NHC-mediated cross-coupling of sugar-derived cyclic nitrones with enals: General and efficient synthesis of polyhydroxylated pyrrolizidines and indolizidines

Article abstract of DOI:10.1039/c3ob40696b

A general and efficient method for the synthesis of polyhydroxylated pyrrolizidines and indolizidines has been developed based on the NHC-catalyzed cross-coupling of sugar-derived cyclic nitrones with enals, which afforded the key intermediates, γ-hydroxyl amino esters, in good to excellent yields. Thus, a variety of polyhydroxylated pyrrolizidines and indolizidines have been synthesized and assayed against various glycosidases, which showed that aryl or alkyl substituents at C-7 of pyrrolizidines or at C-8 of indolizidines reduced the potency of the glycosidase inhibition of these bicyclic iminosugars. is

Full text of DOI:10.1039/c3ob40696b

Organic &
Biomolecular Chemistry
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NHC-mediated cross-coupling of sugar-derived cyclic
nitrones with enals: general and efficient synthesis of
polyhydroxylated pyrrolizidines and indolizidines†
Cite this: Org. Biomol. Chem., 2013, 11,
4622
Wen-Yuan Xu,a,c Ren Iwaki,b Yue-Mei Jia,a Wei Zhang,a Atsushi Kato*b and
Chu-Yi Yu*a
A general and efficient method for the synthesis of polyhydroxylated pyrrolizidines and indolizidines has
been developed based on the NHC-catalyzed cross-coupling of sugar-derived cyclic nitrones with enals,
which afforded the key intermediates, γ-hydroxyl amino esters, in good to excellent yields. Thus, a variety
of polyhydroxylated pyrrolizidines and indolizidines have been synthesized and assayed against various
glycosidases, which showed that aryl or alkyl substituents at C-7 of pyrrolizidines or at C-8 of indolizidines
reduced the potency of the glycosidase inhibition of these bicyclic iminosugars.
Received 7th April 2013,
Accepted 13th May 2013
DOI: 10.1039/c3ob40696b
www.rsc.org/obc
Introduction
Naturally-occurring polyhydroxylated pyrrolizidine and indoli-
zidine alkaloids, the bicyclic iminosugars, and their deriva-
tives1 have attracted significant attentions due to their
important bioactivities and potential clinical applications in
treating diseases such as diabetes, lysosomal storage disorders
and viral infections.2 Important representatives of the natu-
rally-occurring bicyclic iminosugars include casuarine (1) from
Casuarina equisetifolia3 (an inhibitor of α-glucosidase), hya-
cinthacine A2 (2) from Muscari armeniacum4 (an inhibitor of
amyloglucosidase and lactase), castanospermine (3) from
Castanospermum australe5 (an inhibitor of α-glucosidases) and
swainsonine (4) from Swainsona canescens6 (an inhibitor of
α-mannosidases) (Fig. 1).
Fig. 1 Selected natural bicyclic polyhydroxylated alkaloids.
for the synthesis of this kind of compounds, especially the
diversity-oriented ones which are badly needed for the study of
structure–activity relationships. More efforts are still required
into the development of general and efficient methods for the
synthesis of bicyclic iminosugars.
Since a number of enantiomers7 of the naturally-occurring
iminosugars are found to be even more potent inhibitors of
the same enzymes as themselves,8 and/or inhibitors of
different glycosidases,9 the bicyclic iminosugars together with
their enantiomers and analogues have attracted considerable
attention.10 Many efforts have thus been made on the syn-
thesis of both the natural bicyclic iminosugars and the syn-
thetic analogues including the enantiomers of the natural
products.11 However, there is still a lack of efficient methods
Among the numerous methods developed for the synthesis
of polyhydroxylated alkaloids, those employing cyclic nitrones
as key intermediates could be one of the most efficient strat-
egies for the construction of this kind of compounds. This is
because nitrones, with the ability to participate in a variety of
synthetically useful reactions such as 1,3-dipolar cycloaddition,
nucleophilic additions and cross-coupling reactions,12 have
proved to be powerful building blocks for the construction of
numerous nitrogen-containing compounds, natural and/or
synthetic.13 In particular, sugar-derived cyclic nitrones14
(Fig. 2) have already been shown to be powerful synthons for
the synthesis of polyhydroxylated alkaloids, including poly-
hydroxylated pyrrolizidines and indolizidines.15 Therefore, we
are interested in developing novel and efficient methods for
aBeijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100191, China. E-mail: yucy@iccas.ac.cn
bDepartment of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama
930-0194, Japan
cUniversity of Chinese Academy of Sciences, Beijing 100049, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ob40696b
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Table 1 Optimization of reaction conditionsa
Fig. 2 Nitrones used in this study.
Entry
Cat.
Time/h
Conv. (%)
Yieldb (%)
drd
1
2
3
4
5
Ac
Bc
C
D
E
24
24
24
8
0
0
99
99
30
0
0
56
93
20
—
—
>95 : 5
>95 : 5
>95 : 5
the synthesis of bicyclic iminosugars using sugar-derived
cyclic nitrones as key intermediates.
To further exploit the potential applications of sugar-
derived cyclic nitrones in the synthesis of iminosugars, we
have recently been interested in the NHCs-catalysed coupling
reactions of cyclic nitrones with enals, because the predictable
products, γ-hydroxyl amino esters, could be versatile precur-
sors of bicyclic iminosugars.
24
a 2 : 1 ratio of 5a to 6a; 20 mol% base. b Isolated yield. c Under different
temperatures (−10 °C, 0 °C, 25 °C) and solvents (CH2Cl2, THF, EtOH),
no reactions occurred. d dr determined by 1H NMR spectroscopy.
In the past decades, N-heterocyclic carbenes16 (NHCs) have
been extensively studied as versatile ligands in transition metal
catalysis17 and organocatalysts themselves.18 An important
application of NHCs is that they can react with enals to generate
homoenolates, which are unique three-carbon synthons for
unconventional C–C bond formation. Considerable excellent
work has appeared focusing on the reactivity of NHC-mediated
homoenolates,19 but few examples have been used in natural
product synthesis.20 In 2008, Scheidt et al. reported the first use
of NHCs in the cross-coupling reaction of nitrones with α,β-un-
saturated aldehydes to afford γ-hydroxyl amino ester products.21
In the context of our continuing interests in iminosugars22
and their derivatives,23 herein we report a new method for the
general and efficient synthesis of polyhydroxylated pyrrolizi-
dines and indolizidines based on the NHC-catalyzed cross-
coupling of sugar-derived cyclic nitrones with enals.
entry 5). Therefore, triazolium salt D was chosen as the catalyst
for the coupling reactions.
It is worth noting that the coupling reaction of nitrone 5a
and cinnamaldehyde 6a initially formed an intermediate, the
six-membered-ring cyclic γ-hydroxylamine lactone 7aa, which
was isolable and found to be stable enough during purification
on silica gel chromatography, and could be stored for months
at below 0 °C. However, since lactone 7aa can be easily trans-
formed into the desired final product, i.e. γ-hydroxyl amino
esters 8, we decided not to separate the intermediate 7aa in
the latter study. Thus, γ-hydroxyl amino ester 8aa was obtained
in “one-pot” reaction when the reaction was immediately
quenched with NaOMe–MeOH after the consumption of enals.
Scope of the substrates
To investigate the scope of the substrates, a variety of cyclic
nitrones and enals were attempted in the coupling reactions
under the optimal reaction conditions (Table 2). Although the
(Z)-enals should have similar reactivities according to the
reported homoenolate addition mechanism of this kind of
reactions,19a,24 only the readily available (E)-enals were used in
our study. It was found that enals substituted with alkenyls or
electron-rich aryls (i.e. 6a–d) were good substrates for the coup-
ling reaction with cyclic nitrones, while enals substituted with
alkyls or electron-deficient aryls were poor substrates for the
reactions, possibly due to the relatively poor nucleophilicity of
the homoenolates formed from the addition of these sub-
strates and NHC.
Results and discussion
Optimization of the reaction conditions
Nitrone 5a and cinnamaldehyde 6a were employed as the
substrates for the investigation of optimal conditions of the
coupling reactions, while a variety of different diazolium
and triazolium salts have been explored as catalysts (Table 1).
Under similar conditions, thiazolium salt A and diazolium salt
B were found to be ineffective in catalysing the coupling reac-
tions (Table 1, entry 1–2), while diazolium salt C was effective
in catalysing the reaction which afforded the desired coupling
product, γ-hydroxyl amino ester (8aa), in moderate yield (56%,
Table 1, entry 3). Triazolium salt D showed similar efficiency
as catalyst and the reaction took shorter time to finish, yield-
ing the desired product in better yield with better diastereo-
selectivity (dr > 95 : 5) (Table 1, entry 4). Diazolium salt E can
also effect the reaction but gave much poorer yield (Table 1,
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Table 2 Scope of the substratesa,b
a General conditions: 5 (2.0 equiv.), 6 (1.0 equiv.), D (20 mol%), DBU (20 mol%). Given are isolated yields. Diastereomeric ratio determined after
separation. b R: 6a = Ph, 6b = 4-MeOPh; 6c = 2-furyl; 6d = 1-propenyl.
Under the optimized reaction conditions, a variety of
cyclic nitrones (i.e. 5a–5f) were used in the coupling reactions
with various enals (6a–d). It was found that all the
cyclic nitrones (i.e. 5a–5f) were good substrates for the NHC-
catalysed coupling reactions, which produced the desired pro-
ducts in good to excellent yields. For most of the reactions,
products with 1,7,7α-cis configuration were isolated as single
products.
The relative configuration of the coupling products 7aa can
be explained by the relative topicity of the transition state of
the reaction proposed in Fig. 3. The benzyloxy group at C-2 of
nitrone shields the Re face of the CvN bond of the nitrone.
Therefore, the homoenolate, formed during the catalytic cycle,
approaches the nitrone from the less hindered Si face. The
intermolecular H-bridge between nitrone and the hydroxyl
group of the homoenolate may preorganize the two substrates
Fig. 3 Postulated transition-state model for the cis selectivity.
in such a way that the homoenolate approaches nitrone with
its Re face, thus lead to the all cis-configuration of the two
newly formed stereogenic centers and benzyloxy group at C-2
of nitrones.16a,25
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Fig. 4 NOE interactions in 7aa and 9db.
The relative configurations of the two newly introduced
stereocenters were assigned on the basis of NOESY experi-
ments of 9db. The observed interactions of H-1–H-7 indicate a
cis configuration between H-1 and H-7. The cis configuration
between H-7α and H-3 was assigned through the interactions
Scheme 1 Synthesis of (7R)-7-phenylhyacinthacine A2.
between H-7α–H-3, thus
a 1,7,7α-cis configuration was
Evaluation of glycosidase inhibitions of the synthesized
bicyclic iminosugars
assigned with respect to the benzyloxy groups already present
in the molecule. The cis configuration could be further con-
firmed on the basis of the NOESY experiment of the intermedi-
ate lactone (i.e. 7aa) (Fig. 4).
All the synthesized bicyclic iminosugars were assayed as poten-
tial inhibitors of a range of glycosidase (as shown in ESI†).
The best inhibition was observed in lactams 10eb and 10fa
(IC50 57 μM and 58 μM, respectively, against β-glucuronidase
from E. coli). Most of the lactams had no inhibition against
glycosidases. Only few lactams had moderate inhibition; for
example, lactam 10bb had moderate inhibition (IC50 480 μM
against β-glucosidase and IC50 259 μM against β-galactosidase,
both from bovine liver). Besides, the bicyclic azepane
lactam 10fa had inhibitions against various glycosidases. The
bulk of the pyrrolizidines were less potent than original
natural products. Therefore, the aryl and alkyl substituents
at C-7 of pyrrolizidines or at C-8 of indolizidines had caused
loss of glycosidase inhibitory activity.27 The biological
study results observed herein might be valuable for further
structure–activity studies on polyhydroxylated pyrrolizidines
and indolizidines.
Synthesis of bicyclic iminosugars
With the γ-hydroxyl amino esters in hand, a few steps of
simple transformations would lead to the synthesis of the
target compounds, i.e. polyhydroxylated pyrrolizidines and
indolizidines. Taken the synthesis of (7R)-phenylhyacinthacine
A2 as an example, reduction of 8ba by Zn–Cu(OAc)2–AcOH26 or
Fe–Cu(OAc)2–AcOH gave the corresponding γ-amino ester,
which was immediately treated with K2CO3/MeOH to afford
lactam 9ba. Direct hydrogenolysis of 9ba gave polyhydroxylated
lactam 10ba. Reduction of lactam 9ba by LiAlH4 gave the
corresponding tertiary amine 11ba, which was further hydro-
genated to afford (7R)-7-phenylhyacinthacine A2 (i.e. 12ba) in
excellent yield (Scheme 1).
Thus, a number of polyhydroxylated pyrrolizidines and
indolizidines have been prepared by this methodology. How-
ever, when the 2-furyl substituted lactams (i.e. 9) were
subjected to debenzylation by catalytic hydrogenation or BCl3,
Conclusions
a mixture of complicated products were obtained (Fig. 5, In summary, a general and efficient method for the synthesis
overall yields from enals 6).
of polyhydroxylated pyrrolizidines and indolizidines has been
Fig. 5 Synthesized polyhydroxylated pyrrolizidines and indolizidines.
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developed based on the NHC-catalyzed cross-coupling of 5 (1.0 mmol). The mixture was dissolved in CH2Cl2 (10 mL,
sugar-derived cyclic nitrones with enals, which afforded the 0.1 M) and cooled to 0 °C. To the flask was sequentially added
key intermediates, γ-hydroxyl amino esters, in good to excel- the enal (0.50 mmol) and DBU (15 μL, 0.10 mmol) via syringe
lent yields. Thus, a variety of polyhydroxylated pyrrolizidines under Ar atmosphere. The reaction mixture was stirred over-
and indolizidines have been synthesized starting from the night at room temperature and 0.50 mL NaOMe (1.0 M in
γ-hydroxyl amino esters via a few steps of simple transform- MeOH) was added via syringe. After 30 min the reaction was
ations in good to excellent yields. The resulting polyhydroxy- diluted with diethyl ether and filtered through a pad of Celite.
lated pyrrolizidines and indolizidines were assayed against The reaction mixture was concentrated and purified by
various glycosidases, which showed that most of the poly- flash column chromatography on silica gel (EtOAc–petroleum
hydroxylated lactams have no inhibition, while several syn- ether = 1/5) to afford the γ-hydroxyl amino ester product as 8 a
thesized pyrrolizidines and indolizidines only had moderated yellow or colourless syrup.
inhibition. This indicated that the aryl or alkyl substitutions at
C-7 of pyrrolizidines or C-8 of indolizidines reduced the inhibi-
tory activity of glycosidases. These results might be valuable
(4R,4aS,5S,6S)-5,6-Bis(benzyloxy)-4-phenylhexahydro-2H-
pyrrolo[1,2-b][1,2]oxazin-2-one (7aa)
for further structure–activity studies of substituted imino- According to general procedure without addition of NaOMe,
sugars and for design and synthesis of more potent and selective prepared from enal 6a (0.25 mL, 2.00 mmol) and nitrone 5a
glycosidase inhibitors. The application of this methodology in (1.21 g, 4.00 mmol) to afford 7aa (0.69 g, 81%) as colourless
the synthesis of naturally-occurring iminosugars, including oil; [α]2D0 +10.6 (c 2.65 in CH2Cl2); νmax/cm−1 3062, 3031, 2922,
bicyclic iminosugars and nortropane iminosugars, was under 2860, 1756, 1621, 1496, 1454, 1097, 740, 699; δH (CDCl3,
way and will be reported in due course.
300 MHz) 7.42–7.29 (m, 13 H), 7.11–7.07 (m, 2H), 4.64 (d, J =
11.7 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.33 (s, 2H), 4.17–4.13
(m, 2H), 4.02 (dd, J1 = 2.7 Hz, J2 = 9.0 Hz, 1H), 3.89 (s, 1H),
3.44 (dt, J1 = 8.7 Hz, J2 = 11.7 Hz, 1H), 3.25 (dd, J1 = 4.2 Hz, J2 =
12.6 Hz, 1H), 2.92 (dd, J1 = 12.0 Hz, J2 = 15.9 Hz, 1H), 2.77 (dd,
J1 = 8.5 Hz, J2 = 15.9 Hz, 1H); δC (CDCl3, 75 MHz) 175.6, 140.1,
137.5, 137.2, 129.0, 128.6, 128.5, 128.0, 127.96, 127.92, 127.7,
127.4, 85.6, 83.0, 72.6, 71.6, 71.2, 46.9, 46.7, 41.9; HRMS (ESI)
calcd for C27H28NO4+ [M + H]+ 430.2013, found 430.2009.
Experimental
Material and methods
All reagents were used as received from commercial sources
without further purification or prepared as described in the lit-
erature. Dichloromethane was distilled from calcium hydride.
NaOMe was prepared from sodium and methanol before use.
Methanol was dried over 4 Å molecular sieves. Tetrahydrofuran
was distilled from sodium and benzophenone immediately
before use. Analytical TLC was performed with 0.20 mm silica
gel 60F plates with 254 nm fluorescent indicator. TLC plates
were visualized by ultraviolet light or by treatment with a spray
of Pancaldi reagent ((NH4)6MoO4, Ce(SO4)2, H2SO4, H2O) or a
0.5% solution of KMnO4 in acetone. Chromatographic purifi-
cation of products was carried out by chromatography on silica
gel (200–300 mesh). Acidic ion exchange chromatography was
performed on Amberlite IR-120 (H+) or Dowex 50WX8-400 H+
form. Melting points were determined using an electrothermal
melting point apparatus. Melting points are uncorrected. Infra-
red spectra were recorded on a JASCOFT/IR-480 plus Fourier
transform spectrometer. NMR spectra were measured in CDCl3
(with TMS as internal standard) or D2O on a Broker AV300 or
AV600 magnetic resonance spectrometer (1H at 300 MHz or
600 MHz, 13C at 75 MHz). High-resolution mass spectra (HRMS)
were recorded on a Thermo Scientific LTQ/FT mass spectrometer
or a GCT mass spectrometer. Polarimetry was carried out
using an Optical Activity AA-10R polarimeter and the measure-
ments were made at the sodium D-line with a 0.5 dm path
length cell. Concentrations (c) are given in gram per 100 mL.
(R)-Methyl 3-((2S,3S,4S)-3,4-bis(benzyloxy)-1-hydroxypyrrolidin-
2-yl)-3-phenylpropanoate (8aa)
According to general procedure, prepared from enal 6a
(0.85 mL, 6.75 mmol) and nitrone 5a (4.0 g, 13.45 mmol) to
afford 8aa (2.45 g, 78%) as colourless oil; [α]2D0 +10.4 (c 3.45 in
CH2Cl2); νmax/cm−1 3446, 3030, 2918, 2857, 1735, 1496, 1454,
1094, 739, 699; δH (CDCl3, 300 MHz) 7.26–7.07 (m, 13H),
6.81–6.78 (m, 2H), 5.62 (s, br, 1H), 4.42 (d, J = 12.0 Hz, 1H),
4.30 (d, J = 12.0 Hz, 1H), 4.01 (d, J = 11.1 Hz, 1H), 3.90 (d, J =
11.1 Hz, 1H), 3.75–3.69 (m, 2H), 3.59 (d, J = 6.0 Hz, 1H), 3.49
(s, 3H), 3.27 (d, J = 10.8 Hz, 1H), 3.03 (t, J = 5.7 Hz, 1H), 2.93
(q, J = 5.4 Hz, 2H), 2.59 (dd, J1 = 6.3 Hz, J2 = 15.9 Hz, 1H); δC
(CDCl3, 75 MHz) 174.3, 141.0, 138.0, 137.5, 128.5, 128.4, 128.2,
128.1, 127.7, 127.6, 126.7, 83.5, 79.3, 76.7, 71.3, 70.9, 59.8,
+
51.8, 41.0, 34.9; HRMS (ESI) calcd for C28H32NO5 [M + H]+
462.2281, found 462.2273.
(R)-Methyl 3-(2S,3S,4S)-3,4-bis(benzyloxy)-1-hydroxypyrrolidin-
2-yl)-3-(4-methoxyphenyl)propanoate (8ab)
According to general procedure, prepared from enal 6b (0.69 g,
4.28 mmol) and nitrone 5a (2.58 g, 8.68 mmol) to afford 8ab
(1.92 g, 91%) as colourless oil; [α]2D0 +6.7 (c 1.50 in CH2Cl2);
νmax/cm−1 3447, 3030, 2947, 2905, 1735, 1513, 1455, 1113, 739,
699; δH (CDCl3, 300 MHz) 7.28–7.23 (m, 5H), 7.16–7.14 (m,
3H), 7.06 (d, J = 8.7 Hz, 2H), 6.86–6.83 (m, 2H), 6.73 (d, J =
General procedure for cross-coupling of cyclic nitrones with
α,β-unsaturated aldehydes and subsequent in situ methanolysis
To an oven-dried flask containing a magnetic stirring bar 8.7 Hz, 2H), 5.47 (s, br, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.33
was added catalyst D (27 mg, 0.10 mmol) and nitrone (d, J = 12.0 Hz, 1H), 4.08 (d, J = 11.4 Hz, 1H), 3.97 (d, J =
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11.4 Hz, 1H), 3.77 (d, J = 5.1 Hz, 1H), 3.67–3.66 (m, 4H), 3.58 127.7, 127.69, 127.6, 127.5, 126.7, 83.8, 82.7, 74.3, 73.3, 71.3,
(d, J = 5.7 Hz, 1H), 3.52 (s, 3H), 3.29 (d, J = 10.8 Hz, 1H), 71.2, 68.2, 66.1, 51.7, 41.5, 35.2; HRMS (ESI) calcd for
3.01–2.91 (m, 2H), 2.89–2.81 (m, 1H), 2.57 (dd, J1 = 6.6 Hz, J2 = C11H20NO3+ [M + H]+ 582.2850, found 582.2839.
15.9 Hz, 1H); δC (CDCl3, 75 MHz) 174.4, 158.4, 138.0, 137.6,
(R)-Methyl 3-((2S,3S,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)-3-(4-methoxyphenyl)-
propanoate (8bb)
133.0, 129.0, 128.5, 128.3, 127.84, 127.80, 127.79, 127.71,
113.9, 83.7, 79.3, 77.4, 71.4, 71.0, 59.9, 55.2, 51.9, 40.4, 35.4;
+
HRMS (ESI) calcd for C29H34NO6 [M + H]+ 492.2386, found
492.2371.
According to general procedure, prepared from enal 6b (0.71 g,
4.41 mmol) and nitrone 5b (3.66 g, 8.77 mmol) to afford 8bb
(2.21 g, 88%) as colourless oil; [α]2D0 +17.1 (c 2.10 in CH2Cl2);
νmax/cm−1 3445, 3031, 2909, 1736, 1513, 1454, 1249, 1113, 738,
(S)-Methyl 3-((2S,3S,4S)-3,4-bis(benzyloxy)-1-hydroxypyrrolidin-
2-yl)-3-(furan-2-yl)propanoate (8ac)
According to general procedure, prepared from enal 6c (0.58 g, 698; δH (CDCl3, 300 MHz) 7.32–7.20 (m, 13H), 7.10 (d, J =
4.80 mmol) and nitrone 5a (2.89 g, 9.70 mmol) to afford 8ac 8.7 Hz, 2H), 6.92–6.89 (m, 2H), 6.79 (d, J = 8.7 Hz, 2H), 5.63 (s,
(1.12 g, 51%) as colourless oil; [α]2D0 +14.9 (c 2.15 in CH2Cl2); br, 1H), 4.61–4.60 (m, 1H), 4.52–4.40 (m, 3H), 4.10 (q, J =
νmax/cm−1 3446, 3031, 2949, 2861, 1736, 1454, 1365, 1094, 731, 11.4 Hz, 2H), 3.97 (s, 1H), 3.89 (dd, J1 = 3.0 Hz, J2 = 7.8 Hz,
698; δH (CDCl3, 300 MHz) 7.36–7.25 (m, 9H), 7.11–7.08 (m, 1H), 3.79–3.77 (m, 1H), 3.71–3.66 (m, 4H), 3.58–3.52 (m, 5H),
2H), 6.27 (q, J = 1.8 Hz, 1H), 6.10 (d, J = 3.0 Hz, 1H), 5.66 (s, br, 3.37 (t, J = 6.0 Hz, 1H), 2.94 (dd, J1 = 8.1 Hz, J2 = 15.9 Hz, 1H),
1H), 4.52 (d, J = 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 2.60 (dd, J1 = 6.6 Hz, J2 = 15.9 Hz, 1H); δC (CDCl3, 75 MHz)
4.23–4.14 (m, 2H), 3.92–3.84 (m, 2H), 3.74 (d, J = 5.4 Hz, 1H), 174.2, 158.3, 138.3, 138.1, 137.7, 133.1, 129.0, 128.3, 128.1,
3.64 (s, 3H), 3.39 (d, J = 10.5 Hz, 1H), 3.20 (t, J = 5.4 Hz, 1H), 128.0, 127.7, 127.66, 127.60, 127.5, 113.8, 83.9, 82.7, 74.3, 73.3,
3.04 (dd, J1 = 5.4 Hz, J2 = 10.5 Hz, 1H), 2.90 (dd, J1 = 7.7 Hz, J2 71.3, 71.2, 68.2, 66.2, 55.1, 51.7, 40.8, 35.5; HRMS (ESI) calcd
= 16.2 Hz, 1H), 2.66 (dd, J1 = 6.3 Hz, J2 = 16.2 Hz, 1H); δC for C37H42NO7+ [M + H]+ 612.2961, found 612.2955.
(CDCl3, 75 MHz) 174.1, 154.9, 141.7, 138.0, 137.7, 128.5, 128.3,
(S)-Methyl 3-((2S,3S,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)-3-(furan-2-yl)propanoate
(8bc)
127.84, 127.77, 110.3, 106.1, 83.4, 79.3, 75.3, 71.6, 70.9, 59.8,
+
52.0, 35.2, 33.5; HRMS (ESI) calcd for C26H30NO6 [M + H]+
452.2073, found 452.2069.
According to general procedure, prepared from enal 6c (0.55 g,
4.50 mmol) and nitrone 5b (3.75 g, 9.0 mmol) to afford 8bc
(1.69 g, 72%) as colourless oil; [α]2D0 +1.3 (c 1.50 in CH2Cl2);
(R,E)-Methyl 3-((2S,3S,4S)-3,4-bis(benzyloxy)-1-
hydroxypyrrolidin-2-yl)hex-4-enoate (8ad)
According to general procedure, prepared from enal 6d νmax/cm−1 3436, 3031, 2919, 2866, 1736, 1454, 1109, 736, 698;
(0.50 mL, 4.50 mmol) and nitrone 5a (2.69 g, 9.0 mmol) to δH (CDCl3, 300 MHz) 7.34–7.21 (m, 14H), 7.06–7.02 (m, 2H),
afford 8ad (1.28 g, 66%) as colourless oil; [α]2D0 −5.5 (c 3.30 in 6.26–6.25 (m, 1H), 6.06 (d, J = 3.0 Hz, 1H), 5.54 (s, br, 1H),
CH2Cl2); νmax/cm−1 3438, 3030, 2916, 2861, 1736, 1454, 1103, 4.65–4.40 (m, 4H), 4.20–4.11 (m, 2H), 3.96–3.93 (m, 2H),
738, 698; δH (CDCl3, 300 MHz) 7.36–7.27 (m, 10H), 5.85 (s, br, 3.87–3.78 (m, 2H), 3.66–3.56 (m, 5H), 3.49 (t, J = 5.7 Hz, 1H),
1H), 5.52–5.35 (m, 2H), 4.56–4.38 (m, 4H), 3.90 (d, J = 5.8 Hz, 2.89 (dd, J1 = 7.8 Hz, J2 = 16.2 Hz, 1H), 2.64 (dd, J1 = 6.0 Hz, J2
1H), 3.68 (d, J = 6.6 Hz, 1H), 3.62 (s, 3H), 3.38 (d, J = 10.7 Hz, = 16.2 Hz, 1H); δC (CDCl3, 75 MHz) 174.2, 155.0, 141.6, 138.4,
1H), 3.08–3.00 (m, 2H), 2.90–2.86 (m, 1H), 2.59 (dd, J1
=
138.2, 137.9, 128.41, 128.40, 128.3, 128.1, 127.9, 127.7, 127.68,
6.9 Hz, J2 = 15.3 Hz, 1H), 2.31 (dd, J1 = 7.2 Hz, J2 = 15.6 Hz, 127.62, 110.3, 106.1, 83.4, 82.5, 73.4, 72.3, 71.5, 71.2, 68.0,
+
1H), 1.63 (d, J = 5.7 Hz, 3H); δC (CDCl3, 75 MHz) 174.4, 137.9, 65.9, 52.0, 35.7, 33.4; HRMS (ESI) calcd for C34H38NO7
137.7, 130.6, 128.5, 128.4, 127.9, 127.9, 127.8, 126.8, 83.4, 79.4, [M + H]+ 572.2648, found 572.2643.
75.5, 71.6, 71.0, 60.4, 51.7, 39.4, 35.7, 18.1; HRMS (ESI) calcd
for C26H32NO5+ [M + H]+ 546.2855, found 546.2842.
(R,E)-Methyl 3-((2S,3S,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)hex-4-enoate (8bd)
(R)-Methyl 3-((2S,3S,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)-3-phenylpropanoate (8ba)
According to general procedure, prepared from enal 6d
(0.50 mL, 4.53 mmol) and nitrone 5b (3.78 g, 9.05 mmol) to
According to general procedure, prepared from enal 6a afford 8bd (1.60 g, 65%) as colourless oil; [α]2D0 +11.4 (c 0.35 in
(0.60 mL, 4.77 mmol) and nitrone 5b (4.00 g, 9.58 mmol) to CH2Cl2); νmax/cm−1 3421, 3030, 2917, 2861, 1736, 1454, 1363,
afford 8ba (2.18 g, 78%) as colourless oil; [α]2D0 +15.4 (c 1.95 in 1109, 737, 698; δH (CDCl3, 300 MHz) 7.36–7.21 (m, 15H),
CH2Cl2); νmax/cm−1 3435, 3030, 2886, 1736, 1453, 1098, 738, 5.52–5.33 (m, 2H), 4.67 (s, 1H), 4.62–4.52 (m, 3H), 4.48–4.32
698; δH (CDCl3, 300 MHz) 7.32–7.16 (m, 18H), 6.88–6.85 (m, (m, 3H), 3.98–3.95 (m, 1H), 3.91 (d, J = 4.8 Hz, 1H), 3.74 (dd,
2H), 5.57 (s, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.52–4.39 (m, 3H), J1 = 2.1 Hz, J2 = 6.9 Hz, 1H), 3.64–3.57 (m, 5H), 3.19–3.15 (m,
4.07 (t, J = 11.1 Hz, 2H), 3.99–3.96 (m, 1H), 3.89 (dd, J1
=
1H), 3.07–2.98 (m, 1H), 2.56 (dd, J1 = 7.5 Hz, J2 = 15.3 Hz, 1H),
3.6 Hz, J2 = 8.4 Hz, 1H), 3.80–3.73 (m, 2H), 3.63–3.52 (m, 5H), 2.28 (dd, J1 = 6.6 Hz, J2 = 15.6 Hz, 1H), 1.63 (d, J = 5.7 Hz, 1H);
3.40 (t, J = 6.0 Hz, 1H), 2.97 (dd, J1 = 8.4 Hz, J2 = 15.9 Hz, 1H), δC (CDCl3, 75 MHz) 174.5, 138.4, 138.2, 138.0, 130.8, 128.6,
2.62 (dd, J1 = 6.0 Hz, J2 = 15.9 Hz, 1H); δC (CDCl3, 75 MHz) 128.42, 128.37, 128.1, 127.72, 127.65, 127.0, 126.6, 83.5, 83.0,
174.3, 141.2, 138.3, 138.1, 137.7, 128.5, 128.3, 128.2, 128.1, 73.4, 72.5, 71.6, 71.3, 68.3, 66.3, 65.4, 51.6, 39.8, 35.6, 18.1;
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HRMS (ESI) calcd for C33H40NO6 [M + H]+ 546.2856, found (R,E)-Methyl 3-((2S,3S,4R,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
+
546.2848.
methyl)-1-hydroxypyrrolidin-2-yl)hex-4-enoate (8cd)
According to general procedure, prepared from enal 6d
(0.58 mL, 5.35 mmol) and nitrone 5c (4.39 g, 10.50 mmol) to
afford 8cd (2.75 g, 96%) as colourless oil; [α]2D0 −52.0 (c 1.15 in
CH2Cl2); νmax/cm−1 3343, 2927, 1654, 1453, 1122, 703; δH
(CDCl3, 300 MHz) 7.30–7.27 (m, 15H), 5.60–5.58 (m, 1H),
5.23–5.21 (m, 1H), 4.77–4.71 (m, 1H), 4.66–4.59 (m, 3H),
4.53–4.46 (m, 2H), 4.40–4.36 (m, 1H), 4.08–4.05 (m, 1H), 3.92
(d, J = 6.3 Hz, 2H), 3.65–3.62 (m, 1H), 3.60 (s, 3H), 3.24–3.17
(m, 1H), 3.39–3.33 (m, 1H), 2.77–2.73 (m, 1H), 2.60–2.39 (m,
2H), 1.55–1.53 (m, 3H); δC (CDCl3, 75 MHz) 173.3, 138.2, 138.1,
138.0, 129.5, 128.49, 128.45, 128.1, 127.9, 127.8, 127.7, 80.9,
77.6, 76.3, 73.5, 73.4, 72.7, 67.5, 65.9, 51.4, 40.8, 37.6, 18.0;
(R)-Methyl 3-((2S,3S,4R,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)-3-phenylpropanoate (8ca)
According to general procedure, prepared from enal 6a
(0.75 mL, 5.96 mmol) and nitrone 5c (5.00 g, 12.00 mmol) to
afford 8ca (2.96 g, 85%) as colourless oil; [α]2D0 −26.0 (c 1.00 in
CH2Cl2); νmax/cm−1 3419, 3036, 2920, 2866, 1736, 1454, 1093,
737, 699; δH (CDCl3, 300 MHz) 7.32–7.08 (m, 20H), 5.55 (s, br,
1H), 4.70 (d, J = 11.7 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H),
4.52–4.42 (m, 3H), 4.16 (d, J = 11.7 Hz, 1H), 3.94 (d, J = 3.9 Hz,
1H), 3.89–3.87 (m, 2H), 3.65–3.61 (m, 1H), 3.53 (s, 3H),
3.48–3.44 (m, 2H), 2.98–2.90 (m, 2H), 2.79 (dd, J1 = 7.8 Hz, J2 =
15.9 Hz, 1H); δC (CDCl3, 75 MHz) 173.2, 140.4, 138.2, 138.1,
138.0, 128.8, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 126.9,
81.1, 77.4, 76.9, 73.4, 72.5, 67.0, 65.8, 51.6, 42.2, 37.6; HRMS
(ESI) calcd for C36H40NO6+ [M + H]+ 582.2856, found 582.2839.
HRMS (ESI) calcd for C36H40NO4 [M + H]+ 550.2957, found
+
550.2947.
(S)-Methyl-((2R,3R,4R,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)-3-phenylpropanoate (8da)
(R)-Methyl 3-((2S,3S,4R,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)-3-(4-methoxyphenyl)-
propanoate (8cb)
According to general procedure, prepared from enal 6a
(0.55 mL, 4.37 mmol) and nitrone 5d (3.63 g, 8.62 mmol) to
afford 8da (2.14 g, 84%) as colourless oil; [α]2D0 +17.4 (c 2.30 in
CH2Cl2); νmax/cm−1 3452, 3027, 2910, 2863, 1735, 1453, 1169,
1095, 738, 699; δH (CDCl3, 300 MHz) 7.34–7.16 (m, 18H),
6.81–6.78 (m, 2H), 5.46 (s, br, 1H), 4.54–4.49 (m, 4H),
3.88–3.82 (m, 3H), 3.79–3.75 (m, 2H), 3.69–3.63 (m, 1H), 3.56
(s, 3H), 3.52 (d, J = 4.8 Hz, 1H), 3.44–3.38 (m, 1H), 3.22 (t, J =
3.4 Hz, 1H), 2.89 (dd, J1 = 6.0 Hz, J2 = 15.9 Hz, 1H), 2.59 (dd, J1
= 5.7 Hz, J2 = 15.9 Hz, 1H); δC (CDCl3, 75 MHz) 174.6, 140.9,
138.4, 138.3, 137.5, 128.5, 128.37, 128.36, 128.2, 128.1, 127.8,
127.7, 127.6, 127.58, 127.4, 126.7, 81.7, 79.0, 77.9, 73.4, 71.8,
71.1, 67.9, 67.2, 51.7, 40.8, 34.4; HRMS (ESI) calcd for
C36H40NO6+ [M + H] + 582.2856, found 582.2844.
According to general procedure, prepared from enal 6b (1.02 g,
6.30 mmol) and nitrone 5c (5.27 g, 12.63 mmol) to afford 8cb
(3.21 g, 84%) as colourless oil; [α]2D0 −8.5 (c 1.65 in CH2Cl2);
νmax/cm−1 3404, 3030, 2926, 1735, 1512, 1454, 1111, 737, 698;
δH (CDCl3, 300 MHz) 7.34–7.23 (m, 15H), 6.99 (d, J = 8.4 Hz,
2H), 6.70 (d, J = 8.4 Hz, 2H), 5.58 (s, br, 1H), 4.72 (d, J =
11.7 Hz, 1H), 4.59 (m, 1H), 4.54 (d, J = 3.9 Hz, 1H), 4.50–4.47
(m, 2H), 4.21 (d, J = 12.0 Hz, 1H), 3.95 (t, J = 3.9 Hz, 1H),
3.89–3.87 (m, 2H), 3.73 (s, 3H), 3.63–3.59 (m, 1H), 3.54 (s, 3H),
3.46–3.35 (m, 2H), 2.95–2.89 (m, 2H), 2.88–2.79 (m, 1H); δC
(CDCl3, 75 MHz) 173.2, 158.4, 138.2, 138.15, 138.0, 129.8,
128.51, 128.46, 128.43, 128.42, 128.0, 127.92, 127.9, 127.84,
127.82, 127.7, 113.7, 81.4, 73.5, 73.4, 72.6, 67.0, 65.8, 55.2,
51.6, 41.5, 38.0; HRMS (ESI) calcd for C37H42NO7 [M + H]+
+
(S)-Methyl 3-((2R,3R,4R,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)-3-(4-methoxyphenyl)-
propanoate (8db)
612.2961, found 612.2951.
According to general procedure, prepared from enal 6b (1.16 g,
7.16 mmol) and nitrone 5d (6.00 g, 14.3 mmol) to afford 8db
(3.39 g, 77%) as colourless oil; [α]2D0 +97.1 (c 0.35 in CH2Cl2);
νmax/cm−1 3454, 3031, 2918, 2863, 1735, 1611, 1513, 1454,
(S)-Methyl 3-((2S,3S,4R,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)-3-(furan-2-yl)propanoate
(8cc)
According to general procedure, prepared from enal 6c (0.57 g, 1250, 1095, 738, 698; δH (CDCl3, 300 MHz) 7.33–7.25 (m, 15H),
4.68 mmol) and nitrone 5c (3.91 g, 9.37 mmol) to afford 8cc 7.13 (d, J = 8.7 Hz, 2H), 6.87–6.84 (m, 2H), 6.80 (d, J = 8.7 Hz,
(2.26 g, 84%) as colourless oil; [α]2D0 −5.2 (c 1.55 in CH2Cl2); 2H), 5.49 (s, br, 1H), 4.55–4.46 (m, 4H), 3.96 (d, J = 11.1 Hz,
νmax/cm−1 3419, 3030, 2924, 2868, 1736, 1454, 1099, 737, 698; 1H), 3.87–3.83 (m, 2H), 3.80–3.77 (m, 2H), 3.73 (s, 3H), 3.68
δH (CDCl3, 300 MHz) 7.30–7.21 (m, 16H), 6.24–6.23 (m, 1H), (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H), 3.57 (s, 3H), 3.52 (d, J =
6.01 (d, J = 3.0 Hz, 1H), 5.58 (s, br, 1H), 4.69–4.61 (m, 3H), 4.8 Hz, 1H), 3.44–3.38 (m, 1H), 3.19 (t, J = 4.8 Hz, 1H), 2.86
4.50–4.44 (m, 4H), 4.25 (d, J = 11.4 Hz, 1H), 3.96–3.90 (m, 3H), (dd, J1 = 9.0 Hz, J2 = 15.6 Hz, 1H), 2.56 (dd, J1 = 5.7 Hz, J2 =
3.69–3.61 (m, 2H), 3.59 (s, 3H), 3.26–3.23 (m, 1H), 2.78–2.75 15.9 Hz, 1H); δC (CDCl3, 75 MHz) 174.6, 158.5, 138.4, 138.3,
(m, 1H); δC (CDCl3, 75 MHz) 173.0, 154.6, 141.5, 138.3, 138.2, 137.6, 132.8, 129.1, 128.4, 128.2, 127.8, 127.7, 127.5, 114.0,
138.1, 128.4, 128.37, 128.0, 127.8, 127.7, 110.4, 106.7, 80.3, 81.8, 79.0, 77.9, 73.5, 71.9, 71.2, 68.2, 67.3, 55.3, 51.7, 40.2,
75.3, 73.5, 73.2, 72.7, 66.8, 65.8, 51.8, 36.4, 35.3; HRMS (ESI) 34.9; HRMS (ESI) calcd for C37H42NO7 [M + H]+ 612.2961,
calcd for C34H38NO7+ [M + H]+ 572.2648, found 572.2640.
found 612.2955.
4628 | Org. Biomol. Chem., 2013, 11, 4622–4639
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Paper
(R)-Methyl 3-((2R,3R,4R,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)-1-hydroxypyrrolidin-2-yl)-3-(furan-2-yl)propanoate
(8dc)
(S)-Methyl 3-(4-methoxyphenyl)-3-((2R,3R,4R,5R)-3,4,5-
tris(benzyloxy)-1-hydroxypiperidin-2-yl)propanoate (8eb)
According to general procedure, prepared from enal 6b (0.50 g,
According to general procedure, prepared from enal 6c (0.70 g, 3.08 mmol) and nitrone 5e (2.59 g, 6.20 mmol) to afford 8eb
5.75 mmol) and nitrone 5d (4.80 g, 11.5 mmol) to afford 8dc (1.34 g, 71%) as colourless oil; [α]2D0 +32.0 (c 0.50 in CH2Cl2);
(1.82 g, 55%) as colourless oil; [α]2D0 +21.1 (c 1.80 in CH2Cl2); νmax/cm−1 3446, 3031, 2919, 1667, 1514, 1456, 1123; δH (CDCl3,
νmax/cm−1 3448, 3030, 2949, 2864, 1735, 1454, 1094, 736, 698; 300 MHz) 7.34–7.12 (m, 15H), 6.86–6.80 (m, 4H), 5.28 (s, br,
δH (CDCl3, 300 MHz) 7.31–7.23 (m, 14H), 7.07–7.05 (m, 2H), 1H), 4.53–4.50 (m, 4H), 3.95 (d, J = 11.1 Hz, 1H), 3.86–3.82 (m,
6.29–6.27 (m, 1H), 6.10 (d, J = 3.3 Hz, 1H), 5.35 (s, br, 1H), 3H), 3.79–3.75 (m, 4H), 3.66 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H),
4.59–4.46 (m, 4H), 4.08 (s, 2H), 3.94–3.87 (m, 2H), 3.79 (t, J = 3.58 (m, 3H), 3.51 (d, J = 4.8 Hz, 1H), 3.40 (d, J = 4.5 Hz, 1H),
9.0 Hz, 1H), 3.68 (dd, J1 = 4.5 Hz, J2 = 9.0 Hz, 1H), 3.62 (d, J = 3.17 (t, J = 4.8 Hz, 1H), 2.85 (dd, J1 = 9.0 Hz, J2 = 15.9 Hz, 1H),
4.8 Hz, 1H), 3.60 (s, 3H), 3.46–3.40 (m, 1H), 3.32 (t, J = 4.5 Hz, 2.56 (dd, J1 = 5.4 Hz, J2 = 15.6 Hz, 1H); δC (CDCl3, 75 MHz)
1H), 2.83 (dd, J1 = 8.7 Hz, J2 = 16.2 Hz, 1H), 2.57 (dd, J1
=
174.7, 158.5, 138.5, 138.4, 137.7, 133.0, 129.1, 128.5, 128.4,
6.0 Hz, J2 = 16.2 Hz, 1H); δC (CDCl3, 75 MHz) 174.3, 155.0, 128.3, 127.8, 127.73, 127.70, 127.5, 114.0, 82.0, 79.1, 77.9, 73.6,
141.6, 138.4, 138.36, 137.8, 128.45, 128.42, 128.3, 127.8, 71.9, 71.3, 68.1, 67.4, 55.3, 51.8, 40.3, 35.0; HRMS (ESI) calcd
127.75, 127.68, 127.64, 127.5, 110.3, 106.1, 81.9, 79.2, 75.7, for C37H42NO7+ [M + H]+ 612.2961, found 612.2955.
73.5, 71.9, 71.4, 67.9, 67.3, 51.9, 35.4, 33.3; HRMS (ESI) calcd
for C34H38NO7+ [M + H]+ 572.2648, found 572.2640.
(4S,4aR,5R,6R,7R,8R)-5,6,7,8-Tetrakis(benzyloxy)-4-
(S,E)-Methyl 3-((2R,3R,4R,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)-
phenyloctahydro-2H-[1,2]oxazino[2,3-a]azepin-2-one (7fa)
methyl)-1-hydroxypyrrolidin-2-yl)hex-4-enoate (8dd)
According to general procedure, prepared from enal 6a
According to general procedure, prepared from enal 6d (0.35 mL, 2.78 mmol) and nitrone 5f (2.99 g, 5.56 mmol) to
(0.80 mL, 7.24 mmol) and nitrone 5d (6.00 g, 14.30 mmol) to afford 7fa (1.50 g, 81%) as colourless oil; [α]2D0 +7.3 (c 3.0 in
afford 8dd (2.43 g, 62%) as colourless oil; [α]D20 +40.0 (c 1.05 in CH2Cl2); νmax/cm−1 3062, 3029, 2922, 1761, 1495, 1454, 1101,
CH2Cl2); νmax/cm−1 3449, 3031, 2949, 2866, 1736, 1454, 1109, 738, 698; δH (CDCl3, 300 MHz) 7.36–7.20 (m, 20H), 7.04–7.03
736, 698; δH (CDCl3, 300 MHz) 7.33–7.23 (m, 15H), 5.52–5.45 (m, 5H), 4.76–4.58 (m, 4H), 4.49–4.42 (m, 1H), 4.31–4.29 (m,
(m, 1H), 5.40–5.34 (m, 1H), 5.33 (s, br, 1H), 4.56–4.47 (m, 4H), 3H), 3.95–3.75 (m, 5H), 3.68 (m, 1H), 3.40 (d, J = 14.5 Hz, 1H),
4.40–4.27 (m, 2H), 3.91 (d, J = 5.4 Hz, 1H), 3.83–3.77 (m, 1H), 3.26 (m, 1H), 3.07 (dd, J1 = 9.6 Hz, J2 = 14.7 Hz, 1H), 2.49 (dd,
3.69 (dd, J1 = 4.5 Hz, J2 = 9.0 Hz, 1H), 3.58 (s, 3H), 3.54 (d, J = J1 = 2.7 Hz, J2 = 14.7 Hz, 1H); δC (CDCl3, 75 MHz) 174.9, 143.2,
5.4 Hz, 1H), 3.41–3.35 (m, 1H), 3.12–3.06 (m, 1H), 2.97 (t, J = 138.8 138.42, 138.40, 137.4, 128.8, 128.5, 128.38, 128.36,
5.1 Hz, 1H), 2.51 (dd, J1 = 7.8 Hz, J2 = 15.6 Hz, 1H), 2.27–2.16 127.95, 127.92, 127.90, 127.8, 127.74, 127.70, 127.6, 127.1,
(m, 1H), 1.63 (d, J = 6.0 Hz, 3H); δC (CDCl3, 75 MHz) 174.8, 78.2, 77.4, 76.0, 73.7, 73.4, 72.5, 72.3, 71.5, 52.4, 42.3, 36.0;
+
138.5, 138.4, 137.9, 130.8, 128.5, 128.48, 128.46, 127.90, HRMS (ESI) calcd for C43H44NO5 [M + H]+ 670.3159, found
127.88, 127.7, 127.6, 127.5, 82.0, 79.1, 75.9, 73.6, 71.9, 71.5, 670.3159.
68.4, 67.5, 51.7, 39.3, 35.4, 18.2; HRMS (ESI) calcd for
C33H40NO6+ [M + H]+ 546.2856, found 546.2842.
General procedure for reduction of γ-hydroxyl amino esters 8
and subsequent cyclization to lactams 9
(S)-Methyl 3-phenyl-3-((2R,3R,4R,5R)-3,4,5-tris(benzyloxy)-
1-hydroxypiperidin-2-yl)propanoate (8ea)
Activated Zn (0.65 g, 10 mmol) and Cu(OAc)2·H2O (20 mg,
According to general procedure, prepared from enal 6a 0.1 mmol) were added to HOAc (15 mL), and the suspension
(0.50 mL, 3.97 mmol) and nitrone 5e (3.60 g, 8.60 mmol) to was stirred for five minutes at room temperature. Hydroxyl-
afford 8ea (1.50 g, 64%) as colourless oil; [α]2D0 +24.0 (c 0.25 in amine 8 (1 mmol) in HOAc (5 mL) was added to the suspension,
CH2Cl2); νmax/cm−1 3439, 3030, 2923, 2860, 1735, 1453, 1119, and then stirred at 50 °C until TLC indicated that the starting
737, 698; δH (CDCl3, 300 MHz) 7.35–7.19 (m, 18H), 6.83–6.82 material disappeared. The mixture was filtered through Celite,
(m, 2H), 5.41 (s, br, 1H), 4.69–4.46 (m, 4H), 3.90–3.77 (m, 5H), concentrated under reduced pressure, and then redissolved in
3.66 (dd, J1 = 4.2 Hz, J2 = 8.7 Hz, 1H), 3.59 (s, 3H), 3.53 (d, J = dichloromethane. The solution was washed with sat. aq.
4.5 Hz, 1H), 3.43–3.37 (m, 1H), 3.22 (t, J = 5.1 Hz, 1H), 2.88 NaHCO3 and brine, dried over MgSO4, and concentrated
(dd, J1 = 9.0 Hz, J2 = 15.9 Hz, 1H), 2.59 (dd, J1 = 5.1 Hz, J2 = again. The residue was redissolved in MeOH, K2CO3 (0.18 g,
15.9 Hz, 1H); δC (CDCl3, 75 MHz) 174.7, 141.0, 138.5, 138.4, 1.30 mmol) was added. The mixture was stirred at 55 °C until
137.6, 128.6, 128.48, 128.47, 128.3, 128.2, 127.9, 127.8, 127.72, TLC showed the intermediate disappeared. The reaction
127.69, 127.6, 126.8, 81.9, 79.2, 78.0, 73.6, 72.0, 71.2, mixture was concentrated and purified by silica gel chromato-
+
68.0, 67.3, 51.8, 41.0, 34.7; HRMS (ESI) calcd for C36H40NO6
[M + H]+ 582.2856, found 582.2842.
graphy (EtOAc–petroleum ether) to give compound 9 as colour-
less oil.
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(1R,6S,7S,7aS)-6,7-Bis(benzyloxy)-1-phenyltetrahydro-1H-
pyrrolizin-3(2H)-one (9aa)
(dd, J1 = 6.0 Hz, J2 = 12.3 Hz, 1H), 3.16–3.06 (m, 1H), 2.86–2.78
(m, 1H), 2.16 (dd, J1 = 1.6 Hz, J2 = 16.5 Hz, 1H), 1.58 (d, J =
6.0 Hz, 3H); δC (CDCl3, 75 MHz) 174.4, 137.7, 137.4, 129.6,
128.5, 128.4, 127.9, 127.8, 127.7, 127.5, 84.3, 81.7, 72.0, 71.5,
Following general procedure, starting from 8aa (1.44 g,
3.10 mmol) to give 9aa (1.10 g, 86%) as colourless oil;
[α]2D0 +120.0 (c 0.75 in CH2Cl2); νmax/cm−1 3030, 2918, 1696,
1454, 1110, 739, 699; δH (CDCl3, 300 MHz) 7.31–7.11 (m, 15H),
4.37 (d, J = 11.7 Hz, 1H), 4.31–4.25 (m, 2H), 4.21–4.12 (m, 2H),
+
68.3, 46.3, 40.1, 39.0, 17.8; HRMS (ESI) calcd for C24H28NO3
[M + H]+ 378.2069, found 378.2057.
(1R,5S,6S,7S,7aS)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-
1-phenyltetrahydro-1H-pyrrolizin-3(2H)-one (9ba)
4.04 (d, J = 11.4 Hz, 1H), 3.84–3.78 (m, 1H), 3.68 (dd, J1
4.2 Hz, J2 = 12.3 Hz, 1H), 3.41–3.31 (m, 2H), 3.08 (dd, J1
=
=
Following general procedure, starting from 8ba (1.06 g,
1.83 mmol) to give 9ba (0.89 g, 90%) as colourless oil;
[α]2D0 +44.0 (c 3.00 in CH2Cl2); νmax/cm−1 3031, 2866, 1695,
1412, 1113, 741, 699; δH (CDCl3, 300 MHz) 7.32–7.24 (m, 14H),
7.18–7.14 (m, 4H), 7.07–7.04 (m, 2H), 4.58–4.33 (m, 4H),
4.29–4.18 (m, 3H), 4.08 (q, J = 4.5 Hz, 1H), 3.89 (d, J = 11.1 Hz,
1H), 3.80–3.67 (m, 2H), 3.56 (dd, J1 = 4.2 Hz, J2 = 9.6 Hz, 1H),
3.38 (dd, J1 = 5.4 Hz, J2 = 8.1 Hz, 1H), 3.07 (dd, J1 = 9.0 Hz, J2 =
17.1 Hz, 1H), 2.60 (dd, J1 = 2.7 Hz, J2 = 17.1 Hz, 1H); δC (CDCl3,
75 MHz) 174.0, 140.1, 137.9, 137.7, 137.6, 128.8, 128.4, 128.36,
128.32, 128.0, 127.9, 127.8, 127.7, 127.4, 87.7, 83.0, 73.3, 72.3,
72.2, 69.0, 67.4, 58.9, 40.26, 40.24; HRMS (ESI) calcd for
C14H18NO4+ [M + H]+ 534.2639, found 534.2623.
9.0 Hz, J2 = 17.1 Hz, 1H), 2.62 (dd, J1 = 2.7 Hz, J2 = 17.1 Hz,
1H); δC (CDCl3, 75 MHz) 174.4, 140.1, 137.6, 137.3, 128.8,
128.47, 128.41, 128.0, 127.9, 127.8, 127.4, 84.6, 81.8, 72.3, 71.6,
+
68.5, 46.4, 40.5, 40.3; HRMS (ESI) calcd for C27H28NO3
[M + H]+ 414.2069, found 414.2062.
(1R,6S,7S,7aS)-6,7-Bis(benzyloxy)-1-(4-methoxyphenyl)-
tetrahydro-1H-pyrrolizin-3(2H)-one (9ab)
Following general procedure, starting from 8ab (0.89 g,
1.81 mmol) to give 9ab (0.68 g, 85%) as colourless oil;
[α]2D0 +124.0 (c 1.00 in CH2Cl2); νmax/cm−1 3031, 2932, 1695,
1514, 1454, 1250, 1111, 832, 740, 699; δH (CDCl3, 300 MHz)
7.31–7.13 (m, 10H), 7.02 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz,
2H), 4.35 (t, J = 11.4 Hz, 2H), 4.26 (d, J = 11.7 Hz, 1H),
4.17–4.10 (m, 3H), 3.77–3.71 (m, 4H), 3.67 (d, J = 4.2 Hz, 1H),
3.40–3.32 (m, 2H), 3.05 (dd, J1 = 9.0 Hz, J2 = 16.9 Hz, 1H), 2.55
(dd, J1 = 2.7 Hz, J2 = 16.9 Hz, 1H); δC (CDCl3, 75 MHz) 174.3,
158.6, 137.6, 137.3, 132.1, 128.9, 128.4, 128.3, 127.8, 127.77,
127.74, 127.72, 114.0, 84.7, 81.7, 72.2, 71.5, 68.7, 55.1, 46.3,
(1R,5S,6S,7S,7aS)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-3(2H)-one (9bb)
Following general procedure, starting from 8bb (0.65 g,
1.07 mmol) to give 9bb (0.50 g, 82%) as colourless oil;
[α]2D0 +46.7 (c 1.20 in CH2Cl2); νmax/cm−1 3030, 2864, 1694,
1454, 1251, 1114, 739, 698; δH (CDCl3, 300 MHz) 7.32–7.16 (m,
13H), 7.16–7.05 (m, 4H), 6.80 (d, J = 8.7 Hz, 2H), 4.59–4.52 (m,
2H), 4.46 (d, J = 11.1 Hz, 1H), 4.36 (d, J = 11.7 Hz, 1H),
4.30–4.20 (m, 3H), 4.07 (q, J = 4.5 Hz, 1H), 3.98 (d, J = 11.4 Hz,
1H), 3.75–3.67 (m, 5H), 3.57 (dd, J1 = 3.9 Hz, J2 = 9.6 Hz, 1H),
3.39 (dd, J1 = 5.1 Hz, J2 = 8.1 Hz, 1H), 3.08 (dd, J1 = 9.0 Hz, J2 =
16.8 Hz, 1H), 2.56 (dd, J1 = 5.4 Hz, J2 = 16.8 Hz, 1H); δC (CDCl3,
75 MHz) 174.0, 158.8, 138.0, 137.8, 137.7, 132.2, 129.0, 128.45,
128.40, 128.36, 128.0, 127.8, 114.2, 87.9, 83.0, 73.3, 72.3, 72.2,
69.0, 67.7, 58.9, 55.3, 40.6, 39.7; HRMS (ESI) calcd for
C36H38NO5+ [M + H]+ 564.2750, found 564.2743.
+
40.6, 39.9; HRMS (ESI) calcd for C28H30NO4 [M + H]+
444.2175, found 444.2168.
(1S,6S,7S,7aS)-6,7-Bis(benzyloxy)-1-(furan-2-yl)tetrahydro-1H-
pyrrolizin-3(2H)-one (9ac)
Following general procedure, starting from 8ac (0.74 g,
1.65 mmol) to give 9ac (0.50 g, 75%) as colourless oil;
[α]2D0 +74.8 (c 2.30 in CH2Cl2); νmax/cm−1 3031, 2875, 1700,
1454, 1111, 738, 698; δH (CDCl3, 300 MHz) 7.35–7.23 (m, 11H),
6.26 (q, J = 1.5 Hz, 1H), 6.11 (d, J = 3.3 Hz, 1H), 4.47–4.41 (m,
2H), 4.38–4.29 (m, 2H), 4.16 (q, J = 2.1 Hz, 1H), 4.08 (t, J = 7.2
Hz, 1H), 3.88–3.81 (m, 1H), 3.65 (dd, J1 = 4.8 Hz, J2 = 12.0 Hz,
1H), 3.42–3.34 (m, 2H), 2.96 (dd, J1 = 8.7 Hz, J2 = 16.8 Hz, 1H),
2.59 (dd, J1 = 3.3 Hz, J2 = 16.8 Hz, 1H); δC (CDCl3, 75 MHz)
173.9, 153.6, 142.0, 137.7, 137.4, 128.4, 128.36, 127.9, 127.8,
127.75, 110.4, 107.2, 84.5, 82.5, 72.6, 71.7, 67.7, 46.3, 38.1,
34.8; HRMS (ESI) calcd for C25H25NO4Na+ [M + Na]+ 426.1681,
found 426.1675.
(1S,5S,6S,7S,7aS)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-
1-(furan-2-yl)tetrahydro-1H-pyrrolizin-3(2H)-one (9bc)
Following general procedure, starting from 8bc (0.58 g,
1.00 mmol) to give 9bc (0.45 g, 85%) as colourless oil;
[α]D20 +56.7 (c 1.2 in CH2Cl2); νmax/cm−1 3030, 2864, 1698, 1454,
1363, 1115, 737, 698; δH (CDCl3, 300 MHz) 7.35–7.19 (m, 16H),
6.30 (t, J = 2.4 Hz, 1H), 6.16 (d, J = 3.0 Hz, 1H), 4.67–4.45 (m,
4H), 4.39 (d, J = 11.4 Hz, 1H), 4.30 (t, J = 4.8 Hz, 1H), 4.24–4.14
(m, 2H), 4.04 (q, J = 4.5 Hz, 1H), 3.86–3.80 (m, 1H), 3.69 (dd, J1
= 5.4 Hz, J2 = 9.9 Hz, 1H), 3.55 (dd, J1 = 3.6 Hz, J2 = 9.9 Hz, 1H),
(1R,6S,7S,7aS)-6,7-Bis(benzyloxy)-1-((E)-prop-1-en-1-yl)-
tetrahydro-1H-pyrrolizin-3(2H)-one (9ad)
Following general procedure, starting from 8ad (0.56 g, 3.46 (dd, J1 = 5.4 Hz, J2 = 8.1 Hz, 1H), 2.97 (dd, J1 = 9.0 Hz, J2 =
1.33 mmol) to give 9ad (0.40 g, 80%) as colourless oil; 16.8 Hz, 1H), 2.60 (dd, J1 = 3.3 Hz, J2 = 16.8 Hz, 1H); δC (CDCl3,
[α]2D0 +15.5 (c 3.10 in CH2Cl2); νmax/cm−1 3031, 2917, 1698, 75 MHz) 173.6, 153.6, 142.2, 138.1, 137.9, 128.48, 128.45,
1453, 1416, 1110, 738, 698; δH (CDCl3, 300 MHz) 7.37–7.29 (m, 128.42, 128.0, 127.9, 127.8, 110.6, 107.3, 87.8, 83.8, 73.4, 72.8,
10H), 5.53–5.30 (m, 2H), 4.58–4.43 (m, 4H), 4.18–4.15 (m, 1H), 72.4, 69.2, 66.9, 59.0, 38.2, 34.7; HRMS (ESI) calcd for
3.97–3.91 (m, 2H), 3.78 (dd, J1 = 3.0 Hz, J2 = 12.3 Hz, 1H), 3.28 C33H34NO5+ [M + H]+ 524.2437, found 524.2428.
4630 | Org. Biomol. Chem., 2013, 11, 4622–4639
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Paper
(1R,5S,6S,7S,7aS)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
((E)-prop-1-en-1-yl)tetrahydro-1H-pyrrolizin-3(2H)-one (9bd)
4.02–3.95 (m, 2H), 4.18–4.08 (m, 1H), 3.76 (t, J = 8.7 Hz, 2H),
3.16 (dd, J1 = 4.5 Hz, J2 = 7.5 Hz, 1H), 3.03 (dd, J1 = 8.4 Hz, J2 =
16.2 Hz, 1H), 2.50 (dd, J1 = 1.5 Hz, J2 = 13.5 Hz, 1H); δC (CDCl3,
75 MHz) 175.2, 154.3, 142.1, 138.3, 138.2, 137.7, 128.5, 128.47,
128.43, 128.06, 127.99, 127.91, 127.8, 127.7, 110.5, 107.2, 79.4,
73.9, 73.3, 72.9, 66.9, 66.5, 57.0, 39.6, 35.8; HRMS (ESI) calcd
for C33H34NO5+ [M + H]+ 524.2437, found 524.2435.
Following general procedure, starting from 8bd (1.00 g,
1.83 mmol) to give 9bd (0.75 g, 82%) as colourless oil;
[α]2D0 +32.9 (c 0.85 in CH2Cl2); νmax/cm−1 3031, 2919, 2862,
1687, 1453, 1110, 737, 698; δH (CDCl3, 300 MHz) 7.33–7.24 (m,
15H), 5.54–5.35 (m, 2H), 4.60–4.45 (m, 6H), 4.31 (t, J = 4.2 Hz,
1H), 4.11–4.05 (m, 1H), 4.06–4.01 (m, 1H), 3.99–3.91 (m, 1H),
3.66–3.54 (m, 2H), 3.11–3.06 (m, 1H), 2.84–2.76 (m, 1H), 2.19
(dd, J1 = 3.0 Hz, J2 = 16.5 Hz, 1H), 1.63 (d, J = 5.7 Hz, 3H); δC
(1R,5S,6R,7S,7aS)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
((E)-prop-1-en-1-yl)tetrahydro-1H-pyrrolizin-3(2H)-one (9cd)
(CDCl3, 75 MHz) 174.2, 138.1, 137.9, 137.8, 129.3, 128.5, 128.0, Following general procedure, starting from 8cd (0.88 g,
127.9, 127.8, 127.77, 127.71, 87.7, 82.9, 73.4, 72.3, 72.2, 69.1, 1.62 mmol) to give 9cd (0.72 g, 90%) as colourless oil;
67.3, 59.0, 39.7, 38.5, 18.0; HRMS (ESI) calcd for [α]2D0 +8.0 (c 1.5 in CH2Cl2); νmax/cm−1 3062, 3030, 2918, 2874,
C32H35NO4Na+ [M + Na]+ 520.2464, found 520.2458.
1697, 1453, 1139, 738, 698; δH (CDCl3, 300 MHz) 7.31–7.25 (m,
15H), 5.56–5.44 (m, 1H), 5.28–5.20 (m, 1H), 4.71–4.62 (m, 2H),
4.56–4.52 (m, 3H), 4.38 (d, J = 11.7 Hz, 1H), 4.23–4.11 (m, 3H),
3.96–3.91 (m, 1H), 3.79–3.73 (m, 1H), 3.68 (dd, J1 = 4.2 Hz, J2 =
(1R,5S,6R,7S,7aS)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
phenyltetrahydro-1H-pyrrolizin-3(2H)-one (9ca)
7.5 Hz, 1H), 3.08–3.01 (m, 1H), 2.84 (dd, J1 = 7.8 Hz, J2
=
Following general procedure, starting from 8ca (0.72 g,
1.27 mmol) to give 9ca (0.50 g, 76%) as colourless oil;
[α]2D0 +47.8 (c 1.80 in CH2Cl2); νmax/cm−1 3029, 2924, 2873,
1696, 1454, 1142, 737, 699; δH (CDCl3, 300 MHz) 7.23–7.15 (m,
16H), 7.04–6.99 (m, 4H), 4.77–4.45 (m, 4H), 4.43–4.38 (m, 1H),
4.04–3.88 (m, 4H), 3.78 (d, J = 11.1 Hz, 1H), 3.71–3.61 (m, 2H),
3.06 (dd, J1 = 8.4 Hz, J2 = 16.5 Hz, 1H), 2.91 (dd, J1 = 4.2 Hz,
J2 = 8.1 Hz, 1H), 2.46 (d, J = 16.8 Hz, 1H); δC (CDCl3, 75 MHz)
175.6, 140.6, 138.23, 138.16, 137.5, 128.9, 128.45, 128.42,
128.40, 128.0, 127.9, 127.8, 127.7, 127.68, 127.5, 79.2, 79.13,
73.9, 73.3, 72.4, 67.0, 66.3, 57.0, 41.5, 41.2; HRMS (ESI) calcd
for C35H36NO4+ [M + H]+ 534.2644, found 534.2633.
16.2 Hz, 1H), 2.16 (d, J = 16.2 Hz, 2H), 1.60 (d, J = 6.0 Hz, 3H);
δC (CDCl3, 75 MHz) 175.4, 138.2, 138.1, 137.6, 128.6, 128.4,
128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 79.3, 78.0, 73.8, 73.2,
72.2, 66.4, 66.2, 56.6, 40.3, 38.4, 17.9; HRMS (ESI) calcd for
C32H36NO4+ [M + H]+ 498.2644, found 498.2640.
(1S,5S,6R,7R,7aR)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
phenyltetrahydro-1H-pyrrolizin-3(2H)-one (9da)
Following general procedure, starting from 8da (1.52 g,
2.61 mmol) to give 9da (1.19 g, 86%) as colourless oil;
[α]2D0 −45.2 (c 1.55 in CH2Cl2); νmax/cm−1 3030, 2870, 1692,
1454, 1109, 736, 698; δH (CDCl3, 300 MHz) 7.32–7.02 (m, 20H),
4.57–4.45 (m, 4H), 4.38 (d, J = 8.4 Hz, 1H), 4.24–4.14 (m, 2H),
4.10–4.02 (m, 2H), 3.95–3.91 (m, 1H), 3.75 (d, J = 6.4 Hz, 1H),
3.66 (t, J = 7.8 Hz, 1H), 3.49 (t, J = 7.8 Hz, 1H), 3.05 (dd, J1 =
8.7 Hz, J2 = 16.8 Hz, 1H), 2.59 (d, J = 17.1 Hz, 1H); δC (CDCl3,
75 MHz) 172.7, 140.2, 138.3, 138.0, 137.7, 128.3, 128.2, 127.9,
127.7, 127.68, 127.66, 127.4, 127.1, 85.8, 79.1, 73.2, 73.1, 72.6,
(1R,5S,6R,7S,7aS)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-3(2H)-one (9cb)
Following general procedure, starting from 8cb (1.50 g,
2.46 mmol) to give 9cb (1.13 g, 81%) as colourless oil;
[α]2D0 +37.3 (c 0.75 in CH2Cl2); νmax/cm−1 3030, 2930, 2870,
1694, 1513, 1454, 1251, 1115, 737, 698; δH (CDCl3, 300 MHz)
7.31–7.21 (m, 13H), 7.14–7.11 (m, 2H), 6.98 (d, J = 8.7 Hz, 2H),
6.80 (d, J = 8.7 Hz, 2H), 4.55–4.53 (m, 4H), 4.43 (t, J = 7.2 Hz,
1H), 4.17 (d, J = 11.4 Hz, 1H), 4.11–3.91 (m, 4H), 3.79–3.74 (m,
4H), 3.64 (t, J = 4.5 Hz, 1H), 3.10 (dd, J1 = 8.4 Hz, J2 = 16.5 Hz,
1H), 3.02 (dd, J1 = 4.2 Hz, J2 = 7.8 Hz, 1H), 2.47 (d, J = 16.8 Hz,
1H); δC (CDCl3, 75 MHz) 175.6, 158.8, 138.2, 138.1, 137.5,
132.5, 128.7, 128.38, 128.36, 127.88, 127.85, 127.7, 127.65,
127.61, 114.1, 79.1, 78.9, 73.7, 72.3, 67.2, 66.3, 56.8, 55.3, 41.6,
+
66.2, 64.0, 55.3, 41.9, 40.6; HRMS (ESI) calcd for C35H36NO4
[M + H]+ 534.2644, found 534.2643.
(1S,5S,6R,7R,7aR)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-3(2H)-one (9db)
Following general procedure, starting from 8db (1.70 g,
2.79 mmol) to give 9db (1.12 g, 71%) as colourless oil;
[α]2D0 −41.9 (c 1.05 in CH2Cl2); νmax/cm−1 3030, 2917, 2870,
1697, 1514, 1454, 1113, 832, 740, 699; δH (CDCl3, 300 MHz)
7.30–7.16 (m, 15H), 7.07 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 8.7 Hz,
2H), 4.58–4.44 (m, 4H), 3.39 (d, J = 11.4 Hz, 1H), 4.24 (t, J =
7.5 Hz, 1H), 4.20–4.17 (m, 1H), 4.12–4.03 (m, 2H), 3.96–3.92
(m, 1H), 3.79–3.75 (m, 1H), 3.65 (s, 3H), 3.60 (d, J = 7.5 Hz,
+
40.5; HRMS (ESI) calcd for C34H38NO5 [M + H]+ 564.2744,
found 564.2744.
(1S,5S,6R,7S,7aS)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
(furan-2-yl)tetrahydro-1H-pyrrolizin-3(2H)-one (9cc)
Following general procedure, starting from 8cc (0.54 g, 1H), 3.54 (t, J = 7.5 Hz, 1H), 3.05 (dd, J1 = 8.7 Hz, J2 = 17.1 Hz,
0.94 mmol) to give 9cc (0.40 g, 81%) as colourless oil; 1H), 2.53 (d, J = 17.1 Hz, 1H); δC (CDCl3, 75 MHz) 172.7, 158.5,
[α]2D0 +40.0 (c 0.50 in CH2Cl2); νmax/cm−1 3030, 2927, 2872, 138.4, 138.1, 137.8, 132.4, 129.3, 128.34, 128.31, 128.2, 127.9,
1699, 1455, 1139, 737, 698; δH (CDCl3, 300 MHz) 7.35–7.20 (m, 127.67, 127.61, 127.4, 113.6, 85.8, 79.1, 73.2, 73.1, 72.5, 66.4,
+
16H), 6.29–6.28 (m, 1H), 6.10 (d, J = 3.3 Hz, 1H), 4.69 (m, 2H), 64.2, 55.3, 55.2, 42.3, 39.9; HRMS (ESI) calcd for C36H40NO6
4.54 (m, 2H), 4.38–4.32 (m, 2H), 4.20 (d, J = 8.4 Hz, 1H), [M + H]+ 582.2856, found: 582.2844.
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Organic & Biomolecular Chemistry
(1R,5S,6R,7R,7aR)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
(furan-2-yl)tetrahydro-1H-pyrrolizin-3(2H)-one (9dc)
(dd, J1 = 5.1 Hz, J2 = 9.6 Hz, 1H), 4.12–4.05 (m, 2H), 3.97–3.93
(m, 1H), 3.77 (dd, J1 = 1.9 Hz, J2 = 9.6 Hz, 1H), 3.68 (s, 3H),
3.65–3.62 (m, 1H), 3.56–3.51 (m, 1H), 3.07 (dd, J1 = 8.9 Hz, J2 =
17.2 Hz, 1H), 2.54 (d, J = 17.0 Hz, 1H); δC (CDCl3, 75 MHz)
172.9, 158.8, 138.6, 138.3, 137.9, 132.6, 129.5, 128.5, 128.48,
128.39, 128.1, 127.84, 127.80, 127.6, 113.8, 86.0, 79.4, 73.4,
73.3, 72.7, 66.7, 55.5, 55.4, 42.5, 40.1; HRMS (ESI) calcd for
C35H38NO3+ [M + H]+ 564.2750, found 564.2759.
Following general procedure, starting from 8dc (0.42 g,
0.74 mmol) to give 9dc (0.35 g, 91%) as colourless oil;
[α]2D0 −43.3 (c 0.60 in CH2Cl2); νmax/cm−1 3030, 2921, 2866,
1696, 1454, 1415, 1112, 736, 698; δH (CDCl3, 300 MHz)
7.37–7.17 (m, 16H), 6.12–6.08 (m, 2H), 4.69–4.55 (m, 3H),
4.52–4.42 (m, 3H), 4.24 (t, J = 7.2 Hz, 1H), 4.02–3.93 (m, 3H),
3.80–3.74 (m, 2H), 3.57 (t, J = 7.5 Hz, 1H), 2.98 (dd, J1 = 8.4 Hz,
J2 = 16.8 Hz, 1H), 2.60 (d, J = 16.5 Hz, 1H); δC (CDCl3, 75 MHz)
172.3, 153.8, 141.6, 138.5, 138.3, 137.9, 128.5, 128.3, 127.9,
127.8, 127.4, 110.5, 107.5, 85.6, 79.8, 73.3, 73.26, 73.1, 66.1,
(1S,6R,7R,8R,9R,9aR)-6,7,8,9-Tetrakis(benzyloxy)-1-
phenylhexahydro-1H-pyrrolo[1,2-a]azepin-3(2H)-one (9fa)
Following general procedure, starting from 8fa (0.60 g,
0.85 mmol) to give 9fa (0.40 g, 72%) as colourless oil;
[α]2D0 −45.0 (c 0.80 in CH2Cl2); νmax/cm−1 3030, 2921, 2878,
1698, 1496, 1454, 1109, 736, 698; δH (CDCl3, 300 MHz)
7.50–7.19 (m, 21H), 7.08–7.00 (m, 4H), 4.80 (d, J = 12.3 Hz,
1H), 4.73–4.63 (m, 3H), 4.64–4.57 (m, 2H), 4.50 (d, J = 12.0 Hz,
+
64.3, 55.3, 40.2, 35.8; HRMS (ESI) calcd for C33H34NO5
[M + H]+ 524.2437, found 524.2435.
(1S,5S,6R,7R,7aR)-6,7-Bis(benzyloxy)-5-((benzyloxy)methyl)-1-
((E)-prop-1-en-1-yl)tetrahydro-1H-pyrrolizin-3(2H)-one (9dd)
1H), 4.37 (d, J = 12.0 Hz, 1H), 4.24 (dd, J1 = 6.9 Hz, J2
14.1 Hz, 1H), 4.04–3.96 (m, 2H), 3.89–3.85 (m, 2H), 3.67 (d, J =
3.3 Hz, 1H), 3.04–2.91 (m, 2H), 2.65 (dd, J1 = 6.0 Hz, J2
=
Following general procedure, starting from 8dd (1.24 g,
2.28 mmol) to give 9dd (0.95 g, 84%) as colourless oil;
[α]2D0 −25.6 (c 1.80 in CH2Cl2); νmax/cm−1 3034, 2916, 1694, 153,
1123, 736, 696; δH (CDCl3, 300 MHz) 7.33–7.22 (m, 15H),
5.49–5.30 (m, 2H), 4.75–4.70 (m, 1H), 4.66–4.62 (m, 1H),
4.60–4.55 (m, 2H), 4.51–4.46 (m, 2H), 4.30–4.17 (m, 3H),
3.89–3.81 (m, 2H), 3.67 (d, J = 9.6 Hz, 1H), 2.98–2.91 (m, 1H),
2.81 (dd, J1 = 6.9 Hz, J2 = 16.2 Hz, 1H), 2.11 (d, J = 16.2 Hz,
1H), 1.28 (d, J = 5.1 Hz, 3H); δC (CDCl3, 75 MHz) 172.8, 138.4,
138.3, 138.1, 130.0, 128.4, 128.36, 128.3, 128.0, 127.7, 127.65,
127.58, 127.51, 127.5, 127.3, 85.2, 79.0, 73.5, 73.2, 72.2, 66.2,
64.0, 55.0, 42.2, 41.1, 17.5; HRMS (ESI) calcd for
C32H35NO4Na+ [M + Na]+ 520.2464, Found 520.2457.
=
16.8 Hz, 1H), 2.45 (dd, J1 = 9.0 Hz, J2 = 17.1 Hz, 1H); δC (CDCl3,
75 MHz) 173.4, 140.8, 138.9, 138.8, 138.7, 137.7, 128.9, 128.6,
128.4, 128.3, 128.29, 128.1, 128.0, 127.8, 127.69, 27.66,
127.6, 127.5, 127.4, 127.2, 127.0, 79.7, 79.0, 75.7, 74.0, 73.7,
72.2, 71.8, 66.5, 42.2, 39.6, 38.8; HRMS (ESI) calcd for
C43H43NO5Na+ [M + Na]+ 676.3039, found 676.3029.
General procedure for the reduction of lactams 9 to 11
LiAlH4 (104 mg, 3 mmol) was added to a solution of the
lactam 9 (1 mmol) in THF (10 mL) at 0 °C. The reaction
mixture was refluxed for 2 h, then quenched with water
(30 μL), an aqueous 10% NaOH (20 μL), and water (60 μL) and
stirred for 1 h at room temperature. Sodium sulphate was
added and the mixture was stirred for 1 h and filtered through
Celite, and the filtrate was concentrated under vacuum to give
a residue, which was purified by silica gel chromatography
(EtOAc–petroleum ether) to give an oil product.
(1S,6R,7R,8R,8aR)-6,7,8-Tris(benzyloxy)-1-
phenylhexahydroindolizin-3(2H)-one (9ea)
Following general procedure, starting from 8ea (1.16 g,
1.99 mmol) to give 9ea (0.80 g, 75%) as colourless oil;
[α]2D0 −70.0 (c 0.20 in CH2Cl2); νmax/cm−1 3355, 3030, 2924,
1690, 1453, 1100, 737, 698; δH (CDCl3, 300 MHz) 7.37–7.11 (m,
18H), 7.08–7.03 (m, 2H), 4.54–4.40 (m, 4H), 4.38 (d, J =
11.1 Hz, 1H), 4.23 (t, J = 7.2 Hz, 1H), 4.18–4.13 (m, 1H),
4.10–4.02 (m, 1H), 3.96–3.92 (m, 1H), 3.78–3.75 (m, 1H), 3.70
(t, J = 8.1 Hz, 1H), 3.50 (t, J = 7.8 Hz, 1H), 3.08 (dd, J1 = 8.7 Hz,
J2 = 17.1 Hz, 1H)), 2.61 (d, J = 17.1 Hz, 1H); δC (CDCl3, 75 MHz)
172.9, 140.4, 138.5, 138.2, 137.8, 128.5, 128.4, 128.0, 127.9,
127.8, 127.5, 127.3, 86.0, 79.3, 73.4, 73.2, 72.7, 66.5, 64.2, 55.5,
42.1, 40.8; HRMS (ESI) calcd for C35H36NO4 [M + H]+ 534.2644,
found 534.2639.
General procedure for hydrogenation of 9 or 11 to bicyclic
iminosugars 10 or 12
Conc. HCl (1.3 mL) and 10% Pd/C (13 mg) were added to a
solution of compound 9 or 11 (0.25 mmol) in methanol
(13 mL). The mixture was then stirred at room temperature
under an atmosphere of H2 overnight. After completion of the
reaction, the solution was filtered through Celite and washed
with methanol. The solvent was removed under reduced
pressure. For compound 10, the residue was purified by silica
gel chromatography (EtOAc–MeOH). And for compound 12,
the residue was neutralized by NH3·H2O (25%, 10 mL), then
purified by acid ion exchange resin column to give colourless
(1S,6R,7R,8R,8aR)-6,7,8-Tris(benzyloxy)-1-(4-methoxyphenyl)-
hexahydroindolizin-3(2H)-one (9eb)
Following general procedure, starting from 8eb (0.46 g, syrup 12.
0.75 mmol) to give 9eb (0.33 g, 78%) as colourless oil;
(1R,6S,7S,7aS)-6,7-Dihydroxy-1-phenyltetrahydro-1H-pyrrolizin-
3(2H)-one (10aa)
[α]D20 −52.0 (c 5.0 in CH2Cl2); νmax/cm−1 3031, 2924, 1686, 1513,
1454, 1251, 1104, 736, 698; δH (CDCl3, 300 MHz) 7.33–7.15 (m,
15H), 7.07 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 8.7 Hz, 2H), 4.59–4.37 Following general procedure, starting from 9aa (0.21 g,
(m, 4H), 4.38 (d, J = 11.3 Hz, 1H), 4.25 (t, J = 7.4 Hz, 1H), 4.18 0.50 mmol) to give 10aa (0.11 g, 94%) as colourless oil; [α]D20
4632 | Org. Biomol. Chem., 2013, 11, 4622–4639
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+104.0 (c 0.50 in CH3OH); νmax/cm−1 3342, 1658, 1125; δH (1R,5S,6S,7S,7aS)-6,7-Dihydroxy-5-(hydroxymethyl)-1-
(D2O, 300 MHz) 7.47–7.35 (m, 3H), 7.19 (d, J = 6.9 Hz, 2H), phenyltetrahydro-1H-pyrrolizin-3(2H)-one (10ba)
4.33 (q, J = 7.2 Hz, 1H), 4.25 (t, J = 7.8 Hz, 1H), 3.94 (t, J =
Following general procedure, starting from 9ba (0.19 g,
7.8 Hz, 1H), 3.61 (dd, J1 = 8.1 Hz, J2 = 12.0 Hz, 1H), 3.28 (dd, J1
0.35 mmol) to give 10ba (93 mg, 99%) as colourless oil;
= 8.4 Hz, J2 = 17.2 Hz, 1H), 3.20–3.10 (m, 2H), 2.62 (d, J =
[α]2D0 +27.6 (c 1.45 in CH3OH); νmax/cm−1 3316, 1659, 1406,
17.2 Hz, 1H); δC (D2O, 75 MHz) 176.0, 139.5, 128.9, 127.5,
1123, 618; δH (D2O, 300 MHz) 7.44–7.32 (m, 3H), 7.16 (d, J =
7.2 Hz, 2H), 4.23–4.13 (m, 2H), 3.96–3.87 (m, 2H), 3.69 (dd,
J1 = 3.3 Hz, J2 = 12.3 Hz, 1H), 3.51–3.49 (m, 1H), 3.27 (dd, J1 =
127.4, 77.3, 74.5, 67.8, 48.8, 46.0, 40.2; HRMS (ESI) calcd for
C14H18NO4+ [M + H]+ 264.1230, found 264.1229.
8.4 Hz, J2 = 17.1 Hz, 1H), 3.11 (t, J = 8.4 Hz, 1H), 2.57 (d, J =
17.1 Hz, 1H); δC (D2O, 75 MHz) 177.2, 139.6, 129.1, 127.7,
(1R,6S,7S,7aS)-6,7-Dihydroxy-1-(4-methoxyphenyl) tetrahydro-
1H-pyrrolizin-3(2H)-one (10ab)
127.6, 78.9, 74.3, 67.2, 60.6, 59.5, 40.25, 40.18; HRMS (ESI)
calcd for C14H18NO4+ [M + H]+ 264.1230, found 264.1229.
Following general procedure, starting from 9ab (0.12 g,
0.27 mmol) to give 10ab (70 mg, 99%) as colourless oil;
(1R,5S,6S,7S,7aS)-6,7-Dihydroxy-5-(hydroxymethyl)-1-
(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-3(2H)-one (10bb)
[α]2D0 +80.0 (c 0.20 in CH3OH); νmax/cm−1 3329, 2919, 1667,
1514, 1456, 1251, 1123, 618; δH (D2O, 300 MHz) 7.04 (d, J =
Following general procedure, starting from 9bb (0.17 g,
0.29 mmol) to give 10bb (85 mg, 99%) as colourless oil;
[α]D20 +108.0 (c 0.50 in CH3OH); νmax/cm−1 3338, 2931, 1662,
1514, 1437, 1122, 830, 618; δH (D2O, 300 MHz) 7.11 (d, J =
8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 4.22–4.16 (m, 2H), 3.95
(dd, J1 = 3.6 Hz, J2 = 12.3 Hz, 1H), 3.86 (t, J = 7.8 Hz, 1H), 3.81
(s, 3H), 3.72 (dd, J1 = 3.6 Hz, J2 = 12.0 Hz, 1H), 3.54–3.51 (m,
1H), 3.27 (dd, J1 = 8.4 Hz, J2 = 17.1 Hz, 1H), 3.17–3.11 (m, 1H),
2.53 (dd, J1 = 1.2 Hz, J2 = 17.1 Hz, 1H); δC (D2O, 75 MHz) 177.2,
158.1, 132.2, 128.8, 114.4, 78.9, 74.3, 67.4, 60.5, 59.4, 55.4,
8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.26 (q, J = 7.2 Hz, 1H),
4.14 (t, J = 7.8 Hz, 1H), 3.83–3.78 (m, 1H), 3.76 (s, 3H),
3.57–3.48 (m, 1H), 3.19 (dd, J1 = 8.4 Hz, J2 = 17.1 Hz, 1H),
3.11–3.03 (m, 2H), 2.49 (dd, J1 = 0.9 Hz, J2 = 17.1 Hz, 1H); δC
(D2O, 75 MHz) 176.3, 158.0, 132.2, 128.7, 114.3, 77.3, 74.5,
+
68.0, 55.2, 46.0, 40.4, 39.6; HRMS (ESI) calcd for C14H18NO4
[M + H]+ 264.1230, found 264.1229.
(1S,6S,7S,7aS)-6,7-Dihydroxy-1-propyltetrahydro-1H-pyrrolizin-
3(2H)-one (10ad)
40.4, 39.5; HRMS (ESI) calcd for C15H20NO5 [M + H]+
+
294.1336, found 294.1334.
Following general procedure, starting from 9ad (0.11 g,
0.29 mmol) to give 10ad (57 mg, 99%) as colourless oil;
[α]2D0 +40.0 (c 0.20 in CH3OH); νmax/cm−1 3313, 2929, 1660,
1448, 1123, 618; δH (D2O, 300 MHz) 4.41–4.34 (m, 1H), 3.97 (t,
J = 3.0 Hz, 2H), 3.61–3.54 (m, 1H), 3.25 (dd, J1 = 6.0 Hz, J2 =
12.0 Hz, 1H), 2.86 (dd, J1 = 8.4 Hz, J2 = 17.1 Hz, 1H), 2.63–2.61
(m, 1H), 2.22 (dd, J1 = 5.7 Hz, J2 = 17.1 Hz, 1H), 1.56–1.26 (m,
4H), 0.92 (t, J = 7.2 Hz, 3H); δC (D2O, 75 MHz) 177.2, 77.5, 74.1,
67.2, 46.3, 38.6, 33.2, 31.5, 19.8, 13.2; HRMS (ESI) calcd for
C10H18NO3+ [M + H]+ 200.1281, found 200.1281.
(1S,5S,6S,7S,7aS)-6,7-Dihydroxy-5-(hydroxymethyl)-1-
propyltetrahydro-1H-pyrrolizin-3(2H)-one (10bd)
Following general procedure, starting from 9bd (0.25 g,
0.51 mmol) to give 10bd (99 mg, 84%) as colourless oil;
[α]2D0 +32.0 (c 0.25 in CH3OH); νmax/cm−1 3342, 2929, 1661,
1418, 1085; δH (D2O, 300 MHz) 4.24–4.20 (m, 1H), 4.00–3.97
(m, 2H), 3.93 (dd, J1 = 3.6 Hz, J2 = 12.0 Hz, 1H), 3.75 (dd, J1 =
3.9 Hz, J2 = 12.0 Hz, 1H), 3.64–3.60 (m, 1H), 2.91 (dd, J1
8.6 Hz, J2 = 17.1 Hz, 1H), 2.66–2.65 (m, 1H), 2.25 (dd, J1
=
=
3.3 Hz, J2 = 8.2 Hz, 1H), 1.64–1.55 (m, 1H), 1.49–1.30 (m, 3H),
0.95 (t, J = 6.9 Hz, 3H); δC (D2O, 75 MHz) 178.2, 79.0, 73.9,
66.2, 60.7, 59.9, 38.3, 31.5, 19.9, 13.2; HRMS (ESI) calcd for
C11H20NO4+ [M + H]+ 230.1387, found 230.1386.
(1R,6S,7S,7aS)-6,7-Dihydroxy-1-((E)-prop-1-en-1-yl)tetrahydro-
1H-pyrrolizin-3(2H)-one (10ad′)
To a solution of 9ad (36 mg, 0.095 mmol) in dried CH2Cl2
(5 mL) at 0 °C was added BBr3 (37 μL, 4 eq.) under N2 atmos-
phere. The resulting mixture was stirred for 1 h, and then
quenched with MeOH (2 mL) at 0 °C. NH3·H2O was added and
the solvent was removed under reduced pressure. The residue
(1R,5S,6R,7S,7aS)-6,7-Dihydroxy-5-(hydroxymethyl)-1-
phenyltetrahydro-1H-pyrrolizin-3(2H)-one (10ca)
was purified by silica gel chromatography (EtOAc–MeOH, 20 : 1 Following general procedure, starting from 9ca (0.11 g,
v/v) give colourless syrup 10ad′ (18 mg, 96%) as colourless oil; 1.27 mmol) to give 10ca (51 mg, 91%) as colourless oil;
[α]D20 +33.3 (c 0.30 in CH3OH); νmax/cm−1 3341, 2924, 1656, [α]2D0 +120.0 (c 0.30 in CH3OH); νmax/cm−1 3374, 2946, 1660,
1456, 1093; δH (D2O, 300 MHz) 5.65–5.58 (m, 1H), 5.50–5.42 1418, 1122, 703; δH (D2O, 300 MHz) 7.51–7.42 (m, 3H),
(m, 1H), 4.32 (t, J = 6.0 Hz, 1H), 3.99–3.88 (m, 2H), 3.50 (q, J = 7.25–7.22 (m, 2H), 4.49 (t, J = 7.2 Hz, 1H), 4.24 (t, J = 4.8 Hz,
7.5 Hz, 1H), 3.26–3.20 (m, 2H), 2.96 (dd, J1 = 7.5 Hz, J2
=
1H), 4.03–3.96 (m, 2H), 3.92–3.86 (m, 2H), 3.42 (dd, J1 =
17.1 Hz, 1H), 2.21 (d, J = 16.8 Hz, 1H), 1.67–1.65 (m, 3H); δC 8.4 Hz, J2 = 17.1 Hz, 1H), 3.34 (dd, J1 = 4.8 Hz, J2 = 8.7 Hz, 1H),
(D2O, 75 MHz) 176.5, 128.6, 128.0, 127.6, 77.6, 74.5, 68.0, 46.5, 2.67 (d, J = 17.1 Hz, 1H); δC (D2O, 75 MHz) 178.3, 139.8, 129.0,
39.6, 37.6, 17.1; HRMS (ESI) calcd for C36H40NO4 [M + H]+ 127.8, 127.6, 74.2, 70.2, 68.2, 58.9, 58.5, 41.1, 40.6; HRMS (ESI)
+
550.2957, found 550.2947.
calcd for C14H18NO4+ [M + H]+ 264.1230, found 264.1229.
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(1R,5S,6R,7S,7aS)-6,7-Dihydroxy-5-(hydroxymethyl)-1-
(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-3(2H)-one (10cb)
[α]2D0 −5.3 (c 1.50 in CH3OH); νmax/cm−1 3341, 2958, 2927,
1654, 1119; δH (D2O, 300 MHz) 4.37 (t, J = 8.1 Hz, 1H),
4.14–4.06 (m, 2H), 3.92–3.71 (m, 3H), 2.84 (dd, J1 = 7.2 Hz, J2 =
13.5 Hz, 1H), 2.49 (m, 1H), 2.25 (d, J = 17.1 Hz, 1H), 1.54–1.25
(m, 4H), 0.89 (t, J = 6.6 Hz, 3H); δC (D2O, 75 MHz) 175.7, 78.1,
71.5, 65.6, 56.6, 56.2, 39.9, 33.9, 30.8, 19.6, 13.3; HRMS (ESI)
calcd for C11H20NO4+ [M + H]+ 230.1387, found 230.1387.
Following general procedure, starting from 9cb (0.17 g,
0.31 mmol) to give 10cb (80 mg, 89%) as colourless oil;
[α]D20+90.0 (c 0.20 in CH3OH); νmax/cm−1 3175, 1653, 1123, 618;
δH (D2O, 300 MHz) 7.13 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz,
2H), 4.42 (t, J = 7.5 Hz, 1H), 4.19 (t, J = 4.8 Hz, 1H), 3.95–3.90
(m, 2H), 3.88–3.84 (m, 5H), 3.42–3.36 (m, 1H), 3.33–3.28 (m,
1H), 2.58 (d, J = 17.1 Hz, 1H); δC (D2O, 75 MHz) 178.3, 158.1,
132.3, 128.8, 114.3, 74.1, 70.2, 68.3, 58.9, 58.4, 55.4, 41.2, 39.9;
(1S,6R,7R,8R,8aR)-6,7,8-Trihydroxy-1-
phenylhexahydroindolizin-3(2H)-one (10ea)
+
Following general procedure, starting from 9ea (0.10 g,
0.19 mmol) to give 10ea (43 mg, 90%) as colourless oil;
[α]2D0 −75.0 (c 0.40 in CH3OH); νmax/cm−1 3315, 1653, 1406,
1123, 618; δH (D2O, 300 MHz) 7.46–7.38 (m, 3H), 7.27 (d, J =
6.9 Hz, 2H), 4.37 (t, J = 8.4 Hz, 1H), 4.21–4.18 (m, 1H), 4.03
HRMS (ESI) calcd for C15H20NO5 [M + H]+ 294.1336, found
294.1334.
(1S,5S,6R,7S,7aS)-6,7-Dihydroxy-5-(hydroxymethyl)-1-
propyltetrahydro-1H-pyrrolizin-3(2H)-one (10cd)
Following general procedure, starting from 9cd (90 mg, (dd, J1 = 3.6 Hz, J2 = 12.3 Hz, 1H), 3.92–3.87 (m, 2H), 3.74 (dd,
0.18 mmol) to give 10cd (41 mg, 99%) as colourless oil; J1 = 3.0 Hz, J2 = 12.3 Hz, 1H), 3.30 (dd, J1 = 7.8 Hz, J2 = 17.1 Hz,
[α]2D0 +20.0 (c 0.60 in CH3OH); νmax/cm−1 3353, 2933, 1662, 1417, 1H), 3.14 (t, J = 8.7 Hz, 1H), 2.70 (d, J = 17.4 Hz, 1H); δC (D2O,
1119; δH (D2O, 300 MHz) 4.47 (t, J = 4.5 Hz, 1H), 4.19–4.07 (m, 75 MHz) 175.7, 139.3, 128.7, 128.0, 127.5, 78.1, 72.4, 66.3, 56.8,
2H), 3.97–3.93 (m, 1H), 3.84 (m, 2H), 2.94 (dd, J1 = 8.4 Hz, J2 = 56.7, 41.0, 40.0; HRMS (ESI) calcd for C15H19NO5Na+ [M + Na]+
17.1 Hz, 1H), 2.66–2.64 (m, 1H), 2.23 (d, J = 17.1 Hz, 1H), 316.1155, found 316.1153.
1.58–1.28 (m, 4H), 0.92 (t, J = 6.6 Hz, 3H); δC (D2O, 75 MHz)
(1S,6R,7R,8R,8aR)-6,7,8-Trihydroxy-1-(4-methoxyphenyl)-
hexahydroindolizin-3(2H)-one (10eb)
179.1, 74.0, 69.5, 66.4, 59.2, 58.3, 39.4, 33.1, 19.8, 13.3; HRMS
(ESI) calcd for C11H20NO4+ [M + H]+ 230.1387, found 230.1387.
Following general procedure, starting from 9eb (90 mg,
(1S,5S,6R,7R,7aR)-6,7-Dihydroxy-5-(hydroxymethyl)-1-
0.16 mmol) to give 10eb (46 mg, 98%) as colourless oil;
phenyltetrahydro-1H-pyrrolizin-3(2H)-one (10da)
[α]D20 −120.0 (c 0.40 in CH3OH); νmax/cm−1 3326, 1653, 1406,
Following general procedure, starting from 9da (0.20 g,
1123, 618; δH (D2O, 300 MHz) 7.19 (d, J = 8.4 Hz, 2H), 7.00 (d,
0.36 mmol) to give 10da (96 mg, 99%) as colourless oil;
J = 8.4 Hz, 2H), 4.35 (t, J = 8.4 Hz, 1H), 4.15–4.12 (m, 1H), 4.01
[α]D20 −128.4 (c 0.95 in CH3OH); νmax/cm−1 3343, 2927, 1654,
(dd, J1 = 3.6 Hz, J2 = 12.3 Hz, 1H), 3.90–3.80 (m, 5H), 3.72 (dd,
1453, 1122, 703; δH (D2O, 300 MHz) 7.45–7.37 (m, 3H),
J1 = 3.3 Hz, J2 = 12.3 Hz, 1H), 3.25 (dd, J1 = 8.1 Hz, J2 = 17.4 Hz,
7.28–7.25 (m, 2H), 4.36 (t, J = 8.4 Hz, 1H), 4.17 (t, J = 8.1 Hz,
1H), 3.14 (d, J = 17.4 Hz, 1H), 2.63 (d, J = 17.4 Hz, 1H); δC (D2O,
1H), 4.03 (dd, J1 = 3.3 Hz, J2 = 12.0 Hz, 1H), 3.90–3.86 (m, 2H),
75 MHz) 175.7, 158.0, 131.9, 129.2, 114.0, 78.1, 72.4, 66.4, 56.9,
3.73 (d, J = 12.0 HZ, 1H), 3.28 (dd, J1 = 8.1 Hz, J2 = 17.1 Hz,
1H), 3.14 (t, J = 8.7 Hz, 1H), 2.69 (d, J = 17.1 Hz, 1H); δC
(D2O,75 MHz) 175.7, 139.3, 128.7, 128.0, 127.5, 78.1, 72.4,
+
56.7, 55.4, 41.2, 39.3; HRMS (ESI) calcd for C15H20NO5
[M + H]+ 294.1342, found 294.1334.
+
66.3, 56.8, 56.7, 41.0, 40.0; HRMS (ESI) calcd for C14H18NO4
(1S,6R,7R,8R,9R,9aR)-6,7,8,9-Tetrahydroxy-1-phenylhexahydro-
1H-pyrrolo[1,2-a]azepin-3(2H)-one (10fa)
[M + H]+ 264.1230, found 264.1229.
(1S,5S,6R,7R,7aR)-6,7-Dihydroxy-5-(hydroxymethyl)-1-
(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-3(2H)-one (10db)
Following general procedure, starting from 9fa (87 mg,
0.13 mmol) to give 10fa (37 mg, 95%) as colourless oil;
[α]2D0 +13.3 (c 0.15 in CH3OH); νmax/cm−1 3357, 2923, 1660,
1455, 1093, 702; δH (D2O, 300 MHz) 7.50–7.42 (m, 5H),
4.20–4.17 (m, 2H), 4.13–4.05 (m, 2H), 4.03–3.98 (m, 2H), 3.36
(q, J = 9.6 Hz, 1H), 3.14 (d, J = 13.5 Hz, 1H), 2.88 (dd, J1 = 8.7
Hz, J2 = 17.1 Hz, 1H), 2.71 (dd, J1 = 10.5 Hz, J2 = 16.8 Hz, 1H);
δC (D2O, 75 MHz) 176.9, 139.5, 129.1, 128.0, 127.7, 72.6, 70.9,
Following general procedure, starting from 9db (0.21 g,
0.37 mmol) to give 10db (96 mg, 87%) as colourless oil;
[α]D20 −44.0 (c 0.50 in CH3OH); νmax/cm−1 3131, 1652, 1404, 1123,
618; δH (D2O, 300 MHz) 7.17 (d, J = 8.7 Hz, 2H), 6.97 (d, J =
8.7 Hz, 2H), 4.33 (t, J = 8.7 Hz, 1H), 4.10 (dd, J1 = 6.6 Hz, J2 =
9.3 Hz, 1H), 3.99 (dd, J1 = 3.9 Hz, J2 = 12.3 Hz, 1H), 3.85–3.82
(m, 1H), 3.81 (s, 3H), 3.70 (dd, J1 = 3.3 Hz, J2 = 12.3 Hz, 1H),
3.23 (dd, J1 = 8.1 Hz, J2 = 17.1 Hz, 1H), 3.11 (t, J = 8.7 Hz, 1H),
2.60 (d, J = 17.1 Hz, 2H); δC (D2O, 75 MHz) 175.7, 158.0, 131.9,
129.2, 114.0, 78.1, 72.4, 66.4, 56.8, 56.7, 55.3, 41.2, 39.3; HRMS
(ESI) calcd for C15H20NO5+ [M + H]+ 294.1336, found 294.1338.
+
69.7, 68.3, 42.4, 42.2, 38.5; HRMS (ESI) calcd for C15H20NO5
[M + H]+ 294.1336, found 294.1335.
(1S,2S,7R,7aS)-1,2-Bis(benzyloxy)-7-phenylhexahydro-1H-
pyrrolizine (11aa)
Following general procedure, starting from 9aa (0.52 g,
1.26 mmol) to give 11aa (0.46 g, 92%) as colourless oil;
[α]D20 +113.3 (c 0.90 in CH2Cl2); νmax/cm−1 3029, 2905, 2865, 1603,
(1R,5S,6R,7R,7aR)-6,7-Dihydroxy-5-(hydroxymethyl)-1-
propyltetrahydro-1H-pyrrolizin-3(2H)-one (10dd)
Following general procedure, starting from 9dd (0.20 g, 1453, 1122, 737, 697, 619; δH (CDCl3, 300 MHz) 7.32–7.12 (m,
0.40 mmol) to give 10dd (84 mg, 92.8%) as colourless oil; 13H), 6.98–6.95 (m, 2H), 4.44 (s, 2H), 4.10 (d, J = 11.1 Hz, 1H),
4634 | Org. Biomol. Chem., 2013, 11, 4622–4639
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4.02 (q, J = 5.1 Hz, 1H), 3.72–3.65 (m, 3H), 3.49 (t, J = 4.5 Hz, [α]2D0 +64.3 (c 1.40 in CH2Cl2); νmax/cm−1 3030, 2863, 1611,
1H), 3.35 (dd, J1 = 5.4 Hz, J2 = 11.4 Hz, 1H), 3.18–3.09 (m, 1H), 1513, 1454, 1121, 736, 698; δH (CDCl3, 300 MHz) 7.31–7.18 (m,
2.96–2.83 (m, 2H), 2.28–2.14 (m, 1H), 1.96–1.88 (m, 1H); δC 15H), 6.98–6.93 (m, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.56–4.49 (m,
(CDCl3, 75 MHz) 140.1, 138.28, 138.25, 128.5, 128.4, 128.3, 4H), 4.08 (d, J = 11.1 Hz, 1H), 3.98 (t, J = 6.0 Hz, 1H), 3.76 (s,
127.9, 127.8, 127.7, 127.5, 126.6, 85.0, 84.9, 73.0, 72.0, 71.9, 3H), 3.72–3.67 (m, 1H), 3.61–3.52 (m, 5H), 3.19–2.99 (m, 3H),
+
58.2, 54.8, 47.5, 27.8; HRMS (ESI) calcd for C27H30NO2
[M + H]+ 400.2279, found 400.2271.
2.13–2.04 (m, 1H), 1.92–1.85 (m, 1H); δC (CDCl3, 75 MHz)
158.3, 138.5, 138.4, 138.3, 131.9, 129.4, 128.4, 128.39, 128.2,
127.8, 127.7, 127.66, 127.60, 127.4, 113.8, 86.1, 84.9, 73.4, 72.8,
72.0, 71.0, 69.1, 55.3, 54.6, 46.9, 28.2; HRMS (ESI) calcd for
C36H40NO4+ [M + H]+ 550.2957, found 550.2963.
(1S,2S,7R,7aS)-1,2-Bis(benzyloxy)-7-(4-methoxyphenyl)-
hexahydro-1H-pyrrolizine (11ab)
Following general procedure, starting from 9ab (0.32 g,
0.72 mmol) to give 11ab (0.31 g, 99%) as colourless oil;
[α]2D0 +89.3 (c 1.50 in CH2Cl2); νmax/cm−1 2906, 2870, 1611,
1513, 1454, 1248, 1120, 830, 737, 698; δH (CDCl3, 300 MHz)
7.32–7.19 (m, 10H), 7.00–6.97 (m, 2H), 6.84 (d, J = 8.7 Hz, 2H),
4.45 (s, 2H), 4.15 (d, J = 11.1 Hz, 1H), 4.03 (q, J = 4.8 Hz, 1H),
3.81–3.77 (m, 4H), 3.63–3.59 (m, 2H), 3.50 (t, J = 4.5 Hz, 1H),
3.35 (dd, J1 = 5.4 Hz, J2 = 11.4 Hz, 1H), 3.15–3.08 (m, 1H),
2.95–2.83 (m, 2H), 2.23–2.09 (m, 1H), 1.93–1.87 (m, 1H); δC
(CDCl3, 75 MHz) 158.2, 138.3, 138.2, 132.1, 129.2, 128.5, 128.2,
127.8, 127.7, 127.6, 127.4, 113.7, 85.0, 84.7, 73.0, 71.9, 71.8,
(1S,2S,3S,7R,7aS)-1,2-Bis(benzyloxy)-3-((benzyloxy)methyl)-
7-((E)-prop-1-en-1-yl)hexahydro-1H-pyrrolizine (11bd)
Following general procedure, starting from 9bd (0.29 g,
0.59 mmol) to give 11bd (0.26 g, 90%) as colourless oil yield;
[α]2D0 +23.2 (c 0.95 in CH2Cl2); νmax/cm−1 3030, 2859, 1453,
1096, 735, 697; δH (CDCl3, 300 MHz) 7.32–7.25 (m, 15H),
5.50–5.36 (m, 2H), 4.65–4.50 (m, 6H), 4.07 (t, J = 6.3 Hz, 1H),
3.93 (t, J = 6.3 Hz, 1H), 3.59–3.48 (m, 3H), 3.10–3.02 (m, 1H),
2.96–2.91 (m, 1H), 2.84–2.77 (m, 2H), 1.90–1.70 (m, 2H), 1.65
(d, J = 5.7 Hz, 3H); δC (CDCl3, 75 MHz) 138.6, 138.56, 138.50,
131.2, 128.5, 128.43, 128.41, 127.9, 127.85, 127.79, 127.7,
127.60, 126.4, 86.4, 84.1, 73.5, 73.0, 72.09, 70.4, 69.1, 53.8,
+
58.2, 55.3, 54.7, 46.6, 28.1;HRMS (ESI) calcd for C28H32NO3
[M + H]+ 430.2382, found 430.2375.
+
45.2, 31.5, 18.2; HRMS (ESI) calcd for C32H38NO3 [M + H]+
(1S,2S,7R,7aS)-1,2-Bis(benzyloxy)-7-((E)-prop-1-en-1-yl)-
hexahydro-1H-pyrrolizine (11ad)
484.2852, found 484.2850.
Following general procedure, starting from 9ad (0.19 g,
0.52 mmol) to give 11ad (0.16 g, 85%) as colourless oil;
[α]2D0 +120.0 (c 0.25 in CH2Cl2); νmax/cm−1 3328, 3030, 2922,
2856, 1668, 1454, 1092, 736, 696; δH (CDCl3, 300 MHz)
7.37–7.25 (m, 10H), 5.56–5.42 (m, 2H), 4.63–4.49 (m, 4H),
4.19–4.13 (m, 1H), 3.92–3.85 (m, 1H), 3.51–3.46 (m, 1H),
3.42–3.37 (m, 1H), 3.09–3.03 (m, 1H), 2.89–2.86 (m, 1H),
2.79–2.70 (m, 2H), 1.80–1.74 (m, 2H), 1.65 (d, J = 6.3 Hz, 3H);
δC (CDCl3, 75 MHz) 138.4, 138.2, 130.6, 128.57, 128.45, 128.40,
127.9, 127.88, 127.78, 127.73, 126.7, 84.9, 83.5, 72.3, 72.0, 71.8,
(1S,2R,3S,7R,7aS)-1,2-Bis(benzyloxy)-3-((benzyloxy)methyl)-7-
phenylhexahydro-1H-pyrrolizine (11ca)
Following general procedure, starting from 9ca (0.24 g,
0.45 mmol) to give 11ca (0.23 g, 98%) as colourless oil;
[α]2D0 +35.2 (c 1.25 in CH2Cl2); νmax/cm−1 3061, 3029, 2914, 2865,
1603, 1496, 1453, 1367, 1095, 734, 698; δH (CDCl3, 300 MHz)
7.32–7.18 (m, 18H), 6.85–6.82 (m, 2H), 4.70 (d, J = 12.0 Hz,
1H), 4.53–4.43 (m, 3H), 4.03–3.94 (m, 2H), 3.83–3.78 (m, 2H),
3.67–3.55 (m, 2H), 3.48 (d, J = 7.8 Hz, 1H), 3.41 (dd, J1 = 3.6 Hz,
J2 = 9.0 Hz, 1H), 3.13–3.04 (m, 1H), 2.97–2.86 (m, 2H),
2.11–2.01 (m, 1H), 1.93–1.86 (m, 1H); δC (CDCl3, 75 MHz)
139.1, 138.9, 138.3, 137.6, 128.4, 128.3, 128.12, 128.1, 128.0,
127.85, 127.76, 127.5, 127.3, 126.5, 81.7, 73.52, 73.49, 71.9,
69.9, 68.9, 67.4, 53.2, 46.6, 27.1; HRMS (ESI) calcd for
C35H38NO3+ [M + H]+ 520.2852, found 520.2843.
+
57.8, 54.1, 44.9, 30.7, 18.2; HRMS (ESI) calcd for C24H30NO2
[M + H]+ 364.2276, found 364.2266.
(1S,2S,3S,7R,7aS)-1,2-Bis(benzyloxy)-3-((benzyloxy)methyl)-7-
phenylhexahydro-1H-pyrrolizine (11ba)
Following general procedure, starting from 9ba (0.25 g,
0.47 mmol) to give 11ba (0.23 g, 90%) as colourless oil;
[α]2D0 +51.7 (c 1.20 in CH2Cl2); νmax/cm−1 3030, 2871, 1603,
1496, 1453, 1119, 736, 698; δH (CDCl3, 300 MHz) 7.33–6.92 (m,
20H), 4.60–4.48 (m, 4H), 4.08–3.96 (m, 2H), 3.74 (t, J = 7.5 Hz,
1H), 3.66–3.46 (m, 5H), 3.19–3.00 (m, 3H), 2.22–2.03 (m, 1H),
1.93–1.86 (m, 1H); δC (CDCl3, 75 MHz) 139.8, 138.5, 138.4,
138.3, 128.6, 128.44, 128.39, 128.2, 127.8, 127.7, 127.6, 127.4,
126.6, 86.1, 84.9, 73.5, 72.8, 72.0, 70.9, 69.0, 54.6, 47.7, 27.9;
(1S,2R,3S,7R,7aS)-1,2-Bis(benzyloxy)-3-((benzyloxy)methyl)-7-
(4-methoxyphenyl)hexahydro-1H-pyrrolizine (11cb)
Following general procedure, starting from 9cb (0.29 g,
0.52 mmol) to give 11cb (0.25 g, 88%) as colourless oil;
[α]D20+31.1 (c 0.90, CH2Cl2); νmax/cm−1 3030, 2903, 2864, 1610,
1513, 1453, 1249, 1096, 734, 697; δH (CDCl3, 300 MHz)
7.31–7.20 (m, 15H), 6.89–6.80 (m, 4H), 4.72 (d, J = 11.7 Hz,
1H), 4.53–4.44 (m, 3H), 4.04 (m, 1H), 3.93–3.89 (m, 2H), 3.80
(t, J = 8.4 Hz, 1H), 3.74 (s, 3H), 3.56–3.52 (m, 3H), 3.39 (dd, J1 =
3.6 Hz, J2 = 9.0 Hz, 1H), 3.08–2.99 (m, 1H), 2.95–2.83 (m, 2H),
2.04–1.94 (m, 1H), 1.89–1.84 (m, 1H); δC (CDCl3, 75 MHz)
HRMS (ESI) calcd for C35H38NO3 [M + H]+ 520.2852, found
+
520.2850.
(1S,2S,3S,7R,7aS)-1,2-Bis(benzyloxy)-3-((benzyloxy)methyl)-7-
(4-methoxyphenyl)hexahydro-1H-pyrrolizine (11bb)
Following general procedure, starting from 9bb (0.53 g, 158.3, 139.0, 138.4, 137.8, 131.3, 129.3, 128.5, 128.2, 128.1,
0.95 mmol) to give 11bb (0.48 g, 91%) as colourless oil; 128.0, 127.89, 27.88, 127.7, 127.5, 127.4, 113.7, 82.0, 77.8, 73.6,
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73.58,, 72.1, 70.3, 69.1, 67.5, 55.3, 53.4, 46.0, 27.6; HRMS (ESI) (1R,2R,3S,7S,7aR)-1,2-Bis(benzyloxy)-3-((benzyloxy)methyl)-7-
calcd for C36H40NO4+ [M + H]+ 550.2957, found 550.2942.
((E)-prop-1-en-1-yl)hexahydro-1H-pyrrolizine (11dd)
Following general procedure, starting from 9dd (0.31 g,
0.62 mmol) to give 11dd (0.26 g, 85%) as colourless oil;
[α]D20 −3.3 (c 0.60 in CH2Cl2); νmax/cm−1 3032, 2917, 2859, 1452,
1097, 735, 697; δH (CDCl3, 300 MHz) 7.33–7.24 (m, 15H),
(1S,2R,3S,7R,7aS)-1,2-Bis(benzyloxy)-3-((benzyloxy)methyl)-7-
((E)-prop-1-en-1-yl)hexahydro-1H-pyrrolizine (11cd)
Following general procedure, starting from 9cd (0.19 g, 5.53–5.35 (m, 2H), 4.60–4.49 (m, 3H), 4.45–4.38 (m, 3H),
0.39 mmol) to give 11cd (0.61 g, 87%) as colourless oil; 4.02–4.00 (m, 1H), 3.87–3.76 (m, 3H), 3.52–3.47 (m, 1H),
[α]2D0 +22.9 (c 0.35 in CH2Cl2);νmax/cm−1 3030, 2914, 2860, 1453, 3.39–3.33 (m, 1H), 3.10–3.03 (m, 1H), 2.99–2.90 (m, 1H),
1120, 734, 697; δH (CDCl3, 300 MHz) 7.33–7.24 (m, 15H), 2.74–2.66 (m, 1H), 1.93–1.83 (m, 1H), 1.67–1.60 (m, 4H); δC
5.56–5.39 (m, 2H), 4.78 (d, J = 12.0 Hz, 1H), 4.64 (t, J = 11.4 Hz, (CDCl3, 75 MHz) 138.5, 138.4, 131.6, 128.45, 128.43, 127.8,
1H), 4.54–4.45 (m, 3H), 4.33 (d, J = 11.4 Hz, 1H), 4.17 (t, J = 127.7, 127.6, 127.4, 126.1, 86.5, 84.0, 75.3, 73.4, 71.7, 71.6,
3.0 Hz, 1H), 3.79 (t, J = 8.7 Hz, 1H), 3.73–3.67 (m, 1H), 3.62 67.0, 64.0, 46.7, 43.0, 31.6, 18.1. HRMS (ESI) calcd for
(dd, J1 = 3.3 Hz, J2 = 8.7 Hz, 1H), 3.51 (dd, J1 = 5.1 Hz, J2
=
C32H38NO3+ [M + H]+ 484.2852, found 484.2828.
9.0 Hz, 1H), 2.95–2.79 (m, 3H), 2.70–2.63 (m, 1H), 1.78–1.71
(m, 1H), 1.66 (d, J = 5.7 Hz, 3H), 1.63–1.52 (m, 1H); δC (CDCl3,
75 MHz) 139.1, 138.4, 138.1, 130.1, 128.5, 128.2, 128.1, 128.0,
127.95, 127.8, 127.7, 127.4, 125.7, 81.4, 78.1, 73.7, 73.6, 72.2,
68.6, 67.9, 53.3, 44.2, 29.9, 18.3; HRMS (ESI) calcd for
C32H38NO3+ [M + H]+ 484.2852, found 484.2846.
(1S,2S,7R,7aS)-1,2-Dihydroxy-7-phenylhexahydro-1H-
pyrrolizine (12aa)
Following general procedure, starting from 11aa (0.38 g,
0.94 mmol) to give 12aa (0.20 g, 97%) as colourless oil;
[α]2D0 +108.6 (c 0.35 in CH3OH); νmax/cm−1 3342, 2919, 1122; δH
(D2O, 300 MHz) 7.46–7.40 (m, 4H), 7.37–7.31 (m, 1H),
4.05–3.97 (m, 1H), 3.67–3.59 (m, 1H), 3.57–3.52 (m, 1H),
3.49–3.44 (m, 1H), 3.38–3.32 (m, 1H), 3.04–2.89 (m, 2H), 2.60
(t, J = 9.6 Hz, 1H), 2.37–2.22 (m, 1H), 2.01–1.92 (m, 1H); δC
(D2O, 75 MHz) 138.2, 128.6, 128.4, 126.9, 76.5, 75.3, 69.8, 56.8,
(1R,2R,3S,7S,7aR)-1,2-Bis(benzyloxy)-3-((benzyloxy)methyl)-7-
phenylhexahydro-1H-pyrrolizine (11da)
Following general procedure, starting from 9da (0.50 g,
0.94 mmol) to give 11da (0.44 g, 90%) as colourless oil;
[α]2D0 −47.5 (c 0.80 in CH2Cl2); νmax/cm−1 3061, 3029, 2910,
2866, 1603, 1496, 1454, 1098, 735, 697; δH (CDCl3, 300 MHz)
7.34–7.19 (m, 18H), 7.01–6.97 (m, 2H), 4.62–4.54 (m, 2H), 4.38
(d, J = 12.0 Hz, 1H), 4.27 (d, J = 12.0 Hz, 1H), 3.93–3.91 (m,
3H), 3.86 (d, J = 6.6 Hz, 2H), 3.73 (q, J = 7.5 Hz, 1H), 3.66–3.62
(m, 1H), 3.56–3.50 (m, 1H), 3.42 (d, J = 4.5 Hz, 1H), 3.28–3.21
(m, 1H), 2.86 (q, J = 8.4 Hz, 1H), 2.15–2.02 (m, 2H); δC (CDCl3,
75 MHz) 141.2, 138.5, 138.46, 138.1, 128.44, 128.41, 128.3,
127.8, 127.65, 127.63, 127.60, 127.3, 126.5, 86.4, 85.1, 76.5,
73.4, 71.8, 71.4, 67.1, 64.6, 46.9, 45.0, 29.6. HRMS (ESI) calcd
for C35H38NO3+ [M + H]+ 520.2851, found 520.2841.
53.5, 46.4, 26.4; HRMS (ESI) calcd for C13H18NO2 [M + H]+
+
220.1332, found 220.1332.
(1S,2S,7R,7aS)-1,2-Dihydroxy-7-(4-methoxyphenyl)hexahydro-
1H-pyrrolizine (12ab)
Following general procedure, starting from 11ab (0.23 g,
0.53 mmol) to give 12ab (0.13 g, 97%) as colourless oil;
[α]D20 +115.6 (c 1.80 in CH3OH); νmax/cm−1 3358, 2916, 1612,
1514, 1463, 1248, 1035, 831; δH (D2O, 300 MHz) 7.22 (d, J =
8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.00–3.93 (m, 1H), 3.74 (s,
3H), 3.47–3.40 (m, 2H), 3.38–3.34 (m, 1H), 3.32–3.22 (m, 1H),
2.87–2.75 (m, 2H), 2.49 (t, J = 9.6 Hz, 1H), 2.16–2.04 (m, 1H),
1.85–1.75 (m, 1H); δC (D2O, 75 MHz) 157.5, 130.9, 129.4, 113.8,
76.7, 75.5, 69.9, 57.0, 55.2, 53.4, 45.7, 26.8; HRMS (ESI) calcd
for C14H20NO3+ [M + H]+ 250.1438, found 250.1434.
(1R,2R,3S,7S,7aR)-1,2-Bis(benzyloxy)-3-((benzyloxy)methyl)-7-
(4-methoxyphenyl)hexahydro-1H-pyrrolizine (11db)
Following general procedure, starting from 9db (0.35 g,
0.62 mmol) to give 11db (0.33 g, 97%) as colourless oil;
[α]2D0 −13.3 (c 0.90 in CH2Cl2); νmax/cm−1 3358, 3062, 3031,
2928, 2866, 1603, 1496, 1453, 1367, 1095, 734, 698; δH (CDCl3,
(1S,2S,7S,7aS)-1,2-Dihydroxy-7-propylhexahydro-1H-pyrrolizine
(12ad)
300 MHz) 7.34–7.18 (m, 15H), 7.02–7.00 (m, 2H), 6.82 (d, J = Following general procedure, starting from 11ad (0.10 g,
8.4 Hz, 2H), 4.39 (d, J = 12.0 Hz, 1H), 4.29 (d, J = 12.0 Hz, 1H), 0.27 mmol) to give 12ad (55 mg, 100%) as colourless oil;
4.03–3.97 (m, 2H), 3.92 (d, J = 4.5 Hz, 1H), 3.85 (d, J = 6.6 Hz, [α]2D0 +40.0 (c 0.20 in CH3OH); νmax/cm−1 3328, 2958, 2928,
2H), 3.79 (s, 3H), 3.68–3.60 (m, 3H), 3.56–3.51 (m, 1H), 3.44 (d, 1457, 1123, 618; δH (D2O, 300 MHz) 4.16–4.09 (m, 1H), 3.98 (t,
J = 4.2 Hz, 1H), 3.26–3.19 (m, 1H), 2.90–2.81 (m, 1H), 2.07–2.02 J = 7.5 Hz, 1H), 3.64–3.53 (m, 2H), 3.17–3.07 (m, 1H), 3.02–2.96
(m, 2H), 1.66–1.62 (m, 1H); δC (CDCl3, 75 MHz) 158.2, 138.38, (m, 1H), 2.76–2.70 (m, 1H), 2.37–2.26 (m, 1H), 2.04–1.92 (m,
138.36, 138.0, 132.9, 129.2, 128.4, 128.3, 127.8, 127.75, 127.6, 1H), 1.77–1.42 (m, 5H), 0.93 (t, J = 7.2 Hz, 3H); δC (D2O,
127.59, 127.3, 113.8, 86.0, 84.8, 73.4, 71.7, 71.4, 66.9, 64.6, 75 MHz) 75.0, 74.6, 70.1, 56.7, 54.6, 40.6, 30.4, 28.3, 21.3, 13.4;
62.6, 55.3, 46.8, 44.3, 30.2; HRMS (ESI) calcd for C36H40NO4 HRMS (ESI) calcd for C10H20NO2 [M + H]+ 186.1489, found
+
[M + H]+ 550.2957, found 550.2947.
186.1487.
4636 | Org. Biomol. Chem., 2013, 11, 4622–4639
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(1S,2S,3S,7R,7aS)-1,2-Dihydroxy-3-(hydroxymethyl)-7-
phenylhexahydro-1H-pyrrolizine (12ba)
2H), 6.97 (d, J = 8.4 Hz, 2H), 4.08 (t, J = 3.3 Hz, 1H), 3.90–3.76
(m, 4H), 3.70–3.65 (m, 1H), 3.55–3.47 (m, 2H), 2.92–2.90 (m,
3H), 2.19–2.05 (m, 1H), 1.84 (d, J = 9.1 Hz, 1H); δC (D2O,
75 MHz) 157.5, 130.6, 129.5, 113.8, 72.5, 72.2, 69.3, 68.6, 60.0,
Following general procedure, starting from 11ba (50 mg,
0.096 mmol) to give 12ba (22 mg, 92%) as colourless oil;
[α]D20 +66.7 (c 0.75 in CH3OH); νmax/cm−1 3297, 1403, 1123, 618;
δH (D2O, 300 MHz) 7.44–7.43 (m, 4H), 7.38–7.34 (m, 1H), 3.86
(dd, J1 = 3.3 Hz, J2 = 12.0 Hz, 1H), 3.78–3.57 (m, 5H), 3.16–3.11
(m, 2H), 2.93–2.87 (m, 1H), 2.41–2.27 (m, 1H), 2.09–2.01 (m,
1H); δC (D2O, 75 MHz) 137.0, 128.6, 128.5, 127.1, 75.4, 74.9,
68.5, 68.4, 61.2, 53.7, 45.9, 26.3; HRMS (ESI) calcd for
C15H20NO3+ [M + H]+ 250.1438, found 250.1434.
+
55.3, 53.1, 45.2, 26.6; HRMS (ESI) calcd for C15H22NO4 [M +
H]+ 280.1543, found 280.1541.
(1S,2R,3S,7S,7aS)-1,2-Dihydroxy-3-(hydroxymethyl)-7-
propylhexahydro-1H-pyrrolizine (12cd)
Following general procedure, starting from 11cd (0.14 g,
0.39 mmol) to give 12cd (60 mg, 95%) as colourless oil;
[α]2D0 +22.5 (c 0.80 in CH3OH); νmax/cm−1 3357, 2957, 2927,
1124; δH (D2O, 300 MHz) 4.23–4.17 (m, 2H), 3.96–3.90 (m, 1H),
3.77 (dd, J1 = 6.6 Hz, J2 = 11.4 Hz, 1H), 3.61 (t, J = 8.4 Hz, 1H),
3.13–3.09 (m, 1H), 2.98 (d, J = 6.9 Hz, 2H), 2.28–2.24 (m, 1H),
1.98–1.94 (m, 1H), 1.66–1.36 (m, 5H), 0.93 (t, J = 6.9 Hz, 3H);
δC (D2O, 75 MHz) 72.5, 71.4, 69.3, 69.0, 59.2, 53.8, 40.1, 30.0,
(1S,2S,3S,7R,7aS)-1,2-Dihydroxy-3-(hydroxymethyl)-7-
(4-methoxyphenyl)hexahydro-1H-pyrrolizine (12bb)
Following general procedure, starting from 11bb (0.38 g,
0.69 mmol) to give 12bb (0.19 g, 96%) as colourless oil;
[α]2D0 +64.0 (c 0.50 in CH3OH); νmax/cm−1 3327, 2924, 1613,
1514, 1456, 1248, 1124; δH (D2O, 300 MHz) 7.37 (d, J = 8.7 Hz,
2H), 7.03 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H), 3.83 (d, J = 8.4 Hz,
1H), 3.80–3.71 (m, 2H), 3.70–3.51 (m, 2H), 3.45–3.38 (m, 1H),
3.04–2.99 (m, 2H), 2.80–2.74 (m, 1H), 2.30–2.16 (m, 1H),
1.97–1.93 (m, 1H); δC (D2O, 75 MHz) 157.6, 130.4, 129.5, 114.0,
76.2, 75.4, 68.5, 68.3, 62.6, 55.4, 53.6, 45.5, 26.8; HRMS (ESI)
calcd for C15H22NO4+ [M + H]+ 280.1543, found 280.1539.
28.2, 21.4, 13.5; HRMS (ESI) calcd for C11H22NO3 [M + H]+
+
216.1594, found 216.1596.
(1S,2R,3S,7R,7aS)-1,2-Dihydroxy-3-(hydroxymethyl)-7-((E)-prop-
1-en-1-yl)hexahydro-1H-pyrrolizine (12cd′)
To a solution of 11ad (0.19 g, 0.095 mmol) in dried CH2Cl2
(5 mL) at 0 °C was added BBr3 (0.20 mL, 6 eq.) under N2
atmosphere. The resulting mixture was stirred for 1 h, and
then quenched with MeOH (2 mL) at 0 °C. The solvent was
removed under reduced pressure. The residue was neutralized
by NH3·H2O (25%, 10 mL), then purified by acid ion exchange
resin column to give 12cd′ (0.089 g, 91%) as colourless oil;
[α]D20 +70.8 (c 0.65, CH3OH); νmax/cm−1 3342, 2920, 1123, 618;
δH (D2O, 300 MHz) 5.75–5.54 (m, 2H), 4.18 (t, J = 3.0 Hz, 1H),
4.09–4.04 (m, 1H), 3.88–3.82 (m, 1H), 3.65 (dd, J1 = 6.0 Hz, J2 =
11.1 Hz, 1H), 3.37 (t, J = 8.7 Hz, 1H), 2.95–2.82 (m, 4H),
1.76–1.66 (m, 5H); δC (D2O, 75 MHz) 128.1, 127.9, 72.7, 71.9,
69.1, 68.9, 59.9, 53.1, 43.4, 28.7, 17.3; HRMS (ESI) calcd for
C11H20NO3+ [M + H]+ 214.1438, found 214.1437.
(1S,2S,3S,7S,7aS)-1,2-Dihydroxy-3-(hydroxymethyl)-7-
propylhexahydro-1H-pyrrolizine (12bd)
Following general procedure, starting from 11bd (96 mg,
0.20 mmol) to give 12bd (43 mg, 99%) as colourless oil yield;
[α]D20 +20.0 (c 0.20 in CH3OH); νmax/cm−1 3310, 1404, 1124, 618;
δH (D2O, 300 MHz) 4.01 (t, J = 8.1 Hz, 1H), 3.93–3.76 (m, 3H),
3.56 (t, J = 8.1 Hz, 1H), 3.14–3.11 (m, 2H), 3.00–2.94 (m, 1H),
2.36–2.28 (m, 1H), 2.09–2.03 (m, 1H), 1.76–1.37 (m, 5H), 0.94
(t, J = 6.9 Hz, 3H); δC (D2O, 75 MHz) 74.6, 73.8, 69.0, 68.2, 59.4,
54.2, 40.5, 29.7, 28.1, 21.3, 13.4; HRMS (ESI) calcd for
C11H22NO3 [M + H]+ 216.1594, found 216.1593.
(1R,2R,3S,7S,7aR)-1,2-Dihydroxy-3-(hydroxymethyl)-7-
phenylhexahydro-1H-pyrrolizine (12da)
(1S,2R,3S,7R,7aS)-1,2-Dihydroxy-3-(hydroxymethyl)-7-
phenylhexahydro-1H-pyrrolizine (12ca)
Following general procedure, starting from 11da (0.38 g,
0.94 mmol) to give 12da (0.17 g, 91%) as colourless oil;
[α]2D0 −57.1 (c 0.35 in CH3OH); νmax/cm−1 3357, 2949, 1455,
1029, 699; δH (D2O, 300 MHz) 7.47–7.35 (m, 5H), 4.08 (d, J =
4.2 Hz, 1H), 3.98–3.94 (m, 2H), 3.79–3.67 (m, 2H), 3.59–3.55
(m, 1H), 3.47–3.41 (m, 1H), 3.32 (t, J = 9.9 Hz, 1H), 3.02–2.93
(m, 1H), 2.37–2.13 (m, 2H); δC (D2O, 75 MHz) 141.7, 131.2,
130.7, 129.4, 82.0, 78.4, 68.0, 60.0, 48.5, 47.2, 30.1; HRMS (ESI)
calcd for C14H20NO3 [M + H]+ 250.1438, found 250.1435.
Following general procedure, starting from 11ca (0.18 g,
0.34 mmol) to give 12ca (86 mg, 100%) as colourless oil;
[α]D20 +106.7 (c 0.60 in CH3OH); νmax/cm−1 3201, 2938, 2878,
1520, 1144, 1050, 765, 701; δH (D2O, 300 MHz) 7.42–7.32 (m,
5H), 4.11 (t, J = 3.3 Hz, 1H), 3.94–3.86 (m, 2H), 3.76–3.70 (m,
1H), 3.67–3.57 (m, 2H), 3.05–3.02 (m, 3H), 2.26 (t, J = 10.2 Hz,
1H), 1.99–1.95 (m, 1H); δC (D2O, 75 MHz) 137.5, 128.5, 128.4,
127.0, 72.4, 72.0, 69.4, 68.8, 59.7, 53.2, 45.7, 26.3; HRMS (ESI)
calcd for C14H20NO3+ [M + H]+ 250.1438, found 250.1434.
(1R,2R,3S,7S,7aR)-1,2-Dihydroxy-3-(hydroxymethyl)-7-(4-
methoxyphenyl)hexahydro-1H-pyrrolizine (12db)
(1S,2R,3S,7R,7aS)-1,2-Dihydroxy-3-(hydroxymethyl)-7-
(4-methoxyphenyl)hexahydro-1H-pyrrolizine (12cb)
Following general procedure, starting from 11db (140 mg,
Following general procedure, starting from 11cb (0.14 g, 0.25 mmol) to give 12db (65 mg, 92.0%) as colourless oil;
0.52 mmol) to give 12cb (73 mg, 99%) as colourless oil; [α]2D0 −40.0 (c 0.40 in CH3OH); νmax/cm−1 3332, 2919, 1515,
[α]2D0 +104.0 (c 0.50 in CH3OH); νmax/cm−1 3297, 2943, 1612, 1112; δH (D2O, 300 MHz) 7.34 (d, J = 8.7 Hz, 2H), 7.02 (d, J =
1514, 1250, 1034, 826; δH (D2O, 300 MHz) 7.31 (d, J = 8.4 Hz, 8.7 Hz, 2H), 4.08 (dd, J1 = 0.9 Hz, J2 = 4.2 Hz, 1H), 3.96 (dd, J1 =
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3.3 Hz, J2 = 6.9 Hz, 1H), 3.83 (s, 3H), 3.74–3.60 (m, 3H),
3.55–3.49 (m, 1H), 3.40–3.33 (m, 1H), 3.06–2.97 (m, 1H),
2.35–2.11 (m, 2H); δC (D2O, 75 MHz) 157.6, 131.2, 129.3, 114.0,
79.1, 78.9, 76.1, 65.8, 57.2, 55.3, 46.2, 43.8, 27.6; HRMS (ESI)
calcd for C36H40NO6 [M + H]+ 280.1543, found 280.1543.
5 L. D. Hohenschutz, E. A. Bell, P. J. Jewess, D. P. Leworthy,
R. J. Pryce, E. Arnold and J. Clardy, Phytochemistry, 1981,
20, 811.
6 S. M. Colegate, P. R. Dorling and C. R. Huxtable,
Aust. J. Chem., 1979, 32, 2257.
7 (a) A. Kato, N. Kato, E. Kano, I. Adachi, K. Ikeda, L. Yu,
T. Okamoto, Y. Banba, H. Ouchi, H. Takahata and
N. Asano, J. Med. Chem., 2005, 48, 2036; (b) K. Clinch,
G. B. Evans, G. W. J. Fleet, R. H. Furneaux, S. W. Johnson,
D. H. Lenz, S. P. H. Mee, P. R. Rands, V. L. Schramm,
E. A. Taylor Ringia and P. C. Tyler, Org. Biomol. Chem.,
2006, 4, 1131; (c) N. Asano, K. Ikeda, L. Yu, A. Kato,
K. Takebayashi, I. Adachi, I. Kato, H. Ouchi, H. Takahata
and G. W. J. Fleet, Tetrahedron: Asymmetry, 2005, 16, 223.
8 (a) A. M. Scofield, L. E. Fellows, R. J. Nash and
G. W. J. Fleet, Life Sci., 1986, 39, 645; (b) C.-Y. Yu, N. Asano,
K. Ikeda, M. X. Wang, T. D. Butters, M. R. Wormald,
R. A. Dwek, A. L. Winters, R. J. Nash and G. W. J. Fleet,
Chem. Commun., 2004, 1936; (c) D. Best, P. Chairatana,
A. F. G. Glawar, E. Crabtree, T. D. Butters, F. X. Wilson,
C.-Y. Yu, W.-B. Wang, Y.-M. Jia, I. Adachi, A. Kato and
G. W. J. Fleet, Tetrahedron Lett., 2010, 51, 2222.
9 (a) A. E. Håkansson, J. van Ameijde, L. Guglielmini,
G. Horne, R. J. Nash, E. L. Evinson, A. Kato and
G. W. J. Fleet, Tetrahedron: Asymmetry, 2007, 18, 282;
(b) D. Best, C. Wang, A. C. Weymouth-Wilson,
R. A. Clarkson, F. X. Wilson, R. J. Nash, S. Miyauchi,
A. Kato and G. W. J. Fleet, Tetrahedron: Asymmetry, 2010,
21, 311.
(1R,2R,3S,7R,7aR)-1,2-Dihydroxy-3-(hydroxymethyl)-7-
propylhexahydro-1H-pyrrolizine (12dd)
Following general procedure, starting from 11dd (0.19 g,
0.38 mmol) to give 12dd (73 mg, 89%) as colourless oil;
[α]2D0 −13.3 (c 0.75 in CH3OH); νmax/cm−1 3311, 2955, 1123,
618; δH (D2O, 300 MHz) 4.16 (d, J = 3.6 Hz, 1H), 4.08 (d, J =
5.1 Hz, 1H), 3.96–3.82 (m, 2H), 3.50–3.46 (m, 1H), 3.30 (t, J =
6.0 Hz, 1H), 3.14 (t, J = 9.0 Hz, 1H), 2.84 (q, J = 9.0 Hz, 1H),
2.35–2.30 (m, 1H), 1.98–1.95 (m, 1H), 1.67–1.36 (m, 5H), 0.90
(t, J = 7.8 Hz, 3H); δC (D2O, 75 MHz) 79.5, 78.4, 74.6, 65.2, 57.3,
45.9, 39.2, 31.8, 29.3, 21.2, 13.5; HRMS (ESI) calcd for
C11H22NO3+ [M + H]+ 216.1594, found 216.1594.
(1R,2R,3S,7S,7aR)-1,2-Dihydroxy-3-(hydroxymethyl)-7-((E)-prop-
1-en-1-yl)hexahydro-1H-pyrrolizine (12dd′)
Following the procedure of 12cd′, starting from 11dd (0.10 g,
0.20 mmol) to give 12dd′ (50 mg, 96%) as colourless oil;
[α]2D0 −33.8 (c 0.65 in CH3OH); νmax/cm−1 3326, 2921, 1123,
618; δH (D2O, 300 MHz) 5.79–5.55 (m, 2H), 4.21 (d, J = 4.5 Hz,
1H), 4.14 (d, J = 4.5 Hz, 1H), 4.03–3.90 (m, 2H), 3.63–3.57 (m,
1H), 3.55–3.48 (m, 1H), 3.37–3.28 (m, 1H), 3.13–2.97 (m, 2H),
2.05–1.87 (m, 2H), 1.72 (d, J = 6.3 Hz, 3H); δC (D2O, 75 MHz)
128.7, 128.4, 78.6, 78.1, 75.4, 65.5, 56.9, 46.5, 42.2, 29.7, 17.3;
+
10 (a) A. E. Stűtz, Iminosugars as Glycosidase Inhibitors: Nojiri-
mycin and Beyond, Wiley-VCH, Weinheim, 1999;
(b) T. D. Heightman and A. T. Vasella, Angew. Chem., Int.
Ed., 1999, 38, 750.
HRMS (ESI) calcd for C11H20NO3 [M + H]+ 214.1438, found
214.1438.
11 (a) D. X. Yang and G. C. Micalizio, J. Am. Chem. Soc., 2012,
134, 15237; (b) G. M. J. Lenagh-Snow, N. Araújo,
S. F. Jenkinson, R. F. Martínez, Y. Shimada, C. Y. Yu,
A. Kato and G. W. J. Fleet, Org. Lett., 2012, 14, 2142;
(c) M. Mondon, N. Fontelle, J. Désiré, F. Lecornué,
J. Guillard, J. Marrot and Y. Blériot, Org. Lett., 2012, 14,
870; (d) W. Zhang, K. Sato, A. Kato, Y.-M. Jia, X.-G. Hu,
F. X. Wilson, R. van Well, G. Horne, G. W. J. Fleet,
R. J. Nash and C.-Y. Yu, Org. Lett., 2011, 13, 4414;
(e) Z.-L. Zhang, S. Nakagawa, A. Kato, Y.-M. Jia, X.-G. Hu
and C.-Y. Yu, Org. Biomol. Chem., 2011, 9, 7713;
(f) T. Ritthiwigrom and S. G. Pyne, Org. Lett., 2008, 10,
2769.
Acknowledgements
This work is supported by the National Basic Research
Program of China (No. 2011CB808603 and No.
2012CB822101), The Natural Science Foundation of China (No.
21272240) and the Chinese Academy of Sciences.
Notes and references
1 (a) N. Asano, R. J. Nash, R. J. Molyneux and G. W. J. Fleet,
Tetrahedron: Asymmetry, 2000, 11, 1645; (b) A. A. Watson,
G. W. J. Fleet, N. Asano, R. J. Molyneux and R. J. Nash,
Phytochemistry, 2001, 56, 265; (c) B. G. Winchester, Tetra- 12 (a) P. Merino, S. Franco, F. L. Merchan and T. Tejero,
hedron: Asymmetry, 2009, 645.
Synlett, 2000, 442; (b) G. Masson, S. Py and Y. Vallée, Angew.
Chem., Int. Ed., 2002, 41, 1772; (c) D. Riber and
T. Skrydstrup, Org. Lett., 2003, 5, 229; (d) G. Masson,
P. Cividino, S. Py and Y. Vallée, Angew. Chem., Int. Ed.,
2003, 42, 2265; (e) F. Cardona and A. Goti, Angew. Chem.,
Int. Ed., 2005, 44, 7832; (f) P. Merino, C. R. Chim., 2005, 8,
775; (g) C. Berini, F. Minassian, N. Pelloux-Léon,
J.-N. Denis, Y. Vallée and C. Phiouze, Org. Biomol. Chem.,
2008, 6, 2574; (h) E. Demory, D. Farran, B. Baptiste,
2 (a) N. Asano, Glycobiology, 2003, 13, 93R; (b) T. D. Butters,
R. A. Dwek and F. M. Platt, Glycobiology, 2005, 15, 43R.
3 R. J. Nash, P. I. Thomas, R. D. Waigh, G. W. J. Fleet,
M. R. Wormald, P. M. de Q. Lilley and D. J. Watkin, Tetra-
hedron Lett., 1994, 35, 7849.
4 N. Asano, H. Kuroi, K. Ikeda, H. Kizu, Y. Kameda, A. Kato,
I. Adachi, A. A. Watson, R. J. Nash and G. W. J. Fleet, Tetra-
hedron: Asymmetry, 2000, 11, 1.
4638 | Org. Biomol. Chem., 2013, 11, 4622–4639
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
P. Y. Chavant and V. Blandin, J. Org. Chem., 2012, 77, 17 (a) N-Heterocyclic Carbenes in Transition Metal Catalysis;
7901; (i) S.-F. Wu, X. Zheng, Y.-P. Ruan and P.-Q. Huang,
Chem. Commun., 2009, 2967; ( j) P. Gilles and S. Py, Org.
Lett., 2012, 14, 1042.
Topics in Organometallic Chemistry, ed. F. Glorius, Springer-
Verlag, Berlin/Heidelberg, 2007, vol. 21; (b) O. Kühl, Chem.
Soc. Rev., 2007, 36, 592; (c) L. Mercs and M. Albrecht, Chem.
Soc. Rev., 2010, 39, 1903.
13 (a) K. V. Gothelf and K. A. Jörgensen, Chem. Rev., 1998, 98,
863; (b) P. Merino, S. Franco, F. L. Merchan, P. Romero, 18 (a) D. Bourissou, O. Guerret, F. P. Gabbaï and G. Bertrand,
T. Tejero and T. S. Uriel, Tetrahedron: Asymmetry, 2003, 14,
3713.
Chem. Rev., 2000, 100, 39; (b) D. Enders and T. Ballensiefer,
Acc. Chem. Res., 2004, 37, 534; (c) L. Benhamou,
E. Chardon, G. Lavigne, S. Bellemin-Laponnaz and
V. César, Chem. Rev., 2011, 11, 2705; (d) A. Grossmann and
D. Enders, Angew. Chem., Int. Ed., 2012, 51, 314;
(e) X. Bugaut and F. Glorius, Chem. Soc. Rev., 2012, 41,
3511; (f) Z. Q. Fu, H. Sun, S. J. Chen, B. Tiwari, G. H. Li
and Y. G. R. Chi, Chem. Commun., 2013, 49, 261.
14 (a) S. Cicchi, I. Höld and A. Brandi, J. Org. Chem., 1993, 58,
5274; (b) S. Cicchi, M. Marradi, A. Goti and A. Brandi, Tetra-
hedron Lett., 2001, 42, 6503; (c) J. Revuelta, S. Cicchi,
A. Goti and A. Brandi, Synthesis, 2007, 484; for the synth-
eses of nitrones 5a–5f, see: (d) E.-L. Tsou, Y.-T. Yeh,
P.-H. Liang and W.-C. Cheng, Tetrahedron, 2009, 65, 93;
(e) W.-B. Wang, M.-H. Huang, Y.-X. Li, P.-X. Rui, X.-G. Hu, 19 (a) E. M. Phillips, A. Chan and K. A. Scheidt,
W. Zhang, J.-K. Su, Z.-L. Zhang, J.-S. Zhu, W.-H. Xu,
X.-Q. Xie, Y.-M. Jia and C.-Y. Yu, Synlett, 2010, 488;
(f) W.-B. Zhao, S. Nakagawa, A. Kato, I. Adachi, Y.-M. Jia,
X.-G. Hu, G. W. J. Fleet, F. X. Wilson, G. Horne,
A. Yoshihara, K. Izumori and C.-Y. Yu, J. Org. Chem., 2013,
78, 3208.
Aldrichimica Acta, 2009, 42, 55; (b) V. Nair, C. R. Sinu,
B. P. Babu, W. Varghese, A. Jose and E. Suresh, Org. Lett.,
2009, 11, 5570; (c) B. Cardinal-David, D. E. A. Raup and
K. A. Scheidt, J. Am. Chem. Soc., 2010, 132, 5345;
(d) J. Dugal-Tessier, E. A. O’Bryan, T. B. H. Schroeder,
D. T. Cohen and K. A. Scheidt, Angew. Chem., Int. Ed., 2012,
51, 4963.
15 (a) F. Cardona, G. Moreno, F. Guarna, P. Vogel, C. Schuetz,
P. Merino and A. Goti, J. Org. Chem., 2005, 70, 6552; 20 J. Izquierdo, G. E. Hutson, D. T. Cohen and K. A. Scheidt,
(b) S. Desvergnes, S. Py and Y. Vallée, J. Org. Chem., 2005, Angew. Chem., Int. Ed., 2012, 51, 11686.
70, 1459; (c) S. G. Pyne and M. Y. Tang, Curr. Org. Chem., 21 E. M. Phillips, T. E. Reynolds and K. A. Scheidt, J. Am.
2005, 9, 1393; (d) A. Brandi, F. Cardona, S. Cicchi, Chem. Soc., 2008, 130, 2416.
F. M. Cordero and A. Goti, Chem.–Eur. J., 2009, 15, 7808; 22 (a) C.-Y. Yu and M.-H. Huang, Org. Lett., 2006, 8, 3021;
(e) C. Parmeggiani, D. Martella, F. Cardona and A. Goti,
J. Nat. Prod., 2009, 72, 2058; (f) I. Delso, T. Tejero, A. Goti
(b) X.-G. Hu, Y.-M. Jia, J. Xiang and C.-Y. Yu, Synlett, 2010,
982.
and P. Merino, Tetrahedron, 2010, 66, 1220; (g) X.-G. Hu, 23 (a) Y.-X. Li, M.-H. Huang, Y. Yamashita, A. Kato, Y.-M. Jia,
B. Bartholomew, R. J. Nash;, F. X. Wilson, G. W. J. Fleet,
S. Nakagawa, A. Kato, Y.-M. Jia, R. van Well and C.-Y. Yu,
Org. Lett., 2010, 12, 2562; (h) C. Bonaccini, M. Chioccioli,
C. Parmeggiani, F. Cardona, D. Lo Re, G. Soldaini, P. Vogel,
W.-B. Wang, G. W. J. Fleet, R. J. Nash and C.-Y. Yu, Org.
Biomol. Chem., 2011, 9, 3405; (b) J.-K. Su, Y.-M. Jia, R. He,
P.-X. Rui, N. Han, X. He, J. Xiang, X. Chen, J. Zhu and
C.-Y. Yu, Synlett, 2010, 160.
C. Bello, A. Goti and P. Gratteri, Eur. J. Org. Chem., 2010, 24 V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu, R. R. Paul,
5574; (i) I. Delso, T. Tejero, A. Goti and P. Merino, J. Org.
Chem., 2011, 76, 4139; ( j) G. Podolan, L. Kleščíková,
A. Jose and V. Sreekumar, Chem. Soc. Rev., 2011, 40,
5336.
L. Fišera, J. Kožíšek and M. Fronc, Synlett, 2011, 1668; 25 D. Enders and U. Kallfass, Angew. Chem., Int. Ed., 2002, 41,
(k) G. D’Adamio, A. Goti, C. Parmeggiani, E. Moreno- 1743.
Clavijo, I. Robina and F. Cardona, Eur. J. Org. Chem., 2011, 26 D. D. Dhavale, L. Gentilucci, M. G. Piazza and C. Trombini,
7155; (l) T. Ritthiwigrom, C. W. G. Au and S. G. Pyne, Curr.
Org. Synth., 2012, 9, 583.
16 (a) D. Enders, O. Niemeier and A. Henseler, Chem. Rev.,
2007, 107, 5606; (b) N. Marion, S. Díez-González and
S. P. Nolan, Angew. Chem., Int. Ed., 2007, 46, 2988.
Justus Liebigs Ann. Chem., 1992, 1289.
27 (a) D. J. Wardrop and S. L. Waidyarachchi, Nat. Prod. Rep.,
2010, 27, 1431; (b) Iminosugars: From Synthesis to Thera-
peutic Applications, ed. P. Compain and O. R. Martin, 1st
edn, Wiley, 2007.
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