Stereocontrolled Debenzylative Cycloetherification Reaction as a Route to Enantiopure C-Furanosides with Amino Substituents in the Side Chain

Article abstract of DOI:10.1021/acs.joc.9b03247

A highly efficient methodology of the preparation of synthetically important tetrahydrofuran derivatives with an amino substituent in the side chain is reported. This process is based on the stereocontrolled debenzylative cycloetherification (DBCE) reaction applied for chirons from the d-gluco-and d-manno-series and provides derivatives with new stereogenic centers. The influence of the electron-withdrawing group (EWG), present in the acyclic substrates with the mesyl leaving group, on the reactivity in the DBCE reaction was investigated both in the flask and by density functional theory (DFT) calculations. It was demonstrated that tetrahydrofuran derivatives with the benzoxime group (EWG = CHNOBn) are very good candidates for the subsequent highly stereoselective Grignard reaction.

Full text of DOI:10.1021/acs.joc.9b03247

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Article
Stereocontrolled Debenzylative Cycloetherification Reaction as a Route
to Enantiopure C-Furanosides with Amino Substituents in the Side Chain
Karolina Tiara, Mykhaylo A. Potopnyk, Pawe# #wider, and Slawomir Jarosz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03247 • Publication Date (Web): 23 Jan 2020
Downloaded from pubs.acs.org on January 27, 2020
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Stereocontrolled Debenzylative Cycloetherification Reaction as a Route to Enantiopure
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C-Furanosides with Amino Substituents in the Side Chain
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Karolina Tiara, Mykhaylo A. Potopnyk,* Paweł Świder, Sławomir Jarosz*
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Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224, Warsaw, Poland,
e-mail: slawomir.jarosz@icho.edu.pl
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Abstract
Highly efficient methodology of the preparation of synthetically important tetrahydrofuran
derivatives with an amino substituent in the side chain is reported. This process is based on the
stereocontrolled debenzylative cycloetherification (DBCE) reaction applied for chirons from
the D-gluco- and D-manno-series and provides derivatives with new stereogenic centers. The
influence of the electron-withdrawing group (EWG), present in the acyclic substrates with the
mesyl leaving group, on the reactivity in the DBCE reaction was investigated both "in the flask"
and by DFT calculations. It was demonstrated that tetrahydrofuran derivatives with benzoxime
group (EWG = CHNOBn) are very good candidates for the subsequent highly stereoselective
Grignard reaction.
.
OBn
DBCE
reaction
OBn
BnO
N
OMs OBn
*
O
*
BnO
EWG
stereo-
selective
Grignard
reaction
OBn OBn
EWG = CHNOBn
EWG = CN (no cyclization)
OBn
D-gluco
D-manno
INTRODUCTION
The evolution of pharmaceutical industry entails intensive scientific research in the area of
biologically active compounds. One of the most important types of such compounds are
carbohydrates, which play an exclusive role due to their natural genesis, chirality, water
solubility, etc.1 Most of carbohydrate derivatives have cyclic, usually pyranose or furanose
structures. Carbohydrates in the furanose form occur as building blocks in nucleic acids,
therefore, many nucleoside analogs have been prepared for pharmaceutical investigation. Some
of these compounds are used as commercial drugs, such as i.e. cytarabine, a medicament in
leukemia chemotherapy2 or vidarabine, an antiviral drug with the activity against herpes
simplex and varicella zoster viruses.3 The development and improvement of the efficient
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synthetic methods for the preparation of such type of compounds are actual challenge for
organic chemists.
Among different types of furanose carbohydrates, we focused our attention on
C-furanosides.4 They are present in biologically active, naturally occurring molecules among
others in polyether antibiotics. For example, pyrazofurin – isolated from the culture filtrate of
a strain of Streptomyces candidus – is effective against parasitic infections5 and (+)-Varitriol,
isolated from marine strain of the fungus Emericella Variecolor (M75-2), exhibit potent
cytotoxicity against a variety of cancer cell lines.6,7,8 Amino acid A has been incorporated as a
scaffold into anticancer peptides, inhibiting growth of cancer cells.4,9 A library of 10-α/β-D-
arabinofuranosyl-undecenes (B) are potential antimycobacterial agents, targeting enzymes
involved in the biosynthesis of the cell wall of Mycobacterium tuberculosis (Figure 1).4,10
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H
HO
N NH
H
O
Me
HO
O
CONH2
OMe
OH
OH
HO
HO
OH
(+)-Varitriol
Pyrazofurin
R2O
O
H
O
O
HO
NH2
9
R1O
OR1
HO
OH
A
B
Figure 1. Examples of biologically active C-furanosides.
Typical methods of the synthesis of C-furanosides, which are based on the nucleophilic
substitution reaction of the O-, N-, S-, or Hal-furanose derivatives by the corresponding
C-nucleophiles, often yield a mixture of both anomers. The efficient preparation of the minor
diastereomeric product can thus be problematic when this process is highly stereoselective.4
This problem can be overcome by a stereospecific cyclization of linear carbohydrates i.e. the
SN2 reaction between the nucleophilic free hydroxyl group and the reactive sp3-center located
at the 1,5-position to each other. Although this method is usually limited to compounds with
one unprotected hydroxyl group and one leaving group (LG),4 it can be applied also to fully
protected linear derivatives containing a leaving group. The protected, as a benzyl ether,
oxygen function can also act as a nucleophile and attack the sp3-carbon atom connected with
the effective leaving group in debenzylative cycloetherification (DBCE) process.11,12 13 14 15
This methodology was successfully used for the preparation of C-ethynyl13 and C-vinyl14
furanosides as shown in Scheme 1a. During the synthesis of higher carbon sugars we observed
similar rearrangement in which the protected oxygen nucleophile attacked the allylic analog in
,
,
,
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the SN2’ mode which afforded the corresponding tetrahydrofuran derivative (Scheme 1b).16
The process was also used for the selective deprotection of the 2-OH group in a fully benzylated
C-allyl glycoside as reported recently by Bleriot and co-workers (Scheme 1c).17
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a) synthesis of C-ethynyl and C-vinyl
furanosides by the SN2 reaction
b) the SN2' process in formation
of tetrahydrofurans
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SN2
PivO
OBn OBn
OBn OBn
O
Gluc
O
CMe2
O
OTf
OBn
OBn
OPiv OBn OTs
BnO
BnO
OBn
SN2'
BnO
CMe2
O
O
OTf OBn
BnO
O
H
O
H
BnO
MeO
O
OBn OBn
BnO
OBn
OBn
SN2
BnO
c) selective debenzylation of C-allyl
glycosides
OBn
5
X
1
5
1
X
I2
3
I
BnO
OBn
3
OBn
OBn
X = O, NBn
OBn
X
5
1
X
Zn
3
BnO
OH
O
I
OBn
Scheme 1. Application of DBCE reaction in the synthesis of C-furanosides via the SN2 (1a)
and SN2’ (1b) processes and in selective deprotection (1c).
It seemed reasonable that such process can be also adapted for the preparation of C-furanose
derivatives containing the nitrile or oxime functionality attached directly to the 5-membered
ring. The synthesis could be initiated from the corresponding linear carbohydrate derivatives
containing the terminal nitrile or oxime groups; this concept is shown in Figure 2.
LG OBn NOBn
OBn OBn
OBn
BnO
LG OBn
OBn
BnO
NOBn
N
N
O
O
BnO
BnO
OBn OBn
OBn
DBCE
OBn
DBCE
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Figure 2. Retrosynthetic analysis to prepare C-nitrile- and C-benzoxime-furanosides
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RESULTS AND DISCUSSION
Synthesis
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We have initiated our syntheses of functionalized tetrahydrofurans from known tetra-O-
benzylated derivatives of glucose and mannose (1 and 2 respectively).18 These hexoses were
converted, under the standard conditions, either to oximes 3, 5 (in 80–90% yield) or protected
oximes 4, 6 (Scheme 2). Products 3–6 could exist in four dynamic isomeric forms: anti-oxime
(A), syn-oxime (B), α-pyranoside (C), and β-pyranoside (D).
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OR
OBn
OR
N
O
OH
RONH2·HCl,
Py
O
NH
BnO
BnO
OH
BnO
BnO
OBn
OBn
BnO
OBn
OBn
OBn
1
OBn
3C 4C
,
(anomer )
(anomer )
3A 4A
,
(anti)
(syn)
3
4
R = H; R = Bn
3D 4D
,
3B 4B
,
OR
OBn
OR
N
RONH2·HCl,
OH
O
NH
O
OH
BnO
BnO
BnO
BnO
Py
OBn
OBn
BnO
OBn
2
OBn
OBn
OBn
5A 6A
5B 6B
5C 6C
5D 6D
,
,
(anomer )
(anomer )
,
,
(anti)
(syn)
5
6
R = H; R = Bn
Scheme 2. Synthesis of hydroxyoximes 3,5 and benzoxyoximes 4,6.
All synthesized compounds were fully characterized by the one- (1H, 13C) and two-
1
dimensional (1H–1H COSY, and H–13C HSQC) NMR, elemental analysis, as well as high-
resolution mass spectrometry (HRMS). Careful analysis of the NMR data of products 3–6
allowed us to detect the presence of isomers A, B, C, D. The cyclic forms (C, D) were observed
in the spectra of benzyloxy derivative 5 (corresponding signals from anomeric protons HC-1
and HD-1 were observed at  = 5.05 and 4.32 ppm, respectively); the ratio of all isomers was
assigned at 5A:5B:5C:5D ≈ 5:1.25:1:1. In the spectra of analogous 3, 4 and 6, only the syn-
1
and anti-isomers were observed in each case in the ratio ~ 1:4, respectively. In the H NMR
spectra of compounds 3–6 the signals from H-1 are located at 7.44–7.56 ppm for anti-isomers
A, and at 6.88–6.93 ppm for syn-isomers B.
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It is well documented, that the mesylation of ω-hydroxy carbohydrate hydroximes affords
ω-methylatocarbohydrate nitriles.19 Application of this reaction to compounds 3 and 4 allowed,
as expected, the preparation of nitryl-methanesulfonates 7 and 8 (in 70% and 78% yield,
respectively; Scheme 3). However, all attempts to convert these useful intermediates into
tetrahydrofuran derivatives (9 and 10) failed. In all cases – including refluxing of substrates in
different solvents (toluene, acetonitrile, 1,4-dioxane, pyridine) with or without a base
(triethylamine, sodium acetate, potassium carbonate, pyridine) even for 7 days – only the
starting material was isolated which indicated that nitriles 7 and 8 are very inert under the
debenzylative cycloetherification conditions leading to C-furanosides.
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OH
N
OH
N
OH
OH
BnO
BnO
BnO
BnO
OBn
OBn
OBn
OBn
3
4
MsCl, Et3N,
DMAP
MsCl, Et3N,
DMAP
N
OMs
N
OMs
BnO
BnO
BnO
BnO
OBn
base
OBn
OBn
7
OBn
8
X
X
base
OBn
BnO
BnO
N
O
N
O
BnO
OBn
BnO
9
10
Scheme 3. Synthesis of nitriles 7 and 8 and unsuccessful attempts of their cyclization.
However, much better results were obtained in the cyclization reaction of the protected
oximes under analogous conditions. Mesylation of benzoximes 5 and 6 afforded compounds
11 and 12 in good yields (76% and 70%, respectively). Heating of these mesylates in toluene
at reflux induced the desired cyclization and furnished furanosides 13 and 14 in very high yields
(90% and 99%, respectively; Scheme 4).
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OBn
OBn
N
OBn
OBn
N
OH
OH
7
8
BnO
OBn
BnO
OBn
9
OBn
OBn
10
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12
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5
6
MsCl, Et3N,
DMAP
MsCl, Et3N,
DMAP
OBn
OBn
OBn
OBn
OMs
OMs
N
N
BnO
OBn
BnO
OBn
OBn
OBn
11
12
110 °C
110 °C
OBn
OBn
BnO
N
H
BnO
N
H
O
O
BnO
13
OBn
BnO
14
OBn
(syn/anti)
(syn/anti)
Scheme 4. Formation of tetrahydrofurans 13 and 14.
Because of the dynamic isomerization of the benzoxime group, compounds 13 and 14 were
obtained as syn/anti pairs as can be judged from the NMR data (i.e. signals of the H-1 atom are
located at  = 6.97 and 7.56 ppm for syn-13 and anti-13 isomers, respectively; while in the case
of syn/anti-14, the corresponding signals are located at  = 6.82 and 7.47 ppm).
Since the benzoxime group is a good acceptor of nucleophilic species its presence should
allow the efficient preparation of a number of interesting amino derivatives. Therefore, we
decided to test benzoximes 13 and 14 in the Grignard reaction. Indeed, reaction of both isomers
with allylmagnesium bromide afforded the corresponding amines 15 and 16 in good yields (70
and 68%, respectively). It is worth to mention that both reactions were highly stereoselective
and only one stereoisomer was isolated in each case (Scheme 5).
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OBn
OBn
BnO
HN
AllMgBr,
-78 °C
H
O
13
1
BnO
OBn
15
10
11
12
13
14
15
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BnO
HN
AllMgBr,
-78 °C
H
O
14
1
BnO
OBn
16
Scheme 5. Grignard reaction of benzoximes 13 and 14 with allylmagnesium bromide.
The configuration at the C-1 center in products 15 and 16 can be assigned with high
probability by the conformation analysis which is shown in Scheme 6. According to the Cram
chelating model, the simultaneous coordination of magnesium to the benzoxime nitrogen and
the α-endocyclic oxygen atoms of compounds 13 and 14 forms cyclic α-chelates 13A and 14A,
respectively. In case of intermediate 13A, the attack of the allylic nucleophile should be favored
from the Re-side, giving product 15 with the R-configuration at the C-1 stereocenter.
Meanwhile, α-chelate 14A could be evidently attacked by the C-nucleophile from the Si-side,
leading isomer 16 with the 1S-configuration. Such predicted stereochemical outcome is in good
agreement with that previously described for the addition reactions of nucleophiles with C-
furanosyl carbaldehydes or their imines.20
All
Br
Mg
O
OBn
BnO
C
OBn
NHOBn
H
BnO
N
Re-face
attack
Mg
BnO
HN
OBn
H
H
BnO
N
Nu
O
H
N
H
O
O
R
O
1
H
H
Nu
C
H
H
BnO
OBn
BnO
OBn
BnO
OBn
Nu = All
13
15
13A
All
Mg
Mg
Br
OBn
OBn
OBn
C
NHOBn
O
BnO
N
Si-face
attack
BnO
HN
H
OBn
H
BnO
N
H
Nu
O
N
O
S
O
H
O
1
H
H
Nu
H
C
H
BnO
OBn
BnO
OBn
H
BnO
OBn
14
16
14A
Scheme 6. Proposed mechanism of Grignard reaction of benzoximes 13 and 14 with
allylmagnesium bromide.
DFT calculation
To gain better understanding of the different reactivity of the investigated mesylates vs
nitriles, the density functional theory (DFT) computational studies were performed for
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transformations 7→9 and 11→13. Geometrical structures of substrates 7 and 11, products 9
and 13, intermediates im-7,9 and im-11,13, as well as transition states TS-7, TS-11, imTS-7,9,
and imTS-11,13 (Figures 3 and 4) were optimized and the relative Gibbs free energy (ΔG)
values were calculated with the addition of toluene solvent effect utilizing the Solvation Model
based on Density (SMD).
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Comparison of the ΔG values of each component in both DBCE transformations clearly
demonstrates that in case of nitrile 7 (Figure 3), the transition energy barriers are higher than
for benzoxime analog 11 (Figure 4). The relative Gibbs free energies for TS-7 and TS-11 were
estimated as 35.7 kcal/mol and 30.7 kcal/mol, respectively, while the corresponding energies
of transition states imTS-7,9 and imTS-11,13 were 37.3 kcal/mol and 35.3 kcal/mol. In
addition, the intermediate product of the reaction 7→9 (im-7,9, ΔG = 26.36 kcal/mol) is less
stable by approximately 5.5 kcal/mol, than analogous im-11,13 (ΔG = 20.84 kcal/mol).
Moreover, the relative Gibbs free energy of C-furanoside 11 (ΔG = -5.13 kcal/mol) is lower
than the corresponding value of product 9 (ΔG = -2.82 kcal/mol). It can be unequivocally
postulated that reaction 11→13 is thermochemically and kinetically more favorable than
reaction 7→9, which is in accordance with the results of the experiments "in the flask" but does
not fully explain why we do not obtain the expected products in the reaction 7→9.
Bn
O
Bn
BnO
N
BnO
MsO
OMs
BnO
MsO
H
H
H
N
O
BnO
BnO
N
N
O
- BnOMs
OBn
imTS-7,9
BnO
OBn
OBn
BnO
OBn
BnO
OBn
9
7
im-7,9
TS-7
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Figure 3. Gibbs free energy diagram of transformation of linear compounds 7 into C-
furanoside 9.
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OBn
N
OBn
Bn
O
OBn
Bn
O
OBn
BnO
N
BnO
N
OMs
BnO
MsO
N
O
BnO
BnO
- BnOMs
H
H
H
MsO
BnO
im-11,13
imTS-11,13
OBn
BnO
OBn
OBn
BnO
OBn
TS-11
OBn
13
11
9
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Figure 4. Gibbs free energy diagram of transformation of linear compounds 11 into C-
furanoside 13.
On the other hand, one of the key aspects that affect the course of these reactions is the
electron density on the oxygen atom involved in the intramolecular SN2 reaction. Presence of
the highly electron-withdrawing nitrile group in close proximity of the "nucleophilic" oxygen
atom in compound 7 induces the decrease of the electron density at this oxygen atom. We
decided to illustrate the impact of the substituents by calculation of partial charges (Figures
S1–S10 in the Supporting Information). Natural bond orbital (NBO) analysis was used to
calculate the charges, as it gives much more reliable results than the default Mulliken method
implemented in Gaussian package. The partial charge on the oxygen atom involved in the
cyclization reaction at each stage (except for intermediate stage) of the transformation of
compounds 11 into furanoside 13 is more negative than in the transformation of substrate 7
into product 9 (Table 1). Indirectly, the electron density at the oxygen atom affects its
nucleophilicity. Therefore, the calculated values of partial charges demonstrate, that in the case
of transformation 11→13 nucleophilic strength of the reactive oxygen atom is definitely
stronger than that in reaction 7→9. These theoretical results indicate the differences in
reactivity of mesylates 7 and 11, and are in good correlation with the experimental data.
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Table 1. NBO Atomic Charges on the Oxygen Atom Involved in the Intramolecular SN2
5
6
Reaction.
7
8
9
reaction 7→9
Bn-O-CH-CN
-0.582
reaction 11→13
Bn-O-CH-CH=N-O
-0.629
structure
7
structure
11
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TS-7
-0.566
TS-11
-0.581
im-7,9
imTS-7,9
-0.458
im-11,13
imTS-11,13
-0.456
-0.524
-0.546
-0.587
-0.608
9
(oxygen from
tetrahydrofuran ring)
13
(oxygen from
tetrahydrofuran ring)
CONCLUSIONS
In conclusion, we have investigated the debenzylative cycloetherification reaction of 1,3,4,5-
tetrakis(benzyloxy)-5-cyanopentan-2-yl methanesulfonates 7, and 2,3,4,6-tetrakis
8
(benzyloxy)-5-hydroxyhexanal O-benzyl oximes 11, 12. The compounds with benzoxime
group (11 and 12) are apparently more reactive in the DBCE reaction than the cyano-analogs
(7 and 8). These differences in the reactivity are caused by the stronger electron-withdrawing
effect of the nitrile group on the nucleophilicity of the reactive oxygen atom at the α-position,
comparatively with the corresponding influence of the benzoxime group. The experimental
results were confirmed by DFT calculation. The obtained C-furanosides with benzoxime group
in the side chain (tetrahydrofurans 13 and 14) are good candidates for stereoselective
modification in Grignard reaction with allylmagnesium bromide.
EXPERIMENTAL SECTION
General
The NMR spectra were recorded with Varian VNMRS 500 MHz or Varian VNMRS 600 MHz
spectrometers for solutions in CDCl3 at 25°C. The structures were assigned, whenever necessary,
with help of the 2D correlation experiments (COSY, HSQC, HMBC). Chemical shifts were
reported with reference to TMS. Optical rotations were measured with a Jasco P 1020 polarimeter
(sodium light) in chloroform at room temp. Mass spectra were recorded with Synapt G2-S HDMS
(Waters Inc) mass spectrometer equipped with an electrospray ion source and q-TOF type mass
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analyzer. The instrument was controlled and recorded data were processed using MassLynx V4.1
software package (Waters Inc). Thin layer chromatography (TLC) was performed on silica gel
plates coated with fluorescent indicator. Column chromatography was performed on silica gel
(Merck, 230-400 mesh). Organic solutions were dried over anhydrous MgSO4.
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Synthesis
Synthesis of compounds 3–6 (General Procedure A).
To a solution of alcohol 1 or 2 (200–230 mg, 0.37–0.43 mmol) in pyridine (8 mL), hydroxy-
ammonium chloride or O-benzylhydroxylamine hydrochloride (2.5 equiv, 0.92–1.07 mmol)
was added. The mixture was stirred for 3 h at room temperature, (for HONH2∙HCl) or for 8
hours at 55ºC (for BnONH2∙HCl). Then pyridine was evaporated in vacuum, ethyl acetate (40
mL) was added, and the residue was washed with 1 M H2SO4 (15 mL), water (25 mL), brine
(15 mL). The organic phase was dried and concentrated. The products 3–6 were purified by
flash chromatography (hexanes/ethyl acetate = 85:15, v/v).
(2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexanal oxime (3A + 3B).
8
7
OH
7
OH
6
OH
5
8
OH
6
N
5
1
N
BnO
BnO
1
BnO
BnO
2
4
2
3
4
3
OBn
OBn
OBn
3B
OBn
3A
1.00 : 0.25
This compound was obtained in 87% yield (193 mg) from 1 (215 mg, 0.40 mmol) and
hydroxylammonium chloride (69 mg, 1.00 mmol) as an isomeric mixture in 1.00:0.25 ratio;
colorless oil. TLC (hexanes/AcOEt = 2:1): Rf = 0.60. [α]D22 = +21.7. 1H NMR (600 MHz): δ
8.36 (0.25H, br s, HB-8), 7.97 (1H, br s, HA-8), 7.44 (1H, d, J1,2 = 8.0 Hz, HA-1), 7.15–7.34
(25H, m, ArH), 6.92 (0.25H, d, J1,2 = 7.3 Hz, HB-1), 5.12 (0.25H, dd, J2,1 = 7.3 Hz, J2,3 = 5.0
Hz, HB-2), 4.64–4.73 (2.50H, m, 2 ×OCHA Ph, 2 × OCHB Ph), 4.58 (1H, J = 11.7 Hz,
2
2
OCHA Ph), 4.55 (0.50H, J = 11.5 Hz, 2 × OCHB Ph), 4.41–4.51 (4.75H, m, 4 × OCHA Ph, 3 ×
2
2
2
OCHB Ph), 4.35 (0.25H, J = 11.7 Hz, OCHB Ph), 4.27 (1H, d, J = 11.7 Hz, OCHA Ph), 4.27
2
2
2
(1H, dd, J2,1 = 8.0 Hz, J2,3 = 6.3 Hz, HA-2), 3.99–4.07 (2.50H, m, HA-3, HA-5, HB-3, HB-5),
3.78 (1H, dd, J4,5 = 7.8 Hz, J4,3 = 3.3 Hz, HA-4), 3.75 (0.25H, dd, J4,5 = 7.4 Hz, J4,3 = 5.1 Hz,
HB-4), 3.62 (1H, dd, J6,6,’ = 9.6 Hz, J6,5 = 3.4 Hz, HA-6), 3.62 (0.25H, m, HB-6), 3.57 (1H, dd,
J6’,6 = 9.6 Hz, J6’,5 = 5.2 Hz, HA-6’), 3.57 (0.25H, m, HB-6’), 2.86 (0.25H, d, J7,5 = 5.7 Hz,
HB-7), 2.75 (1H, d, J7,5 = 5.9 Hz, HA-7) ppm. 13C NMR (150 MHz): δ 150.61 (CB-1), 150.06
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(CA-1), 138.12, 137.93, 137.81, 137.59 (Cquat, 4 × CA-Ph), 137.59–138.18 (Cquat, 4 × CB-Ph),
127.55–128.41 (20 × CA-Ph, 20 × CB-Ph), 79.51 (CA-3), 79.43 (CB-3), 78.71 (CB-4), 78.51 (CA-
4), 76.59 (CA-2), 74.33, 74.00, 73.33, 70.60 (4 × OCAH2Ph), 74.16, 74.06, 73.33, 71.69 (4 ×
OCBH2Ph), 71.00 (CA-6), 71.00 (CB-6), 70.60 (CB-2), 70.41 (CB-5), 69.96 (CA-5) ppm. HRMS
(ESI-TOF) calcd for C34H37NO6Na [M+Na]+: C34H37NO6Na [M + Na]+: 578.2518, found:
578.2514. Analysis calcd for C34H37NO6 (540.67): C, 73.49; H, 6.71; N, 2.52; found: C,73.42;
H, 6.61; N, 2.35.
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(2R,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexanal oxime (4A + 4B).
8
7
OH
7
OH
6
OH
5
8
OH
6
N
5
1
N
BnO
BnO
1
BnO
BnO
2
4
2
3
4
3
OBn
OBn
OBn
4B
OBn
4A
1.00 : 0.30
This compound was obtained in 88% yield (209 mg) from 2 (230 mg, 0.43 mmol) and
hydroxylammonium chloride (74 mg, 1.07 mmol) as an isomeric mixture in 1.00:0.30 ratio;
colorless oil. TLC (hexanes/AcOEt = 2:1): Rf = 0.50. 1H NMR (600 MHz,): δ 7.85 (0.30H, br
s, HB-8), 7.52 (1H, br s, HA-8), 7.44 (1H, d, J = 8.0 Hz, HA-1), 7.36–7.15 (26H, m, ArH), 6.93
(0.30H, d, J = 7.2 Hz, HB-1), 5.12 (0.30H, dd, J2,1 = 7.2 Hz, J2,3 = 5.2 Hz, HB-2), 4.98 (0.3H,
d, J = 11.4 Hz, OCHB Ph), 4.87 (0.3H, d, J = 10.7 Hz, OCHB Ph), 4.72 (0.3H, d, J = 11.3 Hz,
2
2
OCHB Ph), 4.70 (1H, d, J = 11.3 Hz, OCHA Ph), 4.67 (1H, d, J = 11.3 Hz, OCHA Ph), 4.66
2
2
2
(0.3H, d, J = 11.3 Hz, OCHB Ph), 4.59 (1H, J = 11.7 Hz, OCHA Ph), 4.56 (0.3H, J = 11.7 Hz,
2
2
2 × OCHB Ph), 4.55 (0.3H, J = 11.2 Hz, 2 × OCHB Ph), 4.45–4.52 (3.3H, m, 3 ×OCHA Ph,
2
2
2
OCHB Ph), 4.43 (1H, J = 11.4 Hz, OCHA Ph), 4.36 (0.3H, J = 11.7 Hz, OCHB Ph), 4.29 (1H,
2
2
2
d, J = 11.5 Hz, OCHA Ph), 4.27 (1H, dd, J2,1 = 8.0 Hz, J2,3 = 6.2 Hz, HA-2), 4.02–4.06 (0.6H,
2
m, HB-3, HB-5), 4.04 (1H, dd, J3,2 = 6.2 Hz, J3,4 = 3.2 Hz, HA-3), 4.01 (1H, m, HA-5), 3.78 (1H,
dd, J4,5 = 7.8 Hz, J4,3 = 3.2 Hz, HA-4), 3.75 (0.3H, dd, J4,5 = 7.4 Hz, J4,3 = 4.0 Hz, HB-4), 3.63
(1H, dd, J4,5 = 7.8 Hz, J4,3 = 3.2 Hz, HA-6), 3.62 (0.3H, m, HB-6), 3.58 (1H, dd, J4,5 = 7.8 Hz,
J4,3 = 3.2 Hz, HA-6), 3.58 (0.3H, m, HB-6), 2.78 (0.3H, d, J7,5 = 5.8 Hz, HB-7), 2.66 (1H, d, J7,5
= 5.9 Hz, HA-7) ppm. 13C NMR (150 MHz, CDCl3, only major isomer quoted): δ 150.26 (C-
1), 138.14, 137.96, 137.86, 137.61 (Cquat, 4 × C-Ph), 127.58–128.44 (20 × C-Ph), 79.48 (C-3),
78.52 (C-4), 76.59 (C-2), 74.33, 74.01, 73.36 (3 × OCH2Ph), 71.00 (C-6), 70.63 (OCH2Ph),
69.97 (C-5) ppm. HRMS (ESI-TOF) calcd for C34H37NO6Na [M + Na]+: 578.2519, found:
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578.2514. Analysis calcd for C34H37NO6 (555.67): C, 73.49; H, 6.71; N, 2.52; found: C, 73.26;
H, 6.73; N, 2.40.
7
8
(2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexanal O-benzyl oxime (5A + 5B +
9
5C + 5D).
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7
OBn
N
OBn
NH7
OBn
NH7
7
OH
6
OH
6
5
6
6
N
5
1
O
5
O
BnO
BnO
OBn
5
1
BnO
BnO
BnO
BnO
BnO
1
2
1
2
2
4
2
3
4
4
4
3
3
3
OBn
OBn
BnO
OBn
OBn
OBn
5B
5A 5B 5C 5D
= 1.00 : 0.25 : 0.20 : 0.20
OBn
5A
OBn
5C
OBn
5D
:
:
:
This compound was obtained in 80% yield (199 mg) from 1 (208 mg, 0.38 mmol) and O-
benzylhydroxylamine hydrochloride (154 mg, 0.96 mmol) as an isomeric mixture in
1.00:0.25:0.20:0.20 ratio; yellowish oil. TLC (hexanes/AcOEt = 2:1): Rf = 0.70. 1H NMR (600
MHz): δ 7.56 (1H, d, J1,2 = 7.8 Hz, HA-1), 7.06–7.43 (41.25H, m, ArH), 6.92 (0.25H, d, J1,2
=
6.4 Hz, HB-1), 6.15 (0.20H, s, HC-7), 5.83 (0.20H, d, J7,1 = 6.5 Hz, HD-7), 5.09 (2H, s,
OCHA Ph), 5.05 (0.20H, d, J1,2 = 4.9 Hz, HC-1), 5.03 (0.40H, s, OCHC/D2Ph), 5.00 (0.20H, dd,
2
J2,1 = 6.4 Hz, J2,3 = 4.1 Hz, HB-2), 4.90 (0.20H, d, J = 11.0 Hz, OCHC/D2Ph), 4.38–4.86 (13.90H,
m, OCHA Ph, OCHB Ph, OCHC Ph, OCHD Ph), 4.36 (1H, dd, J2,1 = 7.8 Hz, J2,3 = 6.7 Hz, HA-
2
2
2
2
2), 4.32 (0.2H, dd, J1,2 = 9.0 Hz, J1,7 = 6.5 Hz, HD-1), 4.14 (0.20H, m, HD-5), 3.89–3.95 (1.70H,
m, HA-5, HB-5, HB-3, HC-5), 3.89 (1H, dd, J = 6.6 Hz, J = 3.4 Hz, HA-3), 3.77–3.84 (0.70H, m,
HC-4, HB-4, HB-6), 3.75 (0.25H, dd, J6’,6 = 10.8 Hz, J6’,5 = 3.8 Hz, HB-6’), 3.65–3.73 (1.00H,
m, HC-2, HD-3, HC-6, HC-6’, HD-6), 3.69 (1H, dd, J = 7.2 Hz, J = 3.5 Hz, HA-4), 3.62 (0.20H,
dd, J3,4 = 9.9 Hz, J3,2 = 8.5 Hz, HD-4), 3.47–3.59 (2.40H, m, HC-3, HA-6, HA-6’, HD-6’), 3.37
(0.20H, dd, J2,1 = 9.0 Hz, J2,3 = 8.5 Hz, HD-2), 2.79 (0.25H, d, J7,5 = 4.6 Hz, HB-7), 2.63 (1H,
d, J7,5 = 5.6 Hz, HA-7) ppm. 13C NMR (150 MHz;, only major isomer quoted): δ 148.90 (C-1),
136.12, 137.97, 137.92, 137.66, 137.62 (Cquat, 5 × C-Ph), 127.54–128.50 (25 × C-Ph), 79.46
(C-3), 77.70 (C-4), 76.84 (C-2), 75.93, 74.42, 73.45, 73.32, 71.26 (5 × OCH2Ph), 70.96 (C-6),
70.26 (C-5) ppm. HRMS (ESI-TOF) calcd for C41H43NO6Na [M + Na]+: 668.2988, found:
668.2990. Analysis calcd for C41H43NO6 (645.80): C, 76.25; H, 6.71; N, 2.17; found: C, 76.04;
H, 6.72; N, 2.15.
(2R,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexanal O-benzyl oxime (6A + 6B).
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8
9
7
OBn
N
7
OH
6
OH
5
6
N
5
1
BnO
BnO
OBn
1
BnO
BnO
2
4
2
3
4
3
OBn
OBn
OBn
6B
OBn
6A
1.00 : 0.25
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This compound was obtained in 90% yield (215 mg) from 2 (200 mg, 0.37 mmol) and O-
benzylhydroxylamine hydrochloride (147 mg, 0.92 mmol) as an isomeric mixture in 1.00:0.25
ratio; yellowish oil. TLC (hexanes/AcOEt = 2:1): Rf = 0.70. 1H NMR (600 MHz): δ 7.46 (1H,
d, J1,2 = 8.1 Hz, HA-1), 7.03–7.43 (31.25H, m, ArH), 6.88 (0.25H, d, J1,2 = 7.3 Hz, HB-1), 5.11
(1H, d, J = 12.0 Hz, OCHA Ph), 5.07 (1H, d, J = 12.0 Hz, OCHA Ph), 5.06–5.10 (0.75H, m,
2
2
HB-2, 2 × OCHB Ph), 4.68 (1H, d, J = 11.2 Hz, OCHA Ph), 4.67 (0.25, d, J = 11.4 Hz,
2
2
OCHB Ph), 4.65 (1H, d, J = 11.2 Hz, OCHA Ph), 4.61 (0.25, d, J = 11.4 Hz, OCHB Ph), 4.53
2
2
2
(1H, d, J = 11.7 Hz, OCHA Ph), 4.44–4.50 (4.00H, m, 3 × OCHA Ph, 4 × OCHB Ph), 4.40 (1H,
2
2
2
d, J = 11.4 Hz, OCHA Ph), 4.36 (0.25, d, J = 11.4 Hz, OCHB Ph), 4.30 (0.25, d, J = 11.7 Hz,
2
2
OCHB Ph), 4.26 (1H, d, J = 11.7 Hz, OCHA Ph), 4.25 (1H, dd, J2,1 = 8.1 Hz, J2,3 = 6.3 Hz, HA-
2
2
2), 4.03 (1H, dd, J3.2 = 6.3 Hz, J3,4 = 3.1 Hz, HA-3), 4.03 (0.25, m, HB-5), 3.97–4.01 (1.25H, m,
HA-5, HB-3), 3.75 (1H, dd, J4,5 = 7.8 Hz, J4,3 = 3.1 Hz, HA-4), 3.71 (0.25, dd, J4,5 = 7.6 Hz, J4,3
= 4.0 Hz, HB-4), 3.60 (1H, dd, J6,6’ = 9.6 Hz, J6,5 = 3.5 Hz, HA-6), 3.56 (1H, dd, J6’,6 = 9.6 Hz,
J6’,5 = 5.0 Hz, HA-6’), 3.53–3.59 (0.50H, m, HB-6, HB-6’), 2.70 (0.25H, d, J7,5 = 5.7 Hz, HB-7),
13
2.56 (1H, d, J7,5 = 6.1 Hz, HA-7) ppm. C NMR (150 MHz; only major isomer quoted): δ
148.99 (C-1), 138.18, 138.03, 137.90, 137.65, 137.49 (Cquat, 5 × C-Ph), 127.51–128.41 (25 ×
C-Ph), 79.50 (C-3), 78.51 (C-4), 76.54 (C-2), 76.01, 74.22, 73.92, 73.32 (4 × OCH2Ph), 70.96
(C-6), 70.41 (OCH2Ph), 69.93 (C-5) ppm. HRMS (ESI-TOF) calcd for C41H43NO6Na [M +
Na]+: 668.2988, found: 668.2985. Analysis calcd for C41H43NO6 (645.80): C, 76.25; H, 6.71;
N, 2.17; found: C, 76.12; H, 6.69; N, 2.17.
Synthesis of mesylates 7, 8, 11, 12 (General procedure B).
To a solution of compound 3–6 (140–180 mg, 0.25–0.28 mmol) in CH2Cl2 (5 mL), DMAP
(cat. amount ~1.5 mg) and Et3N (144–157 µL, 1.03–1.20 mmol) were added and the mixture
was stirred for 20 min at room temperature. Then the mixture was cooled to -78 ºC and a
solution of methanesulfonyl chloride (80–87 µL, 1.03–1.20 mmol) in CH2Cl2 (1 mL) was
added dropwise. The mixture was stirred for 3 hours at -78 ºC and allowed to reach room
temperature. Water (8 mL) was added and the product was extracted with CH2Cl2 (3 × 10 mL).
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The combined organic solutions were washed with brine (10 mL), dried, concentrated, and the
crude product was isoated by flash chromatography (hexanes/ethyl acetate = 85:15, v/v).
(2R,3S,4R,5S)-1,3,4,5-tetrakis(benzyloxy)-5-cyanopentan-2-yl methanesulfonate (7).
7
8
9
6
N
OMs
5
BnO
1
10
11
12
13
14
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2
4
3
BnO
OBn
OBn
This compound was obtained in 70% yield (121 mg) from oxime 3 (156 mg, 0.28 mmol) as a
22
1
white solid. TLC (hexanes/AcOEt = 3:1): Rf = 0.50. [α]D = +35.5. H NMR (600 MHz): δ
7.24–7.37 (20H, ArH), 4.94 (1H, ddd, J5,6 = 6.8 Hz, J5,4 = 4.3 Hz, J5.6’ = 3.1 Hz, H-5), 4.83
(1H, d, J = 11.4 Hz, OCH2Ph), 4.71 (1H, d, J = 11.2 Hz, OCH2Ph), 4.69 (1H, d, J = 11.2 Hz,
OCH2Ph), 4.67 (1H, d, J = 11.0 Hz, OCH2Ph), 4.66 (1H, d, J = 11.0 Hz, OCH2Ph), 4.50 (1H,
d, J = 11.4 Hz, OCH2Ph), 4.44 (1H, d, J = 11.4 Hz, OCH2Ph), 4.43 (1H, d, J = 11.4 Hz,
OCH2Ph), 4.34 (1H, d, J2,3 = 6.3 Hz, H-2), 4.16 (1H, dd, J4,5 = 4.3 Hz, J4,3 = 3.6 Hz, H-4), 3.95
(1H, dd, J3,2 = 6.3 Hz, J3,4 = 3.6 Hz, H-3), 3.89 (1H, dd, J6’,6 = 11.2 Hz, J6’,5 = 3.1 Hz, H-6’),
3.68 (1H, dd, J6,6’ = 11.2 Hz, J6,5 = 6.8 Hz, H-6), 2.91 (s, 3H, CH3) ppm. 13C NMR (150 MHz):
δ 137.27, 137.01, 136.99, 135.27 (Cquat, 4 × Ph), 127.85–128.72 (20 × C-Ph), 116.38 (C-1),
81.18 (C-5), 78.16 (C-4), 78.06 (C-3), 75.11, 74.98, 73.36, 72.94 (4 × OCH2Ph), 68.63 (C-6),
68.59 (C-2), 38.67 (CH3) ppm. HRMS (ESI-TOF) calcd for C35H37NO7SNa [M + Na]+:
638.2188, found: 638.2179. Analysis calcd for C35H37NO7S (615.74): C, 68.27; H, 6.06; N,
2.27; found: C, 68.37; H, 6.18; N, 2.17.
(2R,3S,4R,5R)-1,3,4,5-tetrakis(benzyloxy)-5-cyanopentan-2-yl methanesulfonate (8).
6
N
5 OMs
BnO
1
2
4
3
BnO
OBn
OBn
This compound was obtained in 78% yield (125 mg) from oxime 4 (144 mg, 0.26 mmol) as a
22
1
white solid. TLC (hexanes/AcOEt = 2:1): Rf = 0.70. [α]D = +30.8. H NMR (600 MHz): δ
7.16–7.39 (20H, ArH), 4.96 (1H, ddd, J5,6 = 7.0 Hz, J5,4 = 3.6 Hz, J5.6’ = 3.2 Hz, H-5), 4.93
(1H, d, J = 10.4 Hz, OCH2Ph), 4.78 (1H, d, J = 11.0 Hz, OCH2Ph), 4.68 (1H, d, J = 10.4 Hz,
OCH2Ph), 4.65 (1H, d, J = 11.4 Hz, OCH2Ph), 4.47 (1H, d, J = 11.7 Hz, OCH2Ph), 4.45 (1H,
d, J = 11.7 Hz, OCH2Ph), 4.38 (1H, d, J = 11.4 Hz, OCH2Ph), 4.34 (1H, d, J = 11.0 Hz,
OCH2Ph), 4.33 (1H, d, J2,3 = 6.8 Hz, H-2), 3.98 (1H, dd, J3,2 = 6.8 Hz, J3,4 = 3.4 Hz, H-3), 3.94
(1H, dd, J4,5 = 3.6 Hz, J4,3 = 3.4 Hz, H-4), 3.89 (1H, dd, J6’,6 = 11.3 Hz, J6’,5 = 3.2 Hz, H-6’),
3.76 (1H, dd, J6,6’ = 11.3 Hz, J6,5 = 7.0 Hz, H-6), 2.91 (s, 3H, CH3) ppm. 13C NMR (150 MHz,
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CDCl3): δ 137.27, 136.88, 136.67, 135.26 (Cquat, 4 × Ph), 128.84 (2C-Ph), 128.66 (2C-Ph),
128.59 (C-Ph), 128.50 (2C-Ph), 128.47 (2C-Ph), 127.46 (2C-Ph), 128.43 (2C-Ph), 128.20
(C-Ph), 128.13 (2C-Ph), 128.08 (C-Ph), 127.98 (C-Ph), 127.81 (2C-Ph), 117.26 (C-1), 81.65
(C-5), 78.49 (C-3), 77.83 (C-4), 75.20, 74.07, 73.41, 72.45 (4 × OCH2Ph), 68.78 (C-6), 68.78
(C-2), 38.64 (CH3) ppm. HRMS (ESI-TOF) calcd for C35H37NO7SNa [M + Na]+: 638.2188,
found: 638.2187. Analysis calcd for C35H37NO7S (615.74): C, 68.27; H, 6.06; N, 2.27; found:
C, 68.22; H, 6.06; N, 2.17.
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(2R,3S,4R,5S)-1,3,4,5-tetrakis(benzyloxy)-6-((benzyloxy)imino)hexan-2-yl
methanesulfonate (11A + 11B).
OBn
6
OMs
6
5
N
OMs
5
1
2
N
BnO
BnO
OBn
1
BnO
BnO
4
2
3
3
4
OBn
OBn
OBn
11B
OBn
11A
1.00 : 0.30
This compound was obtained in 76% yield (144 mg) from benzoxime 5 (169 mg, 0.26 mmol)
as an isomeric mixture in 1.00:0.30 ratio; colorless oil. TLC (hexanes/AcOEt = 2:1): Rf = 0.50.
1H NMR (600 MHz): δ 7.50 (1H, d, J1,2 = 7.8 Hz, HA-1), 7.20–7.36 (32.5H, m, ArH), 6.94
(0.3H, d, J1,2 = 6.4 Hz, HB-1), 5.09 (2H, s, OCHA Ph), 5.02 (0.3H, d, J = 11.6 Hz, OCHB Ph),
2
2
5.00 (0.3H, d, J = 11.6 Hz, OCHB Ph), 4.96 (1H, ddd, J5,6 = 7.5 Hz, J5,4 = 3.5 Hz, J5,6’ = 3.0
2
Hz, HA-5), 4.92 (0.3H, ddd, J5,6 = 7.6 Hz, J5.6’ = 3.7 Hz, J5,4 = 3.0 Hz, HB-5), 4.87 (0.3H, dd,
J2,1 = 6.4 Hz, J2,3 = 4.1 Hz, HB-2), 4.68 (1.6H, m, OCHA Ph, OCHB Ph), 4.56–4.60 (3.6H, m,
2
2
3 × OCHA Ph, OCHB Ph), 4.52 (1H, d, J = 11.1 Hz, OCHA Ph), 4.51 (0.3H, d, J = 11.0 Hz,
2
2
2
OCHB Ph), 4.37–4.44 (3.3H, m, 3 × OCHA Ph, OCHB Ph), 4.29 (1H, dd, J2,1 = 7.8 Hz, J2,3
=
2
2
2
6.2 Hz, HA-2), 4.29 (0.6H, m, OCHB Ph), 4.13 (0.3H, dd, J4,3 = 6.4 Hz, J4,5 = 3.0 Hz, HB-4),
2
4.02 (1H, dd, J4,3 = 4.6 Hz, J4.5 = 3.5 Hz, HA-4), 3.86 (1H, dd, J6’,6 = 11.2 Hz, J6’,5 = 3.0 Hz,
HA-6’), 3.83 (0.3H, dd, J3,4 = 6.4 Hz, J3,2 = 4.1 Hz, HB-3), 3.80 (1H, dd, J3,2 = 6.2 Hz, J3,4 = 4.6
Hz, HA-3), 3.70 (1H, dd, J6,6’ = 11.2 Hz, J6,5 = 7.5 Hz, HA-6), 3.68–3.72 (0.6H, m, HB-6, HB-
6’), 2.87 (3H, s, CHA ), 2.84 (0.9H, s, CHB ) ppm. C NMR (150 MHz): δ 150.84 (CB-1),
13
3
3
148.36 (CA-1), 136.96–137.93 (Cquat, 5 × CA-Ph, 5 × CB-Ph), 127.57–128.53 (25 × CA-Ph, 25
× CB-Ph), 82.64 (CA-5), 82.25 (CB-5), 79.75 (CB-4), 79.50 (CA-3), 79.44 (CA-4), 78.79 (CB-3),
76.52 (OCBH2Ph), 76.39 (CA-2), 75.96 (OCAH2Ph), 74.97, 74.68 (2 × OCBH2Ph), 74.59, 74.31,
73.26 (3 × OCAH2Ph), 73.14, 72.29 (2 × OCBH2Ph), 71.36 (OCAH2Ph), 71.16 (CB-2), 68.96
(CA-6), 68.59 (CB-6), 38.35 (CAH3), 38.35 (CBH3) ppm. HRMS (ESI-TOF) calcd for
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C42H45NO8SNa [M + Na]+: 746.2764, found: 746.2758. Analysis calcd for C42H45NO8S
(723.88): C, 69.69; H, 6.27; N, 1.93; found: C, 69.60; H, 6.19; N, 1.71.
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(2R,3S,4R,5R)-1,3,4,5-tetrakis(benzyloxy)-6-((benzyloxy)imino)hexan-2-yl
9
methanesulfonate (12A + 12B).
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OBn
6
OMs
6
5
N
OMs
5
1
2
N
BnO
BnO
OBn
1
BnO
BnO
4
2
3
3
4
OBn
OBn
OBn
12B
OBn
12A
1.00 : 0.30
This compound was obtained in 70% yield (141 mg) from benzoxime 6 (179 mg, 0.28 mmol)
as an isomeric mixture in 1.00:0.30 ratio; Colorless oil. TLC (hexanes/AcOEt = 2:1): Rf = 0.50.
(600 MHz): δ 7.47 (1H, d, J1,2 = 8.1 Hz, HA-1), 7.13–7.36 (32.5H, m, ArH), 6.87 (0.3H, d, J1,2
= 7.2 Hz, HB-1), 5.07–5.13 (2.6H, m, 2 × OCHA Ph, 2 × OCHB Ph), 4.99–5.05 (1.6H, m, HA-
2
2
5, HB-5, HB-2), 4.59–4.69 (3.9H, m, 3 × OCHA Ph, 3 × OCHB Ph), 4.48–4.55 (2.3H, m, 2 ×
2
2
OCHA Ph, OCHB Ph), 4.36–4.47 (2.9H, m, 2 × OCHA Ph, 3 × OCHB Ph), 4.29 (0.3H, d, J =
2
2
2
2
11.6 Hz, OCHB Ph), 4.26 (1H, d, J = 11.6 Hz, OCHA Ph), 4.19 (1H, dd, J2,1 = 8.0 Hz, J2,3 = 6.3
2
2
Hz, HA-2), 4.03 (1H, dd, J4,3 = 4.5 Hz, J4.5 = 3.6 Hz, HA-4), 4.01 (0.3H, dd, J4,3 = 5.3 Hz, J4,5
3.6 Hz, HB-4), 3.83–3.87 (2.3H, m, HA-3, HA-6, HB-3), 3.79 (0.3H, dd, J6,6’ = 11.2 Hz, J6,5
=
=
3.1 Hz, HB-6), 3.75 (1H, dd, J6’,6 = 11.1, J6’,5 = 7.2 Hz, HA-6’), 3.74 (0.3H, m, HB-6’), 2.89
(3H, s, CHA ), 2.86 (0.9H, s, CHB ) ppm. 13C NMR (150 MHz): δ 149.63 (CB-1), 148.43 (CA-
3
3
1), 137.33–137.90 (Cquat, 5 × CA-Ph, 5 × CB-Ph), 127.62–128.42 (25 × CA-Ph, 25 × CB-Ph),
82.22 (CA-5), 82.22 (CB-5), 79.93 (CB-4), 79.87 (CA-4), 79.67 (CA-3), 79.40 (CB-3), 76.74 (CA-
2), 76.39 (OCBH2Ph), 76.15 (OCAH2Ph), 74.83 (OCBH2Ph), 74.72, 74.43 (2 × OCAH2Ph), 74.17
(OCBH2Ph), 73.29 (OCAH2Ph), 73.19, 71.76 (2 × OCBH2Ph), 71.26 (CB-2), 70.64 (OCAH2Ph),
68.83 (CA-6), 68.80 (CB-6), 38.46 (CAH3), 38.46 (CBH3) ppm. HRMS (ESI-TOF) calcd for
C42H45NO8SNa [M + Na]+: 746.2764, found: 746.2740. Analysis calcd for C42H45NO8S
(723.88): C, 69.69; H, 6.27; N, 1.93; found: C, 69.60; H, 6.19; N, 1.71.
Synthesis of tetrahydrofurans 13 and 14 (General procedure C).
A solution of benzoxime 11 or 12 in toluene (10 mL) was boiled under reflux for 5 h, cooled
to room temp. The solvent was removed in vacuum and the product was isolated by flash
chromatography (hexanes/ethyl acetate = 85:15, v/v).
3,4-Bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbaldehyde O-benzyl
oxime (13A + 13B).
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BnO
H
OBn
N
BnO
BnO
N
H
O
O
1
6
6
1
5
2
5
2
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3
4
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BnO
OBn
BnO
OBn
13A
13B
0.50 : 1.00
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This compound was obtained in 90% yield (71 mg) 11 (106 mg, 0.146 mmol) as an isomeric
mixture in 0.50:1.00 ratio. TLC (hexanes/AcOEt = 2:1): Rf = 0.50. 1H NMR (600 MHz): δ 7.56
(0.5H, d, J1,2 = 7.8 Hz, HA-1), 7.15–7.40 (30H, m, ArH), 6.97 (1H, d, J1,2 = 4.3 Hz, HB-1), 5.20
(1H, dd, J2,1 = 4.3 Hz, J2,3 = 4.0 Hz, HB-2), 5.10 (2H, s, OCHB Ph), 5.10 (1.0H, s, OCHA Ph),
2
2
4.70 (0.5H, dd, J2,1 = 7.8 Hz, J2,3 = 4.2 Hz, HA-2), 4.62 (1H, d, J = 12.0 Hz, OCHB Ph), 4.62
2
(0.5H, d, J = 12.0 Hz, OCHA Ph), 4.51 (1H, d, J = 12.0 Hz, OCHB Ph), 4.50 (0.5H, d, J = 12.0
2
2
Hz, OCHA Ph), 4.46 (1H, d, J = 12.2 Hz, OCHB Ph), 4.41–4.45 (3.0H, m, HA-5, HB-5, 3 ×
2
2
OCHA Ph), 4.33–4.40 (3.5H, m, 3 × OCHB Ph, OCHA Ph), 4.24 (1H, dd, J3,2 = 4.0 Hz, J3,4
=
2
2
2
1.1 Hz, HB-3), 4.05 (0.5H, dd, J3,2 = 4.2 Hz, J3,4 = 1.5 Hz, HA-3), 4.03 (0.5H, dd, J4,5 = 3.8 Hz,
J4,3 = 1.5 Hz, HA-4), 3.94 (1H, dd, J4,5 = 3.7 Hz, J4,3 = 1.1 Hz, HB-4), 3.67–3.73 (3.0H, m, HA-6,
HA-6’, HB-6, HB-6’) ppm. 13C NMR (150 MHz): δ 151.13 (CB-1), 148.42 (CA-1), 138.14,
137.62, 137.53, 137.38 (Cquat, 4 × CA-Ph), 138.14, 137.71, 137.70, 137.62 (Cquat, 4 × CB-Ph),
127.58–128.44 (20 × CA-Ph, 20 × CB-Ph), 83.29 (CA-3), 82.06 (CB-3), 81.70 (CB-4), 81.52 (CA-
4), 79.72 (CA-5), 79.64 (CB-5), 77.76 (CA-2), 76.24 (OCBH2Ph), 75.99 (CB-2), 75.96, 73.48 (2
× OCAH2Ph), 73.45, 72.32 (2 × OCBH2Ph), 72.24, 72.21 (2 × OCAH2Ph), 72.15 (OCBH2Ph),
68.36 (CB-6), 68.29 (CA-6) ppm. HRMS (ESI-TOF) calcd for C34H35NO5Na [M + Na]+:
560.2413, found: 560.2415. Analysis calcd for C34H35NO5 (537.66): C, 75.95; H, 6.56; N, 2.61;
found: C, 76.06; H, 6.58; N, 2.64.
3,4-Bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbaldehyde
oxime (14A + 14B)
O-benzyl
BnO
H
OBn
BnO
N
BnO
N
H
O
O
1
6
6
1
5
2
5
2
3
4
3
4
BnO
OBn
BnO
OBn
14A
14B
1.00 : 0.90
This compound was obtained in 99% yield (81 mg) from 12 (110 mg, 0.152 mmol) as an
isomeric mixture in 1.00:0.90 ratio; colorless oil. TLC (hexanes/AcOEt = 3:1): Rf = 0.60. 1H
NMR (500 MHz): δ 7.47 (1H, d, J1,2 = 7.0 Hz, HA-1), 7.08–7.44 (38H, m, ArH), 6.82 (0.9H, d,
J1,2 = 4.5 Hz, HB-1), 5.08–5.13 (2.9H, m, 2 × OCHA Ph, HB-2), 5.07 (1.8H, s, 2× OCHB Ph),
2
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4.60 (1H, d, J = 12.0 Hz, OCHA Ph), 4.59 (0.9H, d, J = 12.0 Hz, OCHB Ph), 4.48–4.56 (5.7H,
2
2
m, 2× OCHA Ph, HA-2, 3× OCHB Ph), 4.44 (1H, d, J = 11.9 Hz, OCHA Ph), 4.41 (1H, d, J =
2
2
2
12.0 Hz, OCHA Ph), 4.36–4.39 (2.7H, m, HB-5, 2× OCHB Ph), 4.29 (1H, m, HA-5), 4.26 (1H,
2
2
7
8
9
d, J = 11.9 Hz, OCHA Ph), 4.08 (0.9H, br s, HB-3), 4.06 (1H, dd, J3,2 = 2.7 Hz, J3,4 = 1.4 Hz,
2
HA-3), 4.00 (1H, dd, J4,5 = 3.9 Hz, J4,3 = 1.4 Hz, HA-4), 3.90 (1H, br d, J4,5 = 3.0 Hz, HB-4),
3.69–3.77 (3.8H, m, HA-6, HA-6’, HB-6, HB-6’) ppm. 13C NMR (150 MHz): δ 153.47 (CB-1),
149.89 (CA-1), 138.17, 138.09, 137.77, 137.59, 137.51, 137.38, 137.38, 137.36 (Cquat, 4 × CA-
Ph, 4 × CB-Ph), 127.32–128.43 (20 × CA-Ph, 20 × CB-Ph), 85.18 (CA-3), 84.62 (CB-3), 82.28
(CA-4), 81.04 (CB-4), 81.00 (CA-2), 80.70 (CB-5), 80.39 (CA-5), 78.22 (CB-2), 76.49
(OCAH2Ph), 76.04 (OCBH2Ph), 73.45 (OCBH2Ph), 73.38 (OCAH2Ph), 71.72 (OCAH2Ph), 71.64
(OCBH2Ph), 71.51 (OCAH2Ph), 71.42 (OCBH2Ph), 68.48 (CB-6), 68.29 (CA-6) ppm. HRMS
(ESI-TOF) calcd for C34H35NO5 [M + Na]+: 560.2413, found:560.2407. Analysis calcd for
C34H35NO5 (537.66): C, 75.95; H, 6.56; N, 2.61; found: C, 75.82; H, 6.51; N, 2.61.
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Synthesis of compounds 15 and 16 (General procedure D).
A solution of imine 13 or 14 (45 mg, 0.084 mmol) in dry toluene (4 mL) was cooled -78 ºC
and a 1.0M solution of allylmagnesium bromide in diethyl ether (250 µL) was added. The
mixture was stirred for 30 min at -78 ºC and allowed to reach room temperature. Water (10
mL) was added and the crude product was extracted with ethyl acetate (3 × 10 mL). The
combined organic phases were washed with water (5 mL), brine (5 mL), dried, concentrated,
and the residue was purified by flash chromatography (hexanes/ethyl acetate = 90:10, v/v).
O-Benzyl-N-((R)-1-((2S,3R,4R,5S)-3,4-bis(benzyloxy)-5-
((benzyloxy)methyl)tetrahydrofuran-2-yl)but-3-en-1-yl)hydroxylamine (15).
OBn
BnO
HN
H
O
8
6
1
5
2
9
4
3
7
BnO
OBn
This compound was obtained in 70% yield (34 mg) from 13 as a colorless oil. TLC
(hexanes/AcOEt = 2:1): Rf = 0.50. [α]D22 = +16.8. 1H NMR (600 MHz): δ 7.20–7.36 (20H, m,
ArH), 6.24 (1H, br s, NH), 5.89 (1H, m, H-8), 5.00 (1H, dd, J9,8 = 10.6 Hz, J9,9’ = 1.6 Hz, H-
9), 4.97 (1H, dd, J9’,8 = 17.4 Hz, J9’,9 = 1.6 Hz, H-9’), 4.71 (2H, s, 2H, OCH2Ph), 4.58 (1H, d,
J = 11.9 Hz, OCH2Ph), 4.54 (2H, s, 2H, OCH2Ph), 4.52 (1H, d, J = 11.9 Hz, OCH2Ph), 4.48
(1H, d, J = 11.7 Hz, OCH2Ph), 4.34 (1H, ddd, J5,6 = 6.7 Hz, J5,6’ = 6.2 Hz, J5,4 = 3.8 Hz, H-5),
4.30 (1H, d, J = 11.6 Hz, OCH2Ph), 4.13 (1H, dd, J2,1 = 9.6 Hz, J2,3 = 3.5 Hz, H-2), 4.06 (1H,
d, J4,5 = 3.8 Hz, H-4), 3.85 (1H, d, J3,2 = 3.5 Hz, H-3), 3.73 (1H, dd, J6,6’ = 9.7 Hz, J6,5 = 6.7
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Hz, H-6), 3.66 (1H, dd, J6’,6 = 9.7 Hz, J6’,5 = 6.2 Hz, H-6’), 3.25 (1H, ddd, J1,2 = 9.6 Hz, J1,7
=
7.5 Hz, J1,7’ = 4.3 Hz, H-1), 2.27 (1H, m, H-7), 2.15 (1H, m, H-7’) ppm. 13C NMR (150 MHz):
δ 138.27, 138.16, 137.95, 137.45 (Cquat, 4 × Ph), 136.03 (C-8) 128.45 (2C-Ph), 128.40 (2C-
Ph), 128.34 (2C-Ph), 128.30 (2C-Ph), 128.23 (2C-Ph), 127.88 (C-Ph), 127.86 (C-Ph), 127.80
(2C-Ph), 127.71 (2C-Ph), 127.67 (2C-Ph), 127.57 (C-Ph), 127.55 (C-Ph), 116.21 (C-9), 81.13
(C-3), 80.83 (C-4), 79.18 (C-2), 78.97 (C-5), 76.57, 73.46, 72.47, 71.61 (4 × OCH2Ph), 68.27
(C-6), 59.72 (C-1), 33.05 (C-7) ppm. HRMS (ESI-TOF) calcd for C37H42NO5 [M + H]+:
580.3063, found: 580.3055. Analysis calcd for C37H41NO5 (579.74): C, 76.66; H, 7.13; N, 2.42;
found: C, 76.86; H, 7.19; N, 2.29.
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O-Benzyl-N-((S)-1-((2R,3R,4R,5S)-3,4-bis(benzyloxy)-5-
((benzyloxy)methyl)tetrahydrofuran-2-yl)but-3-en-1-yl)hydroxylamine (16).
OBn
BnO
HN
H
O
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7
BnO
OBn
This compound was obtained in 68% yield (33 mg) from 14 as a colorless oil. TLC
(hexanes/AcOEt = 2:1): Rf = 0.50. [α]D22 = +27.3. 1H NMR (500 MHz): δ 7.20–7.36 (20H, m,
ArH), 6.09 (1H, s, NH), 5.84 (1H, m, H-8), 5.01–5.06 (2H, m, H-9, H-9’), 4.65 (1H, d, J = 12.2
Hz, OCH2Ph), 4.54 (1H, d, J = 11.8 Hz, OCH2Ph), 4.58 (1H, d, J = 12.0 Hz, OCH2Ph), 4.52
(1H, d, J = 12.0 Hz, OCH2Ph), 4.51 (1H, d, J = 12.0 Hz, OCH2Ph), 4.49 (1H, d, J = 12.2 Hz,
OCH2Ph), 4.43 (1H, d, J = 11.8 Hz, OCH2Ph), 4.42 (1H, d, J = 12.0 Hz, OCH2Ph), 4.21 (1H,
ddd, J5,6 = 5.9 Hz, J5,6’ = 6.0 Hz, J5,4 = 3.8 Hz, H-5), 4.01 (1H, d, J3,2 = 3.4 Hz, H-3), 3.98 (1H,
J2,1 = 6.8 Hz, J2,3 = 3.4 Hz, H-2), 3.95 (1H, d, J4,5 = 3.8 Hz, H-4), 3.76 (1H, dd, J6,6’ = 9.9 Hz,
J6,5 = 5.9 Hz, H-6), 3.70 (1H, dd, J6’,6 = 9.9 Hz, J6’,5 = 6.0 Hz, H-6’), 3.05 (1H, ddd, J1,7 = 7.2
Hz, J1,2 = 6.8 Hz, J1,7’ = 5.3 Hz, H-1), 2.29 (1H, m, H-7), 2.24 (1H, m, H-7’) ppm. 13C NMR
(125 MHz): δ 138.20, 138.06, 137.90, 137.76 (Cquat, 4 × Ph), 135.97 (C-8) 128.43 (2C-Ph),
128.41 (2C-Ph), 128.34 (2C-Ph), 128.32 (2C-Ph), 128.23 (2C-Ph), 127.82 (C-Ph), 127.77 (2C-
Ph), 127.74 (C-Ph), 127.65 (2C-Ph), 127.58 (4C-Ph), 116.73 (C-9), 83.68 (C-3), 83.59 (C-2),
82.31 (C-4), 79.88 (C-5), 76.38, 73.39, 71.60, 71.60 (4 × OCH2Ph), 68.09 (C-6), 62.06 (C-1),
33.24 (C-7) ppm. HRMS (ESI-TOF) calcd for C37H41NO5 [M + H]+: 580.3063, found:
580.3060. Analysis calcd for C37H41NO5 (579.74): C, 76.66; H, 7.13; N, 2.42; found: C, 76.79;
H, 7.24; N, 2.33.
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DFT calculations.
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All calculations were performed using a four steps approach: 1) Conformational search using
the Spartan’18 Parallel Suite21 at MMFF level of theory. 2) All structures obtained in previous
step were optimized using MOPAC201622 with PM7 semiempirical method. 3) All structures
from step 2 with energy < 22 kJ/mol (with reference to the lowest energy conformer) were
optimized using the Gaussian 16 program23 at m062x/6-31+g(d) level of theory. 4) For all
structures from step 3 with energy < 22 kJ/mol vibrational frequency calculations was carried
out at the same level of theory as of optimization theory. Each conformer contribution to Gibbs
free energy was calculated according to a Boltzmann distribution. SMD implicit solvent model
was used to simulate the toluene environment (Radii=Bondi, Surface=SAS).
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Key words
Debenzylative cycloetherification, SN2 reaction, C-furanoside, O-functionalized
tetrahydrofuran, stereocontrolled synthesis.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the Internet at http://pubs.acs.org at
DOI:
NBO charges distribution of compound 7, 9, 11, 13, transition states TS-7, TS-11, imTS-7,9,
imTS-11,13, intermediates im-7,9, im-11,13; cartesian coordinates of calculated structures;
NMR spectra of all synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: slawomir.jarosz@icho.edu.pl
*E-mail: potopnyk@gmail.com
ORCID
Karolina Tiara: 0000-0001-5726-6887
Mykhaylo A. Potopnyk: 0000-0002-4543-2785
Paweł Świder: 0000-0002-8306-045X
Sławomir Jarosz: 0000-0002-9212-6203
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ACKNOWLEDGMENTS
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We gratefully acknowledge the financial support from Institute of Organic Chemistry of the
Polish Academy of Sciences. The calculation research was supported in part by the PLGrid
Infrastructure.
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