Asymmetric syntheses of 2,5-dideoxy-2,5-imino-d-glucitol [(+)-DGDP] and 1,2,5-trideoxy-1-amino-2,5-imino-d-glucitol [(+)-ADGDP]

Article abstract of DOI:10.1016/j.tet.2014.03.100

The asymmetric syntheses of 2,5-dideoxy-2,5-imino-d-glucitol [(+)-DGDP] and 1,2,5-trideoxy-1-amino-2,5-imino-d-glucitol [(+)-ADGDP] were achieved via the ring-closing iodoamination of an enantiopure bishomoallylic amine, followed by functionalisation of the resultant iodomethyl substituted pyrrolidine. In the case of (+)-DGDP, formation of the corresponding aziridinium ion followed by regioselective ring-opening with H₂O gave the desired hydroxymethyl substituted pyrrolidine as a single diastereoisomer (>99:1 dr), with subsequent deprotection giving (+)-DGDP in good yield. Whereas in the case of (+)-ADGDP, displacement of iodide with NaN₃ proved to be optimal, giving (+)-ADGDP in good yield after reduction and deprotection.

Full text of DOI:10.1016/j.tet.2014.03.100

Tetrahedron 70 (2014) 3601e3607
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric syntheses of 2,5-dideoxy-2,5-imino-
D-glucitol
[(þ)-DGDP] and 1,2,5-trideoxy-1-amino-2,5-imino-
D
-glucitol
[(þ)-ADGDP]
*
Stephen G. Davies , Aude L.A. Figuccia, Ai M. Fletcher, Paul M. Roberts,
James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric syntheses of 2,5-dideoxy-2,5-imino-
D
-glucitol [(þ)-DGDP] and 1,2,5-trideoxy-1-amino-
Received 31 January 2014
Accepted 31 March 2014
Available online 5 April 2014
2,5-imino-
D
-glucitol [(þ)-ADGDP] were achieved via the ring-closing iodoamination of an enantiopure
bishomoallylic amine, followed by functionalisation of the resultant iodomethyl substituted pyrrolidine.
In the case of (þ)-DGDP, formation of the corresponding aziridinium ion followed by regioselective ring-
opening with H2O gave the desired hydroxymethyl substituted pyrrolidine as a single diastereoisomer
(>99:1 dr), with subsequent deprotection giving (þ)-DGDP in good yield. Whereas in the case of
(þ)-ADGDP, displacement of iodide with NaN3 proved to be optimal, giving (þ)-ADGDP in good yield
after reduction and deprotection.
Keywords:
(þ)-DGDP
(þ)-ADGDP
Pyrrolidine alkaloids
Asymmetric synthesis
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Many polyhydroxylated pyrrolidines occur within Nature. Given
the potent and specific inhibitory activity toward carbohydrate
processing enzymes that many members of this class of compounds
display, polyhydroxylated pyrrolidines have been the targets of
numerous synthetic endeavours,1 and have been documented as
highly promising candidates for the development of new thera-
peutic agents for the treatment of disorders such as diabetes, cancer
and viral infections (e.g., HIV).2 For example, 2,5-dideoxy-2,5-
imino-
D
-mannitol [(þ)-DMDP] 1, 2,5-dideoxy-2,5-iminogalactitol
(DGADP) 2 and 2,5-dideoxy-2,5-imino-
D
-glucitol [(þ)-DGDP] 3
are known inhibitors of several galactosidase and glucosidase en-
zymes.3,4 Furthermore, the synthetic 1-deoxy-1-amino-analogue of
DMDP [(þ)-ADMDP] 4, and N(1)-substituted derivatives, have also
been shown to display significantly enhanced selectivity and po-
tency toward the inhibition of glucosidases.5 Most syntheses of
compounds such as (þ)-DGDP 3 concern the elaboration of readily
available carbohydrate precursors;6,7 in contrast, relatively few
asymmetric syntheses of (þ)-DGDP 3 have been reported (Fig. 1).8
Herein we report asymmetric syntheses of both (þ)-DGDP 3 and its
Fig. 1. Biologically active polyhydroxylated pyrrolidines 1e4.
reaction, followed by functionalisation of the resultant iodomethyl
substituted pyrrolidine.
As part of our ongoing research programme concerning the
asymmetric syntheses of enantiopure pyrrolidines,9 piperidines,10
and related natural products,11 we have recently reported the
asymmetric syntheses of (ꢀ)-1-deoxymannojirimycin 14 and its
diastereoisomer (þ)-1-deoxyallonojirimycin.12 Our synthetic
strategy for the construction of the piperidine ring relied on the
ring-closing iodoamination of an enantiopure bishomoallylic
amine such as 9, which proceeds with concomitant N-debenzyla-
tion, followed by ring-expansion of the resultant C(2)-iodomethyl
1-deoxy-1-amino-analogue 1,2,5-trideoxy-1-amino-2,5-imino-D-
glucitol [(þ)-ADGDP], employing a ring-closing iodoamination
* Corresponding author. Tel.: þ44 (0)1865 275695; fax: þ44 (0)1865 275633;
e-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.100

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S.G. Davies et al. / Tetrahedron 70 (2014) 3601e3607
substituted pyrrolidine 10. Bishomoallylic amine 9 was prepared in
five steps from -unsaturated ester 5: conjugate addition of
lithium (R)-N-benzyl-N-(
-methylbenzyl)amide to 5,13 followed by
in situ oxidation of the intermediate lithium (Z)-
-amino enolate14
with (ꢀ)-camphorsulfonyloxaziridine [(ꢀ)-CSO] gave -hydroxy-
2. Results and discussion
a,b
a
We envisaged that repetition of the protocol for the generation
of aziridinium ion 11, followed by treatment of 11 with dioxane/H2O
(i.e., omitting the addition of NaHCO3) would produce pyrrolidine
15 preferentially, as a result of ring-opening with H2O at the least
hindered C(6)-position within aziridinium ion 11. Thus, treatment
of 10 with AgBF4 in CH2Cl2 gave quantitative conversion to azir-
idinium ion 11, which was then treated with a 3:1 mixture of di-
oxane and H2O, which produced a 90:10 mixture of pyrrolidine 15
and the known piperidine 16,12 respectively. The relative configu-
ration within pyrrolidine 15 was initially assigned on the basis that
substitution occurs with overall retention of configuration, and this
assignment was subsequently confirmed unambiguously via single
crystal X-ray diffraction analysis of a derivative. O-Silyl depro-
tection of the mixture of 15 and 16, followed by peracetylation of
the mixture of 17 and 18 facilitated the isolation of both 19 and 20
in 65 and 4% yield (from 10), respectively, as single
diastereoisomers (>99:1 dr) in each case (Scheme 2).
b
a
b-
amino ester 6 in >99:1 dr;13 subsequent O-benzyl protection, re-
duction of the ester moiety within 7, oxidation of the resultant al-
cohol 8, and reaction with vinylmagnesium bromide gave 9, which
was isolated as a single diastereoisomer (>99:1 dr). Treatment of 9
with I2 and NaHCO3 in MeCN gave C(5)-iodomethyl substituted
pyrrolidine 10, which could then be converted into carbonate 12 via
the intermediacy of aziridinium ion 11, following intramolecular
ring-opening of the aziridinium intermediate by a carbonate group
tethered at the C(4)-position.15 However, it was found that under
optimised conditions a superior yield of carbonate 12 could be
obtained directly from 9. In this case, subsequent O-silyl depro-
tection of 12, methanolysis, and hydrogenolysis of 13 gave (ꢀ)-1-
deoxymannojirimycin 14, which was isolated in good yield as
a single diastereoisomer (Scheme 1).
Scheme 2.
Transesterification of pyrrolidine 19 upon treatment with K2CO3
in MeOH was followed by conversion to the corresponding hy-
drochloride salt 21, which was isolated in quantitative yield and
>99:1 dr. The relative configuration within 21 was assigned un-
ambiguously by single crystal X-ray diffraction analysis;16 further-
more, the determination of a Flack x parameter17 of ꢀ0.057(13) for
the crystal structure of 21$H2O allowed the assigned absolute
Scheme 1.

S.G. Davies et al. / Tetrahedron 70 (2014) 3601e3607
3603
(2R,3R,4R,5S)-configuration within 21 to be confirmed un-
ambiguously (Fig. 2), thereby also confirming the assigned config-
urations within 15, 17 and 19. Subsequent hydrogenolytic N- and O-
debenzylation of 21 upon treatment with Pearlman’s catalyst
[Pd(OH)2/C] under an atmosphere of H2 (5 atm) gave hydrochloride
salt 22 in quantitative yield and >99:1 dr. Further purification of
this sample by ion exchange chromatography on Dowex 50WX8
(Hþ form) resin gave (þ)-DGDP 3 in quantitative yield as a single
diastereoisomer (Scheme 3). The melting point, specific rotation,
and 1H and 13C NMR spectroscopic data for 3 were in excellent
agreement with literature values18 for both the natural product and
synthetic samples {mp 124e127 ꢁC; lit.3c for sample isolated from
the natural source mp 127e130 ꢁC; lit.8 mp 139e141 ꢁC; lit.6 mp
Attempts to effect ring-opening of aziridinium ion 11 with
nitrogen-centred nucleophiles (e.g., azide, ammonia, etc.) were not
efficacious, although when 9 was subjected to our standard ring-
closing iodoamination protocol (i.e., treatment with I2 and
NaHCO3 in MeCN),9b,c,d followed by immediate treatment of the
crude reaction mixture with NaN3 in DMF, a 49:10:41 mixture of
the corresponding pyrrolidine 23, piperidine 24,19 and returned
starting material 9, respectively, was produced; chromatographic
purification of this mixture gave azide 23 in 23% isolated yield.
O-Silyl deprotection of 23 was then achieved upon treatment of 23
with HF$pyridine, giving 25 in quantitative yield and >99:1 dr.
Tandem hydrogenolysis/reduction of 25 upon treatment with
Pearlman’s catalyst [Pd(OH)2/C] under a hydrogen atmosphere
(5 atm) gave (þ)-ADGDP, which was isolated as the corresponding
dihydrochloride salt 26 in quantitative yield and >99:1 dr (Scheme
4). The spectroscopic data for 26 were also consistent with litera-
136e138 ꢁC; [
a
]
20 þ22.2 (c 0.5, H2O); lit.3c for sample isolated from
D
the natural source [
a]
D þ26.1 (c 0.84, H2O); lit.7k
[
a]
28 þ22.7 (c 0.14,
D
H2O); lit.18a
[
a
]
22 þ24.1 (c 1.0, H2O)}.
D
ture values {mp>170 ꢁC; lit.7p mp >150 ꢁC; [
a
]
20 þ33.2 (c 0.6, H2O);
D
25
lit.7p
[
a
]
D
þ43 (c 1.43, H2O)}.
Scheme 3.
Scheme 4.
3. Conclusion
In conclusion, the ring-closing iodoamination of an enantiopure
bishomoallylic amine provided an enantiopure pyrrolidine scaffold.
Subsequent elaboration of the iodomethyl substituted pyrrolidine
by either formation of the corresponding aziridinium ion followed
by regioselective ring-opening with H2O, or direct displacement
with NaN3 gave (þ)-DGDP and (þ)-ADGDP, respectively, in good
yield after reduction/deprotection.
4. Experimental
4.1. General experimental
All reactions involving organometallic or other moisture sensi-
tive reagents were carried out under a nitrogen or argon atmo-
sphere using standard vacuum line techniques and glassware that
Fig. 2. X-ray crystal structure of (2R,3R,4R,5S)-21$H2O (H2O and selected H atoms are
omitted for clarity).

3604
S.G. Davies et al. / Tetrahedron 70 (2014) 3601e3607
was flame dried and cooled under nitrogen before use. Solvents
were dried according to the procedure outlined by Grubbs and co-
workers.20 Water was purified by an ElixÒ UVe10 system. BuLi was
purchased as a solution in hexanes and titrated against diphenyl-
acetic acid before use. All other reagents were used as supplied
without prior purification. Organic layers were dried over MgSO4.
Thin layer chromatography was performed on aluminium plates
coated with 60 F254 silica. Plates were visualised using UV light
(254 nm), iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic
acid. Flash column chromatography was performed on Kieselgel 60
silica.
Melting points are uncorrected. Optical rotations were recor-
ded in a water-jacketed 10 cm cell. Specific rotations are reported
in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100 mL. IR spectra
were recorded using an ATR module. Selected characteristic peaks
are reported in cmꢀ1. NMR spectra were recorded in the deuter-
ated solvent stated. Spectra were recorded at rt. The field was
locked by external referencing to the relevant deuteron reso-
nance. 1He1H COSY, 1He13C HSQC, and 1He13C HMBC analyses
were used to establish atom connectivity. Accurate mass mea-
surements were run on a TOF spectrometer internally calibrated
with polyalanine.
mixture was then diluted with Et2O (15 mL) and washed with 2.0 M
aq KOH (15 mL), then dried and concentrated in vacuo to give
a 90:10 mixture of 15 and 16 (124 mg), respectively. Data for
mixture: nmax (ATR) 3406 (OeH), 2942, 2866 (CeH); m/z (ESIþ) 500
([MþH]þ, 100%); HRMS (ESIþ) C29H46NO4Siþ ([MþH]þ) requires
500.3191; found 500.3166. Data for 15: dH (400 MHz, CDCl3)
0.90e1.08 (21H, m, Si(CHMe2)3), 3.00 (1H, app q, J 3.4, C(2)H),
3.11e3.16 (1H, m, C(5)H), 3.51 (1H, app t, J 4.4, C(2)CH2), 3.57 (2H,
dd, J 11.6, 4.8, C(5)CHAHB), 3.70 (1H, dd, J 11.6, 1.6, C(5)CHAHB), 3.77
(1H, d, J 13.7, NCHAHBPh), 3.82e3.87 (2H, m, C(3)H, NCHAHBPh),
4.18e4.25 (1H, m, C(4)H), 4.52 (1H, d, J 11.7, OCHAHBPh), 4.64 (1H, d,
J 11.7, OCHAHBPh), 7.18e7.31 (10H, m, Ph); dC (100 MHz, CDCl3) 11.8
(Si(CHMe2)3), 18.0 (Si(CHMe2)3), 58.2 (NCH2Ph), 60.0 (C(5)CH2),
63.8 (C(2)CH2), 66.7 (C(5)), 70.4 (C(2)), 71.5 (OCH2Ph), 76.8 (C(4)),
85.4 (C(3)), 127.6, 127.6, 128.4, 128.5, 128.5, 129.0 (o,m,p-Ph), 138.2
(2ꢂi-Ph). Data for 16: dH (400 MHz, CDCl3) 1.02e1.14 (21H, m,
Si(CHMe2)3), 2.24 (1H, d, J 12.4, C(6)HA), 2.38e2.47 (1H, m, C(2)H),
2.92 (1H, dd, J 12.4, 4.6, C(6)HB), 3.36 (1H, d, J 13.3, NCHAHBPh), 3.57
(1H, app t, J 8.1, C(3)H), 3.65 (1H, dd, J 8.1, 3.3, C(4)H), 3.72e3.80 (1H,
m, C(5)H), 4.03 (1H, dd, J 11.1, 4.0, C(2)CHAHB), 4.22 (1H, dd, J 11.1,
1.8, C(2)CHAHB), 4.43 (1H, d, J 13.3, NCHAHBPh), 4.65 (1H, d, J 11.4,
OCHAHBPh), 5.03 (1H, d, J 11.4, OCHAHBPh), 7.26e7.40 (10H, m, Ph);
dC (100 MHz, CDCl3) 12.0 (Si(CHMe2)3), 18.1 (Si(CHMe2)3), 54.1
(C(6)), 57.2 (NCH2Ph), 61.9 (C(2)CH2), 66.6 (C(2)), 67.9 (C(5)), 74.3
(OCH2Ph), 75.8 (C(4)), 78.6 (C(3)), 127.2, 127.6, 127.9, 128.4, 128.5,
129.0 (o,m,p-Ph), 138.5 (2ꢂi-Ph).
4.2. (R,R,R,R)-N(1)-Benzyl-2-[(triisopropylsilyloxy)methyl]-3-
benzyloxy-4-hydroxy-5-(iodomethyl)pyrrolidine 10
I2 (518 mg, 2.04 mmol) and NaHCO3 (171 mg, 2.04 mmol) were
added to a stirred solution of 912 (400 mg, 0.68 mmol, >99:1 dr) in
MeCN (20 mL) at rt, and the resultant mixture was stirred at rt for
16 h. The reaction mixture was diluted with Et2O (50 mL) and
washed with satd aq Na2S2O3 (50 mL), then dried and concentrated
Step 2: HF$pyridine (70% in pyridine, 0.19 mL, 7.50 mmol) was
added dropwise to a stirred solution of the 90:10 mixture of 15 and
16 (124 mg), respectively, in THF (4 mL) at 0 ꢁC. The resultant
mixture was allowed to warm to rt and was stirred at rt for 16 h. The
reaction mixture was then cooled to 0 ꢁC and satd aq NaHCO3
(0.5 mL) was added carefully. The resultant mixture was concen-
trated in vacuo and the residue was partitioned between H2O
(10 mL) and CHCl3/iPrOH (3:1, 10 mL). The aqueous layer was
extracted with CHCl3/iPrOH (3:1, 2ꢂ5 mL) and the combined or-
ganic extracts were then concentrated in vacuo. The residue was
dissolved in CHCl3 (10 mL) and the resultant solution was washed
with satd aq NaHCO3 (10 mL), then dried and concentrated in vacuo
to give a 90:10 mixture of 17 and 18 (85 mg), respectively. Data for
mixture: nmax (ATR) 3368 (OeH), 2926 (CþeH); m/z (ESIþ) 344
([MþH]þ, 100%); HRMS (ESIþ) C20H26NO4 ([MþH]þ) requires
344.1856; found 344.1846. Data for 17: dH (400 MHz, CDCl3)
3.02e3.06 (1H, m, C(2)H), 3.15e3.19 (1H, m, C(5)H), 3.39 (1H, dd, J
11.3, 3.5, C(2)CHAHB), 3.54 (1H, dd, J 11.3, 1.6, C(2)CHAHB), 3.70 (1H,
dd, J 11.8, 4.6, C(5)CHAHB), 3.77e3.84 (3H, m, C(3)H, C(5)CHAHB,
NCHAHBPh), 3.88 (1H, d, J 13.4, NCHAHBPh), 4.29 (1H, dd, J 5.4, 2.5,
C(4)H), 4.59 (1H, d, J 12.0, OCHAHBPh), 4.69 (1H, d, J 12.0,
OCHAHBPh), 7.25e7.39 (10H, m, Ph); dC (100 MHz, CDCl3) 57.8
(NCH2Ph), 60.7 (C(5)CH2), 61.5 (C(2)CH2), 66.6 (C(5)), 69.6 (C(2)),
71.8 (OCH2Ph), 76.6 (C(4)), 86.2 (C(3)), 127.6, 127.6, 127.8, 128.5,
128.7, 128.8 (o,m,p-Ph), 138.0, 138.7 (i-Ph). Data for 18: dH (400 MHz,
CDCl3) 2.29e2.34 (2H, m, C(2)H, C(6)HA), 3.04 (1H, dd, J 12.6, 3.8,
C(6)HB), 3.39 (1H, d, J 13.2, NCHAHBPh), 3.60 (1H, dd, J 8.7, 3.3,
C(4)H), 3.77 (1H, app t, J 8.7, C(3)H), 3.85 (1H, br s, C(5)H), 3.93 (1H,
dd, J 12.0, 1.6, C(2)CHAHB), 4.03 (1H, dd, J 12.0, 2.7, C(2)CHAHB), 4.14
(1H, d, J 13.2, NCHAHBPh), 4.78 (1H, d, J 11.3, OCHAHBPh), 4.93 (1H, d,
J 11.3, OCHAHBPh), 7.26e7.42 (10H, m, Ph); dC (100 MHz, CDCl3) 54.8
(C(6)), 57.0 (NCH2Ph), 58.3 (C(2)CH2), 65.7 (C(2)), 67.8 (C(5)), 75.0
(OCH2Ph), 75.2 (C(4)), 77.2 (C(3)), 127.5, 128.0, 128.1, 128.6, 128.7,
128.8 (o,m,p-Ph), 137.7, 138.3 (i-Ph).
in vacuo to give a 50:50 mixture of 10 and N-(a-methylbenzyl)-
acetamide. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/EtOAc, 50:1) gave 10 as a yellow oil (83 mg, 20%,
20
>99:1 dr);12
[
a
]
þ50.7 (c 1.0, CHCl3); dH (400 MHz, CDCl3)
D
0.95e1.04 (21H, m, Si(CHMe2)3), 3.11 (1H, dd, J 8.9, 3.1, CHAHBI), 3.19
(1H, m, C(2)H), 3.22e3.28 (1H, m, C(2)CHAHB), 3.30 (1H, d, J 8.9,
CHAHBI), 3.40 (1H, app dt, J 11.1, 3.1, C(5)H), 3.48 (1H, d, J 10.4,
C(2)CHAHB), 3.68 (1H, d, J 14.0, NCHAHBPh), 3.86 (1H, app s, C(3)H),
3.95e4.02 (2H, m, NCHAHBPh, OH), 4.23 (1H, dd, J 11.1, 3.2, C(4)H),
4.53 (1H, d, J 12.0, OCHAHBPh), 4.66 (1H, d, J 12.0, OCHAHBPh),
7.22e7.40 (10H, m, Ph).
4.3. (1S,2R,3R,4R,5S)-N(1)-Benzyl-2-[(triisopropylsilyloxy)-
methyl]-3-benzyloxy-4-hydroxy-1-azabicyclo[3.1.0]hexanium
tetrafluoroborate 11
AgBF4 (58 mg, 0.30 mmol) was added to a stirred solution of 102
(150 mg, 0.25 mmol, >99:1 dr) in CH2Cl2 (4 mL) at rt, and the re-
sultant mixture was allowed to stir at rt for 1 h. The reaction
mixture was then filtered through CeliteÒ (eluent CH2Cl2) and
concentrated in vacuo to give 11 as an orange oil (138 mg, quant,
20
>99:1 dr);2
[a
]
þ0.6 (c 0.4, CHCl3); dH (400 MHz, CD2Cl2)
D
0.94e1.24 (21H, m, Si(CHMe2)3), 3.09 (1H, dd, J 8.0, 4.5, C(6)HA),
3.56 (1H, dd, J 6.3, 4.5, C(6)HB), 3.76e3.86 (2H, m, C(2)H, C(3)H),
3.98e4.04 (2H, m, C(2)CHAHB, OH), 4.07e4.20 (2H, m, C(2)CHAHB,
C(5)H), 4.42 (1H, d, J 13.1, NCHAHBPh), 4.54 (1H, d, J 11.6,
OCHAHBPh), 4.77 (1H, d, J 13.1, NCHAHBPh), 4.82 (1H, d, J 11.6,
OCHAHBPh), 4.83e4.88 (1H, m, C(4)H), 7.28e7.58 (10H, m, Ph).
4.4. (2R,3R,4R,5S)-N(1)-Benzyl-2,5-bis(acetoxymethyl)-3-
benzyloxy-4-acetoxypyrrolidine 19 and (R,R,R,R)-N(1)-benzyl-
2-(acetoxymethyl)-3-benzyloxy-4,5-diacetoxypiperidine 20
Step 3: Ac2O (0.24 mL, 2.50 mmol) and DMAP (6 mg, 0.05 mmol)
were added to a stirred solution of the 90:10 mixture of 17 and 18
(85 mg), respectively, in pyridine (4 mL) at 0 ꢁC. The resultant
mixture was allowed to warm to rt and was stirred at rt for 16 h. The
reaction mixture was then diluted with H2O (15 mL) and EtOAc
(15 mL), and the aqueous layer was extracted with EtOAc (2ꢂ5 mL).
Step 1: A solution of 11 (138 mg, 0.25 mmol, >99:1 dr) in di-
oxane/H2O (3:1, 4 mL) was allowed to stir at rt for 16 h. The reaction

S.G. Davies et al. / Tetrahedron 70 (2014) 3601e3607
3605
The combined organic extracts were washed with brine (20 mL),
then dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30e40 ꢁC petrol/acetone, 9:1) gave 19 as
resultant suspension was stirred at rt for 48 h under an atmosphere
of H2 (5 atm). HCl (2.0 M in Et2O, 1 mL) was then added and the
resultant suspension was stirred for 5 min before being filtered
through CeliteÒ (eluent MeOH), and concentrated in vacuo to give
22. Purification via ion exchange chromatography on Dowex
50WX8 resin (hydrogen form, 100e200 mesh, eluent H2O) gave 3
as a white solid (21 mg, quant, >99:1 dr); mp 124e127 ꢁC; {lit.3c for
sample isolated from the natural source mp 127e130 ꢁC; lit.8 mp
a yellow oil (76 mg, 65%, >99:1 dr); [
a
]
20 þ50.8 (c 1.0, CHCl3); nmax
D
(ATR) 1741 (C]O); dH (400 MHz, CDCl3) 1.87 (3H, s, COMe),1.99 (3H,
s, COMe), 2.08 (3H, s, COMe), 3.16 (1H, ddd, J 8.2, 5.6, 2.1, C(2)H), 3.51
(1H, app dt, J 7.6, 5.2, C(5)H), 3.67e3.73 (2H, m, C(3)H, C(2)CHAHB),
3.86 (1H, d, J 13.9, NCHAHBPh), 3.93e4.01 (2H, m, C(2)CHAHB,
NCHAHBPh), 4.03e4.14 (2H, m, C(5)CH2), 4.58 (1H, d, J 12.1,
OCHAHBPh), 4.68 (1H, d, J 12.1, OCHAHBPh), 5.30 (1H, dd, J 5.2, 1.6,
C(4)H), 7.25e7.38 (10H, m, Ph); dC (100 MHz, CDCl3) 20.7, 20.8, 21.0
(COMe), 59.1 (NCH2Ph), 62.4 (C(5)CH2), 63.4 (C(5)), 64.5 (C(2)CH2),
68.0 (C(2)), 71.4 (OCH2Ph), 76.1 (C(4)), 86.3 (C(3)), 127.4, 127.7, 127.8,
128.4, 128.4, 128.8 (o,m,p-Ph), 137.7, 138.6 (i-Ph), 170.2, 170.6, 170.6
(COMe); m/zþ (ESIþ) 492 ([MþNa]þ, 100%); HRMS (ESIþ)
20
20
139e141 ꢁC; lit.6 mp 136e138 ꢁC}; [
a
]
þ22.2 (c 0.5, H2O); [
a]
D
D
þ14.4 (c 0.5, MeOH); {lit.3 for sample isolated from the natural
source [
a
]
D þ26.1 (c 0.84, H2O); lit.7k
[a
]
28 þ22.7 (c 0.14, H2O); lit.18a
D
22
[a
]
þ24.1 (c 1.0, H2O)}; nmax (ATR) 3300 (OeH), 2926 (CeH); dH
D
(400 MHz, D2O) 2.99 (1H, app q, J 5.2, C(2)H), 3.30 (1H, app q, J 5.5,
C(5)H), 3.60e3.67 (2H, m, C(2)CHAHB, C(5)CHAHB), 3.70e3.78 (2H,
m, C(2)CHAHB, C(5)CHAHB), 3.84 (1H, dd, J 5.2, 2.8, C(3)H), 4.08 (1H,
dd, J 5.5, 2.8, C(4)H); dC (100 MHz, D2O) 59.9 (C(5)CH2), 60.8 (C(5)),
62.1 (C(2)CH2), 64.8 (C(2)), 77.2 (C(4)), 78.9þ(C(3)); m/z (ESIþ) 164
([MþH]þ, 100%); HRMS (ESIþ) C6H14NO4 ([MþH]þ) requires
164.0917; found 164.0913.
C
26H31NNaO7 ([MþNa]þ) requires 492.1993; found 492.1983.
20
Further elution gave 20 as a yellow oil (5 mg, 4%, >99:1 dr); [a]
D
þ1.5 (c 0.4, CHCl3); nmax (ATR) 1740 (C]O); dH (400 MHz, CDCl3)
2.03 (3H, s, COMe), 2.05 (3H, s, COMe), 2.09 (3H, s, COMe), 2.50 (1H,
dd, J 13.1, 2.7, C(6)HA), 2.81e2.85 (1H, m, C(2)H), 3.00 (1H, dd, J 13.1,
6.0, C(6)HB), 3.58 (1H, d, J 13.9, NCHAHBPh), 3.85 (1H, app t, J 7.0,
C(3)H), 4.08 (1H, d, J 13.9, NCHAHBPh), 4.37 (1H, dd, J 12.3, 4.7,
C(2)CHAHB), 4.51 (1H, dd, J 12.3, 3.8, C(2)CHAHB), 4.62 (1H, d, J 11.3,
OCHAHBPh), 4.73 (1H, d, J 11.3, OCHAHBPh), 5.13 (1H, dd, J 7.0, 3.5,
C(4)H), 5.28 (1H, ddd, J 6.0, 3.5, 2.7, C(5)H), 7.24e4.38 (10H, m, Ph);
dC (100 MHz, CDCl3) 20.9, 21.0 (3ꢂCOMe), 49.9 (C(6)), 57.2
(NCH2Ph), 60.9 (C(2)CH2), 61.8 (C(2)), 66.9 (C(5)), 73.2 (C(4)), 74.0
(OCH2Ph), 74.8 (C(3)), 127.2, 127.7, 127.8, 128.3, 128.5, 128.5 (o,m,p-
Ph), 137.8, 138.4 (i-Ph), 170.0, 170.2, 170.7 (COMe); m/z (ESIþ) 470
4.7. (2R,3R,4R,5S)-N(1)-Benzyl-2-[(triisopropylsilyloxy)-
methyl]-3-benzyloxy-4-hydroxy-5-(azidomethyl)pyrrolidine 23
Step 1: I2 (453 mg, 1.79 mmol) and NaHCO3 (150 mg, 1.79 mmol)
were added to a stirred solution of 912 (350 mg, 0.60 mmol, >99:1
dr) in MeCN (20 mL) at rt, and the resultant mixture was stirred at
rt for 16 h. The reaction mixture was diluted with Et2O (50 mL) and
washed with satd aq Na2S2O3 (50 mL), then dried and concentrated
([MþH]þ, 100%); HRMS (ESIþ) C26H31NNaO7 ([MþNa]þ) requires
in vacuo to give a 50:50 mixture of 10 and N-(a-methylbenzyl)-
acetamide (397 mg).
þ
492.1993; found 492.1981.
Step 2: NaN3 (193 mg, 2.98 mmol) was added to a stirred solu-
tion of the residue of 10 and N-( -methylbenzyl)acetamide (50:50,
4.5. (2R,3R,4R,5S)-N(1)-Benzyl-2,5-bis(hydroxymethyl)-3-
a
benzyloxy-4-hydroxypyrrolidine hydrochloride 21
397 mg) in DMF (15 mL). The resultant mixture was heated at 80 ꢁC
for 16 h before being allowed to cool to rt. The reaction mixture was
then diluted with H2O (50 mL) and EtOAc (50 mL), and the aqueous
layer was extracted with EtOAc (2ꢂ20 mL). The combined organic
extracts were washed with brine/H2O (1:1, 5ꢂ50 mL), then dried
and concentrated in vacuo to give an 49:10:41 mixture of 23, 24 and
9, respectively. Purification via flash column chromatography (el-
uent 30e40 ꢁC petrol/EtOAc, 50:1) gave 23 as a pale yellow oil
Step 1: K2CO3 (54 mg, 0.39 mmol) was added to a stirred solu-
tion of 19 (61 mg, 0.13 mmol, >99:1 dr) in MeOH (4 mL) at rt and
the resultant mixture was allowed to stir at rt for 16 h. The reaction
mixture was then concentrated in vacuo and the residue was par-
titioned between H2O (15 mL) and CHCl3/iPrOH (3:1, 15 mL). The
aqueous layer was extracted with CHCl3/iPrOH (3:1, 2ꢂ5 mL) and
the combined organic extracts were then dried and concentrated in
vacuo to give 17 as a yellow oil (55 mg, quant, >99:1 dr); [
(c 1.0, CHCl3).
Step 2: HCl (2.0 M in Et2O, 1 mL) was added to a stirred solution
of 17 (55 mg, >99:1 dr) in Et2O (4 mL) and the resultant mixture
was stirred at rt for 10 min. The reaction mixture was then con-
(72 mg, 23%, >99:1 dr); [
a]
20 þ46.8 (c 1.0, CHCl3); nmax (ATR) 3406
D
a
]
20 þ11.9
(OeH), 2942, 2866 (CeH), 2100 (N3); dH (400 MHz, CDCl3)
0.97e1.04 (21H, m, Si(CHMe2)3), 3.05 (1H, br s, C(2)H), 3.16e3.22
(1H, m, C(5)H), 3.25e3.30 (2H, m, C(5)CHAHB, C(2)CHAHB), 3.50 (1H,
dd, J 10.1, 2.5, C(2)CHAHB), 3.63 (1H, dd, J 11.8, 8.7, C(5)CHAHB), 3.71
(1H, d, J 14.2, NCHAHBPh), 3.85 (1H, app s, C(3)H), 3.96e4.02 (2H, m,
NCHAHBPh, OH), 4.11 (1H, dd, J 11.0, 3.8, C(4)H), 4.53 (1H, d, J 12.0,
OCHAHBPh), 4.64 (1H, d, J 12.0, OCHAHBPh), 7.23e7.38 (10H, m, Ph);
dC (100 MHz, CDCl3) 11.8 (Si(CHMe2)3), 17.9 (Si(CHMe2)3), 50.3
(C(5)CH2), 59.0 (NCH2Ph), 64.6 (C(2)CH2), 67.3 (C(5)), 71.3
(OCH2Ph), 72.7 (C(2)), 73.5 (C(4)), 85.4 (C(3)), 127.2, 127.6, 127.7,
128.3, 128.4, 128.8 (o,m,p-Ph), 138.0, 139.6 (i-Ph); m/z (ESIþ) 525
([MþH]þ, 100%); HRMS (ESIþ) C29H45N4O3Siþ ([MþH]þ) requires
525.3255; found 525.3248. Data for 24: dH (400 MHz, CDCl3)
0.89e1.12 (21H, m, Si(CHMe2)3), 2.47 (1H, dd, J 12.6, 3.5, C(6)HA),
2.68e2.74 (1H, m, C(2)H), 3.11 (1H, dd, J 12.6, 7.4, C(6)HB), 3.60 (1H,
d, J 13.9, NCHAHBPh), 3.68 (1H, t, J 5.7, C(3)H), 3.78 (1H, app dt, J 7.4,
3.5, C(5)H), 3.88 (1H, dd, J 10.7, 4.7, C(2)CHAHB), 3.92e3.98 (1H, m,
C(4)H), 4.15 (1H, dd, J 10.7, 3.5, C(2)CHAHB), 4.28 (1H, d, J 13.9,
NCHAHBPh), 4.64 (1H, d, J 11.4, OCHAHBPh), 4.72 (1H, d, J 11.4,
OCHAHBPh), 7.21e7.40 (10H, m, Ph); dC (100 MHz, CDCl3) 11.9
(Si(CHMe2)3), 18.0 (Si(CHMe2)3), 49.2 (C(6)), 58.0 (C(5)), 58.5
(NCH2Ph), 63.0 (C(2)CH2), 63.7 (C(2)), 72.2 (C(4)), 73.4 (OCH2Ph),
78.7 (C(3)), 127.0, 127.6, 128.3, 128.5, 128.6, 128.8, 129.0 (o,m,p-Ph),
138.2, 139.1 (i-Ph).
D
centrated in vacuo to give 21 as a yellow solid (49 mg, quant, >99:1
20
dr); mp 64e66 ꢁC; [
a
]
þ18.3 (c 1.0, CHCl3); nmax (ATR) 3307
D
(OeH), 2929 (CeH); dH (400 MHz, CDCl3) 3.74e3.87 (4H, m, C(2)H,
C(3)H, C(5)H, C(5)CHAHB), 4.09e4.17 (2H, m, C(5)CHAHB,
NCHAHBPh), 4.32 (1H, d, J 13.1, NCHAHBPh), 4.43e4.49 (3H, m,
C(4)H, C(2)CHAHB, OCHAHBPh), 4.54 (1H, d, J 12.0, OCHAHBPh), 4.72
(1H, d, J 13.1, C(2)CHAHB), 4.74 (1H, br s, OH), 5.16 (1H, br s, OH), 5.46
(1H, d, J 4.7, OH), 7.12e7.16 (2H, m, Ph), 7.31e7.38 (3H, m, Ph),
7.44e7.49 (3H, m, Ph), 7.60e7.64 (2H, m, Ph); dC (100 MHz, CDCl3)
57.7 (NCH2Ph), 60.1 (C(5)CH2), 61.1 (C(2)CH2), 70.7 (C(2)), 71.9
(OCH2Ph), 73.9 (C(4)), 74.1 (C(5)), 83.4 (C(3)), 127.5, 128.3, 128.6,
129.4, 130.5, 132.1 (o,m,p-Ph), 136.4 (2ꢂi-Ph); m/z (ESIþ) 344
þ
([MþH]þ, 100%); HRMS (ESIþ) C20H26NO4 ([MþH]þ) requires
344.1856; found 344.1851.
4.6. 2,5-Dideoxy-2,5-imino-D-glucitol [(D)-DGDP] 3
Pd(OH)2/C (22 mg, 20% w/w) was added to a stirred solution of
21 (44 mg, 0.13 mmol, >99:1 dr) in degassed MeOH (4 mL) and the

3606
S.G. Davies et al. / Tetrahedron 70 (2014) 3601e3607
4.8. (2R,3R,4R,5S)-N(1)-Benzyl-2-(hydroxymethyl)-3-
benzyloxy-4-hydroxy-5-(azidomethyl)pyrrolidine 25
dimensions¼0.12ꢂ0.22ꢂ0.25 mm. A total of 8578 unique re-
flections were measured for 4< <76 and 7291 reflections were
q
used in the refinement. The final parameters were wR2¼0.158 and
HF$pyridine (70% in pyridine, 0.06 mL, 2.40 mmol) was added
dropwise to a stirred solution of 23 (42 mg, 0.080 mmol, >99:1 dr)
in THF (2 mL) at 0 ꢁC, and the resultant mixture was allowed to
warm to rt and was stirred at rt for 16 h. The reaction mixture was
cooled to 0 ꢁC and satd aq NaHCO3 (0.5 mL) was then carefully
added. The resultant mixture was concentrated in vacuo and the
residue was partitioned between H2O (5 mL) and CHCl3/iPrOH (3:1,
5 mL). The aqueous layer was extracted with CHCl3/iPrOH (3:1,
2ꢂ5 mL) and the combined organic extracts were then concen-
trated in vacuo. The residue was dissolved in CHCl3 (10 mL), and the
resultant solution was washed with satd aq NaHCO3 (10 mL), then
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent CHCl3/MeOH, 50:1) gave 25 as a yellow oil
R1¼0.047 [I>ꢀ3.0
s
(I)], with Flack enantiopole¼ꢀ0.057(13).17
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.03.100.
References and notes
1. For example, see: (a) Blanco, O.; Pato, C.; Ruiz, M.; Ojea, V. Org. Biomol. Chem.
2009, 7, 2310; (b) Tsou, E.-L.; Yeh, Y.-T.; Liang, P.-H.; Cheng, W.-C. Tetrahedron
2009, 65, 93.
2. (a) Dwek, R. A.; Butters, T. D.; Platt, F. M.; Zitzmann, N. Nat. Rev. Drug Discovery
2002, 1, 65; (b) Iminosugars. From Synthesis to Therapeutic Applications; Com-
pain, P., Martin, O. R., Eds.; Wiley & Sons: Chichester, UK, 2007.
(29 mg, quant, >99:1 dr); [
a
]
20 þ41.5 (c 1.0, CHCl3); nmax (ATR) 3381
D
(OeH), 2927 (CeH), 2100 (N3); dH (400 MHz, CDCl3) 3.02e3.04 (1H,
m, C(2)H), 3.17 (1H, dd, J 11.3, 3.5, C(2)CHAHB), 3.26 (1H, dt, J 7.6, 4.7,
C(5)CHAHB), 3.34 (1H, app dd, J 12.3, 4.7, C(5)H), 3.45 (1H, app d, J
11.3, C(2)CHAHB), 3.51 (1H, dd, J 12.3, 7.6, C(5)CHAHB), 3.74 (1H, d, J
13.6, NCHAHBPh), 3.83 (1H, app t, J 2.5, C(3)H), 3.92 (1H, d, J 13.6,
NCHAHBPh), 4.17 (1H, br s, C(4)H), 4.58 (1H, d, J 12.0, OCHAHBPh),
4.68 (1H, d, J 12.0, OCHAHBPh), 7.27e7.40 (10H, m, Ph); dC (100 MHz,
CDCl3) 50.4 (C(5)CH2), 58.5 (NCH2Ph), 61.5 (C(2)CH2), 66.4 (C(5)),
70.6 (C(2)), 71.8 (OCH2Ph), 74.2 (C(4)), 86.5 (C(3)), 127.6, 127.7, 127.9,
128.5, 128.7, 128.7 (o,m,p-Ph), 137.9, 138.8 (þi-Ph); m/z (ESIþ) 369
([MþH]þ, 100%); HRMS (ESIþ) C20H25N4O3 ([MþH]þ) requires
369.1921; found 369.1924.
3. (a) Liu, K. K. C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong, C.-H. J. Org.
Chem. 1991, 56, 6280; (b) Wang, Y. F.; Takaoka, Y.; Wong, C.-H. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1242; (c) Asano, N.; Yamauchi, T.; Kagamifuchi, K.; Shimizu,
N.; Takahashi, S.; Takatsuka, H.; Ikeda, K.; Kizu, H.; Chuakul, W.; Kettawan, A.;
Okamoto, T. J. Nat. Prod. 2005, 68, 1238; (d) Liang, P. H.; Cheng, W. C.; Lee, Y. L.;
Yu, H. P.; Wu, Y. T.; Lin, Y. L.; Wong, C. H. ChemBioChem 2006, 7, 165.
4. N-Substituted derivatives have also shown potential as therapeutic agents; for
example, see: (a) Liu, J.; Numa, M. M. D.; Liu, H.; Huang, S.-J.; Sears, P.;
Shikhman, A. R.; Wong, C.-H. J. Org. Chem. 2004, 69, 6273; (b) Yu, Z.; Sawkar, A.
R.; Whalen, L. J.; Wong, C.-H.; Kelly, J. W. J. Med. Chem. 2007, 50, 94.
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€
A. J.; Stutz, A. E.; Tarling, C. A.; Withers, S. G.; Wolfler, H. Bioorg. Med. Chem.
2004, 12, 3485.
6. Blanco, O.; Pato, C.; Ruiz, M.; Ojea, V. Org. Biomol. Chem. 2008, 6, 3967.
7. For example, see: (a) Legler, G.; Korth, A.; Berger, A.; Ekhart, C.; Gradnig, G.;
€
Stutz, A. E. Carbohydr. Res. 1993, 250, 67; (b) Baxter, E. W.; Reitz, A. B. J. Org.
Chem. 1994, 59, 3175; (c) Lee, R. E.; Smith, M. D.; Nash, R. J.; Griffiths, R. C.;
McNeil, M.; Grewal, R. K.; Yan, W.; Besra, G. S.; Brennan, P. J.; Fleet, G. W. J.
Tetrahedron Lett. 1997, 38, 6733; (d) Long, D. D.; Frederiksen, S. M.; Marquess, D.
G.; Lane, A. L.; Watkin, D. J.; Winkler, D. A.; Fleet, G. W. J. Tetrahedron Lett. 1998,
39, 6091; (e) Fechter, M. H.; Stutz, A. E. Carbohydr. Res. 1999, 319, 55; (f) Don-
doni, A.; Giovannini, P. P.; Perrone, D. J. Org. Chem. 2002, 67, 7203; (g) Singh, S.;
Han, H. Tetrahedron Lett. 2004, 45, 6349; (h) Gautier-Lefebvre, I.; Behr, J.-B.;
Guillerm, G.; Muzard, M. Eur. J. Med. Chem. 2005, 40, 1255; (i) García-Moreno,
4.9. 1,2,5-Trideoxy-1-amino-2,5-imino-D-glucitol dihydro-
chloride [(D)-ADGDP$2HCl] 26
Pd(OH)2/C (14 mg) and HCl (2.0 M in Et2O, 0.5 mL) were added
to a stirred solution of 25 (27 mg, 0.07 mmol, >99:1 dr) in degassed
MeOH (2 mL), and the resultant suspension was stirred at rt for 48 h
under an atmosphere of H2 (5 atm). The resultant suspension was
filtered through CeliteÒ (eluent MeOH) and the filtrate was con-
centrated in vacuo. Purification via ion exchange chromatography
on Dowex-50WX8 resin (hydrogen form, 100e200 mesh, eluent
H2O) gave (þ)-ADGDP as a colourless oil. HCl (2.0 M in Et2O, 1 mL)
was added to a stirred solution of (þ)-ADGDP in Et2O (2 mL) and
the resultant mixture was stirred at rt for 10 min then concentrated
in vacuo to give 26 as pale yellow glassy solid (16 mg, quant, >99:1
ꢁ
M. I.; Aguilar, M.; Ortiz Mellet, C.; García Fernandez, J. M. Org. Lett. 2006, 8, 297;
(j) Izquierdo, I.; Plaza, M. T.; Rodríguez, M.; Tamayo, J. A.; Martos, A. Tetrahedron
2006, 62, 2693; (k) Kumar, V.; Ramesh, N. G. Tetrahedron 2006, 62, 1877; (l)
ꢁ
€
Izquierdo, I.; Plaza, M. T.; Yanez, V. Tetrahedron 2007, 63, 1440; (m) Doyaguez, E.
ꢁ
ꢁ
G.; Calderon, F.; Sanchez, F.; Fernandez-Mayoralas, A. J. Org. Chem. 2007, 72,
9353; (n) Vyavahare, V. P.; Chattopadhyay, S.; Puranik, V. G.; Dhavale, D. D.
Synlett 2007, 559; (o) Malle, B. M.; Lundt, I.; Wrodnigg, T. M. Org. Biomol. Chem.
2008, 6, 1779; (p) Merino, P.; Delso, I.; Tejero, T.; Cardona, F.; Marradi, M.; Faggi,
E.; Parmeggiani, C.; Goti, A. Eur. J. Org. Chem. 2008, 2929; (q) Ayers, B. J.; Ngo, N.;
Jenkinson, S. F.; Martínez, R. F.; Shimada, Y.; Adachi, I.; Weymouth-Wilson, A. C.;
Kato, A.; Fleet, G. W. J. J. Org. Chem. 2012, 77, 7777.
dr); mp >170 ꢁC; {lit.7p mp >150 ꢁC}; [
a
]
20 þ33.2 (c 0.6, H2O); {lit.9
8. For an alternative asymmetric synthesis of (þ)-DGDP 3, see: Donohoe, T. J.;
Cheeseman, M. D.; O’Riordan, T. J. C.; Kershaw, J. A. Org. Biomol. Chem. 2008, 6,
3896.
D
25
[
a
]
þ43 (c 1.43, H2O)}; nmax (ATR) 3300 (OeH), 3300 (NeH); dH
D
9. (a) Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.;
Smith, A. D.; Rodríguez-Solla, H.; Thomson, J. E.; Toms, S. M. Org. Biomol. Chem.
2007, 5, 1961; (b) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Savory, E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry
2009, 20, 758; (c) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C.
J. Tetrahedron Lett. 2011, 52, 6477; (d) Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Thomson, J. E.; West, C. J. Tetrahedron 2012, 68, 4302; (e) Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Thomson, J. E.; Yin, J. Org. Lett. 2012, 14, 218; (f) Davies, S. G.;
Foster, E. M.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2013, 69, 8680.
10. (a) Davies, S. G.; Hughes, D. G.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A.
D.; Thomson, J. E.; Williams, O. M. H. Synlett 2010, 567; (b) Bagal, S. K.; Davies,
S. G.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E. J. Org. Chem. 2010, 75,
8133; (c) Davies, S. G.; Fletcher, A. M.; Hughes, D. G.; Lee, J. A.; Price, P. D.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H.
Tetrahedron 2011, 67, 9975; (d) Davies, S. G.; Huckvale, R.; Lorkin, T. J. A.;
Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2011, 22, 1591; (e) Bagal,
S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.;
Thomson, J. E. Tetrahedron Lett. 2011, 52, 2216; (f) Davies, S. G.; Fletcher, A. M.;
Lee, J. A.; Roberts, P. M.; Russell, A. J.; Taylor, R. J.; Thomson, A. D.; Thomson, J. E.
Org. Lett. 2012, 14, 1672; (g) Davies, S. G.; Huckvale, R.; Lee, J. A.; Lorkin, T. J. A.;
Roberts, P. M.; Thomson, J. E. Tetrahedron 2012, 68, 3263.
(400 MHz, D2O) 3.46 (1H, dd, J 13.9, 6.0, C(1)HA), 3.58 (1H, dd, J 13.9,
7.0, C(1)HB), 3.64e3.68 (1H, m, C(5)H), 3.81 (1H, dd, J 12.1, 9.0,
C(6)HA), 3.94 (1H, dd, J 12.1, 4.7, C(6)HB), 4.05 (1H, app td, J 6.5, 3.6,
C(2)H), 4.08e4.11 (1H, m, C(4)H), 4.29e4.32 (1H, m, C(3)H); dC
(100 MHz, D2O) 35.4 (C(1)), 58.7 (C(2)), 59.3 (C(6)), 68.3 (C(5)), 74.5
(C(3)), 75.6 (C(4)); m/z (ESIþ) 163 ([MþH]þ, 100%); HRMS (ESIþ)
þ
C6H15N2O3 ([MþH]þ) requires 163.1077; found 163.1073.
4.10. X-ray crystal structure determination for 21$H2O
Data were collected using an Oxford Diffraction SuperNova
diffractometer with graphite monochromated Cu-K
a radiation,
using standard procedures at 150 K. The structures were solved by
direct methods (SIR92); all non-hydrogen atoms were refined with
anisotropic thermal parameters. Hydrogen atoms were added at
idealised positions. The structure was refined using CRYSTALS.21
X-ray crystal structure data for 21$H2O [C20H28ClNO5]:
11. (a) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett.
ꢁ
2011, 13, 2544; (b) Csatayova, K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell,
ꢀ
M¼397.90, monoclinic, space group P21, a¼16.4392(3) A,
A. J.; Thomson, J. E.; Wilson, D. L. Org. Lett. 2011, 13, 2606; (c) Brock, E. A.; Davies,
S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 1594; (d) Brock,
E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2012, 14,
ꢀ
ꢀ
b¼7.4924(2)
A,
c¼16.8150(4)
A,
b
¼93.3685(19)ꢁ,
3
ꢀ
V¼2067.51(8) A , Z¼4,
m
¼1.886 mmꢀ1, colourless plate, crystal

S.G. Davies et al. / Tetrahedron 70 (2014) 3601e3607
3607
ꢁ
4278; (e) Davies, S. G.; Fletcher, A. M.; Lebee, C.; Roberts, P. M.; Thomson, J. E.;
Lett. 2000, 2, 3555; (g) Ortiz, G. X., Jr.; Kang, B.; Wang, Q. J. Org. Chem. 2014, 79,
571; For a review, see: (h) Metro, T.-X.; Duthion, B.; Gomez Pardo, D.; Cossy, J.
Chem. Soc. Rev. 2010, 39, 89.
ꢁ
Yin, J. Tetrahedron 2013, 69, 1369; (f) Davies, S. G.; Fletcher, A. M.; Lee, J. A.;
Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2013, 15, 2050; (g) Brock,
E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Biomol. Chem.
2013, 11, 3187; (h) Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Lorkin, T. J. A.; Roberts,
P. M.; Thomson, J. E. Tetrahedron 2013, 69, 9779.
16. Crystallographic data (excluding structure factors) for compound 21 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 982801.
12. Davies, S. G.; Figuccia, A. L. A.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Org.
Lett. 2013, 15, 2042.
13. Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith,
A. D. Org. Biomol. Chem. 2008, 6, 1655.
14. Davies, S. G.; Foster, E. M.; McIntosh, C. R.; Roberts, P. M.; Rosser, T. E.; Smith, A.
D.; Thomson, J. E. Tetrahedron: Asymmetry 2011, 22, 1035.
15. For examples of studies concerning the regioselective ring-opening of azir-
idinium intermediates, see: (a) Graham, M. A.; Wadsworth, A. H.; Thornton-
Pett, M.; Rayner, C. M. Chem. Commun. 2001, 966; (b) Ori, M.; Toda, N.; Takami,
K.; Tago, K.; Kogen, H. Tetrahedron 2005, 61, 2075; (c) D’hooghe, M.; Van
Speybroeck, V.; Waroquier, M.; De Kimpe, N. Chem. Commun. 2006, 1554; (d)
Metro, T. X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2007, 72, 6556; (e) Jarvis, S. B.;
Charette, A. B. Org. Lett. 2011, 13, 3830; (f) Chuang, T. H.; Sharpless, K. B. Org.
17. (a) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876; (b) Flack, H. D.; Bernar-
dinelli, G. Acta Crystallogr., Sect. A 1999, 55, 908; (c) Flack, H. D.; Bernardinelli, G.
J. Appl. Crystallogr. 2000, 33, 1143.
18. For example, see: (a) Kim, I.-S.; Kim, S.-J.; Lee, J. K.; Li, Q.-R.; Jung, Y.-H. Car-
bohydr. Res. 2007, 342, 1502; (b) Minami, Y.; Kuriyama, C.; Ikeda, K.; Kato, A.;
Takebayashi, K.; Adachi, I.; Fleet, G. W. J.; Kettawan, A.; Okamoto, T.; Asano, N.
Bioorg. Med. Chem. 2008, 16, 2734. See also Refs. 1b,3c,6,7g,7k and 8.
19. The relative configuration within 24 was established by 1H NMR NOE analysis.
20. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
21. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J. J. Appl.
Crystallogr. 2003, 36, 1487.