Iodine-mediated ring-closing iodoamination with concomitant N-debenzylation for the asymmetric synthesis of polyhydroxylated pyrrolidines

Article abstract of DOI:10.1016/j.tetasy.2009.02.014

Treatment of a range of homochiral unsaturated β-amino esters (containing a cis-dioxolane unit) with iodine promotes a novel ring-closing alkene iodoamination reaction which proceeds with concomitant N-debenzylation, providing a simple and stereoselective

Full text of DOI:10.1016/j.tetasy.2009.02.014

Tetrahedron: Asymmetry 20 (2009) 758–772
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Iodine-mediated ring-closing iodoamination with concomitant
N-debenzylation for the asymmetric synthesis of polyhydroxylated pyrrolidines
*
Stephen G. Davies , Rebecca L. Nicholson, Paul D. Price, Paul M. Roberts, Angela J. Russell, Edward D. Savory,
Andrew D. Smith, James E. Thomson
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 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:
Treatment of a range of homochiral unsaturated b-amino esters (containing a cis-dioxolane unit) with
iodine promotes a novel ring-closing alkene iodoamination reaction which proceeds with concomitant
N-debenzylation, providing a simple and stereoselective route to iodomethyl pyrrolidines. Functional
group interconversion of the resulting iodomethyl pyrrolidines upon treatment with AgOAc proceeds
via the corresponding aziridinium ion, with subsequent deprotection giving access to polyhydroxylated
pyrrolidines.
Received 27 January 2009
Accepted 10 February 2009
Available online 3 April 2009
This paper is dedicated to Professor George
Fleet, on the occasion of his 65th birthday
Ó 2009 Elsevier Ltd. All rights reserved.
Pyrrolidine
Piperidine
1. Introduction
OH
OH
OH
H
N
H
N
Polyhydroxylated nitrogen-containing heterocycles have re-
ceived enormous attention as glycosidase inhibitors.1 These
multifunctional compounds bear a structural resemblance to car-
bohydrates, and can be divided into a range of families, including
the polyhydroxylated pyrrolidines such as 1, piperidines such as
1-deoxynojirimycin 2, indolizidines such as castanospermine 3
and pyrrolizidines such as alexine 4 (Fig. 1). As a result of their di-
verse biological activities and their potent glycosidase inhibitory
effects, a range of methodologies for their synthesis have been
developed, including manipulation of carbohydrates,2 synthesis
HO
OH
OH
HO
OH
1
1-deoxynojirimycin 2
Indolizidine
Pyrrolizidine
OH
a
-amino acids3 and asymmetric synthesis.4
OH
OH
from
The conjugate addition of homochiral lithium amides to
N
a,b-
N
OH
unsaturated esters and amides has been widely used in this and
in other laboratories for the asymmetric synthesis of b-amino acid
derivatives.5 We recently demonstrated the doubly diastereoselec-
tive conjugate addition of homochiral lithium amides to homochi-
H
HO
OH
H
HO
OH
castanospermine 3
alexine 4
ral a,b-unsaturated esters containing cis- and trans-dioxolane units
for the asymmetric synthesis of polyoxygenated b-amino esters,6
and delineate herein the utility of the b-amino ester products from
this protocol for the asymmetric synthesis of polyhydroxylated
pyrrolidines. It was envisaged that the b-amino ester products of
conjugate addition 5 would act as suitable precursors for a novel,
stereoselective iodine-mediated ring-closing alkene iodoamina-
tion7 with concomitant N-debenzylation protocol that would allow
access to iodomethyl pyrrolidines 6. Functional group manipula-
tion and deprotection were anticipated to facilitate the asymmetric
Figure 1. Representative polyhydroxylated nitrogen-containing heterocycles 1–4.
synthesis of polyhydroxylated pyrrolidines 7 (Fig. 2). We report
herein our full investigations within this area, part of which has
been communicated previously.8
2. Results and discussion
2.1. Development of a ring-closing iodoamination reaction
Initial studies of the proposed ring-closing iodoamination reac-
* Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
tion focused upon the cyclisation of homochiral b-amino ester 8.6
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.014

S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
759
trans-relationship the signal appears between 10.1 and 11.4 ppm,
irrespective of their configuration at C(5). For example, the 13C
NMR signal corresponding to the iodomethyl carbon of the minor
diastereoisomer 10 (cis-relationship between iodomethyl group
and the neighbouring acetonide group) appears at 2.4 ppm, while
the corresponding 13C NMR signal of the major diastereoisomer 9
(trans-relationship between iodomethyl group and the neighbour-
ing acetonide group) appears at 11.4 ppm (Fig. 3).
Ph
Ph
t
I
CO2 Bu
alkene
iodoamination
Ph
N
N
t
CO2Bu
5
6
O
O
O
O
functionalisation
and
deprotection
Ph
Ph
I
OH
CO 2H
H
t
N 1
I
CO2 Bu
2
5
N
R
N
*
3
4
7
O
O
HO
OH
δ
C = 11.4 ppm
9
O
O
Figure 2. Proposed synthetic route to polyhydroxylated pyrrolidines 7.
trans
C(2)-C(3)-
-configured
iodomethyl pyrrolidines
* 10.1 ppm ≤ δC ≤ 11.4 ppm
Treatment of 8 with iodine (1 equiv) and NaHCO3 in MeCN gave
64% conversion to an 81:19:1 mixture of N-benzyl iodomethyl pyr-
Ph
rolidines 9 and 10, respectively (along with racemic
zyl acetamide 11), in which ring closure to the pyrrolidine and
chemoselective removal of the -methylbenzyl group had been ef-
fected in a single reaction step. Use of 3 equiv of iodine proved
optimal, giving quantitative conversion to an 81:19 mixture of N-
benzyl iodomethyl pyrrolidines 9:10. Chromatography allowed
separation, giving the major 2,5-cis-diastereoisomer 9 in 63% yield,
and the minor 2,5-trans-diastereoisomer 10 in 17% yield, in >98%
a-methylben-
I
N1
Ph
2
5
R
t
*
I
CO2 Bu
a
N
3
4
O
O
δ
C = 2.4 ppm
10
O
O
C(2)-C(3)-cis-configured
iodomethyl pyrrolidines
* 1.9 ppm ≤ δC ≤ 3.2 ppm
de in both cases, and essentially racemic a-methylbenzyl acetam-
ide 11 {½a 2D5
ꢀ
¼ ꢁ3:8 (c 0.7 in CHCl3); lit.9 for (R)-11 ½a D19
¼ þ129:5
ꢀ
Figure 3. Diagnostic 13C NMR chemical shifts for 2-iodomethyl-3,4-O-isopropyli-
(c 1.0 in CHCl3)} in 72% yield (Scheme 1).
dene-pyrrolidines.
The relative configuration within the major diastereoisomeric
iodomethyl pyrrolidine 9 could not be identified unambiguously
using 1H NMR spectroscopic analysis; it was subsequently deter-
mined by single-crystal X-ray analysis of a derivative (vide infra).10
However, consistent with the observations of Yoshida et al. in re-
lated systems,11 the 13C NMR chemical shift of the iodomethyl car-
bon of the pyrrolidines described herein is diagnostic of their
relative configuration. When the iodomethyl group and the neigh-
bouring acetonide group have a cis-relationship, the 13C NMR sig-
nal corresponding to the iodomethyl carbon appears between 1.9
and 3.2 ppm, while for those in which the two groups have a
This iodoamination protocol shows remarkable chemoselectiv-
ity, with the selective removal of the N-a-methylbenzyl group in
the presence of the N-benzyl group being entirely complementary
to the previously reported chemoselective N-debenzylations under
oxidative12 or hydrogenative13 conditions that have been devel-
oped within this laboratory. The isolation of essentially racemic
a
-methylbenzyl acetamide 11 from this reaction protocol is consis-
tent with a mechanism involving initial formation of iodonium ion
12 followed by intramolecular trapping by the tertiary amine to
give quaternary ammonium species 13. The preponderance of the
5-exo cyclisation pathway leading to the corresponding pyrrolidine
products rather than a 6-endo cyclisation pathway leading to the
corresponding piperidine products is to be expected on stereoelec-
Ph
tronic grounds.14 Preferential SN1 loss of the N-
protecting group from 13 gives iodomethyl pyrrolidines 9 and
10. Trapping of the -methylbenzyl cation 14 by MeCN and inter-
a
-methylbenzyl-
Ph
O
N
CO2tBu
a
O
8, >98% de
ception by water in a Ritter reaction lead to (RS)-
a-methylbenzyl
acetamide 11 (Fig. 4).
(i)
Assuming that there is a geometrical requirement for the nitro-
gen atom to attack anti to the iodonium ion (i.e., in an SN2-type
process), the stereoselective formation of iodomethyl pyrrolidine
9 from this reaction protocol may be due to either (i) stereoselec-
tive, irreversible formation of one diastereoisomer of iodonium ion
12 followed by ring closure and N-debenzylation; or (ii) reversible
formation of iodonium 12 followed by preferential cyclisation of
one of the diastereoisomers of 12 to the corresponding diastereo-
isomer of the ammonium ion 13 and subsequent N-debenzylation.
In order to probe this hypothesis, the effect of changing the reac-
tion solvent to one of lower polarity was investigated. Reaction
in PhMe, THF or CHCl3 gave >90% conversion to iodomethyl
pyrrolidines 9 and 10, but proceeded with a noticeable decrease
in stereoselectivity as compared to the reaction in MeCN
9:10
81:19
Ph
Ph
I
CO2tBu
I
CO2tBu
N
N
O
+
+
Ph
N
H
O
O
O
O
(RS)-11
9, 63%
10, 17%
>98% de
>98% de
72%
Scheme 1. Reagents and conditions: (i) I2 (3 equiv), NaHCO3, MeCN, ꢁ20 °C, 2 h,
then rt, 20 h.

760
S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
Ph
Ph
Ph
Ph
I
t
CO2 Bu
Ph
N
N
Ph
N
I2
t
t
CO2 Bu
CO2 Bu
12
O
O
8, >98% de
8
O
O
O
O
(i)
ring
closure
Ph
Ph
t
I
CO2 Bu
I
CO2tBu
Ph
Ph
O
Ph
I
N
N
t
t
I
CO2 Bu
CO2 Bu
MeCN
+
N
N
SN1
9
10
+
Ph
14
O
O
O
O
13
O
O
O
+H2O
(Ritter
reaction)
Solvent
MeCN
PhMe
THF
Conversion %
Ratio 9:10
81:19
iodomethyl
pyrrolidines
9 and 10
100
100
100
93
56:44
56:44
44:56
O
CHCl3
Ph
N
H
Scheme 2. Reagents and conditions: (i) I2 (3 equiv), NaHCO3, solvent, ꢁ20 °C, 2 h,
racemic
then rt, 20 h.
α-methylbenzyl acetamide
(RS)-11
Figure 4. Proposed mechanism of iodoamination of 8 with concomitant, chemo-
selective N-debenzylation.
2.2. Substrate scope of the ring-closing iodoamination reaction
Analogues of b-amino ester 8 containing substituted N-benzyl-
protecting groups with electron-donating groups on the arene ring
were prepared in order to probe their effect upon the stereo- and
chemoselectivity of the iodoamination/N-debenzylation protocol.
Doubly diastereoselective ‘matched’6,15 conjugate addition of
(Scheme 2). These results are consistent with a rapid equilibration
of the two diastereoisomeric iodonium ions 12 in the polar solvent
MeCN, followed by rate determining cyclisation of one of the dia-
stereoisomeric iodonium ions 12 to the corresponding ammonium
ion 13, and subsequent N-debenzylation.
With an efficient procedure for ring-closing iodoamination and
concomitant N-debenzylation of b-amino ester 8 established, sub-
sequent studies focused on probing the substrate scope of this
reaction, in order to gain further mechanistic insights and to gen-
erate a range of iodomethyl pyrrolidines for subsequent elabora-
tion into the corresponding polyhydroxylated derivatives.
homochiral lithium (R)-N-benzyl-N-(
zyl)amide 15 and lithium (R)-N-(4-methoxybenzyl)-N-(
benzyl)amide 16 to homochiral
,b-unsaturated ester 176 both
a-methyl-4-methoxyben-
a-methyl-
a
proceeded with high stereoselectivity (>98% de and 92% de, respec-
tively) to furnish the corresponding b-amino esters 18 and 19,
which were isolated as single diastereoisomers (>98% de), in 41%
and 47% yields after purification. The product of c-deprotonation
20 was also isolated in 5% yield in each case6 (Scheme 3).
Ph
t
CO2 Bu
PMP
O
N
t
+
CO2Bu
Ph
O
O
20, 5%
18, 41%
>98% de
O
N
Li
MeO
(i)
15
t
CO2 Bu
OMe
O
O
17
PMP
(ii)
Ph
N
Li
16
t
CO2 Bu
Ph
O
N
t
+
CO2Bu
O
O
20, 5%
19, 47%
>98% de
O
Scheme 3. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(
methylbenzyl)amide 16, THF, ꢁ78 °C, 2 h [PMP = 4-methoxyphenyl].
a-methyl-4-methoxybenzyl)amide 15, THF, ꢁ78 °C, 2 h; (ii) lithium (R)-N-(4-methoxybenzyl)-N-(a-

S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
Ph Ph
761
Ph
t
t
I
CO2 Bu
I
CO2Bu
N
PMP
O
N
N
(i)
t
CO2 Bu
+
9:10
89:11
O
O
O
O
O
18, >98% de
9, 51%, >98% de
10
PMP
CO2Bu
PMP
PMP
t
t
CO2 Bu
I
I
Ph
N
N
N
(i)
t
+
CO2 Bu
21:22
80:20
O
O
O
O
O
O
19, >98% de
21, 52%, >98% de
22
Scheme 4. Reagents and conditions: (i) I2 (3 equiv), NaHCO3, MeCN, ꢁ20 °C, 2 h, then rt, 20 h.
Treatment of b-amino esters 18 and 19 with iodine in MeCN
Ph
promoted iodoamination and concomitant N-debenzylation in
both cases, giving an 89:11 and 80:20 mixture of iodomethyl pyr-
rolidine diastereoisomers 9:10 and 21:22, respectively (>90% crude
yield in both cases), with chromatographic purification giving the
major diastereoisomers 9 and 21 in 51% and 52% yields, and
>98% de in both cases (Scheme 4). The relative configuration within
21 was inferred by a combination of 1H NMR NOE and 13C NMR
chemical shift analyses. These results suggest that the incorpora-
tion of electron donor groups has a slight impact on the stereose-
lectivity of the reaction, but has no effect upon the
chemoselectivity of the N-debenzylation protocol, with SN1 loss
of the more bulky a-methylbenzyl substituent (vs the benzyl sub-
stituent) from the sterically congested nitrogen atom being pre-
ferred in both cases.
The iodine-promoted cyclisation of all diastereoisomers of b-
amino ester 5 resulting from variation of the C(3) and N-a-meth-
Ph
N
t
CO2 Bu
O
O
23, >98% de
(i)
9:10
27:73
Ph
Ph
t
t
I
CO2 Bu
I
CO2 Bu
N
N
+
9, 9%
>98% de
10, 28%
>98% de
O
O
O
O
ylbenzyl stereocentres was next investigated in order to deter-
mine the effect of the configuration of these stereocentres
upon the stereoselectivity of the iodoamination reaction. Treat-
Scheme 5. Reagents and conditions: (i) I2 (3 equiv), NaHCO3, MeCN, ꢁ20 °C, 2 h,
then rt, 20 h.
ment of b-amino ester (3S,
ceeded to give a 27:73 mixture of iodomethyl pyrrolidines 9
and 10, respectively, along with racemic -methylbenzyl acetam-
ide 11. While the same three products are obtained as for the
cyclisation of b-amino ester (3S, R)-8, in this case the 2,5-trans
a
S)-23,6 with iodine in MeCN pro-
Treatment of the (3R)-configured b-amino esters (3R,
(3R,
R)-256 with iodine in MeCN furnished a single diastereoiso-
meric iodomethyl pyrrolidine 2,5-cis-26 (and (RS)- -methylbenzyl
acetamide 11) in both cases. The results from cyclisation of 24 and
25 indicate that the configuration of the -methylbenzyl stereo-
a
S)-246 or
a
a
a
a
a
iodomethyl pyrrolidine 10 was the major diastereoisomer. This
centre has no effect on the stereoselectivity of the iodocyclisation
reaction, and are in direct contrast to the results obtained from
cyclisation of the (3S)-configured b-amino esters 8 and 23 (vide su-
pra). Iodomethyl pyrrolidine 26 was isolated in 65% yield from 24
and in 70% yield from 25 after chromatography (Scheme 6). The
configuration within 26 was assigned by a combination of 1H
suggests that with a (3S)-configuration within the b-amino ester
framework, the configuration of the
a-methylbenzyl stereocentre
has a major impact on the stereoselectivity of the ring-closing
reaction. Chromatography allowed the isolation of 9 in 9% yield,
10 in 28% yield, and (RS)-
a
-methylbenzyl acetamide 11 in 59%
yield (Scheme 5).
Ph
Ph
Ph
t
I
CO2Bu
Ph
N
N
Ph
N
(i)
(i)
>98% de
t
t
CO2 Bu
CO2 Bu
>98% de
O
O
O
O
O
O
24, >98% de
26, >98% de
65% from 24
70% from 25
25, >98% de
Scheme 6. Reagents and conditions: (i) I2 (3 equiv), NaHCO3, MeCN, ꢁ20 °C, 2 h, then rt, 20 h.

762
S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
NMR NOE and 13C NMR chemical shift analyses, with dC 1.9 ppm
for the iodomethyl carbon consistent with this group lying on
the same face of the pyrrolidine ring as the acetonide group.
t
CO2 Bu
O
O
Ph
The formation of iodomethyl pyrrolidine 26 as
a single
diastereoisomer from the cyclisation of either b-amino ester 24
or 25 may be rationalised by the reaction occurring through the fa-
voured ‘chair-boat’16 transition state 27. In this low-energy confor-
17
Ph
N
Li
(i)
28
mation the ester, iodonium ion and N-
all able to occupy pseudoequatorial positions around the forming
pyrrolidine ring. Steric interactions with the -methylbenzyl group
a-methylbenzyl groups are
Ph
a
are presumably unimportant contributors to the overall energy of
the transition states for cyclisation of 24 and 25, since the config-
uration of the N-a-methylbenzyl group exerts no influence on the
outcome of the cyclisation. This is consistent with the formation of
iodomethyl pyrrolidine 26 with high stereoselectivity from both
epimeric b-amino esters 24 and 25 (Fig. 5). However, with a config-
Ph
N
N
S
t
CO2 Bu
O2
O
(−)-CSO
O
O
OH
29, 61%
>98% de
urational change at C(3), the all-equatorial disposition of the
a-
methylbenzyl, ester and iodonium ion groups is no longer possible.
Several alternative, higher energy transition states may therefore
be available, the relative energies of which may depend upon min-
Scheme 7. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(
zyl)amide 28, THF, ꢁ78 °C, 2 h, then (ꢁ)-CSO, THF, ꢁ78 °C to rt, 12 h.
a-methylben-
imisation of steric interactions with the
abling the configuration of the -methylbenzyl stereocentre to
exert an influence on the stereochemical course of the reaction.
Thus, cyclisation of b-amino esters (3S, R)-8 and (3S, S)-23 give
opposite outcomes, producing 2,5-cis-9 and 2,5-trans-10 as the
major diastereoisomers, respectively.
a-methylbenzyl group, en-
a
pylidene stereocentres (Fig. 6). The stereochemical outcome of this
aminohydroxylation reaction is consistent with the established
anti-selectivity of the conjugate addition/enolate oxidation
protocol.17
a
a
Ph
H
tBuO2C
Ph
N
I2
t
CO2 Bu
R*
N
O
I
O
O
O
Ph
(αS)-24 or (αR)-25
27
R* = (S)- or (R)-α-methylbenzyl
Ph
t
I
CO2 Bu
N
O
O
26
Figure 5. Postulated transition state 27 for the ring-closing iodoamination with
concomitant N-debenzylation of b-amino esters 24 and 25 to iodomethyl pyrrol-
idine 26.
Figure 6. Chem 3D representation of the X-ray crystal structure of 29 (some H
atoms omitted for clarity).
The effect of incorporation of an a-hydroxyl substituent within
the b-amino ester scaffold upon the stereoselectivity of the iodo-
amination and N-debenzylation protocol was next investigated.
Treatment of anti-a-hydroxy-b-amino ester 29 with iodine in
anti-
addition of lithium (R)-N-benzyl-N-(
,b-unsaturated ester 17, followed by oxidation of the resultant
a-Hydroxy-b-amino ester 29 was prepared by the conjugate
MeCN promoted iodoamination and concomitant N-debenzylation,
furnishing 2,5-trans-iodomethyl pyrrolidine 33 as a single diaste-
reoisomer in 42% isolated yield. The configuration within 33 was
assigned by a combination of 1H NMR NOE and 13C NMR chemical
shift analyses, with the chemical shift of dC 3.2 ppm for the iodo-
methyl carbon being consistent with this group lying on the same
face of the pyrrolidine ring as the acetonide group. This result dem-
a-methylbenzyl)amide 28 to
a
b-amino enolate with (ꢁ)-camphorsulfonyloxaziridine [(ꢁ)-
CSO],17 giving 29 in >98% de and in 61% isolated yield and >98%
de after column chromatography (Scheme 7). The relative configu-
ration within anti-
unambiguously by single-crystal X-ray analysis. The absolute
(2R,3S,4S,5R, R)-configuration within 29 was assigned from the
known configurations of the N- -methylbenzyl and 4,5-O-isopro-
a-hydroxy-b-amino ester 29 was established
onstrates that the incorporation of the
a-hydroxyl functionality
a
has a marked effect upon the product distribution of the reaction:
iodoamination of the parent b-amino ester 8 gives preferentially
a

S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
763
Ph
Ph
I
OH
Ph
N
N
(ii)
t
CO2 Bu
CO2tBu
O
O
O
O
OH
29
33, >98% de
42% from 29
94% from 31
(i)
(iii)
Ph
Ph
Ph
I
OAc
N
I
OAc
CO2tBu
N
Ph
N
(ii)
t
CO2 Bu
+
CO2tBu
31:32
70:30
O
O
OAc
O
O
O
O
30, 94%
>98% de
31, 28%
>98% de
32, 9%
>98% de
Scheme 8. Reagents and conditions: (i) Ac2O, DMAP, pyridine, DCM, rt; (ii) I2, NaHCO3, MeCN, ꢁ20 °C, 2 h, then rt, 20 h; (iii) K2CO3, MeOH, rt.
Ph
Ph
BF4
t
t
I
CO2 Bu
CO2Bu
2,5-cis-iodomethyl pyrrolidine 9 with modest selectivity (81:19),
whereas iodoamination of -hydroxy-substituted b-amino ester
N
N
(i)
a
29 gives 2,5-trans-iodomethyl pyrrolidine 33 exclusively. Although
the reasons for this change in stereoselectivity are unclear, it is
possible that the presence of the a-oxygen atom may alter the pre-
O
O
O
O
ferred conformation of the molecule in the transition state leading
to cyclisation, possibly through formation of a hydrogen bond.18 In
9, >98% de
34, quant, >98% de
order to investigate this hypothesis, anti-
29 was treated with Ac2O, DMAP and pyridine to give
amino ester 30 in 94% yield. Treatment of -acetoxy-b-amino ester
30 with iodine in MeCN proceeded to give a 70:30 mixture of iodo-
methyl pyrrolidines 2,5-trans-31 and 2,5-cis-32, suggesting that
a
-hydroxy-b-amino ester
a-acetoxy-b-
(iii)
(ii)
a
Ph
t
OAc
CO2 Bu
N
the inability of the
nor within 30 may have a deleterious effect on the diastereoselec-
tivity of the cyclisation reaction when compared to the parent
a-acetoxy group to act as a hydrogen bond do-
a
-
O
O
hydroxyl system 29. Chromatographic purification of the crude
reaction mixture gave the major 2,5-trans-diastereoisomer 31 in
28% yield, and the minor 2,5-cis-diastereoisomer 32 in 9% yield,
as single diastereoisomers (>98% de) in each case, along with
35, >98% de
79% from 9
70% from 34
(RS)-a-methylbenzyl acetamide 11 in 52% yield. The configuration
of the major diastereoisomeric iodomethyl pyrrolidine 31 was pro-
ven by chemical correlation, with deprotection of 31 with K2CO3 in
MeOH furnishing 33 in 94% yield (Scheme 8).
Scheme 9. Reagents and conditions: (i) AgBF4, DCM, rt; (ii) NaOAc, PhMe, rt; (iii)
AgOAc, PhMe, rt.
2.3. Asymmetric synthesis of polyhydroxylated pyrrolidines
Treatment of the diastereoisomeric iodomethyl pyrrolidine 10
with AgBF4 gave aziridinium 36 in quantitative yield, which upon
treatment with NaOAc in toluene gave a 45:55 mixture of the
inseparable pyrrolidine and piperidine acetates 37 and 38, respec-
tively, in 62% isolated yield, indicating that the ring opening of azi-
ridine 36 does not proceed in a regioselective manner. This
transformation could also be achieved in one pot upon treatment
of iodomethyl pyrrolidine 10 with AgOAc, which gave an insepara-
ble 45:55 mixture of the pyrrolidine and piperidine acetates 37 and
38, respectively, in 82% combined yield (Scheme 10).
AgOAc-promoted iodide displacement of iodomethyl pyrroli-
dine 26 also furnished a mixture of the corresponding pyrrolidine
and piperidine products 39 and 40 as an 89:11 mixture, respec-
tively, with chromatographic purification furnishing pyrrolidine
acetate 39 in 88% yield and piperidine acetate 40 in 10% yield
Elaboration of iodomethyl pyrrolidine scaffolds 9, 10 and 26 to
polyhydroxylated pyrrolidines, via functional group manipulation
and deprotection, was next investigated. It was envisaged that
replacement of the iodide for a hydroxyl functionality could be
achieved via the intermediacy of the corresponding aziridinium
ion.19 Iodomethyl pyrrolidine 9 (>98% de) was treated with AgBF4,
giving the isolable aziridinium 34 in quantitative yield. Subsequent
ring opening of 34 upon treatment with NaOAc in toluene pro-
ceeded with complete regioselectivity to give pyrrolidine acetate
35 as a single diastereoisomer in 70% yield. The possibility of
achieving this transformation in one pot was next examined by
treatment of 9 with AgOAc in toluene, which gave the correspond-
ing pyrrolidine acetate 35 as a single diastereoisomer in 79% yield
after purification (Scheme 9).

764
S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
was investigated. N-Debenzylation of 35 followed by methanolysis
Ph
O
Ph
BF4
t
t
CO2 Bu
of the acetate gave pyrrolidine 42 in good yield and as a single dia-
stereoisomer. The relative configuration within 42 was established
unambiguously by single-crystal X-ray analysis, with the absolute
(2R,3R,4S,5S)-configuration being assigned from the known stereo-
I
CO2 Bu
N
N
(i)
O
centres of the 3,4-O-isopropylidene moiety, derived from D-ri-
O
O
bose.10 This analysis also allowed the assigned relative
configuration within iodomethyl pyrroldine 9 to be unambigu-
ously confirmed. Subsequent acidic hydrolysis of 42 followed by
ion-exchange chromatography gave the b-amino acid derived,
polyhydroxylated pyrroldine 43 in 78% yield as a single diastereo-
isomer (Scheme 12). Similarly, N-debenzylation of 39 followed by
methanolysis gave 45 in excellent yield and as a single diastereo-
isomer, with subsequent acidic hydrolysis and ion-exchange chro-
matography giving polyhydroxylated pyrrolidine 46 in 47% yield as
a single diastereoisomer (Scheme 13).
10, >98% de
36, quant, >98% de
(iii)
(ii)
Ph
Ph
t
CO2 Bu
t
OAc
CO2 Bu
N
N
+
AcO
O
O
O
O
Ph
t
37
38
OAc
CO2Bu
t
H
N
OAc
CO2 Bu
37:38 45:55
N
(i)
82% combined yield from 10
62% combined yield from 36
O
O
O
Scheme 10. Reagents and conditions: (i) AgBF4, DCM, rt; (ii) NaOAc, PhMe, rt; (iii)
O
AgOAc, PhMe, rt.
44, 99%
>98% de
39, >98% de
Ph
Ph
Ph
t
(ii)
CO2 Bu
t
t
I
CO2 Bu
OAc
CO2Bu
N
t
N
N
OH
CO2Bu
(i)
H
N
OH
CO2H
H
N
+
(iii)
39:40
89:11
AcO
O
O
O
O
O
O
O
O
OH
HO
26, >98% de
39, 88%, >98% de
40, 10%, >98% de
46, 47%
>98% de
45, 94%
>98% de
Scheme 11. Reagents and conditions: (i) AgOAc, PhMe, rt.
Scheme 13. Reagents and conditions: (i) Pd(OH)2/C, H2 (1 atm), MeOH; (ii) K2CO3,
MeOH; (iii) TFA, then Dowex 50WX8-200.
(Scheme 11). This product distribution is consistent with an azirid-
inium ion intermediate being involved in this reaction.
With homogenous pyrrolidine acetates 35 and 39 in hand,
deprotection to the corresponding polyhydroxylated pyrrolidines
3. Conclusion
In conclusion, treatment of a range of homochiral, unsaturated
b-amino esters (containing a cis-dioxolane unit) with iodine pro-
motes a novel ring-closing iodoamination with N-debenzylation
reaction that provides a simple and stereoselective route to iodo-
methyl pyrrolidines. The stereoselectivity of this iodoamination
protocol is dependent upon both the absolute configuration of
Ph
t
OAc
CO2Bu
t
H
N
OAc
CO2 Bu
N
(i)
the N-a-methylbenzyl-protecting group and upon the configura-
O
O
tion at C(3) within the b-amino ester substructure. Functional
group interconversion of the resulting iodomethyl pyrrolidines
with AgOAc proceeds via the corresponding aziridinium ion, with
subsequent deprotection giving access to b-amino acid-derived
polyhydroxylated pyrrolidines.
O
O
41, 66%
>98% de
35, >98% de
(ii)
t
OH
CO 2Bu
4. Experimental
H
N
OH
CO2H
H
N
(iii)
4.1. General experimental
O
O
All reactions involving organometallic or other moisture-sensi-
tive reagents were carried out under a nitrogen or argon atmo-
sphere using standard vacuum line techniques and glassware
that was flame dried and cooled under nitrogen before use. Sol-
vents were dried according to the procedure outlined by Grubbs
and co-workers.20 Water was purified by an ElixÒ UV-10 system.
OH
HO
43, 78%
>98% de
42, 82%
>98% de
Scheme 12. Reagents and conditions: (i) Pd(OH)2/C, H2 (1 atm), MeOH; (ii) K2CO3,
MeOH; (iii) TFA, then Dowex 50WX8-200.

S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
765
All other solvents 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.
Elemental analyses were recorded by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford, UK.
Melting points were recorded on a Gallenkamp Hot Stage appara-
tus and were uncorrected. Optical rotations were recorded on a
Perkin–Elmer 241 polarimeter with a water-jacketed 10 cm cell.
Specific rotations are reported in 10ꢁ1 deg cm2 gꢁ1 and concentra-
tions in g/100 mL. IR spectra were recorded on 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 cmꢁ1. NMR spectra were recorded on Bruker Avance spectrom-
eters in the deuterated solvent stated. The field was locked by
external referencing to the relevant deuteron resonance. Low-res-
olution mass spectra were recorded on either a VG MassLab 20–
250 or a Micromass Platform 1 spectrometer. Accurate mass mea-
surements were run on either a Bruker MicroTOF internally cali-
brated with polyalanine, or a Micromass GCT instrument fitted
in MeCN (20 mL) gave a mixture containing 9, 10 and 11 (the ratio
of 9:10 was 81:19). Purification via flash column chromatography
(eluent pentane/Et2O, 11:1) gave 10 as a colourless oil (36 mg, 17%,
>98% de); Rf 0.4 (pentane/Et2O, 9:1); ½a D25
¼ þ52:8 (c 0.9 in CHCl3);
ꢀ
mmax (film) 1726 (C@O); dH (400 MHz, CDCl3) 1.37 (3H, s, MeCMe),
1.42 (9H, s, CMe3), 1.57 (3H, s, MeCMe), 2.09 (1H, dd, J 14.6, 9.9,
t
t
CHAHBCO2 Bu), 2.43 (1H, dd, J 14.6, 3.8, CHAHBCO2 Bu), 3.10–3.16
(3H, m, C(2)H, CH2I), 3.62 (1H, app dd, J 9.9, 4.1, C(5)H), 3.70 (1H,
d, J 14.6, NCHA), 3.84 (1H, d, J 14.6, NCHB), 4.56 (1H, app d, J 6.3,
C(3)H), 4.77 (1H, dd, J 6.3, 3.0, C(4)H), 7.24–7.37 (5H, m, Ph); dC
(100 MHz, CDCl3) 2.4 (CH2I), 25.3, 26.4 (CMe2), 28.1 (CMe3), 31.5
t
(CH2CO2 Bu), 51.3 (NCH2), 64.1 (C(5)), 66.9 (C(2)), 80.6 (C(3)), 81.0
(CMe3), 81.7 (C(4)), 111.6 (CMe2), 127.0 (p-Ph), 128.1, 128.4 (o-,
t
m-Ph), 139.1 (i-Ph), 171.1 (CO2 Bu); m/z (APCI+) 488 ([M+H]+,
100%), 432 (59); HRMS (ESI+) C21H31INO4 ([M+H]+) requires
þ
488.1292; found 488.1293. Further elution gave 9 as a colourless
oil (133 mg, 63%, >98% de); Rf 0.37 (pentane/Et2O, 9:1);
½
a 2D4
ꢀ
¼ þ2:1 (c 0.8 in CHCl3); mmax (film) 1727 (C@O); dH
(400 MHz, CDCl3) 1.32 (3H, s, MeCMe), 1.45 (9H, s, CMe3), 1.48
t
(3H, s, MeCMe), 2.32 (1H, dd, J 14.7, 7.9, CHAHBCO2 Bu), 2.46 (1H,
dd, J 14.7, 4.6, CHAHBCO2 Bu), 2.86–2.93 (2H, m, C(2)H, CHAHBI),
t
3.10 (1H, dd, J 9.7, 2.2, CHAHBI), 3.33–3.38 (1H, m, C(5)H), 3.84
(2H, ABq, J 14.2, NCH2), 4.39 (1H, dd, J 6.2, 3.1, C(3)H), 4.55 (1H,
dd, J 6.2, 3.9, C(4)H), 7.25–7.32 (5H, m, Ph); dC (100 MHz, CDCl3)
with
a
Scientific Glass Instruments BPX5 column (15 m ꢂ
t
0.25 mm) using amyl acetate as a lock mass.
11.4 (CH2I), 25.3, 28.1 (CMe2), 28.6 (CMe3), 40.3 (CH2CO2 Bu), 57.5
(NCH2), 67.5 (C(5)), 69.5 (C(2)), 81.2 (CMe3), 83.5 (C(4)), 85.0
(C(3)), 113.0 (CMe2), 127.8 (p-Ph), 128.8, 129.3 (o-, m-Ph), 138.7
4.2. General procedure for iodocyclisation of tertiary amines
t
(i-Ph), 171.3 (CO2 Bu); m/z (APCI+) 488 ([M+H]+, 100%), 432 (92);
HRMS (ESI+) C21H31INO4 ([M+H]+) requires 488.1292; found
þ
NaHCO3 (3.0 equiv) and I2 (3.0 equiv) were added sequentially
to a stirred solution of the requisite tertiary amine (1.0 equiv) in
MeCN at ꢁ20 °C. After stirring for 2 h, the reaction mixture was al-
lowed to warm to rt over 20 h. The reaction mixture was diluted
with Et2O, washed sequentially with satd aq Na2S2O3 and water,
dried and concentrated in vacuo.
488.1297. Further elution (eluent pentane/Et2O, 1:6) gave 11 as a
white solid (51 mg, 72%); Rf 0.21 (pentane/Et2O, 1:6); mp 82–
83 °C (pentane/Et2O); ½a D25
ꢀ
¼ ꢁ3:8 (c 0.7 in CHCl3); {lit.9 for (R)-11
½
a 1D9
ꢀ
¼ þ129:5 (c 1.0 in CHCl3)}; dH (400 MHz, CDCl3) 1.48 (3H, d, J
7.1, C(
a
)Me), 1.97 (3H, s, COMe), 5.08–5.16 (1H, m, C(
a
)H), 5.98
(1H, br s, NH), 7.24–7.36 (5H, m, Ph).
4.2.1. (2S,3R,4S,5S)- and (2R,3R,4S,5S)-N(1)-Benzyl-2-
iodomethyl-3,4-O-isopropylidene-5-(tert-
butoxycarbonylmethyl)pyrrolidine (2S,3R,4S,5S)-9 and
(2R,3R,4S,5S)-10
Ph
PMP
O
N
t
CO2 Bu
Ph
O
Ph
N
18
CO2tBu
O
O
Ph
Ph
8
t
t
I
CO2 Bu
I
CO2 Bu
N
N
O
+
+
Ph
N
H
Ph
Ph
O
O
O
O
I
CO2tBu
I
CO2tBu
N
N
O
9
10
11
+
+
Ph
N
H
O
O
O
O
From 18: Following the General Procedure, NaHCO3 (81 mg,
0.96 mmol), I2 (243 mg, 0.96 mmol) and 18 (158 mg, 0.32 mmol) in
MeCN (15 mL) gave a mixture containing 9, 10 and 11 (the ratio of
9:10 was 89:11). Purification via flash column chromatography (elu-
ent pentane/Et2O, 20:1) gave 9 as a colourless oil (79 mg, 51%, >98%
de).
9
10
11
From 8: Following the General Procedure, NaHCO3 (108 mg,
1.29 mmol), I2 (328 mg, 1.29 mmol) and 8 (200 mg, 0.430 mmol)

766
S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
less oil (159 mg, 41%, >98% de); Rf 0.11 (pentane/Et2O, 10:1);
¼ þ12:1 (c 0.9 in CHCl3); mmax (film) 1729 (C@O); 1610
(C@C); dH (400 MHz, CDCl3) 1.29 (3H, s, MeCMe), 1.35 (3H, d,
J 7.0, C( )Me), 1.42 (3H, s, MeCMe), 1.46 (9H, s, CMe3), 2.15–
2.25 (2H, m, C(2)H2), 3.69–3.77 (2H, m, NCH2), 3.77–3.82
(1H, m, C(3)H), 3.80 (3H, s, OMe), 3.89 (1H, q, J 7.0, C( )H),
4.20 (1H, app t, J 6.2, C(4)H), 4.58–4.62 (1H, m, C(5)H), 5.29–
5.32 (1H, m, C(7)HA), 5.36–5.41 (1H, m, C(7)HB), 5.94–6.01
(1H, m, C(6)H), 6.81–6.85 (2H, m, C(30)H, C(50)H), 7.21–7.34
(7H, m, C(20)H, C(60)H, Ph); dC (100 MHz, CDCl3) 19.1
Ph
½ ꢀ
a 2D5
Ph
N
a
CO2tBu
a
O
O
23
(C(a)Me), 25.1, 27.6 (CMe2), 28.1 (CMe3), 36.0 (C(2)), 50.1
(NCH2), 54.1 (C(3)), 55.2 (OMe), 58.3 (C(
a
)), 78.9 (C(4)), 79.7
(C(5)), 80.0 (CMe3), 107.9 (CMe2), 113.3 (C(30), C(50)), 119.0
(C(7)), 126.6 (p-Ph), 128.1, 128.2, 129.2 (C(20), C(60), o-, m-Ph),
134.7 (C(6)), 134.8 (i-Ph), 141.4 (C(10)), 158.6 (C(40)), 171.5
(C(1)); m/z (APCI+) 496 ([M+H]+, 21%), 362 (100), 306 (57);
Ph
Ph
I
CO2tBu
I
CO2tBu
N
N
O
+
+
HRMS (ESI+) C30H42NO5 ([M+H]+) requires 496.3057; found
þ
Ph
N
H
496.3057.
O
O
O
O
9
10
11
4.2.3. tert-Butyl (3S,4S,5R,
N-(
enoate 19
a
R)-3-[N-(40-methoxybenzyl)-
a
-methylbenzyl)amino]-4,5-O-isopropylidene-hept-6-
From 23: Following the General Procedure, NaHCO3 (26 mg,
0.30 mmol), I2 (77 mg, 0.30 mmol) and 23 (47 mg, 0.10 mmol) in
MeCN (5 mL) gave a mixture containing 9, 10 and 11 (the ratio of
9:10 was 27:73). Purification via flash column chromatography
(eluent pentane/Et2O, 12:1) gave 10 as a colourless oil (14 mg,
28%, >98% de). Further elution gave 9 as a colourless oil (5 mg,
9%, >98% de). Further elution (eluent pentane/Et2O, 1:6) gave 11
as a white solid (10 mg, 59%).
PMP
N
Ph
t
CO2 Bu
O
O
4.2.2. tert-Butyl (3S,4S,5R,aR)-3-[N-benzyl-N-(a
-methyl-40-
methoxybenzyl)amino]-4,5-O-isopropylidene-hepta-6-enoate
18
BuLi (1.6 M in hexanes, 0.76 mL, 1.22 mmol) was added
dropwise to a stirred solution of (R)-N-(40-methoxybenzyl)-N-
(a-methylbenzyl)amine (304 mg, 1.26 mmol) in THF (4 mL) at
Ph
ꢁ78 °C, and the resulting solution was stirred for 30 min. A
solution of 17 (200 mg, 0.79 mmol) in THF (4 mL) at ꢁ78 °C
was added dropwise via cannula. The reaction mixture was
stirred for 2 h before addition of satd aq NH4Cl (10 mL). The
reaction mixture was warmed to rt and concentrated in vacuo.
The residue was dissolved in DCM (10 mL) and washed
sequentially with 10% aq citric acid (10 mL), satd aq NaHCO3
(10 mL) and brine (10 mL), dried and concentrated in vacuo.
Purification via flash column chromatography (eluent pentane/
Et2O, 15:1) gave 20 as a colourless oil (11 mg, 5%, >98% de).6
PMP
O
N
t
CO2 Bu
O
BuLi (2.5 M in hexanes, 0.49 mL, 1.22 mmol) was added
dropwise to a stirred solution of (R)-N-benzyl-N-( -methyl-4-
a
Further elution gave 19 as
a colourless oil (184 mg, 47%,
>98% de); Rf 0.15 (pentane/Et2O, 10:1); ½a D25
¼ þ11:4 (c 1.25
ꢀ
methoxybenzyl)amine (304 mg, 1.26 mmol) in THF (5 mL) at
ꢁ78 °C, and the resulting solution was stirred for 30 min. A
solution of 17 (200 mg, 0.79 mmol) in THF (5 mL) at ꢁ78 °C
was added dropwise via cannula. The reaction mixture was
stirred for 2 h before addition of satd aq NH4Cl (10 mL). The
reaction mixture was warmed to rt and concentrated in vacuo.
The residue was dissolved in DCM (10 mL) and washed
sequentially with 10% aq citric acid (10 mL), satd aq NaHCO3
(10 mL) and brine (10 mL), dried and concentrated in vacuo.
Purification via flash column chromatography (eluent pentane/
Et2O, 15:1) gave 20 as a colourless oil (10 mg, 5%, >98% de);6
in CHCl3); mmax (film) 1729 (C@O), 1612 (C@C); dH (400 MHz,
CDCl3) 1.30 (3H, s, MeCMe), 1.37 (3H, d, J 7.1, C(a)Me), 1.42
(3H, s, MeCMe), 1.49 (9H, s, CMe3), 2.18 (2H, app dd, J 6.1, J
2.1 C(2)H2), 3.68 (2H, ABq, JAB 15.1, NCH2), 3.76–3.79 (1H, m,
C(3)H), 3.81 (3H, s, OMe), 3.93 (1H, q,
J 7.1, C(a)H), 4.21
(1H, app t, J 6.3, C(4)H), 4.60 (1H, app t, J 6.6, C(5)H), 5.29–
5.41 (2H, m, C(7)H2), 5.93–6.01 (1H, m, C(6)H), 6.85–6.87
(2H, m, C(30)H, C(50)H), 7.22–7.34 (7H, m, C(20)H, C(60)H, Ph);
dC (100 MHz, CDCl3) 18.7 (C(
(CMe3), 36.0 (C(2)), 49.5 (NCH2), 54.0 (C(3)), 55.2 (C(
a
)Me), 25.4, 27.5 (CMe2), 27.9
)), 58.6
a
Rf 0.26 (pentane/Et2O, 20:1); ½a D24
¼ ꢁ35:8 (c 1.15 in CHCl3);
ꢀ
(OMe), 78.8 (C(4)), 79.6 (C(5)), 80.8 (CMe3), 107.9 (CMe2),
113.5 (C(30), C(50)), 118.7 (C(7)), 127.0 (p-Ph), 128.0, 128.2,
129.3 (C(20), C(60), o-, m-Ph), 133.2 (i-Ph), 134.7 (C(6)), 142.8
(C(10)), 158.4 (C(40)), 171.5 (C(1)); m/z (APCI+) 496 ([M+H]+,
dH (400 MHz, CDCl3) 1.43 (3H, s, CMeAMeB), 1.45 (9H, s,
CMe3), 1.52 (3H, s, CMeAMeB), 2.98–3.12 (2H, m, C(2)H2), 4.32
(1H, app td, J 7.0, 1.8, C(3)H), 4.94–4.97 (1H, m, C(5)H), 5.29
(1H, dd, J 10.1, 0.4, C(7)HA), 5.38 (1H, app d, J 17.0, C(7)HB),
5.74–5.83 (1H, m, C(6)H). Further elution gave 18 as a colour-
100%); HRMS (ESI+) C30H42NO5 ([M+H]+) requires 496.3057;
þ
found 496.3066.

S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
767
4.2.4. (2S,3R,4S,5S)-N(1)-(40-Methoxybenzyl)-2-iodomethyl-3,4-
O-isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidine 21
(APCI+) 488 ([M+H]+, 100%); HRMS (ESI+) C21H31INO4 ([M+H]+) re-
quires 488.1292; found 488.1277. Further elution (eluent pentane/
Et2O, 1:6) gave 11 as a white solid (35 mg, 22%).
PMP
t
Ph
Ph
I
CO2 Bu
t
I
CO2 Bu
N
Ph
N
N
O
t
+
CO2 Bu
Ph
N
H
O
O
O
O
O
O
25
26
11
Following the General Procedure, NaHCO3 (457 mg, 5.45 mmol),
I2 (1.38 g, 5.45 mmol) and 19 (900 mg, 1.82 mmol) in MeCN
(75 mL) gave an 80:20 mixture of 21:22. Purification via flash col-
umn chromatography (eluent pentane/Et2O, 15:1) gave 21 as a col-
ourless oil (486 mg, 52%, >98% de); Rf 0.09 (pentane/Et2O, 15:1);
From 25: Following the General Procedure, NaHCO3 (22 mg,
0.26 mmol), I2 (66 mg, 0.26 mmol) and 25 (40 mg, 0.09 mmol) in
MeCN (4 mL) gave a mixture containing 11 and 26 only. Purifica-
tion via flash column chromatography (eluent pentane/Et2O,
20:1) gave 26 as a colourless oil (29 mg, 70%, >98% de). Further elu-
tion (eluent pentane/Et2O, 1:6) gave 11 as a white solid (5 mg,
36%).
½
a 2D5
ꢀ
¼ ꢁ2:9 (c 1.0 in CHCl3); mmax (film) 1727 (C@O), 1612
(C@C); dH (400 MHz, CDCl3) 1.31 (3H, s, MeCMe), 1.45 (9H, s,
t
CMe3), 1.47 (3H, s, MeCMe), 2.32 (1H, dd, J 14.7, 7.9, CHAHBCO2 Bu),
2.45 (1H, dd, J 14.7, 4.5, CHAHBCO2 Bu), 2.81–2.84 (1H, m, C(2)H),
t
2.90 (1H, dd, J 10.2, 7.5, CHAHBI), 3.09 (1H, dd, J 10.2, 2.6, CHAHBI),
3.30–3.34 (1H, m, C(5)H), 3.73 (1H, d, J 14.2, NCHA), 3.80 (1H, d, J
14.2, NCHB), 3.81 (3H, s, OMe), 4.37 (1H, dd, J 6.0, 3.3, C(3)H),
4.53 (1H, dd, J 6.0, 4.2, C(4)H), 6.83–6.86 (2H, m, C(30)H, C(50)H),
7.20–7.24 (2H, m, C(20)H, C(60)H); dC (100 MHz, CDCl3) 11.0
4.2.6. tert-Butyl (2R,3S,4S,5R,aR)-2-hydroxy-3-[N-benzyl-N-(a-
methylbenzyl)amino]-4,5-O-isopropylidene-hept-6-enoate 29
t
(CH2I), 25.6, 27.6 (CMe2), 28.1 (CMe3), 39.8 (CH2CO2 Bu), 55.2
(OMe), 56.2 (NCH2), 66.7 (C(5)), 68.7 (C(2)), 80.7 (CMe3), 83.0
Ph
(C(4)), 84.5 (C(3)), 112.5 (CMe2), 113.7 (C(30), C(50)), 130.0 (C(20),
t
C(60)), 130.1 (C(10)), 158.9 (C(40)), 170.6 (CO2 Bu); m/z (APCI+) 518
Ph
N
([M+H]+, 100%); HRMS (ESI+) C22H33INO5 ([M+H]+) requires
t
þ
CO2Bu
518.1398; found 518.1403.
O
O
OH
4.2.5. (2R,3R,4S,5R)-N(1)-Benzyl-2-iodomethyl-3,4-O-
isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidine 26
BuLi (2.5 M in hexanes, 9.2 mL, 23.0 mmol) was added drop-
wise to stirred solution of (R)-N-benzyl-N-( -methylben-
a
a
Ph
Ph
zyl)amine (4.98 g, 23.6 mmol) in THF (30 mL) at ꢁ78 °C. After
30 min, a solution of 17 (3.0 g, 11.8 mmol) in THF (30 mL) was
added via cannula. After stirring for 2 h, the reaction mixture
was quenched with (ꢁ)-CSO (5.27 g, 23.0 mmol), followed after
12 h by satd aq NH4Cl (10 mL). The mixture was extracted with
Et2O (3 ꢂ 50 mL), and the combined organic extracts were con-
centrated in vacuo. The residue was dissolved in DCM (50 mL)
and washed sequentially with 10% aq citric acid (50 mL) and satd
aq NaHCO3 (50 mL), dried and concentrated in vacuo. The resi-
due was dissolved in Et2O (50 mL), the insoluble CSO residues
were filtered off, and the filter cake was washed with Et2O
(2 ꢂ 20 mL). The filtrate was concentrated in vacuo and the pro-
cess was repeated. Purification via flash column chromatography
(eluent pentane/Et2O, 20:1) gave 29 as a colourless oil (3.44 g,
61%, >98% de); Rf 0.23 (pentane/Et2O, 8:1); mp 79–81 °C (pen-
t
I
CO2 Bu
Ph
N
N
O
t
+
CO2 Bu
Ph
N
H
O
O
O
O
24
26
11
From 24: Following the General Procedure, NaHCO3 (243 mg,
2.89 mmol), I2 (734 mg, 2.89 mmol) and 24 (448 mg, 0.96 mmol)
in MeCN (40 mL) gave a mixture containing 11 and 26 only. Puri-
fication via flash column chromatography (eluent pentane/Et2O,
20:1) gave 26 as a colourless oil (305 mg, 65%, >98% de); Rf 0.26
(pentane/Et2O, 10:1); ½a D25
ꢀ
¼ þ4:5 (c 0.4 in CHCl3); mmax (film)
tane/Et2O); ½a 2D4
¼ þ20:7 (c 0.8 in CHCl3); mmax (film) 3502 (br,
ꢀ
1727 (C@O); dH (400 MHz, CDCl3) 1.36 (3H, s, MeCMe), 1.43 (9H,
OꢁH), 1731 (C@O); dH (400 MHz, CDCl3) 1.26 (3H, s, MeCMe),
t-
s, CMe3), 1.53 (3H, s, MeCMe), 2.40 (1H, dd, J 16.6, 4.2, CHAHBCO2
Bu), 2.70 (1H, dd, J 16.6, 9.3, CHAHBCO2 Bu), 2.75–2.79 (1H, m,
1.36–1.38 (6H, m, MeCMe, C(a)Me), 1.54 (9H, s, CMe3), 3.01
t
(1H, d, J 7.2, OH), 3.77 (1H, d, J 16.2, NCHA), 3.83 (1H, app d, J
C(2)H), 2.89–2.93 (1H, m, C(5)H), 3.02 (1H, dd, J 9.1, 3.6, CHAHBI),
3.16 (1H, dd, J 11.0, 9.1, CHAHBI), 3.62 (1H, d, J 16.0, NCHA), 3.78
(1H, d, J 16.0, NCHB), 4.65–4.72 (2H, m, C(3)H, C(4)H), 6.83–6.86
(5H, m, Ph); dC (100 MHz, CDCl3) 1.9 (CH2I), 25.6, 26.2 (CMe2),
7.2, C(2)H), 3.88 (1H, app d, J 9.9, C(3)H), 3.93 (1H, q, J 7.1,
C(
NCHB), 4.60–4.63 (1H, m, C(5)H), 5.28 (1H, dd,
C(7)HA), 5.41–5.45 (1H, m, C(7)HB), 5.86–5.94 (1H, m, C(6)H),
7.25–7.42 (10H, m, Ph); dC (100 MHz, CDCl3) 20.4 (C( )Me),
25.5 (MeCMe), 28.1 (CMe3), 28.2 (MeCMe), 50.9 (NCH2), 57.3
(C(3)), 58.8 (C( )), 71.0 (C(2)), 75.6 (C(4)), 79.1 (C(5)), 82.0
a)H), 4.40 (1H, dd, J 9.8, J 5.4, C(4)H), 4.84 (1H, d, J 16.2,
J
10.3, 0.8,
t
28.1 (CMe3), 34.5 (CH2CO2 Bu), 55.0 (NCH2), 65.0 (C(5)), 70.4
a
(C(2)), 78.4, 79.3 (C(3), C(4)), 80.7 (CMe3), 111.2 (CMe2), 127.1 (p-
t
Ph), 128.0, 128.4 (o-, m-Ph), 135.8 (i-Ph), 171.3 (CO2 Bu); m/z
a

768
S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
(CMe3), 107.6 (CMe2), 118.9 (C(7)), 126.6, 127.4 (p-Ph), 127.7,
128.1, 128.4, 128.7 (o-, m-Ph), 135.0 (C(6)), 141.2, 141.7 (i-Ph),
172.9 (C(1)); m/z (APCI+) 482 ([M+H]+, 88%), 426 (47), 105
128.2, 128.4, 128.5 (o-, m-Ph), 134.9 (C(6)), 141.2, 141.3 (i-Ph),
167.2, 169.8 (C(1), COMe); m/z (ESI+) 546 ([M+Na]+, 53%), 524
(100).
(100); HRMS (ESI+) C29H40NO5 ([M+H]+) requires 482.2901;
þ
found 482.2919.
4.2.9. tert-Butyl (2R,20R,30R,40S,50R)- and (2R,20S,30R,40S,50R)-2-
acetoxy-2-(N(10)-benzyl-20-iodomethyl-30,40-O-isopropylidene-
pyrrolidin-50-yl)acetate (2R,20R,30R,40S,50R)-31 and
(2R,20S,30R,40S,50R)-32
4.2.7. X-ray crystal structure determination for 29
Data were collected using an Enraf-Nonius
j-CCD diffractome-
Ph
ter with graphite-monochromated Mo K radiation using standard
a
procedures at 190 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealised
positions. The structure was refined using CRYSTALS.21
Ph
N
CO2tBu
OAc
O
O
X-ray crystal structure data for 29 [C29H39NO5]: M = 481.63,
orthorhombic,
space
group
P212121,
a = 11.6031(2) Å,
= 0.078
b = 12.8707(2) Å, c = 18.6428(3) Å, V = 2784.1 Å3, Z = 4,
l
30
mmꢁ1, colourless plate, crystal dimensions = 0.4 ꢂ 0.6 ꢂ 0.8 mm3.
A total of 3554 unique reflections were measured for 5 < h < 27,
and 2797 reflections were used in the refinement. The final param-
eters were wR2 = 0.041 and R1 = 0.038 [I > 3r(I)].
Ph
Ph
Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC 693429. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223–336033 or e-mail:
deposit@ccdc.cam.ac.uk].
I
OAc
CO2tBu
I
OAc
CO2tBu
N
N
O
+
+
Ph
N
H
O
O
O
O
31
32
11
4.2.8. tert-Butyl (2R,3R,4S,5R,
N-(
enoate 30
a
R)-2-acetoxy-3-[N-benzyl-
a
-methylbenzyl)amino]-4,5-O-isopropylidene-hepta-6-
Following the General Procedure, NaHCO3 (94 mg, 1.12 mmol), I2
(284 mg, 1.12 mmol) and 30 (195 mg, 0.37 mmol) in MeCN (20 mL)
gave a mixture containing 11, 31 and 32 (the ratio of 31:32 was
70:30). Purification via exhaustive flash column chromatography
(eluent pentane/Et2O, 8:1) gave 31 as a white solid (57 mg, 28%,
>98% de), 32 as a colourless oil (19 mg, 9%, >98% de) and 11 as a
white solid (32 mg, 52%).
Ph
N
Ph
t
CO2Bu
Data for 31: Rf 0.28 (pentane/Et2O, 6:1); mp 82–84 °C (pen-
a 2D4
ꢀ
¼ þ66:6 (c 0.9 in CHCl3); mmax (KBr) 1748
O
O
OAc
tane/Et2O);
½
(C@O), 1738 (C@O); dH (400 MHz, CDCl3) 1.35 (12H, s, CMe3,
MeCMe), 1.55 (3H, s, MeCMe), 2.18 (3H, s, COMe), 3.16–3.18
(2H, m, CH2I), 3.43–3.48 (1H, m, C(2)H), 3.60–3.64 (2H, m,
C(5)H, NCHA), 3.97 (1H, d, J 14.8, NCHB), 4.66 (1H, app d, J 6.1,
Pyridine (0.05 mL, 0.62 mmol), DMAP (cat.) and Ac2O (0.2 mL,
2.10 mmol) were added sequentially to a stirred solution of 29
(200 mg, 0.42 mmol) in DCM (4 mL). The resultant solution was
stirred for 15 h, diluted with Et2O (4 mL), washed sequentially with
10% aq CuSO4 (2 ꢂ 10 mL) and brine (2 ꢂ 10 mL), dried and con-
centrated in vacuo. Purification via flash column chromatography
(eluent pentane/Et2O, 5:1) gave 30 as a white solid (309 mg, 94%,
>98% de); Rf 0.15 (pentane/Et2O, 5:1); C31H41NO6 requires C,
71.1; H, 7.9; N, 2.7. Found: C, 70.9; H, 8.0; N, 2.7; mp 93–95 °C
C(4)H), 4.84 (1H, app t,
CHCO2 Bu), 7.23–7.37 (5H, m, Ph); dC (100 MHz, CDCl3) 2.8
(CH2I), 21.2 (COMe), 25.2, 26.4 (CMe2), 27.8 (CMe3), 51.0
J 5.7, C(3)H), 5.26 (1H, d, J 1.8,
t
t
(NCH2), 66.4 (C(5)), 68.6 (C(2)), 70.1 (CHCO2 Bu), 78.8 (C(4)),
81.0 (CMe3), 82.9 (C(3)), 111.5 (CMe2), 127.2 (p-Ph), 128.0,
t
128.5 (o-, m-Ph), 138.2 (i-Ph), 167.5, 169.5 (COMe, CO2 Bu); m/z
(ESI+) 546 (100%, [M+H]+); HRMS (ESI+) C23H33INO6 ([M+H]+)
þ
requires 546.1347; found 546.1356.
(pentane/Et2O); ½a D27
¼ þ37:9 (c 1.0 in CHCl3); mmax (KBr) 1761
ꢀ
Data for 32: Rf 0.12 (pentane/Et2O, 6:1); ½a D21
¼ ꢁ10:4 (c 0.65
ꢀ
(C@O), 1748 (C@O), 1601 (C@C); dH (400 MHz, CDCl3) 1.27 (3H, s,
in CHCl3); mmax (film) 1746 (C@O); dH (400 MHz, CDCl3) 1.29 (3H,
s, MeCMe), 1.42 (3H, s, MeCMe), 1.47 (9H, s, CMe3), 2.18 (3H, s,
COMe), 2.91–2.96 (2H, m, C(2)H, CHAHBI), 3.07–3.12 (1H, m,
CHAHBI), 3.51 (1H, dd, J 3.8, 2.3, C(5)H), 3.88 (2H, ABq, J 14.1,
NCH2), 4.36 (1H, dd, J 6.0, 2.6, C(3)H), 4.68 (1H, dd, J 6.0, 3.8,
MeCMe), 1.34 (3H, d, J 6.9, C(
(9H, s, CMe3), 2.09 (3H, s, COMe), 3.63 (1H, d, J 15.7, NCHA), 3.93
(1H, q, J 6.9, C( )H), 3.98 (1H, app d, J 9.4, C(3)H), 4.15 (1H, d, J
a)Me), 1.38 (3H, s, MeCMe), 1.46
a
15.7, NCHB), 4.43 (1H, dd, J 9.8, 5.4, C(4)H), 4.57–4.61 (1H, m,
C(5)H), 5.15 (1H, app s, C(2)H), 5.23–5.26 (1H, m, C(7)HA), 5.43
(1H, app d, J 17.1, C(7)HB), 5.87–5.95 (1H, m, C(6)H), 7.26–7.37
(10H, m, Ph); dC (100 MHz, CDCl3) 20.3 (C(
25.3 (MeCMe), 28.0 (CMe3), 28.2 (MeCMe), 50.5 (NCH2), 56.4
(C(3)), 59.8 (C( )), 71.0 (C(2)), 75.4 (C(4)), 79.0 (C(5)), 81.6
(CMe3), 107.7 (CMe2), 119.1 (C(7)), 126.8, 127.6 (p-Ph), 127.5,
t
C(4)H), 4.98 (1H, d, J 2.3, CHCO2 Bu), 7.27–7.35 (5H, m, Ph); dC
(100 MHz, CDCl3) 10.1 (CH2I), 21.0 (COMe), 25.6, 27.6 (CMe2),
28.0 (CMe3), 56.5 (NCH2), 68.2 (C(2)), 69.8 (C(5)), 71.4
a)Me), 21.0 (COMe),
t
(CHCO2 Bu), 78.9 (CMe3), 82.7 (C(4)), 84.3 (C(3)), 112.5 (CMe2),
a
127.9 (p-Ph), 128.4, 129.1 (o-, m-Ph), 137.0 (i-Ph), 167.1, 170.0
t
(COMe, CO2 Bu); m/z (ESI+) 546 ([M+H]+, 100%,), 450 (75), 418

S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
769
(65); HRMS (ESI+) C23H33INO6 ([M+H]+) requires 546.1347;
found 546.1342.
AgBF4 (30 mg, 0.16 mmol) was added to a solution of 9 (63 mg,
0.13 mmol) in DCM (5 mL). The resultant solution was stirred for
2 h, filtered through Celite (eluent DCM) and concentrated in va-
cuo to give 34 as a colourless oil (59 mg, quant, >98% de);
þ
4.2.10. tert-Butyl (2R,20R,30R,40S,50S)-2-hydroxy-2-(N(10)-benzyl-
20-iodomethyl-30,40-O-isopropylidene-pyrrolidin-50-yl)acetate 33
½
a 2D6
ꢀ
¼ ꢁ15:1 (c 1.6 in CHCl3); mmax (film) 1731 (C@O), 1634
(C@C); dH (400 MHz, CDCl3) 0.97 (3H, s, MeCMe), 1.19 (3H, s,
t-
MeCMe), 1.45 (9H, s, CMe3), 2.75 (1H, dd, J 16.5, 8.3, CHAHBCO2
Bu), 3.04 (1H, dd, J 16.5, 5.8, CHAHBCO2 Bu), 3.31 (1H, dd, J 6.5,
Ph
Ph
t
I
OH
5.1, C(6)HA), 3.63 (1H, dd, J 8.4, 5.1, C(6)HB), 3.98–4.02 (1H, m,
C(2)H), 4.17 (1H, d, J 14.3, NCHAHBPh), 4.32 (1H, app dd, J 8.5,
6.9, C(5)H), 4.55 (1H, dd, J 5.7, 4.4, C(3)H), 4.80 (1H, d, J 14.3,
NCHAHBPh), 5.00 (1H, app d, J 5.9, C(4)H), 7.46–7.59 (5H, m, Ph);
Ph
N
N
t
CO2 Bu
CO2tBu
O
O
O
O
OH
t-
dC (100 MHz, CDCl3) 24.6, 26.4 (CMe2), 27.9 (CMe3), 34.7 (CH2CO2
Bu), 40.1 (C(6)), 55.5 (C(5)), 60.5 (NCH2Ph), 66.5 (C(2)), 78.6 (C(4)),
82.8 (CMe3), 84.2 (C(3)), 114.5 (CMe2), 129.0, 129.4, 130.5, 131.6
29
33
t
(Ph), 167.9 (CO2 Bu); m/z (ESI+) 360 ([MꢁBF4]+, 100%), 304 (56);
HRMS (ESI+) C21H30NO4 ([MꢁBF4]+) requires 360.2169; found
þ
From 29: Following the General Procedure, NaHCO3 (103 mg,
1.23 mmol), I2 (312 mg, 1.23 mmol) and 29 (200 mg, 0.41 mmol)
in MeCN (20 mL) gave 33 in >98% de. Purification via flash column
chromatography (eluent pentane/Et2O, 12:1) gave 33 as a colour-
less oil (88 mg, 42%, >98% de); Rf 0.17 (pentane/Et2O, 8:1);
360.2175.
4.2.12. (2R,3R,4S,5S)-N(1)-Benzyl-2-acetoxymethyl-3,4-O-
isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidine 35
½
a 2D2
ꢀ
¼ þ66:8 (c 1.2 in CHCl3); mmax (film) 3482 (OꢁH), 1723
Ph
Ph
(C@O); dH (500 MHz, CDCl3) 1.39 (3H, s, MeCMe), 1.44 (9H, s,
CMe3), 1.60 (3H, s, MeCMe), 2.97 (1H, d, J 3.0, OH), 3.18–3.20 (2H,
m, CH2I), 3.59 (1H, app s, C(5)H), 3.76–3.80 (1H, m, C(2)H), 3.89
(1H, d, J 14.8, NCHA), 4.07 (1H, d, J 14.8, NCHB), 4.42 (1H, d, J 6.1,
t
t
I
CO2 Bu
OAc
CO2 Bu
N
N
t
C(4)H), 4.40–4.47 (1H, m, CHCO2 Bu), 4.82 (1H, app t, J 5.6,
C(3)H), 7.19–7.39 (5H, m, Ph); dC (125 MHz, CDCl3) 3.2 (CH2I),
25.2, 26.5 (CMe2), 27.8 (CMe3), 51.3 (NCH2), 68.2 (C(2)), 68.4
O
O
O
O
t
9
35
(CHCO2 Bu), 69.0 (C(5)), 79.0 (C(4)), 81.2 (C(3)), 83.5 (CMe3),
111.1 (CMe2), 127.0 (p-Ph), 127.8, 128.4 (o-, m-Ph), 139.2 (i-Ph),
From 9: AgOAc (154 mg, 0.92 mmol) was added to a stirred
solution of 9 (300 mg, 0.62 mmol) in PhMe (25 mL) at rt. After
stirring for 2 h, the reaction mixture was filtered through Celite
(eluent EtOAc) and concentrated in vacuo to give 35 in >98% de.
Purification via flash column chromatography (eluent pentane/
Et2O, 4:1) gave 35 as a colourless oil (203 mg, 79%, >98% de); Rf
t
173.4 (CO2 Bu); m/z (APCI+) 504 ([M+H]+, 35%), 448 (100); HRMS
(ESI+) C21H31INO5 ([M+H]+) requires 504.1241; found 504.1256.
þ
Ph
O
Ph
I
OAc
CO2 Bu
I
OH
0.14 (pentane/Et2O, 4:1); ½a D26
ꢀ
¼ þ10:3 (c 0.6 in CHCl3);
mmax (film)
N
N
t
t
CO2Bu
1741 (C@O), 1732 (C@O); dH (400 MHz, CDCl3) 1.30 (3H, s,
MeCMe), 1.44 (9H, s, CMe3), 1.47 (3H, s, MeCMe), 2.01 (3H, s,
t
COMe), 2.28 (1H, dd, J 14.7, 8.0, CHAHBCO2 Bu), 2.44 (1H, dd, J
O
O
O
t
14.7, 4.4, CHAHBCO2 Bu), 3.11–3.15 (1H, m, C(2)H), 3.28–3.32
(1H, m, C(5)H), 3.86–3.96 (4H, m, CH2OAc, NCH2), 4.45 (1H, dd, J
6.3, 3.4, C(3)H), 4.55 (1H, dd, J 6.3, 3.6, C(4)H), 7.22–7.34 (5H,
m, Ph); dC (100 MHz, CDCl3) 20.8 (COMe), 25.5, 27.6 (CMe2), 28.0
31
33
t
From 31: K2CO3 (7.6 mg, 0.055 mmol) was added to a stirred
solution of 31 (30.0 mg, 0.055 mmol) in MeOH (2 mL). After stir-
ring for 2 h, satd aq NH4Cl (5 mL) was added, and the mixture
was extracted with EtOAc (3 ꢂ 5 mL). The combined organic layers
were dried and concentrated in vacuo. Purification via flash col-
umn chromatography (eluent pentane/Et2O, 12:1) gave 33 as a col-
ourless oil (26 mg, 94%, >98% de).
(CMe3), 39.7 (CH2CO2 Bu), 57.5 (NCH2), 64.7 (CH2OAc), 66.7
(C(5)), 67.6 (C(2)), 80.6 (CMe3), 81.9 (C(3)), 83.7 (C(4)), 112.4
(CMe2), 127.1 (p-Ph), 128.2, 128.7 (o-, m-Ph), 138.5 (i-Ph), 170.5,
t
170.7 (COMe, CO2 Bu); m/z (APCI+) 420 ([M+H]+, 82%), 364 (100);
HRMS (ESI+) C23H34NO6 ([M+H]+) requires 420.2381; found
þ
420.2390.
Ph
Ph
O
4.2.11. (1S,2S,3S,4R,5R)-N(1)-Benzyl-2-(tert-butoxycarbonyl-
methyl)-3,4-O-isopropylidene-1-azoniabicyclo[3.1.0]hexane
tetrafluoroborate 34
BF4
t
t
CO2 Bu
OAc
CO2 Bu
N
N
Ph
O
O
BF4
O
t
CO2 Bu
N
34
35
From 34: NaOAc (16 mg, 0.2 mmol) was added to a stirred solu-
tion of 34 (58 mg, 0.13 mmol) in PhMe (2 mL), and the resultant
suspension was stirred for 2 h. The solid residue was filtered off,
O
O

770
S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
and the filtrate was concentrated in vacuo to give 35 in >98% de.
Purification via flash column chromatography (eluent pentane/
Et2O, 4:1) gave 35 as a colourless oil (38 mg, 70%, >98% de).
app d, J 6.3, C(4)H), 4.72 (1H, dd, J 6.2, 5.3, C(3)H), 7.20–7.34 (5H,
obsc m, Ph); dC (100 MHz, CDCl3) 21.0 (COMe), 25.3, 26.4 (CMe2),
28.0 (CMe3), 31.2 (CH2CO2 Bu), 51.2 (NCH2), 62.7 (C(2), C(5)), 63.2
t
(CH2OAc), 80.0 (CMe3), 80.8 (C(3)), 82.5 (C(4)), 109.9 (CMe2),
126.9 (p-Ph), 127.8, 128.3 (o-, m-Ph), 138.7 (i-Ph), 170.2, 171.2
(COMe, CO2 Bu).
t
4.2.13. (1R,2S,3S,4R,5S)-N(1)-Benzyl-2-(tert-butoxycarbonyl-
methyl)-3,4-O-isopropylidene-1-azoniabicyclo[3.1.0]hexane
tetrafluoroborate 36
Data for 38: dH (400 MHz, CDCl3) 1.37 (3H, s, MeCMe), 1.45 (9H,
s, CMe3), 1.60 (3H, s, MeCMe), 2.04 (3H, s, COMe), 2.36–2.44 (2H, m,
t
t
C(6)HA, CHAHBCO2 Bu), 2.65–2.70 (2H, m, C(6)HB, CHAHBCO2 Bu),
2.95 (1H, app td, J 8.4, 3.8, C(2)H), 3.22 (1H, d, J 13.0, NCHA), 3.96
(1H, obsc d, NCHB), 4.06 (1H, dd, J 8.5, 4.6, C(3)H), 4.47 (1H, app
t, J 4.4, C(4)H), 5.01–5.06 (1H, m, C(5)H), 7.20–7.34 (5H, m, obsc
Ph); dC (100 MHz, CDCl3) 21.1 (COMe), 25.5, 26.4 (CMe2), 28.0
Ph
BF4
t
CO2 Bu
N
t
(CMe3), 37.2 (CH2CO2 Bu), 49.1 (C(6)), 56.4 (NCH2), 60.6 (C(2)),
67.7 (C(5)), 72.9 (C(4)), 77.3 (C(3)), 81.9 (CMe3), 111.8 (CMe2),
127.1 (p-Ph), 128.4, 128.5 (o-, m-Ph), 138.9 (i-Ph), 170.8, 171.3
(COMe, CO2 Bu).
O
O
t
AgBF4 (22 mg, 0.11 mmol) was added to a solution of 10 (46 mg,
0.09 mmol) in DCM (5 mL). The resultant solution was stirred for
2 h, filtered through Celite (eluent DCM) and concentrated in vacuo
Ph
Ph
Ph
t
BF4
CO2 Bu
t
t
CO2Bu
OAc
CO2Bu
to give 36 as a colourless oil (42 mg, quant, >98% de); ½a D22
ꢀ
¼ ꢁ8:4
N
N
N
(c 1.4 in CHCl3); mmax (film) 1724 (C@O), 1634 (C@C); dH (400 MHz,
+
CDCl3) 1.30 (3H, s, MeCMe), 1.47 (3H, s, MeCMe), 1.51 (9H, s, CMe3),
AcO
t
O
3.05 (1H, dd, J 7.9, J 4.2, CHAHBCO2 Bu), 3.11 (1H, dd, J 18.6, 3.9,
O
O
O
O
t
O
C(6)HA), 3.20 (1H, dd, J 6.5, 4.2, CHAHBCO2 Bu), 3.39 (1H, dd, J
18.6, 6.2, C(6)HB), 3.74–3.80 (1H, m, C(2)H), 4.35 (1H, d, J 12.1,
NCHAHBPh), 4.65 (1H, app t, J 4.6, C(5)H), 4.84–4.89 (2H, m,
C(4)H, NCHAHBPh), 5.47 (1H, app t, J 5.6, C(3)H), 7.44–7.50 (5H,
m, Ph); dC (100 MHz, CDCl3) 24.1, 25.9 (CMe2), 27.9 (CMe3), 35.0
36
37
38
t
From 36: NaOAc (16 mg, 0.2 mmol) was added to a stirred solu-
tion of 36 (42 mg, 0.09 mmol) in PhMe (3 mL), and the resultant
suspension was stirred for 2 h. The solid residue was filtered off,
and the filtrate was concentrated in vacuo to give a 45:55 mixture
of 37:38. Purification via flash column chromatography (eluent
pentane/Et2O, 4:1) gave a 45:55 mixture of 37:38 as a colourless
oil (24 mg, 62%).
(C(6)), 39.9 (CH2CO2 Bu), 53.7 (C(2)), 56.8 (NCH2Ph), 71.0 (C(5)),
77.3 (CMe3), 83.5 (C(3)), 86.4 (C(4)), 114.4 (CMe2), 127.4, 129.7,
t
130.8, 131.8 (Ph), 169.6 (CO2 Bu); m/z (ESI+) 360 ([MꢁBF4]+,
100%), 304 (12); HRMS (ESI+) C21H30NO4 ([MꢁBF4]+) requires
þ
360.2169; found 360.2182.
4.2.14. (2S,3R,4S,5S)-N(1)-Benzyl-2-acetoxymethyl-3,4-O-
isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidine 37
and (2S,3S,4R,5R)-N(1)-benzyl-2-(tert-butoxycarbonylmethyl)-
3,4-O-isopropylidene-5-acetoxy-piperidine 38
4.2.15. (2S,3R,4S,5R)-N(1)-Benzyl-2-acetoxymethyl-3,4-O-
isopropylidene-5-(tert-butoxycarbonylmethyl)pyrrolidine 39
and (2R,3S,4R,5R)-N(1)-benzyl-2-(tert-butoxycarbonylmethyl)-
3,4-O-isopropylidene-5-acetoxy-piperidine 40
Ph
Ph
Ph
CO2tBu
t
t
Ph
I
CO2 Bu
OAc
CO2 Bu
Ph
t
CO2 Bu
N
t
N
N
OAc
CO2 Bu
N
N
+
+
AcO
O
O
O
O
O
AcO
O
O
O
O
O
10
37
38
39
40
From 10: AgOAc (21 mg, 0.13 mmol) was added to a stirred
solution of 10 (41 mg, 0.08 mmol) in PhMe (5 mL) at rt. After stir-
ring for 2 h, the reaction mixture was filtered through Celite (elu-
ent EtOAc) and concentrated in vacuo to give a 45:55 mixture of
37:38. Purification via flash column chromatography (eluent pen-
tane/Et2O, 4:1) gave a 45:55 mixture of 37:38 as a colourless oil
(29 mg, 82%); Rf 0.1 (pentane/Et2O, 4:1); mmax (film) 1732 (br,
AgOAc (115 mg, 0.69 mmol) was added to a stirred solution of
26 (223 mg, 0.46 mmol) in PhMe (10 mL) at rt. After stirring for
2 h, the reaction mixture was filtered through Celite (eluent EtOAc)
and concentrated in vacuo to give an 89:11 mixture of 39:40. Puri-
fication via flash column chromatography (eluent pentane/Et2O,
5:1) gave a 39 as a white solid (169 mg, 88%, >98% de); Rf 0.18
(pentane/Et2O, 4:1); C23H33NO6 requires C, 65.85; H, 7.9; N, 3.3.
Found: C, 65.75; H, 7.9; N, 3.4; mp 60–61 °C (pentane/Et2O);
C@O); m/z (APCI+) 420 ([M+H]+, 100%); HRMS (ESI+) C23H34NO6
þ
([M+H]+) requires 420.2381; found 420.2392.
½
a 2D5
ꢀ
¼ þ10:1 (c 0.5 in CHCl3); mmax (film) 1733 (C@O), 1726
Data for 37: dH (400 MHz, CDCl3) 1.33 (3H, s, MeCMe), 1.40 (9H,
s, CMe3), 1.55 (3H, s, MeCMe), 2.03 (3H, s, COMe), 2.01–2.06 (1H, m,
(C@O), 1602 (C@C); dH (400 MHz, CDCl3) 1.33 (3H, s, MeCMe),
t
t
CHAHBCO2 Bu), 2.42–2.48 (1H, m, CHAHBCO2 Bu), 3.03 (1H, app q, J
5.4, C(2)H), 3.45–3.51 (1H, m, C(5)H), 3.66 (1H, d, 14.3,
1.43 (9H, s, CMe3), 1.52 (3H, s, MeCMe), 2.00 (3H, s, COMe), 2.42
t
J
(1H, dd, J 16.4, 3.9, CHAHBCO2 Bu), 2.63–2.71 (2H, m, C(2)H,
t
NCHAHBPh), 3.96 (1H, obsc d, NCHAHBPh), 4.19 (1H, dd, J 11.4,
5.4, CHAHBOAc), 4.31 (1H, dd, J 11.4, 5.8, CHAHBOAc), 4.56 (1H,
CHAHBCO2 Bu), 2.82–2.87 (1H, m, C(5)H), 3.77 (2H, app s, NCH2),
4.17 (1H, dd, J 11.1, 7.4, CHAHBOAc), 4.25 (1H, dd, J 11.1, 4.8,

S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
771
CHAHBOAc), 4.61 (1H, dd, J 6.5, 4.9, C(3)H), 4.69 (1H, dd, J 6.5, 4.9,
C(4)H), 7.21–7.31 (5H, m, Ph); dC (100 MHz, CDCl3) 21.0 (COMe),
25.6, 26.2 (CMe2), 28.1 (CMe3), 34.2 (CH2CO2 Bu), 54.9 (NCH2),
K2CO3 (55 mg, 0.4 mmol) was added to a stirred solution of 41
(130 mg, 0.4 mmol) in MeOH (12 mL). After stirring for 2 h, satd
aq NH4Cl (12 mL) was added. The mixture was extracted with
EtOAc (2 ꢂ 15 mL), and the combined organic layers were dried
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent CHCl3/MeOH/Et3N, 80:1:1) gave 42 as a white
crystalline solid (94 mg, 82%, >98% de); mp 55–60 °C (CHCl3/
t
62.5 (CH2OAc), 64.3 (C(5)), 66.0 (C(2)), 78.8 (C(3)), 79.2 (C(4)),
80.4 (CMe3), 111.4 (CMe2), 126.9 (p-Ph), 128.1, 128.2 (o-, m-Ph),
t
138.6 (i-Ph), 170.8, 171.4 (COMe, CO2 Bu); m/z (ESI+) 442
([M+Na]+, 80%), 420 (89), 364 (100); HRMS (ESI+) C23H34NO6
þ
([M+H]+) requires 420.2381; found 420.2387. Further elution gave
MeOH); ½a 2D2
¼ ꢁ37:2 (c 1.6 in CHCl3); mmax (KBr) 3444 (OꢁH),
ꢀ
40 as a colourless oil (21 mg, 10%, >98% de); Rf 0.11 (pentane/
3130 (NꢁH), 1721 (C@O); dH (400 MHz, CDCl3) 1.30 (3H, s,
MeCMe), 1.44 (9H, s, CMe3), 1.50 (3H, s, MeCMe), 2.43 (1H, dd, J
Et2O, 4:1); ½a 2D4
¼ ꢁ11:1 (c 0.7 in CHCl3); mmax (film) 1733 (C@O);
ꢀ
t
t
dH (400 MHz, CDCl3) 1.36 (3H, s, MeCMe), 1.46 (9H, s, CMe3), 1.59
(3H, s, MeCMe), 2.08 (3H, s, COMe), 2.40 (1H, dd, J 12.3, 3.9,
16.3, 9.6, CHAHBCO2 Bu), 2.66 (1H, dd, J 16.3, 4.5, CHAHBCO2 Bu),
3.41–3.47 (3H, m, C(2)H, OH, NH), 3.49–3.55 (1H, m, C(5)H), 3.60
(1H, app dd, J 11.4, 4.8, CHAHBOH), 3.69 (1H, app dd, J 11.4, 4.1,
CHAHBOH), 4.26 (1H, app t, J 6.4, C(4)H), 4.52 (1H, dd, J 6.7,
C(3)H); dC (100 MHz, CDCl3) 25.2, 27.3 (CMe2), 28.1 (CMe3), 39.5
t
C(6)HA), 2.65 (1H, dd, J 16.3, 5.6, CHAHBCO2 Bu), 2.75 (1H, dd, J
t
16.3, 7.6, CHAHBCO2 Bu), 2.91 (1H, dd, J 12.3, 8.3, C(6)HB), 3.29–
3.33 (1H, m, C(2)H), 3.57 (1H, d, J 14.0, NCHAHBPh), 3.85 (1H, d, J
14.0, NCHAHBPh), 4.41–4.46 (2H, m, C(3)H, C(4)H), 4.95–4.99 (1H,
m, C(5)H), 7.22–7.35 (5H, m, Ph); dC (100 MHz, CDCl3) 21.3 (COMe),
t
(CH2CO2 Bu), 60.7 (C(5)), 62.1 (CH2OH), 64.6 (C(2)), 81.2 (CMe3),
81.6 (C(3)), 84.0 (C(4)), 113.5 (CMe2), 171.1 (CO2 Bu); m/z (APCI+)
t
t
288 ([M+H]+, 35%), 232 (100); HRMS (ESI+) C14H26NO5 ([M+H]+)
þ
24.8, 26.2 (CMe2), 28.1 (CMe3), 36.1 (CH2CO2 Bu), 46.9 (C(6)), 56.0
(C(2)), 57.7 (NCH2Ph), 66.9 (C(5)), 71.9, 75.0 (C(3), C(4)), 80.7
(CMe3), 109.4 (CMe2), 127.1 (p-Ph), 128.1, 128.6 (o-, m-Ph), 138.9
requires 288.1805; found 288.1812.
t
(i-Ph), 170.5, 171.6 (COMe, CO2 Bu); m/z (ESI+) 442 ([M+Na]+,
20%), 420 (100); HRMS (ESI+) C23H34NO6 ([M+H]+) requires
þ
4.2.18. (20R,30R,40S,50S)-(20-Hydroxymethyl-30,40-dihydroxy-
pyrrolidin-50-yl)ethanoic acid 43
420.2381; found 420.2374.
4.2.16. (2R,3R,4S,5S)-2-Acetoxymethyl-3,4-O-isopropylidene-5-
(tert-butoxycarbonylmethyl)pyrrolidine 41
OH
CO2H
H
N
t
OAc
CO2Bu
H
N
HO
OH
Compound 42 (130 mg, 0.45 mmol) was dissolved in TFA (5 mL).
The resultant solution stirred for 3 h, diluted with H2O (3.3 mL),
stirred for a further 1 h and concentrated in vacuo. Ion-exchange
chromatography (DOWEX 50WX8-200, eluent 1 M aq NH4OH)
gave 43 as a white solid (67 mg, 78%, >98% de); mp 166–167 °C
O
O
Compound 35 (370 mg, 0.88 mmol) was dissolved in MeOH
(15 mL), and the resultant solution was degassed. Pd(OH)2/C
(120 mg) was added and the mixture was placed under H2
(1 atm). After stirring for 15 h, the reaction mixture was filtered
through Celite (eluent MeOH) and concentrated in vacuo. Purifica-
tion via flash column chromatography (eluent pentane/Et2O, 2:1;
containing 2% Et3N) gave 41 as a colourless oil (191 mg, 66%,
(H2O); ½a 2D4
¼ þ20:3 (c 0.9 in H2O); mmax (KBr) 3370–2337 (O–H,
ꢀ
N–H), 1651 (N–H bend), 1560 (CO2ꢁ); dH (500 MHz, D2O) 2.51
(1H, dd, J 17.2, 6.9, CHAHBCO2H), 2.63 (1H, dd, J 17.2, 4.9,
CHAHBCO2H), 3.55–3.57 (1H, m, C(20)H), 3.66–3.74 (2H, m, C(50)H,
CHAHBOH), 3.80–3.83 (1H, m, CHAHBOH), 3.97–3.99 (1H, m,
C(40)H), 4.11–4.14 (1H, m, C(30)H); dC (125 MHz, D2O) 35.3
(CH2CO2H), 58.5 (CH2OH), 60.2 (C(50)), 64.3 (C(20)), 70.4 (C(30)),
73.1 (C(40)), 177.8 (CO2H); m/z (ESI+) 192 ([M+H]+, 100%); HRMS
>98% de); Rf 0.2 (pentane/Et2O, 1:1); ½a D24
¼ ꢁ19:2 (c 1.0 in CHCl3);
ꢀ
mmax (film) 3355 (N–H), 1743 (C@O), 1729 (C@O); dH (400 MHz,
CDCl3) 1.32 (3H, s, MeCMe), 1.45 (9H, s, CMe3), 1.51 (3H, s, MeCMe),
(ESI+) C7H14NO5 ([M+H]+) requires 192.0866; found 192.0880.
þ
t
2.08 (3H, s, COMe), 2.38 (1H, dd, J 16.4, 9.1, CHAHBCO2 Bu), 2.66
4.2.19. (2S,3R,4S,5R)-2-Acetoxymethyl-3,4-O-isopropylidene-5-
(tert-butoxycarbonylmethyl)pyrrolidine 44
t
(1H, dd, J 16.4, 4.1, CHAHBCO2 Bu), 3.38–3.44 (2H, m, C(2)H,
C(5)H), 4.02 (1H, dd, J 11.4, 7.1, C(3)H), 4.21–4.27 (2H, m, C(4)H,
CHAHBOAc), 4.35 (1H, dd, J 6.8, 4.4, CHAHBOAc); dC (100 MHz,
CDCl3) 21.3 (COMe), 25.8, 27.8 (CMe2), 28.5 (CMe3), 40.1
t
OAc
CO2 Bu
H
N
t
(CH2CO2 Bu), 60.9 (C(5)), 62.7 (C(2)), 66.5 (CH2OAc), 81.4 (CMe3),
t
82.2 (C(4)), 84.4 (C(3)), 114.4 (CMe2), 171.3, 171.7 (COMe, CO2 Bu);
m/z (CI+) 330 ([M+H]+, 100%), 274 (42); HRMS (CI+) C16H28NO6
þ
([M+H]+) requires 330.1911; found 330.1914.
O
O
4.2.17. (2R,3R,4S,5S)-2-Hydroxymethyl-3,4-O-isopropylidene-5-
(tert-butoxycarbonylmethyl)pyrrolidine 42
Compound 39 (32 mg, 0.08 mmol) was dissolved in MeOH
(5 mL), and the resultant solution was degassed. Pd(OH)2/C
(15 mg) was added and the mixture was placed under H2
(1 atm). After stirring for 15 h, the reaction mixture was filtered
through Celite (eluent MeOH) and concentrated in vacuo to give
t
OH
CO2 Bu
H
N
44 as a colourless oil (25 mg, 99%, >98% de); ½a D25
¼ þ4:0 (c 1.0 in
ꢀ
O
O
CHCl3); mmax (film) 3439 (N–H), 1732 (C@O); dH (400 MHz, CDCl3)
1.28 (3H, s, MeCMe), 1.43 (3H, s, MeCMe), 1.44 (9H, s, CMe3), 2.06

772
S. G. Davies et al. / Tetrahedron: Asymmetry 20 (2009) 758–772
t
(3H, s, COMe), 2.10 (1H, br s, NH), 2.53–2.64 (2H, m, CH2CO2 Bu),
3.03–3.08 (1H, m, C(2)H), 3.10–3.14 (1H, m, C(5)H), 4.17 (1H, dd,
J 11.4, 7.6, CHAHBOAc), 4.33 (1H, dd, J 11.4, 5.3, CHAHBOAc), 4.57–
4.61 (2H, m, C(3)H, C(4)H); dC (100 MHz, CDCl3) 21.0 (COMe),
References
1. Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645.
2. For selected examples, see: Fleet, G. W. J.; Son, J. C. Tetrahedron 1988, 44, 2637;
Esposito, A.; Falorni, M.; Taddei, M. Tetrahedron Lett. 1998, 39, 6543;
Momotake, A.; Mito, J.; Yamaguchi, K.; Togo, H.; Yokoyama, M. J. Org. Chem.
1998, 63, 7207; Baxter, E. W.; Reitz, A. B. J. Org. Chem. 1994, 59, 3175.
3. For selected examples, see: Burley, I.; Hewson, A. T. Tetrahedron Lett. 1994, 35,
7099; Huang, Y.; Dalton, D. R.; Carroll, P. J. J. Org. Chem. 1997, 62, 372;
Lombardo, M.; Licciulli, S.; Trombini, C. Tetrahedron Lett. 2003, 44, 9147; Razavi,
H.; Polt, R. Tetrahedron Lett. 1998, 39, 3371.
t
24.3, 25.7 (CMe2), 28.1 (CMe3), 34.9 (CH2CO2 Bu), 58.1 (C(5)), 60.3
(C(2)), 63.5 (CH2OAc), 80.5, 81.3 (C(3), C(4)), 80.7 (CMe3), 111.4
t
(CMe2), 170.9, 171.6 (COMe, CO2 Bu); m/z (ESI+) 352 ([M+Na]+,
20%), 330 (100), 274 (30); HRMS (ESI+) C16H28NO6 ([M+H]+) re-
þ
quires 330.1911; found 330.1916.
4. For selected examples, see: Donohoe, T. J.; Headley, C. E.; Cousins, R. P. C.;
Cowley, A. Org. Lett. 2003, 5, 999; O’Neil, I. A.; Cleator, E.; Hone, N.; Southern, J.
M.; Tapolczay, D. Synlett 2000, 1408; Hulme, A. N.; Montgomery, C. H.;
Henderson, D. K. J. Chem. Soc., Perkin Trans. 1 2000, 1837.
4.2.20. (2S,3R,4S,5R)-2-Hydroxymethyl-3,4-O-isopropylidene-5-
(tert-butoxycarbonylmethyl)pyrrolidine 45
5. For a review, see: Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry
2005, 16, 2833.
6. Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly, P. M.; Kurosawa, W.; Lee, J. A.;
Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A. D.
Org. Biomol. Chem. 2009, 7, 761.
t
OH
CO2 Bu
H
N
7. For reviews, see: Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321; French, A.
N.; Bissmire, S.; Wirth, T. Chem. Soc. Rev. 2004, 33, 354.
8. Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Smith, A. D. Synlett
2004, 901.
O
O
9. Kahara, T.; Hashimoto, Y.; Saigo, K. Tetrahedron 1999, 55, 6453.
10. Crystallographic data (excluding structure factors) has been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication number
CCDC 225944; see Ref.8 within.
11. Tamaru, Y.; Kawamura, S.; Tanaka, K.; Yoshida, Z. Tetrahedron Lett. 1984, 25,
1063; A similar observation has also been made by Jäger; see: Palmer, A. M.;
Jäger, V. Synlett 2000, 1405.
12. Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A. D.
Chem. Commun. 2003, 337; Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A.
W.; Prasad, R. S.; Smith, A. D. J. Chem. Soc., Perkin Trans. 1 2000, 3765.
13. Davies, S. G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P.
D.; Price Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry
2006, 17, 1793.
K2CO3 (36 mg, 0.26 mmol) was added to a stirred solution of 44
(85 mg, 0.26 mmol) in MeOH (5 mL). After stirring for 2 h, satd aq
NH4Cl (5 mL) was added. The mixture was extracted with EtOAc
(2 ꢂ 15 mL), and the combined organic layers were dried and con-
centrated in vacuo to give 45 as a colourless oil (73 mg, 94%, >98%
de); ½a 2D5
ꢀ
¼ ꢁ12:8 (c 1.0 in CHCl3);
mmax (film) 3350 (br, O–H, N–H),
1728 (C@O); dH (400 MHz, CDCl3) 1.28 (3H, s, MeCMe), 1.44 (9H, s,
t
CMe3), 1.49 (3H, s, MeCMe), 2.66 (1H, dd, J 16.9, 6.4, CHAHBCO2 Bu),
2.74 (1H, dd, J 16.9, 7.8, CHAHBCO2 Bu), 3.13 (1H, app q, J 4.6,
14. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 738.
t
15. For reviews concerning the application of double diastereoinduction in
synthesis, see: Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem. Int. Ed. Engl. 1985, 24, 1; Kolodiazhnyi, O. I. Tetrahedron 2003, 59,
5953.
C(2)H), 3.32 (1H, app td, J 7.2, 3.3, C(5)H), 3.90 (1H, dd, J 12.2,
4.7, CHAHBOH), 3.97–4.01 (3H, m, CHAHBOH, NH), 4.69–4.73 (2H,
m, C(3)H, C(4)H); dC (100 MHz, CDCl3) 23.8, 25.5 (CMe2), 28.1
16. Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
t
17. Bunnage, M. E.; Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin
Trans. 1 1994, 2373; For other synthetic applications of this transformation,
see: Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. Synlett 1993, 731; Bunnage, M.
E.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1993, 1375;
Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Goodwin, C. J. Tetrahedron: Asymmetry
1994, 5, 203; Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin
Trans. 1 1994, 2385; Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Goodwin, C. J.
Tetrahedron: Asymmetry 1995, 6, 165; Burke, A. J.; Davies, S. G.; Hedgecock, C. J.
R. Synlett 1996, 621; 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;
Davies, S. G.; Hughes, D. G.; Nicholson, R. L.; Smith, A. D.; Wright, A. J. Org.
Biomol. Chem. 2004, 2, 1549; Abraham, E.; Candela-Lena, J. I.; Davies, S. G.;
Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Sánchez-Fernández,
E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2007, 18, 2510;
Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith,
A. D. Org. Biomol. Chem. 2008, 6, 1655; 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.; Sánchez-Fernández, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E.
Org. Biomol. Chem. 2008, 6, 1665.
(CMe3), 33.8 (CH2CO2 Bu), 58.2 (C(5)), 60.2 (CH2OH), 62.8 (C(2)),
t
81.0 (CMe3), 81.2, 81.5 (C(3), C(4)), 111.5 (CMe2), 170.7 (CO2 Bu);
m/z (ESI+) 310 ([M+Na]+, 20%), 288 (100), 232 (30); HRMS (ESI+)
C14H26NO5 ([M+H]+) requires 288.1805; found 288.1820.
þ
4.2.21. (20S,30R,40S,50R)-(20-Hydroxymethyl-30,40-dihydroxy-
pyrrolidin-50-yl)ethanoic acid 46
OH
CO2H
H
N
OH
HO
18. Srivastava, R. M.; Sweet, F.; Murray, T. P.; Brown, R. K. J. Org. Chem. 1971, 36,
3633; Williams, D. R.; White, F. H. Tetrahedron Lett. 1979, 26, 2529.
19. For selected examples of aziridinium ions in synthesis see: Horning, D. E.;
Muchowski, J. M. Can. J. Chem. 1974, 52, 1321; Moragues, J.; Prieto, J.; Spickett,
R. G. W.; Vega, A. J. Chem. Soc., Perkin Trans. 1 1975, 938; Cossy, J.; Dumas, C.;
Pardo, D. G. Eur. J. Org. Chem. 1999, 1693; Fuson, R. C.; Zirkle, C. L. J. Am. Chem.
Soc. 1948, 70, 2760; Reitsema, R. H. J. Am. Chem. Soc. 1949, 71, 2041; Hammer,
C. F.; Heller, S. R. J. Chem. Soc., Chem. Commun. 1966, 919; Hammer, C. F.; Heller,
S. R.; Craig, J. H. Tetrahedron 1972, 28, 239; Harding, K. E.; Burks, S. R. J. Org.
Chem. 1984, 49, 40; Graham, M. A.; Wadsworth, A. H.; Thornton-Pett, M.;
Rayner, C. M. J. Chem. Soc., Chem. Commun. 2001, 966; Williams, D. R.; Brown, D.
L.; Benbow, J. W. J. Am. Chem. Soc. 1989, 111, 1923; Verhelst, S. H. L.; Martinez,
B. P.; Timmer, M. S. M.; Lodder, G.; van der Marel, G. A.; Overkleeft, H. S.; van
Boom, J. H. J. Org. Chem. 2003, 68, 9598; Dondoni, A.; Richichi, B.; Marra, A.;
Perrone, D. Synlett 2004, 1711.
Compound 45 (45 mg, 0.16 mmol) was dissolved in TFA (2 mL).
The resultant solution was stirred for 3 h, diluted with H2O
(1.3 mL), stirred for a further 1 h and concentrated in vacuo. Ion-
exchange chromatography (DOWEX 50WX8-200, eluent 1 M aq
NH4OH) gave 46 as a white solid (14 mg, 47%, >98% de); mp
168–170 °C (H2O); ½a D23
¼ ꢁ30:3 (c 0.8 in H2O); mmax (KBr) 2368–
ꢀ
3322 (O–H, N–H), 1626 (N–H bend), 1569 (CO2ꢁ); dH (500 MHz,
D2O) 2.65 (1H, dd, J 16.8, 7.5, CHAHBCO2H), 2.74 (1H, dd, J 16.8,
6.7, CHAHBCO2H), 3.78 (1H, app td, J 7.0, 5.0, C(20)H), 3.82–3.88
(2H, m, C(50)H, CHAHBOH), 3.94 (1H, dd, J 12.2, 4.9, CHAHBOH),
4.36 (1H, app t, J 4.7, C(40)H), 4.50 (1H, dd, J 6.8, 4.7, C(30)H); dC
(125 MHz, D2O) 34.2 (CH2CO2H), 58.3 (C(50)), 58.5 (CH2OH), 61.4
(C(20)), 70.4 (C(30)), 71.0 (C(40)), 178.0 (CO2H); m/z (ESIꢁ) 190
20. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
21. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J.
CRYSTALS, 2001, Chemical Crystallography Laboratory, University of Oxford,
UK.
ꢁ
([M–H]ꢁ, 100%); HRMS (ESIꢁ) C7H12NO5 ([M–H]ꢁ) requires
190.0721; found 190.0714.