Substrate-Controlled Diastereoselective Synthesis of Sugar-Based Chlorinated Perhydrofuro[2,3-b]pyrans via Copper(I)-Catalyzed Radical Cyclization

Article abstract of DOI:10.1002/adsc.201600895

The work describes the first copper(I) chloride/2,2′-bipyridine-catalyzed atom transfer radical cyclization (ATRC) of unsaturated carbohydrate-derived chloroacetals to generate chlorinated perhydrofuro[2,3-b]pyrans via an effective diastereoselective route. Various glycals (glucal, galactal and lactal) underwent the Ferrier rearrangement with 2,2,2-trichloroethanols to give acetal precursors stereoselectively, R-selective with galactal in contrast to S-selective with glucal. The radical cyclization of the Ferrier products occurred smoothly to afford cis-fused bicyclic products with the transfer of the chlorine atom at the non-anomeric carbon in the cyclized radical intermediate predominantly from the equatorial direction. The carbohydrate templates controlled the stereochemistry of both Ferrier rearrangement and ATRC steps. The stereostructures of the products were also supported by single crystal X-ray diffraction crystallography. The products possess biologically important structural segments such as a glycosidic linkage, a fused bicyclic acetal unit and a chlorosugar unit which are potential sources for biological studies and further synthetic elaborations. (Figure presented.).

Full text of DOI:10.1002/adsc.201600895

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DOI: 10.1002/adsc.201600895
Substrate-Controlled Diastereoselective Synthesis of Sugar-Based
Chlorinated Perhydrofuro[2,3-b]pyrans via Copper(I)-Catalyzed
Radical Cyclization
a
a,b,
a,b,
Ram N. Ram, Neeraj Kumar, * and Dharmendra Kumar Gupta *
a
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi – 110016, India
Fax : (+91)-11-2658-1102; phone: (+91)-11-2659-1501; e-mail: dkgiitd@gmail.com
Micro Labs Ltd., Plot No. 43–45, KIADB, Jigni-Bommasandra Link Road, Bangalore – 560105, India
b
E-mail: neerajkumar@microlabs.in
Received: August 12, 2016; Revised: November 7, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600895.
Abstract: The work describes the first copper(I) rial direction. The carbohydrate templates controlled
chloride/2,2’-bipyridine-catalyzed atom transfer radi- the stereochemistry of both Ferrier rearrangement
cal cyclization (ATRC) of unsaturated carbohydrate- and ATRC steps. The stereostructures of the prod-
derived chloroacetals to generate chlorinated perhy- ucts were also supported by single crystal X-ray dif-
drofuro[2,3-b]pyrans via an effective diastereoselec- fraction crystallography. The products possess biolog-
tive route. Various glycals (glucal, galactal and ically important structural segments such as a glycosi-
lactal) underwent the Ferrier rearrangement with dic linkage, a fused bicyclic acetal unit and a chloro-
2,2,2-trichloroethanols to give acetal precursors ste- sugar unit which are potential sources for biological
reoselectively, R-selective with galactal in contrast to studies and further synthetic elaborations.
S-selective with glucal. The radical cyclization of the
Ferrier products occurred smoothly to afford cis-
fused bicyclic products with the transfer of the chlor- Keywords: catalysis; chlorinated perhydrofuro[2,3-
ine atom at the non-anomeric carbon in the cyclized b]pyrans; chloroacetals; copper(I) chloride/bipyri-
radical intermediate predominantly from the equato- dine; diastereoselectivity
Introduction
the hydroxyl group such as polarity and hydrogen
[
5]
bonding and can impart physico-chemical effects in
[
6]
Fused bicyclic acetals, the perhydrofuro[2,3-b]pyrans, the sugar units. Thus, an incorporation of chlorine(s)
are frequently encountered as structural constituents in the sugar-derived perhydrofuro[2,3-b]pyran struc-
of many natural products possessing important biolog- ture is potentially a powerful tool to modulate the
[1]
ical activities (Figure 1). They are important syn- physical and biological properties of a sugar and is
thetic intermediates and their utility increases further useful especially in SAR studies. Chlorosugars are
[
2]
with the incorporation of a halogen in the rings.
They have been frequently used in the synthesis of biology also.
chiral and functionalized carbocycles, tetrahydrofur- Several reactions such as substitution, dehaloace-
ans, lactones, pyrans, bioactive molecules and natural toxylation and dehydrochlorination to an olefin
well known commercial artificial sweeteners in glyco-
[
5a,c,7]
[
8b]
[2]
[2h,8a,c,d]
[8e,f]
products. With a chlorine atom at the non-anomeric bond,
and selective dehalogenation
of chlor-
position in the sugar-derived pyran ring (a chlorosu- ine incorporated pyran and tetrahydrofuran rings are
gar) and/or at the b-position in the tetrahydrofuran known, and can be used to transform chlorinated per-
ring, they are potential substrates to study structure- hydrofuro[2,3-b]pyrans to bioactive molecules and
[
3,4]
[1f,2d,3,4]
activity relationships (SAR) for drug design.
Many natural products.
Despite high synthetic and
[3]
[4]
chlorosugars and the 3-chloro-tetrahydrofuran ring
biological potentials, there is scarcity of good regio-
are the structural constituents of many biologically and stereoselective methods of general applicability
active molecules and some have been used in the for the synthesis of the sugar-derived chlorinated per-
[
4]
[3-7]
treatment of viral diseases, AIDS and cancer. Fur- hydrofuro[2,3-b]pyrans.
The radical cyclization re-
thermore, a chlorine can mimic some properties of action is an attractive milder route to synthesize halo-
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tolerance towards functional groups and halogen
[
15]
atoms. However, this protocol is dominated by the
synthesis of various heterocycles using simple unsatu-
rated haloalkyls. The synthesis and stereochemistry of
heterocycles using a naturally occurring template with
predefined stereochemistry, has not been investigated
[
8,14]
so far.
Our interest in the synthesis of polyhalo-
[
15a,b,16]
alkyl substrates
ATRC reactions
and their Cu(I)-catalyzed
leads us to report a stereose-
[
8,15a,b,16]
lective Ferrier rearrangement of 1,2-unsaturated car-
[
17]
[18]
bohydrates (glycals)
with 2,2,2-trichloroethanols
to give 2,3-unsaturated glycosidic chloroacetals which
[19]
furnish perhydrofuro[2,3-b]pyrans stereoselectivity
under Cu(I)-catalyzed radical conditions. Crich et
[
20]
al. reported a gluco-template promoted diastereose-
lective radical cyclization via a radical cation/phos-
phate anion pair using Bu SnH/AIBN.
3
Results and Discussion
The reaction of d-glucal 1a (Scheme 1) with 2,2,2-tri-
chloroethanol 2a (1.5 equiv.) in the presence of a cata-
lytic amount of BF ·Et O and subsequent purification
Figure 1. Some naturally occurring compounds containing
the furo[2,3-b]pyran moiety.
3
2
of the crude product by silica gel column chromatog-
genated and functionalized heterocycles. However, raphy furnished the Ferrier product, trichloroethyl
[
9]
only one intermolecular atom transfer radical addi- acetal 3a in 65% yield. The unobservable small vicinal
[10]
tion (ATRA) of tosyl chloride (TsCl) to a carbohy- coupling between the singlet of anomeric proton at C-
drate diene under photochemical reaction conditions 1 (Supporting Information, Figure S1) and the olefinic
giving [ chlorinated perhydrofuro[2,3-b]pyran is proton at C-2 suggested that the acetal 3a, was an a-
10a]
[2j,10]
known.
However, it is less efficient as it uses anomer.
Next, the feasibility of a Cu(I)-catalyzed
5
equivalents of TsCl and is applicable to terminal al- ATRC reaction of the acetal 3a was studied using
kenes only. Chloroacetals derived from dihydropyr- varying amounts of CuCl (20 and 30 mol%) and the
[11]
[2i,12]
ans or unsaturated carbohydrates
are potential commercially available ligand 2,2’-bipyridine (bpy) in
alternative sources for chlorinated perhydrofuro[2,3- 1,2-dichloroethane (DCE) and acetonitrile at reflux
[
8]
b]pyrans under oxidative radical conditions. Howev- under a nitrogen atmosphere. The cyclization of
er, to date, only a few reductive radical cyclization re- acetal 3a with 20 mol% CuCl/bpy could not reach
actions using expensive and stoichiometric tin hydride completion (nearly 80%) despite a longer reaction
or similar radical initiators have been reported on
these chloroacetals. Importantly, their cyclization
[
3,8]
products lose the desired chlorine atom.
Addition-
ally, the formation of reduced starting material and
toxic residues in these reactions complicates the pu-
rification of the product. The atom transfer radical
cyclization (ATRC) protocol preserves all the halogen
atoms in the cyclization product of the haloalkyl sub-
[9]
strate. However, only a few ATRC reactions using
indium metal, sodium dithionite and boranes have
been reported so far, which are generally non-catalyt-
ic, costly and their application is limited to
the production of iodoperhydrofuro[2,3-b]pyrans
[2h,13]
only.
Over the years, copper(I)-catalyzed ATRC
[
8,14]
has
emerged as a catalytic, highly selective, cost-effective,
high-yielding, safe, energy efficient, and environmen-
tally benign (or least toxic) protocol for the synthesis Scheme 1. Preparation of chloroacetal 3a and chlorinated
[
8,9,14,15]
of various heterocycles
with very high degree of perhydrofuro[2,3-b]pyran 4a.
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time of 6 h. Only a 60% yield of the product 4a was ATRC reaction on other radical precursors 3b–
obtained after purification of the crude product by i (Table 1). They were obtained through Ferrier rear-
column chromatography. With 30 mol% CuCl/bpy rangement of 3,4,6-tri-O-acetyl-d-glucal 1a, 3,4,6-tri-
(
1:1 mol ratio) in DCE at reflux for 4 h, the cycliza- O-acetyl-d-galactal 1b and hexa-O-acetyl lactal 1c
tion of 3a occurred completely and a relatively high with 2,2,2-trichloroethanols 2 under the same reaction
yield (72%) of the product 4a was obtained after the conditions as described for 3a in Scheme 1. The struc-
purification of the crude product by column chroma- tures of the Ferrier products 3b–i were established by
1
13
tography. The reaction of 3a in acetonitrile was com-
H NMR, C NMR, IR, mass spectra and single crys-
pleted in a slightly shorter time (3.5 h) probably due tal X-ray diffraction analysis. The Ferrier rearrange-
to the better solubility of the copper complex catalyst, ment of glycals with 2,2,2-trichloroethanols was highly
the very same solubility characteristic made the re- diastereoselective leading to the formation of the a-
[
2j,10]
moval of the copper complex difficult during work- anomer exclusively in all cases.
Reactions involv-
up. This led to loss of the product yield (68%). Thus, ing racemic trichloroethanols 2b–d led to the forma-
the optimized conditions were 30 mol% CuCl/bpy tion of a mixture of two diastereomeric products in
(
1:1 mol ratio) in DCE for 4 h arising due to the variable proportions due to the chirality in the side
better purification of the reaction mass involving chain. Two epimers 3f (A) and 3f (B) could be sepa-
a simple filtration of insoluble copper complex resi- rated by fractional crystallization and their stereo-
dues followed by purification of the crude product on structures were established by their single crystal X-
[
21]
column chromatography. The structure of 4a was es- ray diffraction. Their ORTEP diagrams are shown
1
13
tablished by H and C NMR (Supporting Informa- in Figure 3 and Figure 4. It was found that both the
tion, Figures S21 and S22), DEPT-135 NMR, IR spec- epimers arose from the a-anomer. The major epimer
troscopy and mass spectrometry. These assignments 3f (A) was shown to have the R configuration at the
1
1
were also supported by DQF H- H COSY spectrum stereogenic centre in the exo-cyclic side-chain bearing
Supporting Information, Figure S23) and HSQC the phenyl group and the minor epimer 3f (B) was
(
spectrum (Supporting Information, Figure S24). The
observed splitting pattern and the coupling constant
values (J) confirmed that both the rings were cis-
fused and the chlorine at the C-3 carbon was present
in the equatorial position of the six membered ring.
The stereostructure of 4a was further supported by its
[
21]
single crystal X-ray diffraction data.
The ORTEP
diagram of 4a is shown in Figure 2. The single crystal
X-ray data of the product (vide infra) 4a also revealed
the acyclic precursor 3a to be the a-anomer.
The effect of the a-substituents of 2,2,2-trichloro-
ACHTUNGTRENNUNGe thanols, and also of other carbohydrate templates on
the regio- and stereoselectivity in the cyclization step
was examined by performing the Cu(I)-catalyzed
Figure 3. ORTEP diagram of major epimer 3f (A).
Figure 2. ORTEP diagram of the chlorinated perhydro-
furo[2,3-b]pyran 4a.
Figure 4. ORTEP diagram of minor epimer 3f (B).
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Table 1. Preparation of the sugar-derived trichloroethyl acetals 3 and their chlorine atom transfer radical cyclization re-
action to chlorinated perhydrofuro[2,3-b]pyrans 4.
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Table 1. (Continued)
[
a]
All the reactions were performed with 2.0 mmol of the glycal 1 and 1.5 equiv. of 2,2,2-trichloroethanols 2 at 208C
for 10 min in dry benzene.
[
[
[
[
b]
c]
d]
e]
Yield of isolated a-anomer products after silica gel chromatography.
1
Epimeric ratio was determined by H NMR spectroscopy after column chromatography.
R/S configuration was determined by single crystal X-ray diffraction analysis of the epimers.
All the cyclizations were performed with 1.0 mmol of Ferrier product and 30 mol% each of CuCl and bpy in DCE
at reflux under an N atmosphere for 4 h.
Isolated yield after purification by silica gel column chromatography.
Combined yield of 3f (A+B), 4b (A+B), and 4e (A+B).
2
[
[
f]
g]
found to have the S configuration of the correspond- plex residues. Purification of the concentrated filtrate
ing carbon atom. The configurations of the stereogen- on silica gel chromatography gave 4b–i in very good
ic centres at C-7 in Ferrier products 3g, 3h and 3b (or yields. The results are summarized in Table 1. The
analogs 3c and 3d) were plausibly interpreted from structures of all the cyclized products were estab-
1
13
their ATRC products 4g, 4h and 4b, respectively.
lished by H NMR, C NMR, IR and mass spectral
All the radical precursors 3b–i were successfully cy- data and by single crystal X-ray diffraction spectros-
clized to the corresponding tetrahydrofuro[2,3- copy (in the case of solid crystalline compounds). The
b]pyrans 4b–i by 30 mol% each of CuCl and bpy in axial-equatorial cis-ring fusion and position of the
DCE at reflux for 4 h under a nitrogen atmosphere. chlorine atom at C-3 and stereochemistry of the
Simple filtration of the heterogeneous reaction mass chiral centre at C-7 were established by splitting pat-
through a small Celite pad at room temperature was terns and coupling constant values (J) of the protons
advantageously used to remove the solid copper com- at C-1, C-2, C-3 and C-4 (Table 1) from their
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1
H NMR spectra and their single crystal X-ray struc- equatorial chlorine with those of the major epimer 4b
tures or by analogy with other similar cyclization (A). As this isomer 4b (B) should arguably differ
products. from 4b (A) in the stereochemistry of the chiral
The cyclization of the epimeric mixture of Ferrier centre at C-7, the phenyl group in 4b (B) should be
product 3b gave a mixture of the bicyclic products 4b oriented endo to the bicyclic ring.
(
A) and 4b (B) as a white solid in a 65:35 epimeric
ratio in 68% combined yield after column chromatog- mixtures 3c and 3d, only major epimers 4c and 4d, re-
raphy. spectively, could be isolated from column chromatog-
In the case of radical cyclization of the epimeric
The major epimer 4b (A) was isolated in pure form raphy as viscous liquids in 65% yield in each case.
as a white solid in 54% yield by fractional crystalliza- This was understandable because the proportion of
tion. The cis-ring fusion and exclusive equatorial the other epimer in the mixture of the starting materi-
transfer of the chlorine atom on ATRC were estab- als was small. Both epimers 4c and 4d showed the
lished by the splitting patterns and the coupling con- above trend in stereochemistry, had cis-ring fusion
stant values of the protons at C-1, C-2, C-3 and C-4 and equatorial positions of the chlorine atom at C-3
1
(
Table 1) as shown by its H NMR spectrum (Support- (Supporting Information, Figures S29 and S31) and
ing Information, Figure S25). The stereostructure of arguably exo position of the alkyl substituents at C-7
b (A) was further supported by single crystal X-ray (Table 1).
4
[
21]
diffraction analysis. The ORTEP diagram is shown
The radical cyclization of d-galactose-derived Ferri-
in Figure 5. It clearly shows the cis-ring fusion and the er product 3e furnished an inseparable mixture of the
presence of the chlorine atom at the equatorial posi- epimeric cyclized products 4e (A) and 4e (B) in 61:39
1
tion. The phenyl ring at the C-7 position of the tetra- ratio [Supporting Information, Figure S33 ( H NMR)
hydrofuran ring 4b (A) was seen to occupy the exo and Figure S35 (COSY spectrum)]. The splitting pat-
position (S configuration at C-7). Thus, the configura- tern and coupling constant (J) values of protons at C-
tion of the corresponding stereogenic centre in the 1, C-2, C-3 and C-4 indicate the axial-equatorial cis-
major epimer of the Ferrier product 3b was also plau- ring fusion in both major and minor epimers similar
sibly S, assuming that no epimerization had occurred to the glucal-derived cyclized product 4a. Contrary to
during the ATRC. Accordingly, the minor epimer of the glucal-derived cyclized product 4a, in which the
3b had the R configuration of this centre. The split- chlorine atom at C-3 was equatorial, in the galactose-
ting patterns and the J values of the protons at C-1, derived major cyclized product 4e (A) the chlorine
C-2, C-3 and C-4 (Supporting Information, Fig- atom at C-3 occupied the axial position. In the minor
ure S27) of the minor product 4b (B) [from mother cyclized product 4e (B), the chlorine atom at C-3 oc-
liquor, 4b (A):4b (B) = 20:80] showed the same ste- cupied the equitorial position. This is probably to
reochemistry of the sugar ring, i.e., cis-fusion and minimize the dipole-dipole repulsion between the
axial C-4–OAc bond and the newly formed C–Cl
bond.
The radical cyclization of the major Ferrier product
f (A) (Table 1) afforded only one isomer 4f in 68%
3
yield as a viscous liquid. The cis-ring fusion and equa-
torial position of the chlorine atom at C-3 were de-
duced from the coupling constant values for the pro-
tons at C-1, C-2 and C-3 (Supporting Information,
Figure S36) as described earlier. These couplings are
shown in Figure 6. However, in the case of radical
cyclization of the minor Ferrier product 3f (B), an in-
separable epimeric mixture of 4f was obtained in
6
6
6:33 ratio (Supporting Information, Figure S38) in
2% combined yield. They appeared to differ proba-
Figure 5. ORTEP diagram of the fused bicyclic acetal 4b
A) (major epimer).
Figure 6. Vicinal proton-proton coupling constant values for
4f (endo, single isomer).
(
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bly in the stereochemistry at the C-3 position. The
stereochemistry of C-1 and S-configuration of the
chiral centre at C-7 of the product were predefined
by the radical precursor 3f (B). Thus, the exo orienta-
tion of the phenyl ring and probably also the cis-ring
fusion in the products were predetermined.
The radical cyclization of the epimeric mixture of
3g (Table 1) furnished a single cyclization product 4g
as a white solid in 60% isolated yield after purifica-
tion by column chromatography. This product should
be the cyclization product of only the major epimer
of 3g. The cis-ring fusion and equatorial position of
chlorine at the C-3 carbon were established by the
Figure 8. ORTEP diagram of fused bicyclic acetal 4h.
The endo-orientation of the C-7 substituent in the
1
coupling constant values obtained from its H NMR
spectrum (Supporting Information, Figure S40). The
stereochemistry was further supported by single crys-
[
21]
tal X-ray structure. The ORTEP diagram of 4g is major/exclusive cyclization products (4g and 4h,
shown in Figure 7. In the crystal structure of 4g, it Figure 7 and Figure 8) of these galactose-derived radi-
was also observed that the ethyl group at C-7 was cal precursors revealed that the Ferrier rearrange-
present at the endo position.
ment of the tri-O-acetyl-d-galactal 1b with racemic
,2,2-trichlroethanols was R-selective towards the al-
cohols (E>F, Scheme 2), contrary to the S-selectivity
C>B, Scheme 2) of the Ferrier rearrangement of tri-
O-acetyl-d-glucal 1a with racemic 2,2,2- trichloroetha-
2
(
Figure 7. ORTEP diagram of fused bicyclic acetal 4g.
Similarly, in the radical cyclization of 3h (Table 1),
the cyclization product 4h of the major epimer of 3h
could only be isolated. The cis-ring fusion and equato-
rial position of the chlorine at C-4 were established
by the coupling constant values obtained from its
1
H NMR spectrum (Supporting Information, Fig-
ure S42). The stereostructure of 4h was also supported
[
21]
by single crystal X-ray diffraction analysis.
The
ORTEP diagram of 4h is shown in Figure 8. In this
case also, the propyl group at C-7 occupied the endo
position.
The radical cyclization of 3i (Table 1) afforded the
corresponding cyclized product 4i in 70% isolated
yield (Supporting Information, Figure S44). By analo-
gy with the cyclization products derived from d-
glucal, the cis-fusion of the two rings and equatorial
Scheme 2. Plausible mechanism of stereoselective Ferrier re-
position of the chlorine atom at C-3 of the glucose arrangement of glucal (C>B) and galactal (E>F) with
ring were deduced with a reasonable possibility.
2,2,2-trichloroethanols 2b–d.
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nols as revealed from the exo- orientation of the sub-
stituent at C-7 in 4b (A) (Figure 5).
Since the two glycals differ only in the configura-
tion of the C-4 carbon atom of the ring (equatorial
OAc in glucal and axial OAc in galactal), the configu-
ration of this atom appears to play a major role in the
chiral recognition during these Ferrier rearrange-
ments. The stereoselective recognition of an achiral
radical species attacking onto the a-face of the
double bond of the galactal under the influence of
steric hinderance posed by a pseudoaxial OAc at C-4
[22]
is known also. This points towards a high possibility
of preferential recognition of one of the enantiomers
of the racemic 2,2,2-trichloroethanol 2b–d by the
chiral centres at C-4 on the carbohydrate templates in
the present case also (Scheme 2).
Mechanistically, the reaction followed a general
form of atom transfer radical cyclization (ATRC),
where an activator, the Cu(I)/L complex reversibly ab-
stracts a chlorine atom from the halide substrates and
generates a radical along with a deactivator the Cl–
Cu(II)/L complex via a concerted inner-sphere elec-
[
14a]
tron transfer (ET).
The radical cyclization step
showed a general trend with regard to the stereo-
chemistry at C-1–C-2 and C-3, and at C-7 in the prod-
ucts (Scheme 3). The radical cyclization of the Ferrier
products occurred smoothly to afford C-1–C-2 cis-
fused bicyclic products with the transfer of chlorine
atom at C-3 in the cyclized radical intermediate pre-
dominantly from the equatorial direction (B!C, E!
[
2h,j,10]
F, K!L).
The cis-ring fusion, observed in every
case, was predetermined by the axial selectivity of the
Ferrier rearrangement.
[
2h,j,10]
Single crystal X-ray struc-
tures [4a, Figure 2 and 4b (A), Figure 5] revealed
that, in the solid state, the pyran ring was in the chair
conformation in the d-glucal-derived perhydro-
furo[2,3-b]pyrans, which is consistent with the chair- Scheme 3. Plausible chair-like (A & D in glycal) and boat-
like transition state model proposed by Beck- like (G & J in galactal) transition states, equatorial/axial at-
[
10a,b,23]
tacks of chlorine radical and endo/exo-orientations of sub-
stituents (R) at C-7.
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
with,
whereas it adopted a pseudo-boat confor-
mation (4g and 4h, Figure 7 and Figure 8) in the cor-
responding d-galactal derivatives; although generally
less favorable, the formation of these boat-like transi-
tion states may sometimes be helped by the configu- the substituents on the neighboring carbons are like-
[
10a,19c]
[10b]
ration at the C-4 centre.
The transfer of the wise equatorial.
As expected, on the contrary, in
chlorine atom to the radical intermediate after cycli- the case of galactal-derived Ferrier products, a slight
zation was more stereoselective in the case of d- preference for the transfer of chlorine atom at C-3
glucal-derived radical precursors (Scheme 3) in com- from the side of the cavity, i.e., from the axial direc-
parison to the d-galactal derivatives, as pointed out tion was observed, probably in order to avoid dipole-
by Houk the boat-like conformations may be slightly dipole repulsion from the C-4 axial acetoxy group in
destabilized with respect to chair-like conformation the transition state (H!I). However, this preference
ꢀ1
[10a,23c]
(
nearly ca.1 kcalmol ).
In all the cases of glu- was reversed, as expected, in the presence of an endo
cose-based cyclization precursors in which the C-7 substituent at C-7, probably due to increased steric
substituent was either absent or destined to be exo, crowding in the cavity which might outweigh the
the chlorine atom was transferred at C-3 from the moderate axial-equatorial dipole-dipole repulsion
[
2h,10]
less crowded equatorial direction (Scheme 3).
It (K!L). Such a reversal in the preferences due to an
is in agreement with the favored introduction of an increase in the bulkiness of the endo-oriented sub-
equatorial substituent on the carbohydrate ring when stituents of the cyclizing radical, is known in a few
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[
10]
cases also. The stereochemistry at a-C(HRCCl ) of phase. Solvents were evaporated on a rotary evaporator
3
under reduced pressure using an aspirator. d-Glucose, d-gal-
the Ferrier product 3 (Table 1) might be retained at
actose, d-lactose, acetic anhydride, perchloric acid, red phos-
C-7 in the corresponding ATRC product 4 as no epi-
phorus, bromine, sodium acetate, zinc dust, cupric sulfate
merization could occur during the ATRC reaction
[
8e,f,24]
pentahydrate, calcium chloride, sodium carbonate, sodium
bicarbonate diethyl ether, petroleum ether, 2,2,2-trichloro-
with a milder Cu(I)/bpy catalyst.
AHCTUNGTRENNUGNe thanol 2a and bpy were purchased and were used as re-
ceived. Chloroform and DCE were dried by distilling over
anhydrous P O . The commercial grade nitrogen gas was
used after passing successively through traps containing sol-
Conclusions
2
5
The Ferrier rearrangement of glycals with 2,2,2-tri- utions of alkaline anthraquinone-sodium dithionite, alkaline
chloroethanols followed by CuCl/bpy-catalyzed pyrogallol, concentrated H
SO and KOH pellets. The nitro-
gen atmosphere was created by using the Schlenk technique
in all the experiments.
2
4
ATRC constitutes an effective diastereoselective
route to bicyclic fused chlorosugars. The stereochem-
istry of the products was controlled at both steps by
the carbohydrate templates. Thus, OAc at C-4 in the
carbohydrates and substituents at the a-carbon in the
Preparation of Glycals 1
Tri-O-acetyl-d-glucal 1a and 3,4,6-tri-O-acetyl-d-galactal 1b
2,2,2-trichloroethanol subunit in the Ferrier products were prepared from inexpensive d-glucose and d-galactose
[17c]
played the decisive role. The scope of this method is by following a reported three-step reaction procedure
potentially wider as variously substituted glycals and volving acetylation with acetic anhydride, bromination with
in-
Br /red phosphorus, and debromoacetoxylation with zinc
dust successively. Hexa-O-acetyl-d-lactal 1c was prepared
from d-lactose by the reported
used for the preparation of the glycals 1a and 1b. 2,2,2-Tri-
2
,2,2-trichloroethanols can be easily prepared by
2
simple chemistry. Furthermore, the stereoselectivity
can be raised further simply by using enantiopure
[17f]
method similar to that
2,2,2-trichloroethanols in the Ferrier rearrangement
chloroethanols 1b and 1c were prepared from CHCl and
3
with glycals and this is under investigation. These
sugar-based chlorinated perhydrofuro[2,3-b]pyrans
possess a rare combination of biologically important
structural segments such as a glycosidic linkage,
a fused bicyclic acetal unit and a chlorosugar unit,
which are potential sources for SAR studies and fur-
ther chemical transformations to access biologically
active compounds. The method provides an easy
route to chlorosugars, generally prepared through hal-
ogenation reactions, which usually suffer from less
regio- and stereoselectivity and less yield due to the
formation of other side products.
the corresponding aldehydes in the presence of DBU as
a base by a procedure reported in literature.
[19]
Preparation of Sugar-Derived Trichloroethyl Acetals
3a–i: Ferrier Rearrangement of the Glycals 1a–c
General Procedure: These compounds were prepared ac-
cording to the literature procedure for Ferrier rearrange-
[2i]
ment. Glycal 1a, 1b or 1c (0.002 mol) and 2,2,2-trichloro-
ethanol 2a or 1-substituted 2,2,2-trichloroethanol 2b–d
0.003 mol, 1.5 equiv.) were dissolved in 20 mL of dry ben-
AHCTUNGTRENNUNG
(
zene under an N atmosphere at 208C. To this solution was
2
added 0.5 equiv. of BF ·Et O (0.142 g, 0.12 mL, 0.001 mol)
3
2
through a syringe at 208C. After the addition of BF ·Et O to
3
2
the reaction mixture, the solution turned purple to dark
brown within 5–7 min and some precipitation occurred. TLC
of the reaction mixture showed the disappearance of the
starting material and formation of a product along with
some side products as indicated by appearance of a dark
spot at the base of the chromatogram. After 10 min, the re-
action was quenched with aqueous NaH PO solution,
Experimental Section
General Information
IR spectra were recorded on a Nicolet 6700 FT-IR spec-
trometer by taking solid samples as KBr pellets and liquids
as thin films on KBr disks. NMR spectra were recorded on
2
4
washed with saturated sodium bicarbonate solution (3ꢁ
10 mL), dried over Na SO , filtered and evaporated under
a 300 MHz FT NMR spectrometer in CDCl with TMS as
3
2
4
internal standard. Multiplicities were indicated by the fol-
lowing abbreviations: s (singlet), d (doublet), t (triplet), q
reduced pressure on a rotary evaporator. The residue was
purified by silica gel column chromatography (n-hexane:E-
tOAc=90:10 v/v) to obtain the pure Ferrier products; yield:
40–65%. In all the cases, only the major a-anomer could be
isolated. All the Ferrier product 2,2,2-trichloroethyl acetals
were obtained as viscous liquids except 3f and 3i which
were white solids.
(
(
quartet), m (multiplet), dd (doublet of doublet) and ddd
doublet of doublet of doublet). DEPT spectra were rou-
tinely recorded to identify different types of carbons. Mass
spectra were recorded on high-resolution mass spectrometer
(
ESI-TOF) in positive-ion mode. Melting points were deter-
mined on an electrically heated apparatus by taking the
samples in a glass capillary sealed at one end and are uncor-
rected. The progress of the reaction was monitored by TLC
using a glass plate coated with a TLC grade silica gel.
Iodine was used for visualizing the spots. For column chro-
matography, silica gel was used as the stationary phase and
n-hexane and n-hexane-ethyl acetate mixtures as the mobile
Preparation of Chlorinated Perhydrofuro[2,3-
b]pyrans 4a–i: Copper(I) Chloride/bpy-Catalyzed
ATRC of 3a–i
A two-neck round-bottom flask fitted with a rubber septum
was connected to a Schlenk tube through a condenser. The
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flask was evacuated and dried by heating with a flame while
the vacuum pump was kept running. The flask was then
filled with dry nitrogen. A mixture of the trichloroethyl
acetal 3 (0.001 mol), CuCl (0.03 g, 0.0003 mol) and a magnet-
ic bar were placed in the flask under a continuous flow of
nitrogen, which was immediately followed by the addition
of degassed DCE (5 mL). To this suspension was injected
a solution of bpy (0.047 g, 0.0003 mol) in degassed DCE
Sridhar, P. Suguna, S. Chandrasekaran, Org. Lett. 2007,
9, 1331–1343 (dehydrohalogenation of 3-halotetrahy-
drofuran to a dihydrofuran; e) H. Xie, T. Morikawa, H.
Matsuda, S. Nakamura, O. Muraoka, M. Yoshikawa,
Chem. Pharm. Bull. 2006, 54, 669–675 (application of
a 3-chloro substituent to bioactive molecules); f) J.
Marco-Contelles, J. Ruiz-Caro, Carbohydr. Res. 2001,
3
35, 63–70 (DIBALH-mediated exclusive tetrahydro-
(
1 mL) and the mixture was heated at reflux with stirring.
furan ring opening of bicyclic acetal to afford chiral
and functionalized products); g) J. Marco-Contelles, J.
Ruiz-Caro, Tetrahedron Lett. 2001, 42, 1515–1517 (syn-
thesis of chiral and functionalized products); h) M.
Hein, R. Miethchen, Eur. J. Org. Chem. 1999, 2429–
The progress of the reaction was monitored by TLC, which
indicated completion of the reaction after 4 h. The reaction
mixture was cooled, filtered through a small pad of Celite
and the filtrate was evaporated to give the crude perhydro-
furo[2,3-b]pyran. Purification of the crude product on silica
gel column using a mixture of n-hexane and ethyl acetate
2
432 (and references therein, synthetic application of
a halogen at C-3 and OAc at C-4 and C-5 of the sugar
moity); i) R. J. Ferrier, P. M. Petersen, Tetrahedron
(
90:10 v/v) as the eluting solvent furnished the perhydro-
furo[2,3-b]pyrans 4a–i; yield: 60–70%.
1
990, 46, 1–11 (synthesis of a carbocyclic ring on a bicy-
clic acetal template); j) A. De Mesmaeker, P. Hoff-
mann, B. Ernst, Tetrahedron Lett. 1988, 29, 6585–6588
(
bicyclic acetal cleavage to pyran and lactone); k) K.
Ishihara, A. Mori, H. Yamamoto, Tetrahedron Lett.
987, 28, 6613–6616 (DIBAH-mediated reductive re-
Acknowledgements
1
Financial assistance by CSIR, New Delhi, and IIT Delhi, is
gratefully acknowledged.
generation of chiral pyran and tetrahydrofuran from bi-
cyclic acetals).
[
3] Review: a) H. Koch, Pharma Int. 1983, 4, 1–2; b) A.
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1
2 Substrate-Controlled Diastereoselective Synthesis of Sugar-
Based Chlorinated Perhydrofuro[2,3-b]pyrans via
Copper(I)-Catalyzed Radical Cyclization
Adv. Synth. Catal. 2017, 359, 1 – 12
Ram N. Ram, Neeraj Kumar,* Dharmendra Kumar Gupta*
Adv. Synth. Catal. 0000, 000, 0 – 0
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