Sugar-derived cyclic imines: One-pot synthesis and direct functionalization

Article abstract of DOI:10.1016/j.tet.2014.01.039

A simple method for the synthesis of sugar-derived imines by a Schwartz's reagent reduction of easily available sugar lactams has been described. A direct addition of nucleophiles to the generated in situ cyclic imines and subsequent deprotection of hydroxyl function allows to convert sugar lactams in polyhydroxylated pyrrolidines and piperidines.

Full text of DOI:10.1016/j.tet.2014.01.039

Tetrahedron 70 (2014) 1880e1888
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sugar-derived cyclic imines: one-pot synthesis and direct
functionalization
*
ꢀ
Piotr Szczesniak, Sebastian Stecko, Olga Staszewska-Krajewska, Bart1omiej Furman
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple method for the synthesis of sugar-derived imines by a Schwartz’s reagent reduction of easily
available sugar lactams has been described. A direct addition of nucleophiles to the generated in situ
cyclic imines and subsequent deprotection of hydroxyl function allows to convert sugar lactams in
polyhydroxylated pyrrolidines and piperidines.
Received 12 November 2013
Received in revised form 7 January 2014
Accepted 20 January 2014
Available online 25 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Imines
Activation of amides
Pyrrolizidines
Sugar-derived lactams
Iminosugars
1. Introduction
Cyclic imines have a broad utility for the synthesis of various
pharmaceutical and agrochemical intermediates.1e6 Principally, the
sugar-derived imines are attractive building blocks for the stereo-
controlled synthesis of natural products owing to the diversity of
sugar sources, enantiomeric purity and high stereoselectivity of
their transformations.7e13
A common method for the synthesis of cyclic imines relies on N-
chlorination of the corresponding cyclic amines followed by an
elimination (Scheme 1).11,14 An alternative strategy utilizes a Stau-
dinger/aza-Wittig cyclization.14a,15 Cyclic imines can be also ob-
tained through deoxygenation of the corresponding nitrones by
treatment with phosphines16 at elevated temperature.
Scheme 1.
Unfortunately, all of these methods suffer from some draw-
backs, which tends to diminish their overall synthetic value. The
treatment of a-substituted N-chloroamines with base usually leads
to a mixture of regioisomeric imines. To a certain extent, the course
of elimination can be controlled by the choice of base; for example,
the use of DBU at room temperature leads to cyclic ketimines,11,14
while a treatment of N-chloroamine with sterically hindered ba-
ses (e.g., LiTMP) at low temperature (ꢀ78 ꢁC) provides kinetic
aldimines.11,14 Nevertheless, in many cases such aldimines are still
accompanied by their regioisomeric forms, which cannot be easily
removed using chromatographic methods due to the limited sta-
bility of imines.
The use of nitrones as precursor of imines avoids the limited
regioselectivity problem and the phosphine-mediated de-
oxygenation of nitrones is an effective way to get the corresponding
imines. However, in many cases resultant product contains phos-
phine (or its oxide) contamination, which must be removed before
further imine transformations, particularly those catalyzed by the
transition metals. Additionally, although five-membered cyclic
nitrones are readily available, their six- or larger membered con-
geners are less accessible due to their complicated synthesis and
lower stability.17 The third approach based on Staudinger/aza-
Wittig cyclization usually requires multiple-step synthesis of
starting materials.15
* Corresponding author. E-mail addresses: bartlomiej.furman@icho.edu.pl, fur-
bar@icho.edu.pl (B. Furman).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.039

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P. Szczesniak et al. / Tetrahedron 70 (2014) 1880e1888
1881
Bearing in mind these drawbacks, we considered other potential
precursors of cyclic imines and our attention was focused on lactam
derivatives. Although the amides are one of the most important
classes of the organic molecules, due to their widespread presence
in nature, their chemistry is rather limited. In fact, it is mostly
concentrated on the formation of the amide bond and not on its
further transformations, which is the result of a high stability of the
amide bond. For example, the reduction of amides usually requires
quite harsh conditions. Thus, the most common approaches to their
reduction employ nucleophilic metallic hydride donors, such as
aluminum and boron reagents.18 Although such reagents are suit-
able for the synthesis of amines, their use to access imines can be
problematic due to the intrinsic high reactivity of the hydrides
needed to effect the reduction.18
Recently, several examples of the reduction of secondary amides
to the corresponding imines were reported. Charette et al.19 dem-
onstrated a chemoselective activation of secondary amide with
Tf2O in the presence of 2-fluoropyridine followed by the reduction
to aldimines using triethylsilane. The same group also reported
a general and chemoselective method based on an activation/ad-
dition sequence applicable to secondary amides and allowing the
controlled isolation of structurally diverse ketones and ketimines.20
Alternatively, the use of stoichiometric or excess amounts of
Schwartz’s reagent (Cp2Zr(H)Cl) can lead to the formation of a va-
riety of aldehydes or imines with a great functional group toler-
ance.21 It has been also demonstrated that this protocol works for
simple 2-pyrrolidinones.21d
under the conditions developed by Charette and co-workers,19 the
imine 2a was not detected and only starting material was
recovered.
Following the reaction sequence presented in Scheme 2, lactams
1bef were synthesized starting from commercially available ben-
zylated sugars and submitted to the reduction using the same
protocol as in 1a. With the exception of the 2,3,4,5-O-tetrabenzy-
lated mannose, all other sugars gave corresponding lactams as
a single C-5 isomers (1cef), which was corroborated by the 1H NMR
analysis. Only in the case of mannose derivative, the final reduction
(Scheme 2) provided lactam 1b along with its C6-epimer (6-epi-1b)
in a ratio 3:2. The same outcome was observed by Overkleeft.23 The
lack of the selectivity in this single case was rationalized consid-
ering the unfavorable stereoelectronic features of the transition
states of the hydride addition step resulting in the formation of
epimeric products.23 Epimeric lactams 1b and 6-epi-1b were sep-
arated by the chromatography on silica gel.
Bearing in mind the limited stability of the imines, initially cyclic
imines 2aef were isolated and purified by chromatography on
Florisil. Nevertheless, the yields varied from moderate to good
(Table 1). We ascribed that to the general instability of imines
during the isolation and purification operations rather than to the
moderate efficiency of the reduction itself. To prove it, the trapping
experiments were performed where the crude imine was directly
treated with a nucleophile. We expected such a one-pot protocol to
be even more attractive since it should provide directly function-
alized sugar-derived cyclic amines.
Inspired by these reports, we focused our attention on sugar
lactams and considered them as promising precursors of the cor-
responding sugar-derived cyclic imines.
As previously described, lactam 1a was treated with slight ex-
cess of Cp2Zr(H)Cl in THF at ꢀ25 ꢁC to afford imine 2a. When the
reaction mixture became clear (ca. 30 min), allyltributylstannane
(3 equiv) and Yb(OTf)3 (1 equiv) were added directly to the solution
of the crude imine 2a to afford a mixture of diastereomeric
homoallylic amines 3a/4a in a ratio 89:11 and in overall yield 84%
after two steps. The presented one-pot protocol proved to be effi-
cient also for other lactams (1bef) leading to the corresponding
amines 3bef in good yield and with moderate to good stereo-
selectivity (Table 2).
2. Results and discussion
The potential synthesis of sugar-derived cyclic imines was ini-
tially evaluated for -gluco-lactam 1a. The lactam 1a can be readily
D
obtained from the corresponding 2,3,4,6-O-tetrabenzylated glucose
following Vasella’s protocol (Scheme 2).22
Scheme 2.
Lactam 1a was treated with 1.6 equiv Cp2Zr(H)Cl at ꢀ25 ꢁC in
THF to give desired imine 2a in a 90% yield (Scheme 3). The prog-
ress of the reaction can be easily followed since the initial white
suspension turns into a clear solution indicating the end of the
reduction process. In contrast to a zirconium-mediated reaction,
when the same lactam 1a was subjected to reaction with Tf2O in the
presence of 2-fluoropyridine, followed by treatment with Et3SiH,
The stereochemical assignment at the newly generated stereo-
chemical center (C-2) for all products was firmly established by
NOE experiments. In case of six-membered imines addition of
allyltributyltin proceeded syn to the BnO substituent at the C-3
position. This is a result of conformational control of the process,
according to Woerpel’s model.24 On the other hand, for the five-
membered imines the nucleophile addition is controlled by steric
effects leading to the product with anti-arrangement of the BnO at
the C-3 position and allyl group at the C-2 position (Fig. 1).8,11,14a,14b
Subsequently, other types of nucleophiles were examined with
the one-pot reduction/nucleophilic addition protocol (Table 3).
Lactams 1a and 1f were selected as a model compounds for this
part of the study. As shown in Table 3 the corresponding cyclic
amines were obtained in a moderate to good yield (after two steps)
and with good selectivity. It is particularly interesting that cyclic
imines react smoothly with silylated enol ethers to provide
b-
aminoketones (entries 3,6). To the best of own knowledge such
transformation has not been reported so far.
Scheme 3.

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P. Szczesniak et al. / Tetrahedron 70 (2014) 1880e1888
Table 1
Table 2
Synthesis of sugar-derived imines via reduction of the lactams 1aef with Schwartz’s
One-pot reduction/allylation sugar lactams 1aefa
reagenta
Entry
1
Lactam/imine
Yield [%]b
90
Entry
1
Lactam
Major product
Yield [%]b
84
drc
1a
90:10
2
70
2
3
4
5
1b
1c
1d
68
91
55
95:5
3
4
5
73
71
69:31
60:40
72
94
1e
1f
69
70
81:19
79:21
6
6
a
Reaction was performed with Cp2Zr(H)Cl (1.6 equiv) and sugar lactam
(1.0 equiv) in dry THF at ꢀ25 ꢁC to rt for 45 min.
a
b
Reaction was performed with Cp2Zr(H)Cl (1.6 equiv) and sugar lactam
Yields of isolated product after chromatography on Florisil.
(1.0 equiv) in dry THF at ꢀ25 ꢁC to rt for 45 min.
b
Yields of isolated product.
c
Determined by 1H NMR and/or HPLC.
The presented methodology for the one-pot lactam reduction/
nucleophilic addition offers an access to a biologically important
class of carbohydrate mimeticseiminosugars.25 To demonstrate
this, our protocol was applied for the preparation of two pyrrolidine
derivatives: 6-deoxy-DMDP (10) and radicamine B (11). Both
Although the five-membered cyclic nitrones have been exten-
sively used for the synthesis of pyrrolidine-based iminosugars via
nucleophilic addition,10,17,30e32 the use of six-membered chiral
nitrones as key intermediates during synthesis of piperidine-based
iminosugars has been barely investigated.33 Most likely, the main
limitation for such study is lack of efficient synthetic methods and
a low stability of six-membered nitrones.33a,33b,33d In contrast to
the sugar-derived six-membered nitrones, the corresponding
sugar-based lactams are easily available and stable. For example,
treatment of imine derived from lactam 1g with vinylMgBr led to
the 2-vinylpiperidine 3g in 63% and de >95% (Scheme 5). The latter
can be further transformed into the 6-epi-deoxymannojiromycin
18.25b,25c,34 Previously reported approach to compound 3g was
based on the corresponding nitrone obtained through six-step
synthesis.33e
In summary, we have shown that the reduction of sugar-derived
lactams to the corresponding cyclic imines can be conveniently
achieved using Cp2Zr(H)Cl. As it was demonstrated, the resultant
imines can be used directly for further transformations without
their isolation and purification. Bearing in mind the general in-
stability of imines, such one-pot procedure offers advantages over
stepwise approach. A direct addition of nucleophiles to the in situ
generated cyclic imines provides opportunity for the synthesis of
compounds are important iminosugars and display, respectively,
b-
mannosidase26 and -glucosidase27 inhibitory activity.
a
The Schwartz reagent mediated reduction of arabino-lactam 1f
gave imine 2f, which upon direct treatment with MeMgBr provided
pyrrolidine 12 along with its 5-epimer in overall 62% yield after two
steps (dr 1.7:1) (Scheme 4). The mixture of epimers was separated
by column chromatography. Similar addition with BnOC6H4MgBr
provided radicamine B precursor 13 with a high stereoselectivity
and in a good overall yield (55%, dr >95:5, Scheme 4). Final
debenzylation of 12 in the presence of Pd/C according to literature
procedure28 yielded 10 in 98%. Hydrogenolysis of 13 under condi-
tions applied for 12 led to the decomposition of 13, however re-
28
placement of Pd/C with PdCl2 provided pyrrolidine 11 in 92%
yield.
The presented approach to polyhydroxylated pyrrolidines via
reduction/addition sequence is shorter in comparison to the other
known protocols. For example, the synthesis of 10 reported by Zhou
et al.28 requires four separate steps. Our protocol is complementary
to the synthesis based on the Grignard reagent addition to sugar-
derived nitrones, reported by Goti and Merino.10,29

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P. Szczesniak et al. / Tetrahedron 70 (2014) 1880e1888
1883
Fig. 1. Stereocontrol of addition of nucleophile to sugar-derived cyclic imines.
Table 3
variety of polyhydroxylated pyrrolidines and piperidines that may
be of interest as natural products as well as biosynthetic
intermediates.
One-pot reduction/addition of lactams 1a and 1fa
3. Experimental section
3.1. General information
Entry Lactam Nucleophile (eq.)
Lewis acid (eq.)
Major product
Yieldb drc
[%]
1H NMR and 13C NMR spectra were recorded on a Varian VNMRS
500 and Varian VNMRS 600 spectrometers, in CDCl3, unless oth-
erwise stated, and with TMS used as an internal standard. Chemical
1
2
3
1a
TMSCN (2)/TMSOTf (1)
65
72
94
>95:5
shifts (d) were given in parts per million and coupling constants (J)
were given in Hertz (Hertz). Infrared spectra were recorded on a FT-
IR Jasco 6200 and FT-IR Spectrum 2000 Perkin Elmer spectropho-
tometer. High-resolution mass spectra were recorded on ESI-TOF
Mariner Spectrometer, SYNAPT G2-S HDMS or AMD 604 mass
spectrometer. Optical rotations were measured with Jasco P-2000
polarimeter. Melting points were determined on a Koefler hot-plate
microscope and were uncorrected. Thin layer chromatography
was performed on Merck aluminium sheet Silica Gel 60 F254. Col-
umn chromatography was carried out using Merck silica gel
(230e400 mesh).
Ph2Mg (6)d
2.3:1
>95:5
3.2. Synthesis of sugar-lactamsdgeneral procedure
4
5
6
1f
TMSCN (2)/TMSOTf (1)
PhMgBr (6)
88
65
65
60:40
>95:5
60:40
3.2.1. 2,3,4,6-Tetra-O-benzyl-
D
-gluconolactone. Oxalyl
chloride
(41.3 mmol, 3.5 mL) in dry DCM (150 mL) was treated at ꢀ60 ꢁC
with DMSO (6.3 mL) in DCM (110 mL). After 20 min a solution of
2,3,4,6-tetra-O-benzyl-D-glucopyranose (18.5 mmol, 10.0 g) in DCM
(100 mL) and DMSO (1.4 mL) was added slowly keeping the tem-
perature below ꢀ50 ꢁC. The mixture was stirred for 1 h, and then
Et3N (111 mmol, 15.5 mL) was added over 10 min. The mixture was
warmed to rt over 1 h. Then the mixture was washed with water
(2ꢂ50 mL), brine (2ꢂ50 mL) and organic layer was dried over
MgSO4. The solvent was removed under diminished pressure and
the residue (9.91 g, 95%) was used directly in the next step. Ana-
lytical sample was obtained by flash chromatography (hexanes/
nd¼not determined.
a
Reaction was performed with Cp2Zr(H)Cl (1.6 equiv) and sugar lactam (1 equiv)
in dry THF at ꢀ25 ꢁC to rt for 45 min; then nucleophile and Lewis acid (if required)
were added at ꢀ25 ꢁC and reaction was adjusted slowly to rt.
Et2O 2:1). Colorless oil; [
CDCl3)
a
]
20 þ75 (c 1.2, CH2Cl2); 1H NMR (500 MHz,
D
d
: 7.45e7.16 (m, 20H), 5.15 (d, J 11.5 Hz, 1H), 4.78 (d, J 11.2 Hz,
b
Yield of isolated product (2 steps).
1H), 4.75 (d, J 11.2 Hz, 1H), 4.66 (d, J 11.5 Hz, 1H), 4.59 (d, J 11.3 Hz,
1H), 4.50 (d, J 11.3 Hz, 1H), 4.47 (d, J 12.0 Hz, 1H), 4.45 (d, J 12.0 Hz,
1H), 4.42 (dt, J 6.3, 2.8 Hz, 1H), 4.12 (d, J 6.5 Hz, 1H), 3.97 (br t, J
6.8 Hz, 1H), 3.90 (br t, J 6.4 Hz, 1H), 3.72 (dd, J 11.0, 2.5 Hz, 1H), 3.69
c
Determined by 1H NMR of the crude reaction mixture.
d
In the presence of PhMgBr lactam 1a underwent reduction/addition process
followed by elimination. The generation of Ph2Mg by addition of PhMgBr to dioxane
led to the desired product 5 along with a small amount of elimination product.

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P. Szczesniak et al. / Tetrahedron 70 (2014) 1880e1888
Scheme 4.
(ESI-TOF) m/z calcd for C34H35NNaO5 [MþNaþ] 560.2407, found
560.2394.
3.2.4. (3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)piper-
idin-2-one (1b). Synthesis was performed as for lactam 1a; waxy
Scheme 5.
solid, [
a
]
D
20 ꢀ21 (c 0.22, CHCl3) (lit.23
[
a]
D ꢀ18.9 (c 0.28, CHCl3)); 1H
NMR (600 MHz, CDCl3) d: 7.44e7.11 (m, 20H), 6.19 (s, 1H), 5.02 (d, J
12.2 Hz, 1H), 4.71 (d, J 12.1 Hz, 1H), 4.67 (d, J 12.2 Hz, 1H), 4.57 (d, J
12.1 Hz, 1H), 4.54 (d, J 11.5 Hz, 1H), 4.44 (d, J 11.9 Hz, 1H), 4.41 (d, J
11.9 Hz, 1H), 4.38 (d, J 11.5 Hz, 1H), 4.15 (d, J 2.8 Hz, 1H), 3.92 (dd, J
5.2, 2.8 Hz, 1H), 3.66 (t, J 5.1 Hz, 1H), 3.56e3.49 (m, 2H), 3.42e3.36
(dd, J 11.0, 3.3 Hz, 1H); IR (film) v: 1760, 1120, 1101 cmꢀ1; HRMS
(ESI-TOF) m/z calcd for C34H34O6Na [MþNaþ] 651.2253. Found
651.2250.
(m, 1H); 13C NMR (151 MHz, CDCl3)
d: 169.5, 137.9, 137.8, 137.32,
3.2.2. 2,3,4,6-Tetra-O-benzyl-
condensed into the ampule containing the soln of 2,3,4,6-tetra-O-
benzyl- -gluconolactone (10.3 g, crude) in dry Et2O (50 mL) at
D
-gluconoamide (1a). Ammonia was
137.30, 128.3, 128.28, 128.2, 128.1, 127.8, 127.7, 127.74, 127.72, 127.71,
127.6, 127.57, 127.53, 74.8, 74.7, 73.1, 72.9, 72.5, 71.0, 55.2. HRMS
(ESI-TOF) m/z calcd for C34H35NO5Na [MþNaþ], 560.2407, found
560.2405; IR (film) v: 3251, 3015, 2847, 1697, 1435, 1469, 1125, 734,
D
ꢀ60 ꢁC. The mixture was warmed to rt and stirred for 6 h. Next the
mixture was cooled to ꢀ78 ꢁC and then ampule was opened, and
left overnight for slow warming up with evolution of gas ammonia.
The remaining solvent was removed under diminished pressure.
The crude residue (10.0 g, 94%) was dissolved in DMSO (88 mL) and
Et3N (1.03 mol 144 mL) was added. Next, a soln of pyridine-SO3
complex (37 mmol, 5.60 g) in DMSO (30 mL) was added and
resulting mixture was stirred at rt for 4 h. After consumption of
starting material (TLC monitoring) reaction mixture was por-
tionwised between water (100 mL) and ether (100 mL). Organic
phase was separated and the aqueous one washed twice with Et2O.
The combined organic layers were dried over Na2SO4 and after
filtration the solvent was removed under diminished pressure. In
separate flask, BF3$Et2O (90 mmol,11.3 mL) was added at to a cooled
(ꢀ25 ꢁC) soln of Et3SiH (90 mmol, 14.4 mL) in MeCN (340 mL) and
resulting mixture was stirred for 15 min. Then, this mixture was
cooled to 0 ꢁC and a solution of crude mixture of hydroxy lactam
(18 mmol 9.94 g) in DCM (340 ml) was added dropwise over 1 h and
stirred for additional 30 min at 0 ꢁC. The reaction was quench by
addition of satd NaHCO3 (150 mL), diluted with DCM (150 mL).
Aqueous phase was washed with DCM and the combined organic
solutions were dried over MgSO4. The removal of solvent gave
crude product, which was recrystallized twice from MeOH to yield
lactam 1a as white needles (4.60 g, 48%).
697 cmꢀ1
.
3.2.5. (3S,4S,5R,6S)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)piper-
20
idin-2-one (6-epi-1b). Waxy solid, [
a
]
D
ꢀ72 (c 0.20, CHCl3) (lit.23
[a
]
ꢀ73.2 (c 0.4, CHCl3)); 1H NMR (600 MHz, CDCl3)
d: 7.42e7.24
D
(m, 18H), 7.02e6.96 (m, 2H), 5.88 (s, 1H), 5.13 (d, J 12.4 Hz, 1H), 4.86
(d, J 12.1 Hz, 1H), 4.72 (d, J 12.4 Hz, 1H), 4.59 (d, J 12.1 Hz, 1H), 4.49
(d, J 11.8 Hz,1H), 4.45 (d, J 11.8 Hz,1H), 4.26 (d, J 11.6 Hz,1H), 4.22 (d,
J 2.8 Hz, 1H), 4.20 (d, J 11.6 Hz, 1H), 4.00e3.93 (m, 2H), 3.66e3.60
(m, 1H), 3.52 (t, J 9.2 Hz, 1H), 3.43 (dd, J 9.1, 4.2 Hz, 1H); 13C NMR
(151 MHz, CDCl3) d: 171.1, 138.2, 138.1, 137.5, 136.9, 128.41, 128.40,
128.3, 128.2, 128.0, 127.8, 127.7, 127.68, 127.67, 127.65, 74.9, 74.1,
73.9, 73.6, 73.4, 72.3, 70.1, 52.6; HRMS (ESI-TOF) m/z calcd for
C
34H35NNaO5 [MþNaþ], 560.2407, found 560.2410; IR (film) v:
3248, 1680, 1435, 1469, 1125 cmꢀ1
.
3.2.6. (3R,4S,5S,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)piper-
idin-2-one (1c). Synthesis was performed as for lactam 1a; yellow
oil, [
a
]
20 þ64 (c 0.35, CHCl3) (lit.35
[
a
]
D þ62 (c 0.1, CHCl3)); 1H NMR
D
(600 MHz, CDCl3) d: 7.37e7.19 (m, 20H), 6.06 (s, 1H), 4.92e4.89 (m,
1H), 4.65 (d, J 11.8 Hz, 1H), 4.61 (d, J 12.2 Hz, 1H), 4.56e4.54 (m, 1H),
4.48 (dd, J 7.6, 4.1 Hz, 2H), 4.36 (d, J 11.7 Hz, 1H), 3.96 (d, J 4.2 Hz,
1H), 3.92 (td, J 8.7, 3.2 Hz, 1H), 3.87 (dd, J 4.2, 2.1 Hz, 1H), 3.77 (dd, J
8.4, 2.1 Hz, 1H), 3.68 (dd, J 9.1, 3.4 Hz, 1H), 3.31 (t, J 9.1 Hz, 1H); 13
C
3.2.3. (3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)pi-
NMR (151 MHz, CDCl3) d: 171.1,137.7,137.5,137.4,128.5,128.4,128.3,
peridin-2-one (1a). White crystals, mp 105e106 ꢁC (lit.22
127.97, 127.94, 127.85, 127.78, 127.72, 75.1, 73.6, 73.4, 73.3, 73.1, 72.4,
71.7, 71.2, 52.2; IR (film) v: 3211, 3030, 2867, 1676, 1453, 1454, 1107,
736, 697 cmꢀ1; HRMS (ESI-TOF) m/z calcd for C34H35NNaO5
[MþNaþ] 560.2407, found 560.2402.
22
104.2e104.6 ꢁC); [
a
]
D
þ121.1 (c 0.08, CH2Cl2) (lit.22 þ102 (c 0.67,
CHCl3)); 1H NMR (600 MHz, CDCl3)
d: 7.45e7.14 (m, 20H), 5.98 (s,
1H), 5.17 (d, J 11.2 Hz, 1H), 4.84 (t, J 11.0 Hz, 2H), 4.77 (d, J 11.2 Hz,
1H), 4.72 (d, J 11.1 Hz, 1H), 4.48 (d, J 11.3 Hz, 1H), 4.45 (d, J 6.0 Hz,
2H), 4.00 (d, J 8.0 Hz, 1H), 3.90 (t, J 8.2 Hz, 1H), 3.63e3.55 (m, 2H),
3.53 (t, J 8.8 Hz, 1H), 3.32e3.20 (m, 1H); 13C NMR (151 MHz, CDCl3)
3. 2. 7. (3S, 4R, 5R)-3, 4, 5-Tri(benzyloxy)piperidin-2-one
(1d). Synthesis was performed as for lactam 1a; white solid, mp
25
d: 170.4138.0, 137.8, 137.5, 137.2, 128.5, 128.4, 128.4, 128.3, 128.1,
84 ꢁC; [
a
]
D
ꢀ13.3 (c 0.59, CH2Cl2); 1H NMR (600 MHz, CDCl3)
d:
128.0, 127.9, 127.8, 127.7, 82.3, 78.7, 77.0, 74.7, 74.6, 73.31, 70.0, 53.7;
7.39e7.26 (m, 15H), 5.99 (s, 1H), 5.05 (d, J 11.5 Hz, 1H), 4.73 (d, J
11.5 Hz, 1H), 4.69e4.63 (m, 2H), 4.63e4.57 (m, 2H), 4.14 (d, J 6.5 Hz,
IR (film) v: 3206, 3030, 2867, 1682, 1454, 1070, 696 cmꢀ1; HRMS

ꢀ
P. Szczesniak et al. / Tetrahedron 70 (2014) 1880e1888
1885
1H), 4.04 (ddd, J 6.2, 4.1, 2.1 Hz, 1H), 3.85 (dd, J 6.5, 2.0 Hz, 1H), 3.47
(ddd, J 12.0, 6.3, 2.4 Hz, 1H), 3.26 (ddd, J 12.0, 4.0, 2.1 Hz, 1H); 13C
127.61, 127.5, 127.4, 117.5, 83.3, 82.0, 80.5, 75.5, 75.2, 73.0, 72.5, 70.6,
53.6, 52.6, 29.8; HRMS (ESI-TOF) m/z calcd for C37H42NO4 [MþHþ],
564.3114, found 564.3114; IR (film) v: 3030, 2920, 2858, 1496, 1453,
1100, 1068, 735, 697 cmꢀ1; (2-epi-3a) (minor isomer) selected sig-
NMR (151 MHz, CDCl3)
d: 170.4, 138.0, 137.8, 128.4, 128.4, 128.3,
128.1, 127.8, 127.70, 127.68, 127.65, 77.1, 76.6, 74.5, 72.6, 71.9, 70.5,
42.2; IR (film) v: 3230, 2871, 1677, 1495, 1454, 1095, 736, 697 cmꢀ1
;
nals: 1H NMR (600 MHz, CDCl3)
d: 5.70e5.63 (m, 1H); HPLC:
HRMS (ESI-TOF) m/z calcd for C26H27NNaO4 [MþNaþ] 440.1832,
ChiralpakÒ AD-H, 1% i-PrOH in hexanes, flow 0.5 mL/min, UV
218 nm, Rt 40.0 min (3a), 52.6 min (2-epi-3a).
found 440.1839.
3.2.8. (3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
3.3.2. (2S,3R,4R,5R,6R)-2-Allyl-3,4,5-tris(benzyloxy)-6-(benzylox-
2-one (1e). Synthesis was performed as for lactam 1a; low-melting
ymethyl)piperidine (3b). Colorless oil; isolated yield 68%, dr 95:5
25
solid; [
a
]
þ192 (c 0.085, CH2Cl2); 1H NMR (600 MHz, CDCl3)
d:
(crude reaction mixture), Rf 0.36 (20% AcOEt/hexanes); chroma-
D
25
7.43e7.21 (m, 15H), 6.07 (s, 1H), 4.92 (d, J 11.9 Hz, 1H), 4.76 (d, J
12.0 Hz, 1H), 4.62 (d, J 11.8 Hz, 1H), 4.51e4.42 (m, 3H), 4.03 (d, J
5.3 Hz,1H), 3.86 (d, J 5.3 Hz, 2H), 3.54 (dd, J 9.7, 3.4 Hz,1H), 3.34 (dd,
tography (20% AcOEt in hexanes); [
NMR (600 MHz, CDCl3)
a
]
ꢀ6.4 (c 0.6, CH2Cl2); 1H
D
d
: 7.46e7.15 (m, 20H), 5.66 (ddt, J 17.2, 10.1,
7.1 Hz, 1H), 5.06e4.93 (m, 2H), 4.80 (d, J 11.1 Hz, 1H), 4.68 (d, J
12.3 Hz, 1H), 4.62e4.54 (m, 3H), 4.53 (d, J 12.0 Hz, 1H), 4.49 (d, J
11.1 Hz, 1H), 4.43 (d, J 12.0 Hz, 1H), 3.89 (t, J 8.2 Hz, 1H), 3.77 (dd, J
9.1, 4.7 Hz, 1H), 3.69 (dd, J 8.2, 2.8 Hz, 1H), 3.64e3.62 (m, 1H), 3.54
(dd, J 9.1, 3.2 Hz, 1H), 3.08 (td, J 7.6, 3.8 Hz, 1H), 2.91e2.85 (m, 1H),
J 9.7, 6.2 Hz, 1H); 13C NMR (151 MHz, CDCl3)
d: 173.0, 137.5, 137.4,
137.3, 128.5, 128.4, 128.37, 128.31, 128.0, 127.96, 127.93, 127.85,
127.65, 75.8, 74.1, 73.4, 72.1, 71.9, 70.5; IR (film) v: 3238, 2849, 1737,
1465, 1111, 736, 698 cmꢀ1
C
; HRMS (ESI-TOF) m/z calcd for
26H27NNaO4 [MþNaþ], 440.1832, found 440.1845.
2.26e2.16 (m, 2H); 13C NMR (151 MHz, CDCl3)
d: 138.7, 138.6,
138.5, 138.4, 135.3, 128.35, 128.33, 128.30, 128.1, 127.8, 127.7, 127.6,
127.5, 127.4, 117.1, 79.1, 76.7, 76.57, 74.6, 73.1, 72.0, 71.7, 69.5, 54.9,
53.6, 34.8; IR (film) v: 3029, 2920, 2857, 1453, 1095, 734,
696 cmꢀ1; HRMS (ESI-TOF) m/z calcd for C37H42NO4 [MþHþ]
564.3114. Found 564.3113; HPLC: ChiralpakÒ AD-H, 10% i-PrOH in
hexanes, flow 1 mL/min, UV 220 nm, Rt 5.9 min (3c) and 12.2 min
(2-epi-3c).
3.2.9. (3S,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-one (1f). Synthesis was performed as for lactam 1a; mp 56e58 ꢁC
(Lit.28 58e59 ꢁC); [
a]
ꢀ1.9 (c 0.92, CHCl3) (lit.28e2.1 (c 1.1,
25
D
CHCl3)); 1H NMR (600 MHz, CDCl3)
d: 7.42e7.21 (m, 15H), 5.95 (s,
1H), 5.11 (d, J 11.6 Hz, 1H), 4.79 (d, J 11.6 Hz, 1H), 4.60 (d, J 11.7 Hz,
1H), 4.51e4.44 (m, 2H) 4.21 (d, J 6.2 Hz, 1H), 3.88 (t, J 6.0 Hz, 1H),
3.69e3.64 (m, 1H), 3.60 (dd, J 9.4, 3.5 Hz, 1H), 3.33e3.29 (m, 1H);
13C NMR (151 MHz, CDCl3)
d
: 172.7, 137.5, 137.4, 128.5, 128.46,
3.3.3. (2R,3S,4R,5S,6R)-2-Allyl-3,4,5-tris(benzyloxy)-6-(benzylox-
128.43, 128.3, 127.99, 127.97, 127.9, 127.8, 127.7, 81.0, 80.6, 73.5, 72.6,
72.3, 71.5, 55.9; IR (film) v: 3217, 2865, 1712, 1454, 1102, 736,
697 cmꢀ1; HRMS (ESI-TOF) m/z calcd for C26H27NNaO4 [MþNaþ]
440.1832, found 440.1838.
ymethyl)piperidine (3c) (major isomer). Colorless oil; isolated yield
91%, dr 69:31 (crude reaction mixture); Rf 0.22 (2:3 AcOEt/hex-
25
anes); chromatography (1:4 AcOEt/hexanes); [
a
]
ꢀ9.5 (c 0.7,
D
CH2Cl2); 1H NMR (600 MHz, CDCl3)
d
: 7.34e7.23 (m, 22H), 5.76
(ddt, J 17.2, 10.2, 7.1 Hz, 1H), 5.13e5.03 (m, 2H), 4.77e4.70 (m, 1H),
4.61e4.51 (m, 4H), 4.46 (s, 2H), 3.82 (dd, J 5.3, 3.0 Hz, 1H), 3.67 (dd,
J 7.0, 3.0 Hz, 1H), 3.61e3.57 (m, 2H), 3.47 (dd, J 9.0, 5.8 Hz, 1H), 3.33
(dd, J 11.4, 5.7 Hz, 1H), 2.81 (dd, J 12.2, 6.8 Hz, 1H), 2.58e2.53 (m,
3.3. One-pot reduction/allylation of sugar-lactamsdgeneral
procedure
A solution of sugar lactam (0.5 mmol) in THF (5 mL) was added
dropwise to suspension of Cp2Zr(H)Cl (1.6 equiv, 0.8 mmol,
206 mg) in THF (5 mL) at ꢀ25 ꢁC under argon atmosphere. The
mixture was warmed slowly to room temperature and stirred
until white suspension disappeared (ca. 1.5 h) and clear solution
arisen. Then the solution was cooled to ꢀ25 ꢁC and Yb(OTf)3 was
added (1.0 equiv, 0.5 mmol, 310 mg). After 10 min allyltributyl-
1H), 2.37e2.30 (m, 1H); 13C NMR (151 MHz, CDCl3)
d: 138.6, 138.5,
138.4, 138.2, 135.6, 128.4, 128.33, 128.30, 128.27, 127.93, 127.91,
127.8, 127.6, 127.57, 127.53, 117.4, 73.2, 72.2, 71.7, 54.7, 35.9; IR
(film) v: 3030, 2922, 2860, 1454, 1095, 911, 735, 697 cmꢀ1; HRMS
(ESI-TOF) m/z calcd for C37H42NO4 [MþHþ] 564.3114, found
564.3114; (2-epi-3c) (minor isomer) selected signals: 1H NMR
(600 MHz, CDCl3) d: 5.86e5.80 (m, 1H), 4.76 (d, J 2.5 Hz, 1H), 4.02
stannane (3 equiv, 1.5 mmol, 460
m
l) was added dropwise. The
(dd, J 5.5, 3.5 Hz, 1H), 3.52 (dd, J 9.2, 6.9 Hz, 1H), 3.18 (td, J 6.6,
4.4 Hz, 1H), 2.50e2.43 (m, 1H); HPLC: ChiralpakÒ AD-H, 1% i-PrOH
in hexanes, flow 0.5 mL/min, UV 218 nm, Rt 52.9 min (3c), 87.4 min
(2-epi-3c).
mixture was warmed gradually to ambient temperature and stir-
red overnight. Solvent was removed under diminished pressure
and the residue was diluted with MeCN (5 mL), and washed with
hexanes (3 x 5 mL). Acetonitrile solution was separated, and
concentrated under reduced pressure. The residue was chroma-
tographed on silica gel to afford the corresponding cyclic amines
3aef. Diastereomeric ratio of products was determined by HPLC of
crude reaction mixture. The spectral data for major isomer are
given.
3.3.4. (2S,3R,4R,5R)-2-Allyl-3,4,5-tris(benzyloxy)piperidine (3d) and
2-epimer (2R,3R,4R,5R)-2-allyl-3,4,5-tris(benzyloxy)piperidine (2-
epi-3d). Colorless oil; isolated yield 55%, dr 60:40; chromatography
(3:2 AcOEt/hexanes); inseparable mixture of diastereoisomers;
(3d) selected signals: 1H NMR (600 MHz, CDCl3)
d 5.86e5.77 (m,
1H), 5.14e5.05 (m, 2H), 3.77 (d, J 0.9 Hz, 1H), 3.55 (t, J 9.3 Hz, 1H),
3.12 (dd, J 14.2, 2.9 Hz, 1H), 2.65e2.60 (m, 1H), 2.57e2.52 (m, 1H),
2.47 (dd, J 14.2, 0.9 Hz, 1H), 2.24e2.20 (m, J 12.9, 7.1 Hz, 1H); (2-epi-
3.3.1. (2R,3S,4R,5R,6R)-2-Allyl-3,4,5-tris(benzyloxy)-6-(benzylox-
ymethyl)piperidine (3a) (major isomer). Colorless oil; (overall yield
84%, dr 90:10); Rf 0.25 (25% AcOEt in hexanes); chromatography
3d) selected signals 1H NMR (600 MHz, CDCl3)
d: 5.71 (ddt, J 17.2,
25
(20% AcOEt in hexanes); [
a
]
þ47.9 (c 0.5, CH2Cl2); 1H NMR
10.1, 7.1 Hz, 1H), 5.05e4.98 (m, 2H), 3.86e3.83 (m, 1H), 3.74e3.70
(m, 1H), 3.39 (d, J 2.3 Hz, 1H), 3.03e2.97 (m, 3H), 2.20e2.17 (m, 1H),
2.12 (dt, J 13.8, 6.8 Hz, 1H); 13C NMR (150 MHz, CDCl3, mixture of 3d
D
(600 MHz, C6D6)
d
: 7.40e7.10 (m, 20H), 5.78e5.67 (m, 1H),
5.10e5.02 (m, 2H), 4.98 (d, J 11.2 Hz, 1H), 4.91 (d, J 11.4 Hz, 1H), 4.78
(d, J 11.2 Hz, 1H), 4.46 (d, J 11.3 Hz, 1H), 4.40 (d, J 5.4 Hz, 1H), 4.25 (d,
J 12.0 Hz, 1H), 4.17 (d, J 12.0 Hz, 1H), 3.74e3.69 (m, 2H), 3.61 (dd, J
9.5, 5.6 Hz, 1H), 3.47 (dd, J 8.8, 6.7 Hz, 1H), 3.38e3.34 (m, 1H),
3.10e3.02 (m, 2H), 2.53e2.43 (m, 1H), 2.31 (ddd, J 14.4, 11.6, 8.2 Hz,
and 2-epi-3d) d: 138.8, 138.7, 138.7, 138.6, 138.5, 138.2, 135.9, 135.2,
128.4,128.3,128.0,128.0,127.8, 127.78, 127.72,127.66, 127.61, 127.57,
127.5, 117.6, 116.9, 84.4, 80.2, 75.4, 74.9, 73.6, 72.9, 72.6, 71.7, 71.4,
70.9, 59.7, 53.6, 46.9, 44.6, 36.4, 27.8, 26.8. HRMS (ESI-TOF) m/z
calcd for C29H34NO3 [MþHþ] 444.2539, found 444.2538; IR (film) v:
1H); 13C NMR (151 MHz, CDCl3)
d
: 138.9, 138.5, 138.3, 138.2, 135.8,
128.38, 128.35, 128.34, 128.33, 128.30, 128.0, 127.9, 127.7, 127.68,
3313, 2923, 2869, 1496, 1453, 1095, 734, 696 cmꢀ1
; HPLC:

ꢀ
P. Szczesniak et al. / Tetrahedron 70 (2014) 1880e1888
1886
ChiralpakÒ AD-H, 2% i-PrOH in hexanes, flow 0.5 mL/min, UV
218 nm, Rt 29.3 min (2-epi-3d), 32.0 min (3d).
mixture was warmed room temperature and stirred overnight. The
reaction was quenched by addition of aq NaHCO3 and stirred for
30 min. After dilution with Et2O (5 mL), aqueous phase was sepa-
rated and washed twice with Et2O (2ꢂ5 mL). The combined organic
solutions were dried over anhyd. MgSO4, filtered and solvents were
removed under diminished pressure. The residue was chromato-
graphed on silica gel to afford the corresponding amine derivatives
4 and 7.
3.3.5. (2S,3S,4R,5R)-2-Allyl-3,4-bis(benzyloxy)-5-(benzyloxymethyl)
pyrrolidine (3e) (major isomer). Colorless oil; isolated yield 69%, dr
81:19 (crude reaction mixture); Rf 0.23 (1:2 AcOEt/hexanes);
25
chromatography (3:2 AcOEt/hexanes); 3e: [
a]
þ33 (c 0.53,
D
CH2Cl2); 1H NMR (600 MHz, CDCl3)
d
: 7.38e7.21 (m, 15H), 5.76 (ddt,
J 17.1, 10.2, 7.0 Hz, 1H), 5.09 (br d, J 17.1 Hz, 1H), 5.02 (dd, J 10.2,
0.9 Hz, 1H), 4.81 (d, J 11.6 Hz, 1H), 4.61 (d, J 12 Hz, 1H), 4.58 (d, J
11.7 Hz, 1H), 4.55e4.44 (m, 4H), 3.91e3.86 (m, 2H), 3.55e3.43 (m,
2H), 3.20e3.16 (m, 1H), 2.46e2.39 (m, 1H), 2.36e2.31 (m, 1H); 13C
3.4.1. (2S,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)pi-
peridine-2-carbonitrile (4). White crystals, mp 144 ꢁC; isolated
yield 65%, dr >95:5 (from 1H NMR of the crude reaction mixture); Rf
0.32 (1:5 AcOEt/hexanes); chromatography (1:7 AcOEt/hexanes);
NMR (151 MHz, CDCl3) d: 138.7, 138.31, 138.30, 136.0,128.31, 128.29,
128.23, 127.7, 127.60, 127.5, 127.4, 116.6, 82.0, 78.6, 73.2, 73.1, 72.5,
71.5, 60.1, 59.5, 34.6, 27.8, 26.8, 13.6; IR (film) v: 3331, 2922, 2857,
1496, 1454, 1361, 1091 cmꢀ1; HRMS (ESI-TOF) m/z calcd for
[a
]
25 þ52.6 (c 0.78, CH2Cl2); 1H NMR (600 MHz, CDCl3)
d: 7.42e7.18
D
(m, 20H), 4.97 (d, J 10.7 Hz,1H), 4.84 (dd, J 14.8,10.9 Hz, 2H), 4.77 (d,
J 11.9 Hz, 1H), 4.68 (d, J 11.9 Hz, 1H), 4.48 (d, J 11.1 Hz, 1H), 4.46 (d, J
11.9 Hz, 1H), 4.41 (d, J 11.9 Hz, 1H), 4.08 (d, J 5.6 Hz, 1H), 3.84 (t, J
8.9 Hz, 1H), 3.69 (dd, J 9.4, 2.4 Hz, 1H), 3.59 (dd, J 9.4, 5.6 Hz, 1H),
C
39H34NO3 [MþHþ] 444.2539, found 444.2542; (2-epi-3e) (minor
isomer): selected signals 1H NMR (600 MHz, CDCl3)
d: 3.73 (t, J
5.2 Hz, 1H), 3.41 (dd, J 9.3, 4.6 Hz, 1H), 3.34e3.29 (m, 1H); HPLC:
ChiralpakÒ AD-H, 2% i-PrOH in hexanes, flow 0.5 mL/min, UV
215 nm, Rt 26.1 min (3e), 48.7 min (2-epi-3e).
3.36 (dd, J 9.2, 7.3 Hz, 1H), 3.27e3.23 (m, 1H), 3.23e3.19 (m, 1H); 13
C
NMR (151 MHz, CDCl3) d: 138.4, 138.0, 137.6, 137.5, 128.6, 128.5,
128.41, 128.40, 128.1,128.0,127.97,127.90,127.87,127.77, 127.7, 117.5,
84.2, 79.0, 78.6, 76.0, 75.1, 73.3, 73.2, 69.9, 55.6, 49.7; IR (film) v:
2909, 2861, 2230, 1453, 1072, 745, 696 cmꢀ1; HRMS (ESI-TOF) m/z
calcd for C35H36N2NaO4 [MþNaþ], 571.2573, found 571.2581.
3.3.6. (2R,3R,4R,5R)-2-Allyl-3,4-bis(benzyloxy)-5-(benzyloxymethyl)
pyrrolidine (3f) (major isomer). Colorless oil; isolated yield 70%
yield, dr 79:21 (crude reaction mixture); Rf 0.38 (3:2 AcOEt/hex-
25
anes); chromatography (1:1 AcOEt/hexanes); [
a]
þ19.1 (c 0.24,
3.4.2. (2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrroli-
dine-2-carbonitrile (7). Major isomer, colorless oil; overall yield 88%
(2 isomers), dr 60:40 (determined by 1H NMR of crude reaction
D
CH2Cl2); 1H NMR (600 MHz, CDCl3)
d
: 7.36e7.21 (m, 17H), 5.79 (ddt,
J 17.2, 10.2, 7.1 Hz, 1H), 5.11e5.04 (m, 2H), 4.56e4.48 (m, 6H),
3.89e3.87 (m, 1H), 3.74e3.73 (m, 1H), 3.51 (dd, J 6.1, 3.2 Hz, 1H),
3.40 (dt, J 10.2, 5.2 Hz, 1H), 3.19 (dd, J 12.8, 5.5 Hz, 1H), 2.36 (dt, J
mixture); Rf 0.34 (1:2 AcOEt/hexanes); chromatography (1:3
25
AcOEt/hexanes); [
a
]
þ23.6 (c 0.2 CH2Cl2); 1H NMR (600 MHz,
D
13.4, 6.5 Hz, 1H), 2.29e2.21 (m, 1H); 13C NMR (151 MHz, CDCl3)
d:
CDCl3) d: 7.38e7.20 (m,15H), 4.64 (d, J 11.9 Hz,1H), 4.59 (d, J 11.9 Hz,
138.19, 138.17, 138.16, 135.2, 128.38, 128.34, 128.33, 128.30, 127.78,
127.74, 127.7, 127.65, 127.64, 127.63, 127.60, 127.59, 117.3, 88.6, 86.3,
73.2, 71.8, 71.7, 70.8, 61.7, 61.3, 38.0; IR (film) v: 3422, 2923, 2856,
1453, 1362, 1094, 912, 735, 697 cmꢀ1; HRMS (ESI-TOF) m/z calcd for
1H), 4.53 (d, J 11.9 Hz, 1H), 4.49 (d, J 11.9 Hz, 1H), 4.48e4.45 (m, 2H),
4.15e4.07 (m, 2H), 3.93e3.90 (m, 1H), 3.60e3.53 (m, 2H),
3.38e3.33 (m, 1H); 13C NMR (151 MHz, CDCl3)
d: 137.8, 137.4, 136.9,
128.6, 128.5, 128.4, 128.1, 128.0, 127.95, 127.74, 127.72, 117.6, 83.3,
C
39H34NO3 [MþHþ] 444.2539, found 444.2574; (2-epi-3f) (minor
82.8, 73.3, 72.5, 72.0, 70.4, 62.7, 51.2; IR (film) v: 3354, 3030, 2924,
isomer) selected signals: 1H NMR (600 MHz, CDCl3)
d
: 5.01 (d, J
2854, 2246, 1495, 1454, 1376, 1364, 1206, 1091, 1072, 733, 695 cmꢀ1
;
10.2 Hz,1H), 3.82 (d, J 3.9 Hz,1H), 3.77 (d, J 4.0 Hz, 1H), 3.56 (m, 2H),
3.27 (dd, J 9.5, 5.4 Hz, 1H), 2.42 (dt, J 13.8, 6.8 Hz, 1H). HPLC:
ChiralpakÒ AD-H, 5% i-PrOH in hexanes, flow 0.5 ml/min, UV
218 nm, Rt 23.5 min (2-epi-3f), 26.0 min (3f).
HRMS (ESI-TOF) m/z calcd for C27H29N2O3 [MþHþ] 429.2178, found
429.2184.
3.4.3. (2S,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrroli-
dine-2-carbonitrile (2-epi-7). Minor isomer; colorless oil; Rf 0.45
25
3.3.7. (2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-2-vinylpiperidine
(1:2 AcOEt/hexanes); chromatography (1:3 AcOEt/hexanes); [a]
D
(3g). Colorless oil; isolated yield 62% yield, de >95%; Rf 205.15 (3:7
ꢀ4.7 (c 0.85, CH2Cl2); 1H NMR (600 MHz, CDCl3)
d: 7.40e7.23 (m,
AcOEt/DCM); chromatography (3:7 AcOEt/DCM); [
a
]
þ34.9
15H), 4.59 (d, J 11.7 Hz, 1H), 4.55 (d, J 11.9 Hz, 1H), 4.52 (d, J 11.7 Hz,
1H), 4.50 (d, J 12.0 Hz, 1H), 4.47 (d, J 12.0 Hz, 1H), 4.28 (t, J 3.1 Hz,
1H), 4.04 (d, J 2.9 Hz, 1H), 3.85 (dd, J 5.6, 3.2 Hz, 1H), 3.60 (dd, J 8.9,
D
(c 0.78, CH2Cl2); 1H NMR (600 MHz, CDCl3)
d 7.35e7.29 (m, 13H),
7.22e7.20 (m, 2H), 5.90e5.84 (m, 1H), 5.26 (d, J 17.4 Hz, 1H), 5.15 (d,
J 10.6 Hz, 1H), 4.77 (d, J 12.2 Hz, 1H), 4.57 (dd, J 15.0, 12.2 Hz, 2H),
4.49 (dd, J 17.2, 12.0 Hz, 2H), 4.42 (d, J 11.9 Hz, 1H), 3.84e3.82 (m,
1H), 3.76 (ddd, J 9.0, 6.2, 2.7 Hz, 1H), 3.63 (d, J 4.9 Hz, 1H), 3.53e3.51
(m, 1H), 3.07 (dd, J 12.7, 9.0 Hz, 2H); 13C NMR (151 MHz, CDCl3)
3.3 Hz, 1H), 3.54e3.45 (m, 2H); 13C NMR (151 MHz, CDCl3)
d: 137.7,
137.5, 136.6, 128.6, 128.4, 128.3, 127.99, 128.0, 127.81, 127.78, 127.7,
119.0, 87.2, 84.0, 73.3, 72.6, 72.2, 69.5, 62.1, 51.7; IR (film) v: 3343,
3064, 3031, 2922, 2863, 2240, 1496, 1454, 1363, 1097, 1028, 738,
698 cmꢀ1; HRMS (ESI-TOF) m/z calcd for C27H29N2O3 [MþHþ]
429.2178, found 429.2189.
d
138.8, 138.6, 138.2, 128.4, 128.3, 128.3, 127.9, 127.8, 127.7, 127.6,
116.0, 78.3, 74.6, 73.1, 72.9, 71.0, 56.6, 44.1; IR (film) v: 3309, 3030,
2925, 2868, 1496, 1454, 1093, 736, 697 cmꢀ1; HRMS (ESI-TOF) m/z
calcd for C28H32NO3 [MþHþ] 430.2393, found 430.2382.
3.5. One-pot synthesis of compounds 5, 8, 12, 13
3.4. One-pot synthesis of compounds 4 and 7
A solution of sugar lactam 1a or 1f (0.5 mmol) in THF (5 mL) was
added dropwise to the cooled to ꢀ25 ꢁC suspension Cp2Zr(H)Cl
(0.8 mmol, 206 mg) in THF (5 mL) under argon atmosphere. The
mixture was warmed slowly to room temperature and stirred until
white suspension disappeared (ca. 1.5 h) and clear solution arisen.
Next, the imine solution was cannulated to solution of Grignard
reagent (3 mmol) in Et2O at ꢀ40 ꢁC. The mixture was gradually
warmed to ambient temperature and stirred until all imine was
consumed. Then, the mixture was diluted with Et2O, cooled down
to ꢀ25 ꢁC and quenched by dropwise addition of H2O. The aqueous
A solution of sugar lactam 1a or 1f (0.5 mmol) in THF (5 mL) was
added dropwise to the cooled to ꢀ25 ꢁC suspension Cp2Zr(H)Cl
(0.8 mmol, 206 mg) in THF (5 mL) under argon atmosphere. The
mixture was warmed slowly to room temperature and stirred until
white suspension disappeared (ca. 1.5 h) and clear solution arisen.
Next, the imine solution was cooled to ꢀ40 ꢁC and TMSOTf was
added (1.0 equiv, 0.5 mmol, 60
mL). The mixture was stirred for
10 min and TMSCN (1.0 mmol, 125
mL) was added dropwise. The

ꢀ
P. Szczesniak et al. / Tetrahedron 70 (2014) 1880e1888
1887
phase was separated and washed with Et2O (2 x 5 mL). The com-
bined organic layers were dried over anhyd. Na2SO4, filtered and
solvents were removed under diminished pressure to give the
residue, which was chromatographed on silica gel.
isolated in pure form; 1H NMR (600 MHz, CDCl3)
d
: 7.36e7.24 (m,
15H), 4.57e4.48 (m, 6H), 4.43 (d, J 12.0 Hz, 1H), 3.84 (d, J 3.8 Hz, 1H),
3.73 (d, J 4.0 Hz, 1H), 3.61 (dd, J 9.4, 5.3 Hz, 1H), 3.57 (dd, J 9.4,
5.4 Hz, 1H), 3.32 (dt, J 6.5, 4.5 Hz,1H), 3.29 (dd, J 9.7, 5.2 Hz,1H), 1.25
(d, J 6.6 Hz, 3H); 13C NMR (151 MHz, CDCl3)
d: 138.4, 138.2, 138.1,
3.5.1. (2S,3R,4R,5S,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-6-
phenylpiperidine (5) (major isomer). Isolated yield 72% (both epi-
mers), dr 2.3:1 (determined by 1H NMR of the crude reaction
128.39, 128.36, 128.33, 127.7, 127.6, 127.5, 127.4, 85.5, 85.0, 73.1, 71.7,
71.0, 70.9, 64.5, 57.2, 13.9; IR (film, CH2Cl2) v: 3030, 2861, 1496,
1454, 1326, 1098, 736, 697 cmꢀ1 HRMS (ESI-TOF) m/z calcd for
mixture); colorless oil; Rf 0.48 (1:4 AcOEt/hexanes); chromatogra-
C
27H32NO3 [MþHþ], 418.2382, found 418.2390.
25
phy (1:10 AcOEt/hexanes); [
a
]
þ34.9 (c 0.78, CH2Cl2); 1H NMR
D
(600 MHz, CDCl3)
d
: 7.78 (d, J 7.7 Hz, 2H), 7.41e7.28 (m, 20H), 7.24
3.5.6. (2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(4-(benzyloxy)phenyl)-5-
(benzyloxymethyl)pyrrolidine (13). White solid; mp 79e80 ꢁC, yield
55%, de >95% (determined by 1H NMR of crude reaction mixture);
(d, J 6.5 Hz, 2H), 5.01 (d, J 11.0 Hz, 1H), 4.88 (d, J 11.0 Hz, 1H), 4.82 (d,
J 11.0 Hz,1H), 4.72e4.67 (m, 2H), 4.55 (m, 3H), 4.47 (d, J 11.9 Hz,1H),
4.12 (t, J 8.3 Hz, 1H), 3.99 (dd, J 8.6, 5.1 Hz, 1H), 3.71e3.65 (m, 2H),
3.63 (t, J 8.5 Hz, 1H), 3.04e3.00 (m, 1H); 13C NMR (151 MHz, CDCl3)
colorless oil; Rf 0.10 (1:1 AcOEt/hexanes); chromatography (1:1
25
AcOEt/hexanes); [
a]
þ32.0 (c 1.04, CHCl3); 1H NMR (600 MHz,
D
d: 138.8, 138.5, 138.4, 138.2, 128.6, 128.4, 128.4, 128.4, 128.3, 128.3,
CDCl3) d: 7.56e7.12 (m, 22H), 7.00e6.95 (m, 2H), 5.08 (s, 2H),
128.0, 128.0, 127.8, 127.8, 127.7, 127.7, 127.6, 127.6, 126.9, 82.7, 82.3,
79.9, 75.0, 74.7, 73.2, 72.6, 69.9, 55.5, 53.8. IR (film) v: 3343, 3030,
2913, 2863, 1496, 1454, 1092, 1070, 735, 697 cmꢀ1; HRMS (ESI-TOF)
m/z calcd for C40H42NO4 [MþHþ] 600.3114, found 600.3123.
4.64e4.54 (m, 4H), 4.47e4.40 (m, 2H), 4.20 (d, J 6.7 Hz, 1H), 4.08
(dd, J 6.6, 4.4 Hz, 1H), 3.99 (t, J 4.2 Hz, 1H), 3.66e3.55 (m, 3H); 13C
NMR (151 MHz, CDCl3) d: 158.2, 138.2, 138.1, 138.0, 137.0, 128.6,
128.4, 128.37, 128.31, 128.2, 127.9, 127.8, 127.72, 127.70, 127.68,
127.67, 127.58, 127.49, 114.9, 91.1, 85.7, 73.2, 72.3, 71.9, 70.8, 70.0,
64.9, 61.4; IR (KBr) v: 3330, 2857, 1515, 1453, 1246, 1063, 739,
698 cmꢀ1; HRMS (ESI-TOF) m/z calcd for C39H40NO4 [MþHþ]
586.2957, found 586.2950.
3.5.2. (2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
6-phenylpiperidine (2-epi-5) (minor isomer). Colorless oil; Rf 0.52
(1:4 AcOEt/hexanes); chromatography (1:10 AcOEt/hexanes);
[
a
]
25 þ17.1 (c 0.78, CH2Cl2); 1H NMR (600 MHz, CDCl3)
d
: 1H NMR
D
(600 MHz, C6D6)
d
: 7.23e7.16 (m, 2H), 7.06 (d, J 7.4 Hz, 2H), 6.96 (d, J
3.6. One-pot synthesis of compounds 6 and 9
7.3 Hz, 2H), 6.91e6.69 (m, 19H), 4.71 (d, J 11.3 Hz, 1H), 4.65 (d, J
11.3 Hz, 1H), 4.59 (d, J 11.3 Hz, 1H), 4.25 (d, J 11.3 Hz, 1H), 4.14 (d, J
10.6 Hz, 1H), 3.98 (s, 2H), 3.57e3.52 (m, 2H), 3.44 (t, J 8.3 Hz, 1H),
3.33e3.22 (m, 3H), 2.79 (t, J 8.0 Hz, 1H); 13C NMR (151 MHz, CDCl3)
A solution of sugar lactam 1a or 1f (0.5 mmol) in THF (5 mL) was
added dropwise to the cooled to ꢀ25 ꢁC suspension Cp2Zr(H)Cl
(0.8 mmol 206 mg) in THF (5 mL) under argon atmosphere. The
mixture was warmed slowly to room temperature and stirred until
white suspension disappeared (ca. 1.5 h) and clear solution arisen.
Next, the imine solution was cooled to ꢀ40 ꢁC and TMSOTf was
d: 138.8, 138.2, 137.8, 128.4, 128.3, 128.18, 128.13, 127.9, 127.8, 127.7,
127.6, 87.8, 75.8, 75.2, 75.1, 73.5, 64.7, 59.7, 29.7; IR (film) v: 3339,
3030, 2902, 2859, 1496, 1453, 1360, 1090, 1069, 735, 698 cmꢀ1
;
HRMS (ESI-TOF) m/z calcd for C40H42NO4 [MþHþ] 600.3114, found
added (0.5 mmol, 60
m
L). The mixture was stirred for 10 min and
600.3123.
trimethyl(1-phenylvinyloxy)silane (1.0 mmol, 212
mL) was added
dropwise. The mixture was warmed gradually to ambient tem-
perature and stirred for overnight. Then, reaction was quenched by
addition of aq NaHCO3 and stirred for 30 min. After dilution with
Et2O (5 mL), aqueous phase was separated and washed twice with
Et2O (2ꢂ5 mL). The combined organic layers were dried over
anhyd. MgSO4, filtered and solvents were removed under di-
minished pressure to afford the residue, which was chromato-
graphed on silica gel.
3.5.3. (2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-
phenylpyrrolidine (8). Colorless oil; yield 65%, dr 95:5 (determined
by 1H NMR of crude reaction mixture); Rf 0.45 (1:2 AcOEt/hexanes);
chromatography (1:6 AcOEt/hexanes); [
a
]
25 þ15.1 (c 0.55 CH2Cl2);
D
1H NMR (600 MHz, CDCl3)
d: 7.54e7.05 (m, 20H), 4.59e4.50 (m,
4H), 4.42e4.37 (m, 2H), 4.23 (d, J 6.7 Hz, 1H), 4.09 (dd, J 6.7, 4.5 Hz,
1H), 3.99 (t, J 4.3 Hz, 1H), 3.65e3.61 (m, 1H), 3.59e3.53 (m, 2H); 13
NMR (151 MHz, CDCl3) : 138.1, 138.0, 137.9, 128.5, 128.4, 128.3,
C
d
128.2, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 73.2, 72.3, 71.9, 65.4
61.4; IR (film) v: 3340, 3030, 2861, 1495, 1454, 1362, 1206, 1097,
1028, 736, 697 cmꢀ1; HRMS (ESI-TOF) m/z calcd for C32H34NO3
[MþHþ] 480.2539, found 480.2551.
3.6.1. (2S,3S,4R,5R,6R)-1-Phenyl-2-(3,4,5-tris(benzyloxy)-6-(benzy-
loxymethyl)piperidin-2yl)ethanone (6). Yield 94%, dr >95:5 (de-
termined by 1H NMR of crude reaction mixture); colorless oil; Rf
0.47 (1:2 AcOEt/hexanes); chromatography (1:4 AcOEt/hexanes);
[a
]
25 þ56.7 (c 0.99, CHCl3); 1H NMR (600 MHz, CDCl3)
d: 8.01e7.95
D
3.5.4. (2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-
methylpyrrolidine (12 major isomer). Isolated yield 62% (both epi-
mers), dr 1.7:1 (determined by 1H NMR of crude reaction mixture);
colorless oil; Rf 0.15 (1:1 AcOEt/hexanes); chromatography (1:1
(m, 2H), 7.62e7.19 (m, 23H), 5.02 (d, J 10.8 Hz, 1H), 4.89 (d, J 10.8 Hz,
1H), 4.87 (d, J 10.9 Hz,1H), 4.72e4.66 (m, 2H), 4.52 (d, J 10.8 Hz,1H),
4.49 (d, J 12.0 Hz, 1H), 4.44 (d, J 12.0 Hz, 1H), 4.17e4.11 (m, 1H), 3.82
(dd, J 9.6, 5.5 Hz, 1H), 3.77 (t, J 9.1 Hz, 1H), 3.64 (dd, J 9.1, 2.5 Hz, 1H),
3.54 (dd, J 9.1, 6.1 Hz, 1H), 3.45 (t, J 9.2 Hz, 1H), 3.41 (dd, J 17.0,
3.5 Hz, 1H), 3.28 (dd, J 17.0, 9.6 Hz, 1H), 3.06e3.00 (m, 1H); 13C NMR
AcOEt/hexanes); [
a
]
25 þ17.8 (c 0.47, CHCl3); [
a
]
D Lit.27 þ16.4 (c 0.3,
D
CHCl3). 1H NMR (600 MHz, CDCl3)
d: 7.40e7.15 (m, 15H), 4.53 (m,
6H), 3.91 (t, J 3.8 Hz, 1H), 3.65 (dd, J 5.4, 3.6 Hz, 1H), 3.57e3.48 (m,
2H), 3.44 (dd, J 10.2, 5.9 Hz, 1H), 3.29e3.23 (m, 1H), 1.24 (d, J 6.6 Hz,
(151 MHz, CDCl3) d: 198.2, 137.8, 137.2, 137.1, 136.9, 136.2, 132.0,
127.5, 127.4, 127.32, 127.30, 127.0, 126.9, 126.85, 126.8, 126.7, 126.68,
126.63, 126.57, 126.50, 82.6, 80.3, 79.3, 74.6, 74.2, 72.1, 71.7, 69.2,
52.4, 49.5, 33.5; IR (film) v: 3357, 2923, 2856, 1681, 1453, 1094,
1067 cmꢀ1; HRMS (ESI-TOF) m/z calcd for C42H44NO5 [MþHþ]
642.3219, found 632.3226.
3H); 13C NMR (151 MHz, CDCl3)
d
: 138.18, 138.15, 138.14, 128.4,
127.8, 127.7, 127.65,127.61, 90.8, 86.5, 73.2, 71.9, 71.8, 70.6, 61.7, 57.3,
19.3; IR (film) v: 3087, 2924, 2856, 1453, 1363, 1096, 736, 697 cmꢀ1
;
HRMS (ESI-TOF) m/z calcd for C27H32NO3 [MþHþ], 418.2382, found
418.2389.
3.6.2. Compound 9:inseparable mixture of two diastereoisomers 2-
((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-2-
yl)-1-phenylethanone and 2-((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-
(benzyloxymethyl)pyrrolidin-2-yl)-1-phenylethanone. Colorless oil;
3.5.5. (2R,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-
methylpyrrolidine (2-epi-12, minor isomer). Colorless oil; Rf 0.10
(1:1 AcOEt/hexanes); chromatography (1:1 AcOEt/hexanes); not

ꢀ
P. Szczesniak et al. / Tetrahedron 70 (2014) 1880e1888
1888
6. Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K. Org. Lett. 2013, 15, 258e261.
7. Bonger, K. M.; Wennekes, T.; Filippov, D. V.; Lodder, G.; van der Marel, G. A.;
Overkleeft, H. S. Eur. J. Org. Chem. 2008, 2008, 3678e3688.
8. Bosco, M.; Bisseret, P.; Bouix-Peter, C.; Eustache, J. Tetrahedron Lett. 2001, 42,
7949e7952.
9. Wennekes, T.; Bonger, K. M.; Vogel, K.; van den Berg, R. J. B. H. N.; Strijland, A.;
Donker-Koopman, W. E.; Aerts, J. M. F. G.; van der Marel, G. A.; Overkleeft, H. S.
Eur. J. Org. Chem. 2012, 2012, 6420e6454.
10. Merino, P.; Delso, I.; Tejero, T.; Cardona, F.; Marradi, M.; Faggi, E.; Parmeggiani,
C.; Goti, A. Eur. J. Org. Chem. 2008, 2008, 2929e2947.
11. Maughan, M. A. T.; Davies, I. G.; Claridge, T. D. W.; Courtney, S.; Hay, P.; Davis, B.
G. Angew. Chem., Int. Ed. 2003, 42, 3788e3792.
12. Shao, J.; Yang, J.-S. J. Org. Chem. 2012, 77, 7891e7900.
13. Kondakal, V. V. R.; Ilyas Qamar, M.; Hemming, K. Tetrahedron Lett. 2012, 53,
4100e4103.
14. (a) Davis, B. G.; Maughan, M. A. T.; Chapman, T. M.; Villard, R.; Courtney, S. Org.
Lett. 2002, 4, 103e106; (b) Chapman, T. M.; Courtney, S.; Hay, P.; Davis, B. G.
Chem.dEur. J. 2003, 9, 3397e3414; (c) Mayer, A.; Leumann, C. J. Eur. J. Org. Chem.
2007, 4038e4049.
15. (a) Li, X.; Qin, Z.; Yang, T.; Zhang, H.; Wei, S.; Li, C.; Chen, H.; Meng, M.
Bioorg. Med. Chem. Lett. 2012, 22, 2712e2716; (b) Chen, H.; Li, R.; Liu, Z.;
Wei, S.; Zhang, H.; Li, X. Carbohydr. Res. 2013, 365, 1e8; (c) Bruce, I.; Fleet,
G. W. J.; di Bello, I. C.; Winchester, B. Tetrahedron 1992, 48, 10191e10200; (d)
Martin, S. F.; Chen, H. J.; Yang, C. P. J. Org. Chem. 1993, 58, 2867e2873; (e)
Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5537e5545; (f) Pearson,
W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546e5556; (g) Takayama, S.;
Martin, R.; Wu, J.; Laslo, K.; Siuzdak, G.; Wong, C.-H. J. Am. Chem. Soc. 1997,
119, 8146e8151.
16. Cividino, P.; Dheu-Andries, M.-L.; Ou, J.; Milet, A.; Py, S.; Toy, P. H. Tetrahedron
Lett. 2009, 50, 7038e7042.
17. Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Synthesis 2007, 2007, 485e504.
18. (a) Homer, R. B.; Johnson, C. D. Chemistry of Amides; Interscience: New York, NY,
1970; (b) Seyden-Penne, J. Reductions by the Alumino and Borohydrides in Or-
ganic Synthesis, 2 ed.; Wiley: New York, NY, 1997.
yield 65% (overall yield) dr 60:40; Rf 0.22 (1:1 AcOEt/hexanes);
chromatography (1:2 AcOEt/hexanes); 1H NMR (600 MHz, CDCl3)
d:
7.93e7.89 (m, 3H), 7.54e7.51 (m, 1H), 7.43e7.39 (m, 3H), 7.37e7.20
(m, 18H), 7.19e7.13 (m, 1H), 4.65e4.43 (m, 8H), 4.32e4.30 (m, 1H),
4.03e4.00 (m, 1H), 3.95e3.86 (m, 3H), 3.86e3.80 (m, 1H),
3.62e3.60 (m, 1H), 3.56e3.52 (m, 2H), 3.48e3.46 (m, 1H),
3.44e3.38 (m, 1H), 3.35e3.32 (m, 1H), 3.29 (m, 1H), 3.16e3.14 (m,
1H). 13C NMR (151 MHz, CDCl3)
d 197.95, 197.89, 137.20, 137.19,
137.08, 137.02, 136.97, 135.95, 135.9, 132.10, 131.99, 127.53, 127.47,
127.38, 127.36, 127.32, 127.30, 127.2, 127.06, 127.03, 126.79, 126.76,
126.74, 126.65, 126.62, 126.60, 126.59, 126.53, 86.96, 84.89, 83.54,
82.73, 72.21, 72.14, 70.9, 70.7, 70.6, 70.4, 70.3, 69.7, 62.7, 61.1, 56.6,
56.3, 41.3, 37.4; IR (film) v: 2923, 2858, 1683, 1453, 1095, 738,
697 cmꢀ1; HRMS (ESI-TOF) m/z calcd for C34H36NO4 [MþHþ],
522.2644, found 522.2646.
3.7. 6-deoxy-DMDP (10)
A methanolic solution (1 mL) of 12 (60 mg, 0.15 mmol), HCOOH
(3 drops) and 10% Pd/C (200 mg) was saturated with hydrogen in
ambient temperature for 24 h. The catalyst was removed by fil-
tration and the reaction mixture was concentrated. Further evap-
oration under high vacuum gave 6-deoxy-DMDP (10) as a pale
yellow oil (21 mg, yield, 98%), which was pure enough to give
20
satisfactory physical and spectral data. [
a]
þ39 (c 0.2, MeOH)
D
(lit.28 þ40.5 (c 0.3, MeOH)); 1H NMR (600 MHz, D2O)
d: 3.96 (dd, J
19. Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc. 2010, 132,
12817e12819.
7.2, 6.8 Hz, 1H), 3.85 (dd, J 12.1, 3.9 Hz, 1H), 3.81 (dd, J 7.2, 7.0 Hz,
1H), 3.75 (dd, J 12.1, 6.8 Hz, 1H), 3.47 (td, J 6.8, 3.9 Hz, 1H), 3.41 (dq, J
20. Bechara, W. S.; Pelletier, G.; Charette, A. B. Nat. Chem. 2012, 4, 228e234.
21. (a) Schedler, D. J. A.; Godfrey, A. G.; Ganem, B. Tetrahedron Lett. 1993, 34,
5035e5038; (b) Schedler, D. J. A.; Li, J.; Ganem, B. J. Org. Chem. 1996, 61,
4115e4119; (c) Xia, Q.; Ganem, B. Org. Lett. 2001, 3, 485e487; (d) Xia, Q.; Ga-
nem, B. Tetrahedron Lett. 2002, 43, 1597e1598; (e) Ganem, B.; Franke, R. R. J. Org.
Chem. 2007, 72, 3981e3987.
7.0, 6.8 Hz, 1H), 1.32 (d, J 6.8 Hz, 3H); 13C NMR (151 MHz, D2O)
d:
79.1, 74.6, 62.2, 58.0, 57.1, 14.6; IR (film) v: 3373, cmꢀ1; HRMS (ESI-
TOF) m/z calcd for C6H14NO3 [MþHþ] 148.0968; found: 148.0966.
22. Hoos, R.; Naughton, A. B.; Vasella, A. Helv. Chim. Acta 1992, 75, 1802e1807.
23. Overkleeft, H. S.; van Wiltenburg, J.; Pandit, U. K. Tetrahedron 1994, 50,
4215e4224.
24. (a) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 122,
168e169; (b) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel, K.
A. J. Am. Chem. Soc. 2003, 125, 15521e15528.
3.8. Radicamine B (11)
A solution of 13 (35 mg, 0.06 mmol) and PdCl2 (183 mg) in EtOH
(5 mL) was saturated with hydrogen at rt for 12 h. The catalyst was
removed by filtration and the reaction mixture was concentrated.
Further evaporation under high vacuum gave 11 (12 mg, yield 92%),
which was pure enough to give satisfactory physical and spectral
25. (a) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phyto-
€
chemistry 2001, 56, 265e295; (b) Stutz, A. E. Iminosugars as Glycosidase In-
hibitors; Wiley-VCH: Weinheim, Germany, 2004; (c) Compain, P.; Martin, O. R.
Iminosugars: From Synthesis Therapeutic Applications; Wiley-VCH: Weinheim,
Germany, 2007.
data. [
a
]
20 þ48.1 (c 0.34, EtOH) (lit.28 þ47.7 (c 0.3, MeOH)); 1H NMR
D
(600 MHz, D2O) d: 7.30 (d, J 8.5 Hz, 2H), 6.86 (d, J 8.5 Hz, 2H), 4.30 (d,
26. (a) Welter, A.; Jadot, J.; Dardenne, G.; Marlier, M.; Casimir, J. Phytochemistry
1976, 15, 747e749; (b) Nash, R. J.; Asano, N.; Eatson, A. A. In Alkaloids: Chemical
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27. (a) Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.; Kusano, G. Chem. Pharm.
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3021e3024.
J 2.3 Hz, 1H), 4.12 (dd, J 2.2, 1.2 Hz, 1H), 3.95 (dd, J 12.1, 4.8 Hz, 1H),
3.85 (dd, J 12.1, 8.6 Hz, 1H), 3.68e3.60 (m, 1H), 3.58e3.50 (m, 1H);
13C NMR (151 MHz, D2O)
d: 156.0, 129.6, 121.8, 115.6, 76.5, 76.0, 67.3,
64.5, 59.2; IR (film): 3388, 1072 cmꢀ1; HRMS (ESI-TOF) m/z calcd for
C
11H16NO4 [MþHþ]: 226.1074; found: 226.1077.
28. Zhou, X.; Liu, W.-J.; Ye, J.-L.; Huang, P.-Q. Tetrahedron 2007, 63, 6346e6357.
29. Carmona, A. T.; Whigtman, R. H.; Robina, I.; Vogel, P. Helv. Chim. Acta 2003, 86,
3066e3073.
Acknowledgements
30. (a) Tsou, E.-L.; Chen, S.-Y.; Yang, M.-H.; Wang, S.-C.; Cheng, T.-R. R.; Cheng, W.-
C. Bioorg. Med. Chem. 2008, 16, 10198e10204; (b) Tsou, E.-L.; Yeh, Y.-T.; Liang, P.-
H.; Cheng, W.-C. Tetrahedron 2009, 65, 93e100.
Financial support by the European Union within European Re-
gional Development Fund, Project POIG.01.01.02.-14-102/09 is
gratefully acknowledged.
31. Cicchi, S.; Marradi, M.; Vogel, P.; Goti, A. J. Org. Chem. 2006, 71, 1614e1619.
ꢀ
32. Desvergnes, S.; Py, S.; Vallee, Y. J. Org. Chem. 2005, 70, 1459e1462.
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(d) Ashoorzadeh, A.; Archibald, G.; Caprio, V. Tetrahedron 2009, 65, 4671e4680;
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