Synthesis of (+)-7a-epi-7-deoxycasuarine via cross metathesis

Article abstract of DOI:10.1016/j.tet.2007.05.007

Olefin cross metathesis of vinyl pyrrolidine derivatives has been explored, culminating in a concise synthesis of (+)-7a-epi-7-deoxycasuarine in nine steps, from commercially available starting materials.

Full text of DOI:10.1016/j.tet.2007.05.007

Tetrahedron 63 (2007) 7112–7119
Synthesis of (D)-7a-epi-7-deoxycasuarine via cross metathesis
*
David Koch, Simon Maechling and Siegfried Blechert
Institute of Chemistry, TU Berlin—Berlin University of Technology, Str. d. 17. Juni 115, 10623 Berlin, Germany
Received 14 February 2007; revised 12 April 2007; accepted 1 May 2007
Available online 6 May 2007
Abstract—Olefin cross metathesis of vinyl pyrrolidine derivatives has been explored, culminating in a concise synthesis of (+)-7a-epi-7-
deoxycasuarine in nine steps, from commercially available starting materials.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the pyrrolizidine skeleton.6 For biological evaluation of
members of this class we were interested in exploring a sim-
ple, rapid and straightforward route to these molecules and
novel congeners. In this communication we report our prog-
ress towards the synthesis of 3-(hydroxymethyl)pyrrolizi-
dine alkaloids from vinyl pyrrolidine derivatives, including
the synthesis of (+)-7a-epi-7-deoxycasuarine. A variety of
approaches towards 3-(hydroxymethyl)pyrrolizidine alka-
loids have so far been disclosed,7 including the only previous
synthesis of 5, a carbohydrate based approach, that utilised
L-xylose as a chiral starting material.8
Polyhydroxylated pyrrolizidine alkaloids constitute an im-
portant class of molecules, which possess biological activity.
Alexine (1), first isolated from Alexa liopetala,1 has been
shown to exhibit antiviral and anti-HIV activity.2 Other
members of the family that have attracted interest include
hyacinthacine A2 (2) and casuarine (3) (Fig. 1). Acting as
sugar mimics, many of these alkaloids possess glycosidase
inhibition activity, which makes them and their analogues
potential drug candidates against viral infections, cancer
and diabetes.3 For example, 2 was found to be a selective
inhibitor of amyloglucosidase (Aspergillus niger) with an
IC50¼8.6 mM,4 and 7-deoxycasuarine (4) has also shown
to be a potent, specific and competitive inhibitor of amylo-
glucosidase (Rhizopus mould) with an IC50¼4.2 mM.5
We were interested in developing a flexible synthesis of 3-
(hydroxymethyl)pyrrolizidine alkaloids and their congeners,
in few synthetic steps from readily available chiral starting
materials. In our analysis of the target molecule (Scheme 1),
the key retrosynthetic steps are (i) reductive cyclisation
followed by (ii) dihydroxylation of the internal C–C double
bond, installing the A ring, and its appropriate stereo-
chemistry. This will enable key intermediate 7 to be synthes-
ised by (iii) olefin cross metathesis (CM) with enone 9
(PG0¼Bn). The CM precursor 8 was planned to be prepared
by simple functional group interconversions from commer-
cially available proline derivatives 10. We anticipated that
this approach would allow access to the target compound 5
and a variety of analogues.
It has been well documented that the biological activity
exhibited by these polyhydroxylated alkaloids varies with
the position and stereochemistry of the hydroxy groups on
OH
H
HO
OH
H
6
7
H
5
OH
OH
7a
OH
N
N
N
1
2
3
OH
OH
OH
OH
OH
OH
R
alexine 1
hyacinthacine A2
HO
2
casuarine 3
R
H
iii
B
OH
ii
N
HO
A
OPG'
i
N
H
H
O
OH
PG
OH
OH
N
N
OH
R
7
6
OH
OH
R
OH
OH
7a-epi-7-deoxycasuarine 5
O
7-deoxycasuarine 4
+
OPG'
N
PG
N
H
O
OH
Figure 1. Structures of selected polyhydroxylated pyrrolizidine alkaloids.
8
9
10
Keywords: Cross metathesis; Deoxycasuarine; Alkaloids; Pyrrolizidines.
* Corresponding author. E-mail: blechert@chem.tu-berlin.de
Scheme 1. General retrosynthesis.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.007

D. Koch et al. / Tetrahedron 63 (2007) 7112–7119
7113
2. Results and discussion
thionyl chloride in methanol, followed by smooth benzyl-
oxycarbonyl (Z) protection using K2CO3 in THF/H2O to
afford 18 in excellent yield over two steps (Scheme 3).
This protocol was found to be vital for high yields, as stan-
dard conditions for Z protection involving DCM and Et3N
as base consistently led to lower isolated yields (w60%).
O-Benzyl protection was achieved with benzyl trichloroace-
timidate and catalytic triflic acid, affording 19 in quantitative
yield. Reduction of ester 19 gave 20 in high isolated yield.
Alcohol 20 was converted via Swern oxidation to the corre-
sponding aldehyde, followed immediately by Wittig olefina-
tion to yield 21 without epimerisation in good yield (over
two steps). The vinyl pyrrolidine derivative 21 was subjected
to the previously optimised CM conditions with enone 9
allowing key intermediate 22 to be isolated in high yield.
With a reliable synthesis of 22 in hand the dihydroxylation
reaction was attempted. Initial investigations probed the
use of sequential catalysis to install the cis diol moiety, uti-
lising recently developed methodology from our group,14
and others.15 After completion of CM the solvent was re-
moved in vacuo and YbCl3 (10 mol %) was added followed
by EtOAc/CH3CN/H2O 3:3:1, after cooling to 0 ꢀC solid
NaIO4 (1.2 equiv) was added. However, although complete
consumption of the starting material was observed, no dia-
stereoselective induction from the remote chiral centre
took place as determined by 1H NMR of the crude reaction
mixture, therefore other methods of dihydroxylation were
pursued. Utilisation of OsO4 in acetone/H2O on purified
22 also led to the formation of a 1:1 mixture of 23:24. By
employing commercially available AD-mix-b the desired
diastereoisomer 23 could be isolated in acceptable yield.
Switching to AD-mix-a furnished diastereoisomer 24 as
anticipated. Diol 24 was treated with Pd/C under 1 atm of
H2. After Z-group deprotection and reductive cyclisation,
HCl was added to ensure quantitative reduction of the benzyl
ethers. To liberate the free amine, we used Amberlite IR 410
to afford 25 in excellent yield and good diastereoselectivity.
Following the same procedure 23 was smoothly transformed
into 5 whose optical rotation [a]2D0 +15.0 (c 0.12, H2O)
closely matches that of previously synthesised material
[a]2D0 +15.8 (c 0.92, H2O).8
Our initial investigations were aimed at scrutinising the fea-
sibility of vinyl pyrrolidines such as 8, to undergo successful
cross metathesis. Intrigued by previous reports regarding the
cross metathesis of vinyl pyrrolidine derivatives,9 where an
excess of the vinyl pyrrolidine was needed to achieve good
yields of the cross metathesis product,9b we investigated
the reactivity of 1110 in representative cross metathesis re-
actions. Our initial results with 11, a type II olefin, according
to Grubbs’ classification were promising (Scheme 2).11 We
were pleased to find that 11 reacted efficiently with ethyl
acrylate (also a type II olefin) utilising the Hoveyda–Grubbs
second generation catalyst [Ru],12 and 13 was isolated in
high yield (Scheme 2, entry 1). CM was also successful
with a racemic allylic alcohol (a type I olefin) affording 14
in good isolated yield (Scheme 2, entry 2). When we reacted
11 with enone 9 (PG0¼Bn)13 (Scheme 2, entry 3), according
to our retrosynthetic scheme, we were delighted to find that
15 could be isolated in a high yield of 80%. Vinyl pyrrolidine
12 also reacted efficiently with 9 affording the desired CM
product 16 in a yield of 64%. The reduced yield compared
to 15 was presumably a result of increased steric hindrance
in the vicinity of the reacting olefin.
R1
R2
R1
R2
a
N
Z
N
Z
[Ru]
Vinyl Pyrrolidine
CM Product
Isolated Yield
OEt
N
Z
N
Z
O
1.
2.
3.
11
13
82%
OBn
OBn
N
Z
OH
14
60%b
80%
11
N
Z
O
11
15
Proof of the stereochemistry of 5 came from NOE experi-
ments (Scheme 3) and the relative stereochemistry of C-1,
C-2 and C-3 was determined starting from the known stereo-
chemistry on C-7a (given by [2S,4R]-(ꢁ)-4-hydroxypyrroli-
dine-2-carboxylic acid). The observation of a large NOE
between H-7a and H-1 indicates a cis orientation. The ob-
served NOE between H-1 and H-3, indicates both protons
being pseudoaxial. Furthermore the NOE between H-5a
and H-7a indicates both protons being pseudoaxial. There
was also a large NOE observed between H-7a and H-7b
(not shown). Interestingly, the NMR chemical shifts of 5
did not match the previously reported data. A similar obser-
vation was recently reported by Donohoe et al.,16 whereby
the chemical shifts of the atoms in the direct environment
of the nitrogen became shifted (Table 1). Wormald et al.
OBn
OBn
OBn
57%c
64%d
N
Z
N
Z
O
4.
12
16
Scheme 2. Cross metathesis of vinyl pyrrolidines. aStandard reaction condi-
tions: 0.1 M, 2 equiv cross partner, CH2Cl2, 5 mol % [Ru],12 40ꢀC, 60 h;
b1:1 mixture of diastereoisomers; c4 equiv cross partner; d0.2 M, 4 equiv
cross partner.
These results highlight the importance of choosing a proper
cross partner for a particular CM reaction and the high re-
activity of the catalyst [Ru]. It is worth to mention that 15
and 16 constitute key retrosynthetic intermediates of our
proposed route towards the synthesis of (ꢁ)-hyacinthacine
A2 and alexine (1). With these results in hand, we embarked
on the synthesis of the target molecule (+)-7a-epi-7-deoxy-
casuarine.
3
described that JHH coupling constants remain unchanged
between different samples,17 even if NMR chemical shifts
differed.
Commercially available [2S,4R]-(ꢁ)-4-hydroxypyrrolidine-
2-carboxylic acid (17) was first esterified by reaction with
The J values of our sample were consistent with that of pre-
3
viously synthesised 5.8 The coupling constant J (4.1 Hz)

7114
D. Koch et al. / Tetrahedron 63 (2007) 7112–7119
NH
HO
HO
BnO
BnO
CCl3
CF3SO3H
O
O
O
1. SOCl2, MeOH
NaBH4, LiCl
THF/EtOH
N
Z
N
Z
N
H
CH2Cl2/hexane
2. Z-Cl, K2CO3
THF/H2O
OMe
OMe
OH
17
90% (over 2 steps)
18
100%
19
86%
1. DMSO
oxalyl chloride
NEt3, CH2Cl2
BnO
BnO
BnO
9 (4 eq)
OH
OBn
5 mol% [Ru]
CH2Cl2
2. Me(PPh3)Br
n-BuLi
THF
N
Z
N
Z
N
Z
O
20
68% (over 2 steps)
21
76%
22
1. H2, Pd/C (10 mol%)
MeOH,
BnO
HO
HO
OH
0.6%
7
H
6
H
H
H
AD mix-
then conc. HCl
HO
5
H
H
2
OBn
OBn
7a
OH
6
3
N
Z
N
1
acetone/H2O
2. Amberlite IR 410
N
HO
H
H
3
2
HO
OH
O
H
OH
(OH--form)
7a
1
H
41%
8
OH
5
H
1.3%H
OH
23
92% (d.r. 3:1)
2.3%
1. H2, Pd/C (10 mol%)
MeOH,
then conc. HCl
BnO
0.9%
1.2%
OH
6
5
7
H
H
0.7%
AD mix-
H
H
H
OH
H
7a
N
Z
N
6
1
HO
2
H
3
acetone/H2O
2. Amberlite IR 410
N
7a
3
2
OH
O
(OH--form)
H
HO
OH
1
27%
8
OH
OH
H
0.7%
H
OH
24
99% (d.r. 10:1)
25
Scheme 3. Synthesis of 7a-epi-7-deoxycasuarine.
3
between H-5a and H-6 indicates a cis relationship, J (8.1,
4.1 Hz) of H-7a indicates a cis relationship to H-6 and
a trans-diaxial to H-7a. J (1.7 Hz) between H-5b and H-6
analysis. The observed NOE between H-5a and H-6 indicate
both protons to be cis, along with the NOE between H-5a
and H-3, indicating a pseudoaxial orientation for both
protons and confirming the stereochemistry at C-3.
3
indicates trans, but not trans-diaxial arrangement and finally
3J (7.9, 1.7 Hz) of H-7b indicates cis relationship to H-7a
and a trans, but not trans-diaxial to H-6. Therefore H-5a
and H-7a are pseudoaxial, H-5b and H-7b are pseudo-
equatorial and in a W-geometry, both showing a long range
coupling of 4J¼1.7 Hz. It is also known that variation in sol-
vent (ionic strength, hydrogen bonding, metal ion chelation)
can exert discrepancies in NMR spectra of polyhydroxylated
alkaloids.17 The stereochemistry of 25 was also determined
in a similar manner by NOE studies starting from known
stereochemistry on C-6 (given by [2S,4R]-(ꢁ)-4-hydroxy-
pyrrolidine-2-carboxylic acid) and by coupling constant
3. Conclusions
In conclusion we present the CM of vinyl pyrrolidine deriv-
atives, culminating in the synthesis of polyhydroxylated pyr-
rolizidine 25 in nine steps and 11% overall yield, and the
synthesis of 7a-epi-7-deoxycasuarine (5) in nine steps and
15% overall yield. Further applications of this methodology
and the synthesis of other polyhydroxylated pyrrolizidines
will be reported in due course.
Table 1. NMR data for 5 in D2O
4. Experimental section
4.1. General
Labela
Ref. 8 (ppm)
This work (ppm)
H-6
H-7a
H-1
4.63
4.23
4.20
3.98
3.90
3.80
3.45
3.26
3.24
2.22
1.95
4.54
3.85
4.16
3.89
3.87
3.87
3.07
3.11
2.93
2.13
1.84
All experiments were carried out in oven-dried glassware
and under an atmosphere of nitrogen. Reagents were
supplied from Aldrich Chemical Company, Fluka, Acros
or Lancaster Synthesis and used without any further purifi-
cation. All solvents were distilled or dried prior to use.
THF and Et2O were distilled from sodium/benzophenone.
CH2Cl2 was distilled from P2O5. Hexane was distilled
H-2
H-8
H-80
H-3
H-5a
H-5b
H-7a
H-7b
˚
from CaH2. MeOH and EtOH were dried over 3 A molecular
C-7a
C-3
C-5
68.2
67.5
58.5
64.0
65.3
55.7
sieves. Analytical thin layer chromatography was performed
on precoated Merck silica gel 60 F254 plates and preparative
chromatography was performed on ICN silica gel 60 (0.040–
1
a: topside; b: bottom side.
0.063 mm). H NMR and 13C NMR spectra were recorded
a

D. Koch et al. / Tetrahedron 63 (2007) 7112–7119
7115
on a Bruker DRX-500 spectrometer. All chemical shifts are
reported in parts per million relative to the internal solvent
peak. IR spectra were measured on a Nicolet FTIR 750
spectrometer. Mass spectra were recorded on a Finnigan
MAT 95 SQ spectrometer and for ESI-MS on a Bruker-
Daltonics esquire 2000. Elemental analyses were obtained
on an Analytic Jena Elementar Vario El. Optical rotations
were measured on a Perkin–Elmer polarimeter 341 in
a 1 dm cell at 20 ꢀC and at a wavelength of 589 nm.
concentrated in vacuo to afford the crude aldehyde in
quantitative yield. Meanwhile n-BuLi (2.5 M in hexane,
1.99 mmol) was added to a suspension of methyl triphenyl-
phosphoniumbromide (776 mg, 2.17 mmol) in THF
(25 mL) at ꢁ78 ꢀC under N2 and stirred for 30 min before
a solution of the aldehyde in THF (5 mL) was added drop-
wise to the bright yellow suspension. The reaction mixture
was allowed to warm to room temperature and stirred
overnight. Satd NH4Cl (120 mL) was added and the mixture
extracted with MTBE (3ꢂ90 mL), dried (MgSO4) and con-
centrated in vacuo. Purification by column chromatography
(4:1 hexanes/MTBE) gave the title compound as a colourless
oil (377 mg, 62%). Rf¼0.24 (3:1 hexanes/MTBE); [a]D20
+3.9 (c 1.2, CHCl3); 1H NMR (500 MHz, DMSO-d6,
373 K) d 7.38–7.23 (m, 10H), 5.78 (m, 1H), 5.13–5.00 (m,
4H), 4.55 (s, 2H), 4.40 (br d, J¼5.4 Hz, 1H), 3.93 (m, 1H),
3.58–3.50 (m, 1H), 3.49–3.42 (m, 1H), 1.99 (m, 2H); 13C
NMR (125 MHz, DMSO-d6, 373 K) d 154.3 (Cq), 138.5
(Cq), 137.3 (Cq), 136.5 (CH), 128.2 (CH), 128.1 (CH),
127.5 (CH), 127.4 (CH), 127.3 (CH), 127.2 (CH), 115.1
(CH2), 82.4 (CH), 70.1 (CH2), 65.9 (CH2), 64.9 (CH), 44.5
(CH2), 28.4 (CH2); IR (ATR) cmꢁ1 3062, 3031, 2948,
2893, 1699, 1409, 1343, 1203, 1096, 1065, 922, 734, 697;
MS (EI, 70 eV) m/z (%) 337 (M+, <1), 246 (6), 202 (43),
91 (100), 69 (6); HRMS (EI) calcd for C21H23NO3 (M+)
337.1678, found 337.1680. Anal. Calcd for C21H23NO3: C,
74.75; H, 6.87; N, 4.15. Found: C, 74.97; H, 6.68; N, 4.15.
4.2. Experimental procedures
4.2.1. 1-(Benzyloxy)but-3-en-2-one (9) via the Weinreb
amide. To a stirred solution of benzyloxyacetylchloride
(1.00 g, 5.42 mmol) and N,O-dimethylhydroxylamine
hydrochloride (528 mg, 5.42 mmol) in CH2Cl2 (35 mL) at
0 ꢀC was added dropwise triethylamine (1.51 mL,
10.8 mmol), and stirring was continued for 4 h at this tem-
perature. After this time MeOH was added before concentra-
tion in vacuo. Purification by column chromatography (2:3
hexanes/MTBE) afforded the Weinreb amide as a colourless
1
oil (1.05 g, 93%). Rf¼0.33 (1:2 hexanes/MTBE); H NMR
(500 MHz, CDCl3) d 7.44–7.28 (m, 5H), 4.68 (s, 2H), 4.28
(s, 2H), 3.64 (s, 3H), 3.20 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 137.6 (Cq), 128.5 (CH), 128.1 (CH), 127.9 (CH),
73.3 (CH2), 67.1 (CH2), 61.5 (CH3), 32.4 (CH3); IR (ATR)
cmꢁ1 3063, 3030, 2938, 2900, 1677, 1454, 1140, 1087,
993, 739, 698; MS (EI, 70 eV) m/z (%) 210 (M+, <1), 103
(48), 91 (100), 73 (13), 65 (12); HRMS (EI) calcd for
C11H15NO3 (MH+) 210.1130, found 210.1130. To a stirred
solution of the Weinreb amide (710 mg, 3.39 mmol) in
absolute Et2O (15 mL) at 0 ꢀC was added dropwise a 1.0 M
solution of vinyl magnesiumbromide in THF (8.5 mL,
8.5 mmol) and stirred at 0 ꢀC for 30 min and then for 1.5 h
at room temperature before cooling to 0 ꢀC, and acetone
(1.3 mL) was added. After stirring for 15 min the solution
was quenched by addition of ice-cold 1 M HCl (20 mL).
The mixture was extracted with MTBE (3ꢂ60 mL), dried
(MgSO4) and concentrated in vacuo. Purification by column
chromatography (20:1 hexanes/MTBE) gave the title
compound as a colourless oil (505 mg, 85%). Rf ¼0.21
(9:1 hexanes/MTBE); 1H NMR (500 MHz, CDCl3) d 7.45–
7.29 (m, 5H), 6.55 (dd, J¼17.6, 10.8 Hz, 1H), 6.35 (dd,
J¼17.6, 1.1 Hz, 1H), 5.83 (dd, J¼10.8, 1.1 Hz, 1H), 4.62
(s, 2H), 4.28 (s, 2H); 13C NMR (125 MHz, CDCl3) d 197.2
(Cq), 137.2 (Cq), 132.5 (CH), 129.3 (CH2), 128.6 (CH),
128.1 (CH), 128.0 (CH), 73.9 (CH2), 73.4 (CH2). IR
(ATR) cmꢁ1 3064, 3031, 2954, 2924, 1728, 1699, 1454,
1102, 741, 698; MS (EI, 70 eV) m/z (%) 107 (10), 91
(100), 70 (26), 55 (34).
4.3. General procedure for cross metathesis
To a stirring solution of the vinyl pyrrolidine in DCM
(0.1 M) was added the freshly prepared cross partner
(2–4 equiv) and the solution was heated to reflux under N2
before the catalyst [Ru] was added (5 mol %). The mixture
was heated at reflux for 60 h, before concentration and puri-
fication by flash chromatography. In order to remove all ru-
thenium residue following metathesis the chromatographed
product was stirred in DCM with 10 parts (w/w) of activated
charcoal (6–12 h) before a second purification by flash
chromatography.
4.3.1. Benzyl 2-((E)-2-(ethoxycarbonyl)vinyl)pyrroli-
dine-1-carboxylate (13). Following the general procedure
for cross metathesis, and purification by column chromato-
graphy (7:3 hexanes/MTBE) afforded the title compound
as a colourless oil (143 mg, 82%). Rf¼0.35 (1:1 hexanes/
MTBE); 1H NMR (500 MHz, CDCl3)* d 7.37–7.22 (m,
5H), 6.80 (m, 1H), 5.85 (d, J¼15.5 Hz, 0.5H), 5.76 (d,
J¼15.5 Hz, 0.5H), 5.15–5.03 (m, 2H), 4.53 (m, 0.5H), 4.46
(m, 0.5H), 4.15 (m, 2H), 3.51–3.39 (m, 2H), 2.10–1.99 (m,
1H), 1.89–1.80 (m, 2H), 1.80–1.70 (m, 1H), 1.29–1.20 (m,
3H); 13C NMR (125 MHz, CDCl3)* d 166.3 (Cq), 154.8
(Cq), 148.0 (CH), 147.5 (CH), 136.8 (Cq), 136.7 (Cq),
128.5 (CH), 128.4 (CH), 128.0 (CH), 127.9 (CH), 121.0
(CH), 67.0 (CH2), 66.9 (CH2), 60.4 (CH2), 58.1 (CH), 57.8
(CH), 46.9 (CH2), 46.5 (CH2), 31.7 (CH2), 30.8 (CH2),
23.6 (CH2), 22.8 (CH2), 14.3 (CH3); MS (EI, 70 eV) m/z
(%) 303 (M+, 1), 189 (12), 168 (13), 140 (3), 114 (3), 91
(100), 65 (5); HRMS (EI) calcd for C17H21NO4 (M+)
303.1471, found 303.1476. (*1:1 Mixture of rotamers.)
4.2.2. (2R,3S)-Benzyl 3-(benzyloxy)-2-vinylpyrrolidine-
1-carboxylate (12). DCM (30 mL) was cooled to ꢁ78 ꢀC
under N2 and DMSO (0.51 mL, 7.24 mmol) was added drop-
wise followed by oxalyl chloride (0.31 mL, 3.62 mmol).
After 45 min (2R,3S)-benzyl 3-(benzyloxy)-2-(hydroxy-
methyl)pyrrolidine-1-carboxylate (618 mg, 1.81 mmol) was
added in DCM (5 mL) and stirring continued for 60 min.
Et3N (2.5 mL, 18 mmol) was then added and the reaction
mixture allowed to warm to room temperature over
45 min. HCl (1 N, 50 mL) was then added and the solution
extracted with DCM (3ꢂ50 mL), washed with satd NaHCO3
(60 mL) and satd NaCl (50 mL), dried (MgSO4) and
4.3.2. Benzyl 2-((E)-4-(benzyloxy)-3-hydroxybut-1-enyl)-
pyrrolidine-1-carboxylate (14). Following the general

7116
D. Koch et al. / Tetrahedron 63 (2007) 7112–7119
procedure for cross metathesis, and purification by column
chromatography (1:2 hexanes/MTBE) afforded the title
compound as a colourless oil (404 mg, 60%). Rf¼0.41
cmꢁ1 3063, 3031, 2945, 2894, 1703, 1634, 1412, 1346,
1099, 739, 698; MS (EI, 70 eV) m/z (%) 394 (M+ꢁC7H7,
4), 350 (10), 244 (2), 188 (2), 91 (100), 65 (2); HRMS
(EI) calcd for C23H24NO5 (M+ꢁC7H7) 394.1654, found
394.1655. (*1:1 Mixture of rotamers.)
1
(MTBE); H NMR (500 MHz, CDCl3)* d 7.40–7.23 (m,
10H), 5.78–5.64 (m, 1H), 5.65 (m, 0.5H), 5.42 (m, 0.5H),
5.19–5.13 (m, 1H), 5.11–4.99 (m, 1H), 4.57–4.47 (m, 2H),
4.47–4.23 (m, 2H), 3.54–3.30 (m, 3.5H), 3.24–3.17 (m,
0.5H), 2.92 (m, 0.5H), 2.75 (m, 0.5H), 1.98 (m, 1H), 1.91–
1.80 (m, 2H), 1.80–1.68 (m, 1H); 13C NMR (125 MHz,
CDCl3)* d 155.1 (Cq), 154.8 (Cq), 138.0 (Cq), 137.1 (Cq),
132.6 (CH), 132.4 (CH), 132.0 (CH), 128.9 (CH), 128.7
(CH), 128.52 (CH), 128.46 (CH), 127.9 (CH), 127.8 (CH),
74.3 (CH2), 73.3 (CH2), 70.7 (CH), 66.7 (CH2), 58.6 (CH),
58.5 (CH), 58.4 (CH), 58.3 (CH), 53.6 (CH2), 49.5 (CH),
46.8 (CH2), 46.4 (CH2), 32.4 (CH2), 32.3 (CH2), 31.4
(CH2), 31.3 (CH2), 27.1 (CH), 27.0 (CH), 23.6 (CH2), 23.5
(CH2), 22.84 (CH2), 22.75 (CH2); MS (EI, 70 eV) m/z (%)
381 (M+, <1), 260 (3), 204 (13), 160 (6), 108 (17), 91
(100), 65 (6), 57 (8). HRMS (EI) calcd for C23H27NO4
(M+) 381.1940, found 381.1945. (*1:1 Mixture of rotamers,
and each rotamer is a 1:1 mixture of diastereoisomers.)
4.3.5. (2S,4R)-1-Benzyl 2-methyl-4-hydroxypyrrolidine-
1,2-dicarboxylate (18). To (2S,4R)-4-hydroxypyrrolidine-
2-carboxylic acid (1.44 g, 11.0 mmol) in MeOH (60 mL)
at 0 ꢀC was added dropwise thionyl chloride (4.0 g,
33 mmol) and stirred for 18 h overnight at room tempera-
ture. Co-evaporation with toluene afforded quantitatively
the methyl ester hydrochloride. The methyl ester hydrochlo-
ride was added directly to a vigorously stirred suspension of
K2CO3 (6.84 g, 49.5 mmol) and benzyl chloroformate
(2.82 g, 16.5 mmol) in THF (60 mL)/water (10 mL). Stirring
was continued under N2 for 4 h before water (10 mL) was
added. The resultant biphasic solution was allowed to stir
under air overnight. The solution was acidified with 1 N
HCl (100 mL) before being extracted with EtOAc
(3ꢂ100 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo to leave a pale yellow residue. Flash
chromatography (1:3 hexanes/EtOAc) afforded the title
compound as a colourless oil (2.76 g, 90%). Rf¼0.39 (1:3
hexanes/EtOAc); [a]2D0 ꢁ62.6 (c 1.0, CHCl3); 1H NMR
(500 MHz, DMSO-d6, 378 K) d 7.33–7.25 (m, 5H), 5.10
(d, J¼12.7 Hz, 1H), 5.06 (d, J¼12.7 Hz, 1H), 4.69 (br d,
J¼3.4 Hz, 1H), 4.40 (dd, J¼7.7, 7.4 Hz, 1H), 4.33 (m,
1H), 3.60 (s, 3H), 3.52 (dd, J¼11.0, 4.7 Hz, 1H), 3.41 (ddd,
J¼11.0, 2.6, 1.4 Hz, 1H), 2.18 (m, 1H), 2.01 (m, 1H); 13C
NMR (125 MHz, DMSO-d6, 378 K) d 172.6 (Cq), 154.2
(Cq), 136.9 (Cq), 128.2 (CH), 127.6 (CH), 127.3 (CH),
68.3 (CH), 66.3 (CH2), 57.9 (CH), 54.8 (CH2), 51.5 (CH3),
38.6 (CH2); IR (ATR) cmꢁ1 3443, 3064, 3033, 2952,
2885, 1744, 1681, 1416, 1202, 1167, 1119, 1082, 769,
697; MS (EI, 70 eV) m/z (%) 279 (M+, 10), 234 (8), 220
(68), 192 (40), 176 (74), 144 (15), 121 (25), 91 (100), 65
(22). HRMS (EI) calcd for C14H17NO5 (M+) 279.1107,
found 279.1109.
4.3.3. Benzyl 2-((E)-4-(benzyloxy)-3-oxobut-1-enyl)-
pyrrolidine-1-carboxylate (15). Following the general
procedure for cross metathesis, and purification by column
chromatography (7:3 hexanes/MTBE) afforded the title
compound as a colourless oil (26 mg, 80%). Rf¼0.27 (1:1
hexanes/MTBE); 1H NMR (500 MHz, CDCl3)* d 7.45–
7.20 (m, 10H), 6.83 (m, 1H), 6.31 (d, J¼15.7 Hz, 0.5H),
6.18 (d, J¼15.7 Hz, 0.5H), 5.20–4.98 (m, 2H), 4.67–4.43
(m, 3H), 4.23 (s, 1H), 4.08 (s, 1H), 3.59–3.40 (m, 2H),
2.18–2.01 (m, 1H), 1.94–1.74 (m, 3H); 13C NMR
(125 MHz, CDCl3)* d 196.8 (Cq), 196.7 (Cq), 154.9 (Cq),
147.1 (CH), 146.7 (CH), 137.3 (Cq), 137.2 (Cq), 136.8
(Cq), 136.6 (Cq), 128.6 (CH), 128.1 (CH), 128.0 (CH),
124.8 (CH), 124.6 (CH), 74.3 (CH2), 73.4 (CH2), 67.0
(CH2), 58.4 (CH), 58.1 (CH), 47.0 (CH2), 46.6 (CH2), 31.8
(CH2), 30.9 (CH2), 23.8 (CH2), 23.0 (CH2); MS (EI,
70 eV) m/z (%) 397 (M+, 1), 273 (14), 248 (8), 204 (9),
160 (13), 138 (18), 91 (100), 65 (16), 57 (9); HRMS (EI)
calcd for C23H25NO4 (M+) 379.1784, found 379.1780.
(*1:1 Mixture of rotamers.)
4.3.6. (2S,4R)-2-Methyl 1-phenyl-4-(benzyloxy)pyrroli-
dine-1,2-dicarboxylate (19). Alcohol 18 (2.75 g,
9.85 mmol) was dissolved in DCM (20 mL) and hexane
(40 mL) was added followed by benzyl trichloroacetimidate
(2.98 g, 11.8 mmol). After stirring for 5 min 15 drops of
triflic acid were added and a white precipitate was formed
immediately. Stirring was continued for 8 h before the sus-
pension was filtered and the filter cake washed with hexanes
(3ꢂ10 mL). The solvent was removed in vacuo and the res-
idue taken up in MTBE (150 mL) and washed with 1 N HCl
(3ꢂ50 mL) and satd NaHCO3 (3ꢂ50 mL). The combined
ethereal extracts were dried (MgSO4) and concentrated.
Purification of the residue by column chromatography (2:1
hexanes/MTBE) gave the title compound as a colourless
oil (3.66 g, 100%). Rf¼0.34 (1:1 hexanes/MTBE); [a]D20
ꢁ36.1 (c 1.5, CHCl3); 1H NMR (500 MHz, DMSO-d6,
373 K) d 7.38–7.23 (m, 10H), 5.11 (d, J¼12.7 Hz, 1H),
5.07 (d, J¼12.7 Hz, 1H), 4.53 (d, J¼12.1 Hz, 1H), 4.50 (d,
J¼12.1 Hz, 1H), 4.39 (dd, J¼8.3, 6.9 Hz, 1H), 4.24 (m,
1H), 3.64–3.55 (m, 5H), 2.38 (dddd, J¼13.5, 8.3, 3.8,
1.3 Hz, 1H), 2.10 (ddd, J¼13.5, 6.9, 5.4 Hz, 1H); 13C
NMR (125 MHz, DMSO-d6, 373 K) d 172.3 (Cq), 154.1
(Cq), 138.4 (Cq), 136.8 (Cq), 128.2 (CH), 128.1 (CH),
4.3.4. (3S)-Benzyl 3-(benzyloxy)-2-((E)-4-(benzyloxy)-3-
oxobut-1-enyl)pyrrolidine-1-carboxylate (16). Following
the general procedure for cross metathesis, and purification
by column chromatography (7:3 hexanes/MTBE) afforded
the title compound as a colourless oil (101 mg, 64%). Rf¼
0.21 (7:3 hexanes/MTBE); [a]2D0 ꢁ24.6 (c 0.78, CHCl3);
1H NMR (500 MHz, CDCl3)* d 7.40–7.10 (m, 15H), 6.79
(m, 1H), 6.35 (d, J¼15.7 Hz, 0.5H), 6.23 (d, J¼15.7 Hz,
0.5H), 5.20–5.10 (m, 1.5H), 5.00 (d, J¼12.4 Hz, 0.5H),
4.70 (br d, J¼4.9 Hz, 0.5H), 4.63–4.47 (m, 4.5H), 4.21 (s,
1H), 4.07 (s, 1H), 3.92 (m, 1H), 3.69 (m, 1H), 3.59 (m,
1H), 2.06 (m, 1H), 1.92 (m, 1H); 13C NMR (125 MHz,
CDCl3)* d 196.6 (Cq), 196.4 (Cq), 155.1 (Cq), 155.0 (Cq),
144.2, 143.9, 137.5 (Cq), 137.3 (Cq), 137.2 (Cq), 137.0
(Cq), 136.6 (Cq), 128.65 (CH), 128.57 (CH), 128.51 (CH),
128.17 (CH), 128.10 (CH), 128.04 (CH), 127.97 (CH),
127.8 (CH), 127.7 (CH), 125.7 (CH), 125.6 (CH), 82.2
(CH), 81.2 (CH), 74.4 (CH2), 73.4 (CH2), 71.1 (CH2),
67.14 (CH2), 67.08 (CH2), 64.10 (CH), 64.06 (CH), 45.2
(CH2), 44.9 (CH2), 29.6 (CH2), 28.5 (CH2); IR (ATR)

D. Koch et al. / Tetrahedron 63 (2007) 7112–7119
7117
127.7 (CH), 127.4 (CH), 127.34 (CH), 127.29 (CH), 76.3
(CH), 70.4 (CH2), 66.4 (CH2), 57.8 (CH), 52.0 (CH2), 51.6
(CH3), 35.7 (CH2); IR (ATR) cmꢁ1 3063, 3031, 2951,
2884, 1747, 1705, 1415, 1204, 1118, 736, 697; MS (EI,
70 eV) m/z (%) 369 (M+, 3), 310 (41), 266 (73), 234 (8),
181 (10), 158 (5), 144 (7), 128 (10), 91 (100), 65 (16).
HRMS (EI) calcd for C21H23NO5 (M+) 369.1576, found
369.1569. Anal. Calcd for C21H23NO5: C, 68.28; H, 6.28;
N, 3.79. Found: C, 67.64; H, 6.12; N, 4.32.
(500 MHz, DMSO-d6, 373 K) d 7.38–7.22 (m, 10H), 5.82
(ddd, J¼17.1, 10.3, 6.0 Hz, 1H), 5.12–5.04 (m, 3H), 5.01
(d, J¼10.3 Hz, 1H), 4.51 (d, J¼12.2 Hz, 1H), 4.48 (d, J¼
12.2 Hz, 1H), 4.42 (m, 1H), 4.17 (m, 1H), 3.61 (br d, J¼
11.6 Hz, 1H), 3.48 (dd, J¼11.6, 4.9 Hz, 1H), 2.20 (m, 1H),
1.91 (ddd, J¼13.0, 5.8, 5.8 Hz, 1H); 13C NMR (125 MHz,
DMSO-d6, 373 K) d 154.5 (Cq), 139.1 (CH), 138.6 (Cq),
137.2 (Cq), 128.6 (CH), 128.2 (CH), 128.1 (CH), 127.5
(CH), 127.4 (CH), 127.3 (CH), 113.9 (CH2), 76.3 (CH),
70.3 (CH2), 66.0 (CH2), 57.9 (CH), 51.7 (CH2), 37.7
(CH2); IR (ATR) cmꢁ1 3064, 3031, 2941, 2881, 1700,
1410, 1354, 1111, 917, 734, 696; MS (EI, 70 eV) m/z (%)
337 (M+, <1), 246 (10), 202 (3), 170 (4), 91 (100), 65 (6);
HRMS (EI) m/z calcd for C21H23NO3 (M+) 337.1678, found
337.1679. Anal. Calcd for C21H23NO3: C, 74.75; H, 6.87; N,
4.15. Found: C, 74.98; H, 6.93; N, 4.19.
4.3.7. (2S,4R)-Benzyl 4-(benzyloxy)-2-(hydroxymethyl)-
pyrrolidine-1-carboxylate (20). To a stirred solution of
ester 19 (2.89 g, 7.82 mmol) under N2 in THF (20 mL)/
EtOH (30 mL) at 0 ꢀC were added NaBH4 (657 mg,
17.4 mmol) and LiCl (738 mg, 17.4 mmol). The suspension
was allowed to warm to room temperature and stirring was
continued for 3 days under N2. To the resultant thick white
suspension was added 1 N HCl (100 mL), and the solution
extracted with EtOAc (5ꢂ50 mL). The organic layer was
dried (MgSO4), and concentrated invacuo to leave a pale yel-
low residue. Flash chromatography (1:2 hexanes/MTBE) af-
forded the title compound as a milky oil (2.30 g, 86%).
Rf ¼0.23 (1:2 hexanes/MTBE); [a]2D0 ꢁ35.6 (c 2.5, CHCl3);
1H NMR (500 MHz, DMSO-d6, 373 K) d 7.38–7.22 (m,
10H), 5.12 (d, J¼12.7 Hz, 1H), 5.09 (d, J¼12.7 Hz, 1H),
4.50 (d, J¼12.1 Hz, 1H), 4.48 (d, J¼12.1 Hz, 1H), 4.22 (m,
2H), 3.97 (m, 1H), 3.60 (br d, J¼11.5 Hz, 1H), 3.54 (m,
2H), 3.45 (dd, J¼11.5, 5.0 Hz, 1H), 2.15–2.03 (m, 2H); 13C
NMR (DMSO-d6, 125 MHz, 373 K) d 154.6 (Cq), 138.7
(Cq), 137.3 (Cq), 128.2 (CH), 128.1 (CH), 127.5 (CH),
127.31 (CH), 127.28 (CH), 127.2 (CH), 76.6 (CH), 70.3
(CH2), 66.0 (CH2), 62.5 (CH2), 58.0 (CH), 52.2 (CH2),
34.3 (CH2); IR (ATR) cmꢁ1 3441, 3063, 3031, 2942, 2880,
1699, 1680, 1418, 1355, 1115, 1083, 735, 697; MS (EI,
70 eV) m/z (%) 341 (M+, <1), 310 (57), 266 (47), 158 (3),
91 (100), 65 (8); HRMS (EI) calcd for C20H23NO4 (M+)
341.1627, found 341.1621. Anal. Calcd for C20H23NO4: C,
70.36; H, 6.79; N, 4.10. Found: C, 70.27; H, 6.59; N, 4.62.
4.3.9. (2S,4R)-Benzyl 4-(benzyloxy)-2-((E)-4-(benzyloxy)-
3-oxobut-1-enyl)pyrrolidine-1-carboxylate (22). To a stir-
ring solution of the vinyl pyrrolidine 21 (192 mg,
0.570 mmol) in DCM (2.9 mL, 0.2 M) was added freshly pre-
pared enone 9 (402 mg, 2.28 mmol), and the solution heated
to reflux before the catalyst [Ru] (18 mg, 5 mol %) was added.
The green solution was heated to reflux for 60 h, before puri-
fication by column chromatography (2:1 hexanes/EtOAc).
Second flash chromatography (3:1 hexanes/EtOAc) afforded
the title compound as a colourless oil (211 mg, 76%).
Rf¼0.18 (3:1 hexanes/EtOAc); [a]2D0 ꢁ24.7 (c 0.70, CHCl3);
1H NMR (500 MHz, DMSO-d6, 373 K) d 7.32–7.21 (m,
15H), 6.80 (dd, J¼15.9, 6.3 Hz, 1H), 6.25 (dd, J¼15.9,
0.9 Hz, 1H), 5.09 (d, J¼12.7 Hz, 1H), 5.04 (d, J¼12.7 Hz,
1H), 4.58–4.50 (m, 4H), 4.48 (d, J¼12.2 Hz, 1H), 4.22 (s,
2H), 4.18 (m, 1H), 3.65 (ddd, J¼11.8, 2.3, 1.7 Hz, 1H),
3.52 (dd, J¼11.8, 4.8 Hz, 1H), 2.29 (dddd, J¼13.3, 7.9, 3.9,
1.5 Hz, 1H), 1.93 (ddd, J¼13.3, 7.1, 5.1 Hz, 1H); 13C NMR
(125 MHz, DMSO-d6, 373 K) d 196.5 (Cq), 154.5 (Cq),
146.7 (CH), 138.5 (Cq), 138.0 (Cq), 137.0 (Cq), 128.2 (CH),
128.14 (CH), 128.13 (CH), 127.61 (CH), 128.55 (CH),
127.5 (CH), 127.4 (CH), 127.32 (CH), 127.30 (CH), 125.3
(CH), 76.2 (CH), 74.1 (CH2), 72.7 (CH2), 70.3 (CH2), 66.2
(CH2), 57.0 (CH), 51.9 (CH2), 37.5 (CH2); IR (ATR) cmꢁ1
3063, 3031, 2936, 2877, 1703, 1632, 1412, 1355, 1113,
739, 698; MS (EI, 70 eV) m/z (%) 485 (M+, 1), 244 (5), 181
(2), 91 (100), 65 (6). HRMS (EI) calcd for C30H31NO5
(M+) 485.2202, found 485.2210. Anal. Calcd for
C30H31NO5: C, 74.21; H, 6.43; N, 2.88. Found: C, 74.38;
H, 6.33; N, 2.97.
4.3.8. (2S,4R)-Benzyl 4-(benzyloxy)-2-vinylpyrrolidine-
1-carboxylate (21). A solution of the alcohol 20 (978 mg,
2.87 mmol) in DCM was cooled to ꢁ78 ꢀC under N2 and
DMSO (0.82 mL, 11.5 mmol) was added dropwise followed
by oxalyl chloride (0.49 mL, 5.73 mmol). Stirring was con-
tinued for 60 min. Et3N (4.0 mL, 29 mmol) was then added
dropwise and the reaction mixture allowed to warm to room
temperature for over 60 min. HCl (1 N, 80 mL) was then
added and the solution extracted with DCM (3ꢂ80 mL),
washed with satd NaHCO3 (100 mL) and satd NaCl
(100 mL), dried (MgSO4) and concentrated in vacuo to
afford the crude aldehyde in quantitative yield. Meanwhile
n-BuLi (2.5 M in hexane, 3.16 mmol) was added to a suspen-
sion of methyl triphenylphosphoniumbromide (1.23 g,
3.44 mmol) in THF (40 mL) at ꢁ78 ꢀC under N2 and stirred
for 30 min before a solution of the aldehyde in THF (8 mL)
was added dropwise to the bright yellow suspension. The re-
action mixture was allowed to warm to room temperature
and stirred overnight. Satd NH4Cl (120 mL) was added
and the mixture extracted with MTBE (3ꢂ90 mL), dried
(MgSO4) and concentrated in vacuo. Purification by column
chromatography (6:1 hexanes/MTBE) gave the title com-
pound as a colourless oil (662 mg, 68%). Rf¼0.33 (2:1
hexanes/MTBE); [a]2D0 +8.0 (c 0.50, CHCl3); 1H NMR
4.3.10. (2S,4R)-Benzyl 4-(benzyloxy)-2-((1R,2S)-4-(benz-
yloxy)-1,2-dihydroxy-3-oxobutyl)pyrrolidine-1-carb-
oxylate (23). To a stirred solution of the enone 22 (55 mg,
0.113 mmol) in acetone (1.5 mL) and water (0.8 mL)
at 0 ꢀC were added sodium bicarbonate (29 mg,
0.339 mmol), methylsulfonamide (11 mg, 0.113 mmol)
and 317 mg of modified AD-mix-b (contains additional
K2Os4(OH)4 to raise the total to 1 mol %). The mixture
was stirred overnight at room temperature. At 0 ꢀC satd
NaHSO3 (5 mL) was added and the mixture extracted with
ethyl acetate (5ꢂ8 mL), the combined organic layers were
dried (MgSO4) and concentrated. The residue was chroma-
tographed (2:1 hexanes/EtOAc) to afford the title compound
as a colourless oil (24 mg, 41%). Rf¼0.40 (1:1 hexanes/
EtOAc); [a]2D0 ꢁ25.5 (c 0.55, CHCl3); 1H NMR

7118
D. Koch et al. / Tetrahedron 63 (2007) 7112–7119
(500 MHz, DMSO-d6, 373 K) d 7.35–7.23 (m, 15H), 5.09 (s,
2H), 4.76 (br d, J¼4.9 Hz, 1H), 4.57 (m, 1H), 4.51 (s, 2H),
4.46 (d, J¼12.0 Hz, 1H), 4.44 (d, J¼12.0 Hz, 1H), 4.39 (s,
2H), 4.24–4.15 (m, 2H), 4.11 (m, 1H), 3.93 (m, 1H), 3.76
(m, 1H), 3.37 (dd, J¼12.0, 4.6 Hz, 1H), 2.16 (m, 1H), 2.07
(m, 1H); 13C NMR (125 MHz, DMSO-d6, 373 K) d 208.3
(Cq), 156.8 (Cq), 138.6 (Cq), 138.2 (Cq), 137.0 (Cq), 128.2
(CH), 128.1 (CH), 127.9 (CH), 127.6 (CH), 127.51 (CH),
127.49, 127.4 (CH), 127.3 (CH), 127.2 (CH), 76.8 (CH),
75.7 (CH), 73.3 (CH2), 73.0 (CH), 72.6 (CH2), 70.1 (CH2),
66.4 (CH2), 59.1 (CH), 52.2 (CH2), 33.9 (CH2); IR (ATR)
cmꢁ1 3425, 3063, 3031, 2926, 2871, 1727, 1671, 1420,
1356, 1103, 738, 698; MS (EI, 70 eV) m/z (%) 520 (MH+,
6), 386 (10), 370 (3), 340 (16), 310 (40), 296 (7), 266 (40),
181 (8), 149 (15), 107 (5), 91 (100), 65 (10); HRMS (EI)
calcd for C30H34NO7 (MH+) 520.2335, found 520.2343.
Anal. Calcd for C30H33NO7: C, 69.35; H, 6.40; N, 2.70.
Found: C, 69.04; H, 6.38; N, 2.52.
filtered (Celite) and lyophilised. The residue was dissolved
in MeOH (3 mL), and stirred with strong basic ion-exchange
resin (200 mg Amberlite IR 410, OHꢁ-form) for 30 min.
Filtration and evaporation afforded 5 mg (92%) of a 3:1 dia-
stereomeric mixture with the title compound as the major
component. Purification on silica (98:2 MeOH/NH4OH)
gave 3.5 mg of the title compound. Rf¼0.21 (98:2 MeOH/
1
NH4OH); [a]2D0 +15.0 (c 0.12, H2O); H NMR (500 MHz,
D2O) d 4.54 (m, 1H, H-6), 4.16 (dd, J¼7.5, 6.2 Hz, 1H,
H-1), 3.92–3.81 (m, 4H, H-8, H-80, H-7a, H-2), 3.11 (dd,
J¼11.1, 4.1 Hz, 1H, H-5a), 3.07 (m, 1H, H-3), 2.93 (ddd,
J¼11.1, 1.7, 1.7 Hz, 1H, H-5b), 2.13 (ddd, J¼13.9, 8.1,
5.6 Hz, 1H, H-7a), 1.84 (dddd, J¼13.9, 7.9, 1.7, 1.7 Hz,
1H, H-7b); 13C NMR (125 MHz, D2O) d 77.3 (C-1), 76.9
(C-2), 72.6 (C-6), 65.3 (C-3), 64.0 (C-7a), 59.9 (C-8), 55.7
(C-5), 33.7 (C-7); IR (ATR) cmꢁ1 3323, 2925, 2853, 2715,
1576, 1411, 1341, 1122, 1044, 985; MS (ESI) m/z 190.1
(MH+), and 1.3 mg of the epimer at C-3 compound 5a.
Rf¼0.30 (98:2 MeOH/NH4OH); 1H NMR (500 MHz, D2O)
d 4.57 (m, 1H, H-6), 4.28 (m, 1H, H-2), 4.05 (m, 1H,
H-1), 3.94 (m, 1H, H-7a), 3.80 (m, 1H, H-8), 3.68 (dd,
J¼11, 6 Hz, 1H, H-80), 2.99–2.92 (m, 2H, H-3 and H-5),
2.81 (dd, J¼11, 5 Hz, 1H, H-50), 2.16 (m, 1H, H-7), 1.74
(m, 1H, H-70). MS (ESI): m/z 190.1 (MH+).
4.3.11. (2S,4R)-Benzyl 4-(benzyloxy)-2-((1S,2R)-4-(benz-
yloxy)-1,2-dihydroxy-3-oxobutyl)pyrrolidine-1-carb-
oxylate (24). To a stirred solution of the enone 22
(65 mg, 0.134 mmol) in acetone (1.8 mL) and water
(0.9 mL) at 0 ꢀC were added sodium bicarbonate (34 mg,
0.402 mmol), methylsulfonamide (13 mg, 0.134 mmol)
and 375 mg of modified AD-mix-a (contains additional
K2Os4(OH)4 to raise the total to 1 mol %). The mixture
was stirred overnight at room temperature. At 0 ꢀC satd
NaHSO3 (6 mL) was added and the mixture extracted with
ethyl acetate (5ꢂ8 mL), the combined organic layers were
dried (MgSO4) and concentrated. The residue was chroma-
tographed (2:1 hexanes/EtOAc) to afford the title compound
as a colourless oil (19 mg, 27%). Rf¼0.32 (1:1 hexanes/
EtOAc); [a]2D0 ꢁ13.1 (c 0.35, CHCl3); 1H NMR
(500 MHz, DMSO-d6, 373 K) d 7.37–7.22 (m, 15H), 5.11
(d, J¼12.8 Hz, 1H), 5.08 (d, J¼12.8 Hz, 1H), 4.74 (br d,
J¼6.2 Hz, 1H), 4.67 (br d, J¼6.7 Hz, 1H), 4.51 (d, J¼
12.0 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.47 (d, J¼12.0 Hz,
1H), 4.45 (d, J¼12.0 Hz, 1H), 4.42 (d, J¼18.0 Hz, 1H),
4.37 (d, J¼18.0 Hz, 1H), 4.22–4.12 (m, 2H), 4.08–4.02
(m, 2H), 3.65 (ddd, J¼11.7, 2.1, 2.1 Hz, 1H), 3.35 (dd,
J¼11.7, 4.7 Hz, 1H), 2.34 (ddd, J¼13.7, 5.8, 5.8 Hz, 1H),
1.98 (dddd, J¼13.7, 8.3, 3.6, 1.5 Hz, 1H); 13C NMR
(125 MHz, DMSO-d6, 373 K) d 208.5 (Cq), 138.7 (Cq),
138.2 (Cq), 137.1 (Cq), 128.2 (CH), 128.10 (CH), 128.09
(CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 127.31 (CH),
127.28 (CH), 127.20 (CH), 77.3 (CH), 77.1 (CH), 73.2
(CH2), 72.5 (CH2), 71.1 (CH), 70.1 (CH2), 66.1 (CH2),
59.3 (CH), 52.0 (CH2), 32.1 (CH2); IR (ATR) cmꢁ1 3424,
3063, 3031, 2916, 2849, 1728, 1674, 1418, 1356, 1103,
737, 697; MS (EI, 70 eV) m/z (%) 520 (MH+, 5), 386 (19),
356 (3), 340 (8), 310 (40), 296 (9), 266 (47), 181 (21), 158
(5), 107 (7), 91 (100), 65 (9); HRMS (EI) calcd for
C30H34NO7 (MH+) 520.2335, found 520.2337. Anal. Calcd
for C30H33NO7: C, 69.35; H, 6.40; N, 2.70. Found: C,
69.40; H, 6.24; N, 2.87.
4.3.13. Compound 25. To a solution of ketodiol 24 (5 mg,
0.00962 mmol) in MeOH (1 mL) was added 5% Pd/C
(4 mg, 50 wt % H2O), and the heterogeneous mixture was
stirred under 1 atm of H2 at room temperature for 24 h. Con-
centrated HCl (1 drop) was added and the suspension stirred
for additional 24 h. The solution was filtered (Celite) and
lyophilised. The residue was dissolved in MeOH (1 mL),
and stirred with strong basic ion-exchange resin (100 mg
Amberlite IR 410, OHꢁ-form) for 30 min. Filtration and
evaporation afforded 1.8 mg (99%) of 10:1 diastereomeric
mixture with the title compound as the major component.
Rf¼0.50 (98:2 MeOH/NH4OH); [a]2D0 ꢁ5.8 (c 0.18, H2O);
1H NMR (500 MHz, D2O) d 4.58 (m, 1H, H-6), 3.88–3.83
(m, 2H, H-1, H-2), 3.79 (dd, J¼11.8, 3.6 Hz, 1H, H-8), 3.64
(dd, J¼11.8, 6.6 Hz, 1H, H-80), 3.38 (m, 1H, H-7a), 2.99
(dd, J¼11.8, 3.6 Hz, 1H, H-5b), 2.93 (dd, J¼11.8, 4.7 Hz,
1H, H-5a), 2.76 (m, 1H, H-3), 2.07 (ddd, J¼13.5, 7.3,
3.9 Hz, 1H, H-7b), 1.99 (ddd, J¼13.5, 7.3, 5.3 Hz, 1H, H-
7a); 13C NMR (125 MHz, D2O) d 81.4 (CH), 78.6 (CH),
72.9 (C-6), 70.8 (C-3), 66.0 (C-7a), 63.5 (C-8), 62.3 (C-5),
38.6 (C-7); IR (ATR) cmꢁ1 3323, 2916, 2848, 1573, 1408,
1337, 1098, 1067, 1039, 963; MS (ESI) m/z 190.1 (MH+).
Acknowledgements
We are grateful to the Fonds der Chemischen Industrie, and
the Graduiertenkolleg ‘Synthetische, mechanistische und
reaktionstechnische Aspekte von Metallkatalysatoren’ for
financial support.
4.3.12. (D)-7a-epi-7-Deoxycasuarine (5). To a solution of
ketodiol 23 (15 mg, 0.0289 mmol) in MeOH (3 mL) was
added 5% Pd/C (12 mg, 50 wt % H2O), and the heteroge-
neous mixture was stirred under 1 atm of H2 at room temper-
ature for 24 h. Concentrated HCl (3 drops) was added and
the suspension stirred for additional 24 h. The solution was
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