Diastereoselective cyclization of γ-δ epoxyketones with (-)-phenylglycinol: Synthesis of both enantiomers of cis-5-alkyl-2-hydroxymethyl pyrrolidines

Article abstract of DOI:10.1055/s-2004-830867

A novel condensation of (-)-phenylglycinol with γ,δ- epoxyketones is reported for the preparation of both enantiomers of cis-5-alkyl-2-hydroxymethyl pyrrolidines. The required epoxy-derivatives were easily prepared by epoxidation of the corresponding γ,δ-

Full text of DOI:10.1055/s-2004-830867

2016
LETTER
Diastereoselective Cyclization of g-d Epoxyketones with (–)-Phenylglycinol:
Synthesis of Both Enantiomers of cis-5-Alkyl-2-hydroxymethyl Pyrrolidines
D
iastereos
o
e
lective
C
yc
s
lization of
é
g
-
d
Epoxyketone
M
s
w
ith (–)-Phenylglyc
.
inol Andrés, Ignacio Herráiz, Rafael Pedrosa,* Alfonso Pérez-Encabo
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47002-Valladolid, Spain
E-mail: pedrosa@qo.uva.es
Received 15 April 2004
totally regioselective, and occurred with the carbonyl
Abstract: A novel condensation of (–)-phenylglycinol with g,d-ep-
group and the most substituted carbon of the epoxide,
leading to an almost equimolar mixture (48:50 for 2a:3a,
oxyketones is reported for the preparation of both enantiomers of
cis-5-alkyl-2-hydroxymethyl pyrrolidines. The required epoxy-de-
rivatives were easily prepared by epoxidation of the corresponding
and 45:50 for 2b:3b) of two of the four possible diastereo-
g,d-unsaturated ketones. Condensation with (–)-phenylglycinol is meric bicyclic oxazolidines13 2a,b and 3a,b in 71% and
regiospecific and stereoselective, giving only two of the four possi-
68% yields, respectively (Scheme 1). Neither the forma-
ble diastereomers. The stereochemistry of the cyclization products
tion of other diastereomers nor the presence of regioiso-
is dictated by the configuration of C-2 in the N-unsubstituted oxazo-
meric piperidine derivatives was detected by 1H NMR in
lidine formed as intermediate.
the reaction mixture.
Key words: 1,2-aminoalcohols, asymmetric Synthesis, cycliza-
tions, oxazolidines, pyrrolidines
OH
O
N
O
N
R
R
Ph
NH2
r.t., 15 h
CHCl3
Both mono-1 and bicyclic2 oxazolidines derived from
enantiopure 1,2-amino alcohols have been widely used in
asymmetric synthesis. In general, the transformation of
the heterocycle, followed by elimination of the chiral ap-
pendage has been used in the diastereoselective synthesis
of enantiopure aza-heterocycles of different sizes.
+
+
O
Ph
Ph
R
O
OH
OH
rac-1a, R = CH3
rac-1b, R = n-C7H15
2a, 50%
2b, 50%
3a, 48%
3b, 45%
Scheme 1
2,5-Disubstituted pyrrolidine derivatives are especially
attractive because of their presence in many natural
products3 and their use as chiral auxiliaries.4 They have
also used as starting materials in the synthesis of a great
variety of compounds.5 As a consequence, the synthesis of
enantiopure 2,5-disubstituted pyrrolidines has been stud-
ied in depth.6 Some of these approaches start from chiral
pool substances7 but other methodologies, such as cy-
clizations,8 palladium-catalyzed additions,9 or trapping
acyliminium ions by nucleophiles5d have been successful-
ly employed.
In both cases the diastereomers were separated by flash
chromatography (silica gel, hexane–EtOAc 4:1) and their
stereochemistry was tentatively established on the basis of
NOESY experiments and corroborated by chemical corre-
lation. To this end, 2a was subjected to reductive ring
opening by reaction with LAH in diethyl ether at 0 °C
yielding 4a in 90% yield as a single diastereomer.14 At-
tempts at debenzylation of 4a under usual reaction condi-
tions [H2, Pd(OH)2/C, EtOH] failed, but it was easily
transformed into N-Boc derivative 5a by hydrogenolysis
with Pearlman’s catalyst in ethyl acetate and 1.5 equiva-
lents of di-tert-butyl dicarbonate. Hydrolysis of urethane
5a with HCl in ethyl acetate, followed by neutralization
with a solution of sodium carbonate gives the known15
Recently, we have prepared enantiopure 2-substituted
pyrrolidines and piperidines from bicyclic oxazolidines
obtained by condensation of g or d-chloroketones with
(R)-phenylglycinol.10 A logical extension of this work
was the study of the condensation of epoxyketones with
the same amino alcohol directed to the synthesis of 2-hy-
droxymethyl-5-alkyl pyrrolidines. This letter reports the
first results of this reaction with epoxyketones 1a,b, pre-
pared by epoxidation of the corresponding unsaturated ke-
tones with potassium coroate and acetone.11
(2S,5S)-2-hydroxymethyl-5-methylpyrrolidine
(6a,
Scheme 2). The same treatment on 3a led to ent-6a, and
their enantiomeric relationship was established on the ba-
sis of the identity of the physical and spectral data and the
opposite signs of their specific rotations.
The stereochemistry of 3b was also determined by chem-
ical correlation by bromination16 with CBr4 and Ph3P in
methylene chloride to 4b, followed by reaction17 with lith-
ium dimethyl cuprate to furnish ethyl derivative 5b in
56% yield over the two steps. Reductive ring opening of
5b as described for 2a yielded compound 6b which exhib-
its specific rotation and physical and spectral data identi-
cal with those previously described18 (Scheme 3). In
Interestingly, the condensation of racemic 1a,b with (R)-
phenylglycinol, at room temperature for 15 hours in chlo-
roform as solvent, was stereoselective.12 The reactions are
SYNLETT 2004, No. 11, pp 2016–2018
0
6
.0
9
.2
0
0
4
Advanced online publication: 06.08.2004
DOI: 10.1055/s-2004-830867; Art ID: D09504ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diastereoselective Cyclization of g-d Epoxyketones with (–)-Phenylglycinol
2017
HO
Ph
OH
R
H3C
N
R
O
CH3
OH
R
1. LAH, Et2O, 0 o
2. H3O+
C
H
O
O
O
N
N
Ph
NH
O
NH
H
O
Ph
Ph
Ph
Ph
Ph
2a
OH
4a
cis-S
cis-R
2a,b
H2/Pd(OH)2
Boc2O, AcOEt
H
O
H
O
N
R
R
O
R
O
NH
NH
Boc
O
H
N
OH
Ph
N
1. HCl, EtOAc
2. Na2CO3
CH3
CH3
trans-R
trans-S
3a,b
HO
HO
Scheme 4
5a
6a
Scheme 2
Acknowledgment
Authors thank the financial support provided by the Spanish Mini-
sterio de Ciencia y Tecnología (Project BQU2002-1046).
addition, 2b and 3b were transformed into the N-Boc de-
rivatives of (2R,5R)-5-heptyl-2-hydroxymethyl pyrroli-
dine and its enantiomer as described for compound 2a in
52% and 60% total yields, respectively.19
References
(1) For a review see: Scolastico, C. Pure Appl. Chem. 1988, 60,
1689.
O
N
O
N
C7H15
C7H15
CBr4, Ph3P, CH2Cl2
(2) (a) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J. J. Org.
Chem. 1999, 64, 1979. (b) Meyers, A. I.; Downing, S. V.;
Weiser, M. J. J. Org. Chem. 2001, 66, 1413; and references
therein. (c) Amat, M.; Pérez, M.; Llor, N.; Bosch, J.; Lago,
E.; Molins, E. Org. Lett. 2001, 3, 611. (d) Mayers, A. I.;
Brengel, G. P. Chem. Commun. 1997, 1. (e) Amat, M.;
Bosch, J.; Hidalgo, J.; Cantó, M.; Pérez, M.; Llor, N.;
Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org.
Chem. 2000, 65, 3074. (f) Munchhof, M. J.; Meyers, A. I. J.
Am. Chem. Soc. 1995, 117, 5299. (g) Amat, M.; Llor, N.;
Hidalgo, J.; Escolano, C.; Boch, J. J. Org. Chem. 2003, 68,
1919; and references cited therein.
Ph
Ph
3b
4b
OH
OH
Br
Me2CuCNLi2
THF, r.t.
Ph
1. LAH, Et2O, 0 o
2. H3O+
C
O
C7H15
N
C7H15
N
Ph
6b
5b
(3) See for instance: (a) Attygalle, A. B.; Morgan, E. D. Chem.
Soc. Rev. 1984, 13, 245. (b) Massiot, G.; Delaude, C. In The
Alkaloids, Vol. 27; Brossi, A., Ed.; Academic Press: New
York, 1986, 269.
Scheme 3
The stereochemical outcome of the reaction is noteworthy
because, as recently noted for a similar cyclization,20 the
configuration at C-2 in the intermediate oxazolidine deter-
mines the absolute configuration of the stereocenter creat-
ed in the opening of the epoxide moiety.
(4) (a) Whitesell, J. K.; Minton, M. A.; Chen, K. M. J. Org.
Chem. 1988, 53, 5383. (b) Schlessinger, R. H.; Iwanowicz,
E. J. Tetrahedron Lett. 1987, 28, 2083. (c) Short, R. P.;
Kennedy, R. M.; Masamune, S. J. Org. Chem. 1989, 54,
1755. (d) Whitessel, J. K. Chem. Rev. 1989, 89, 1581.
(5) (a) Takahata, H.; Takehara, H.; Ohkubo, N.; Momose, T.
Tetrahedron: Asymmetry 1990, 1, 561. (b) Cuny, G. D.;
Buchwald, S. L. Synlett 1995, 519. (c) Manfré, F.; Kern, J.
M.; Biellman, J. F. J. Org. Chem. 1992, 57, 2060.
(d) Dhimane, H.; Vanucci-Balqué, C.; Mamon, L.;
Lhommet, G. Eur. J. Org. Chem. 1998, 1955.
(6) For a recent revision see: Pichon, M.; Figadère, B.
Tetrahedron: Asymmetry 1996, 7, 927.
(7) Wang, Q.; Sasaki, V. A.; Riche, C.; Poitier, P. J. Org. Chem.
1999, 64, 8602; and references therein.
(8) Craig, D.; Jones, P. S.; Rowlands, G. J. Synlett 1997, 1423.
(9) Bäckvall, J.-E.; Schink, H. E.; Renko, Z. D. J. Org. Chem.
1990, 55, 826.
(10) Andrés, J. M.; Herráiz-Sierra, I.; Pedrosa, R.; Pérez-Encabo,
A. Eur. J. Org. Chem. 2000, 1719.
The stereocontrol can be rationalized by taking into ac-
count that the reaction of (–)-phenylglycinol with racemic
epoxyketones initially yields a mixture of pairs of cis and
trans isomers in equilibrium through the corresponding
tautomeric hydroxyimines (Scheme 4).21 The preferential
formation of 2a,b from the equilibrium mixture cis-R/
trans-R is a consequence of the nucleophilic displacement
occurring faster in the former because the approach of the
nitrogen atom to the inner carbon of the epoxide is less
hindered. In the same way, the formation of 3a,b from the
equilibrium mixture cis-S/trans-S takes place in the latter
because it is less hindered than the first one.
In summary, the described protocol allows the easy prep-
aration of enantiopure 5-substituted-2-hydroxymethyl
pyrrolidines from readily available starting products.
(11) Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J. O.; Pater,
R. H. J. Org. Chem. 1980, 45, 4758.
(12) Experimental Procedure: To a solution of epoxyketone
(3.0 mmol) in CHCl3 (3 mL), cooled to 0 °C was added
(–)-phenylglycinol (0.41 g, 3.0 mmol) in CHCl3 (3 mL) and
MgSO4 (0.2 g). The mixture was stirred at that temperature
Synlett 2004, No. 11, 2016–2018 © Thieme Stuttgart · New York

2018
J. M. Andrés et al.
LETTER
for 2 h and then warmed to r.t. and stirred for additional 13
h. The mixture was filtered, the solvent concentrated and the
residue was purified by flash chromatography (silca gel,
EtOAc–hexane 1:4, v/v).
J = 5.7 Hz, 1 H), 3.25–3.38 (m, 2 H), 3.76 (t, J = 8.7 Hz, 1
H), 4.08 (dd, J = 7.2, 8.4 Hz, 1 H), 4.33 (dd, J = 7.2, 8.7 Hz,
1 H), 7.24–7.40 (m, 5 H). 13C NMR (75 MHz, CD3Cl): d =
14.1, 22.6, 25.0, 26.9, 29.2, 29.9, 31.8, 35.0, 39.2, 63.3, 69.7,
71.0, 73.2, 108.2, 126.5 (2 C), 127.4, 128.7 (2 C), 141.7.
(14) (a) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron 1990,
46, 4595. (b) Alexakis, A.; Mangeney, P. Tetrahedron:
Asymmetry 1990, 1, 417. (c) Meyers, A. I.; Burgess, L. E. J.
Org. Chem. 1991, 56, 2294.
(15) Petersson-Fasth, H.; Riesinger, S. W.; Bäckvall, J. E. J. Org.
Chem. 1995, 60, 6091.
(16) Borch, R. F.; Evans, A. J.; Wade, J. J. J. Am. Chem. Soc.
1997, 99, 162.
(13) Spectroscopic data for compounds: 2a: [a]D25 +27.2 (c 0.7,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.50 (s, 3 H),
1.60–1.73 (m, 1 H), 1.81–1.89 (m, 1 H), 1.96–2.09 (m, 2 H),
2.60 (br s, 1 H), 2.78 (dd, J = 5.0, 10.4 Hz, 1 H), 2.97–3.08
(m, 2 H), 3.98 (dd, J = 7.9, 9.9 Hz, 1 H), 4.13 (dd, J = 6.1,
7.9 Hz, 1 H), 4.62 (dd, J = 6.1, 9.9 Hz, 1 H), 7.25–7.5 (m, 5
H). 13C NMR (75 MHz, CD3Cl): d = 25.9, 27.3, 37.9, 59.7,
64.2, 64.3, 67.0, 106.5, 128.1, 128.5 (2 C), 128.9 (2 C),
135.4. Compound 2b: [a]D25 +7.3 (c 0.6, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 0.88 (t, J = 6.5 Hz, 3 H), 1.20–1.57
(m, 10 H), 1.58–1.73 (m, 2 H), 1.74–1.91 (m, 2 H), 1.92–
2.15 (m, 2 H), 2.45 (br s, 1 H), 2.72 (dd, J = 4.7, 10.4 Hz, 1
H), 2.98 (dd, J = 3.7, 10.4 Hz, 1 H), 3.05–3.15 (m, 1 H), 4.0
(dd, J = 7.9, 10.0 Hz, 1 H), 4.11 (dd, J = 6.1, 7.8 Hz, 1 H),
(17) Lipshutz, B. In Organometallics in Synthesis; Schlosser, M.,
Ed.; John Wiley: New York, 1994, 305.
(18) Arseniyadis, S.; Huang, P. Q.; Piveteau, D.; Hüsson, H.-P.
Tetrahedron 1988, 44, 2457.
(19) Data for N-Boc Pyrrolidines: 5a: [a]D25 –9.9 (c 1.2, CHCl3).
4.60 (dd, J = 6.1, 10.0 Hz, 1 H), 7.25–7.52 (m, 5 H). 13
C
ent-5a: [a]D25 +9.95 (c 1.3, CHCl3). N-Boc derivatives of
25
NMR (75 MHz, CD3Cl): d = 14.1, 22.6, 25.2, 27.3, 29,3,
30.0, 31.8, 35.6, 39.2, 59.4, 63.8, 64.5, 66.6, 108.7, 128.2,
128.5 (2 C), 128.9 (2 C), 135.2. Compound 3a: [a]D25 –97.8
(c 0.7, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.48 (s, 3
H), 1.75–1.86 (m, 1 H), 1.92–2.11 (m, 3 H), 2.21–2.27 (m, 1
H), 3.10–3.15 (m, 1 H), 3.26–3.35 (m, 2 H), 3.83 (t, J = 8.6
Hz, 1 H), 4.05 (t, J = 7.6 Hz, 1 H), 4.34 (dd, J = 6.1, 8.6 Hz,
1 H), 7.23–7.40 (m, 5 H). 13C NMR (75 MHz, CD3Cl): d =
26.8, 27.2, 37.8, 63.2, 69.9, 70.8, 73.5, 105.8, 126.5 (2 C),
127.4, 128.7 (2 C), 141.6. Compound 3b: [a]D25 –70.6 (c 0.5,
CHCl3). 1H NMR (300 MHz, CDCl3) d = 0.90 (t, J = 6.5 Hz,
3 H), 1.29–1.61 (m, 11 H), 1.69–1.78 (m, 1 H), 1.81–1.93
(m, 1 H), 1.95–2.12 (m, 3 H), 2.27 (br s, 1 H), 3.13 (tq,
(2R,5R)-5-heptyl-2-hydroxymethyl pyrrolidine: [a]D
+4.1 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): d = 0.88
(t, J = 6.2 Hz, 3 H), 1.25 (m, 10 H), 1.44 (s, 9 H), 1.51–1.65
(m, 3 H), 1.82–1.97 (m, 3 H), 3.51 (t, J = 8.6 Hz, 1 H), 3.67
(t, J = 8.4 Hz, 1 H), 3.72–3.89 (m, 1 H), 3.90–4.01 (m, 1 H),
5.12 (br s, 1 H). 13C NMR (75 MHz, CD3Cl): d = 14.1, 22.6,
26.5, 26.8, 28.4 (3 C), 28.9, 29.2, 29.5, 31.8, 35.4, 59.2, 61.1,
68.8, 80.2, 157.4. N-Boc derivatives of (2S,5S)-5-heptyl-2-
hydroxymethyl pyrrolidine: [a]D25 –4.0 (c 0.9, CHCl3).
(20) Penhoat, M.; Levacher, V.; Dupas, G. J. Org. Chem. 2003,
68, 9517.
(21) Lázár, L.; Fülöp, F. Eur. J. Org. Chem. 2003, 3025.
Synlett 2004, No. 11, 2016–2018 © Thieme Stuttgart · New York