Synthesis of nortropane alkaloid calystegine B2 from methyl α-D-xylopyranoside

Article abstract of DOI:10.1016/j.carres.2018.12.002

A new synthetic route for formation of a central cycloheptanone intermediate leading to the nortropane alkaloid calystegine B₂ is described. The approach installs the desired ketone functionality directly in a ring-closing metathesis step. The

Full text of DOI:10.1016/j.carres.2018.12.002

CarbohydrateResearch472(2019)122–126
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Carbohydrate Research
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Synthesis of nortropane alkaloid calystegine B2 from methyl α-D-
xylopyranoside
Emilie N. Underlin, Henrik H. Jensen∗
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark
A R T I C L E I N F O
A B S T R A C T
Keywords:
A new synthetic route for formation of a central cycloheptanone intermediate leading to the nortropane alkaloid
calystegine B2 is described. The approach installs the desired ketone functionality directly in a ring-closing
metathesis step. The target compound was prepared over 10 steps from commercially available methyl α-D-
xylopyranoside.
Chiral pool synthesis
Ring-closing metathesis
Rotamers
1. Introduction
drawbacks (Scheme 1). We have previously also used this approach
with its inherent disadvantages for the synthesis of noeurostegines
The calystegines with their hydroxylated nortropane skeletons of
which calystegine B2 is a prime example represent a well-studied sub-
group of iminosugars (Fig. 1). The first calystegine was isolated from
Calystegia sepium in 1988 [1], since then more than 10 calystegines have
been found in various plants [2–4] and have been classified into three
types: A (with three hydroxyl groups), B (with four hydroxyl groups),
and C (with five hydroxyl groups) [3]. Despite the presence of a
hemiaminal functionality the bicyclic calystegines are generally very
stable compounds, prevented from breakdown via dehydration and
Amadori rearrangement due to the presence of a bridgehead according
to Bredt's rule [5–7]. Additionally, it has been found, that calystegines
exhibit potent and selective glycosidase inhibition and been shown to
have potential in the treatment of cancer [8,9], diabetes [10], viral
infections [11], and lysosomal storage diseases [12]. Due to difficulty of
purification from natural sources and important biological properties,
synthesis of these compounds have attracted attention.
[30–32] being hybrid molecules of calystegine B2 (1) and noeuromycin
(Fig. 1) [33]. Consequently, we became interested in assembling the
amino cycloheptanone frame of calystegine B2 (1) using an RCM re-
action but in a fashion that installed the oxygen atom of the target
ketone directly thereby avoiding the regioselectivity issues previously
encountered in the hydroboration step, in the hope to develop a general
and efficient access to calystegines and noeurostegines.
Accordingly, we here present our results with regards to the
synthesis of calystegine B2 (1) via an RCM reaction directly installing
the needed ketone functionality, hence eliminating the need of a sub-
sequent hydroboration reaction involving regioselectivity issues.
2. Results and discussion
Methyl α-D-xylopyranoside (2) was chosen as the starting material
as it is readily available and contains three hydroxyl groups with the
required absolute stereochemistry for the synthesis of calystegine B2
(Scheme 2). 2,3,4-Tri-O-benzyl-D-xylopyranose (3) was prepared uti-
lizing standard O-benzyl protection procedures and glycoside hydro-
lysis [34,35]. Next, the N-benzyl glycosyl amine was prepared and
treated with vinyl magnesium bromide to provide the allylic amine 4 as
a single stereoisomer in 75% over 2 steps [36,37]. The high diaster-
eoselectivity of the reaction can be explained by the Cram-chelation
model and is in accordance with previous reports [37,38]. The sec-
ondary amine of 4 was Cbz protected to give the carbamate 5. In-
troduction of the carbamate gave rise to rotamers making NMR char-
acterization challenging even when data was obtained at 60 °C. The
primary alcohol of 5 was next oxidized to the aldehyde using Dess-
Several different approaches to the synthesis of calystegines have
previously been published including ring-closing metathesis (RCM)
[13–19], ring expansion [20–22], cycloaddition [23–25], in-
tramolecular Nozaki–Hiyama–Kishi reaction [26], radical cyclization
[27], and polar cyclisation [28,29]. For many of the syntheses of ca-
lystegines the key step is the RCM reaction, where the popularity arise
due to the efficiency and generality of the construction of a cyclo-
heptanone ring. Previous uses of RCM has produced a cycloheptene
intermediate, which needed further modification to the cycloheptanone
by installation of the hydroxyl group through a hydroboration-oxida-
tion sequence. This, however lead to mixtures of regioisomeric cyclo-
heptanols/cycloheptanones [13,15–19], giving this approach some
∗ Corresponding author.
E-mail address: hhj@chem.au.dk (H.H. Jensen).
https://doi.org/10.1016/j.carres.2018.12.002
Received 13 November 2018; Received in revised form 4 December 2018; Accepted 4 December 2018
Availableonline07December2018
0008-6215/©2018ElsevierLtd.Allrightsreserved.

E.N. Underlin, H.H. Jensen
CarbohydrateResearch472(2019)122–126
Analytical TLC analysis was performed with silica-coated aluminium
plates (Merck Kieselgel 60 F254) and visualized by treatment of KMnO4
(1.5 g KMnO4 in 1.25 g 10% NaOH and 200 mL H2O) or C-mol (0.2%
Cerium(IV) sulfate and 5% ammoniummolydate in 10% sulfuric acid).
Flash column chromatography purification of products were done using
Merck silica gel 60 (230–400 mesh).
3.2. Instrumentation
1H and 13C NMR spectra were recorded on a Varian Mercury 400
spectrometer. Due to the poor data caused by rotamers the NMR spectra
of Cbz-protected compounds were observed at 60 °C for slight im-
provement. Spectral assignments were made according to 2D-COSY,
HMQC and DEPT-135. Numbering of counds can be found in the sup-
porting information document. Melting points were measured on a
Büchi B-540 instrument and are uncorrected. Optical rotation was
measured on an ADP440 + polarimeter and reported in units of deg
cm2 g−1, and concentrations are given in g/100 mL. Mass spectra were
recorded on a Micromass LC-TOF spectrometer with positive electro-
spray ionization.
Fig. 1. Calystegine B2 and synthetic analogues.
3.3. 2,3,4-Tri-O-benzyl-α/β-D-xylopyranose (3)
Scheme 1. Schematic overview of regioselectivity (A:B) of hydroboration.
Different examples of regioselectivity: R: OBn, R1: H, R2: NBnCbz, ratio A/B 2:1
[15]. or R: H, R1: OBn, R2: NBnCbz, ratio A/B 1.7:116 or R: OBn, R1: OBn, R2:
NBnCbz, ratio A/B 3:117,18 or 2.6:119 or R: OBn, R1: CH2OBn, R2: OPMB, ratio
Methyl α-D-xylopyranoside (2) (5.018 g, 30.6 mmol, 1.0 equiv.) was
dissolved in dry DMF (75 mL). NaH as a 60% suspension in mineral oil
(5.505 g, 138 mmol, 4.5 equiv.) was added and the solution was left to
stir for 15 min in a cool water bath before BnBr (16.5 mL, 139 mmol,
4.5 equiv.) was added. The mixture stirred at rt. for 18 h at which point
TLC analysis (EtOAc/MeOH 4:1) showed full consumption of starting
material and TLC (pentane/EtOAc 10:1) indicated the formation of only
one product. The reaction was stopped upon addition of aq. sat. NH4Cl
at 0 °C. Water and EtOAc was added and the phases separated.
Extraction of the aqueous phase with EtOAc was completed before the
combined organic phases were washed with water and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The resulting residue was
purified by flash column chromatography (pentane/EtOAc 12:1) re-
sulting in the product methyl 2,3,4-tri-O-benzyl-α-D-xylopyranoside as
a colorless solid (12.279 g, 93%). Mp(uncorr.) 61.9–63.5 °C (CHCl3), lit.
A/B 3:130 or R: OBn, R1: CH2OBn, R2: OH, ratio A/B; 3:132
.
Martin periodinane (DMP), which subsequently was reacted with vinyl
magnedium bromide to provide the diene 6. Again, oxidation was
performed with the DMP reagent and provided ketone 7, which next
underwent RCM using Grubbs 2nd generation catalyst to produce cy-
cloheptenone 8 in 42% yield (63% corrected yield after isolation of
unreacted starting material). The RCM reaction was also attempted on
the stage of the secondary alcohol (6) as well as its O-acetylated deri-
vative, but inferior yields were obtained. The final step involving alkene
reduction and global deprotection was accomplished using Pearlman's
catalyst (Degussa type), which gave rise to spontaneous cyclization to
calystegine B2 (1). Other Pd-sources were also tried (non-Degussa type),
but these did not provide the target compound. Calystegine B2 (1) was
fully characterized by NMR showing consistency with the previously
reported data of the natural compound [17,39]. Furthermore, the spe-
cific optical rotation of the synthesized compound ([α]D +29.3 (c 0.5,
H2O)) was in accordance with that of the natural compound ([α] +28.1
(c 0.27, H2O)) [17].
295
295
68–69 °C [40]; [α]D
+19.6 (c 1, CHCl3), lit. [α]D
+16 (c 0.7,
CHCl3) [40]; Rf(pentane/EtOAc 7:1): 0.57; 1H NMR (400 MHz, CDCl3):
δH 7.41–7.32 (m, 14H, ArH), 4.96 (d, Jgem 10.9 Hz, 1H, OCH2Ph), 4.90
(d, Jgem 10.9 Hz, 1H, OCH2Ph), 4.84–4.76 (m, 2H, OCH2Ph), 4.70–4.63
(m, 2H, OCH2Ph), 4.56–4.55 (m, J 2.9 Hz, 1H, H-1), 3.93 (t, J 8.4 Hz,
1H, H-3), 3.63–3.53 (m, 3H, H-4, H-5, H-5′), 3.51–3.44 (m, 1H, H-2),
3.40 (s, 3H, OCH3). 13C NMR (101 MHz, CDCl3): δC 139.0, 138.4, 138.3
(ArC), 128.5, 128.5, 128.2, 127.9, 127.9, 127.7 (ArCH), 98.4 (C-1),
81.6 (C-3), 79.7 (C-2), 78.2 (C-4), 75.9 (OCH2Ph), 73.6 (OCH2Ph,
double intensity), 59.9 (C-5), 55.3 (OCH3). HRMS (ESI): calculated
2.1. Conclusion
+
Calystegine B2 (1) was synthesized over 10 steps in an overall yield
of 19% from the readily available methyl α-D-xylopyranoside (2). In
comparison, Wang et al. prepared calystegine B2 over 12 steps (overall
yield 27%) from tri-O-benzyl-D-xylopyranose (3) [26]. Our method
features a stereoselective nucleophilic addition of vinyl magnesium
bromide, two DMP oxidations, and an intra-molecular ring-closing
metathesis to form the central cycloheptenone. To the best of our
knowledge this is the first example of synthesis of calystegine B2 fea-
turing ring-closing metathesis avoiding a hydroboration step for in-
stallation of the impending ketone oxygen atom. The strategy can
provide a general approach to this class of compounds by selection of
other common sugar-derived starting materials.
(calcd.) for C26H28O5NH4 452.2431; found 452.2436. NMR data are
in accordance with previous reported values [35]. Methyl 2,3,4-tri-O-
benzyl-α-D-xylopyranoside (1.617 g, 3.7 mmol, 1.0 equiv.) was dis-
solved in 1 M H2SO4 (2.0 mL) and AcOH (16.0 mL) and heated to 80 °C.
After 8 h TLC analysis (pentane/EtOAc 3:1) indicated full consumption
of starting material. The reaction mixture was poured into ice water
before EtOAc was added and the aqueous phase extracted with addi-
tional EtOAc. The combined organic phases were washed with sat. aq.
NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. The
product 3 was isolated as a colorless powder (1.432 g, 92%) with an α/
β ratio of 3:2 as measured by NMR Mp (uncorr.) 128.0–131.1 °C
(CHCl3), lit. 129–130 °C [41]; Rfα(pentane/EtOAc 2:1): 0.54;
Rfβ(pentane/EtOAc 2:1): 0.62; 1H NMR (400 MHz, CDCl3): δH 7.4–7.2
(m, 26H, ArH), 5.12 (s, 1H, H-1α), 4.93–4.89 (m, 4H, OCH2Ph),
4.80–4.70 (m, 4H, OCH2Ph), 4.67–4.63 (m, 3H, OCH2Ph, H-1β),
3.98–3.88 (m, 2H, H-5β, H-3α), 3.82 (t, J5,5′ 10.7 Hz, 1H, H-5α),
3.70–3.54 (m, 4H, H-5′α, H-4α, H-3β, H-4β, OHβ), 3.51 (d, J2,3 8.9 Hz,
1H, H-2α), 3.36–3.25 (m, 1H, H-2β, H-5′β), 3.21 (bs, 1H, OHα). 13C
3. Experimental
3.1. General methods
All reagents were used as received from commercial sources.
123

E.N. Underlin, H.H. Jensen
CarbohydrateResearch472(2019)122–126
Scheme 2. Synthesis of calystegine B2.
NMR (101 MHz, CDCl3): δC 138.7 (ArCα), 138.6 (ArCβ), 138.4 (ArCβ),
138.3 (ArCα), 138.2 (ArCβ), 137.9 (ArCα)128.6–127.8 (ArCH), 97.9
(C-1β), 91.5 (C-1α), 83.3 (C-3β), 82.5 (C-2β), 80.6 (C-3α), 79.5 (C-2α),
77.7 (C-4β), 77.6 (C-4α), 75.6 (OCH2Phα), 75.6 (OCH2Phβ), 74.9
(OCH2Phβ), 73.5 (OCH2Phα), 73.4 (OCH2Phβ), 73.3 (OCH2Phα), 63.8
Jgem 11.2 Hz, 2H, OCHHPh), 4.72 (d, Jgem 11.4 Hz, 1H, OCH2Ph), 4.61
(d, Jgem 9.3 Hz, 1H, OCH2Ph), 4.58 (d, Jgem 9.7 Hz, 1H, OCH2Ph), 4.36
(d, Jgem 11.7 Hz, 1H, OCH2Ph), 4.06 (dd, J2,3 6.5 Hz, J2,1 4.4 Hz, 1H, H-
2), 3.84–3.75 (m, 3H, H-4, NHCH2Ph), 3.67 (dd, J1,1′ 11.8 Hz, J1,2
4.1 Hz, 1H, H-1), 3.49–3.44 (m, 2H, H-3, H-1’), 3.09 (dd, J5,4 8.2 Hz,
J5,6 3.8 Hz, 1H, H-5), 2.07 (bs, 2H, NH, OH). 13C NMR (101 MHz,
CDCl3): δC 140.6, 138.6, 138.4, 138.2 (ArC), 138.2 (C-6), 128.7, 128.5,
128.5, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.0 (ArCH), 117.4
(C-7), 82.7 (C-4), 80.2 (C-2), 78.3 (C3), 74.9 (OCH2Ph), 74.6 (OCH2Ph),
72.1 (OCH2Ph), 61.8 (NCH2Ph), 60.6 (C-5), 50.6 (C-1). HRMS (ESI):
calcd. for C35H39NO4H+ 538.2952; found 538.2964. NMR data are in
accordance with lit [37].
+
(C-5β), 60.4 (C-5α). HRMS (ESI): calcd. for C26H28O5NH4 438.2275;
found 438.2284. NMR data are in accordance with previously reported
data [42].
3.4. (2R,3R,4S,5R)-5-(N-Benzyl-amino)-2,3,4-tris-(benzyloxy)-hept-6-en-
1-ol (4)
BnNH2 (2.6 mL, 23.8 mmol, 2.05 equiv.) and imidazole (1.580 g,
23.2 mmol, 2.0 equiv.) was added to a solution of lactol 3 (4.880 g,
11.6 mmol, 1.0 equiv.) in dry THF (116.0 mL) and added. The solution
was left to stir at rt. for 5 min before I2 (5.891 g, 23.2 mmol, 2.0 equiv.)
was added and the mixture was stirred further at rt. After 22 h TLC
analysis (pentane/EtOAc 3:1) indicated full consumption of starting
material. A saturated solution of aq. Na2SO3 was added to the reaction
mixture until the dark brown color disappeared. The aqueous layer was
extracted with EtOAc and the combined organic phases were dried over
MgSO4, filtered, and concentrated in vacuo. The residue was used di-
rectly in the next step where it was reacted with vinyl magnesium
bromide (111 mL, 111 mmol, 9.6 equiv. 1 M solution in THF) at 0 °C
and then rt. for a further 18 h at which point TLC analysis (pentane/
EtOAc 2:1) indicated full consumption of starting material. The reaction
was quenched by addition of saturated aq. NH4Cl at 0 °C and diluted
and further extracted with EtOAc. The combined organic phases were
dried over MgSO4, filtered, and concentrated in vacuo.Purification of
the residue by flash column chromatography (pentane/EtOAc 3:1) gave
3.5. (2R,3S,4R,5R)-5-[(N-benzyl-N-(benzyloxycarbonyl))amino]-2,3,4-
tris(benzyloxy)-hept-6-en-1-ol (5)
Secondary amine 4 (1.042 g, 1.94 mmol, 1.0 equiv.) was dissolved
in EtOAc (7 mL) and sat. aq. NaHCO3 (7 mL) before a 50% solution of
benzyl chloroformate in toluene (1.66 mL, 5.81 mmol, 3.0 equiv.) was
added and the mixture let to stir at rt. After 4.5 h TLC analysis (pen-
tane/EtOAc 1:1) indicated reaction completion. The phases were se-
parated, the aqueous phase was extracted with EtOAc and the com-
bined organic phases washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo. Purification of the residue was performed by
flash column chromatography (pentane/EtOAc 3:1) resulting in 5 as a
295
yellow oil (1.163 g, 90%). [α]D
+3.6 (c 1.0, CHCl3); Rf(pentane/
EtOAc 2:1): 0.46; 1H NMR (400 MHz, CDCl3, 60 °C): δH 7.39–7.21 (m,
25H, ArH), 6.08–5.99 (m, 1H, H-6), 5.23–5.16 (m, 2H), 5.04 (d, J7,6
10.4 Hz, 1H, H-7cis), 4.90 (d, J 15.6, 1H, OCH2Ph), 4.82 (d, 1H, H-
7
trans), 4.69–4.41 (m, 9H, H-5), 4.28 (bs, 1H), 3.81–3.60 (m, 4H). 13C
295
the product (4) as a yellow oil (4.663 g, 75% over 2 steps). [α]D
NMR (101 MHz, CDCl3, 60 °C): δC 156.7–156.4 (m, CO, Cbz), 139.1,
138.8, 138.7, 138.7, 138.6, 136.8, 135.1–134.8 (m), 128.9–127.0 (m),
(ArC, ArCH) 119.3–118.8 (m, C-7), 79.8–79.3 (m), 74.7–74.2 (m),
73.3–73.0 (m), 67.7–67.3 (m), 62.4–61.8 (m), 52.3–51.8 (m). HRMS
(ESI): calcd. for C35H39NO4H+ 672.3320; found 672.3328.
295
-17.5 (c 1, CHCl3), lit. [α]D
9.7 (c 0.8, CH2Cl2) [37]; Rf(pentane/
EtOAc 2:1): 0.25; 1H NMR (400 MHz, CDCl3): δH 7.33–7.24 (m, 21H,
ArH), 5.80–5.71 (m, 1H, H6), 5.22 (dd, J7,6 10.2 Hz, J7,7′ 1.7 Hz, 1H, H-
7(cis)), 5.03 (dd, J7′,6 17.3 Hz, J7′,7 1.5 Hz, 1H, H-7′(trans)), 4.79 (d,
124

E.N. Underlin, H.H. Jensen
CarbohydrateResearch472(2019)122–126
3.6. (4R,5R,6S,7R)-7-[N-benzyl-N-(benzyloxycarbonyl)-amine]-4,5,6-tris
7.29–7.05 (m, 30H, ArH), 6.74–6.67 (m, 1H, H2), 6.25 (d, J1,2 17.5 Hz,
1H, H-1trans), 5.97–5.89 (m, 1H, H-8), 5.57 (d, J1,2 10.6 Hz, 1H, H-1cis),
5.15–5.08 (m, 2H, OCH2Ph), 5.01 (d, J9,8 10.2 Hz, 1H, H-9cis), 4.84 (m,
2H, H-9’, OCH2Ph), 4.65–4.58 (m, 4H, H-7, OCH2Ph), 4.45–4.32 (m,
7H, H-4, OCH2Ph), 4.14 (s, 1H, H-6), 3.85 (s, 1H, H-5). 13C NMR
(101 MHz, CDCl3, 60 °C): δC 199.4 (CO, C3), 157.0 (CO, Cbz), 139.2,
138.8, 138.4, 137.7, 136.8, 136.8 (ArC), 135.0–134.8 (m, C-2/C-8),
133.0–132.8 (m, C-2/C-8), 129.0–127.1 (m, ArCH), 84.4, 81.0–80.6
(m), 75.5–75.3 (m), 75.0, 73.7–73.3 (m), 67.9–67.4 (m), 61.7–61.1
(m), 51.5–51.0 (m). HRMS (ESI): calcd. for C45H45NO6NH4+ 713.3585;
found 713.3592. Some signals in the 13C NMR are missing, especially
obvious are C1 and C9 this can be explained by the presence of rota-
mers.
(benzyloxy)-3-hydroxy-nona-1,8-diene (6)
Carbamate 5 (3.357 g, 5.00 mmol, 1.0 equiv.) was dissolved in
CH2Cl2 (40 mL) before Dess Martin periodinane (3.173 g, 7.48 mmol,
1.5 equiv.) was added. The reaction was left to stir for 1 h at rt. before
TLC analysis (pentane/EtOAc 3:1) indicated full consumption of
starting material. The reaction mixture was diluted with Et2O (60 mL),
sat. aq. Na2S2O3 (15 mL) and sat. aq. NaHCO3 (30 mL) and stirred
vigorously for 1.5 h at rt. The phases were separated and the aqueous
phase was extracted with Et2O. The combined organic phases were
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo. The aldehyde product, a yellow oil, was sufficiently clean and
295
used directly in the next step. [α]D
-4.4 (c 1.0, CHCl3); Rf(pentane/
EtOAc 6:1): 0.21; 1H NMR (400 MHz, CDCl3, 60 °C): δH 9.72 (s, 1H, H-
1), 7.36–7.20 (m, 30H, ArH), 6.04 (bs, 1H, H-6), 5.20 (s, 2H, OCH2Ph),
5.00 (d, J7,6 10.1 Hz, 1H, H-7cis), 4.94–4.82 (m, 3H, OCH2Ph), 4.73 (d,
J7,6 17.2 Hz, 1H, H-7trans), 4.61–4.30 (m, 8H, H-4, H-5, OCH2Ph), 4.28
(d, J 15.7 Hz, 1H, OCH2Ph), 4.02 (bs, 1H, H-2), 3.84 (bs, 1H, H-3). 13C
NMR (101 MHz, CDCl3, 60 °C): δC 200.3–200.1 (m, CHO, C-1),
156.3–156.1 (m, CO, Cbz), 138.4, 138.1, 137.7, 137.5, 136.5 (ArC),
134.7–134.5 (m, C-6), 128.9–127.0 (m, ArCH), 119.3–118.9 (m, C-7),
81.3–81.1 (m), 80.4–80.2 (m), 78.4, 74.3–74.2 (m), 73.9–73.8 (m),
73.5–73.3 (m), 67.5–67.1 (m), 62.4–62.2 (m), 52.8–52.5 (m). HRMS
3.8. (2R,3R,4S,5R)-5-[N-benzyl-N-(benzyloxycarbonyl)-amine]-2,3,4-tris
(benzyloxy)-cyclo-hept-6-en-1-one (8)
Diene 7 (2.367 g, 3.40 mmol, 1.0 equiv.) was dissolved in dry to-
luene (17 mL, c = 0.2 M) and heated to 80 °C at which point Hoveyda-
Grubbs 2nd generation catalyst (0.106 g, 0.17 mmol, 0.05 equiv.) was
added. The reaction was stopped after 16.5 h, TLC analysis (pentane/
EtOAc 8:1) did not show complete consumption of starting materials
but showed formation of several products. The reaction mixture was
concentrated in vacuo and purified by flash column chromatography
(pentane/EtOAc 12:1). The product was a yellow oil (0.824 g, 36%),
+
(ESI): calcd. for C43H43NO6NH4 + MeOH 719.3691; found 719.3699
(found as the hemiacetal upon reaction with methanol in which the
sample was dissolved). Vinylmagnesium bromide (1.0 M in THF, 50 mL,
50 mmol, 10 equiv.) was added to the crude aldehyde (5.0 mmol, 1.0
equiv) at 0 °C. After 40 min TLC analysis (pentane/EtOAc 5:1) indicated
full consumption of starting material. The reaction was quenched by
addition of sat. aq. NH4Cl, and extracted with EtOAc. The combined
organic phases were dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography
(pentane/EtOAc 5:1) to give allylic alcohol 6 as a clear oil (2.640 g,
76% over 2 steps). Rf(pentane/EtOAc 4:1): 0.34 and 0.39.; 1H NMR
(400 MHz, CDCl3, 60 °C): δH 7.32–7.26 (m, 25H, ArH), 6.03–5.77 (m,
2H, H-2, H-8), 5.38–4.19 (m, 17H, H-1, H-1′, H-3, H-7, H-9, H-9’,
OCH2Ph), 3.74–3.67 (m, 2H, H-4), 2.86 (bs, 1H, OH), 2.50 (bs, 1H,
OH). 13C NMR (101 MHz, CDCl3, 60 °C): δC 156.8–156.4 (m, CO, Cbz),
139.0, 138.8–138.7 (m), 138.6–138.5 (m), 138.0–137.9 (m) (ArC),
136.8–136.7 (m, C-2/C-8), 135.0–134.8 (m, C-2/C-8), 128.9–127.1 (m,
ArCH), 119.4–118.9 (m, C-1/C-9), 115.8–115.5 (m, C-1/C-9),
82.2–81.9 (m), 80.6–80.1 (m), 79.9–79.5 (m), 75.3–74.8 (m),
74.5–74.2 (m), 73.6–73.4 (m), 72.7–72.5 (m), 67.7–67.3 (m),
62.5–62.2 (m), 52.5–52.1 (m). HRMS (ESI): calcd. for C45H47NO6H+
698.3476; found 698.3485. 1H NMR has been normalized based on the
number of ArH corresponding to one of the diastereoisomers. The ratio
of R/S cannot be decided based on NMR due to the presence of rota-
mers.
additionally was the remaining starting material collected (0.983 g,
295
42%), giving a corrected yield of 63%. [α]D
-78.6 (c 1.0, CHCl3);
Rf(pentane/EtOAc 7:1): 0.46; 1H NMR (400 MHz, CDCl3): δH 7.30–7.13
(m, 44H, ArH), 6.70 (d, J7,6 12.3 Hz, 1H, H-7), 6.51 (d, J7,6 12.2 Hz, 1H,
H-7*), 5.89 (d, J6,7 12.3 Hz, 1H, H-6), 5.77 (d, J6,7 12.7 Hz, 1H, H-6*),
5.23–5.11 (m, 4H, OCH2Ph), 4.91 (bs, 2H, OCH2Ph), 4.71–4.66 (m, 2H,
OCH2Ph), 4.59–4.29 (m, 10H, H-2, H-3, OCH2Ph), 4.16–4.01 (m, 7H, H-
4, H-5, OCH2Ph). 13C NMR (101 MHz, CDCl3): δC 199.4 (CO), 199.3
(C*O), 156.5 (C*O, Cbz), 156.0 (CO, Cbz), 150.1–149.8 (m, C6), 138.5,
138.0, 137.7, 137.5, 137.3, 136.9, 136.8, 136.4, 136.1, 128.7–127.5
(m) (ArC, ArCH), 126.2–126.0 (m, C-7), 83.8, 83.3, 82.5, 81.6, 74.7,
74.2, 72.8, 72.7, 72.5, 72.4, 67.6, 67.4, 59.8, 59.1, 54.1–53.6 (m).
+
HRMS (ESI): calcd. for C43H41NO6NH4 685.3272; found 685.3279.
”*” refer to signals, which are clearly for the other rotamer. Ratio ro-
tomers approx. 1:0.6.
3.9. (+)-Calystegine B2 (1)
Pd/C Degussa type (Pd 20%) (0.024 g, 0.035 mmol, 0.22 equiv.),
then H2 (balloon, 1 atmosphere) was added to a solution of cyclo-
heptenone 8 (0.106 g, 0.16 mmol, 1.0 equiv.) dissolved in MeOH
(3.0 mL) and CHCl3 (1.0 mL).and H2. The reaction mixture was stirred
overnight at rt. before it was filtered and concentrated in vacuo.
Disappearance of the starting material could be monitored by TLC
analysis in pentane/EtOAc 6:1, while TLC analysis in EtOAc/25% am-
monium hydroxide 4:1 was suitable for monitoring the on-going reac-
tion. The reaction mixture was resubmitted by dissolving in MeOH
(3.0 mL) and CHCl3 (1.0 mL) in the presence of fresh Pd/C Degussa type
(Pd 20%) (0.033 g, 0.31 mmol, 0.19 equiv.) and H2 (balloon, 1 atmo-
sphere) The reaction mixture was additionally stirred overnight at rt.
before it was filtered and concentrated in vacuo. The residue was pur-
ified by flash column chromatography (CH2Cl2/EtOH/MeOH/ammonia
3.7. (4R,5R,6S,7R)-7-[N-benzyl-N-(benzyloxycarbonyl)-amine]-4,5,6-tris
(benzyloxy)-3-oxo-nona-1,8-diene (7)
DMP (2.246 g, 5.29 mmol, 1.5 equiv was added to a solution of al-
cohol 6 (2.465 g, 3.53 mmol, 1.0 equiv.) in CH2Cl2 (30 mL). The reac-
tion mixture was to stir for 80 min at rt. before TLC analysis (pentane/
EtOAc 5:1) indicated full consumption of the starting material and
formation of a product. The reaction mixture was added Et2O (40 mL),
sat. aq. Na2S2O3 (20 mL) and sat. aq. NaHCO3 (10 mL) and stirred
vigorously for 2 h at rt. The phases were separated and the aqueous
layer was extracted with Et2O. The combined organic phases were
washed with brine, dried over MgSO4, filtered, and concentrated in
water 5:2:2:1) to give a colorless glass (0.020 g, 73%). [α]D295 +29.3 (c
295
0.5, H2O), lit. [α]D
+28.1 (c 0.27, H2O) [17]; Rf(CH2Cl2/EtOH/
MeOH/ammonium hydroxider 5:2:2:1) 0.31; 1H NMR (400 MHz, D2O):
δH 3.55 (dd, J4,3 8.3 Hz, J4,5 3.7 Hz, 1H, H-4), 3.39 (dd, J2,3 8.6 Hz, J2,4
1.7 Hz, 1H, H-2), 3.35–3.27 (m, 2H, H-3, H-5), 2.02–1.87 (m, 2H, H-6,
H-7), 1.78–1.68 (m, 1H, H-6′), 1.57–1.47 (m, 1H, H-7’). 13C NMR
(101 MHz, D2O): δC 93.3 (C-1), 80.4 (C-2), 77.7 (C-3), 77.6 (C-4), 58.7
(C-5), 31.5 (C-7), 24.5 (C-6). HRMS (ESI): calcd. for C7H13NO4H+
vacuo. The product was obtained as a clear oil (2.367 g, 96%), which
295
was sufficiently pure for further reaction. [α]D
-1.3 (c 1.0, CHCl3);
Rf(pentane/EtOAc 10:1): 0.26; 1H NMR (400 MHz, CDCl3, 60 °C): δH
125

E.N. Underlin, H.H. Jensen
CarbohydrateResearch472(2019)122–126
176.0917; found 176.0918. The 13C NMR have been referenced by
using the C2 chemical shift, δ 80.4 ppm, reported in the literature
[17,39]. The data are in accordance with literature values [17,39].
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