A practical route to enantiopure 3-hydroxy-pyrrolidines: application to a straightforward synthesis of (-)-bulgecinine

Article abstract of DOI:10.1016/j.tetlet.2007.12.051

A practical synthesis of enantiopure substituted 3-hydroxy-pyrrolidines is reported. In four steps, starting from commercially available amino acids as chiral educts, this method allows for an efficient preparation of a variety of 3-hydroxy-pyrrolidines, as well as 3-hydroxy-piperidines and azepanes. Application of this methodology for a straightforward asymmetric synthesis of (-)-bulgecinine is also described.

Full text of DOI:10.1016/j.tetlet.2007.12.051

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1175–1179
A practical route to enantiopure 3-hydroxy-pyrrolidines: application
to a straightforward synthesis of (ꢀ)-bulgecinine
Mathieu Toumi, Franßcois Couty, Gwilherm Evano *
Institut Lavoisier de Versailles, UMR CNRS 8180, Universite´ de Versailles Saint Quentin en Yvelines, 45 Avenue des Etats-Unis,
78035 Versailles Cedex, France
Received 7 November 2007; revised 6 December 2007; accepted 10 December 2007
Available online 15 December 2007
Abstract
A practical synthesis of enantiopure substituted 3-hydroxy-pyrrolidines is reported. In four steps, starting from commercially avail-
able amino acids as chiral educts, this method allows for an efficient preparation of a variety of 3-hydroxy-pyrrolidines, as well as 3-
hydroxy-piperidines and azepanes. Application of this methodology for a straightforward asymmetric synthesis of (ꢀ)-bulgecinine is also
described.
Ó 2007 Elsevier Ltd. All rights reserved.
The 3-hydroxy-pyrrolidine subunit is found in a wide
range of naturally occurring alkaloids and biologically
OH
active molecules.1 For example, a substituted pyrrolidinol
OH
H
OH
nucleus can be found in detoxin A1 1, a natural chemical
detoxification agent (Fig. 1).2 Other interesting hydroxyl-
ated pyrrolidines include retronicine (2, a pyrrolizidine
necine base),3 bulgecin C 3,4 the cyclopeptide alkaloid pali-
urine E 45 and pharmaceuticals such as the antihyperten-
sive Barnidipine 5 (Fig. 1).6 3-Hydroxy-pyrrolidines are
also commonly used as intermediates for the preparation
of a variety of drugs7 and now clearly appear as most use-
ful chiral ligands and promoters in organocatalysis.8
Due to growing interest for this scaffold, a number of
synthetic approaches to the stereoselective synthesis of
3-hydroxy-pyrrolidine and its derivatives have been
developed.9 They include intramolecular displacement of
a leaving group by an amine,10 amidomercuration or
haloamidation reactions,11 asymmetric hydroboration of
3-pyrroline derivatives,12 reduction of lactams obtained by
condensation of amines with malic acid,13 nitroalkenes
[4+2] cycloaddition,14 enzymatic hydroxylation,15 reaction
H
N
2
O
N
OH
O
OH
NH
Detoxin A1
1
Retronecine 2
OMe
NH
HO
O
O
OSO Na
3
O
O
OH
O
AcHN
N
HN
O
O
N
H
Ph
HO
OH
N
Bulgecin C 3
Paliurine E 4
O
NO
2
O
CO Me
2
N
HN
Bn
Barnidipine 5
*
Fig. 1. Natural products and drugs featuring a 3-hydroxy-pyrrolidine
subunit.
Corresponding author. Tel.: +33 1 39 25 44 55; fax: +33 1 39 25 44 52.
E-mail address: evano@chimie.uvsq.fr (G. Evano).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.051

1176
M. Toumi et al. / Tetrahedron Letters 49 (2008) 1175–1179
OH
OH
O
In connection with our interest in the total synthesis of
various cyclopeptide alkaloids,18 we considered the possi-
bility of a short synthesis of 2-substituted 3-hydroxy-
pyrrolidines 6 starting from inexpensive, commercially
available protected amino acids 8 (Scheme 1).
oxidative
nucleophilic
addition /
HO
HN
cleavage /
R
R
R
N
P
HN
P
reduction
reduction
P
6
7
8
Indeed, a nucleophilic addition/substrate-controlled dia-
stereoselective reduction sequence from 8 would allow for
the installation of the oxygenated stereocenter19 in 7. A
two-step cyclization from 720 would next be used to form
the pyrrolidine ring in 6. Recently, we successfully applied
Scheme 1. Four-step synthesis of 3-hydroxy-pyrrolidines from amino
acids.
of epoxysulfonamides with sulfoxonium ylides16 or cycliza-
tion of a-lithio-carbamates.17
Table 1
Asymmetric synthesis of 3-hydroxy-pyrrolidines from amino acids
O
O
OH
OH
OH
1. nBuLi (1 eq.)
THF, -10 ºC
HO
HN
NaBH
OsO NaIO
BF ·OEt , Et SiH
4
4,
4
3
2
3
R
R
R
HO
R
R
MeOH, -78 ºC
THF/H O, rt
CH Cl
2 2
2.
MgBr
(2.3 eq.)
-78 ºC to rt
2
HN
P
HN
P
N
P
N
P
-78 ºC to -20 ºC
P
8
9
7
10
6
Entry Starting amino
Amino alcohol 7
Yield (addition/
reduction)a (%)
drb
Hydroxy-
pyrrolidine 6
Yield (oxidative cleavage/ Overall yield from
acid 8
reduction)a (%)
amino acid 8a (%)
O
OH
OH
HO
1
82c
77:23
70c
57c
HN
HN
Cbz
7a
N
Cbz
Cbz
6a
8a
N
-Cbz-Ala
O
OH
OH
HO
Ph
Ph
Ph
2
3
4
5
6
86
58
64
72
96
92:8
70
35
31
52
72
60
20
20
20
69
HN
Boc
8b -Boc-Phe
HN
N
Boc
Boc
6b
N
7b
O
OH
OH
HO
90:10
89:11
91:9
HN
Boc
8c
HN
Boc
7c
N
Boc
6c
N-Boc-Leu
O
OH
OH
HO
HN
N
HN
Boc
Boc
-Boc-Nle
Boc
7d
8d
N
6d
O
OH
OH
HO
Ph
Ph
Ph
N
HN
Boc
8e
HN
Boc
Boc
N
-Boc-Phg
7e
6e
OH
O
OH
HO
OTBS
OTBS
OTBS
>95:5
N
HN
Boc
-Boc-Ser(OTBS)
HN
Boc
7f
Boc
8f
N
6f
a
b
c
Yield of isolated, pure product.
Determined by 1H NMR analysis of crude reaction mixtures.
Obtained as an inseparable 77:23 mixture of isomer at the C3 stereocenter.

M. Toumi et al. / Tetrahedron Letters 49 (2008) 1175–1179
1177
this straightforward sequence to a gram scale four-step syn-
OH
OH
H
H
thesis of the hydroxy-pyrrolidine core of the cyclopeptide
alkaloid paliurine F18a starting form D-serine. We now
report on the generalization of this method starting from
other amino acids as well as its application for an efficient
asymmetric synthesis of (ꢀ)-bulgecinine.
Ph
Me
N
N
H
H
Cbz
6a
Boc
6b
OH
H
H
To evaluate the scope of this methodology, a set of six
natural and non-natural aminoacids 8a–f was selected for
this study (Table 1). These aminoacids were firstly sub-
jected to the non epimerizing Rapoport’s modification of
the Tegner reaction:21 deprotonation of the acid with
1 equiv of butyllithium followed by the addition of 2 equiv
of allylmagnesium bromide cleanly afforded the corre-
sponding unconjugated ketones 9 in good yields. To avoid
conjugation of the double bond and to install the oxygen-
ated stereocenters, these ketones were immediately reduced
with sodium borohydride in methanol at ꢀ78 °C to give
aminoalcohols 7 with useful levels of diastereoselectivity
(Table 1, dr ranging from 77:23 to 95:5, minor diastereoiso-
mer separated when needed by column chromatography).
The configuration of the newly created stereocenter was
secured through stereochemistry assessment of the final
hydroxy-pyrrolidines 6 (see below) and the observed
diastereoselectivity most certainly arises from chelation
with the carbamate in 9.19
OH
H
N
N
H
OTBS
Boc
6c
Boc
6g
Fig. 2. Assignment of relative stereochemistries of 3-hydroxy-pyrrolidines
through NOE experiments.
or pent-4-enyl-magnesium bromide. To overcome this
problem, the Weinreb amide derivative of 11 was first pre-
pared and then reacted with Grignard reagents. Using this
two-step sequence, the corresponding ketones were
obtained in excellent yields and finally reduced to 12a
and 12b with sodium borohydride (Scheme 2).
Having useful quantities of amino-alkenes 12a and 12b
in hand, we next focused on their cyclization to piperidine
and azepane ring systems, respectively. In a similar fashion,
12a and 12b were treated with catalytic osmium tetroxide
and sodium periodate and cleanly gave the corresponding
cyclized products 13a and 13b in quantitative yields. In this
case, the reaction of protected hemiaminals 13a and 13b
with triethylsilane and boron trifluoride failed to cleanly
give the corresponding deoxygenated heterocycles, which
was attributed to the easier formation of cyclic enamide
derivatives (and their subsequent oligomerization), a side
reaction that could hardly happen with five-membered ring
compounds. This problem could however be easily
overcome by using a hydrogenation reaction for the reduc-
tion step: after reduction and concomitant deprotection,
enantiopure 3-hydroxy-piperidine 14a and azepane 14b
were obtained in excellent yields. These results show that
Formation of the pyrrolidine ring was finally initiated
by oxidative cleavage of the double bond in amino-alkenes
7. Spontaneous cyclization of the intermediate amino-alde-
hydes followed by reduction of the resulting protected ami-
nals 10 using boron trifluoride and triethylsilane22
ultimately gave the desired hydroxy-pyrrolidines 6 in mod-
erate to good yields (Table 1).
As can be seen from results in Table 1, enantiopure 3-
pyrrolidinols 6 could be obtained in overall yields ranging
from 20% to 69%, in four steps only, using substrate-con-
trolled diastereoselective reactions from readily available
amino acids 8. An interesting feature resides in the possibil-
ity of formation of both antipode of each heterocycle since
L- and D-amino acid are all commercially available: an
example of synthesis starting from an unnatural D-amino
acid (N-Boc, O-TBS-D-serine 8f) can be found in entry 6.
Before moving on to further developments and applica-
tion of our synthetic route to 2-substituted-3-hydroxy-pyr-
rolidines, it was necessary to unambiguously ascertain their
relative configuration. Therefore, NOE experiments were
performed on a representative set of 3-pyrrolidinols 6.
Results from these experiments are shown in Figure 2
and clearly confirm the 2,3-trans relative configurations.
Formation of higher homochiral ring systems (i.e.,
3-hydroxy-piperidines and 3-hydroxy-azepanes) using a
similar strategy was next investigated. To this end, 1-
amino-hex-5-ene and 1-amino-hept-6-ene derivatives 12a
and 12b were prepared from N-Cbz-phenylalanine 11
(Scheme 2). In contrast with the reaction of amino acid
derivatives with allylmagnesium bromide, the use of a
modified Tegner reaction failed to give the corresponding
ketones when 11 was reacted with less reactive but-3-enyl-
1. NHMe(OMe)·HCl
EDC, NMM, CH Cl
2
2
2.
MgBr
n
OH
HO
HN
O
THF, O ºC
n
Ph
Ph
3. NaBH MeOH, -78 ºC
4,
HN
n = 1: 81%
dr = 85:15
n = 2: 64%
dr = 81:19
Cbz
Cbz
11
12a (n = 1)
12b (n = 2)
OsO NaIO
4,
4
THF/H O
2
quant.
OH
Ph
OH
Ph
H2, Pd/C, EtOH
n
n
n = 1: 88%
n = 2: 89%
N
HO
N
H
Cbz
14a (n = 1)
14b (n = 2)
13a (n = 1)
13b (n = 2)
Scheme 2. Formation of 3-hydroxy-piperidines and 3-hydroxy-azepanes.

1178
M. Toumi et al. / Tetrahedron Letters 49 (2008) 1175–1179
OH
O
over two steps) and diastereoselectivity (dr = 91:9). It
should be noted here that a concomitant protection of the
hydroxyl group as its TMS ether was observed during the
reaction, a protection that however had no effect on our
synthesis since final acidic cleavage of the TBS ether and
nitrile hydrolysis would with no doubt simultaneously
cleave this extra protecting group. Interestingly, we were
able to reach a quite high level of diastereoselectivity during
the addition of the cyanide ion onto iminium 17. This might
arise from two synergistic effects: steric hindrance of the
protected hydroxymethyl substituent at C2 and assistance
of the free hydroxyl for the delivery of the cyanide ion.
To complete the synthesis, amino-nitrile 18 was trans-
formed into (ꢀ)-bulgecinine hydrochloride4c,23b,24 by
treatment in 6 M HCl at 60 °C. Purification of this hydro-
chloride using Dowex 50W-X4 sulfonic acid ion exchange
resin then gave synthetic (ꢀ)-bulgecinine 19 which exhib-
ited physical, spectroscopic and spectrometric characteris-
tics (1H NMR, 13C NMR, IR, [a]D and MS) identical to
those reported for natural and synthetic products.4c,23,25
Using the six-step asymmetric synthesis depicted in Scheme
3, synthetic bulgecinine was therefore obtained in 54%
overall yield, with a limited use of protecting groups.
In summary, we have developed a practical asymmetric
synthesis of 2-substituted 3-hydroxy-pyrrolidines. Starting
from commercially available amino acids as chiral educts,
this method allows for an efficient preparation of a variety
of 3-hydroxypyrrolidines in only four steps. This method
has also been used for the preparation of trisubstituted
3-pyrrolidinols and has been successfully applied to a
straightforward asymmetric synthesis of (ꢀ)-bulgecinine.
Further applications of this methodology are under inves-
tigation and will be reported in due time.
1. TBSCl, imidazole, DMF, rt
2. nBuLi (1 eq.), THF, -10 ºC
HO
OTBS
OH
then
HN
Boc
7f
HN
Boc
MgBr, -78 ºC to rt
3. NaBH4, MeOH, -78 ºC
15
76%, 3 steps
dr > 95:5
OsO4, NaIO4
THF / H2O
OH
OH
TMSOTf, TMSCN
CH2Cl2, -78 ºC
OTBS
OTBS
HO
N
Boc
N
-
TfO
77%, 2 steps
dr = 91:9
Boc
17
16
OTMS
OTBS
OH
6M HCl, 60 ºC
then Dowex 50W-X4
93%
OH
O
HO
NC
N
N
H
Boc
18
(-)-bulgecinine 19
Scheme 3. Six-step asymmetric synthesis of (ꢀ)-bulgecinine from D-serine.
pyrrolidines as well as higher ring systems can be easily
obtained in few steps from amino acids (Scheme 2).
We finally wanted to address the efficiency of our reac-
tion sequence for the synthesis of trisubstituted hydroxy-
pyrrolidines. With this goal in mind, (ꢀ)-bulgecinine 19
was chosen as target since it possesses the desired pyrroli-
dine core.4c This molecule, which is a common constituent
of Pseudomonas sp. derived glycopeptides (bulgecins A, B
and C), has drawn considerable interest since 24 asymmet-
ric total (or formal) syntheses have, to date, been reported
(number of steps ranging from 7 to 20 and overall yields
from 3% to 37%).23 This molecule therefore appeared as
a good candidate, firstly to further put at test the synthetic
utility of our route and secondly to evaluate whether tri-
substituted pyrrolidines could be formed with useful level
of selectivity using a slight modification of our method.
The beginning of our synthesis closely follows the one
we recently reported for the synthesis of the 3-hydroxy-pyr-
rolidine core of the cyclopeptide alkaloid paliurine F.18a
Commercially available N-Boc-D-serine 15 was chosen as
the starting point of the synthesis (Scheme 3). Its treatment
with excess TBSCl in DMF followed by acidic workup
allowed for a clean protection of the alcohol. As detailed
previously (Table 1, entry 6), a Tegner reaction–reduction
sequence provided the desired protected amino-diol 7f as
a single diastereoisomer. Next, formation of the pyrrolidine
ring was initiated by oxidative cleavage of the double bond.
Spontaneous cyclization of the intermediate amino-alde-
hyde gave the protected aminal 16 (Scheme 3).
Acknowledgments
The authors thank the CNRS for financial support.
`
M.T. acknowledges the Ministere de la Recherche for a
graduate fellowship.
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NMR (300 MHz, D2O): d 4.56 (dd, J = 8.8, 5.2 Hz, 1H), 4.40 (br s,
1H), 3.69–3.89 (m, 3H), 2.59–2.69 (m, 1H), 2.28–2.33 (m, 1H); 13C
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18. (a) Toumi, M.; Couty, F.; Evano, G. Angew. Chem. Int. Ed. 2007, 46,
572; (b) Toumi, M.; Couty, F.; Evano, G. J. Org. Chem. 2007, 72,
9003; (c) Toumi, M.; Couty, F.; Evano, G. Synlett 2008, 29.
19. For related reduction, see, for examples: (a) Hoffman, R. V.;
Maslouh, N.; Cervantes-Lee, F. J. Org. Chem. 2002, 67, 1045; (b)
Sengupta, S.; Mondal, S. Tetrahedron 2002, 58, 7983; and references
cited therein.
20
25. (ꢀ)-Bulgecinine (ꢀ)-19: Mp: 180–185 °C; ½aꢂD ꢀ12 (c 1, 1 M HCl); 1H
NMR (300 MHz, D2O): d 4.30 (app. q, J = 4.6 Hz, 1H), 4.13 (dd,
J = 8.8, 6.6 Hz, 1H), 3.81 (dd, J = 14.4, 6.8 Hz, 1H), 3.61–3.69 (m,
2H), 2.58 (ddd, J = 14.0, 9.0, 5.9 Hz, 1H), 2.08 (app. dt, J = 14.0,
5.5 Hz, 1H); 13C NMR (75 MHz, D2O): d 174.4, 71.4, 67.4, 60.1, 58.9,
37.3; ESIHRMS m/z calcd for C6H11NNaO4 [M+Na]+ 184.0575,
found 184.0586.
20. For related cyclizations to for five-membered rings, see, for examples:
(a) Ndungu, J. M.; Cain, J. P.; Davis, P.; Ma, S.-W.; Vanderah, T.