Asymmetric synthesis via aziridinium ions: Exploring the stereospecificity of the ring opening of aziridinium ions and a formal synthesis of (-)-swainsonine

Article abstract of DOI:10.1016/j.tetasy.2010.03.048

The use of aziridinium ions in two different projects is described. First, the stereospecificity of the ring opening of aziridinium ions with MeNH ₂ as a route to chiral diamines has been explored. When the aziridinium ion contained a phenyl or para-methoxyphenyl substituent, stereospecific ring opening occurred. In contrast, switching the para-methoxy group to a para-N,N-dimethylamino group gave a racemic diamine product. Second, starting from N-Boc pyrrolidine, asymmetric lithiation-trapping-ring expansion (via an aziridinium ion) was used to synthesise a piperidine alcohol. In this way, a formal synthesis of (-)-swainsonine was completed.

Full text of DOI:10.1016/j.tetasy.2010.03.048

Tetrahedron: Asymmetry 21 (2010) 1563–1568
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis via aziridinium ions: exploring the stereospecificity of
the ring opening of aziridinium ions and a formal synthesis of (À)-swainsonine
Sally J. Oxenford a, Stephen P. Moore a, Giorgio Carbone a, Graeme Barker a, Peter O’Brien a,
Mark R. Shipton b, John Gilday c, Kevin R. Campos d
,
*
a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
b GlaxoSmithKline Pharmaceuticals, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
c AstraZeneca, Process R & D, Avlon Works, Severn Road, Hallen, Bristol, BS10 7ZE, UK
d Department of Process Research, Merck Research Laboratories, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of aziridinium ions in two different projects is described. First, the stereospecificity of the ring
opening of aziridinium ions with MeNH2 as a route to chiral diamines has been explored. When the
aziridinium ion contained a phenyl or para-methoxyphenyl substituent, stereospecific ring opening
occurred. In contrast, switching the para-methoxy group to a para-N,N-dimethylamino group gave a race-
mic diamine product. Second, starting from N-Boc pyrrolidine, asymmetric lithiation-trapping-ring
expansion (via an aziridinium ion) was used to synthesise a piperidine alcohol. In this way, a formal syn-
thesis of (À)-swainsonine was completed.
Received 9 March 2010
Accepted 31 March 2010
Available online 11 May 2010
Dedicated to Professor H. B. Kagan in
celebration of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
conversion of (R)-styrene oxide (R)-4 into chiral diamines such as
(R)-6 via aziridinium ion (S)-5 (Scheme 2).9 More recently, we
Aziridinium ions were first implicated as reaction intermediates
in 1946 during investigations of the reactions of the nitrogen mus-
tard gases.1,2 One year later, the structure of the analgesic amidone
was determined and the regioselectivity of its synthesis from a
chloro-amine could only be rationalised via the intermediacy of
an aziridinium ion.3 The first example of a ring enlargement via
an aziridinium ion was described by Fuson and Zirkle in 1948.4
Thus, treatment of pyrrolidine hydrochloride salt 1 with NaOH
gave chloro-piperidine 3 as the only product, with the rearrange-
ment proceeding via aziridinium ion 2 (Scheme 1). Since these
early beginnings, aziridinium ions are now established as useful
intermediates in natural product synthesis5,6 and synthetic
methodology.7,8
described the ring expansion of pyrrolidinyl amino alcohol syn-7,
via aziridinium ion 8, into piperidinyl alcohol syn-9 (Scheme 2)
as a key step in the synthesis of (+)-L-733,060, a neuronkinin-1
substance P receptor antagonist.10
R
NH
H
H
RNH2
O
N
N
Ph
Ph
Ph
(R)-4
(S)-5
(R)-6
CF3CO2
OH
Ph
H
H
Ph (CF3CO)2O
N
N
N
Cl
R1
OH
R2
NaOH
H
Cl
Cl
Cl
syn-7
syn-9
8
N
N
N
Et
3
H2O
H
Et
Et
Scheme 2. Previous work by the O’Brien group with aziridinium ions.
1
2
Scheme 1. Seminal report on the ring expansion of a pyrrolidine to a piperidine via
an aziridinium ion intermediate.
In this paper, our latest developments in the use of aziridinium
ions in synthesis are reported. First, a study on the stereospecificity
of the ring opening of aziridinium ions (S)-10 equipped with an elec-
tron-donating group in the para position (e.g., X = OMe, NMe2) is de-
scribed (Scheme 3). Here, we anticipated that the stereospecificity of
the ring opening could be compromised with the intervention of an
SN1-like pathway in aziridinium ions such as (S)-10. With this study,
Our group has a long-standing interest in the use of aziridinium
ions in synthesis. In 1996, we reported a one-pot method for the
* Corresponding author. Tel.: +44 1904 432535; fax: +44 1904 432516.
E-mail address: paob1@york.ac.uk (P. O’Brien).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.048

1564
S. J. Oxenford et al. / Tetrahedron: Asymmetry 21 (2010) 1563–1568
Me
R
N
specificity of the ring opening of aziridinium ions with different
aromatic substituents as outlined in Scheme 5.
NH
H
R
MeNH2
NR2
Me
R
N
NR2
NH
H
X
X
R
Et3N
MsCl
MeNH2
X
(S)-10
(R)-11
OH
NR2
OH
OH
H
OH
X
X
H
H
(S)-18
(S)-10
(R)-11
N
N
N
N
OH
anti-12
Boc
Scheme 5. Proposed investigation of the stereospecificity of the ring opening of
aziridinium ions.
H
OH
swainsonine
13
anti-14
The stereospecificity of the SN2 ring opening of aziridinium ions
(S)-10 with X = H (phenyl ring) by amines to give (R)-11 (X = H) has
previously been demonstrated by us9,15 and by researchers at Pfiz-
er20 and Amgen.21 To probe the effect of X and to ultimately map
out the scope of the aziridinium ion route to non-phenyl-contain-
ing diamines, we prepared amino alcohols (S)-18 with X = OMe and
NMe2 and studied the stereospecificity of their transformation into
diamines (R)-11.
To start with, amino alcohols (S)-23 and (S)-24 were prepared
using the route outlined in Scheme 6. Sharpless asymmetric amin-
ohydroxylation (AA)24,25 of commercially available 4-methoxysty-
rene 19 using K2OsO2(OH)4, (DHQ)2PHAL and tBuO2CNH2/
NaOH/tBuOCl gave Boc-protected amino alcohol (S)-21 in 65%
yield. In a similar way, substituted styrene 12 (prepared by a Wit-
tig reaction on the corresponding aldehyde26) gave Boc-protected
amino alcohol (S)-22 in 58% yield.
Scheme 3. Synthesis of chiral diamines and (À)-swainsonine via aziridinium ions.
we hoped to mapout the scope and limitationsof the aziridinium ion
route to chiral diamines such as (R)-11. We also report the successful
application of our N-Boc pyrrolidine lithiation-aldehyde trapping-
ring expansion methodology (anti-12?13?anti-14, Scheme 3) to
the formal synthesis of (À)-swainsonine, an inhibitor of lysosomal
a
-mannosidase and mannosidase II.11
2. Results and discussion
2.1. Investigation of the stereospecificity of ring opening of
aziridinium ions
Chiral diamines are important building blocks in synthesis, and
are useful precursors to chiral ligands/catalysts.12 Our one-pot
method for the conversion of (R)-styrene oxide (R)-4 (P99:1 er)
into chiral diamines such as (R)-17 is summarised in Scheme 4.9
The approach was based on a step-wise process previously devel-
oped by Dieter et al.13 and Miao and Rossiter.14 First, (R)-styrene
oxide (R)-4 was ring opened with pyrrolidine to give a mixture of
(R)-15 and (S)-16. Then, mesylation of this mixture gave an azirid-
inium ion (S)-5 in situ which was ring opened at the benzylic posi-
tion to give diamine (R)-17. Our subsequent efforts focused on
developing a route starting from phenylglycinol,15 preparing new
chiral bases from norephedrine,16 synthesising a range of Koga
bases17 and exploring the regiochemistry of ring opening different
aziridinium ions.18
NHBoc
N
OH
(i)
(ii)
OH
X
X
X
19; R = OMe
20; R = NMe2
(S)-21; R = OMe (65%)
(S)-22; R = NMe2 (58%)
(S)-23; R = OMe (64%)
(S)-24; R = NMe2 (54%)
Scheme 6. Synthesis of amino alcohols (S)-15 and (S)-16. Reagents and conditions:
(i) 4 mol % K2OsO2(OH)4, 6 mol % (DHQ)2PHAL, 3 equiv tBuO2CNH2/NaOH/tBuOCl,
nPrOH–water, 0 °C, 1 h; (ii) TFA, CH2Cl2, rt, 1 h then 1,4-dibromobutane, Na2CO3,
nBu4N+IÀ, THF, reflux, 40 h.
Next, both (S)-21 and (S)-22 were converted into their corre-
sponding pyrrolidinyl-substituted amino alcohols (S)-23 and (S)-
24 via a 2-step process of Boc-deprotection and N,N-dialkylation
using 1,4-dibromobutane.15 This delivered (S)-23 (64% yield) and
(S)-24 (54% yield), both of which were shown to be P97:3 er by
chiral shift 1H NMR spectroscopy in the presence of (S)-1-(9-an-
thryl)-2,2,2-trifluoroethanol.
OH
H
N
H
O
Et3N
MsCl
N
N
+
Ph
Ph
OH
Ph
(R)-4
(R)-15
(S)-16
With amino alcohols (S)-23 and (S)-24 in hand, their conversion
into diamines (R)-25 and (R)-26, respectively, was studied. A com-
parison with the known15 stereospecific synthesis of diamine (R)-5
(entry 1) is shown in Table 1. Treatment of amino alcohol (S)-23
(P97:3 er) with Et3N and MsCl (0 °C, Et2O, 1 h) followed by reac-
tion with aqueous methylamine (rt, 16 h) gave diamine (R)-25 in
58% yield. Analysis of (R)-25 by chiral shift 1H NMR spectroscopy
in the presence of (S)-1-(9-anthryl)-2,2,2-trifluoroethanol indi-
cated that its er was P97:3 (entry 2). Thus, despite the presence
of an electron-donating para-methoxy group, the ring opening of
the intermediate aziridinium ion was stereospecific. In contrast,
reaction of amino alcohol (S)-24 (P97:3 er) under the same mesy-
lation-ring-opening conditions delivered diamine (R)-26 in 50%
yield and ꢀ50:50 er (entry 3). With a more electron-donating
N,N-dimethylamino substituent in the para position, complete loss
of er was observed. Thus, it can be concluded that this methodol-
ogy will not tolerate aromatic groups with a strongly electron-
donating para-substituent.
~99:1 er
Me
NH
H
MeNH2
N
90% yield
~98:2 er
N
Ph
Ph
(S)-5
(R)-17
stereospecific
Scheme 4. One-pot synthesis of a chiral diamine.
The styrene oxide/aziridinium ion approach to these types of
chiral diamines has proved useful in academic and industrial labora-
tories: Kerr and co-workers prepared some new chiral diamines;19
researchers at Pfizer prepared 6.3 kg of a j
-opioid receptor agonist20
and 1.3 kg of a Koga base was synthesised by researchers at Am-
gen.21 In all but two cases,13,22 diamines such as (R)-17 contain a
phenyl ring (derived from styrene oxide,9,15,17,20,21 phenylglycinol15
or mandelic acid23). With a view to extending the methodology to
non-phenyl-containing diamines, we have now explored the stereo-

S. J. Oxenford et al. / Tetrahedron: Asymmetry 21 (2010) 1563–1568
1565
Table 1
H
H
(i)
Investigation of the stereospecificity of the ring opening of aziridinium ions derived
from (S)-16, (S)-23 and (S)-24
+
N
N
N
OH
OH
Boc
27
Boc
Boc
anti-12 (35%)
syn-29 (33%)
Me
1. Et3N, MsCl, Et2O
0 °C, 30 min
N
NH
96:4 er
98:2 er
OH
N
H
OH
2. MeNH2(aq), Et3N
rt, 16 h
H
(ii)
N
(iii)
X
X
N
Boc
N
(S)-16; X = H
(R)-17; X = H
OH
OH
(S)-23; X = OMe
(S)-24; X = NMe2
(R)-25; X = OMe
(R)-26; X = NMe2
anti-12
anti-30
(58%)
anti-14
(73%)
Entry
X
SM
er S:R
Prod
Yielda (%)
er S:Rb
c
Scheme 8. Synthesis of piperidine alcohol anti-14. Reagents and conditions: (i) s-
BuLi, (+)-sparteine surrogate 28, Et2O, À78 °C, 3 h then acrolein; (ii) TFA, CH2Cl2, rt,
20 h then K2CO3, allyl bromide, MeOH, rt, 12 h; (iii) (a) (CF3CO)2O, Et3N, CH2Cl2,
À78 °C, 1 h; (b) reflux, 48 h; (c) NaOH(aq), rt, 2 h.
1
2
3
H
OMe
NMe2
(S)-16
(S)-23
(S)-24
P99:1
P97:3
P97:3
(R)-17
(R)-25
(R)-26
—
P98:2
P97:3
ꢀ50:50
58
50
a
Yield after purification by Kugelrohr distillation.
Enantiomer ratio (er) determined by chiral shift 1H NMR spectroscopy in the
b
expansion of pyrrolidinyl alcohol anti-30 to piperidinyl alcohol
anti-14 was accomplished using trifluoroacetic anhydride at reflux
(followed by ester hydrolysis using NaOH). In this way, piperidinyl
alcohol anti-14 was generated in 73% yield.
presence of (S)-1-(9-anthryl)-2,2,2-trifluoroethanol.
90% yield of (R)-17 from (R)-styrene oxide (R)-4 (see Scheme 4).2,5
c
We had anticipated converting anti-14 into its TBDMS-pro-
tected analogue which is an intermediate in Blechert’s synthesis
of (À)-swainsonine.28 However, whilst our work was in progress,
Cossy et al. reported a formal synthesis of (À)-swainsonine6 that
proceeded via piperidinyl alcohol anti-14 (prepared in five steps
from (S)-proline). Thus, our three-step synthesis of a piperidinyl
alcohol anti-14 represents a formal synthesis of (À)-swainsonine.
2.2. From pyrrolidines to piperidines via aziridinium ions:
formal synthesis of (À)-swainsonine
(À)-Swainsonine, an inhibitor of lysosomal
a-mannosidase and
mannosidase II,11 has been the subject of extensive synthetic ef-
forts.6,27 Using our recently developed N-Boc pyrrolidine lithia-
tion-aldehyde trapping-ring expansion methodology, we realised
that a concise synthesis of (À)-swainsonine could be attempted.
Thus, previous work had established that piperidinyl alcohol
anti-14 could be converted into (À)-swainsonine (Scheme 7).6,28
We envisaged that piperidinyl alcohol anti-14 would be derived
from N-Boc pyrrolidinyl alcohol anti-12 via ring expansion through
the key aziridinium ion intermediate 13.4,29 Asymmetric lithiation
of N-Boc pyrrolidine 27 and trapping with acrolein would give ami-
no alcohol anti-12. Notably, to ultimately complete a formal syn-
thesis of the naturally occurring (À)-antipode, it would be
necessary to use the (+)-sparteine surrogate 28 developed in our
group.30
3. Conclusion
In conclusion, we report the first example of a non-stereospe-
cific ring opening of aromatic aziridinium ions (S)-10. Thus, dia-
mine (R)-25 (X = OMe) was formed in P97:3 er but racemic
diamine 26 (X = NMe2) was generated. As a result, the scope and
limitations of this aziridinium ion route to chiral diamines is
now established. In addition, we also report a formal synthesis of
(À)-swainsonine with a shorter synthesis of the key intermediate,
piperidinyl alcohol anti-14. Of note, this synthesis of the natural
(À)-antipode required the use of the (+)-sparteine surrogate 28.
OH
OH
H
OH
H
4. Experimental
4.1. General
N
N
N
H
OH
(–)-swainsonine
anti-14
13
All solvents were distilled before use. Et2O and THF were freshly
distilled from sodium benzophenone ketyl whereas CH2Cl2 was
freshly distilled from calcium hydride. Et3N was stored over KOH
pellets. n-BuLi and s-BuLi were titrated against N-benzylbenza-
mide before use. All non-aqueous reactions were carried out under
O2-free N2 or Ar using flame-dried glassware. Petrol refers to the
fraction of petroleum ether boiling in the range 40–60 °C. Brine re-
fers to a saturated aqueous solution. Flash chromatography was
carried out using Fluka Chemie GmbH silica (220–440 mesh). Thin
layer chromatography was carried out using commercially
available Merck F254 aluminium-backed silica plates. Proton
(400 MHz) and carbon (100.6 MHz) NMR spectra were recorded
on a Jeol ECX-400 instrument using an internal deuterium lock.
For samples recorded as solutions in CDCl3, chemical shifts are
quoted in parts per million relative to CHCl3 (dH 7.27) and CDCl3
(dC 77.0, central line of triplet). Carbon NMR spectra were recorded
with broad band proton decoupling and were assigned using DEPT
experiments. Coupling constants (J) are quoted in hertz. Melting
points were carried out on a Gallenkamp melting point apparatus.
Infrared spectra were recorded on an ATI Mattson Genesis FT-IR
spectrometer. Chemical ionisation high and low resolution mass
Me
H
N
H
N
N
Boc
N
Boc
OH
(+)-sparteine
anti-12
27
surrogate 28
Scheme 7. Proposed formal synthesis of (À)-swainsonine.
Our planned synthesis started with the Beak-style31 asymmet-
ric lithiation of N-Boc pyrrolidine 27. Thus, N-Boc pyrrolidine 27
was lithiated using s-BuLi/(+)-sparteine surrogate 28 and then
trapped with acrolein to give a ꢀ50:50 mixture of diastereomeric
adducts anti-12 and syn-29. Purification by column chromatogra-
phy delivered anti-12 (35% yield; 96:4 er) and syn-29 (33% yield;
98:2 er) (Scheme 8). The relative stereochemistry was established
by comparison with the literature data32 and the ers were deter-
mined by chiral HPLC of the corresponding N-benzamide (formed
by Boc deprotection and N-acylation with benzoyl chloride). Ami-
no alcohol anti-12 was then subjected to Boc deprotection and N-
allylation to give anti-30 in 58% yield. Finally, Cossy-style ring

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S. J. Oxenford et al. / Tetrahedron: Asymmetry 21 (2010) 1563–1568
spectra were recorded on a Fisons Analytical (VG) Autospec spec-
trometer. Electrospray high and low resolution mass spectra were
recorded on a Bruker Daltronics microOTOF spectrometer. Optical
rotations were recorded at room temperature on a Jasco DIP-370
amino)benzaldehyde (1.14 g, 7.65 mmol) in THF (10 mL) was
added dropwise and the resulting mixture was stirred at rt for
16 h. Then, water (30 mL) and Et2O (30 mL) were added and the
two layers were separated. The aqueous layer was extracted with
Et2O (3 Â 40 mL) and the combined organic extracts were dried
(Na2SO4) and evaporated under reduced pressure to give the crude
product. Purification by flash column chromatography with 2:1
petrol–Et2O as eluent gave styrene 20 (990 mg, 82%) as a pale yel-
low oil, RF (1:1 petrol–Et2O) 0.5; dH (400 MHz, CDCl3) 7.34 (d,
J = 9.0 Hz, 2H, m-C6H4NMe2), 6.71 (d, J = 9.0 Hz, 2H o-C6H4NMe2),
6.67 (dd, J = 17.0, 10.5 Hz, 1H, ArCH), 5.58 (dd, J = 17.0, 2.0 Hz,
1H, @CH), 5.06 (dd, J = 10.5, 2.0 Hz, 1H, @CH), 2.99 (s, 6H, NMe2);
dC (100.6 MHz, CDCl3) 150.2 (ipso-Ar), 136.6 (@CH), 127.1 (Ar),
126.2 (ipso-Ar), 112.3 (Ar), 109.3 (@CH2), 40.5 (NMe2). Spectro-
scopic data were consistent with those reported in the literature.26
polarimeter (using the sodium D line; 259 nm) and [a] given in
D
units of 10À1 deg cm3 gÀ1. Chiral stationary phase HPLC was per-
formed on an Agilent 1200 series chromatograph.
4.2. General procedure A: aminohydroxylation
A solution of NaOH(aq) was freshly prepared by dissolving NaOH
(4.6 mmol) in water (12.2 mL). t-Butyl hypochlorite (4.6 mmol)
and then 10 mL of the NaOH(aq) solution were added sequentially
to a stirred solution of t-butyl carbamate (4.65 mmol) in n-PrOH
(6 mL). After stirring for 5 min, the solution was cooled to 0 °C
and a solution of DHQ2PHAL or DHQD2PHAL (0.09 mmol) in n-
PrOH (6 mL) was added. Then, a solution of alkene (1.5 mmol) in
n-PrOH (12.2 mL) was added followed by addition of a solution
of K2OsO2(OH)4 (0.06 mmol) in the remaining 2.2 mL of the NaO-
H(aq) solution. After stirring for 1 h at 0 °C, saturated Na2SO3(aq)
solution (10 mL) was added and the mixture was stirred for
15 min. Then, the two layers were separated and the aqueous layer
was extracted with EtOAc (3 Â 15 mL). The combined organic ex-
tracts were washed with brine (20 mL), dried (Na2SO4) and evapo-
rated under reduced pressure to give the crude product.
4.6. tert-Butyl (1S)-2-hydroxy-1-(4-methyoxyphenyl)-
ethylcarbamate (S)-21
Using general procedure A, t-butyl carbamate (545 mg,
4.65 mmol), NaOH (183 mg, 4.6 mmol) in water (12.2 mL), t-butyl
hypochlorite (0.53 mL, 4.6 mmol), (DHQ)2PHAL (71 mg, 0.09 mmol),
4-methoxystyrene (0.12 mL, 1.5 mmol) and K2OsO2(OH)4 (22.5 mg,
0.06 mmol) in n-PrOH (24.2 mL) gave the crude product. Purification
by flash column chromatography with 3:1 petrol–EtOAc as eluent
gave carbamate (S)-21 (260 mg, 65%) as a white solid, mp 140–
4.3. General procedure B: Boc deprotection–dialkylation
142 °C (lit.,22b mp 139–141 °C); RF (3:1 petrol–Et2O) 0.2; [
a] =
D
+59.3 (c 1.0, EtOH) {lit.,22b
[a]D = +62.6 (c 1.0, EtOH) for 98% ee}; dH
At first, TFA (3.5 mL) was added dropwise to a stirred solution of
the N-Boc-protected amino alcohol (0.90 mmol) in CH2Cl2 (10 mL)
at rt under N2. After stirring for 1 h, the solvent was evaporated un-
der reduced pressure and 20% NaOH(aq) solution (1 mL) was added.
The mixture was extracted with CH2Cl2 (4 Â 10 mL) and the com-
bined organic extracts were dried (Na2SO4) and evaporated under
reduced pressure to give the crude amino alcohol which was suffi-
ciently pure (by 1H NMR spectroscopy) for use in the next step.
Na2CO3 (2.70 mmol), tetra-n-butylammonium iodide (0.45 mmol)
and then 1,4-dibromobutane (0.90 mmol) were added successively
to a stirred solution of the crude amino alcohol in THF (10 mL) at rt
under N2. The resulting suspension was heated at reflux for 40 h.
After being allowed to cool to rt, the solids were removed by filtra-
tion and the filtrate was evaporated under reduced pressure. The
residue was dissolved in Et2O (10 mL), washed with water
(10 mL), dried (Na2SO4) and evaporated under reduced pressure
to give the crude product.
(400 MHz, CDCl3) 7.21 (d, J = 8.5 Hz, 2H, m-C6H4OMe), 6.88 (d,
J = 8.5 Hz, 2H, o-C6H4OMe), 5.24 (br s, 1H, NH), 4.71 (br s, 1H,
CHN), 3.82–3.74 (m, 2H, CH2O), 3.80 (s, 3H, OMe), 2.51 (br s, 1H,
OH), 1.43 (s, 9H, CMe3). Spectroscopic data were consistent with
those reported in the literature.22b
4.7. tert-Butyl (1S)-1-[4-(dimethylamino)phenyl]-2-
hydroxyethylcarbamate (S)-22
Using general procedure A, t-butyl carbamate (545 mg,
4.65 mmol), NaOH (183 mg, 4.6 mmol) in water (12.2 mL), t-butyl
hypochlorite (0.53 mL, 4.6 mmol), (DHQ)2PHAL (71 mg, 0.09 mmol),
styrene 20 (1.2 mL, 1.5 mmol) and K2OsO2(OH)4 (22.5 mg,
0.06 mmol) in n-PrOH (24.2 mL) gave the crude product. Purification
by flash column chromatography with 3:1 petrol–EtOAc as eluent
gave carbamate (S)-22 (244 mg, 58%) as an off-white solid, mp
165–167 °C; RF (1:1 petrol–Et2O) 0.2; [
a]D = +58.9 (c 1.0, CHCl3);
mmax (CDCl3) 3247 (NH), 3054, 2972, 1670 (C=O), 1524, 1364, 1264,
4.4. General procedure C: diamine synthesis
1056, 737 cmÀ1; dH (400 MHz, CDCl3) 7.16 (d, J = 8.5 Hz, 2H, m-
C6H4NMe2), 6.72 (d, J = 8.5 Hz, 2H, o-C6H4NMe2), 5.09 (br d,
J = 6.0 Hz, 1H, NH), 4.71–4.67 (m, 1H, CHN), 3.81 (br s, 2H, CH2O),
2.94 (s, 6H, NMe2), 1.44 (s, 9H, CMe3); dC (100.6 MHz, CDCl3) 150.2
(ipso-Ar), 128.1 (ipso-Ar), 127.4 (Ar), 112.8 (Ar), 79.8 (CMe3), 67.2
(CH2), 56.6 (CHN), 40.6 (NMe2), 28.3 (CMe3); m/z (CI, NH3) 281
[27%, (M+H)+], 225 (68, MÀ55), 207 (43, MÀ73), 164 (100,
MÀ116) [Found: (M+H)+, 281.1867. C15H24N2O3 requires M+H,
281.1865].
At first, MsCl (0.04 mL, 0.46 mmol) was added dropwise to a
stirred solution of the amino alcohol (0.38 mmol) and Et3N
(0.96 mmol) in THF (5 mL) at 0 °C under N2. After stirring at 0 °C
for 30 min, Et3N (0.58 mmol) was added and the solution was al-
lowed to warm to rt. Then, MeNH2 (40% aqueous solution,
5.75 mmol) was added and the resulting two-phase reaction mix-
ture was stirred vigorously for 16 h. The two layers were separated
and the aqueous layer was extracted with Et2O (3 Â 10 mL). The
combined organic extracts were washed with 5% NaHCO3(aq)
(20 mL) and water (20 mL), dried (Na2SO4) and evaporated under
reduced pressure to give the crude product.
4.8. (2S)-2-(4-Methoxyphenyl)-2-(1-pyrrolidinyl)ethanol (S)-23
Using general procedure B, TFA (3.5 mL, 45.0 mmol) and N-Boc-
protected amino alcohol (S)-21 (240 mg, 0.90 mmol) in CH2Cl2
(10 mL) followed by Na2CO3 (286 mg, 2.70 mmol), tetra-n-butyl-
ammonium iodide (165 mg, 0.45 mmol) and 1,4-dibromobutane
(0.11 mL, 0.90 mmol) in THF (10 mL) gave the crude product. Puri-
fication by flash column chromatography with 9:1 CH2Cl2–MeOH
as eluent gave amino alcohol (S)-23 (127 mg, 64%, >97:3 er by 1H
NMR spectroscopy in the presence of (S)-1-(9-anthryl)-2,2,2-tri-
4.5. N,N-Dimethyl-4-vinylaniline 20
At first, n-BuLi (6.2 mL of
a 1.45 M solution in hexanes,
8.95 mmol) was added dropwise to a stirred solution of methyltri-
phenylphosphonium bromide (3.20 g, 8.95 mmol) in THF (20 mL)
at rt under N2. After stirring for 15 min, a solution of 4-(dimethyl-

S. J. Oxenford et al. / Tetrahedron: Asymmetry 21 (2010) 1563–1568
1567
fluoroethanol) as a colourless oil, [
(CDCl3) 3390 (OH), 2954, 2841, 1650, 1514, 1249, 1180,
1024 cmÀ1
dH (400 MHz, CDCl3) 7.24 (d, J = 8.5 Hz, 2H, m-
C6H4OMe), 6.88 (d, J = 8.5 Hz, 2H, o-C6H4OMe), 3.88 (dd, J = 10.5,
6.0 Hz, 1H, CHAHBO), 3.80 (s, 3H, OMe), 3.78 (dd, J = 10.5, 6.0 Hz,
1H, CHAHBO), 3.49 (t, J = 6.0 Hz, 1H, CHN), 3.07 (br s, 1H, OH),
2.59–2.50 (m, 4H, CH2N), 1.78–1.71 (m, 4H, CH2); dC (100.6 MHz,
CDCl3) 159.1 (ipso-Ar), 130.5 (ipso-Ar), 129.7 (Ar), 113.7 (Ar), 69.0
(CHN), 64.1 (CH2O), 55.2 (OMe), 51.1 (CH2N), 23.0 (CH2); m/z (CI,
NH3) 222 [100%, (M+H)+], 190 (75) [Found: (M+H)+, 222.1495.
a
]
D = +54.8 (c 1.0, CHCl3); mmax
the crude product. Purification by Kugelrohr distillation gave dia-
mine rac-26 (48 mg, 50%, ꢀ50:50 er by 1H NMR spectroscopy in
the presence of (S)-1-(9-anthryl)-2,2,2-trifluoroethanol) as a col-
ourless oil, bp 220–230 °C/1 mmHg; mmax (CDCl3) 3324 (NH),
2962, 1614, 1522, 1442, 1349, 1161, 819 cmÀ1; dH (400 MHz,
CDCl3) 7.21 (d, J = 8.5 Hz, 2H, m-C6H4NMe2), 6.73 (d, J = 8.5 Hz,
2H, o-C6H4NMe2), 3.50 (dd, J = 10.5, 3.5 Hz, 1H, CHN), 2.94 (s, 6H,
NMe2), 2.87 (dd, J = 12.0, 10.5 Hz, 1H, CHAHB), 2.65–2.60 (m, 4H,
CH2N), 2.30 (s, 3H, NMe), 2.25 (dd, J = 12.0, 3.5 Hz, 1H, CHAHB),
1.81–1.73 (m, 4H, CH2); dC (100.6 MHz, CDCl3) 149.9 (ipso-Ar),
130.2 (ipso-Ar), 128.1 (Ar), 112.6 (Ar), 63.8 (CH2N), 63.5 (CHN),
54.2 (CH2N), 40.7 (NMe2), 34.5 (NMe), 23.5 (CH2); m/z (CI, NH3)
248 [46%, (M+H)+], 217 (100, MÀ30) [Found: (M+H)+, 248.2124.
C15H25N3 requires M+H, 248.2127].
;
C13H19NO2 requires M+H, 222.1494].
4.9. (2S)-2-[4-(Dimethylamino)phenyl]-2-(1-pyrrolidinyl)-
ethanol (S)-24
Using general procedure B, TFA (3.15 mL, 40.5 mmol) and N-
Boc-protected amino alcohol (S)-22 (228 mg, 0.81 mmol) in CH2Cl2
(10 mL) followed by Na2CO3 (256 mg, 2.41 mmol), tetra-n-butyl-
ammonium iodide (149 mg, 0.40 mmol) and 1,4-dibromobutane
(0.10 mL, 0.81 mmol) in THF (10 mL) gave the crude product. Puri-
fication by flash column chromatography with 10:1 CH2Cl2–MeOH
as eluent gave amino alcohol (S)-24 (103 mg, 54%, >97:3 er by 1H
NMR spectroscopy in the presence of (S)-1-(9-anthryl)-2,2,2-tri-
4.12. 2-(1-Hydroxyallyl)pyrrolidine-1-carboxylic acid tert-butyl
ester (1S,2S)-29 (anti-29) and (1R,2S)-12 (syn-12)
At first, s-BuLi (7.0 mL of a 1.1 M solution in cyclohexanes,
7.6 mmol, 1.3 equiv) was added dropwise to a stirred solution of
N-Boc pyrrolidine 27 (1.00 g, 5.84 mmol) and (+)-sparteine surro-
gate 28 (1.47 g, 7.6 mmol, 1.3 equiv) in Et2O (14 mL) at À78 °C un-
der Ar. The resulting pale yellow solution was stirred at À78 °C for
3 h. Then, a solution of acrolein (0.78 mL, 11.7 mmol) in Et2O
(2 mL) was added dropwise and the resulting solution was allowed
to warm to rt over 20 h. Saturated NH4Cl(aq) (20 mL) was added and
the layers were separated. The aqueous layer was extracted with
Et2O (3 Â 20 mL) and the combined organic layers were dried
(MgSO4) and evaporated under reduced pressure to give the crude
product, which contained a ꢀ50:50 mixture (by 1H NMR spectros-
copy) of pyrrolidines (1S,2S)-29 and (1R,2S)-12. Purification by
flash column chromatography on silica with CHCl3–EtOAc (6:1)
as eluent gave pyrrolidine (1S,2S)-29 (435 mg, 33%, 98:2 er by chi-
ral HPLC of the N-benzamide) as a pale yellow oil, RF (6:1 CHCl3–
fluoroethanol) as
a
yellow oil, RF (10:1 CH2Cl2–MeOH) 0.1;
max(CDCl3) 3382 (OH), 3052, 2963,
[
a]D = À127.4 (c 0.5, CHCl3);
m
2878, 1613, 1522, 1351, 1265, 1164, 1064, 820, 740 cmÀ1; dH
(400 MHz, CDCl3) 7.17 (d, J = 8.5 Hz, 2H, m-C6H4NMe2), 6.71 (d,
J = 8.5 Hz, 2H, o-C6H4NMe2), 3.87 (dd, J = 10.5, 6.5 Hz, 1H, CHAHBO),
3.74 (dd, J = 10.5, 6.0 Hz, 1H, CHAHBO), 3.46 (dd, J = 6.5, 6.0 Hz, 1H,
CHN), 2.95 (s, 6H, NMe2), 2.64 (br s, 1H, OH), 2.54–2.50 (m, 4H,
CH2N), 1.74–1.71 (m, 4H, CH2); dC (100.6 MHz, CDCl3) 150.1
(ipso-Ar), 129.5 (Ar), 125.8 (ipso-Ar), 112.2 (Ar), 68.4 (CHN), 63.9
(CH2O), 50.6 (CH2N), 40.5 (NMe), 23.0 (CH2); m/z (CI, NH3) 235
[69%, (M+H)+], 164 (100, MÀ70) [Found: (M+H)+, 235.1810.
C14H22N2O requires M+H, 235.1810].
EtOAc) 0.2; [
a]
D = À67.1 (c 1.0 in CHCl3) [lit.,32
[
a]D = À86.2 (c
0.905 in CHCl3)]; dH (400 MHz, CDCl3) 5.82 (ddd, J = 17.0, 10.5,
7.0 Hz, 1H, CH@CH2), 5.32 (dt, J = 17.0, 1.5 Hz, 1H, trans-
CH@CHAHB), 5.24 (br s, 1H, OH), 5.19 (br d, J = 10.5 Hz, 1H, cis-
CH@CHAHB), 3.96 (br s, 1H, CHO), 3.87–3.81 (br m, 1H, CHN),
3.51–3.43 (br m, 1H, CHAHBN), 3.36–3.30 (m, 1H, CHAHBN), 1.94–
1.72 (m, 4H), 1.48 (s, 9H, CMe3) and pyrrolidine (1R,2S)-12
(467 mg, 35%, 96:4 er) as a colourless oil, RF (6:1 CHCl3–EtOAc)
4.10. N-[-[(1R)-4-Methoxyphenyl)-2-(1-pyrrolidinyl)ethyl]-N-
methylamine (R)-25
Using general procedure C, MsCl (0.05 mL, 0.65 mmol), amino
alcohol (S)-23 (120 mg, 0.54 mmol, >97:3 er) and Et3N (0.19 mL,
1.36 mmol) in THF (5 mL) followed by Et3N (0.19 mL, 1.36 mmol)
and MeNH2 (0.60 mL of a 40% aqueous solution, 7.73 mmol) gave
the crude product. Purification by Kugelrohr distillation gave dia-
mine (R)-25 (74 mg, 58%, >97:3 er by 1H NMR spectroscopy in
the presence of (S)-1-(9-anthryl)-2,2,2-trifluoroethanol) as a col-
0.2; [a
]
D = À51.4 (c 1.0, CHCl3) [lit.,32
[
a]
D = À63.8 (c 0.853, CHCl3)];
dH (400 MHz, CDCl3) 5.80 (ddd, J = 17.0, 10.5, 6.5 Hz, 1H, CH@CH2),
5.31 (dt, J = 17.0, 1.5 Hz, 1H, trans-CH@CHAHB), 5.25 (br s, 1H, OH),
5.19 (dt, J = 10.5, 1.5 Hz, 1H, cis-CH@CHAHB), 4.16 (br s, 1H, CHO),
4.07 (br s, 1H, CHN), 3.48 (br s, 1H, CHAHBN), 3.21 (br s, 1H,
CHAHBN), 2.05 (br s, 1H), 1.85 (br s, 1H), 1.78–1.69 (m, 2H), 1.46
(s, 9H, CMe3). Spectroscopic data were identical with those re-
ported in the literature.32
ourless oil, bp 150–160 °C/0.3 mmHg; [
a
]
D = À73.2 (c 1.0 in CHCl3);
m
max (CDCl3)/ 3321 (NH), 2962, 1604, 1511, 1440, 1265, 1176, 1034,
738 cmÀ1
; dH (400 MHz, CDCl3) 7.27 (d, J = 8.5 Hz, 2H, m-
C6H4OMe), 6.88 (d, J = 8.5 Hz, 2H, o-C6H4OMe), 3.81 (s, 3H, OMe),
3.55 (dd, J = 10.5, 3.5 Hz, 1H, CHAr), 2.84 (dd, J = 12.0, 10.5 Hz,
1H, CHAHBN), 2.65–2.61 (m, 2H, CH2N), 2.50–2.45 (m, 2H, CH2N),
2.29 (s, 3H, NMe), 2.25 (dd, J = 12.0, 3.5 Hz, 1H, CHAHBN), 2.16 (br
s, 1H, NH), 1.83–1.73 (m, 4H, CH2); dC (100.6 MHz, CDCl3) 158.8
(ipso-Ar), 132.1 (ipso-Ar), 128.4 (Ar), 113.8 (Ar), 63.6 (CH2N), 63.4
(CHN), 55.2 (OMe), 54.2 (CH2N), 34.5 (NMe), 23.6 (CH2); m/z (CI,
NH3) 235 [100%, (M+H)+] [Found: (M+H)+, 235.1811. C14H22N2O re-
quires M+H, 235.1810].
The er of pyrrolidine (1S,2S)-29 was determined by chiral HPLC
of the N-benzamide: Chiralcel OD (95:5 hexane-iso-PrOH,
1.0 mL minÀ1) (1S,2S) 14.9 (major), (1R,2R) 19.1 min (minor).
The er of pyrrolidine (1R,2S)-12 was determined by chiral HPLC
of the N-benzamide: Chiralcel OD (95:5 hexane-iso-PrOH,
1.0 mL minÀ1) (1R,2S) 14.6 (major), (1S,2R) 27.5 min (minor).
4.13. 1-(1-Allylpyrrolidin-2-yl)prop-2-en-1-ol (1R,2S)-30 (anti-30)
4.11. N-[1-[4-(Dimethylamino)phenyl]-2-(1-pyrrolidinyl)ethyl]-
N-methylamine rac-26
At first, TFA (1.00 mL, 11.6 mmol) was added to a stirred solution
of pyrrolidine (1R,2S)-12 (263 mg, 1.16 mmol, 96:4 er) in CH2Cl2
(5 mL) at 0 °C under N2. The resulting pale yellow solution was al-
lowed to warm to rt then stirred for 20 h. 33% NH4OH(aq) (2 mL)
was added and the layers were separated. The aqueous layer was ex-
tracted with CH2Cl2 (3 Â 5 mL) and the combined organics were
dried (MgSO4) and evaporated under reduced pressure to give the
Using general procedure C, MsCl (0.04 mL, 0.46 mmol), amino
alcohol (S)-24 (90 mg, 0.38 mmol, >97:3 er) and Et3N (0.14 mL,
0.96 mmol) in THF (5 mL) followed by Et3N (0.08 mL, 0.58 mmol)
and MeNH2 (0.43 mL of a 40% aqueous solution, 5.75 mmol) gave

1568
S. J. Oxenford et al. / Tetrahedron: Asymmetry 21 (2010) 1563–1568
crudeaminoalcohol. Toastirredsuspensionofthecrudeaminoalco-
hol and K2CO3 (240 mg, 1.74 mmol) in MeOH (4 mL) at 0 °C under N2
was added allyl bromide (0.12 mL, 1.39 mmol). The resulting sus-
pension was allowed to warm to rt and stirred for 12 h. Water
(5 mL) and CH2Cl2 (5 mL) were added and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (3 Â 5 mL) and the
combined organic layers were dried (MgSO4) and evaporated under
reduced pressure to give the crude product. Immediate purification
by flash column chromatography on silica with CH2Cl2–MeOH
(95:5) then (9:1) as eluent gave pyrrolidine (1R,2S)-30 (113 mg,
References
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58%) as a yellow oil, RF (9:1 CH2Cl2–MeOH) 0.2; [
a
]D = À51.2 (c
0.75, CHCl3) [lit.,6 = À54.3 (c 1.0, CHCl3)]; dH (400 MHz, CDCl3) 5.90
(dddd, J = 17.5, 10.0, 7.5, 5.5 Hz, 1H, CH2-CH@CH2), 5.77 (ddd,
J = 17.0, 10.5, 5.0 Hz, 1H, CH-CH@CH2), 5.35 (dt, J = 17.0, 1.5 Hz, 1H,
trans-CH@CHAHB), 5.21 (dd, J = 17.5, 1.5 Hz, 1H, trans-CH@CHAHB),
5.16 (dt, J = 10.5, 1.5 Hz, cis-CH@CHAHB), 5.12 (d, J = 10.5 Hz, 1H,
cis-CH@CHAHB), 4.27–4.22 (m, 1H, CHO), 3.49 (dd, J = 13.5, 5.5 Hz,
1H, CHAHBCH@CH2), 3.33 (br s, 1H, OH), 3.17–3.13 (m, 1H, CHAHBN),
2.94 (dd, J = 13.5, 7.5 Hz, 1H, CHAHBCH@CH2), 2.58–2.53 (m, 1H),
2.31 (q, J = 9.0 Hz, 1H, CHAHBN), 1.84–1.78 (m, 1H), 1.74–1.60 (m,
3H). Spectroscopic data were consistent with those reported in the
literature.6
15. (a) de Sousa, S. E.; O’Brien, P. Tetrahedron Lett. 1997, 38, 4885; (b) de Sousa, S.
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4.14. 1-Allyl-2-vinylpiperidin-3-ol (2S,3R)-14 (anti-14)
At first, trifluoroacetic anhydride (0.11 mL, 0.81 mmol) was
added to a stirred solution of pyrrolidine (1R,2S)-30 (90 mg,
0.54 mmol) in THF (4 mL) at À78 °C under Ar. The resulting colour-
less solution was stirred at À78 °C for 1 h and then Et3N (0.23 mL,
1.62 mmol) was added. The resulting colourless solution was stirred
at À78 °C for 1 h and then heated at reflux for 48 h. The resulting
brown solution was cooled to 0 °C and 2.0 M NaOH(aq) (2 mL) was
added. The resulting brown mixture was warmed to rt and stirred
for 2 h. CH2Cl2 (5 mL) was added and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (3 Â 5 mL) and the
combined organic layers were dried (MgSO4) and evaporated under
reduced pressure to give the crude product. Purification by flash col-
umn chromatography on silica with CH2Cl2–MeOH–NH4OH
(95:4.5:0.5) as eluent gave piperidine (2S,3R)-14 (68 mg, 73%) as a
Trans.
1 1998, 2519.
23. (a) Saravanan, P.; Singh, V. K. Tetrahedron Lett. 1998, 39, 167; (b) Saravanan, P.;
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brown oil, RF (95:4.5:0.5 CH2Cl2–MeOH–NH4OH) 0.3; [a]D = +68.6
(c 1.5, CHCl3) [lit.,6 = +50.2 (c 1.03, CHCl3)]; dH (400 MHz, CDCl3)
(dddd, J = 17.0, 10.5, 8.0, 5.5 Hz, 1H, CH2-CH@CH2), 5.76 (ddd,
J = 17.0, 10.5, 8.5 Hz, 1H, CH-CH@CH2), 5.36 (d, J = 10.5 Hz, 1H, cis-
CH@CHAHB), 5.34 (d, J = 17.0 Hz, 1H, trans-CH@CHAHB), 5.14 (d,
J = 17.0 Hz, 1H, trans-CH@CHAHB), 5.13 (d, J = 10.5 Hz, 1H, cis-
CH@CHAHB), 3.39–3.33 (m, 2H, CHO and CHAHBCH@CH2), 2.87 (dt,
J = 11.5, 4.0 Hz, 1H, CHAHBN), 2.81 (dd, J = 14.0, 8.0 Hz, 1H,
CHAHBCH@C H2), 2.51 (t, J = 8.5 Hz, 1H, CHN), 2.23 (br s, 1H, OH),
2.06–2.00 (m, 2H), 1.72 (d quintet, J = 13.5, 4.0 Hz, 1H), 1.62–1.51
(m, 1H), 1.31 (dtd, J = 12.0, 10.0, 4.0 Hz, 1H). Spectroscopic data were
consistent with those reported in the literature.6
30. (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am. Chem. Soc.
2002, 124, 11870; (b) Dearden, M. J.; McGrath, M. J.; O’Brien, P. J. Org. Chem.
2004, 69, 5789; (c) Dixon, A. J.; McGrath, M. J.; O’Brien, P. Org. Synth. 2006, 83,
141; (d) O’Brien, P. Chem. Commun. 2008, 655.
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We thank the EPSRC, GlaxoSmithKline AstraZeneca and Merck
for funding.