
NH
OH
Me
N
Scheme 7
2. NH4Cl, r.t.
53%
Ph
O
12
11
On the other hand, we were also able to prepare diastereo-
meric (+)-a-conhydrine by slightly changing the order of
the steps of the synthesis design (Scheme 8). In particular,
direct reduction of a-amino ketone 12 led preferentially to
the formation of the corresponding anti diastereomer,
which can be used as a suitable precursor of (+)-a-conhy-
drine (21). We initially carried out the reduction under the
conditions previously employed by us for the reduction of
7 and 13 [LiBH4 (1 equiv), THF, –78 °C], but this gave a
low conversion, which was solved by using an excess of
reducing agent (4 equiv). In this case, amino alcohol 18
Scheme 6
Continuing with the synthesis, we proceeded to create the
second stereogenic center of the final product through
diastereoselective reduction of the ketone moiety
(Scheme 7). We first protected the amino moiety as the
corresponding benzyloxy carbamate and subsequently
carried out the reduction step by treating ketone 13 with
lithium borohydride at low temperature, isolating N-Cbz-
protected amino alcohol 14 as a single diastereomer, albe-
Synthesis 2011, No. 3, 443–450 © Thieme Stuttgart · New York

446
E. Reyes et al.
PAPER
was obtained as an 84:16 mixture of diastereomers, as in- Grubbs catalyst were also key steps in the synthesis de-
dicated by the 13C NMR spectra of the crude reaction mix- sign.
ture, and which was converted into 19 after Cbz
protection. Comparison of the NMR spectra of this com-
Melting points were determined of samples placed in unsealed cap-
pound 19 with those obtained for 14, which was obtained
previously and the relative configuration of which had
been unambiguously established, allowed us to establish
the proposed anti relative configuration for this com-
pound. We next carried out the metathesis reaction on N-
Cbz derivative 19, which took place smoothly providing
cyclic derivative 20 in good yield. Chiral HPLC analysis
indicated that 20 had been obtained as an 85:15 mixture of
diastereomers, with the major anti diastereomer present in
87% ee. This is consistent with the 86:14 anti/syn ratio of
diastereomers obtained in the diastereoselective reduction
of 12 and also shows that a slight enantiomeric enrich-
ment had been achieved during the synthetic route starting
from a-amino amide 11 (dr 90:10). The syn and anti dia-
stereomers could not be separated by chromatography
and, therefore, compound 20 was directly subjected to cat-
alytic hydrogenation, which also led to removal of the Cbz
protecting group and thus directly delivering (+)-a-conhy-
drine (21) in 75% yield.
illary tubes and are uncorrected. IR spectra were obtained of sam-
ples prepared as KBr pellets (solids) or CH2Cl2 solns (oils). NMR
1
spectra (300 MHz, H; 75 MHz, 13C) were recorded at 20–25 °C;
samples were prepared in CDCl3 soln and resonances are reported
in ppm relative to TMS unless otherwise stated. Mass spectra were
recorded under electron impact at 70 eV. TLC was carried out with
0.2 mm thick silica gel plates (Merck Kiesegel GF254) and visualiza-
tion was accomplish by UV light or by spraying with phospho-
molybdic acid. Flash column chromatography on silica gel was
performed with Merck Kieselgel 60 (230–400 mesh). All solvents
used in reactions were dried and purified according to standard pro-
cedures. All air- or moisture-sensitive reactions were performed un-
der argon. The glassware was oven-dried (140 °C) overnight and
purged with argon prior to use. Grignard reagents were employed as
purchased. Organolithium reagents were titrated periodically with
diphenylacetic acid. All other reagents were used as purchased.
HPLC or NMR was used for the determination of dr and ee values
under the conditions specified in each case. Compounds 1, 2, 3, and
4 were prepared as previously described.5
(S)-N-Benzyl-N-(5-oxohept-1-en-4-yl)acrylamide (5)
Et3N (0.22 mL, 1.55 mmol) and acryloyl chloride (0.11 mL, 1.29
mmol) were added to a stirred soln of a-amino ketone 4 (0.28 g,
1.29 mmol) in anhyd THF (30 mL) and the mixture was stirred for
5 h at r.t. The reaction was then quenched with sat. aq NH4Cl (10
mL) and H2O (10 mL) and the mixture was extracted with CH2Cl2
(3 × 10 mL). The combined organic fractions were dried (Na2SO4)
and filtered and the solvent was removed under reduced pressure.
Acrylamide 5 was isolated as a yellow oil after purification by flash
chromatography (silica gel, hexane–EtOAc, 8:2).
Cbz
NH
LiBH4
Cbz2O, NaOH
N
12
Et
Et
THF, –78 °C
62%
dr 84:16
dioxane–H2O, r.t.
93%
OH
OH
18
19
Grubbs II cat.
(1 mol%)
75%
CH2Cl2, reflux
Yield: 80% (0.28 g, 1.03 mmol); [a]D20 –36.1 (c 1.0, CH2Cl2).
IR (film): 1718 (C=O, ester), 1647 (C=O, amide) cm–1.
Cbz
NH
H2, Pd/C
N
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.1 Hz, 3 H), 2.23–
2.71 (m, 4 H), 4.47 (d, J = 17.4 Hz, 1 H), 4.71–4.75 (m, 3 H), 5.00–
5.05 (m, 2 H), 5.68–5.73 (m, 2 H), 6.45–6.49 (m, 2 H), 7.20–7.33
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 7.4, 32.5, 33.8, 50.0, 62.9, 118.0,
127.0, 127.4, 127.8, 128.8, 129.9, 134.2, 136.8, 167.3, 207.8.
Et
MeOH, r.t.
75%
OH
OH
21
(+)-α−conhydrine
20
Scheme 8
MS (EI, 70 eV): m/z (%) = 271 [M+] (2), 215 (79), 214 (92), 161
(71), 160 (98), 91 (100), 65 (75), 57 (73), 55 (93).
HRMS (CI): m/z [M+] calcd for C17H21NO2: 271.1572; found:
271.1569.
To sum up, we have shown that our recently reported pro-
tocol for carrying out the stereoselective synthesis of a-
amino ketones can be a reliable tool for the asymmetric
synthesis of key chiral building blocks applicable to the
synthesis of valuable natural products such as the piperi-
dine alkaloids (–)-b- and (+)-a-conhydrine. This strategy
(S)-1-Benzyl-6-propionyl-5,6-dihydropyridin-2(1H)-one (6)
Grubbs II cat. (8 mg, 1 mol%) was added to a stirred soln of acryl-
amide 5 (0.26 g, 0.97 mmol) in anhyd CH2Cl2 (130 mL) and the
relies on a sequence of reactions consisting of the diaste- mixture was refluxed for 48 h. The addition of additional portions
of Grubbs II cat. (1 mol%) was repeated every 12 h. The reaction
reoselective 1,2-addition of Grignard reagents to a-imino
amides derived from (+)-(S,S)-pseudoephedrine, followed
by selective 1,2-addition of organolithium reagents across
the amide moiety, and which delivers a-amino ketones in
high optical purities. Simple subsequent transformations
have allowed us to prepare the target compounds in a sim-
ple and reliable way. The diastereoselective reduction of
mixture was then filtered and the solvent was evaporated. The crude
product was purified by flash chromatography (silica gel, hexane–
EtOAc, 1:1) and piridinone 6 was obtained as a yellow oil.
Yield: 75% (0.18 g, 0.73 mmol); [a]D20 +0.9 (c 0.6, CH2Cl2).
IR (film): 1718 (C=O, ester), 1664 (C=O, amide) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.00 (t, J = 7.1 Hz, 3 H), 2.39 (q,
the common synthetic intermediate a-amino ketone 12 J = 7.1 Hz, 2 H), 2.62–2.68 (m, 2 H), 3.76 (d, J = 15.1 Hz, 1 H),
3.93 (dd, J = 1.3, 7.0 Hz, 1 H), 5.50 (d, J = 15.1 Hz, 1 H), 6.00–6.05
and the formation of the piperidine heterocycle by ring-
closing metathesis promoted by the second generation
(m, 1 H), 6.33–6.37 (m, 1 H), 7.23–7.33 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 7.6, 27.0, 32.6, 49.3, 62.6, 125.9,
127.7, 128.3, 128.8, 136.2, 137.0, 164.1, 209.4.
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Stereoselective Synthesis of (–)-b-Conhydrine and (+)-a-Conhydrine
447
MS (EI, 70 eV): m/z (%) = 243 [M+] (1), 215 (79), 186 (87), 91
MS (EI, 70 eV): m/z (%) = 260 [M+] (3), 205 (97), 146 (55), 118
(100), 65 (43), 57 (28).
(100), 91 (77), 77 (53), 56 (56).
HRMS (CI): m/z [M+] calcd for C15H17NO2: 243.1259; found:
243.1266.
HRMS (CI): m/z [M+] calcd for C15H20N2O2: 260.1525; found:
260.1582.
(S)-1-Benzyl-6-propionylpiperidin-2-one (7)
(S)-2-(Allylamino)-N-[(1S,2S)-1-hydroxy-1-phenylpropan-2-
yl]-N-methylpent-4-enamide (11)
Pd/C (3 mol%) and AcOH (2 drops) were added to a stirred soln of
piperidinone 6 (0.16 g, 0.66 mmol) in MeOH (20 mL). The mixture
was stirred under H2 (60 psi) for 12 h. The reaction mixture was then
filtered and the solvent was evaporated. The crude product was pu-
rified by flash chromatography (silica gel, hexane–EtOAc, 1:1) and
piperidinone 7 was obtained as a yellow oil.
Yield: 99% (0.16 g, 0.65 mmol); [a]D20 +20.1 (c 1.0, CH2Cl2).
IR (film): 1719 (C=O, ester), 1645 (C=O, amide) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.99 (t, J = 7.1 Hz, 3 H), 1.57–
1.62 (m, 2 H), 1.91–1.95 (m, 2 H), 2.14–2.16 (m, 1 H), 2.36–2.44
(m, 3 H), 3.50 (d, J = 15.0 Hz, 1 H), 3.99–4.03 (m, 1 H), 5.45 (d,
J = 15.0 Hz, 1 H), 7.10–7.26 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 7.7, 17.9, 25.4, 31.6, 32.7, 49.0,
63.8, 127.6, 128.3, 128.7, 136.5, 170.6, 208.9.
A 2.0 M soln of allylmagnesium chloride in THF (10.91 mL, 21.83
mmol) was carefully added to a soln of morpholinone 10¢ (2.58 g,
9.92 mmol) in anhyd THF (40 mL) at –78 °C and the reaction mix-
ture was stirred at this temperature for 6 h, after which more 2.0 M
soln of allylmagnesium chloride in THF (10.91 mL, 21.83 mmol)
was added at once. The reaction mixture was stirred for a further 12
h at –78 °C and quenched with a sat. aq NH4Cl soln (40 mL). The
mixture was extracted with CH2Cl2 (3 × 30 mL) and the combined
organic fractions were collected, dried (Na2SO4), and filtered, and
the solvent was removed in vacuo; this afforded a-amino amide 11
after purification by flash column chromatography (silica gel,
EtOAc). HPLC analysis indicated that a-amino amide 11 had been
obtained with a dr of 90:10 (Chiralcel IA column, 1.0 mL·min–1,
hexane–i-PrOH, 95:5): minor isomer: tR = 21.62 min; major isomer:
tR = 26.85 min.
MS (EI, 70 eV): m/z (%) = 245 [M+] (2), 189 (36), 188 (83), 91
(100), 65 (43), 57 (45).
HRMS (CI): m/z [M+] calcd for C15H19NO2: 245.1416; found:
245.1423.
Yield: 56% (1.67 g, 5.53 mmol); [a]D20 +140.4 (c 1.0, CH2Cl2).
IR (film): 1624 (C=O), 3374 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d (1:1 rotamer ratio) = 0.96*, 1.13 (d,
J = 6.7 Hz, 3 H), 2.21–2.25, 2.39–2.43* (m, 2 H), 2.81, 2.92* (s, 3
H), 3.12–3.21 (m, 2 H), 3.45, 3.75* (t, J = 6.7 Hz, 1 H), 3.92–4.04
(m, 1 H), 4.47, 4.61* (d, J = 7.1 Hz, 1 H), 5.06–5.15 (m, 4 H), 5.77–
5.84 (m, 2 H), 7.24–7.36 (m, 5 H); * indicates minor rotamer reso-
nances.
13C NMR (75 MHz, CDCl3): d (1:1 rotamer ratio) = 14.5, 15.9*,
27.0, 35.8*, 37.9, 49.4*, 50.4, 56.6, 56.8*, 56.9, 58.0*, 75.1*, 75.8,
116.5, 116.8*, 117.7*, 117.8, 126.2, 126.7, 127.6, 127.7, 128.1,
128.4, 128.6, 133.9, 134.4*, 135.7*, 136.8, 142.3, 166.7*, 167.8;
* indicates minor rotamer resonances.
(6S,1¢S)-1-Benzyl-6-(1-hydroxypropyl)piperidin-2-one (8)
A soln of piperidinone 7 (49 mg, 0.20 mmol) in anhyd THF (10 mL)
was added dropwise to a stirred soln of LiBH4 (0.51 mg, 0.24 mmol)
in anhyd THF (10 mL) at –78 °C. The mixture was stirred for 12 h
at –78 °C. The reaction mixture was then quenched with H2O (10
mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried (Na2SO4), filtered, and evaporated in vacuo. The
crude product was purified by flash chromatography (silica gel,
hexane–EtOAc, 1:9) and piperidinone 8 was obtained as a yellow
oil.
MS (EI, 70 eV): m/z (%) = 175 [M+ – 127] (2), 110 (100).
HRMS (CI): m/z [M+] calcd for C18H26N2O2: 302.1994; found:
Yield: 53% (26 mg, 0.11 mmol); [a]D20 +7.9 (c 0.5, CH2Cl2).
IR (film): 1617 (C=O), 3384 (OH) cm–1.
302.1991.
1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 7.1 Hz, 3 H), 1.34–
1.38 (m, 1 H), 1.50–1.53 (m, 1 H), 1.62–1.91 (m, 4 H), 2.49 (t,
J = 12.0 Hz, 2 H), 3.24 (m, 1 H), 3.74–3.77 (m, 1 H), 4.09–4.11 (m,
1 H), 5.28 (d, J = 7.1 Hz, 1 H), 7.21–7.33 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 10.0, 17.7, 24.9, 26.7, 31.3, 50.2,
59.6, 74.9, 127.2, 127.9, 128.6, 137.7, 171.3.
(S)-4-(Allylamino)hept-6-en-3-one (12)
A 0.7 M soln of EtLi in Et2O (10.30 mL, 7.20 mmol) was added to
a cooled (–78 °C) soln of the starting a-amino amide 11 (0.68 g,
2.25 mmol) in anhyd THF (20 mL), and the resulting soln was im-
mediately warmed to 0 °C, at which temperature an additional
equivalent of 0.7 M EtLi in Et2O (3.23 mL, 2.25 mmol) was added
at once. The reaction mixture was stirred for 30 min and quenched
with sat. aq NH4Cl (15 mL). The mixture was extracted with
CH2Cl2 (3 × 15 mL) and the collected organic fractions were dried
(Na2SO4) and filtered and the solvent was removed in vacuo; this af-
forded a-amino ketone 12 after purification by flash column chro-
matography (silica gel, hexane–EtOAc, 1:1).
MS (EI, 70 eV): m/z (%) = 219 [M+ – 28] (2), 188 (40), 91 (100).
(2R,5S,6S)-2-(Allylamino)-4,5-dimethyl-6-phenylmorpholin-3-
one (10¢)
A suspension of 1 (3.00 g, 13.57 mmol), allylamine (1.25 mL, 16.29
mmol), and anhyd Na2SO4 in Et2O was stirred for 24 h at r.t. The
mixture was then filtered and the solvent was removed in vacuo
yielding the 2-aminomorpholin-3-one 10¢ which was pure enough
(by NMR analysis) to be used in the next step.
Yield: 53% (0.20 g, 1.18 mmol); [a]D20 +15.1 (c 1.0, CH2Cl2).
IR (film): 1717 (C=O) 3370 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.02 (t, J = 7.3 Hz, 3 H), 2.23–
2.56 (m, 4 H), 3.05 (dd, J = 6.2, 13.9 Hz, 1 H), 3.15 (dd, J = 6.2,
13.9 Hz, 1 H), 3.35 (t, J = 6.5 Hz, 1 H), 5.04–5.11 (m, 4 H), 5.71–
5.75 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 7.5, 33.6, 36.9, 50.7, 65.5, 116.3,
118.1, 133.7, 136.5, 213.8.
Yield: 60% (2.11 g, 8.14 mmol).
IR (film): 1654 (C=O), 3313 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.09 (d, J = 6.3 Hz, 3 H), 2.96 (s,
3 H), 3.28–3.34 (m, 2 H), 3.58–3.62 (m, 1 H), 4.77–5.28 (m, 3 H),
5.39 (s, 1 H), 5.84–5.87 (m, 1 H), 7.35–7.40 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 15.8, 16.2*, 30.5, 30.8*, 48.9,
58.2*, 58.4, 74.0*, 74.8, 85.2*, 90.6, 116.3, 127.9, 128.0, 128.6,
128.7, 128.9, 136.0, 137.6, 138.0*, 166.7, 167.8*; * indicates minor
anomer resonances.
MS (EI, 70 eV): m/z (%) = 126 [M+ – 41] (25), 110 (100), 68 (59),
56 (14).
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448
E. Reyes et al.
PAPER
HRMS (CI): m/z [M+] calcd for C10H17NO: 167.1310; found:
IR (film): 2968 (=CH), 1729 (C=O) cm–1.
167.1318.
1H NMR (300 MHz, CDCl3): d (dr 84:16) = 0.98 (t, J = 7.4 Hz, 3
H), 1.05* (t, J = 7.4 Hz, 3 H), 1.59–1.69 (m, 2 H), 1.70–1.84* (m, 2
H), 2.21–2.45 (m, 2 H), 3.41 (ddd, J = 3.9, 5.0, 7.4 Hz, 1 H), 3.58
(dd, J = 7.6, 15.7 Hz, 1 H), 3.79* (dd, J = 6.4, 12.7 Hz, 1 H), 4.04–
4.23 (m, 2 H), 4.37* (ddd, J = 4.2, 7.5, 9.5 Hz, 1 H), 5.31–5.10 (m,
4 H), 5.85–5.57 (m, 2 H); * denotes minor diastereomer.
13C NMR (75 MHz, CDCl3): d (dr 5:1) = 8.9, 10.4*, 22.4*, 27.8,
31.9*, 36.2, 44.6, 44.8*, 56.8*, 58.5, 79.2, 118.5*, 118.6, 118.7*,
119.8, 131.5, 132.2, 132.3*, 132.9*, 157.2; * denotes minor diaste-
reomer.
(S)-4-[Allyl(benzyloxycarbonyl)amino]hept-6-en-3-one (13)
A 4 M aq soln of NaOH (0.20 mL, 0.81 mmol) and Cbz2O (0.39 g,
1.32 mmol) were added to a stirred soln of ketone 12 (90 mg, 0.53
mmol) in dioxane–H2O (1:1; 10 mL). The mixture was stirred for 12
h at r.t. The reaction mixture was diluted with H2O (10 mL) and ex-
tracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were dried (Na2SO4), filtered, and evaporated in vacuo. The crude
product was purified by flash chromatography (silica gel, hexane–
EtOAc, 7:3) and product 13 was obtained as a yellow oil.
MS (EI, 70 eV): m/z (%) = 154 [M+ – 41] (100), 126 (9), 110 (7), 94
(2), 80 (3), 68 (17), 56 (10).
Yield: 99% (159 mg, 0.53 mmol); [a]D20 –52.0 (c 1.0, CH2Cl2).
IR (film): 2975 (=CH), 2935 (=CH), 1696 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.92* (t, J = 7.0 Hz, 3 H), 1.01*
(t, J = 7.1 Hz, 3 H), 2.17–2.77 (m, 4 H), 3.68 (dd, J = 6.3, 15.6 Hz,
2 H), 3.93* (dd, J = 5.5, 16.3 Hz, 1 H), 3.99–4.17 (m, 2 H), 4.46*
(dd, J = 6.3, 8.2 Hz, 1 H), 4.92–5.28 (m, 6 H), 5.62–5.97 (m, 2 H),
7.27–7.45 (m, 5 H); * denotes separated signal for rotamers.
13C NMR (75 MHz, CDCl3): d = 7.4, 7.4, 32.1, 32.4, 32.9, 33.0,
48.5, 50.6, 63.9, 64.5, 67.5, 67.5, 117.6, 117.8, 117.8, 118.5, 127.7,
127.7, 128.0, 128.2, 128.4, 128.4, 133.7, 134.1, 134.1, 134.3, 135.9,
136.3, 155.5, 156.2, 207.8, 208.2.
(1S,8aS)-1-Ethyl-8,8a-dihydro-1H-oxazolo[3,4-a]pyridin-
3(5H)-one (16)
To a stirred soln of carbamate 15 (50 mg, 0.25 mmol) in anhyd
CH2Cl2 (15 mL) Grubbs II cat. (2 mg, 1 mol%) was added and the
mixture was refluxed for 12 h. The reaction mixture was then fil-
tered and the solvent was evaporated. The crude product was puri-
fied by flash chromatography (silica gel, hexane–EtOAc, 7:3) and
product 16 was obtained as a yellow oil.
Yield: 83% (33 mg, 0.20 mmol); [a]D20 –28.0 (c 0.5, CHCl3).
MS (EI, 70 eV): m/z (%) = 245 [M+ – 56] (15), 244 (67), 200 (64),
IR (film): 2935 (=CH), 1752 (C=O) cm–1.
131 (9), 91 (100), 65 (14).
1H NMR (300 MHz, CDCl3): d = 1.03 (t, J = 7.4 Hz, 3 H), 1.64–
1.90 (m, 2 H), 2.06–2.39 (m, 2 H), 3.33–3.48 (m, 1 H), 3.60–3.74
(m, 1 H), 4.04–4.15 (m, 2 H), 5.69–5.87 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 8.9, 27.3, 30.0, 40.8, 55.1, 82.7,
123.0, 123.8, 156.9.
MS (EI, 70 eV): m/z (%) = 167 [M+] (25), 138 (6), 108 (16), 82 (17),
54 (100).
HRMS (CI): m/z [M+] calcd for C9H13NO2: 167.0947; found:
167.1005.
(3S,4S)-4-[Allyl(benzyloxycarbonyl)amino]hept-6-en-3-ol (14)
A soln of a-amino ketone 13 (60 mg, 0.19 mmol) in anhyd THF (10
mL) was added dropwise to a stirred soln of LiBH4 (10 mg, 0.4
mmol) in anhyd THF (10 mL) at –78°C. The mixture was stirred for
12 h at –78 °C. The reaction mixture was then quenched with H2O
(10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined or-
ganic fractions were dried (Na2SO4) and filtered and the solvent was
removed under reduced pressure. The crude product was purified by
flash chromatography (silica gel, hexane–EtOAc, 7:3) and amino
alcohol 14 was obtained as a colorless oil. 1H NMR analysis of the
crude reaction mixture and the purified material indicated the pres-
ence of residual amounts of the (3R,4S)-diastereomer (dr >95:5)
Yield: 35% (20 mg, 0.06 mmol); [a]D20 +15.3 (c 1.0, CH2Cl2).
IR (film): 3441 (OH), 2962 (=CH), 1674 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.99 (t, J = 7.4 Hz, 3 H), 1.30–
1.59 (m, 2 H), 2.24–2.58 (m, 2 H), 3.44–3.65 (m, 1 H), 3.67–4.10
(m, 2 H), 4.95–5.22 (m, 6 H), 5.68–5.94 (m, 2 H), 7.28–7.44 (m, 5
H)
(1S,8aS)-1-Ethyltetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-
one (17)
A suspension of 16 (25 mg, 0.14 mmol) in EtOH (5 mL) was vigor-
ously stirred under an H2 atmosphere in the presence of Pd/C (20%
wt, 5 mg). After 12 h, the crude product was filtered through a small
pad of Celite and concentrated in vacuo. Purification by flash chro-
matography (silica gel, hexane–EtOAc, 7:3) gave product 17 as a
yellow oil.
Yield: 90% (21 mg, 0.12 mmol); [a]D20 +33.2 (c 0.4, CHCl3).
IR (film): 2936 (=CH), 1750 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.01 (t, J = 7.4 Hz, 3 H), 1.14–
1.50 (m, 4 H), 1.55–1.98 (m, 4 H), 2.79 (dt, J = 3.5, 12.8 Hz, 1 H),
3.12–3.25 (m, 1 H), 3.86 (dd, J = 3.8, 12.4 Hz, 1 H), 3.98 (dd,
J = 6.1, 12.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 10.3, 27.7, 33.9, 51.6, 63.7, 67.3,
73.9, 117.4, 117.4, 127.6, 127.9, 128.4, 134.9, 135.1, 136.5, 157.2.
MS (EI, 70 eV): m/z (%) = 262 [M+ – 41] (3), 244 (11), 200 (12),
154 (100), 126 (9), 108 (34), 91 (76), 79 (34), 68 (16).
13C NMR (75 MHz, CDCl3): d = 9.0, 22.7, 24.3, 27.0, 30.6, 41.1,
(4S,5S)-3,4-Diallyl-5-ethyloxazolidin-2-one (15)
A soln of a-amino ketone 13 (90 mg, 0.29 mmol) in anhyd THF (10
mL) was dropwise added to a stirred soln of LiBH4 (14 mg, 0.60
mmol) in anhyd THF (10 mL) at 0 °C. The mixture was then stirred
for 16 h at r.t. The reaction mixture was then quenched with H2O
(10 mL), and extracted with CH2Cl2 (3 × 10 mL). The combined or-
ganic fractions were dried (Na2SO4) and filtered and the solvent was
removed under reduced pressure. The crude product was purified by
flash chromatography (silica gel, hexane–EtOAc, 7:3) and oxazoli-
dinone 15 was obtained as a colorless oil. (Alternatively, and fol-
lowing the reaction pathway presented in Scheme 7, the same
oxazolidinone was obtained quantitatively after treatment of 14
with 4 M KOH over 1 h at r.t.; yield: 99%)
59.5, 81.8, 156.6.
MS (EI, 70 eV): m/z (%) = 169 [M+] (22), 140 (6), 124 (4), 110 (7),
96 (6), 83 (100), 55 (26).
(2¢S,1S)-1-(2-Piperidyl)propan-1-ol [(–)-b-Conhydrine; 9]
A soln of 17 (10 mg, 0.06 mmol) and LiOH·H2O (130 mg, 3.00
mmol) in EtOH–H2O–THF (1:1:1; 6 mL) was refluxed for 5 h. The
reaction mixture was then cooled to r.t. and H2O (10 mL) and
CH2Cl2 (3 × 10 mL) were added. The organic layer was separated
and the aqueous layer was washed with CH2Cl2 (3 × 5 mL). The
combined organic fractions were dried (Na2SO4) and filtered, and
the solvent was removed under reduced pressure.
Yield: 80% (45 mg, 0.23 mmol).
Yield: 45% (3 mg, 0.02 mmol), [a]D20 –28.5 (c 0.4, CHCl3).
Synthesis 2011, No. 3, 443–450 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of (–)-b-Conhydrine and (+)-a-Conhydrine
449
1H NMR (300 MHz, CDCl3): d = 0.98 (t, J = 7.4 Hz, 3 H), 1.08–
1.74 (m, 8 H), 2.48–2.32 (m, 1 H), 2.60 (dt, J = 2.7, 11.7 Hz, 1 H),
3.11 (d, J = 10.4 Hz, 1 H), 3.24 (dt, J = 2.9, 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 9.0, 22.7, 24.3, 27.0, 30.6, 41.1,
59.5, 81.8, 156.6.
the solvent was evaporated. The crude product was purified by flash
chromatography (silica gel, hexane–EtOAc, 7:3) and product 20
was obtained as a yellow oil. HPLC analysis indicated the presence
of two diastereomers (85:15), of which the major diastereomer was
obtained in 87% ee (Chiracel IA, hexanes–i-PrOH, 95:5, flow rate
1.00 mL·min–1): major diastereomer: tR = 16.25 min for (6S,1¢R)
and tR = 17.51 min for (6R,1¢S); minor diastereomer: tR = 15.49 min
and tR = 13.90 min.
The rest of the analytical data were in agreement with literature val-
ues.4j
Yield: 75% (27 mg, 0.10 mmol); [a]D20 +6.9 (c 1.3, CH2Cl2).
IR (film): 3447 (OH), 1684 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95–1.01 (m, 3 H), 1.39–1.43 (m,
1 H), 1.58–1.64 (m, 1 H), 1.77 (br s, 1 H), 2.25–2.29 (m, 2 H), 3.52–
3.58 (m, 2 H), 4.23–4.31 (m, 2 H), 5.12–5.18 (m, 2 H), 5.68–5.73
(m, 2 H), 7.28–7.42 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 9.7, 26.8, 26.9, 41.1, 52.9, 53.0,
67.3, 123.3, 127.8, 127.9, 128.0, 128.5, 136.6, 155.7.
MS (EI, 70 eV): m/z (%) = 275 [M+] (5), 257 (39), 229 (33), 214
(3R,4S)-4-(Allylamino)hept-6-en-3-ol (18)
A soln of a-amino ketone 12 (92 mg, 0.55 mmol) in anhyd THF (10
mL) was dropwise added to a stirred soln of LiBH4 (28 mg, 1.21
mmol) in anhyd THF (10 mL) at –78 °C. The mixture was stirred
for 12 h at –78 °C. The reaction mixture was then quenched with
H2O (10 mL), and extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic fractions were dried (Na2SO4) and filtered and the
solvent was removed under reduced pressure. The crude product
was purified by flash chromatography (silica gel, EtOAc–MeOH,
1
10:3) and amino alcohol 18) was obtained as a colorless oil. H
NMR analysis of the crude reaction mixture and the purified mate-
rial indicated the presence of minor amounts of the (3S,4S)-diaste-
reomer (dr 84:16)
Yield: 62% (58 mg, 0.34 mmol); [a]D20 +15.3 (c 1.0, CH2Cl2).
(46), 160 (100), 91 (72).
HRMS (CI): m/z [M+] calcd for C16H21NO3: 275.1521; found:
275.1501.
IR (film): 3422 (OH, NH) cm–1.
(2¢S,1R)-1-(2-Piperidyl)propan-1-ol [(+)-a-Conhydrine; 21]
Pd/C (3 mol%) and AcOH (2 drops) were added to a stirred soln of
product 20 (19 mg, 0.068 mmol) in MeOH (5 mL). The mixture was
stirred under H2 (60 psi) for 12 h. The reaction mixture was then fil-
tered and the solvent was evaporated. Product 21 was obtained
without further purification as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.97 (t, J = 7.3 Hz, 3 H), 1.39–
1.43 (m, 2 H), 2.22–2.26 (m, 2 H), 2.54–2.62 (m, 1 H), 2.73 (br s, 2
H), 3.17 (dd, J = 6.2, 13.9 Hz, 1 H), 3.27 (dd, J = 6.2, 13.9 Hz, 1 H),
3.55–3.59 (m, 1 H), 5.03–5.21 (m, 4 H), 5.71–5.79 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 10.8, 25.1, 32.6, 49.7, 59.3, 71.1,
116.3, 118.1, 135.7, 136.4.
MS (EI, 70 eV): m/z (%) = 136 [M+ – 33] (3), 128 (17), 110 (100).
HRMS (CI): m/z [M+] calcd for C10H19NO: 169.1467; found:
Yield: 75% (8 mg, 0.05 mmol); [a]D20 +5.7 (c 0.12, CHCl3) [Lit.4a
+8.7 (c = 0.85, CHCl3)].
The rest of the analytical data were in agreement with literature
values.4a
169.1472.
Supporting Information for this article is available online at
(3R,4S)-4-[Allyl(benzyloxycarbonyl)amino]hept-6-en-3-ol (19)
A soln of 4 M aq NaOH (0.11 mL, 0.43 mmol) and Cbz2O (0.21 g,
0.70 mmol) were added to a stirred soln of amino alcohol 18 (48 mg,
0.28 mmol) in dioxane–H2O (1:1; 10 mL). The mixture was stirred
for 12 h at r.t. The reaction mixture was diluted with H2O (10 mL)
and extracted with CH2Cl2 (3 × 10 mL). The combined organic lay-
ers were dried (Na2SO4), filtered, and evaporated in vacuo. The
crude product was purified by flash chromatography (silica gel,
hexane–EtOAc, 7:3) and product 19 was obtained as a yellow oil.
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors thank the University of the Basque Country (Subven-
ción General a Grupos de Investigación, GIU07/06 and a posdocto-
ral grant to E.R.), the Basque Government (Grupos Consolidados,
IT328-10), and the Ministerio de Ciencia e Innovación (CTQ2005-
02131/BQU and a fellowship to N.R.) for financial support. The
authors also acknowledge PETRONOR, S.A. for the generous gift
of solvents.
Yield: 93% (79 mg, 0.26 mmol); [a]D20 –3.0 (c 1.0, CH2Cl2).
IR (film): 3447 (OH), 1676 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 7.3 Hz, 3 H), 1.45–
1.52 (m, 2 H), 2.36–2.70 (m, 2 H), 3.35–3.98 (m, 3 H), 3.98–4.03
(m, 1 H), 5.02–5.18 (m, 6 H), 5.71–5.84 (m, 2 H), 7.26–7.40 (m, 5
H).
13C NMR (75 MHz, CDCl3): d = 10.6, 28.0, 30.6, 51.6, 63.7, 67.3,
76.4, 117.2, 117.3, 126.9, 127.6, 128.0, 128.1, 128.3, 128.5, 134.6,
135.7, 136.5, 157.1.
MS (EI, 70 eV): m/z (%) = 262 [M+ – 41] (20), 244 (61), 200 (78),
154 (82), 91 (100).
HRMS (CI): m/z [M+] calcd for C18H25NO3: 303.1834; found:
303.1827.
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Synthesis 2011, No. 3, 443–450 © Thieme Stuttgart · New York

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PAPER
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