Ring-closing iodoamination of homoallylic amines for the synthesis of polysubstituted pyrrolidines: Application to the asymmetric synthesis of (-)-codonopsinine

Article abstract of DOI:10.1016/j.tet.2012.03.045

Ring-closing iodoamination of (E)-configured, N-α-methyl-p- methoxybenzyl protected homoallylic amines upon treatment with I₂ and NaHCO₃ in MeCN occurs with concomitant loss of the N-α-methyl-p-methoxybenzyl group to give 3-iodopyrrolidines in >99:1 dr. This transformation was used as one of the key steps in the total asymmetric synthesis of (-)-codonopsinine, which was achieved in seven steps (from commercially available tert-butyl crotonate) in 5% overall yield and >99:1 dr.

Full text of DOI:10.1016/j.tet.2012.03.045

Tetrahedron 68 (2012) 4302e4319
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ring-closing iodoamination of homoallylic amines for the synthesis
of polysubstituted pyrrolidines: application to the asymmetric synthesis
of (ꢀ)-codonopsinine
*
Stephen G. Davies , James A. Lee, Paul M. Roberts, James E. Thomson, Callum J. West
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Ring-closing iodoamination of (E)-configured, N-
amines upon treatment with I2 and NaHCO3 in MeCN occurs with concomitant loss of the N-
methoxybenzyl group to give 3-iodopyrrolidines in >99:1 dr. This transformation was used as one of the
key steps in the total asymmetric synthesis of (ꢀ)-codonopsinine, which was achieved in seven steps
(from commercially available tert-butyl crotonate) in 5% overall yield and >99:1 dr.
Ó 2012 Elsevier Ltd. All rights reserved.
a
-methyl-p-methoxybenzyl protected homoallylic
-methyl-p-
Received 23 January 2012
Received in revised form 28 February 2012
Accepted 12 March 2012
a
Available online 17 March 2012
Keywords:
(ꢀ)-Codonopsinine
Lithium amide
Ring-closing iodoamination
Pyrrolidine
1. Introduction
conditions.1 Furthermore, transannular iodoamination of N-
a-
methyl-p-methoxybenzyl substituted 10 gave pyrrolizidine 11 [an
intermediate in our synthesis of (ꢀ)-7a-epi-hyacinthacine A1 13],
We have recently reported a ring-closing iodoamination
protocol (which proceeds with concomitant N-debenzylation)
as the key step in the total asymmetric syntheses of piperidine,1
pyrrolidine2 and pyrrolizidine3 scaffolds. For example, iodoa-
mination of 1 upon treatment with I2 occurs with in situ loss of
whereas reaction of the corresponding N-a-methylbenzyl
the N-a-methylbenzyl protecting group. The reaction pre-
sumably proceeds via reversible iodonium formation and dia-
stereospecific cyclisation to give quaternary ammonium ion 3
that undergoes preferential loss of the N-
which is then trapped by MeCN in a Ritter reaction to give ra-
cemic N- -methylbenzylacetamide (RS)-5 in 72% yield, in ad-
a-methylbenzyl cation,
a
dition to pyrrolidine 4, which was isolated in 63% yield and
>99:1 dr (Scheme 1).
During the course of these studies we observed that the nature
of the N-protecting groups had a dramatic effect on the reaction
outcome. For example, when N-
substituted amine 7 was treated with AgBF4 in MeCN, piperidine 8
was formed in far greater yield than when the corresponding N-
a-methyl-p-methoxybenzyl
a
-
methylbenzyl substituted amine 6 was reacted under identical
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G.
Davies).
Scheme 1. Reagents and conditions: (i) I2, NaHCO3, MeCN, rt, 20 h.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.045

S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4303
substituted analogue 9 under identical conditions gave only am-
monium 12, which could not be N-deprotected (Scheme 2).3
By analogy to our previous results, our strategy for the syn-
thesis of (ꢀ)-codonopsinine 14 involved treatment of a homo-
allylic amine 17 with I2 leading to reversible formation of
iodonium species 18, which may undergo diastereospecific
cyclisation to form ammonium ion 19, with the electron donating
p-methoxyphenyl group being expected to stabilise the transition
state during the ring-closing iodoamination step. Subsequent in
situ loss of one of the nitrogen protecting groups would then give
the corresponding 3-iodopyrrolidine 20. We therefore set out to
screen a range of substrates, incorporating p-methoxy groups on
the different aryl rings of the N-benzyl protecting groups (i.e., R1
and R2) so that the structural/electronic requirements of the
aforementioned N-debenzylation step could be probed further. It
was envisaged that the C(2)-p-methoxyphenyl group within 20
could then be exploited in the manipulation of the C(3)-iodide
functionality: neighbouring group participation of the C(2)-p-
methoxyphenyl group followed by regioselective ring-opening of
phenonium ion intermediate 21 was expected to install oxygen
functionality at C(3) with the correct configuration for
(ꢀ)-codonopsinine 14. It was envisaged that homoallylic amine
17 could be easily synthesised from tert-butyl crotonate 15 using
our asymmetric aminohydroxylation protocol,19,20 whereby con-
jugate addition of enantiopure lithium amides to 15, followed by
in situ oxidation of the intermediate lithium (Z)-b-amino enolate
with (ꢀ)-camphorsulfonyloxaziridine [(ꢀ)-CSO],21 gives anti-
a-
hydroxy-b-amino esters 16 with high diastereoselectivity. Sub-
sequent protection of the hydroxyl group within 16, reduction of
the tert-butyl ester moiety and Wittig olefination of the resultant
aldehyde should then give access to a range of homoallylic
amines 17 (Fig. 2). Part of this work has been communicated
previously.22
Scheme 2. Reagents and conditions: (i) AgBF4, MeCN, 80 ꢁC, 16 h; (ii) I2, NaHCO3,
CH2Cl2 (EtOH stabilised), rt, 12 h [PMP¼p-methoxyphenyl].
We envisaged that this ring-closing iodoamination strategy
would also be applicable to the synthesis of pyrrolidine alkaloids
and selected (ꢀ)-codonopsinine 14 (Fig. 1) as a target to probe
the scope of this methodology. (ꢀ)-Codonopsinine 14 was
isolated in 1969 from Codonopsis clematidea, a flowering plant
native to East Asia.4 Its structure was unambiguously assigned in
1986 by Kibayashi and co-workers via single crystal X-ray
diffraction analysis of an intermediate in their total synthesis of
(þ)-codonopsinine 14.5 Several syntheses of codonopsinine 14
have been reported. Most of these approaches are enantiospe-
cific, starting from either
L
-xylose,6e8
-tartaric acid,13
-ribose.16 In addition, one total racemic synthesis17 and one total
D
-alanine,9,10
L
-threonine,11
D
-tartaric acid,12
L
L
-pyroglutamic acid14,15 or
D
asymmetric synthesis18 of codonopsinine 14 are also known.
range of diverse synthetic strategies have been adopted
A
in these syntheses, including the diastereoselective addition
of Grignard reagents to cyclic nitrones, the decarboxylative
cyclisation of allylic carbamates, the Heck reaction of endocyclic
enecarbamates and intramolecular SN2-type displacement
reactions, amongst other approaches.
Fig. 2. Proposed synthetic strategy towards (ꢀ)-codonopsinine 14 [PMP¼p-
Fig. 1. The structure of (ꢀ)-codonopsinine 14.
methoxyphenyl].

4304
S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
2. Results and discussion
esters 28e30 upon treatment with LiAlH4 gave the corresponding
alcohols 31e33 in 65e87% yield (Scheme 3).
2.1. Development of a ring-closing iodoamination protocol
Oxidation of alcohols 31e33 under Swern conditions, followed
by Wittig olefination of the resultant aldehydes with the ylid
derived from 4-methoxybenzyl triphenylphosphonium chloride
produced w2:1 mixtures of diastereoisomeric olefins, with the
(E)-isomers 37e39 as the major products in each case. After puri-
fication of the crude reaction mixtures, 37, 39, 40 and 42 were all
isolated as single diastereoisomers (>99:1 dr) in reasonable yield,
although mixed fractions were also isolated, whilst 38 and 41
proved to be inseparable by chromatography and were therefore
isolated as a 66:34 mixture in 71% combined yield (Scheme 4). The
configurations within 37e42 were initially assigned from the
diagnostic values of the 1H NMR 3J olefinic coupling constants: for
the (E)-diastereoisomers 37e39, values of 15.8e16.1 Hz were
observed, whereas the (Z)-diastereoisomers 40e42 all displayed
3J olefinic coupling constants of 12.0 Hz. The relative configuration
within 42 was also unambiguously confirmed by single crystal
X-ray diffraction analysis;23 this analysis also allowed the
The conjugate addition of the lithium amides derived from 22,
23 and 24 to tert-butyl crotonate 15, followed by in situ oxidation of
the intermediate lithium (Z)-
b
-amino enolates with (ꢀ)-CSO,21
gave -hydroxy-b-amino esters 25, 26 and 27 in 58, 80 and 82%
a
isolated yield, respectively, as single diastereoisomers (>99:1 dr) in
each case (Scheme 3). The relative configurations within 25 and 27
were unambiguously established by single crystal X-ray diffraction
analyses,23 with the absolute (R,R,R)-configurations within 25 and
27 assigned relative to the known configurations of the (R)-a-
methylbenzyl fragments (Fig. 3); the configuration within 26 was
therefore confidently assigned by analogy. This stereochemical
outcome is entirely consistent with the well-established diaster-
eofacial selectivity observed upon tandem conjugate addition of
a secondary lithium amide derived from a-methylbenzylamine and
in situ enolate oxidation with (ꢀ)-CSO.19,20 Subsequent protection
of the C(2)-hydroxyl groups within b-amino esters 25e27 as the
corresponding O-benzyl ethers was achieved upon treatment with
NaH and BnBr, giving 28e30 in 59e78% yield, and reduction of
Scheme 3. Reagents and conditions: (i) BuLi, THF, ꢀ78 ꢁC, 2.5 h, then (ꢀ)-CSO, ꢀ78 ꢁ
C
Scheme 4. Reagents and conditions: (i) DMSO, (COCl)2, CH2Cl2, ꢀ78 ꢁC, 30 min, then
Et3N, ꢀ78 ꢁC to rt, 1 h; (ii) BuLi, [4-MeOC6H4CH2PPh3]þ [Cl]ꢀ, THF, ꢀ78 ꢁC, 30 min, then
rt, 12 h [a>99:1 dr; bcombined yield; PMP¼p-methoxyphenyl].
to rt, 12 h; (ii) NaH, THF, 0 ꢁC, 1 h, then BnBr, rt, 12 h; (iii) LiAlH4, THF, 0 ꢁC, 30 min, then
rt, 16 h [a>99:1 dr; PMP¼p-methoxyphenyl].
Fig. 3. X-ray crystal structures of 25 [left] and 27 [right] (selected H atoms are omitted for clarity).

S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4305
Scheme 6. Reagents and conditions: (i) NaHCO3, I2, MeCN, ꢀ20 ꢁC, 2 h, then rt, 20 h
[PMP¼p-methoxyphenyl].
ꢀ0.039(8) for the crystal structure of 45$HCl allowed the absolute
(R,R,R,R)-configuration within 45 to be confirmed unambiguously
(Fig. 5). Extensive optimisation studies of this ring-closing iodoa-
mination reaction were conducted, altering the reaction time and
temperature along with increasing the number of equivalents of I2
and NaHCO3, although this did not improve the yield of 45 obtained.
Fig. 4. X-ray crystal structure of 42 (selected H atoms are omitted for clarity).
(3S,4R,aR,Z)-absolute configuration within 42 to be unambiguously
assigned relative to the known configuration of the (R)-a-methyl-p-
methoxybenzyl fragment (Fig. 4).
Ring-closing iodoamination of 37e42 was attempted using our
previously developed conditions, viz treatment with I2 and NaHCO3
in either MeCN2 or CH2Cl2.3 A complex mixture of unidentifiable
products was formed in each case upon reaction of either (E)-37,
(Z)-40, the 66:34 mixture of (E)-38 and (Z)-41, or (Z)-42 according to
the procedure involving CH2Cl2. The analogous reactions
using MeCN as the solvent gave incomplete conversion to
a,b-
unsaturated aldehyde 43 and p-anisaldehyde 44 by analysis of the
1H NMR spectra of the crude reaction mixtures. Presumably, 43 and
44 are formed as a result of a single electron oxidation process fol-
lowed by fragmentation. Upon reaction of (E)-39 with I2 according
to the protocol using CH2Cl2 as the solvent a complex mixture of
unidentifiable products was again formed (Scheme 5). However,
upon treatment of (E)-39 (>99:1 dr) with I2 and NaHCO3 in MeCN
the ring-closing iodoamination reaction proceeded to give 3-
iodopyrrolidine 45 in 90% conversion and >99:1 dr. Purification of
the crude reaction mixture enabled isolation of 45 in 41% yield and
>99:1 dr (Scheme 6). Single crystal X-ray diffraction analysis of the
corresponding hydrochloride salt 45$HCl allowed the relative con-
figuration within 45 to be unambiguously assigned.23 The absolute
(R,R,R,R)-configuration within 45 was initially assigned relative to
the known configurations of the C(4)- and C(5)-stereocentres.
Furthermore, the determination of a Flack x parameter24,25 of
Fig. 5. X-ray crystal structure of 45$HCl (selected H atoms are omitted for clarity).
As hypothesised, the nature of the nitrogen protecting groups
was found to have a dramatic effect on the reactivity of the
homoallylic amine substrates 37e42, although the olefin geometry
was also found to be important: the N-
substrate (E)-39 successfully produced 3-iodopyrrolidine 45 in 90%
conversion, whereas the N- -methylbenzyl substrates 37, 38, 40
a-methyl-p-methoxybenzyl
a
and 41, and also (Z)-42 gave only returned starting material or
degradation products. In the former case, the formation of 45 as
a single diastereoisomer in the ring-closing iodoamination step
suggests that cyclisation occurs via the attack of an iodonium
species (which is presumably formed reversibly from 39), as cyc-
lisation via the corresponding carbonium ion at C(1) would be
expected to give rise to a mixture of diastereoisomeric pyrrolidines.
The diastereoselectivity of the ring-closing iodoamination step can
then be rationalised by considering the intermediate iodonium
species 46 and 49. Within transition state 50 for the cyclisation of
iodonium 49, both the C(3)-benzyloxy and C(4)-methyl groups
occupy pseudo-axial positions and experience unfavourable steric
interactions with the nitrogen protecting groups (i.e., R1 and R2, one
of which is a-branched). For cyclisation of iodonium 46, the C(3)-
benzyloxy and C(4)-methyl groups occupy pseudo-equatorial po-
sitions and do not suffer unfavourable steric interactions with the
nitrogen protecting groups in transition state 47. In fact, the
N-benzyl or N-a
-methyl-p-methoxybenzyl group at R2 within
transition state 47 can minimise 1,2-strain with the C(1)-p-
methoxyphenyl substituent by adopting a conformation with the
aryl group away from the site of reaction; this is not possible within
the disfavoured transition state 50 as, regardless of the conforma-
tion of the R2 group, unfavourable steric interactions will be en-
countered between R2 and either the C(1)-p-methoxyphenyl or
C(4)-methyl groups (Fig. 6). It is noteworthy that the corresponding
(Z)-configured substrate 42 did not undergo selective ring-closing
iodoamination, rather it gave returned starting material and pro-
duced degradation product 43. It is observed in the crystal structure
Scheme 5. Reagents and conditions: (i) NaHCO3, I2, CH2Cl2, rt, 12 h; (ii) NaHCO3, I2,
MeCN, ꢀ20 ꢁC, 2 h, then rt, 20 h [PMP¼p-methoxyphenyl].

4306
S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
Fig. 6. The origin of diastereoselectivity in the ring-closing iodoamination reaction [PMP¼p-methoxyphenyl].
of 42 that the C(20)eC(10)eC(1)eC(2) dihedral angle is 42.1ꢁ and
therefore the extent of conjugation between the p-methoxyphenyl
ring and the olefin will be significantly reduced compared to the
idealised coplanar structure. Two potential rationales for the dif-
fering reactivities of (E)-39 and (Z)-42 can therefore be proposed:
firstly, in (Z)-42, the alkene is less nucleophilic and so reacts with I2
at a slower rate, allowing degradation pathways to compete with
iodoamination. This is in contrast with (E)-39, where it is assumed
that the same dihedral angle is closer to 0ꢁ to maximise conjuga-
tion, thus making the double bond more electron-rich and nucle-
ophilic. Alternatively, adverse steric effects may dictate that
iodonium intermediates formed from (Z)-42 are unstable and so
decompose to give degradation product 43.
Scheme 7. Reagents and conditions: (i) AgOAc, AcOH, 30 ꢁC, 12 h [PMP¼p-
2.2. The asymmetric synthesis of (L)-codonopsinine
methoxyphenyl].
C(3)-acetoxy analogue [dH¼5.23 ppm for C(3)H within 54]. Un-
fortunately, 1H NMR NOE spectroscopic analyses of 55 and 56 were
not conclusive and therefore their relative configurations could not
be confidently assigned. The appearance of regioisomers 55 and 56
in the product distribution lends support to the original hypothesis
that a mechanism involving neighbouring group participation via
phenonium ion intermediate 53 was occurring, and giving rise to
retention of configuration upon attack of the acetate anion at C(3)
within 53. Interestingly, resubjection of 55 to the reaction condi-
tions for a further 12 h produced an 81:19 mixture of 55 and 56,
respectively, although 54 was not observed in this case.
With 54 in hand, deprotection towards (ꢀ)-codonopsinine 14
was commenced. The deprotection strategy involved removing the
N- and O-benzyl groups upon hydrogenolysis before trans-
esterification and N-methylation (under literature conditions)28 to
afford (ꢀ)-codonopsinine 14. Upon hydrogenolysis of 54, in the
presence of Pd/C under an atmosphere of H2, N-debenzylation was
found to occur readily to give 57, although O-debenzylation was not
observed (Scheme 8). As a result, 57 was resubjected to the reaction
conditions but this afforded a complex mixture. A range of condi-
tions were subsequently screened in an attempt to remove the
O-benzyl protecting group within 57, but without success.
As (ꢀ)-codonopsinine 14 possesses the same ‘all-trans’ config-
uration as 3-iodopyrrolidine 45, elaboration of 45 to enable the
total synthesis of (ꢀ)-codonopsinine 14 required substitution of the
iodide substituent at C(3) with retention of configuration. A double
inversion strategy [e.g., SN2 displacement with acetate, hydrolysis
of the resultant C(3)-acetoxy substituted pyrrolidine then Mitsu-
nobu reaction] was considered, but a strategy reliant on neigh-
bouring group participation by the C(2)-p-methoxyphenyl group
(i.e., a stereoselective SN1-type process) was envisaged to be more
efficient in installing the oxygen functionality at C(3) with the
correct configuration, with subsequent deprotection then pro-
viding access to (ꢀ)-codonopsinine 14. In order to promote an SN1-
type reaction, 45 was treated with AgOAc in AcOH. Under these
reaction conditions, a 63:30:7 mixture of 54 and two different
regioisomers, 55 and 56, was produced. Upon purification of this
mixture, the major product 54 was isolated in 34% yield as a single
diastereoisomer, and the regioisomeric pyrrolidines 55 and 56 were
also isolated in 15 and 6% yield, respectively, and >99:1 dr in each
case (Scheme 7). The relative configuration within 54 was de-
termined by 1H NMR NOE spectroscopic analysis. The atom con-
nectivity within the regioisomeric products 55 and 56 was
established by a combination of 1H NMR COSY, and 1H and 13C NMR
HSQC and HMBC analyses. Crucially, in both cases the peaks cor-
responding to the C(2)H protons were found at significantly higher
It was therefore decided that selection of an alternative O-pro-
tecting group at the start of the synthesis would be a suitable
solution to this O-debenzylation problem. Protection of the C(2)-
hydroxyl group within 27 as the O-MOM ether was anticipated to
chemical shifts
[
dH¼5.79 ppm for C(2)H within 55 and
dH¼5.68 ppm for C(2)H within 56] relative to the corresponding

S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4307
gave 3-iodopyrrolidine 61 as the major product. As 61 could not be
separated from an unidentified impurity, this mixture was immedi-
ately subjected to AgOAc in AcOH, giving 62 as a single di-
astereoisomer (>99:1 dr) in 37% isolated yield (from 59). The relative
configurations within both 61 and 62 were determined by 1H NMR
NOE spectroscopic analyses. Removalof the O-MOMprotecting group
from within 62 was achieved upon treatment with methanolic HCl to
give 63, which wasimmediately reacted with K2CO3 inMeOHtoeffect
transesterification to the corresponding diol 64. Unfortunately,
attempted elaboration of 64 directly to (ꢀ)-codonopsinine 14 via an
N-debenzylation/reductive methylation protocol was not successful,
and instead cleavage of the N(1)eC(2) bond within 64 was observed
instead to give ring-opened N,N-dimethylamine 65 as the major
product (Scheme 10).
It was envisaged that N-debenzylation of diacetoxy species 66
would have a greater chance of proceeding without ring-opening,
since N-debenzylation of bis-O-protected 54 had previously
occurred without reductive cleavage of the N(1)eC(2) bond. There-
fore, the C(4)-hydroxyl group within 63 was O-acetyl protected upon
treatment with Ac2O and pyridine to give 66 in 83% isolated yield and
>99:1 dr. Subsequent hydrogenolysis of 66 in the presence of
Pd(OH)2/C gave quantitative conversion to N-debenzylated pyrrol-
idine 67, which was isolated in 71% yield. Transesterification of 67
gave a small sample of diol 68, which was found to be difficult to
purify and isolate. Unfortunately, attempted N-methylation of 68
upontreatmentoftheproductmixturewithMeI, usingtheconditions
kindly supplied by Reissig and Chowdhury17 gave a complex mixture
from which (ꢀ)-codonopsinine 14 could not be isolated (Scheme 11).
Due to the problematic nature of the N-debenzylation step, it
was decided that changing the nature of the substrate from the
Scheme 8. Reagents and conditions: (i) Pd/C, MeOH, H2 (1 atm), rt, 24 h
[PMP¼p-methoxyphenyl].
be a suitable alternative to the O-benzyl group strategy used pre-
viously. Thus, O-MOM protection of 27 was achieved using MOMCl
and NaH in DMF giving 58 in 86% yield and >99:1 dr after chro-
matographic purification. It was then found that reduction of
b
-amino ester 58 to the corresponding aldehyde could be achieved
directly upon treatment with DIBAL-H at ꢀ78 ꢁC. Subsequent
Wittig olefination using the same conditions as for the analogous
O-benzyl substituted aldehydes 34e36 afforded a w2:1 mixture of
O-MOM protected olefins (E)-59 and (Z)-60, which were isolated in
39 and 16% yield over two steps, respectively, and in >99:1 dr in
each case; a 50:50 mixture of 59 and 60 was also isolated in 13%
combined yield after purification (Scheme 9). In each case, the
configurations of the newly formed double bonds within 59 and 60
were assigned by 1H NMR 3J coupling constant analyses, with
diagnostic olefinic coupling constants being observed [J1,2¼15.9 Hz
for (E)-59; J1,2¼11.9 Hz for (Z)-60].
With enantiopure homoallylic amine (E)-59 in hand, ring-closing
iodoamination of 59 upon treatment with NaHCO3 and I2 in MeCN
Scheme 9. Reagents and conditions: (i) MOMCl, NaH, DMF, 0 ꢁC, 30 min,þthen rt, 12 h;
(ii) DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 30 min; (iii) BuLi, [4-MeOC6H4CH2PPh3] [Cl]ꢀ, THF,
ꢀ78 ꢁC, 30 min, then rt, 12 h [PMP¼p-methoxyphenyl].
Scheme 11. Reagents and conditions: (i) Ac2O, pyridine, CH2Cl2, rt, 16 h; (ii) Pd(OH)2/C,
H2 (1 atm), MeOH, rt, 8 h; (iii) K2CO3, MeOH, rt, 6 h [PMP¼p-methoxyphenyl].
Scheme 10. Reagents and conditions: (i) NaHCO3, I2, MeCN, rt, 20 h; (ii) AgOAc, AcOH, 30 ꢁC, 24 h; (iii) HCl, MeOH, 50 ꢁC, 5 h; (iv) K2CO3, MeOH, rt, 6 h; (v) Pd(OH)2/C, (CH2O)n, H2
(1 atm), MeOH, rt, 48 h [PMP¼p-methoxyphenyl].

4308
S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
N-benzyl substituted compound to the corresponding N-methyl
substituted analogue (prior to ring-closing iodoamination) would
be advantageous as the N-methyl group would then be retained
throughout the entire synthesis. This approach would then negate
the requirement for an N-deprotection step and therefore improve
both the atom and step economy of the synthesis. Thus, the con-
jugate addition of enantiopure lithium amide (R)-69 to tert-butyl
steps) and >99:1 dr, after purification of the crude reaction mix-
ture, thus completing the total asymmetric synthesis of this pyr-
rolidine natural product (Scheme 14).
crotonate 15 gave
a-hydroxy-b-amino ester 70 as a single di-
astereoisomer (>99:1 dr), which was isolated in 71% yield after
chromatographic purification. Subsequent protection of the C(2)-
hydroxyl group within 70 as the corresponding O-MOM ether
gave 71 in 70% yield and >99:1 dr. Reduction of the ester func-
tionality within 71 with DIBAL-H, followed by Wittig olefination of
the resultant aldehyde 72 gave a mixture of homoallylic amines
(E)-73 and (Z)-74, which were isolated in 57 and 9% yield (over two
steps), respectively, and in >99:1 dr in each case (Scheme 12).26 The
configurations of the newly formed double bonds within (E)-73 and
(Z)-74 were assigned by 1H NMR 3J coupling constant analyses, with
diagnostic trans [J1,2¼16.0 Hz for (E)-73] and cis [J1,2¼12.0 Hz for
(Z)-74] olefinic coupling constants being observed.
Scheme 13. Reagents and conditions: (i) NaHCO3, I2, MeCN, rt, 20 h; (ii) HCl, MeOH, rt,
48 h [PMP¼p-methoxyphenyl].
Ring-closing iodoamination was then attempted on homoallylic
amine (E)-73: following our previously optimised procedure,2
treatment of 73 with I2 and NaHCO3 in MeCN gave
3-iodopyrrolidine 75 in 54% yield and >99:1 dr. The relative con-
figuration within 75 was unambiguously established by derivati-
sation to the corresponding alcohol 76 (which was achieved upon
treatment with HCl in MeOH), followed by single crystal X-ray
diffraction analysis of the corresponding hydrochloride salt 76$HCl
(Scheme 13).23 These crystallographic data allowed the relative
configuration within 76 to be unambiguously assigned, with the
absolute (R,R,R,R)-configuration within 76 being assigned relative
to the known configurations of the C(4) and C(5) stereocentres.
Furthermore, the determination of a Flack x parameter24,25 of
ꢀ0.03(3) for the crystal structure of 76$HCl allowed its absolute
configuration, and therefore also the absolute configurations
within 70e75, to be confirmed unambiguously (Fig. 7).
Fig. 7. X-ray crystal structure of 76$HCl (selected H atoms are omitted for clarity).
3-Iodopyrrolidine 75 was then treated with AgOAc in AcOH,
which gave a 75:25 mixture of 78 (>99:1 dr) and regioisomeric
product 79 (>99:1 dr), presumably via the intermediacy of phe-
nonium ion intermediate 77. Despite exhaustive efforts at purifi-
cation this mixture proved to be inseparable by flash column
chromatography, although there was sufficient resonance disper-
sion in the 1H NMR spectrum of this mixture (in CDCl3) to allow the
relative configurations within both 78 and 79 to be determined by
1H NMR NOE spectroscopic analysis. Subsequently, treating the
75:25 mixture of 78 and 79 with methanolic HCl at 50 ꢁC for 48 h
was found to give (ꢀ)-codonopsinine 14 in 30% yield (over two
Scheme 14. Reagents and conditions: (i) AgOAc, AcOH, 40 ꢁC, 24 h; (ii) HCl, MeOH,
50 ꢁC, 48 h [PMP¼p-methoxyphenyl].
Scheme 12. Reagents and conditions: (i) THF, ꢀ78 ꢁC, 2 h, then (ꢀ)-CSO, ꢀ78 ꢁC to rt, 12 h; (ii) MOMCl, NaH, DMF, 0 ꢁC, 30 min, then rt, 12 h; (iii) DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 30 min;
(iv) BuLi, [4-MeOC6H4CH2PPh3]þ [Cl]ꢀ, THF, ꢀ78 ꢁC, 30 min, then rt, 12 h [PMP¼p-methoxyphenyl].

S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4309
The spectroscopic data for our synthetic sample of (ꢀ)-codo-
nopsinine 14 were found to be in excellent agreement with
those corresponding to the sample isolated from the natural source
241 polarimeter with a water-jacketed 10 cm cell. Specific rota-
tions are reported in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/
100 mL. IR spectra were recorded on a Bruker Tensor 27 FT-IR
spectrometer as either a thin film on NaCl plates (film) or a KBr
disc (KBr), as stated. Selected characteristic peaks are reported in
cmꢀ1. NMR spectra were recorded on Bruker Avance spectrome-
ters in the deuterated solvent stated. Spectra were recorded at rt.
The field was locked by external referencing to the relevant
deuteron resonance. Low-resolution mass spectra were recorded
on either a VG MassLab 20e250 or a Micromass Platform 1
spectrometer. Accurate mass measurements were run on either
a Bruker MicroTOF internally calibrated with polyalanine, or
a Micromass GCT instrument fitted with a Scientific Glass In-
struments BPX5 column (15 mꢃ0.25 mm) using amyl acetate as
a lock mass.
{½a 2D0
ꢂ
ꢀ9.1 (c 0.1 in MeOH); lit.4b
½
a 2D0
ꢂ
ꢀ8.8 (c 0.1 in MeOH)} and
other samples obtained by total synthesis.27 Furthermore,
recrystallisation of (ꢀ)-codonopsinine 14 from pyridine produced
colourless plates, which were subjected to X-ray diffraction analy-
sis,23 unambiguously confirming the relative configuration within
codonopsinine 14 (Fig. 8).
4.2. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]butanoate 25
Fig. 8. X-ray crystal structure of (ꢀ)-codonopsinine 14 (selected H atoms are omitted
for clarity).
BuLi (2.4 M, 4.50 mL, 10.9 mmol) was added to a stirred solution
of 2229 (2.37 g, 11.3 mmol) in THF (30 mL) at ꢀ78 ꢁC. The resultant
solution was stirred at ꢀ78 ꢁC for 30 min before the addition of
a solution of 15 (1.00 g, 7.00 mmol) in THF (20 mL) at ꢀ78 ꢁC via
cannula. The reaction mixture was stirred for 2 h, (ꢀ)-CSO21 (2.74 g,
12.0 mmol) was added and the reaction mixture was allowed to
warm to rt over 12 h. The reaction mixture was then quenched with
satd aq NH4Cl (5 mL) and concentrated in vacuo. The residue was
partitioned between 10% aq citric acid (50 mL) and CH2Cl2 (50 mL)
and the aqueous layer was extracted with CH2Cl2 (2ꢃ50 mL). The
combined organic extracts were washed sequentially with satd aq
NaHCO3 (100 mL) and brine (100 mL), then dried and concentrated
in vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 9:1) gave 25 as a white crystalline solid
3. Conclusion
In summary, the ring-closing iodoamination of (E)-configured,
N-
treatment with I2 and NaHCO3 in MeCN occurs with concomitant
loss of the N- -methyl-p-methoxybenzyl group to give
a-methyl-p-methoxybenzyl protected homoallylic amines upon
a
3-iodopyrrolidines in >99:1 dr. This transformation was used as
one of the key steps in the total asymmetric synthesis of
(ꢀ)-codonopsinine, which was achieved in seven steps (from
commercially available tert-butyl crotonate) in 5% overall yield and
>99:1 dr.
(1.50 g, 58%, >99:1 dr);31 mp 85e88 ꢁC; ½a D20
ꢀ27.9 (c 1.0 in CHCl3);
ꢂ
4. Experimental
{lit.31
½
a 2D5
ꢂ
ꢀ34.4 (c 1.0 in CHCl3)}; dH (400 MHz, CDCl3) 1.08 (3H, d, J
7.0, C(4)H3),1.32 (3H, d, J 6.7, C(
s, OH), 3.24e3.27 (1H, m, C(3)H), 3.95 (1H, ABd, J 15.0, NCHA),
4.05e4.12 (3H, m, C( )H, C(2)H, NCHB), 7.21e7.36 (8H, m, Ph), 7.48
(2H, dd, J 7.6, 0.5, Ph).
a)Me),1.36 (9H, s, CMe3), 3.02 (1H, br
4.1. General experimental
a
Reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen before use. BuLi was
purchased from SigmaeAldrich (as a solution in hexanes) and
titrated against diphenylacetic acid before use. Solvents were
dried according to the procedure outlined by Grubbs and co-
workers.28 Water was purified by an ElixÒ UV-10 system. All other
reagents were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over MgSO4. Thin
layer chromatography was performed on aluminium plates coated
with 60 F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic acid.
Flash column chromatography was performed on Kieselgel 60
silica.
4.3. tert-Butyl (R,R,R)-2-hydroxy-3-[N-(40-methoxybenzyl)-N-
(a
-methylbenzyl)amino]butanoate 26
BuLi (2.5 M, 24.1 mL, 60.3 mmol) was added to a stirred solution
Elemental analyses were recorded by the microanalysis ser-
vice of the London Metropolitan University, U.K. Melting points
were recorded on a Gallenkamp Hot Stage apparatus and are
uncorrected. Optical rotations were recorded on a PerkineElmer
of 232b (15.0 g, 62.2 mmol) in THF (150 mL) at ꢀ78 ꢁC. The resultant
solution was stirred at ꢀ78 ꢁC for 30 min before the addition of
a solution of 15 (5.50 g, 38.9 mmol) in THF (100 mL) at ꢀ78 ꢁC. The

4310
S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
reaction mixture was stirred for 2 h, (ꢀ)-CSO21 (15.1 g, 66.1 mmol)
was added and the reaction mixture was allowed to warm to rt over
12 h. The reaction mixture was then quenched with satd aq NH4Cl
(25 mL) and concentrated in vacuo. The residue was partitioned
between 10% aq citric acid (150 mL) and CH2Cl2 (150 mL) and the
aqueous layer was extracted with CH2Cl2 (2ꢃ150 mL). The com-
bined organic extracts were washed sequentially with satd aq
NaHCO3 (300 mL) and brine (300 mL), then dried and concentrated
in vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 3:1) gave 26 as a colourless oil (12.4 g, 80%,
4.5. tert-Butyl (R,R,R)-2-benzyloxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]butanoate 28
>99:1 dr); ½a 2D0
ꢀ7.2 (c 1.0 in CHCl3); nmax (film) 2922 (CeH), 1718
ꢂ
(C]O); dH (400 MHz, CDCl3) 1.10 (3H, d, J 7.1, C(4)H3), 1.33 (3H, d, J
A solution of 25 (1.49 g, 4.03 mmol) in THF (30 mL) was added to
a stirred slurry of NaH (60% dispersion in mineral oil, 170 mg,
4.25 mmol) in THF (20 mL) at 0 ꢁC. The resultant mixture was
allowed to warm to rt and stirred for 1 h. BnBr (753 mg, 4.39 mmol)
was then added dropwise and the reaction mixture was stirred for
a further 12 h before satd aq NH4Cl (15 mL) was added. The organic
layer was washed with brine (50 mL) and the aqueous layer was
then extracted with Et2O (3ꢃ50 mL). The combined organic layers
were then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 9:1) gave
6.8, C(
a)Me), 1.38 (9H, s, CMe3), 3.22e3.26 (1H, m, C(3)H), 3.81 (1H,
ABd, J 14.4, NCHA), 3.82 (3H, s, OMe), 3.88 (1H, ABd, J 14.4, NCHB),
3.93 (1H, d, J 2.8, C(2)H), 4.02 (1H, q, J 6.8, C(a)H), 6.87e6.92 (2H, m,
C(30)H, C(50)H), 7.18e7.23 (1H, m, Ph), 7.28e7.34 (4H, m, Ph),
7.36e7.41 (2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) 12.6 (C(4)),
15.7 (C(
(C(
a)Me), 27.8 (CMe3), 50.0 (NCH2), 53.9 (C(3)), 55.3 (OMe), 57.2
a
)), 73.6 (C(2)), 81.9 (CMe3), 113.6 (C(30), C(50)), 126.7 (p-
Ph), 127.8, 128.1 (o,m-Ph), 129.5 (C(20), C(60)), 131.2, 134.0 (i-Ph,
C(10)), 158.3 (C(40)), 173.7 (C(1)); m/z (ESIþ) 400 ([MþH]þ, 100%);
þ
HRMS (ESIþ) C24H34NO4 ([MþH]þ) requires 400.2482; found
28 as a colourless oil (1.21 g, 65%, >99:1 dr); ½a D23
þ36.6 (c 1.0 in
ꢂ
400.2477.
CHCl3); vmax (film) 2917 (CeH), 1738 (C]O); dH (400 MHz, CDCl3)
1.17 (3H, d, J 6.9, C(4)H3), 1.32 (3H, d, J 6.9, C(
CMe3), 3.35 (1H, qd, J 6.9, 3.5, C(3)H), 3.81 (1H, ABd, J 14.7, NCHA),
3.83 (1H, d, J 3.5, C(2)H), 3.96 (1H, q, J 6.9, C( )H), 4.08 (1H, ABd, J
14.7, NCHB), 4.32 (1H, d, J 11.3, OCHA), 4.63 (1H, d, J 11.3, OCHB),
7.19e7.40 (15H, m, Ph); dC (100 MHz, CDCl3) 12.9 (C(4)), 17.8 (C(
Me), 28.0 (CMe3), 50.6 (NCH2), 54.5 (C(3)), 58.9 (C( )), 72.3 (OCH2),
a)Me), 1.42 (9H, s,
4.4. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a
-methyl-40-
methoxybenzyl)amino]butanoate 27
a
a
)
a
80.9 (CMe3), 82.0 (C(2)), 126.6 (p-Ph), 127.6, 128.0, 128.8 (o,m-Ph),
137.8, 142.5, 144.4 (i-Ph), 171.2 (C(1)); m/z (ESIþ) 482 ([MþNa]þ,
þ
100%), 460 ([MþH]þ, 94%); HRMS (ESIþ) C30H38NO3 ([MþH]þ)
requires 460.2846; found 460.2845.
4.6. tert-Butyl (R,R,R)-2-benzyloxy-3-[N-(40-methoxybenzyl)-
N-(a-methylbenzyl)amino]butanoate 29
BuLi (2.4 M, 7.60 mL, 18.5 mmol) was added to a stirred solution
of 2430 (4.61 g, 19.1 mmol) in THF (70 mL) at ꢀ78 ꢁC. The resultant
solution was stirred at ꢀ78 ꢁC for 30 min before the addition of
a solution of 15 (1.70 g, 11.9 mmol) in THF (30 mL) at ꢀ78 ꢁC. The
reaction mixture was stirred for 2 h, (ꢀ)-CSO21 (4.66 g, 20.3 mmol)
was added and the reaction mixture was allowed to warm to rt over
12 h. The reaction mixture was then quenched with satd aq NH4Cl
(15 mL) and concentrated in vacuo. The residue was partitioned
between 10% aq citric acid (50 mL) and CH2Cl2 (50 mL) and the
aqueous layer was extracted with CH2Cl2 (2ꢃ50 mL). The combined
organic extracts were washed sequentially with satd aq NaHCO3
(100 mL) and brine (100 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O, 2:1) gave 27 as a white crystalline solid (3.91 g, 82%,
>99:1 dr); C24H33NO4 requires C, 72.15; H, 8.3; N, 3.5%; found C,
A solution of 26 (11.6 g, 28.9 mmol) in THF (150 mL) was added
to a stirred slurry of NaH (60% dispersion in mineral oil, 1.22 g,
50.7 mmol) in THF (100 mL) at 0 ꢁC. The resultant mixture was
allowed to warm to rt and stirred for 1 h. BnBr (5.40 g, 31.6 mmol)
was then added dropwise and the reaction mixture was stirred for
a further 12 h before satd aq NH4Cl (50 mL) was added. The organic
layer was washed with brine (250 mL) and the aqueous layer was
then extracted with Et2O (3ꢃ250 mL). The combined organic layers
were then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 9:1) gave
29 as a colourless oil (11.1 g, 78%, >99:1 dr); C31H39NO4 requires C,
72.3; H, 8.2; N, 3.45%; mp 60e62 ꢁC; ½a D20
ꢀ8.4 (c 1.0 in CHCl3); nmax
ꢂ
(film) 2917 (CeH), 1721 (C]O); dH (400 MHz, CDCl3) 1.10 (3H, d, J
7.1, C(4)H3), 1.32 (3H, d, J 7.0, C(a)Me), 1.39 (9H, s, CMe3), 3.25e3.29
76.0; H, 8.0; N, 2.9%; found C, 75.9; H, 7.9; N, 2.7%; ½a D20
þ30.5 (c 1.0
ꢂ
(1H, m, C(3)H), 3.79 (3H, s, OMe), 3.87 (1H, ABd, J 14.7, NCHA), 3.96
(1H, ABd, J 14.7, NCHB), 3.97 (1H, d, J 2.8, C(2)H), 3.98 (1H, q, J 7.0,
in CHCl3); vmax (film) 2973 (CeH),1738 (C]O); dH (400 MHz, CDCl3)
a
)H), 6.82e6.86 (2H, m, C(30)H, C(50)H), 7.22e7.37 (5H, m, Ph),
1.13 (3H, d, J 7.1, C(4)H3),1.29 (3H, d, J 7.0, C(a)Me),1.39 (9H, s, CMe3),
3.33e3.35 (1H, m, C(3)H), 3.75 (1H, d, J 3.8, C(2)H), 3.76 (1H, ABd,
J 14.7, NCHA), 3.82 (3H, s, OMe), 3.94 (1H, ABd, J 14.7, NCHB), 3.95
C(
7.47e7.50 (2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) 12.6 (C(4)),
16.1 (C( )Me), 28.0 (CMe3), 50.7 (NCH2), 53.9 (C(3)), 55.2 (OMe),
57.0 (C(
)), 73.6 (C(2)), 82.0 (CMe3), 113.5 (C(30), C(50)), 126.6
a
a
(1H, q, J 7.0, C(
OCHB), 6.84e6.87 (2H, m, C(30)H, C(50)H), 7.27e7.35 (12H, m, Ph,
C(20)H, C(60)H); dC (100 MHz, CDCl3) 12.8 (C(4)), 17.4 (C(
)Me), 28.1
(CMe3), 49.9 (NCH2), 54.3 (C(3)), 55.2 (OMe), 58.5 (C( )), 72.3
(OCH2), 80.9 (C(2)), 82.4 (CMe3), 113.5 (C(30), C(50)), 126.6 (p-Ph),
a)H), 4.30 (1H, ABd, J 11.4, OCHA), 4.60 (1H, ABd, J 11.4,
(p-Ph), 127.8, 128.1, 129.5 (C(20), C(60), o,m-Ph), 136.3, 142.2 (i-Ph,
C(10)), 158.4 (C(40)), 173.8 (C(1)); m/z (ESIþ) 400 ([MþH]þ, 100%);
HRMS (ESIþ) C24H34NO4þ([MþH]þ) requires 400.2482; found
400.2482.
a
a

S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4311
127.6, 128.2, 129.3 (C(20), C(60), o,m-Ph), 134.3, 137.9, 144.4 (C(10), i-
Ph), 158.3 (C(40)), 171.2 (C(1)); m/z (ESIþ) 490 ([MþH]þ, 100%);
4.56 (1H, d, J 11.3, OCHB), 7.22e7.42 (15H, m, Ph); dC (100 MHz,
CDCl3) 14.0 (C( )Me), 14.4 (C(4)), 51.0 (NCH2), 54.1 (C(3)), 57.0
(C(
a
þ
HRMS (ESIþ) C31H40NO4 ([MþH]þ) requires 490.2952; found
a)), 63.1 (C(1)), 72.7 (OCH2), 81.1 (C(2)), 127.3, 127.8, 128.0, 128.7,
490.2948.
129.4 (o,m,p-Ph), 138.5, 140.0, 143.3 (i-Ph); m/z (ESIþ) 41þ2
([MþNa]þ, 76%), 390 ([MþH]þ, 74%); HRMS (ESIþ) C26H32NO2
([MþH]þ) requires 390.2428; found 390.2427.
4.7. tert-Butyl (R,R,R)-2-benzyloxy-3-[N-benzyl-N-(a-methyl-
40-methoxybenzyl)amino]butanoate 30
4.9. (R,R,R)-2-Benzyloxy-3-[N-(40-methoxybenzyl)-N-
(a
-methylbenzyl)amino]butan-1-ol 32
A solution of 27 (2.53 g, 6.34 mmol) in THF (50 mL) was added to
a stirred slurry of NaH (60% dispersion in mineral oil, 266 mg,
11.1 mmol) in THF (30 mL) at 0 ꢁC. The resultant mixture was
allowed to warm to rt and stirred for 1 h. BnBr (1.18 g, 6.91 mmol)
was then added dropwise and the reaction mixture was stirred for
a further 12 h before satd aq NH4Cl (20 mL) was added. The organic
layer was washed with brine (60 mL) and the aqueous layer was
then extracted with Et2O (3ꢃ50 mL). The combined organic layers
were then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 9:1) gave
LiAlH4 (945 mg, 24.9 mmol) was added portionwise to a stirred
solution of 29 (11.1 g, 22.6 mmol) in THF (250 mL) at 0 ꢁC and the
resultant mixture was allowed to warm to rt and stirred for 16 h.
The reaction mixture was then cooled to 0 ꢁC and ice/cold EtOAc
was added to excess. The reaction mixture was then stirred for 1 h
and filtered through CeliteÒ (eluent Et2O). The filtrate was then
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O doped with 1% Et3N,
1:1) gave 32 as a colourless oil (7.30 g, 77%, >99:1 dr); C27H33NO3
30 as a colourless oil (1.82 g, 59%, >99:1 dr); ½a D20
þ39.8 (c 1.0 in
ꢂ
requires C, 77.3; H, 7.9; N, 3.3%; found C, 77.3; H, 7.9; N, 3.2%; ½a D20
ꢂ
CHCl3); nmax (film) 2917 (CeH), 1737 (C]O); dH (400 MHz, CDCl3)
þ18.4 (c 1.0 in CHCl3); nmax (film) 2970 (CeH); dH (400 MHz, CDCl3)
1.15 (3H, d, J 7.1, C(4)H3), 1.29 (3H, d, J 6.8, C(
CMe3), 3.36e3.38 (1H, m, C(3)H), 3.80 (1H, d, J 1.1, C(2)H), 3.81 (1H,
ABd, J 14.9, NCHA), 3.82 (3H, s, OMe), 3.91 (1H, q, J 6.8, C( )H), 4.02
a)Me), 1.42 (9H, s,
1.29 (3H, d, J 7.1, C(4)H3),1.43 (3H, d, J 7.1, C(a)Me), 3.01e3.04 (1H, m,
C(1)HA), 3.07e3.10 (1H, m, C(3)H), 3.22e3.25 (1H, m, C(2)H),
3.48e3.51 (1H, m, C(1)HB), 3.69 (1H, ABd, J 13.1, NCHA), 3.84 (3H, s,
OMe), 3.77 (1H, ABd, J 13.1, NCHB), 3.97 (1H, q, J 7.1, C(a)H), 4.33 (1H,
a
(1H, ABd, J 14.9, NCHB), 4.32 (1H, ABd, J 11.1, OCHA), 4.62 (1H, ABd,
J 11.1, OCHB), 6.82e6.86 (2H, m, C(30)H, C(50)H), 7.21e7.34 (10H, m,
Ph), 7.39e7.42 (2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) 12.9
ABd, J 11.4, OCHA), 4.55 (1H, ABd, J 11.4, OCHB), 6.89e6.93 (2H, m,
C(30)H, C(50)H), 7.19e7.36 (12H, m, C(20)H, C(60)H, Ph); dC (100 MHz,
(C(4)), 17.8 (C(
(OMe), 58.2 (C(
a
a
)Me), 28.1 (CMe3), 50.6 (NCH2), 54.3 (C(3)), 55.2
)), 72.4 (C(2)), 80.9 (OCH2), 82.2 (CMe3),113.4 (C(30),
CDCl3) 13.4 (C(
(OMe), 56.5 (C(
a)Me), 14.4 (C(4)), 50.2 (NCH2), 54.2 (C(3)), 55.3
a
)), 63.1 (C(1)), 72.7 (OCH2), 80.7 (C(2)), 113.9 (C(30),
C(50)), 126.4 (p-Ph), 127.7, 128.2, 128.8 (C(20), C(60), o,m-Ph),þ136.4,
C(50)), 126.6 (p-Ph), 127.1, 128.0, 128.3 (C(20), C(60þ), o,m-Ph), 130.þ5,
137.8, 142.5 (C(10), i-Ph), 158.3 (C(40)), 171.2 (C(1)); m/z (ESI ) 490
138.2, 139.5 (C(10), i-Ph), 158.2 (C(40)); m/z (ESI ) 420 ([MþH] ,
þ
([MþH]þ, 100%); HRMS (ESIþ) C31H40NO4 ([MþH]þ) requires
þ
100%); HRMS (ESIþ) C27H34NO3 ([MþH]þ) requires 420.2533;
490.2952; found 490.2940.
found 420.2525.
4.8. (R,R,R)-2-Benzyloxy-3-[N-benzyl-N-(a-methylbenzyl)-
amino]butan-1-ol 31
4.10. (R,R,R)-2-Benzyloxy-3-[N-benzyl-N-(a
-methyl-40-
methoxybenzyl)amino]butan-1-ol 33
LiAlH4 (111 mg, 2.93 mmol) was added portionwise to a stirred
solution of 28 (1.22 g, 2.66 mmol) in THF (15 mL) at 0 ꢁC and the
resultant mixture was allowed to warm to rt and stirred for 16 h.
The reaction mixture was then cooled to 0 ꢁC and ice/cold EtOAc
was added to excess. The reaction mixture was then stirred for 1 h
and filtered through CeliteÒ (eluent Et2O). The filtrate was then
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O, 1:1) gave 31 as
LiAlH4 (156 mg, 4.09 mmol) was added portionwise to a stirred
solution of 30 (1.82 g, 3.72 mmol) in THF (25 mL) at 0 ꢁC and the
resultant mixture was allowed to warm to rt and stirred for 16 h.
The reaction mixture was then cooled to 0 ꢁC and ice/cold EtOAc
was added to excess. The reaction mixture was then stirred for 1 h
and filtered through CeliteÒ (eluent Et2O). The filtrate was then
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O doped with 1% Et3N,
1:1) gave 33 as a colourless oil (1.01 g, 65%, >99:1 dr); C27H33NO3
a colourless oil (895 mg, 87%, >99:1 dr); ½a D20
þ3.8 (c 1.0 in CHCl3);
ꢂ
vmax (film) 3440 (OeH), 2872 (CeH), 2972 (CeH); dH (400 MHz,
requires C, 77.3; H, 7.9; N, 3.3%; found C, 77.2; H, 8.0; N, 3.2%; ½a D20
ꢂ
CDCl3) 1.30 (3H, d, J 6.7, C(a)Me), 1.44 (3H, d, J 6.7, C(4)H3), 3.02 (1H,
br s, OH), 3.08e3.12 (2H, m, NCH2), 3.24 (1H, dt, J 6.7, 3.2, C(3)H),
3.50 (1H, app s, C(2)H), 3.77 (1H, app d, J 13.3, C(1)HA), 3.84 (1H, app
þ16.1 (c 1.0 in CHCl3); nmax (film) 2970 (CeH); dH (400 MHz, CDCl3)
1.30 (3H, d, J 6.6, C(4)H3), 1.41 (3H, d, J 7.1, C(
a)Me), 3.08e3.10 (1H,
d, J 13.3, C(1)HB), 3.97 (1H, d, J 6.7, C(a)H), 4.44 (1H, d, J 11.3, OCHA),
m, C(1)HA), 3.10e3.12 (1H, m, C(3)H), 3.25e3.29 (1H, m, C(2)H),

4312
S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
3.53e3.55 (1H, m, C(1)HB), 3.75 (1H, ABd, J 13.3, NCHA), 3.79 (3H, s,
OMe), 3.83 (1H, ABd, J 13.3, NCHB), 3.93 (1H, q, J 7.1, C( )H), 4.45 (1H,
6.87e6.90 (2H, m, C(20)H, C(60)H), 7.20e7.37 (15H, m, Ph); dC
(100 MHz, CDCl3) 12.8 (C(5)),14.4 (C( )Me), 51.3 (NCH2), 54.9 (C(4)),
55.2 (OMe), 56.7 (C(
)), 69.7 (OCH2), 78.8 (C(3)), 113.7 (C(30), C(50)),
a
a
ABd, J 11.4, OCHA), 4.57 (1H, ABd, J 11.4, OCHB), 6.83e6.86 (2H, m,
a
C(30)H, C(50)H), 7.13e7.16 (2H, m, C(20)H, C(60)H), 7.27e7.42 (10H, m,
126.4 (p-Ph), 127.8, 128.8, 130.0 (o,m-Ph), 130.2 (C(2)), 130.7 (C(20),
C(60)), 131.6 (C(þ1)), 132.2, 138þ.8, 142.0, 145.0 (i-Pþh, C(10)), 158.þ4
(C(40)); m/z (ESI ) 492 ([MþH] , 100%); HRMS (ESI ) C34H38NO3
([MþH]þ) requires 492.2897; found 492.2890. Further elution gave
Ph); dC (100 MHz, CDCl3) 13.7 (C(
a)Me), 14.4 (C(4)), 50.9 (NCH2),
54.1 (C(3)), 55.2 (OMe), 56.1 (C(
a
)), 63.2 (C(1)), 72.7 (OCH2), 80.8
(C(2)), 113.5 (C(30), C(50)), 126.6 (p-Ph), 127.1, 128.0, 128.3 (C(20),
C(60), o,m-Ph), 135.1, 138.3, 139.7 (C(10), i-Ph), 158.6 (C(40)); m/z
37 as a colourless oil (701 mg, 25%, >99:1 dr); ½a D20
þ129 (c 1.0 in
ꢂ
þ
(ESIþ) 420 ([MþH]þ, 100%); HRMS (ESIþ) C27H34NO3 ([MþH]þ)
CHCl3); nmax (film) 2977 (CeH), 1607 (C]C); dH (400 MHz, CDCl3)
requires 420.2533; found 420.2532.
1.34 (3H, d, J 6.6, C(5)H3), 1.40 (3H, d, J 7.0, C(
m, C(4)H), 3.75e3.78 (1H, m, C(3)H), 3.87e3.90 (2H, m, NCH2), 3.90
(3H, s, OMe), 3.95 (1H, q, J 7.0, C( )H), 4.31 (1H, d, J 11.8, OCHA), 4.56
a)Me), 3.02e3.06 (1H,
a
4.11. (3S,4R,
benzyloxy-4-[N-benzyl-N-(
a
R,E)- and (3S,4R,
a
R,Z)-1-(40-Methoxyphenyl)-3-
a-methylbenzyl)amino]pent-1-ene
(1H, d, J 11.8, OCHB), 5.56 (1H, dd, J 15.9, 8.3, C(2)H), 6.31 (1H, d,
J 15.9, C(1)H), 6.94e6.97 (2H, m, C(30)H, C(50)H), 7.22e7.36 (15H, m,
Ph), 7.44e7.46 (2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) 14.8
37 and 40
(C(5)), 15.0 (C(
a
)Me), 51.3 (NCH2), 55.4 (C(4)), 55.8 (OMe), 57.0
(C(
a
)), 70.7 (OCH2), 84.3 (C(3)), 114.3 (C(30), C(50)), 126.4 (p-Ph),
127.8, 128.3, 130.1 (C(2), C(20), C(60), o,m-Ph), 132.5 (C(1)), 139.2,
142.0, 144.7 (C(10), i-Ph), 159.6 (C(40)þ); m/z (ESIþ) 492
([MþH]þ, 100%); HRMS (ESIþ) C34H38NO2 ([MþH]þ) requires
492.2897; found 492.2888.
4.12. (3S,4R,aR,E)- and (3S,4R,a
R,Z)-1-(40-Methoxyphenyl)-3-
benzyloxy-4-[N-(400-methoxybenzyl)-N-(
a-methylbenzyl)-
amino]pent-1-ene 38 and 41
Step 1: DMSO (1.75 mL, 24.7 mmol) was added dropwise to
a stirred solution of (COCl)2 (0.85 mL, 10.1 mmol) in CH2Cl2
(100 mL) at ꢀ78 ꢁC. After 20 min,
a solution of 31 (2.18 g,
5.62 mmol) in CH2Cl2 (50 mL) at ꢀ78 ꢁC was added dropwise.
After a further 20 min, Et3N (4.65 mL, 33.7 mmol) was added and
the resultant mixture was stirred for 30 min before being allowed
to warm to rt over a period of 30 min. The reaction mixture was
then concentrated in vacuo and the residue was partitioned be-
tween H2O (100 mL) and Et2O (100 mL). The aqueous layer was
then extracted with Et2O (2ꢃ100 mL) and the combined organic
extracts were dried and concentrated in vacuo to give 34 as
a colourless oil (2.03 g); nmax (film) 2973 (CeH), 1728 (C]O);
dH (400 MHz, CDCl3) 1.25 (3H, d, J 3.3, C(4)H3), 1.38 (3H, d,
Step 1: DMSO (5.45 mL, 76.8 mmol) was added dropwise to
a stirred solution of (COCl)2 (2.66 mL, 31.4 mmol) in CH2Cl2
J 7.1, C(
H), 3.78 (2H, d, J 11.4, NCH2), 3.86 (1H, q, J 7.1, C(
J 11.4, OCHA), 4.48 (1H, d, J 11.4, OCHB), 7.20e7.36 (15H, m, Ph),
8.57 (1H, d, J 4.8, C(1)H); dC (100 MHz, CDCl3) 13.3 (C( )Me), 14.3
(C(4)), 50.8 (NCH2), 50.9 (C(3)), 56.2 (C( )), 72.5 (OCH2), 85.5
a
)Me), 3.28e3.33 (1H, m, C(3)H), 3.40e3.42 (1H, m, C(2)
(200 mL) at ꢀ78 ꢁC. After 20 min,
a solution of 32 (7.30 g,
a
)H), 4.31 (1H, d,
17.5 mmol) in CH2Cl2 (100 mL) at ꢀ78 ꢁC was added dropwise. After
a further 20 min, Et3N (14.5 mL, 105 mmol) was added and the
resultant mixture was stirred for 30 min before being allowed to
warm to rt over a period of 30 min. The reaction mixture was then
concentrated in vacuo and the residue was partitioned between
H2O (200 mL) and Et2O (200 mL). The aqueous layer was then
extracted with Et2O (2ꢃ200 mL) and the combined organic extracts
were dried and concentrated in vacuo to give 35 as a colourless oil
(6.84 g); dH (400 MHz, CDCl3) 1.30 (3H, d, J 6.6, C(4)H3), 1.41 (3H, d,
a
a
(C(2)), 127.3 (p-Ph), 128.0, 128.7, 129.4 (o,m-Ph), 138.5, 140.0,
143.3 (i-Ph), 201.2 (C(1)); m/z (ESIþ) 420 ([MþMeOHþH]þ, 100%);
þ
HRMS (ESIþ) C27H34NO3 ([MþMeOHþH]þ) requires 420.2533;
found 420.2525.
Step 2: BuLi (2.5 M, 9.48 mL, 23.7 mmol) was added dropwise to
a
stirred solution of 4-methoxybenzyl triphenylphosphonium
J 6.9, C(
a
)Me), 3.30e3.32 (1H, m, C(3)H), 3.42e3.44 (1H, m, C(2)H),
)H), 4.34
chloride31 (11.5 g, 27.3 mmol) in THF (100 mL) at ꢀ78 ꢁC. After
30 min, a solution of 34 (2.03 g) in THF (50 mL) at ꢀ78 ꢁC was
added. The reaction mixture was then allowed to warm to rt and
stirred for 12 h. Satd aq NH4Cl (30 mL) was then added and the
resultant mixture was partitioned between brine (150 mL) and
Et2O (150 mL). The aqueous layer was then extracted with Et2O
(2ꢃ150 mL) and the combined organic extracts were dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30e40 ꢁC petrol/Et2O, 40:1) gave 40 as a colourless oil
(401 mg, 15%, >99:1 dr); C34H37NO3 requires C, 83.1; H, 7.6; N,
3.73 (2H, s, NCH2), 3.87 (3H, s, OMe), 3.89 (1H, q, J 6.9, C(
a
(1H, ABd, J 11.5, OCHA), 4.51 (1H, ABd, J 11.5, OCHB), 6.93e6.95 (2H,
m, C(30)H, C(50)H), 7.21e7.38 (12H, m, C(20)H, C(60)H, Ph), 8.53 (1H,
d, J 5.1, C(1)H); m/z (ESIþ) 450 ([MþMeOHþH]þ, 100%); HRMS
þ
(ESIþ) C28H36NO4 ([MþMeOHþH]þ) requires 450.2639; found
450.2633.
Step 2: BuLi (2.5 M, 18.0 mL, 45.0 mmol) was added dropwise to
a stirred solution of 4-methoxybenzyl triphenylphosphonium
chloride31 (33.8 g, 52.0 mmol) in THF (200 mL) at ꢀ78 ꢁC. After
30 min, a solution of 35 (6.84 g) in THF (100 mL) at ꢀ78 ꢁC was
added. The reaction mixture was then allowed to warm to rt and
stirred for 12 h. Satd aq NH4Cl (50 mL) was then added and the
resultant mixture was partitioned between brine (200 mL) and
Et2O (200 mL). The aqueous layer was then extracted with Et2O
(2ꢃ200 mL) and the combined organic extracts were dried and
concentrated in vacuo. Purification via flash column chromatog-
raphy (eluent 30e40 ꢁC petrol/Et2O, 10:1) gave a 66:34 mixture of
2.85%; found C, 83.2; H, 7.5; N, 2.8%; ½a D20
þ88.6 (c 1.0 in CHCl3);
ꢂ
nmax (film) 2970 (CeH), 1608 (C]C); dH (400 MHz, CDCl3) 1.34 (3H,
d, J 6.6, C(5)H3), 1.38 (3H, d, J 6.9, C(
3.80 (1H, d, J 14.4, NCHA), 3.84 (3H, s, OMe), 4.04 (1H, q, J 6.9, C(
4.06 (1H, d, J 14.4, NCHB), 4.14 (1H, d, J 11.6, OCHA), 4.38 (1H, d, J 11.6,
OCHB), 4.46 (1H, dd, J 9.8, 4.7, C(3)H), 5.31 (1H, dd, J 12.0, 9.8, C(2)H),
6.53 (1H, d, J 12.0, C(1)H), 6.75e6.79 (2H, m, C(30)H, C(50)H),
a)Me), 3.01e3.04 (1H, m, C(4)H),
a
)H),

S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4313
38 and 41 as a colourless oil (6.64 g, 71%). Data for 38: dH
(400 MHz, CDCl3) [selected peaks] 1.30 (3H, d, J 6.6, C( )Me), 1.36
chromatography (eluent 30e40 ꢁC petrol/Et2O, 3:1) gave 42 as
a white crystalline solid (190 mg, 15%, >99:1 dr); mp 77e80 ꢁC;
a
(3H, d, J 6.9, C(5)H3), 2.98 (1H, app q, J 6.9, C(4)H), 3.70 (1H, app t,
J 7.9, C(3)H), 4.27 (1H, ABd, J 11.7, OCHA), 5.51 (1H, ABd, J 11.7,
OCHB), 5.50 (1H, dd, J 15.8, 8.2, C(2)H), 6.26 (1H, d, J 15.8, C(1)H);
dC (100 MHz, CDCl3) [selected peaks] 54.8 (C(4)), 84.0 (C(3)), 128.3
(C(2)), 132.0 (C(1)). Data for 41: dH (400 MHz, CDCl3) [selected
½
a 2D0
ꢂ
þ123 (c 1.0 in CHCl3); nmax (film) 2966 (CeH), 1607 (C]C); dH
(400 MHz, CDCl3) 1.36 (3H, d, J 6.8, C(5)H3), 1.37 (3H, d, J 6.8, C(
Me), 3.02e3.04 (1H, m, C(4)H), 3.78 (1H, ABd, J 14.2, NCHA), 3.83
(3H, s, OMe), 3.86 (3H, s, OMe), 3.98 (1H, q, J 6.8, C( )H), 4.13 (1H,
a
)
a
ABd, J 14.2, NCHB), 4.17 (1H, d, J 11.6, OCHA), 4.39 (1H, d, J 11.6,
OCHB), 4.44 (1H, dd, J 10.0, 5.8, C(3)H), 5.33 (1H, dd, J 12.0, 10.0,
C(2)H), 6.55 (1H, d, J 12.0, C(1)H), 6.76e6.81 (2H, m, Ar), 6.84e6.88
(4H, m, Ar), 7.11e7.15 (2H, m, Ph), 7.20e7.24 (4H, m, Ph), 7.26e7.32
peaks] 1.32 (3H, d, J 6.9, C(5)H3), 1.34 (3H, d, J 6.6, C(a)Me), 2.98
(1H, dd, J 6.9, 6.0, C(4)H), 4.14 (1H, ABd, J 11.7, OCHA), 4.37 (1H,
ABd, J 11.7, OCHB), 4.41e4.44 (1H, m, C(3)H), 5.28 (1H, dd, J 12.0,
9.8, C(2)H), 6.52 (1H, d, J 12.0, C(1)H); dC (100 MHz, CDCl3) [se-
lected peaks] 54.7 (C(4)), 78.9 (C(3)), 130.7 (C(2)), 131.5 (C(1)). Data
for mixture: nmax (film) 2967 (CeH), 1607 (C]C); m/z (ESIþ) 522
(4H, m, Ph), 7.38e7.44 (2H, m, Ar); dC (100 MHz, CDCl3) 13.3 (C(
a)
Me), 14.3 (C(5)), 51.8 (NCH2), 54.8 (C(4)), 55.6 (C(40)OMe, C(400)
OMe), 56.3 (C(a
)), 70.2 (OCH2), 79.6 (C(3)), 113.6, 114.1 (C(30), C(50),
þ
([MþH]þ, 100%); HRMS (ESIþ) C35H40NO3 ([MþH]þ) requires
C(300), C(500)), 126.9 (p-Ph), 127.8, 128.8, 130.0 (C(20), C(60), C(200),
C(600), o,m-Ph), 131.1 (C(2)), 132.0 (C(1)), 137.5, 139.2, 142.5 (C(10þ),
C(100), i-Ph), 158.5, 158.9 (C(40), C(400)); m/z (ESIþ) 522 ([MþH] ,
522.3003; found 522.2986.
þ
100%); HRMS (ESIþ) C35H40NO3 ([MþH]þ) requires 522.3003;
4.13. (3S,4R,
benzyloxy-4-[N-benzyl-N-(
amino]pent-1-ene 39 and 42
a
R,E)- and (3S,4R,
a
R,Z)-1-(40-Methoxyphenyl)-3-
found 522.2997. Further elution gave a 62:38 mixture of 39 and 42
(63 mg, 5%). Further elution gave 39 as a colourless oil (355 mg,
a
-methyl-400-methoxybenzyl)-
28%, >99:1 dr); ½a D20
ꢂ
þ153 (c 1.0 in CHCl3); nmax (film) 2960 (CeH),
1608 (C]C); dH (400 MHz, CDCl3) 1.36 (3H, d, J 6.8, C(5)H3), 1.37
(3H, d, J 6.8, C(
8.3, C(3)H), 3.81 (3H, s, OMe), 3.85 (2H, s, NCH2), 3.86e3.90 (1H, m,
C( )H), 3.89 (3H, s, OMe), 4.30 (1H, d, J 11.9, OCHA), 4.54 (1H, d, J
a)Me), 3.02e3.04 (1H, m, C(4)H), 3.78 (1H, app t, J
a
11.9, OCHB), 5.54 (1H, dd, J 16.1, 8.3, C(2)H), 6.31 (1H, d, J 16.1, C(1)
H), 6.77e6.96 (4H, m, C(30)H, C(300)H, C(50)H, C(500)H), 7.16e7.45
(14H, m, C(20)H, C(200)H, C(60)H, C(600)H, Ph); dC (100 MHz, CDCl3)
14.8, 14.9 (C(5), C(
a
)Me), 51.2 (NCH2), 55.0 (C(4)), 55.6, 55.8 (C(40)
OMe, C(400)OMe), 56.3 (C(
a
)), 70.7 (OCH2), 84.4 (C(3)), 113.5, 114.3
(C(30), C(50), C(300), C(500)), 127.0 (p-Ph), 127.8, 128.7, 130.5 (C(20),
C(60), C(200), C(600), o,m-Ph), 128.5 (C(2)), 132.5 (C(1)), 136.8,þ139.2,
142.0 (C(10), C(100), i-Ph), 158.5, 159.6 (C(40), C(400)); m/z (ESI ) 522
þ
Step 1: DMSO (0.75 mL, 10.6 mmol) was added dropwise to
a stirred solution of (COCl)2 (0.37 mL, 4.35 mmol) in CH2Cl2
([MþH]þ, 100%); HRMS (ESIþ) C35H40NO3 ([MþH]þ) requires
522.3003; found 522.2995.
(50 mL) at ꢀ78 ꢁC. After 20 min,
a solution of 33 (1.01 g,
2.42 mmol) in CH2Cl2 (30 mL) at ꢀ78 ꢁC was added dropwise.
After a further 20 min, Et3N (2.01 mL, 14.5 mmol) was added and
the resultant mixture was stirred for 30 min before being allowed
to warm to rt over a period of 30 min. The reaction mixture was
then concentrated in vacuo and the residue was partitioned be-
tween H2O (40 mL) and Et2O (40 mL). The aqueous layer was then
extracted with Et2O (2ꢃ50 mL) and the combined organic extracts
were dried and concentrated in vacuo to give 36 as a colourless oil
(700 mg); nmax (film) 2971 (CeH), 1728 (C]O); dH (400 MHz,
4.14. (R,R,R,R)-N(1)-Benzyl-2-(40-methoxyphenyl)-3-iodo-4-
benzyloxy-5-methylpyrrolidine 45
CDCl3) 1.26 (3H, d, J 6.6, C(4)H3), 1.35 (3H, d, J 7.0, C(
3.29e3.31 (1H, m, C(3)H), 3.38e3.42 (1H, m, C(2)H), 3.75 (2H, app
s, NCH2), 3.80 (3H, s, OMe), 3.82 (1H, q, J 7.0, C( )H), 4.32 (1H, ABd,
a)Me),
a
NaHCO3 (48 mg, 0.57 mmol) and I2 (146 mg, 0.57 mmol) were
added to a stirred solution of 39 (100 mg, 0.19 mmol) in MeCN
(10 mL) at ꢀ20 ꢁC. After stirring for 2 h at ꢀ20 ꢁC, the reaction
mixture was allowed to warm to rt over 20 h then diluted with Et2O
(20 mL). The resultant mixture was washed with satd aq Na2S2O3
(15 mL) then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 3:1) gave
J 11.4, OCHA), 4.49 (1H, ABd, J 11.4, OCHB), 6.82e6.85 (2H, m,
C(30)H, C(50)H), 7.10e7.14 (2H, m, C(20)H, C(60)H), 7.25e7.38 (10H,
m, Ph), 8.58 (1H, d, J 5.1, C(1)H); dC (100 MHz, CDCl3) 13.3 (C(
a)Me),
14.4 (C(4)), 50.5 (NCH2), 50.8 (C(3)), 55.2 (OMe), 55.5 (C(
a)), 72.5
(OCH2), 85.6 (C(2)), 113.3 (C(30), C(50)), 127.1 (p-Ph), 128.2, 128.4,
129.2 (C(20), C(60), o,m-Ph), þ135.2, 137.2, 140.1 (C(10), i-Ph), 158.5
(C(40)), 201.2 (C(1)); m/z (ESI ) 450 ([MþMeOHþH]þ, 100%); HRMS
45 as a colourless oil (40 mg, 41%, >99:1 dr); ½a D20
þ0.7 (c 1.0 in
ꢂ
þ
(ESIþ) C28H36NO4 ([MþMeOHþH]þ) requires 450.2639; found
CHCl3); nmax (film) 2962 (CeH); dH (400 MHz, CDCl3) 1.11 (3H, d, J
6.8, C(5)Me), 3.38 (1H, ABd, J 14.2, NCHA), 3.48e3.50 (1H, m, C(5)H),
3.65 (1H, ABd, J 14.2, NCHB), 3.83 (3H, s, OMe), 4.05 (1H, dd, J 8.3, 4.1,
C(3)H), 4.14 (1H, dd, J 4.1, 2.5, C(4)H), 4.17 (1H, d, J 8.3, C(2)H), 4.63
(1H, ABd, J 12.0, OCHA), 4.70 (1H, ABd, J 12.0, OCHB), 6.90e6.94 (2H,
m, C(30)H, C(50)H), 7.21e7.38 (10H, m, Ph), 7.44e7.47 (2H, m, C(20)H,
C(60)H); dC (100 MHz, CDCl3) 13.3 (C(5)Me), 35.2 (C(3)), 50.7 (NCH2),
55.7 (OMe), 60.0 (C(5)), 72.1 (OCH2), 75.2 (C(2)), 93.7 (C(4)), 114.5
(C(30), C(50)), 127.2 (p-Ph), 128.1, 128.4, 128.7 (C(20), C(60), oþ,m-Ph),
129.6, 131.6, 139.4 (i-Ph, C(10)), 155.0 (C(þ40)); m/z (ESI ) 514
([MþH]þ, 100%); HRMS (ESIþ) C26H29INO2 ([MþH]þ) requires
514.1237; found 514.1235.
450.2629.
Step 2: BuLi (2.5 M, 3.02 mL, 7.57 mmol) was added dropwise to
a
stirred solution of 4-methoxybenzyl triphenylphosphonium
chloride31 (3.67 g, 8.75 mmol) in THF (30 mL) at ꢀ78 ꢁC. After
30 min, a solution of 36 (700 mg) in THF (20 mL) at ꢀ78 ꢁC was
added. The reaction mixture was then allowed to warm to rt
and stirred for 12 h. Satd aq NH4Cl (5 mL) was then added and
the resultant mixture was partitioned between brine (50 mL)
and Et2O (50 mL). The aqueous layer was then extracted
with Et2O (2ꢃ50 mL) and the combined organic extracts were
dried and concentrated in vacuo. Purification via flash column

4314
S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4.15. (R,R,R,R)-N(1)-Benzyl-2-(40-methoxyphenyl)-3-acetoxy-
4-benzyloxy-5-methylpyrrolidine 54
Pd/C (4 mg, 15% w/w with respect to 54) was added to a stirred
solution of 54 (23 mg, 0.05 mmol) in degassed MeOH (1 mL) and
placed under an atmosphere of H2. After 24 h, the mixture was
degassed with N2 and filtered through CeliteÒ (eluent MeOH) before
being concentrated in vacuo to give 57 as a colourless oil (16 mg,
87%, >99:1 dr); dH (400 MHz, CDCl3) 1.26 (3H, d, J 6.7, C(5)Me), 2.09
(3H, s, COMe), 3.46e3.51 (1H, m, C(5)H), 3.70 (1H, dd, J 3.8, 2.1,
C(4)H), 3.79 (3H, s, OMe), 4.25 (1H, d, J 3.5, C(2)H), 4.57 (1H, ABd, J
12.0, OCHA), 4.70 (1H, s, NH), 4.71 (1H, ABd, J 12.0, OCHB), 5.35 (1H,
m, C(3)H), 6.84e6.88 (2H, m, C(30)H, C(50)H), 7.24e7.35 (5þH, m, Ph),
7.36e7.38 (2H, m, C(20)H, C(60)H); m/z (ESIþ) 356 ([MþH] , 100%).
AgOAc (91 mg, 0.48 mmol) was added to a stirred solution of 45
(92 mg, 0.16 mmol) in AcOH (1 mL) and the resultant mixture was
heated at 30 ꢁC for 24 h, then allowed to cool to rt. The mixture was
then partitioned between satd aq NaHCO3 (10 mL) and CH2Cl2
(10 mL) and the organic layer was dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O, 3:1) gave 54 as a colourless oil (26 mg, 34%, >99:1 dr);
4.17. tert-Butyl (R,R,R)-2-O-methoxymethyl-3-[N-benzyl-N-
(a
-methyl-40-methoxybenzyl)amino]butanoate 58
½
a 2D0
ꢂ
þ5.5 (c 1.0 in CHCl3); nmax (film) 2964 (CeH), 1741 (C]O); dH
(400 MHz, CDCl3) 1.09 (3H, d, J 6.6, C(5)Me), 2.06 (3H, s, COMe), 3.36
(1H, ABd, J 14.2, NCHA), 3.42 (1H, qd, J 6.6, 2.2, C(5)H), 3.64 (1H, app
d, J 2.2, C(4)H), 3.68 (1H, ABd, J 14.2, NCHB), 3.81 (3H, s, OMe), 3.87
(1H, d, J 4.7, C(2)H), 4.58 (1H, ABd, J 12.3, OCHA), 4.70 (1H, ABd,
J 12.3, OCHB), 5.23 (1H, dd, J 4.7, 2.2, C(3)H), 6.88 (2H, d, J 8.8, C(30)H,
C(50)H), 7.21e7.37 (12H, m, C(20)H, C(60)H, Ph); dC (100 MHz, CDCl3)
12.6 (C(5)Me), 21.2 (COMe), 50.3 (NCH2), 55.2 (OMe), 58.9 (C(5)),
69.8 (C(2)), 71.2 (OCH2), 84.4 (C(3)), 88.5 (C(4)), 113.8 (C(30), C(50)),
126.7 (p-Ph), 127.9, 128.3, 129.5 (C(20), C(60), o,m-þPh), 138.4 (i-Ph),
139.3 (C(10)), 159.1 (C(40)), 169.9 (COMe); m/z (ESI ) 446 ([MþH]þ,
NaH (60% dispersion in mineral oil, 241 mg, 6.02 mmol) was
added portionwise to a solution of 27 (2.00 g, 5.01 mmol) in DMF
(40 mL) at 0 ꢁC and the resultant mixture was stirred for 30 min at
this temperature. MOMCl (484 mg, 6.02 mmol) was added and the
resultant mixture was allowed to warm to rt over 12 h. H2O
(100 mL) was then added and the reaction mixture was extracted
with Et2O (2ꢃ100 mL). The organic layer was washed with brine
(50 mL) then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/EtOAc, 8:1) gave
þ
100%); HRMS (ESIþ) C28H32NO4 ([MþH]þ) requires 446.2326;
found 446.2311. Further elution gave 55 as a colourless oil (12 mg,
15%, >99:1 dr); ½a D20
þ22.2 (c 0.5 in CHCl3); nmax (film) 2919 (CeH),
ꢂ
1736 (C]O); dH (400 MHz, CDCl3) 0.77 (3H, d, J 6.1, C(5)Me), 2.12
(3H, s, COMe), 2.99 (1H, app quintet, J 6.1, C(5)H), 3.24 (1H, ABd,
J 12.3, NCHA), 3.32 (1H, app t, J 5.7, C(3)H), 3.46 (1H, ABd, J 12.3,
NCHB), 3.59 (1H, app t, J 5.7, C(4)H), 3.81 (3H, s, OMe), 4.32 (1H, ABd,
J 11.7, OCHA), 4.38 (1H, ABd, J 11.7, OCHB), 5.79 (1H, d, J 5.7, C(2)H),
6.88 (2H, d, J 8.5, C(30)H, C(50)H), 7.21e7.37 (12H, m, C(20)H, C(60)H,
Ph); dC (100 MHz, CDCl3) 20.4 (C(5)Me), 21.4 (COMe), 55.2 (OMe),
61.6 (NCH2), 66.7 (C(5)), 71.3 (OCH2), 73.0 (C(3)), 75.7 (C(2)), 78.7
(C(4)), 113.7 (C(30), C(50)), 127.8, 128.4, 129.5 (C(20), C(60), o,m,p-Ph),
138.0 (i-Ph), 138.3 (C(10)), 159.4 (C(40)), 170.0 (COMe); m/z (ESIþ)
58 as a colourless oil (1.90 g, 86%, >99:1 dr); ½a D20
þ9.0 (c 1.0 in
ꢂ
CHCl3); vmax (film) 2975 (CeH), 1739 (C]O); dH (400 MHz, CDCl3)
1.12 (3H, d, J 7.1, C(4)H3),1.28 (3H, d, J 6.7, C(
3.29e3.31 (1H, m, C(3)H), 3.36 (3H, s, CH2OMe), 3.79 (3H, s, ArOMe),
3.87 (1H, ABd, J 14.9, NCHA), 3.93e3.95 (1H, m, C( )H), 3.95e3.96
a)Me),1.38 (9H, s, CMe3),
a
(1H, m, C(2)H), 3.99 (1H, ABd, J 14.9, NCHB), 4.62 (2H, s, OCH2),
6.82e6.86 (2H, m, C(30)H, C(50)H), 7.21e7.34 (5H, m, Ph), 7.44e7.46
(2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) 12.7 (C(4)), 17.5
(C(
a)Me), 27.9 (CMe3), 50.5 (NCH2), 54.3 (C(3)), 55.2 (ArOMe), 56.6
þ
446 ([MþH]þ, 100%); HRMS (FIþ) C28H31NO4 ([M]þ) requires
(CH2OMe), 58.4 (C(
a
)), 80.5 (C(2)), 80.8 (CMe3), 96.8 (OCH2), 113.4
(C(30), C(50)), 126.4 (p-Ph), 128.1, 128.2, 128.7 (C(20), C(60), o,þm-Ph),
445.2248; found 445.2534. Further elution gave 56 as a colourless
oil (5 mg, 6%, >99:1 dr); ½a D20
þ5.0 (c 0.2 in CHCl3); nmax (film) 2918
ꢂ
136.4, 142.4 (C(10), i-Ph), 158.3 (C(40)), 171.1 (C(1)); m/z (ESI ) 444
þ
([MþH]þ, 100%); HRMS (ESIþ) C26H38NO5 ([MþH]þ) requires
(CeH), 1740 (C]O); dH (400 MHz, CDCl3) 0.88 (3H, d, J 5.7, C(5)Me),
1.86 (3H, s, COMe), 2.99 (1H, app quintet, J 6.0, C(5)H), 3.32 (1H, app
t, J 5.7, C(4)H), 3.41 (1H, dd, J 5.7, J 7.9, C(3)H), 3.60 (1H, ABd, J 12.8,
NCHA), 3.81 (3H, s, OMe), 3.87 (1H, ABd, J 11.7, OCHA), 3.91 (1H ABd,
J 12.8, NCHB), 3.94 (1H, ABd, J 11.7, OCHB), 5.68 (1H, d, J 8.2, C(2)H),
6.88 (2H, d, J 8.8, C(30)H, C(50)H), 7.21e7.37 (12H, m, C(20)H, C(60)H,
Ph); dC (100 MHz, CDCl3) 20.0 (C(5)Me), 21.0 (COMe), 55.3 (OMe),
62.2 (NCH2), 66.4 (C(5)), 71.2 (OCH2), 73.3 (C(3)), 77.8 (C(2)), 79.0
(C(4)), 113.8 (C(30), C(50)), 127.0, 127.4, 129.0 (C(20), C(60), o,mþ,p-Ph),
137.8 (i-Ph), 138.9 (C(10)), 159.7 (C(40)), 170.1 (COMe); m/z (ESI ) 446
444.2744; found 444.2731.
4.18. (3S,4R,
O-methoxymethyl-4-[N-benzyl-N-(
a
R,E)- and (3S,4R,
a
R,Z)-1-(40-Methoxyphenyl)-3-
-methyl-400-
a
methoxybenzyl)amino]pent-1-ene 59 and 60
þ
([MþH]þ, 100%); HRMS (ESIþ) C28H32NO4 ([MþH]þ) requires
446.2326; found 446.2307.
4.16. (R,R,R,R)-N(1)-2-(40-Methoxyphenyl)-3-acetoxy-4-
benzyloxy-5-methylpyrrolidine 57
Step 1: DIBAL-H (1.0 M in CH2Cl2, 0.86 mL, 0.86 mmol) was
added to a stirred solution of 58 (123 mg, 0.28 mmol) in CH2Cl2
(19 mL) at ꢀ78 ꢁC. After 30 min at this temperature, MeOH (2 mL)
was added and the resultant mixture was allowed to warm to rt
before satd aq Rochelle’s salt (1 mL) was added. The resultant
mixture was stirred for 16 h before being filtered through CeliteÒ

S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4315
(eluent CH2Cl2) and the filtrate was dried and concentrated in
vacuo to give (R,R,R)-2-O-methoxymethyl-3-[N-benzyl-N-(
methyl-40-methoxybenzyl)amino]butanal as
colourless oil
(94 mg); dH (400 MHz, CDCl3) 1.26 (3H, d, J 6.5, C(4)H3), 1.36 (3H, d, J
6.8, C( )Me), 3.26e3.30 (1H, m, C(3)H), 3.31 (3H, s, CH2OMe),
3.34e3.37 (1H, m, C(2)H), 3.62 (1H, q, J 6.8, C( )H), 3.76 (1H, ABd, J
Step 1: NaHCO3 (106 mg, 1.26 mmol) and I2 (321 mg, 1.26 mmol)
were added to a stirred solution of 59 (100 mg, 0.19 mmol) in MeCN
(10 mL) at ꢀ20 ꢁC. After stirring for 2 h at this temperature, the
reaction mixture was allowed to warm to rt and was stirred for
a further 20 h. The reaction mixture was then diluted with Et2O
(25 mL), washed with satd aq Na2S2O3 (25 mL), and the organic
layer was dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 3:1) gave
an impure sample of 61 as a colourless oil (109 mg); dH (400 MHz,
CDCl3) 1.16 (3H, d, J 6.8, C(5)Me), 3.39 (3H, s, CH2OMe), 3.39e3.46
(2H, m, C(5)H, NCHA), 3.65 (1H, ABd, J 14.4, NCHB), 3.82 (3H, s, OMe),
3.98 (1H, dd, J 8.6, 4.8, C(3)H), 4.15 (1H, d, J 8.6, C(2)H), 4.26 (1H, m,
C(4)H), 4.69 (1H, ABd, J 6.8, OCHA), 4.79 (1H, ABd, J 6.8, OCHB),
6.90e6.94 (2H, m, C(30)H, C(50)H), 7.26e7.37 (5H, m, Ph), 7.44e7.48
(2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) [selected peaks] 12.7
(C(5)Me), 35.1 (C(3)), 50.3 (NCH2), 55.3, 55.6 (OMe), 59.8 (C(5)), 74.4
(C(2)), 91.4 (C(4)), 95.2 (OCH2), 113.6, 114.1 (C(30), C(50)), 126.8
(p-Ph), 127.5, 128.0, 128.5 (C(20), C(60), o,mþ-Ph); m/z (ESIþ) 468
([MþH]þ, 100%); HRMS (ESIþ) C21H27INO3 ([MþH]þ) requires
468.1030; found 468.1018.
a
-
a
a
a
13.7, NCHA), 3.79 (3H, s, ArOMe), 3.82 (1H, ABd, J 13.7, NCHB), 4.52
(1H, ABd, J 6.7, OCHA), 4.58 (1H, ABd, J 6.7, OCHB), 6.82e6.85 (2H, m,
C(30)H, C(50)H), 7.11e7.15 (2H, m, C(20)H, C(60)H), 7.24e7.38 (5H, m,
Ph), 8.64 (1H, d, J 4.8, C(1)H); m/z (ESIþ) 404 ([MþMeOHþH]þ,
100%); HRMS (ESIþ) C23H34NO5
404.2431; found 404.2416.
([MþMeOHþH]þ) requires
þ
Step 2: BuLi (2.5 M, 0.58 mL, 1.46 mmol) was added dropwise to
a stirred solution of 4-methoxybenzyl triphenylphosphonium chlo-
ride31 (705 mg, 1.68 mmol) in THF (10 mL) at ꢀ78 ꢁC. After 30 min,
a solution of (R,R,R)-2-O-methoxymethyl-3-[N-benzyl-N-(a-methyl-
40-methoxybenzyl)amino]butanal (94 mg) in THF (5 mL) at ꢀ78 ꢁC
was added. The reaction mixture was then allowed to warm to rt and
stirred for 12 h. Satd aq NH4Cl (1 mL) was then added and the re-
sultant mixture was partitioned between brine (20 mL) and Et2O
(20 mL). The aqueous layer was then extracted with Et2O (2ꢃ20 mL)
and the combined organic extracts were dried and concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/EtOAc, 6:1) gave 60 as a colourless oil (21 mg, 16%,
>99:1 dr); C30H37NO4 requires C, 75.8; H, 7.8; N, 2.9%; found C, 75.6;
Step 2: AgOAc (91 mg, 0.48 mmol) was added to a stirred so-
lution of 61 (92 mg) in AcOH (1 mL) and the resultant mixture was
heated at 30 ꢁC for 24 h, then allowed to cool to rt. The mixture was
then partitioned between satd aq NaHCO3 (10 mL) and CH2Cl2
(10 mL) and the organic layer was dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O, 3:1) gave 62 as a colourless oil (26 mg, 37% from 59,
H, 7.6; N, 2.8%; ½a D20
þ126 (c 1.0 in CHCl3); nmax (film) 2930 (CeH),
ꢂ
1605 (C]C); dH (400 MHz, CDCl3) 1.27 (3H, d, J 6.6, C(5)H3), 1.31 (3H,
d, J 6.8, C(
(1H, ABd, J 13.8, NCHA), 3.80 (3H, s, ArOMe), 3.82 (3H, s, ArOMe), 3.90
(1H, q, J 6.8, C( )H), 3.96 (1H, ABd, J 13.8, NCHB), 4.45 (1H, d, J 6.7,
a)Me), 2.90e2.97 (1H, m, C(4)H), 3.28 (3H, s, CH2OMe), 3.76
>99:1 dr); ½a 2D0
þ3.4 (c 0.5 in CHCl3); nmax (film) 2932 (CeH), 1744
ꢂ
(C]O); dH (400 MHz, C6D6) 1.14 (3H, d, J 6.8, C(5)Me), 1.73 (3H, s,
COMe), 3.29 (3H, s, CH2OMe), 3.39 (1H, ABd, J 14.0, NCHA), 3.41 (3H, s,
ArOMe), 3.63 (1H, app qd, J 6.8, 2.2, C(5)H), 3.81 (1H, ABd, J 14.0,
NCHB), 4.07 (1H, dd, J 2.2, 0.5, C(4)H), 4.11 (1H, d, J 4.7, C(2)H), 4.66
(1H, ABd, J 6.8, OCHA), 4.94 (1H, ABd, J 6.8, OCHB), 5.23 (1H, app ddd,
J 4.7, 2.2, 1.6, C(3)H), 6.91e6.94 (2H, m, C(30)H, C(50)H), 7.25e7.34
(5H, m, Ph), 7.58e7.62 (2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3)
12.2 (C(5)Me), 21.2 (COMe), 50.3 (NCH2), 55.3, 55.6 (OMe), 59.0
(C(5)), 69.6 (C(2)), 85.3 (C(3)), 86.3 (C(4)), 113.9 (C(30), C(50)), 126.7
(p-Ph), 128.3, 129.5 (C(20), C(60), o,m-Ph), 132.4 (i-Ph), 139.2 (C(10)),
159.2 (C(40)), 170.0 (COMe); m/z (ESIþ) 400 ([MþH]þ, 100%); HRMS
a
OCHA), 4.61 (1H, d, J 6.7, OCHB), 4.65 (1H, m, C(3)H), 5.12 (1H, dd, J 11.9,
10.6, C(2)H), 6.43 (1H, d, J 11.9, C(1)H), 6.84e6.88 (4H, m, Ar),
7.00e7.05 (2H, m, Ar), 7.20e7.28 (5H, m, Ph), 7.34e7.38 (2H, m, Ar); dC
(100 MHz, CDCl3) 13.4 (C(a)Me), 14.2 (C(5)), 51.1 (NCH2), 54.8 (C(4)),
55.2, 55.3, 55.9 (OMe), 56.0 (C(
a
)), 80.4 (C(3)), 94.2 (OCH2),113.1,113.7
(C(30), C(50), C(300), C(500)),126.5 (p-Ph),128.0,128.7,128.8 (C(20), C(60),
C(200), C(600), o,m-Ph), 129.9 (C(2)), 131.4 (C(1)), 136.8, 141.8 (C(10),
C(100), i-Ph), 158.5 (C(40), C(400)); m/z (ESIþ) 476 ([MþH]þ, 100%);
þ
HRMS (ESIþ) C30H38NO4 ([MþH]þ) requires 476.2795; found
476.2787. Further elution gave a 50:50 mixture of 59 and 60 (19 mg,
15%). Further elution gave 59 as a colourless oil (50 mg, 39%, >99:1
þ
(ESIþ) C23H30NO5 ([MþH]þ) requires 400.2118; found 400.2104.
dr); ½a 2D0
þ123 (c 1.0 in CHCl3); nmax (film) 2934 (CeH), 1608 (C]C);
ꢂ
dH (400 MHz, CDCl3) 1.31 (3H, d, J 6.6, C(5)H3), 1.36 (3H, d, J 7.1, C(a)
4.20. (R,R,R,R)-N(1)-Benzyl-2-(40-methoxyphenyl)-3-acetoxy-
4-hydroxy-5-methylpyrrolidine 63
Me), 2.96e2.98 (1H, m, C(4)H), 3.35 (3H, s, CH2OMe), 3.78e3.83 (4H,
m, ArOMe, NCHA), 3.85e3.91 (2H, m, C( )H, NCHB), 3.86 (3H, s,
a
ArOMe), 3.97 (1H, appt, J 8.6, C(3)H), 4.42(1H, d, J 6.7, OCHA), 4.69(1H,
d, J 6.7, OCHB), 5.54 (1H, dd, J 15.9, 8.6, C(2)H), 6.31 (1H, d, J 15.9, C(1)
H), 6.73e6.93 (4H, m, C(30)H, C(50)H, C(300)H, C(500)H), 7.17e7.43 (9H,
m, C(20)H, C(60)H, C(200)H, C(600)H, Ph); dC (100 MHz, CDCl3) 14.0 (C(
a)
Me), 14.8 (C(5)), 50.7 (NCH2), 54.3 (C(4)), 55.2, 55.3 (C(40)OMe, C(400)
OMe), 55.6 (OMe), 55.8 (C(a)), 80.4 (C(3)), 93.5 (OCH2), 113.1, 113.8
(C(30), C(50), C(300), C(500)),126.6 (p-Ph),127.4 (C(2)), 127.5, 128.1, 129.6
(C(20), C(60), C(200), C(600), o,m-Ph), 132.7 (C(1)), 136þ.3, 141.1 (C(10),
C(100), i-Ph),159.1(C(40),C(400));m/z(ESIþ)476([MþH] ,100%);HRMS
þ
(ESIþ) C30H38NO4 ([MþH]þ) requires 476.2795; found 476.2779.
HCl (2.0 M in MeOH, 0.06 mL, 0.12 mmol) was added to a stirred
solution of 62 (44 mg, 0.11 mmol) in MeOH (2 mL) and the resultant
mixture was heated at 50 ꢁC for 5 h. The mixture was then con-
centrated in vacuo and the residue was partitioned between satd aq
NaHCO3 (5 mL) and CH2Cl2 (5 mL). The organic layer was dried and
concentrated in vacuo to give 63 as an orange oil (39 mg, 98%,
4.19. (R,R,R,R)-N(1)-Benzyl-2-(40-methoxyphenyl)-3-acetoxy-
4-O-methoxymethyl-5-methylpyrrolidine 62
>99:1 dr); ½a 2D0
þ0.9 (c 1.0 in CHCl3); nmax (film) 2964 (CeH), 1731
ꢂ
(C]O); dH (400 MHz, CDCl3) 1.13 (3H, d, J 6.6, C(5)Me), 2.09 (3H, s,
COMe), 3.23 (1H, br s, OH), 3.33 (1H, m, C(5)H), 3.34 (1H, ABd, J 14.1,
NCHA), 3.65 (1H, ABd, J 14.1, NCHB), 3.80 (1H, m, C(4)H), 3.82 (3H, s,
OMe), 3.97 (1H, d, J 6.1, C(2)H), 4.75 (1H, dd, J 6.1, 2.8, C(3)H),
6.89e6.92 (2H, m, C(30)H, C(50)H), 7.26e7.36 (7H, m, C(20)H, C(60)H,

4316
S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
Ph); dC (100 MHz, CDCl3) 12.7 (C(5)Me), 21.0 (COMe), 50.0 (NCH2),
55.3 (OMe), 60.3 (C(5)), 68.5 (C(2)), 82.5 (C(4)), 89.6 (C(3)), 114.0
(C(30), C(50)), 126.7 (p-Ph), 128.1, 128.3, 129.4 (C(20), C(60), o,m-Ph),
131.8 (i-Ph), 139.0 (C(10)),159.3 (C(40)), 172.3 (COMe); m/z (ESIþ) 356
CDCl3) 1.16 (3H, d, J 6.8, C(5)Me), 2.05 (3H, s, COMe), 2.11 (3H, s,
COMe), 3.29 (1H, app q, J 6.8, C(5)H), 3.38 (1H, ABd, J 14.1, NCHA),
3.63 (1H, ABd, J 14.1, NCHB), 3.81 (3H, s, OMe), 3.88 (1H, d, J 6.1,
C(2)H), 4.83 (1H, dd, J 2.3, 1.8, C(4)H), 5.14 (1H, J 6.1, 2.3, C(3)H),
6.89e6.92 (2H, m, C(30)H, C(50)H), 7.26e7.33 (5H, m, Ph), 7.36e7.42
(2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) 11.0 (C(5)Me), 20.9,
21.1 (COMe), 50.0 (NCH2), 55.3 (OMe), 59.3 (C(5)), 69.2 (C(2)), 82.8
(C(4)), 84.0 (C(3)), 114.0 (C(30), C(50)), 126.8 (p-Ph), 128.1, 128.2,
128.4, 129.2 (C(20), C(60), o,m-Ph), 131.8 (i-Ph), 138.8 (C(10)), 159.4
(C(40)), 169.6, 170.3 (COMe); m/z (ESIþ) 398 ([MþH]þ, 100%); HRMS
þ
([MþH]þ, 100%); HRMS (ESIþ) C21H26NO4 ([MþH]þ) requires
356.1856; found 356.1849.
4.21. (R,R,R)-1-(40-Methoxyphenyl)-2,3-dihydroxy-4-(N,N-
dimethylamino)pentane 65
(ESIþ) C23H28NO5 ([MþH]þ) requires 398.1962; found 398.1947.
þ
4.23. (R,R,R,R)-N(1)-2-(40-Methoxyphenyl)-3,4-diacetoxy-5-
methylpyrrolidine 67
Step 1: K2CO3 (311 mg, 2.25 mmol) was added to a stirred so-
lution of 63 (40 mg, 0.11 mmol) in MeOH (5 mL) at rt. After stirring
for 6 h, the mixture was concentrated in vacuo and the residue was
partitioned between H2O (10 mL) and CH2Cl2 (10 mL). The organic
layer was dried and concentrated in vacuo to give 64 as a colour-
less oil (34 mg, >99:1 dr); dH (400 MHz, CDCl3) [selected peaks]
1.13 (3H, d, J 6.8, C(5)Me), 3.20e3.25 (1H, m, C(5)H), 3.44 (1H, ABd,
J 14.0, NCHA), 3.61 (1H, ABd, J 14.0, NCHB), 3.81 (3H, s, OMe), 6.88
(2H, d, J 8.8, C(30)H, C(50)H), 7.25e7.34 (5H,þm, Ph), 7.37 (2H, d, J 8.þ5,
C(20)H, C(60)H); m/z (ESIþ) 314 ([MþH] , 100%); HRMS (ESI )
Pd(OH)2/C (8 mg, 20% w/w with respect to 66) was added to
a stirred solution of 66 (40 mg, 0.10 mmol) in degassed MeOH
(5 mL) and placed under an atmosphere of H2. After 8 h, the mix-
ture was degassed with N2 and filtered through CeliteÒ (eluent
MeOH) before being concentrated in vacuo to give 67 as a colour-
þ
C19H24NO3 ([MþH]þ) requires 314.1751; found 314.1744.
less oil (22 mg, 71%, >99:1 dr); ½a D20
þ7.1 (c 1.0 in CHCl3); nmax (film)
ꢂ
Step 2: Pd(OH)2/C (8 mg, 20% w/w with respect to 64) was
added to a stirred solution of 64 (34 mg, >99:1 dr) and (CH2O)n
(7 mg, 0.23 mmol) in degassed MeOH (5 mL) under H2 (5 atm).
After 48 h, the mixture was degassed with N2 and filtered
through CeliteÒ (eluent MeOH) before being concentrated in
2964 (CeH), 1743 (C]O); dH (400 MHz, CDCl3) 1.43 (3H, d, J 7.1, C(5)
Me), 2.09 (3H, s, COMe), 2.12 (3H, s, COMe), 3.47 (1H, br s, NH), 3.79
(1H, m, C(5)H), 3.80 (3H, s, OMe), 4.62 (1H, d, J 5.1, C(2)H), 4.92 (1H,
m, C(4)H), 5.36 (1H, dd, J 5.1, 2.3, C(3)H), 6.87e6.90 (2H, m, C(30)H,
C(50)H), 7.43e7.46 (2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) 15.7
(C(5)Me), 20.8, 20.9 (COMe), 55.2 (OMe), 59.1 (C(5)), 64.8 (C(2)),
80.7 (C(4)), 81.2 (C(3)), 114.4 (C(30), C(50)), 129.4 (Cþ(20), C(60)), 138þ.8
(C(10)), 160.2 (C(40)), 169.5, 169.9 (COMe); m/z (ESI ) 308 ([MþH] ,
vacuo to give 65 as a colourless oil (6 mg, 21%, >99:1 dr); ½a D20
ꢂ
þ5.7 (c 0.5 in CHCl3); nmax (film) 2930 (CeH); dH (400 MHz,
CDCl3) 1.08 (3H, d, J 6.6, C(5)H3), 2.29 (6H, s, NMe2), 2.72e2.79
(2H, m, C(1)HA, C(4)H), 2.84 (1H, dd, J 13.6, 5.4, C(1)HB), 3.52 (1H,
dd, J 6.6, 3.5, C(3)H), 3.79 (3H, s, OMe), 3.97e4.02 (1H, m, C(2)H),
6.83e6.87 (2H, m, C(30)H, C(50)H), 7.17e7.23 (2H, m, C(20)H, C(60)
H); dC (100 MHz, CDCl3) 8.9 (C(5)), 38.6 (C(1)), 41.5 (NMe2), 55.2
(OMe), 61.7 (C(4)), 73.0 (C(2)), 73.3 (C(3)), 113.9 (C(30), C(50)), 130.3
(C(20), C(60)), 130.7 (C(10)), 158.1 (C(40)); m/z (ESIþ) 254 ([MþH]þ,
100%); HRMS (ESIþ) C16H22NO5 ([MþH]þ) requires 308.1492;
þ
found 308.1486.
4.24. (R,R,R,R)-N(1)-2-(40-Methoxyphenyl)-3,4-dihydroxy-5-
methylpyrrolidine 68
þ
100%); HRMS (ESIþ) C14H24NO3 ([MþH]þ) requires 254.1751;
found 254.1757.
4.22. (R,R,R,R)-N(1)-Benzyl-2-(40-methoxyphenyl)-3,4-
diacetoxy-5-methylpyrrolidine 66
K2CO3 (198 mg, 1.43 mmol) was added to a stirred solution of 67
(22 mg, 0.07 mmol) in MeOH (5 mL) at rt. After stirring for 6 h, the
mixture was concentrated in vacuo and the residue was partitioned
between H2O (5 mL) and CH2Cl2 (5 mL). The aqueous layer was
concentrated in vacuo and the residue was dissolved in CHCl3, then
dried and concentrated in vacuo to give an impure sample of 68 as
a colourless oil (15 mg, >99:1 dr); dH (400 MHz, CDCl3) 1.32 (3H, d,
J 6.5, C(5)Me), 2.01 (1H, br s, NH), 3.34e3.37 (1H, m, C(5)H),
3.78e3.81 (1H, m, C(4)H), 3.81 (3H, s, OMe), 4.00e4.04 (1H, m, C(3)
H), 4.08e4.13 (1H, m, C(2)H), 6.89 (2H, d, J 8.7, C(30)H, C(50)H), 7.35
(2H, d, J 8.7, C(20)H, C(60)H); dC (100 MHz, CDCl3) 14.1 (C(5)Me), 55.3
(OMe), 57.3 (C(5)), 64.8 (C(2)), 83.8 (C(4)), 84.9 (C(3)), 114.1 (C(30),
C(50)), 127.8, 127.9 (C(20), C(60)), 159.1 (C(4þ0));32 m/z (ESIþ) 224
([MþH]þ, 100%); HRMS (ESIþ) C12H18NO3 ([MþH]þ) requires
224.1281; found 224.1280.
Ac2O (23 mL, 0.25 mmol) was added to a stirred solution of 63
(44 mg, 0.12 mmol) in pyridine (5 mL) at rt. After 16 h, the mixture
was partitioned between CH2Cl2 (15 mL) and satd aq Cu2SO4
(15 mL). The aqueous layer was extracted with CH2Cl2 (2ꢃ10 mL)
and the combined organic extracts were washed with H2O (10 mL)
and brine (10 mL) before being dried and concentrated in vacuo to
give 66 as a colourless oil (41 mg, 83%, >99:1 dr); ½a D20
þ4.0 (c 1.0
ꢂ
in CHCl3); nmax (film) 2930 (CeH), 1742 (C]O); dH (400 MHz,

S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4317
4.25. tert-Butyl (R,R,R)-2-hydroxy-3-[N-methyl-N-(
a-methyl-
CDCl3) 9.2 (C(4)), 21.5 (C(
a
)Me), 28.1 (CMe3), 33.1 (NMe), 55.2
40-methoxybenzyl)amino]butanoate 70
(ArOMe), 55.9 (CH2OMe), 56.2 (C(3)), 62.0 (C(a)), 80.6 (CMe3), 81.1
(C(2)), 96.8 (OCH2), 113.4 (C(30), C(50)), 128.5 (C(20), C(60)), 137.7
(C(10)), 158.3 (C(40)), 171.3 (C(1)); m/z (ESIþ) 368 ([MþH]þ, 100%);
HRMS (ESIþ) C20H34NO5 ([MþH]þ) requires 368.2431; found
þ
368.2422.
4.27. (3S,4R,
O-methoxymethyl-4-[N-methyl-N-(
benzyl)amino]pent-1-ene 73 and 74
a
R,E)- and (3S,4R,
a
R,Z)-1-(40-Methoxyphenyl)-3-
-methyl-400-methoxy-
a
BuLi (2.5 M, 0.59 mL, 1.47 mmol) was added to a stirred solution
of (R)-N-methyl-N-(
-methyl-40-methoxybenzyl)amine30 (250 mg,
a
1.52 mmol) in THF (10 mL) at ꢀ78 ꢁC. The resultant solution was
stirred at ꢀ78 ꢁC for 30 min before the addition of a solution of 15
(134 mg, 0.95 mmol) in THF (5 mL) at ꢀ78 ꢁC. The reaction mixture
was stirred for 2 h, (ꢀ)-CSO21 (369 mg, 1.61 mmol) was added and
the reaction mixture was allowed to warm to rt over 12 h. The re-
action mixture was then quenched with satd aq NH4Cl (5 mL) and
concentrated in vacuo. The residue was partitioned between 10% aq
citric acid (15 mL) and CH2Cl2 (15 mL) and the aqueous layer was
extracted with CH2Cl2 (2ꢃ15 mL). The combined organic extracts
were washed sequentially with satd aq NaHCO3 (30 mL) and brine
(30 mL), then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/EtOAc, 2:1) gave
Step 1: DIBAL-H (1.0 M in CH2Cl2, 20.3 mL, 20.3 mmol) was
added dropwise to a stirred solution of 71 (2.40 g, 6.54 mmol) in
CH2Cl2 (120 mL) at ꢀ78 ꢁC. After stirring at this temperature for
30 min, MeOH (10 mL) was added and the resultant mixture was
allowed to warm to rt before satd aq Rochelle’s salt (1.5 mL) was
added. The resultant mixture was stirred for 16 h before being fil-
tered through CeliteÒ (eluent CH2Cl2). The filtrate was then dried
and concentrated in vacuo to give 72 as a colourless oil (1.67 g); nmax
(film) 2960 (CeH), 1730 (C]O); dH (400 MHz, CDCl3) 1.06 (3H, d, J
70 as a colourless oil (221 mg, 71%, >99:1 dr); ½a D20
ꢀ23.5 (c 1.0 in
ꢂ
CHCl3); nmax (film) 3490 (OeH), 2975 (CeH), 1722 (C]O); dH
(400 MHz, CDCl3) 0.94 (3H, d, J 6.8, C(4)H3), 1.36 (3H, d, J 6.6, C(
Me), 1.43 (9H, s, CMe3), 2.23 (3H, s, NMe), 3.15e3.22 (1H, m, C(3)H),
3.72 (1H, q, J 6.8, C( )H), 3.80 (3H, s, OMe), 4.15 (1H, d, J 3.8, C(2)H),
6.82e6.87 (2H, m, C(30)H, C(50)H), 7.22e7.27 (2H, m, C(20)H, C(60)H);
dC (100 MHz, CDCl3) 10.8 (C(4)), 20.2 (C( )Me), 28.0 (CMe3),
)), 71.8 (C(2)), 79.6
a)
a
6.3, C(4)H3), 1.30 (3H, d, J 6.8, C(
CH2OMe), 3.50 (1H, m, C(3)H), 3.62 (1H, q, J 6.8, C(
a
)Me), 2.07 (3H, s, NMe), 3.39 (3H, s,
)H), 3.76
a
a
33.2 (NMe), 55.2 (OMe), 56.6 (C(3)), 61.1 (C(
a
(1H, m, C(2)H), 3.80 (3H, s, ArOMe), 4.64 (1H, ABd, J 6.8, OCHA),
4.67 (1H, ABd, J 6.8, OCHB), 6.82e6.86 (2H, m, C(30)H, C(50)H),
7.14e7.17 (2H, m, C(20)H, C(60)H), 9.46 (1H, d, J 4.0, C(1)H); m/z
(CMe3), 113.6 (C(30), C(50)), 128.5, 128.8 (C(20), C(60)), 136.8
(C(10)), 153.2 (C(40)), 170.7 (C(1)); m/z (ESIþ) 324 ([MþH]þ, 100%);
þ
HRMS (ESIþ) C18H30NO4 ([MþH]þ) requires 324.2169; found
(ESIþ) 328 ([MþMeOHþH]þ, 100%); HRMS (ESIþ) C17H30NO5
þ
324.2162.
([MþMeOHþH]þ) requires 328.2118; found 328.2106.
Step 2: BuLi (2.5 M, 10.2 mL, 25.5 mmol) was added dropwise to
a
stirred solution of 4-methoxybenzyl triphenylphosphonium
4.26. tert-Butyl (R,R,R)-2-O-methoxymethyl-3-[N-methyl-N-
chloride31 (12.3 g, 29.4 mmol) in THF (150 mL) at ꢀ78 ꢁC. After
30 min, a solution of 72 (1.67 g) in THF (50 mL) at ꢀ78 ꢁC was
added. The reaction mixture was then allowed to warm to rt and
stirred for 12 h. Satd aq NH4Cl (20 mL) was then added and the
resultant mixture was partitioned between brine (150 mL) and
Et2O (150 mL). The aqueous layer was then extracted with Et2O
(2ꢃ150 mL) and the combined organic extracts were dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30e40 ꢁC petrol/Et2O, 2:1) gave 74 as a colourless oil
(223 mg, 9%, >99:1 dr); C24H33NO4 requires C, 72.15; H, 8.3; N, 3.5%;
(a
-methyl-40-methoxybenzyl)amino]butanoate 71
NaH (343 mg, 8.58 mmol) was added portionwise to a stirred
found C, 72.1; H, 8.2; N, 3.4%; ½a D20
þ105 (c 1.0 in CHCl3); nmax (film)
ꢂ
solution of 70 (2.31 g, 7.15 mmol) in DMF (100 mL) at 0 ꢁC and the
resultant mixture was stirred for 30 min at this temperature.
MOMCl (690 mg, 8.58 mmol) was added and the resultant mixture
was allowed to warm to rt over 16 h. H2O (100 mL) was added and
the resultant mixture was extracted with Et2O (2ꢃ100 mL). The
organic layer was washed with brine (50 mL) then dried and
concentrated in vacuo. Purification via flash column chromatog-
raphy (eluent 30e40 ꢁC petrol/EtOAc, 2:1) gave 71 as a colourless
oil (1.84 g, 70%, >99:1 dr); C20H33NO5 requires C, 65.4; H, 9.05; N,
2956 (CeH),1608 (C]C); dH (400 MHz, CDCl3) 1.05 (3H, d, J 6.6, C(5)
H3), 1.27 (3H, d, J 6.9, C(
quintet, J 6.8, C(4)H), 3.36 (3H, s, CH2OMe), 3.59 (1H, q, J 6.9, C(
3.81 (3H, s, ArOMe), 3.90 (3H, s, ArOMe), 4.55 (1H, ABd, J 6.6, OCHA),
4.61(1H, dd, J 9.8, 6.6, C(3)H), 4.74 (1H, ABd, J 6.6, OCHB), 5.45 (1H,
dd, J 12.0, 9.8, C(2)H), 6.60 (1H, d, J 12.0, C(1)H), 6.80e6.87 (4H, m,
Ar), 7.18e7.22 (2H, m, Ar), 7.27e7.30 (2H, m, Ar); dC (100 MHz,
a
)Me), 1.99 (3H, s, NMe), 3.09 (1H, app
)H),
a
CDCl3) 10.1 (C(
55.7 (CH2OMe), 57.1 (C(4)), 61.6 (C(
a)Me), 21.0 (C(5)), 34.0 (NMe), 55.2, 55.3 (ArOMe),
a
)), 74.8 (C(3)), 93.9 (OCH2),
3.8%; found C, 65.5; H, 8.9; N, 3.7%; ½a D20
ꢂ
þ9.8 (c 1.0 in CHCl3); nmax
113.4, 114.1, 126.2, 128.3, 130.8 (Ar), 131.1 þ(C(2)), 131.6 (C(1)), 138.4
(film) 2976 (CeH), 1740 (C]O); dH (400 MHz, CDCl3) 0.97 (3H, d, J
(Ar), 158.2, 158.5 (C(40), C(400)); m/z (ESI ) 400 ([MþH]þ, 100%);
þ
6.6, C(4)H3), 1.31 (3H, d, J 6.7, C(
s, NMe), 3.39 (3H, s, CH2OMe), 3.40 (1H, m, C(3)H), 3.54 (1H, q, J
6.7, C( )H), 3.80 (3H, s, ArOMe), 3.87 (1H, d, J 8.1, C(2)H), 4.66 (1H,
a
)Me), 1.48 (9H, s, CMe3), 2.06 (3H,
HRMS (ESIþ) C24H34NO4 ([MþH]þ) requires 400.2482; found
400.2467. Further elution gave a 50:50 mixture of 73 and 74
(107 mg, 5%). Further elution gave 73 as a colourless oil (1.49 g, 57%,
>99:1 dr); C24H33NO4 requires C, 72.15; H, 8.3; N, 3.5%; found C,
a
ABd, J 6.9, OCHA), 4.68 (1H, ABd, J 6.9, OCHB), 6.80e6.83 (2H, m,
C(30)H, C(50)H), 7.18e7.21 (2H, m, C(20)H, C(60)H); dC (100 MHz,
72.3; H, 8.4; N, 3.7%; ½a D20
þ19.7 (c 1.0 in CHCl3); nmax (film) 2965
ꢂ

4318
S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
(CeH), 1609 (C]C); dH (400 MHz, CDCl3) 1.11 (3H, d, J 6.6, C(5)H3),
1.30 (3H, d, J 6.7, C( )Me), 2.09 (3H, s, NMe), 3.13 (1H, dd, J 7.6, 6.6,
C(4)H), 3.41 (3H, s, CH2OMe), 3.66 (1H, q, J 6.7, C( )H), 3.77 (3H, s,
ArOMe), 3.84 (3H, s, ArOMe), 4.10 (1H, app t, J 8.2, C(3)H), 4.53 (1H,
ABd, J 6.6, OCHA), 4.79 (1H, ABd, J 6.6, OCHB), 5.95 (1H, dd, J 16.0, 8.2,
C(2)H), 6.43 (1H, d, J 16.0, C(1)H), 6.75e6.78 (2H, m, Ar), 6.88e6.91
(2H, m, Ar), 7.18e7.21 (2H, m, Ar), 7.33e7.36 (2H, m, Ar); dC
4.30. (R,R,R,R)-N(1)-Methyl-2-(40-methoxyphenyl)-3-acetoxy-
4-O-methoxymethyl-5-methylpyrrolidine 78 and (R,R,R,R)-
N(1)-methyl-2-acetoxy-3-(40-methoxyphenyl)-4-O-
methoxymethyl-5-methylpyrrolidine 79
a
a
(100 MHz, CDCl3) 10.8 (C(a)Me), 21.0 (C(5)), 33.4 (NMe), 55.2, 55.3
(ArOMe), 55.7 (CH2OMe), 57.0 (C(4)), 61.5 (C(
a
)), 79.8 (C(3)), 93.6
(OCH2), 113.5, 114.0 (Ar), 126.9 (C(2)), 127.3, 128.3, 129.8 (Ar), 131.6
(C(1)), 138.3 (Ar), 158.2, 159.1 (C(40), C(400)); m/z (ESIþ) 400
þ
([MþH]þ, 100%); HRMS (ESIþ) C24H34NO4 ([MþH]þ) requires
400.2482; found 400.2473.
AgOAc (641 mg, 3.84 mmol) was added to a stirred solution of
75 (500 mg, 1.28 mmol) in AcOH (10 mL) and the resultant mixture
was heated at 40 ꢁC for 24 h, then allowed to cool to rt. The mixture
was then partitioned between satd aq NaHCO3 (50 mL) and CH2Cl2
(50 mL) and the organic layer was dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O, 1:1) gave a 75:25 mixture of 78 and 79 as a colourless
oil (199 mg, 48%, >99:1 dr). Data for 78: dH (400 MHz, CHCl3) 1.15
(3H, d, J 6.8, C(5)Me), 2.05 (3H, s, COMe), 2.11 (3H, s, NMe), 3.27 (1H,
app qd, J 6.8, 2.7, C(5)H), 3.40 (3H, s, CH2OMe), 3.72 (1H, d, J 4.0, C(2)
H), 3.81 (3H, s, ArOMe), 3.81 (1H, dd, J 2.7, 1.8, C(4)H), 4.70 (1H, ABd,
J 6.6, OCHA), 4.88 (1H, ABd, J 6.6, OCHB), 5.06e5.09 (1H, m, C(3)H),
6.84e6.88 (2H, m, C(30)H, C(50)H), 7.24e7.28 (2H, m, C(20)H, C(60)H);
dC (100 MHz, CDCl3) 12.5 (C(5)Me), 21.1 (COMe), 34.8 (NMe), 55.2,
55.6 (OMe), 63.2 (C(5)), 71.7 (C(2)), 85.0 (C(3)), 85.8 (C(4)), 95.4
(OCH2O), 113.7 (C(30), C(50)), 129.6 (C(20), C(60)), 131.2 (C(10)), 159.1
(C(40)), 170.1 (COMe). Data for 79: dH (400 MHz, CHCl3) 1.15 (3H, d, J
6.8, C(5)Me), 2.02 (3H, s, COMe), 2.08 (3H, s, NMe), 2.72 (1H, m, C(5)
H), 3.04 (1H, m, C(3)H), 3.34 (3H, s, CH2OMe), 3.62 (1H, m, C(4)H),
3.80 (3H, s, ArOMe), 4.53 (1H, ABd, J 6.5, OCHA), 4.56 (1H, ABd, J 6.5,
OCHB), 5.74 (1H, d, J 6.8, C(2)H), 6.85e6.87 (2H, m, C(30)H, C(50)H),
7.33e7.36 (2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) 18.4
(C(5)Me), 21.3 (COMe), 34.8 (NMe), 55.3, 55.6 (OMe), 68.2
(C(5)), 74.7 (C(2)), 75.9 (C(3)), 85.0 (C(4)), 95.3 (OCH2O), 113.7
(C(30), C(50)), 128.8 (C(20), C(60)), 131.2 (C(10)), 159.1 (C(40)), 170.1
(COMe). Data for mixture: m/z (ESIþ) 324 ([MþH]þ, 100%); HRMS
4.28. (R,R,R,R)-N(1)-Methyl-2-(40-methoxyphenyl)-3-iodo-4-
O-methoxymethyl-5-methylpyrrolidine 75
NaHCO3 (941 mg, 11.2 mmol) and I2 (2.85 g, 11.2 mmol) were
added to a stirred solution of 73 (1.49 g, 3.73 mmol) in MeCN
(50 mL) at ꢀ20 ꢁC. After stirring for 2 h at ꢀ20 ꢁC, the reaction
mixture was allowed to warm to rt over 20 h then diluted with Et2O
(100 mL). The resultant mixture was washed with satd aq Na2S2O3
(100 mL) then dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 4:1)
gave 75 as a colourless oil (790 mg, 54%, >99:1 dr); C15H22INO3
requires C, 46.05; H, 5.7; N, 3.6%; found C, 46.2; H, 5.6; N, 3.5%; ½a D20
ꢂ
þ2.9 (c 1.0 in CHCl3); nmax (film) 2934 (CeH); dH (400 MHz, CDCl3)
1.22 (3H, d, J 6.8, C(5)Me), 2.13 (3H, s, NMe), 3.43 (3H, s, CH2OMe),
3.48e3.50 (1H, dq, J 6.8, 2.0, C(5)H), 3.83 (3H, s, ArOMe), 3.90 (1H,
m, C(3)H), 3.93 (1H, m, C(2)H), 4.26 (1H, dd, J 3.7, 2.0, C(4)H), 4.74
(1H, ABd, J 6.8, OCHA), 4.81 (1H, ABd, J 6.8, OCHB), 6.87e6.91 (2H, m,
C(30)H, C(50)H), 7.30e7.34 (2H, m, C(20)H, C(60)H); dC (100 MHz,
CDCl3) 12.3 (C(5)Me), 34.4 (C(3)), 34.5 (NMe), 55.2, 55.7 (OMe), 64.2
(C(5)), 76.0 (C(2)), 90.9 (C(4)), 95.8 (OCH2), 113.9 (C(30), C(50)), 129.0
(C(20), C(60)), 130.9 (C(10)), 159.5 (C(40)); m/z (ESIþ) 392 ([MþH]þ,
(ESIþ) C17H26NO5 ([MþH]þ) requires 324.1805; found 324.1794.
þ
4.31. (R,R,R,R)-N(1)-Methyl-2-(40-methoxyphenyl)-3-hydroxy-
4-hydroxy-5-methylpyrrolidine [(L)-codonopsinine] 14
þ
100%); HRMS (ESIþ) C15H23INO3 ([MþH]þ) requires 392.0717;
found 392.0703.
4.29. (R,R,R,R)-N(1)-Methyl-2-(40-methoxyphenyl)-3-iodo-4-
hydroxy-5-methylpyrrolidine hydrochloride 76$HCl
HCl (2 M in MeOH, 0.59 mL, 1.18 mmol) was added to a stirred
solution of the 75:25 mixture of 78 and 79 (180 mg, 0.56 mmol) in
MeOH (5 mL) and the resultant mixture was heated at 50 ꢁC for
48 h. The mixture was then concentrated in vacuo and the residue
was partitioned between satd aq NaHCO3 (5 mL) and EtOAc (5 mL).
The organic layer was then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent CH2Cl2/
MeOH, 4:1) gave 14 as a white crystalline solid (61 mg, 30% from 75,
HCl (2 M in MeOH, 0.10 mL, 0.20 mmol) was added to a stirred
solution of 75 (34 mg, 0.09 mmol) in MeOH (2 mL) and the re-
sultant mixture was stirred at rt for 48 h to give 76$HCl (16 mg, 52%,
>99:1 dr); ½a 2D0
ꢀ1.4 (c 0.5 in CHCl3); nmax (film) 2965 (CeH); dH
ꢂ
(400 MHz, CD3OD) [selected peaks] 1.54 (3H, d, J 6.8, C(5)Me), 2.49
(3H, br s, NMe), 3.66e3.72 (1H, br s, OH), 3.86 (3H, s, ArOMe),
7.05e7.08 (2H, m, C(30)H, C(50)H), 7.43e7.46 (2H, m, C(20)H, C(60)H);
>99:1 dr);4b mp 147e150 ꢁC; {lit.15 mp 153e155 ꢁC}; ½a 2D0
ꢀ9.1 (c
ꢂ
0.1 in MeOH); {lit.4a
½
a 2D0
ꢂ
ꢀ8.8 (c 0.1 in MeOH)}; dH (400 MHz,
pyridine-d5) 1.34 (3H, d, J 6.8, C(5)Me), 2.23 (3H, s, NMe), 3.64 (3H, s,
OMe), 3.67e3.72 (1H, m, C(5)H), 4.09 (1H, app d, J 6.8, C(2)H), 4.39
(1H, dd, J 4.4, 3.8, C(4)H), 4.65 (1H, dd, J 6.5, 4.4, C(3)H), 5.25 (2H, br
þ
m/z (ESIþ) 348 ([MþH]þ, 100%); HRMS (ESIþ) C13H19INO2
([MþH]þ) requires 348.0455; found 348.0444.

S.G. Davies et al. / Tetrahedron 68 (2012) 4302e4319
4319
s, OH), 6.95 (2H, d, J 8.6, C(30)H, C(50)H), 7.31 (2H, d, J 8.6, C(20)H,
C(60)H); dC (100 MHz, pyridine-d5) 14.3 (C(5)Me), 35.2 (NMe), 55.5
(OMe), 65.7 (C(5)), 74.6 (C(2)), 85.6 (C(4)), 88.0 (C(3)), 114.7þ(C(30),
C(50)), 130.2 (C(20), C(60)), 135.4 (C(10)), 160.1 (C(40)); m/z (ESI ) 238
17. Chowdhury, M. A.; Reissig, H.-U. Synlett 2006, 2383.
18. Uraguchi, D.; Nakamura, S.; Ooi, T. Angew. Chem., Int. Ed. 2010, 49, 7562.
19. For selected examples, see: (a) Bunnage, M. E.; Burke, A. J.; Davies, S. G.;
Goodwin, C. J. Tetrahedron: Asymmetry 1995, 6, 165; (b) Bunnage, M. E.; Burke,
A. J.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D.
Org. Biomol. Chem. 2003, 1, 3708; (c) Abraham, E.; Candela-Lena, J. I.; Davies, S.
þ
([MþH]þ, 100%); HRMS (ESIþ) C13H20NO3 ([MþH]þ) requires
ꢀ
G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Sanchez-
238.1438; found 238.1437.
ꢀ
Fernandez, E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2007, 18,
2510; (d) Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P.
M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655; (e) Abraham, E.; Brock, E. A.;
Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.;
Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Scott, P. M.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 1665.
Supplementary data
ꢀ
ꢀ
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.045.
20. For a review, see: Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry
2005, 16, 2833.
21. (a) Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, G. S.; Carroll, P. J. J. Am.
Chem. Soc. 1988, 110, 8477; (b) Towson, J. C.; Weismiller, M. C.; Lal, G. S.;
Sheppard, A. C.; Kumar, A.; Davis, F. A. Org. Synth. 1990, 69, 158; (c) Chen, B.-C.;
Murphy, C. K.; Kumar, A.; Reddy, R. T.; Clark, C.; Zhou, P.; Lewis, B. M.; Gala, D.;
Mergelsberg, I.; Scherer, D.; Buckley, J.; DiBenedetto, D.; Davis, F. A. Org. Synth.
1996, 73, 159.
References and notes
1. (a) Davies, S. G.; Hughes, D. G.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A.
D.; Thomson, J. E.; Williams, O. M. H. Synlett 2010, 567; (b) Davies, S. G.;
Fletcher, A. M.; Hughes, D. G.; Lee, J. A.; Price, P. D.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Tetrahedron 2011, 67, 9975.
2. (a) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Smith, A. D. Synlett
2004, 901; (b) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Savory,
E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758.
3. Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011,
13, 1594.
4. (a) Matkhalikova, C. F.; Malikov, V. M.; Yunusov, S. Y. Khim. Prir. Soedin. 1969, 5,
606; (b) Yagudaev, M. R.; Matkhalikova, S. F.; Malikov, V. M.; Yusunov, S. Y.
Khim. Prir. Soedin. 1972, 495.
5. Iida, H.; Yamazaki, N.; Kibayashi, C.; Nagase, H. Tetrahedron Lett. 1986, 27, 5393.
6. Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003, 35.
7. Chandrasekhar, S.; Jagadeshwar, V.; Prakash, S. J. Tetrahedron Lett. 2005, 46,
3127.
8. Chandrasekhar, S.; Saritha, B.; Jagadeshwar, V.; Prakash, S. J. Tetrahedron:
Asymmetry 2006, 17, 1380.
9. Reddy, J. S.; Rao, B. V. J. Org. Chem. 2007, 72, 2224.
10. Wang, C. J.; Calabrese, J. C. J. Org. Chem. 1991, 56, 4341.
11. Haddad, M.; Larcheveque, M. Synlett 2003, 274.
12. Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996, 37, 5531.
13. Goti, A.; Cicchi, S.; Mannucci, V.; Cardona, F.; Guarna, F.; Merino, P.; Tejero, T.
Org. Lett. 2003, 5, 4235.
14. Oliveira, D. F.; Severino, E. A.; Correia, C. R. D. Tetrahedron Lett. 1999, 40, 2083.
15. Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039.
16. Kotland, A.; Accadbled, F.; Robeyns, K.; Behr, J. J. Org. Chem. 2011, 76, 4094.
22. Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron Lett.
2011, 52, 6477.
23. Crystallographic data (excluding structure factors) for compounds 14, 25, 27,
42, 45$HCl and 76$HCl have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication numbers CCDC 840036,
843707, 843708, 843709, 843710 and 840035, respectively. Copies of these data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
24. Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
25. Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143.
26. A 50:50 mixture of 73 and 74 was also isolated in 5% combined yield.
27. Ref. 6: ½a 2D8
ꢂ
ꢀ13.2 (c 0.3 in MeOH); Ref. 7: ½a D20
ꢀ8.8 (c 0.1 in MeOH); Ref. 8:
ꢂ
½
a 2D5
ꢂ
ꢀ12.4 (c 0.4 in MeOH); Ref. 9: ½a D34
ꢂ
ꢀ8.7 (c 0.3 in MeOH); Ref.11: ½a D20
ꢀ10.5
ꢂ
(c 1.1 in MeOH); Ref. 13: ½a D20
ꢂ
ꢀ7.2 (c 0.1 in MeOH); Ref. 15: mp 153e155 ꢁC;
½
a 2D0
ꢂ
ꢀ7.3 (c 0.2 in MeOH); Ref. 18: ½a D25
ꢀ13.1 (c 1.3 in MeOH).
ꢂ
28. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
29. Nakagawa, M.; Kawate, T.; Kakikawa, T.; Yamada, H.; Matsui, T.; Hino, T. Tet-
rahedron 1993, 49, 1739.
30. Blacker, A. J.; Brown, J. M.; Knight, F. I.; Lazzari, D.; Ricci, A. Tetrahedron 1997, 53,
11411.
31. Ketcham, R.; Jambotkar, D.; Martinelli, L. J. Org. Chem. 1962, 47, 4666.
32. A peak corresponding to C(10) was not observed in the 13C NMR spectrum of
this compound.