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.
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.
The evolution of the
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 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 cytarabine, a medicament in leukemia chemotherapy,[2] or vidarabine, an antiviral drug with activity
against herpes simplex and varicella zoster viruses.[3] The development and improvement of efficient synthetic
methods for the preparation of such types of compounds are actually
challenging for organic chemists.Among different types of furanosecarbohydrates, 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 infections,[5] and (+)-Varitriol, isolated from the marine strain
of the fungus Emericella Variecolor (M75-2), exhibits potent cytotoxicity
against a variety of cancer cell lines.[6−8] 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) is a potential
antimycobacterial agent, targeting enzymes involved in the biosynthesis
of the cell wall of Mycobacterium tuberculosis (Figure ).[4,10]
Figure 1
Examples
of biologically active C-furanosides.
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. Although this method is usually limited
to compounds with one unprotected hydroxyl group and one leaving group
(LG),[4] it can also be applied to fully
protected linear derivatives containing a leaving group. The protected,
such as a benzyl ether, oxygen function can also act as a nucleophile
and attack the sp3-carbon atom connected to the effective
leaving group in the debenzylative cycloetherification (DBCE) process.[11−15] This methodology was successfully used for the preparation of C-ethynyl[13] and C-vinyl[14] furanosides as shown in Scheme a. During the synthesis
of higher carbon sugars, we observed a similar rearrangement in which
the protected oxygen nucleophile attacked the allylic analog in the
SN2′ mode, which afforded the corresponding tetrahydrofuran
derivative (Scheme b).[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 Blériot
and co-workers (Scheme c).[17]
Scheme 1
Application of the DBCE Reaction in
the Synthesis of C-Furanosides via the SN2 (a) and SN2′
(b) Processes and in Selective Deprotection (c)
It seemed reasonable that such processes 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 .
Figure 2
Retrosynthetic analysis to prepare C-nitrile-
and C-benzoxime-furanosides.
Retrosynthetic analysis to prepare C-nitrile-
and C-benzoxime-furanosides.
Results
and Discussion
Synthesis
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 standard
conditions, either to oximes 3 and 5 (in
80–90% yield) or to protected oximes 4 and 6 (Scheme ). Products 3–6 could exist in four
dynamic isomeric forms: anti-oxime (A), syn-oxime (B), α-pyranoside
(C), and β-pyranoside (D).
Scheme 2
Synthesis
of Hydroxyoximes 3 and 5 and
Benzoxyoximes 4 and 6
All synthesized compounds were fully characterized by
the one-
(1H, 13C) and two-dimensional (2D) (1H–1H COSY and 1H–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, and 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 δ
= 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- and anti-isomers were observed in each case in the ratio ∼1:4, respectively.
In the 1H 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.It is well
documented that the mesylation of ω-hydroxy carbohydrate
hydroximes affords ω-methylatocarbohydratenitriles.[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% yields, respectively; Scheme ). 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.
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 ).
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 δ = 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 δ = 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 mentioning that both reactions were
highly stereoselective and only one stereoisomer was isolated in each
case (Scheme ).
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 . According to the Cram chelating model,
the simultaneous coordination of magnesium to the benzoximenitrogen
and the α-endocyclic oxygen atoms of compounds 13 and 14 forms cyclic α-chelates 13A and 14A, respectively. In the 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 to isomer 16 with the 1S-configuration. Such a 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]
Scheme 6
Proposed Mechanism
of the Grignard Reaction of Benzoximes 13 and 14 with Allylmagnesium Bromide
Density Functional Theory (DFT) Calculation
To gain
a better understanding of the different reactivities of the investigated
mesylates vs nitriles, density functional theory (DFT) computational
studies were performed for transformations 7 → 9 and 11 → 13. Geometrical
structures of substrates 7 and 11, products 9 and 13, intermediates im,9 and im-11,13, as well as transition states TS-7, TS-11, imTS,9, and imTS,13 (Figures and 4) were optimized,
and the relative Gibbs free energy (ΔG) values
were calculated with the addition of the toluene solvent effect utilizing
the solvation model based on density (SMD).
Figure 3
Gibbs free energy diagram
of transformation of linear compounds 7 into C-furanoside 9.
Figure 4
Gibbs
free energy diagram of transformation of linear compounds 11 into C-furanoside 13.
Gibbs free energy diagram
of transformation of linear compounds 7 into C-furanoside 9.Gibbs
free energy diagram of transformation of linear compounds 11 into C-furanoside 13.Comparison of the ΔG values of each
component
in both DBCE transformations clearly demonstrates that in the case
of nitrile 7 (Figure ), the transition energy barriers are higher than for
benzoxime analog 11 (Figure ). The relative Gibbs free energies for TS-7 and TS-11 were estimated as 35.7 and 30.7
kcal/mol, respectively, while the corresponding energies of transition
states imTS,9 and imTS,13 were 37.3 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.On the other hand, one of
the key aspects that affects the course
of these reactions is the electron density of the oxygen atom involved
in the intramolecular SN2 reaction. The presence of the
highly electron-withdrawing nitrile group in close proximity to the
“nucleophilic” oxygen atom in compound 7 induces the decrease of the electron density of 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 the Gaussian
package. The partial charge on the oxygen atom involved in the cyclization
reaction at each stage (except for the 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 ). Indirectly, the electron density of the
oxygen atom affects its nucleophilicity. Therefore, the calculated
values of partial charges demonstrate that in the case of transformation 11 → 13, the 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.
Table 1
NBO Atomic Charges on the Oxygen Atom
Involved in the Intramolecular SN2 Reaction
reaction 7 → 9
structure
Bn–O–CH–CN
7
–0.582
TS-7
–0.566
im-7,9
–0.458
imTS-7,9
–0.524
9
–0.587 (oxygen from tetrahydrofuran ring)
reaction 11 → 13
structure
Bn–O–CH–CH=N–O
11
–0.629
TS-11
–0.581
im-11,13
–0.456
imTS-11,13
–0.546
13
–0.608 (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 8 and 2,3,4,6-tetrakis (benzyloxy)-5-hydroxyhexanal O-benzyl oximes 11 and 12. The
compounds with the benzoxime group (11 and 12) are apparently more reactive in the DBCE reaction than the cyano-analogs
(7 and 8). These differences in 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,
in comparison with the corresponding influence of the benzoxime group.
The experimental results were confirmed by DFT calculation. The obtained C-furanosides with the benzoxime group in the side chain
(tetrahydrofurans 13 and 14) are good candidates
for stereoselective modification in the 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 the help of 2D correlation experiments (COSY, HSQC, HMBC). Chemical
shifts were reported with reference to tetramethylsilane (TMS). Optical
rotations were measured with a Jasco P 1020 polarimeter (sodium light)
in chloroform at room temperature. Mass spectra were recorded with
a Synapt G2-S HDMS (Waters Inc) mass spectrometer equipped with an
electrospray ion source and a q-TOF-type mass analyzer. The instrument
was controlled and recorded data were processed using the MassLynx
V4.1 software package (Waters Inc). Thin-layer chromatography (TLC)
was performed on silica gel plates coated with a fluorescent indicator.
Column chromatography was performed on silica gel (Merck, 230–400
mesh). Organic solutions were dried over anhydrous MgSO4.
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), hydroxyammonium 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 h at 55 °C (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), and 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).
Synthesis of Mesylates 7, 8, 11, and 12 (General
Procedure B)
To
a solution of compounds 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
°C, 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 h at −78
°C and allowed to reach room temperature. Water (8 mL) was added,
and the product was extracted with CH2Cl2 (3
× 10 mL). The combined organic solutions were washed with brine
(10 mL), dried, and concentrated, and the crude product was isolated
by flash chromatography (hexanes/ethyl acetate = 85:15, v/v).
Synthesis of Tetrahydrofurans 13 and 14 (General Procedure C)
A solution
of benzoxime 11 or 12 intoluene (10 mL)
was boiled under reflux for
5 h and cooled to room temperature. The solvent was removed in vacuum,
and the product was isolated by flash chromatography (hexanes/ethyl
acetate = 85:15, v/v).
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 at
−78 °C, and a 1.0 M solution of allylmagnesium
bromide in diethyl ether (250 μL) was added. The mixture was
stirred for 30 min at −78 °C 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) and brine (5 mL), dried, and
concentrated, and the residue was purified by flash chromatography
(hexanes/ethyl acetate = 90:10, v/v).
All calculations were performed using
a four-step approach: (1) conformational search using the Spartan′18
Parallel Suite[21] at the MMFF level of theory;
(2) all structures obtained in the previous step were optimized using
MOPAC2016[22] with the 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 program[23] at the m062x/6-31+g(d)
level of theory; and (4) for all structures from step 3 with energy
<22 kJ/mol, vibrational frequency calculations were carried out
at the same level of theory as of the optimization theory. Each conformer
contribution to Gibbs free energy was calculated according to a Boltzmann
distribution. The SMD implicit solvent model was used to simulate
the toluene environment (radii = bondi, surface = SAS).
Authors: Andrew H Wei; Stephen A Strickland; Jing-Zhou Hou; Walter Fiedler; Tara L Lin; Roland B Walter; Anoop Enjeti; Ing Soo Tiong; Michael Savona; Sangmin Lee; Brenda Chyla; Relja Popovic; Ahmed Hamed Salem; Suresh Agarwal; Tu Xu; Kaffa M Fakouhi; Rod Humerickhouse; Wan-Jen Hong; John Hayslip; Gail J Roboz Journal: J Clin Oncol Date: 2019-03-20 Impact factor: 44.544
Figure 1
Scheme 1
Figure 2
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Figure 3
Figure 4