Povarov reactions of exo-glycals: Preparation of C-linked, quinoline analogues

Article abstract of DOI:10.1016/j.tet.2011.09.077

A one-pot approach based upon the Povarov reaction has been efficiently employed with a number of exo-glycals and para-substituted benzanilines to synthesize novel open-ring, carbohydrate-derived quinolines. The mechanism of this reaction was studied and

Full text of DOI:10.1016/j.tet.2011.09.077

Tetrahedron 67 (2011) 9273e9282
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Povarov reactions of exo-glycals: preparation of C-linked, quinoline analogues
*
Peter H. Dobbelaar, Cecilia H. Marzabadi
Department of Chemistry & Biochemistry, Seton Hall University, 400 South Orange Ave., South Orange, NJ 07079, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 August 2011
Received in revised form 16 September 2011
Accepted 19 September 2011
Available online 24 September 2011
A one-pot approach based upon the Povarov reaction has been efficiently employed with a number of
exo-glycals and para-substituted benzanilines to synthesize novel open-ring, carbohydrate-derived
quinolines. The mechanism of this reaction was studied and an explanation for the observed stereo-
selectivity is proposed. Treatment of the compounds with the Lewis acid, boron trichloride, successfully
removes the benzyl ether protecting groups in good yields. Several of the prepared compounds have
been screened in the National Cancer Institute’s (NCI’s) 60 cell line model. Moderate activity was ob-
served for several leukemia cell lines.
Keywords:
exo-Glycal
Povarov reaction
p-Substituted benzanilines
Quinolines
Ó 2011 Elsevier Ltd. All rights reserved.
Cytotoxicity
1. Introduction
some of the most widely used name reactions include the Camps,
Combes, DoebnereMiller, Friedlander, Knorr, Niementowski, Pfit-
Carbohydrates and glycoconjugates are crucial for the survival of
living entities due to their integral involvement in numerous life
sustaining processes.1 As a result of the diversity and functional
specialization of carbohydrates, stable and bioavailable sugar-based
compounds present themselves as promising platforms for drug
design.2 In fact, saccharide derivatives are recognized as bi-
ologically relevant scaffolds that offer a high density of functional
groups in addition to numerous chiral centers.3 Aside from cell-
surface interactions, sugars are able to pass through membranes
via carbohydrate-specific transport mechanisms and function
within cells.4 Consequently, carbohydrate-derived compounds as
well as glycomimetics have been utilized as therapeutics for a wide
array of medical conditions.5
As is the case with sugars, nitrogen-containing heterocycles,
including quinolines, are present in a variety of biologically active
molecules and have been applied in several therapeutic areas.6 For
example, fluoroquinolones, such as ciprofloxacin7 and levofloxacin8
are used as antibacterial therapies while other quinoline de-
rivatives show promise as antitumor agents.9 Developments in the
area of quinoline chemistry are therefore due, in part, to the
pharmacological properties of their derivatives. Consequently, the
synthesis of quinolines has been a subject of great importance in
the field of organic chemistry.10 Numerous preparative methods for
the formation of substituted quinolines have been developed, and
zinger, PicteteSpengler, PomeranzeFritsch, Riehm, and Skraup
syntheses.11
We became interested in the preparation of sugar-based quin-
olines because of the biological activity associated with both classes
of compounds. The unique structure and glycosidase inhibitory
activity of the spironucleoside natural product (þ)-hydantocidin12
1 and its synthetic glucose analogues13 2 and 3 provided addi-
tional inspiration to target sugar-based heterocycles (Fig. 1). Fur-
thermore, a recent study focused on the synthesis and evaluation of
quinoline-glucose hybrids 4 and 5 also validates the potential ap-
plication of sugar-derived heterocycles as DNA intercalators.14 We
surmised that C-linked monosaccharide-derived quinolines have
the potential to possess antitumor properties as intercalating
agents. The incorporation of a carbohydrate group onto the mole-
cule may facilitate delivery of the compound as well as enhance its
drug-like properties. We hypothesized that the sugar component of
the molecule might also help to stabilize the complex with DNA (via
sugarephosphate backbone interactions), enabling the planar
quinoline to insert between the base pairs of DNA. In addition,
a carbonecarbon bond linkage between the sugar and quinoline is
likely to be more stable toward endogenous enzymes compared to
a
carboneoxygen bond found in other reported carbohy-
drateequinoline hybrids.14,15
Despite the large number of publications covering the synthesis
of quinolines, we chose to focus our research around applications of
the Povarov reaction. We theorized that a variation of the Povarov
reaction would permit access to glycosylidene-linked quinolines.
* Corresponding author. Tel.: þ1 973 761 9032; fax: þ1 973 761 9772; e-mail
address: cecilia.marzabadi@shu.edu (C.H. Marzabadi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.077

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P.H. Dobbelaar, C.H. Marzabadi / Tetrahedron 67 (2011) 9273e9282
a 4:1 mixture of spiroanellated tetrahydroquinolines, as well as the
oxidized, open-ring product (Scheme 2). The percentage of the
open-ring compound present in the reaction mixture was catalyst
dependent. For instance, when Sc(OTf)3 was utilized as the catalyst,
more than 70% of the reaction mixture consisted of the open-ring
product. Lanthanide triflate reaction catalysis, however, produced
nearly a 1:1 mixture of open-ring product and spiro tetrahy-
droquinolines.21 Nuclear Overhauser effect (NOE) experiments
confirmed the stereochemistry of both spiro isomers, 8Major and
8Minor, and extensive 1D and 2D NMR experiments were required
to determine the structure of the open-ring compound 9a. For
8Major, NOEs were observed between the hydrogens attached to
the following carbon atoms (for atom labels, see structure in
Scheme 2): 2 with both j and a, b with both 3 and 5, and 4 with a.
These interactions indicate that the stereochemistry is (R) at both
carbons 1 and j. For 8Minor, NOEs were observed between the
hydrogens attached to the following carbon atoms: b with both 2
and 4, 3 with a, and 5 with j. The stereochemistry of this isomer is
(S) at carbon 1 and (R) at carbon j. Evidence supporting the for-
mation of open-ring compound 9a includes the 13C shift of C1
(145.9 ppm) and the coupling constant for the hydrogen attached
to C2 (3.1 Hz). The broad 13C resonance of C2 (78.5 ppm) sharpened
upon increased temperature, indicating restricted rotation about
the C1eC2 bond. NOEs were observed between the hydrogens at-
tached to the following carbon atoms: 2 with both a and b. COSY
and NOESY signals, observed between the hydrogen and hydroxyl
group attached to C5, also helped to confirm the assignment of 9a.
A unique aspect of this Povarov addition is the observed facial
selectivity and stereocontrol of the reaction. Only two of the four
possible glycosylidene-spiroanellated stereoisomers were formed,
and the isomers with the (S)-configuration at the benzylic carbon j
were absent. The regiochemistry of addition to exo-glycal 6 to
produce the spiroanellated products can be explained on the basis
of a non-concerted reaction pathway.22 According to the two-step
process that has been proposed,23 attack of the imine carbon by
the more nucleophilic C2 carbon of the vinyl ether occurs first. This
is followed by electrophilic attack of the resulting oxonium ion by
the ortho carbon of the aniline ring. The observed axial facial
Fig. 1. Carbohydrate-based heterocycles.
Over 40 years ago, Povarov and colleagues described an addition
reaction between aromatic Schiff bases (dienes) and activated al-
kenes (dienophiles) to give tetrahydroquinolines16 (Scheme 1). In
these manuscripts, they also reported that the tetrahydroquinoline
products could subsequently be oxidized to the corresponding fully
aromatized dihydroquinolines with the elimination of the alkoxy-
or alkyl sulfide group. Interest in the Povarov reaction was rekin-
dled in the 1990s, and significant improvements relating to this
method’s utility have been made. While the mechanism for this
reaction has been the subject of debate, the Povarov reaction has
now grown into a popular and useful strategy for the preparation of
substituted tetrahydroquinolines.17
preference for addition to 6 leading to the b-substituted methylene
group at the anomeric carbon is likely due to the influence of steric
effects experienced by the bicyclic component in the equatorial
plane.24 The steric effects may account for the observation that only
20% of the spiro mixture consists of product (8Minor) in which the
axial substituent from the anomeric carbon is derived from the C2
carbon of the vinyl ether. In addition, we hypothesize that kinetic
and or thermodynamic factors involving the formation of a transi-
tion state also impact the stereocontrol of the reaction and hence
the play a role in the observed spiro product distribution.25
During the course of our experiments, we made note of the
instability of the spiro isomers. In addition to the presence of open-
ring compound 9a in the reaction mixtures, we also observed the
slow, partial conversion of 8Major and 8Minor after chromato-
graphic isolation to 9a at room temperature. We surmise that 9a is
more favorable from the perspective of Gibb’s free energy
Scheme 1. Generalized Povarov reaction sequence.
Previously we have published our preliminary results sur-
rounding the development of a facile one-pot methodology that
was utilized to convert an exo-glycal directly into a novel C-linked,
glycosylidene-based quinoline.18 We herein report additional syn-
thetic efforts in this area, namely the application of the reaction
methodology to several exo-glycals19 and para-substituted benza-
nilines.20 These benzaniline precursors were chosen because steric
effects of the substituents on reactivity would be minimal and
because the product quinolines were desired for subsequent
transformations. We also disclose the results of a series of depro-
tection screening experiments as well as the outcome of the anti-
cancer evaluation of several glucose-derived compounds.
(DG¼
D
HꢀT
DS) than its spiro precursors.
We hypothesize that the observed transformation is driven
enthalpically by the aromatization of the tetrahydroquinoline to
the dihydroquinoline. It is widely accepted that aromatization is an
enthalpically favored process, and it confers additional stability to
the resulting compound due to the delocalization of the pi electrons
2. Results and discussion
within the ring system. Perhaps alkoxy elimination followed by a,b-
unsaturated iminium ion formation and single electron transfer
leads to the formation of the fully aromatized quinoline (Fig. 2).
Aside from enthalpic considerations, 9a has five additional rotat-
able bonds, which make an entropic contribution to the overall
favorability of the process. The capacity for bond rotation of the
In a previous communication, we reported screening experi-
ments utilizing rare earth metal triflates [Sc(OTf)3, Yb(OTf)3, and
Tb(OTf)3] as catalysts for the Povarov reaction between a glucose-
based exo-glycal and benzaniline.18 We observed the formation of

P.H. Dobbelaar, C.H. Marzabadi / Tetrahedron 67 (2011) 9273e9282
9275
Scheme 2. Preparation of sugar-based tetrahydro- and dihydroquinolines.
Table 1
Synthesis of glucose-based quinolines
OBn
BnO
BnO
OH
OBn
R1
OBn
O
R2
Sc(OTf)3, MeCN
MnO2
BnO
BnO
+
N
BnO
CH2
N
R2
R1
7a-k
6
9a-k
Entry
Benzaniline
R1-group
R2-group
Product
Isolated yield
Fig. 2. Proposed mechanism for tetrahydroquinoline conversion to the aromatized
dihydroquinoline.
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
F
H
H
H
H
H
H
F
Br
CN
CF3
OCH3
9a
9b
9c
9d
9e
9f
65%
60%
64%
43%
46%
45%
39%
38%
Br
CN
CF3
OCH3
H
H
H
H
H
open-ring form contrasts with the conformationally ordered py-
ranose sugar and spiroanellated ring system, and the freely rotat-
able bonds create a more disordered compound. We theorize that
the rotational capabilities of 9a provide for an entropic enhance-
ment to the overall favorability of the process. The observed lack of
stability of the spiro conformers also correlates well with the
Povarov addition/oxidation pathway in which alkoxy group elimi-
nation results in an aromatized compound.16
9g
9ha
9i
9
10
11
Not isolated
18%
56%
7j
7k
9ja
9k
a
Reaction required 8 equiv of MnO2 for complete conversion to open-ring
product.
As a result of the instability of the spiro isomers, we decided to
develop reaction conditions to exclusively obtain the open-ring
product, preferably from a one-pot reaction. On the basis of pre-
viously reported catalyst screening results,18 we focused exclusively
on Sc(OTf)3 because it gave the highest ratio of 9a to
8Majorþ8Minor as well as the cleanest reaction.26 In consideration
of original literature by Povarov et al.,16 we decided to add oxidizing
agents to the reaction mixture and quickly determined that 2 equiv
of MnO2 resulted in complete conversion to the open-ring com-
pound 9a in 65% yield.18
diminished yields when compared to the non-substituted phenyl
ring (entries 1, 7e11). Of the substituents evaluated in this series,
the imine substituted with the electron-donating methoxy group
gave the best reaction yield at 56% (entry 11). This compound marks
the only instance in which the product yield in this series is higher
than its counterpart in the series involving the benzaldehyde-
derived phenyl substitutions. The halogen substituted imines 7g
and 7h gave modest yields in the Povarov addition/oxidation se-
quence (entries 7 and 8). For these benzanilines, the electron-
withdrawing inductive effect of the halogens appears to be more
influential than the electron-releasing resonance effect. In addition,
the experiment involving the benzaniline with the electron-
withdrawing trifluoromethyl group gave the lowest yield at 18%
(entry 10). In the case of cyano-substituted imine 7i, the expected
product was not isolated (entry 9). In general, the reaction yield in
the aniline ring substituted series is negatively affected by the
presence of para-substituents. This effect is most pronounced with
imines containing an electron-withdrawing group in the para po-
sition. We theorize that removal of electron density from the
aniline-derived phenyl group renders the pi-bond electrons of the
aromatic ring less available for attack of the positively charged
anomeric carbon. In contrast, release of electron density into the
ring by the methoxy group more favorably impacts ring closure.
Nevertheless, this procedure represents an effective way to access
unique carbohydrate-based quinolines.
With these reaction conditions in hand, we applied this one-pot
Povarov addition/oxidation procedure to
a series of para-
substituted benzanilines in order to evaluate the electronic effect of
substituents on this reaction. First we chose to examine para-
substituted benzanilines in which the R-group is derived from the
benzaldehyde precursor. The halogen substituted benzanilines 7b
and 7c (Table 1, entries 2 and 3) reacted efficiently to form the
resulting open-ring, glucose-based quinolines. The yields, which
exceeded 60%, were very similar when compared to benzaniline 7a
(entry 1). The electron-withdrawing inductive effect of the halo-
gens acts in a manner opposite to the electron-donating resonance
effect, resulting in no net impact on the reaction yields. Reactions of
imines with an electron-withdrawing group, such as a cyano or
trifluoromethyl substituent, resulted in lowered yields of product
(entries 4 and 5). Product recovery was also reduced when ben-
zaniline was substituted with an electron-donating methoxy group
(entry 6).
We next employed this methodology with imines in which the
aniline-derived phenyl ring is para-substituted. In these experi-
ments, reactions of all substituted benzanilines resulted in
In order to probe the generality of the reaction and further ex-
pand our one-pot methodology to other sugars, we chose to utilize
an exo-glycal that is derived from a five-membered ring sugar. This

9276
P.H. Dobbelaar, C.H. Marzabadi / Tetrahedron 67 (2011) 9273e9282
addition/oxidation procedure was successfully applied to exo-glycal
10, and a small series of compounds was prepared. Arabinose-
derived quinoline 11a was synthesized in 57% yield from benzani-
line 7a (Table 2, entry 1). We also attempted this reaction with
several para-substituted benzanilines and isolated open-ring
arabinose-derived quinolines in moderate yields (entries 2e4).
With exception of the reaction with benzaniline 7a, none of the
reaction yields exceeded 50%. Interestingly, all of the oxidations
with arabinose-derived exo-glycal 10 ultimately required 8.0 equiv
of MnO2 to help drive the reaction toward complete conversion to
the open-ring form. This observation indicates that the arabinose-
spiroanellated tetrahydroquinoline diastereomers are less suscep-
tible to ring opening than the spiro products in the glucose series.
Perhaps this is due to entropic factors, as only four rotatable bonds
result from a ring-opening event as compared to five for the glucose
series. This one-pot procedure, however, can be utilized to effec-
tively synthesize novel carbohydrate-based quinolines from
pentose-derived exo-glycals.
derived quinolines 13b and 13g (entries 2 and 3). As with the
arabinose series, the yields for the open-ring products in the ga-
lactose series are lower than the glucose series. This series further
expands the exo-glycal substrate scope and successfully demon-
strates that the method works for hexoses other than glucose.
In order to validate the synthetic utility of the one-pot chem-
istry, we needed to determine conditions to successfully remove
the benzyl protecting groups. Our first attempted debenzylation
experiment with 9a involved a room temperature hydrogenolysis
reaction catalyzed by Pd/C. Unfortunately, after overnight stirring,
no reaction was observed (Table 4, entry 1). We next turned our
focus to Pd-based catalysts at conditions involving higher pressure
and temperature. We did not observe debenzylation of 9a with the
Pd-based catalysts attempted at 40 ꢁC and 40 psi (entries 2 and 3).
Instead we noticed that two double bonds within the quinoline
system were reduced. Subsequent overnight heating of these re-
actions at 60 ꢁC enabled debenzylation, but the remaining three
double bonds of the quinoline system were also hydrogenated
(entries 4 and 5). The results of these screening experiments in-
dicate that conditions involving high pressure and high tempera-
ture do not remove the benzyl groups while leaving the quinoline
system intact.
We next turned our attention to sealed-tube transfer hydroge-
nation conditions with Pearlman’s catalyst and either cyclo-
hexene27 or ammonium formate28 as the hydrogen donor. The
conditions with cyclohexene resulted in debenzylation of com-
pound 9a (entry 6). In addition to 14a, however, we also observed
two unidentified by-products (approximately 25% of the crude re-
action mixture) that were not separable from the desired product.
We attempted similar transfer hydrogenation conditions with
ammonium formate. However, 9a was unreactive toward these
conditions, and we detected only a trace amount of compound in
which one benzyl group was removed (entry 7).
Table 2
Synthesis of arabinose-based quinolines
OH
BnO
R1
OBn
BnO
BnO
Sc(OTf)3, MeCN
MnO2
O
CH2
N
R2
+
Bn
O
R2
N
OBn
R1
7a,b,f,g
10
11a,b,f,g
Entry
Benzaniline
R1-group
R2-group
Product
Isolated yield (%)
1
2
3
4
7a
7b
7f
H
F
OCH3
H
H
H
H
F
11aa
11ba
11fa
11ga
57
47
44
49
7g
Other deprotection attempts focused on the use of Lewis acids to
debenzylate 9a. Although ferric chloride29 successfully removed
the benzyl protecting groups when stirred at room temperature
overnight, the reaction afforded multiple unidentified by-products
(entry 8). Given the promising results with ferric chloride, we de-
cided to try another Lewis acid, boron trichloride.30 To our delight,
this reagent successfully and cleanly cleaved the protecting groups
after 2 h of stirring at ꢀ78 ꢁC (entry 9).18 The boron trichloride-
based deprotection of perbenzylated intermediates 9a, 9b, 11a,
and 13a were carried out, giving the perhydroxylated products in
good yields (Table 5).
a
Reaction required 8 equiv of MnO2 for complete conversion to open-ring
product.
We also decided to target a small series of galactose-derived
quinolines in order to increase the breadth of the one-pot re-
action that we developed with glucose and successfully applied to
arabinose. Galactose was selected as the monosaccharide portion of
the compound because this hexose is a close analogue of glucose,
differing only by the configuration of the C4 chiral center. For this
series of galactose-based compounds, we performed reactions with
several benzanilines (7a, 7b, and 7g) utilized previously. Parent
compound 13a was synthesized in 51% yield (Table 3, entry 1). We
also attempted this reaction with the para-fluoro-substituted
benzanilines and isolated moderate yields of open-ring galactose-
The anticancer properties of several of the synthesized glucose-
based quinolines were evaluated in the National Cancer Institute’s
(NCI’s) 60 cell line screening model.31 Specifically compounds 9a,
14a, 14a HCl Salt32 and 14b were tested at a 10
mM concentration.
Surprisingly, perbenzylated compound 9a displayed the best anti-
cancer profile of the four compounds (Table 6). This compound
exhibited more than 40% growth inhibition for eight separate cell
lines. In addition, leukemia cell lines were most susceptible to 9a.
Deprotected compounds 14a, 14a HCl Salt, and 14b, on the other
hand, displayed an overall similar profile and resulted in little to no
growth inhibitory effect for a majority of the cell lines. The most
favorable results were 20.5% growth inhibition (RXF 393, Renal) for
14a and 17.8% growth inhibition (SR, Leukemia) for 14b. In-
terestingly, 14a HCl Salt was highly effective against the CCRF-CEM
leukemia cell line and led to 68.7% cell growth inhibition. As
a general trend, the tested glucose-based quinolines were most
effective against leukemia cell lines and least effective for mela-
noma cell lines. Despite the modest anticancer properties of 9a, it
was not selected by NCI for dose titration experiments. We con-
clude that the lipophilic benzyl ether protecting groups present in
9a are the structural features responsible for the observed growth
inhibition. Based upon the data, we surmise that the lack of tumor
Table 3
Synthesis of galactose-based quinolines
Entry
Benzaniline
R1-group
R2-group
Product
Isolated yield (%)
1
2
3
7a
7b
7g
H
F
H
H
H
F
13a
13b
13g
51
48
45

P.H. Dobbelaar, C.H. Marzabadi / Tetrahedron 67 (2011) 9273e9282
9277
Table 4
Selected debenzylation screening experiments
OBn
OH
BnO
BnO
HO
HO
OH
OBn
OH
OH
N
N
9a
14a
Entry
1
Reagent
Conditionsa
Resultb
Pd/C (5%, wet)c
H2 balloon, room
No reaction
temperature, ethanol
OBn
BnO
OH
MW¼719e
OBn
2
Pd/C (10%, wet)d
40 ꢁC, 40 psi H2
BnO
N
H
3
4
Pd(OH)2/C (20%, wet)d
Pd/C (10%, wet)d
40 ꢁC, 40 psi H2
60 ꢁC, 40 psi H2
Same as entry 2e
OH
HO
OH
OH
MW¼365e
HO
N
H
5
6
7
8
9
Pd(OH)2/C (20%, wet)d
Pd(OH)2/C (20%, wet)d
Pd(OH)2/C (20%, wet)d
FeCl3 (4.0 equiv per Bn)
BCl3 (1.5e2.0 equiv per Bn)
60 ꢁC, 40 psi H2
Same as entry 4e
90 ꢁC (sealed tube), cyclohexene, ethanol
14a, w25% by-products (MW-18, MW-16)
Mostly 9a, trace loss of 1 Bn group
14a, numerous unidentified by-products
14a, clean
90 ꢁC (sealed tube), ammonium formate, ethanol
Dichloromethane, 0 ꢁC to room temperature, overnight
Dichloromethane, 2 h
a
Stirred overnight in methanol unless otherwise noted.
Determined by HPLC/MS analysis.
Substrate to catalyst ratio is (1:0.5 wtsub/wtcat).
Substrate to catalyst ratio is (1:1 wtsub/wtcat).
Tentative structural assignment.
b
c
d
e
cell growth suppression involving 14a,14a HCl Salt, and 14b may be
attributed to insufficient DNA intercalation.
not possess sufficient broad-based anticancer activity to warrant
further dose titration studies.
3. Conclusion
4. Experimental section
4.1. General remarks
We have developed and expanded the scope of a facile, one-pot
method based upon the Povarov reaction to prepare novel C-gly-
cosylated quinolines. The reaction proceeds through the stereo-
selective formation of sugar-spiroanellated tetrahydroquinoline
intermediates. These compounds are subsequently oxidized and
undergo sugar ring opening to form the fully aromatized quino-
lines. This one-pot methodology has been efficiently employed
with several sugar exo-glycals and a series of para-substituted
benzanilines to prepare novel open-ring, glycosylidene-derived
quinolines. Extensive deprotection experiments were carried out,
and facile debenzylation occurs with the use of boron trichloride.
The successful debenzylation chemistry demonstrates that this
one-pot, scandium triflate-catalyzed Povarov reaction followed by
manganese dioxide oxidation is an expeditious way to obtain novel
C-glycosylated quinolines. Some of the glucose analogues have
been tested in the NCI60 human tumor cell line anticancer screen.
Although several leukemia cell lines experienced modest growth
inhibition when treated with 9a, the glucose-linked quinolines do
All reactions were performed under a nitrogen atmosphere un-
less otherwise noted. Anhydrous solvents were purchased com-
mercially and were used as received. Unless otherwise specified,
commercially available reagents were used without further purifi-
cation. Nuclear magnetic resonance spectra were taken on a 500 or
600 MHz spectrometer in CDCl3, CD3CN, or CD3OD as solvent using
tetramethylsilane as an internal standard. High resolving power
accurate mass measurement electrospray (ESIþ) mass spectral data
were acquired by use of a Fourier transform ion cyclotron resonance
mass spectrometer (FT-ICR MS). External calibration was accom-
plished with oligomers of polypropylene glycol. IR spectra were
obtained as thin films on NaCl plates. Melting points values are
uncorrected unless otherwise noted. Rotation values were obtained
through use of a polarimeter at room temperature. Silica gel column
chromatography was conducted with an automated chromatogra-
phy system and Teledyne Isco columns. Thin layer chromatography

9278
P.H. Dobbelaar, C.H. Marzabadi / Tetrahedron 67 (2011) 9273e9282
Table 5
was carried out with Whatman MK6F silica gel TLC plates. Pre-
Boron trichloride-based debenzylation
parative scale HPLC was conducted with a mass directed reverse
phase HPLC system. Analytical HPLC/MS was conducted on an HPLC
system equipped with a 3.0ꢂ50 mm XTerra C-18 column utilizing
solvents buffered with 0.05% TFA. The following method was used:
a gradient of 10e98% MeCN in H2O for 3.75 min, then 98% MeCN in
H2O for 1.0 min. Lowresolution mass spectrometryelectrospray (ES)
analysis was performed on the analyte. Preparative scale HPLC of
chiral samples was carried out with a semi-preparative HPLC
Entry
Perbenzylated
starting
material
Perhydroxylated
product
Isolated
yield (%)
OH
equipped with a 20ꢂ250 mm ChiralPak IB column, 5
mm, 9 mL/min
HO
HO
flow rate. Screening conditions of chiral samples were performed
OH
OH
with an analytical HPLC equipped with chiral columns.
1
9a
69
63
63
4.2. Procedure for the preparation and separation of
8MajorD8Minor
N
To a solution of exo-glycal 6 (100 mg; 0.186 mmol) in acetoni-
trile (1 mL, unopened Sure/SealÔ bottle) was added benzaniline 7a
(33.7 mg; 0.186 mmol) followed by Sc(OTf)3 (18.3 mg;
0.0372 mmol). The reaction was stirred at room temperature under
an atmosphere of nitrogen for 1 h. The reaction was concentrated in
vacuo, and the crude material was purified over silica gel, eluting
14a
OH
HO
HO
OH
OH
2
9b
with
a gradient of 0e40% ethyl acetate in hexane to give
8Majorþ8Minor as a colorless oil (4:1 mixture of diastereomers) in
65% yield. The isomers were separated by applying the preparative
N
scale version (20ꢂ250 mm ChiralPak IB column, 5
flow rate) of the following analytical chromatography conditions:
m particle size,10% ethanol in
mm, 9 mL/min
F
14b
ChiralPak IB 4.6ꢂ250 mm column, 5
m
OH
OH
heptane (isocratic), 0.5 mL/min flow rate, 254 nm wavelength, re-
tention time: 8Minor (8.48 min), 8Major (13.89 min).
HO
HO
4.2.1. (2R,20R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)
methyl]-20-phenyl-20,3,30,4,5,6-hexahydro-1H0-spiro[pyran-2,40-quin-
3
11a
oline] (8Major). Isolated as a colorless oil; ½a D22
ꢀ13.5 (c 1.0, CHCl3);
ꢃ
N
1H NMR (500 MHz, CDCl3):
d
7.62 (d, J¼7.5 Hz,1H), 7.42e7.37 (m, 2H),
7.36e7.25 (m,19H), 7.20e7.11 (m, 5H), 6.78 (t, J¼7.25 Hz, 1H), 6.58 (d,
J¼6.5 Hz, 1H), 4.73 (d, J¼11.0 Hz, 1H), 4.67e4.54 (m, 4H), 4.54e4.43
(m, 2H), 4.41e4.31 (m, 2H), 4.31e4.24 (m, 1H), 4.15e4.12 (m, 1H),
4.06e4.03 (m, 1H), 4.02e3.97 (m, 1H), 3.84e3.75 (m, 2H), 2.64 (dd,
J¼13.25, 4.75 Hz, 1H), 2.22e2.16 (m,1H); 13C NMR (126 MHz, CDCl3):
15a
OH
HO
HO
OH
OH
d
145.1,144.4,139.0,138.8,138.4,138.2,129.9,128.9,128.7,128.6,128.5,
128.4, 128.1, 128.0, 127.95, 127.91, 127.87, 127.5, 126.9, 123.2, 116.9,
113.7, 84.9, 79.9, 78.9, 76.3, 73.8, 73.6, 73.3, 72.4, 70.2, 55.2, 42.8; IR
4
13a
60
(NaCl):3405, 3038, 2911, 2795,1778,1607,1491,1362,1094,698 cmꢀ1
;
N
HRMS calcd for C48H48NOþ5 [MþHþ]: 718.3527, found 718.3529.
16a
4.2.2. (2S,20R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)
methyl]-20-phenyl-20,3,30,4,5,6-hexahydro-1H0-spiro[pyran-2,40-quin-
oline] (8Minor). Isolated as a colorless oil; ½a D22
þ40.2 (c 1.0,
ꢃ
CHCl3); 1H NMR (500 MHz, CDCl3):
d
7.55 (d, J¼7.5 Hz, 1H),
7.46e7.12 (m, 26H), 6.68 (t, J¼7.25 Hz, 1H), 6.60 (d, J¼8.0 Hz, 1H),
5.07e5.00 (m, 2H), 4.98e4.88 (m, 3H), 4.80e4.67 (m, 2H),
4.68e4.56 (m, 3H), 3.89e3.85 (m, 1H), 3.83e3.75 (m, 2H),
3.68e3.62 (m, 2H), 2.22 (t, J¼12.75 Hz, 1H), 1.91 (dd, J¼12.75,
Table 6
Selected results from the NCI60 human tumor cell line anticancer drug screen assay
Compound
Cell line
Growth percent at 10 mM
3.75 Hz,1H); 13C NMR (126 MHz, CDCl3):
d 145.9,144.4,138.9,138.8,
9a
9a
9a
9a
9a
9a
9a
9a
MOLT-4 (Leukemia)
HL-60(TB) (Leukemia)
HOP-92 (Non-Small Cell Lung)
T-47D (Breast)
40.0
45.8
54.3
56.6
57.1
58.1
58.4
59.9
79.5
31.3
82.2
138.6, 130.8, 129.3, 128.9, 128.7, 128.6, 128.4, 128.3, 128.1, 128.0,
128.0, 127.9, 127.9, 127.8, 127.5, 127.4, 127.2, 117.7, 115.4, 114.9, 87.1,
86.6, 79.9, 76.3, 76.1, 75.8, 75.2, 73.4, 71.3, 69.3, 52.5, 44.4; IR (NaCl):
3405, 3038, 2911, 2795, 1778, 1607, 1491, 1362, 1094, 698 cmꢀ1
;
PC-3 (Prostate)
MDA-MB-468 (Breast)
HCT-116 (Colon)
HRMS calcd for C48H48NOþ5 [MþHþ]: 718.3527, found 718.3529.
NCI-H23 (Non-Small Cell Lung)
14a
14a HCl Salt
14b
RXF 393 (Renal)a
CCRF-CEM (Leukemia)
(SR, Leukemia)a
4.3. Representative example of the general procedure for the
preparation of open-ring glycosylidene-derived quinolines
a
To a solution of exo-glycal 6 (100 mg; 0.186 mmol) in acetoni-
trile (1 mL, unopened Sure/SealÔ bottle) was added substituted
Denotes compound’s best result; no cell line tested for the compound had
a growth percent under 60.

P.H. Dobbelaar, C.H. Marzabadi / Tetrahedron 67 (2011) 9273e9282
9279
benzaniline derivative 7a (33.7 mg; 0.186 mmol) followed by
Sc(OTf)3 (18.3 mg; 0.0372 mmol). The reaction was stirred at room
temperature under an atmosphere of nitrogen. After 2 h, MnO2
(32.4 mg; 0.372 mmol) was added and the mixture was stirred
overnight. The reaction was diluted with ethyl acetate (15 mL),
filtered through Celite, and concentrated. The crude material was
purified over silica gel, eluting with a gradient of 0e40% ethyl ac-
etate in hexane, to give 9a.
J¼7.5 Hz, 2H), 5.66 (d, J¼1.5 Hz, 1H), 4.70e4.54 (m, 6H), 4.44 (d,
J¼11.50 Hz,1H), 4.10e4.05 (m, 2H), 4.02 (br s,1H), 3.94 (m,1H), 3.77
(dd, J¼10.0, 3.5 Hz, 1H), 3.67 (dd, J¼10.0, 5.0 Hz, 1H), 3.01 (br s, 1H);
13C NMR (126 MHz, CDCl3):
d 154.6, 148.7, 146.4, 143.7, 138.4, 138.3,
137.4, 137.3, 132.8, 131.0, 130.0, 129.0, 128.8, 128.7, 128.5, 128.4,
128.24, 128.19, 128.1, 127.9, 127.4, 125.9, 123.2, 119.2, 118.4, 113.0,
82.0, 77.9, 76.9, 75.1, 74.1, 73.8, 72.2, 72.0, 71.3; IR (NaCl): 3556,
3030, 2829, 2227, 1779, 1597, 1073, 699 cmꢀ1; HRMS calcd for
C49H45N2Oþ5 [MþHþ]: 741.3323, found 741.3322.
4.3.1. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-(2-phenylquinolin-4-yl)-D-
arabinitol (9a). Isolated in 65% yield as a colorless oil; ½a D22
ꢃ
þ67.3 (c
4.3.5. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-{2-[4-(trifluoromethyl)phe-
nyl]quinolin-4-yl}-D-arabinitol (9e). Isolated in 46% yield as a color-
1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d
8.27 (d, J¼8.5 Hz, 1H), 8.19
(s, 1H), 8.16 (d, J¼7.0 Hz, 2H), 8.03 (d, J¼6.5 Hz, 1H), 7.74 (t,
J¼7.75 Hz, 1H), 7.56e7.49 (m, 3H), 7.42e7.31 (m, 14H), 7.30e7.25
(m, 2H), 7.08 (t, J¼7.5 Hz, 1H), 7.00 (t, J¼7.5 Hz, 2H), 6.89 (d,
J¼7.5 Hz, 2H), 5.65 (d, J¼1.5 Hz, 1H), 4.67e4.56 (m, 6H), 4.39 (d,
J¼11.5 Hz, 1H), 4.16 (m, 1H), 4.11e4.03 (m, 2H), 3.92 (m, 1H), 3.76
(dd, J¼10.0, 3.75 Hz, 1H), 3.68 (dd, J¼10.0, 5.0 Hz, 1H), 3.05 (br s,
less oil; ½a 2D2
ꢃ
þ53.7 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d 8.26
(d, J¼8.5 Hz, 1H), 8.21 (d, J¼8.0 Hz, 2H), 8.15 (s, 1H), 8.04 (d,
J¼8.0 Hz, 1H), 7.79e7.73 (m, 3H), 7.45e7.31 (m, 14H), 7.29e7.26 (m,
2H), 7.07 (t, J¼7.5 Hz, 1H), 6.97 (t, J¼7.5 Hz, 2H), 6.84 (d, J¼7.5 Hz,
2H), 5.65 (d, J¼2.0 Hz, 1H), 4.68e4.55 (m, 6H), 4.44 (d, J¼11.5 Hz,
1H), 4.14e4.05 (m, 2H), 4.03 (s, 1H), 3.93 (m, 1H), 3.76 (dd, J¼9.75,
3.75 Hz, 1H), 3.67 (dd, J¼10.0, 5.0 Hz, 1H), 3.01 (br s, 1H); 13C NMR
1H); 13C NMR (126 MHz, CDCl3):
d 157.0, 148.7, 145.7, 139.5, 138.4,
138.3, 137.5, 137.3, 130.8, 129.7, 129.6, 129.1, 128.86, 128.77, 128.72,
128.70, 128.66, 128.3, 128.25, 128.18, 128.1, 128.0, 128.0, 127.9, 126.6,
125.6, 123.1, 118.7, 81.7, 78.0, 77.0, 75.1, 74.0, 73.8, 72.1, 71.9, 71.4; IR
(NaCl): 3676, 2836, 2364, 2016, 1724, 1598, 1075, 697 cmꢀ1; HRMS
calcd for C48H46NOþ5 [MþHþ]: 716.3371, found 716.3377.
(126 MHz, CDCl3): d 155.3, 148.5, 146.4, 142.8, 138.4, 138.3, 137.4,
137.2, 130.8, 129.9, 128.83, 128.8, 128.7, 128.5, 128.4, 128.22, 128.18,
128.1, 128.0, 127.9, 127.2, 125.95, 125.92, 125.8, 123.2, 118.5, 81.8,
77.9, 77.3, 75.1, 74.1, 73.8, 72.2, 72.0, 71.3; IR (NaCl): 3549, 3030,
2865, 1598, 1324, 1107, 698 cmꢀ1; HRMS calcd for C49H45F3NOþ5
[MþHþ]: 784.3244, found 784.3242.
Compounds 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9j, 9k, 11a, 11b, 11f, 11g,
13a, 13b, and 13g were prepared in a manner analogous to 9a uti-
lizing the appropriate exo-glycal and benzaniline starting materials.
4.3.6. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-[2-(4-methoxyphenyl)quino-
lin-4-yl]- -arabinitol (9f). Isolated in 45% yield as a colorless oil;
D
4.3.2. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-[2-(4-fluorophenyl)quinolin-
½
a 2D2
ꢃ
þ40.2 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.23 (d,
4-yl]-
D
-arabinitol (9b). Isolated in 60% yield as a colorless oil; ½a D22
ꢃ
J¼8.5 Hz,1H), 8.13 (d, J¼9.0 Hz, 3H), 8.02 (br s, 1H), 7.72 (t, J¼8.5 Hz,
2H), 7.58 (m, 1H), 7.52e7.47 (t, J¼8.5 Hz, 1H), 7.40e7.31 (m, 12H),
7.30e7.26 (m, 2H), 7.12e6.97 (m, 4H), 6.91 (d, J¼7.0 Hz, 2H), 5.63 (br
s, 1H), 4.68e4.53 (m, 6H), 4.44 (d, J¼11.5 Hz,1H), 4.20e4.12 (m, 1H),
4.07 (m, 3H), 3.94 (s, 3H), 3.76 (dd, J¼10.0, 3.75 Hz, 1H), 3.68 (dd,
J¼9.85, 5.0 Hz, 1H), 3.09 (br s, 1H); 13C NMR (126 MHz, CDCl3):
þ74.2 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d
8.24 (d, J¼8.0 Hz,
1H), 8.12 (t, J¼6.7 Hz, 3H), 8.03 (d, J¼7.5 Hz, 1H), 7.74 (t, J¼7.75 Hz,
1H), 7.42e7.31 (m, 14H), 7.30e7.26 (m, 2H), 7.20 (t, J¼8.75 Hz, 2H),
7.09 (t, J¼7.5 Hz,1H), 7.00 (t, J¼7.5 Hz, 2H), 6.88 (d, J¼7.0 Hz, 2H), 5.64
(d, J¼2.0 Hz, 1H), 4.68e4.55 (m, 6H), 4.44 (d, J¼11.5 Hz, 1H),
4.14e4.10 (m,1H), 4.10e4.03(m,1H), 4.04(brs,1H), 3.92(m,1H), 3.76
(dd, J¼9.75, 3.75 Hz, 1H), 3.68 (dd, J¼9.75, 4.75 Hz, 1H), 3.05 (br s,
d
138.4, 138.3, 137.4, 137.1, 133.2, 132.4, 132.3, 132.2, 128.9, 128.8,
128.72, 128.67, 128.4, 128.18, 128.14, 128.1, 128.1, 128.0, 125.2, 123.1,
118.5, 114.6, 81.6, 77.9, 77.0, 75.0, 74.1, 73.8, 72.2, 72.0, 71.3, 55.7; IR
(NaCl): 3555, 2912, 2008, 1601, 1503, 1118, 697 cmꢀ1; HRMS calcd
for C49H48NOþ6 [MþHþ]: 746.3476, found 746.3478.
1H); 13C NMR (126 MHz, CDCl3):
d 165.1, 163.2, 155.9, 148.6, 145.9,
138.4, 138.3, 137.5, 137.3, 130.6, 129.9, 129.8, 129.7, 128.85, 128.79,
128.7, 128.6, 128.4, 128.3, 128.2, 128.18, 128.15, 128.0, 127.9, 126.7,
125.5, 123.1, 118.3, 116.1, 115.9, 81.9, 78.0, 77.0, 75.1, 74.0, 73.8, 72.1,
71.9, 71.3; IR (NaCl): 3649, 2911, 2537, 2356, 2051, 1502, 1090,
697 cmꢀ1; HRMS calcd for C48H45FNO5þ [MþHþ]: 734.3276, found
734.3276.
4.3.7. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-(6-fluoro-2-phenyl quinolin-
4-yl)-
D
-arabinitol (9g). Isolated in 39% yield as a colorless oil; ½a D22
ꢃ
þ48.9 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.26e8.20 (m,
1H), 8.18e8.09 (m, 3H), 7.77 (d, J¼9.25 Hz, 1H), 7.56e7.48 (m, 4H),
7.41e7.28 (m, 15H), 7.06 (t, J¼7.25 Hz, 1H), 6.97 (t, J¼7.5 Hz, 2H),
6.84 (d, J¼7.5 Hz, 2H), 5.48 (d, J¼2.5 Hz, 1H), 4.69e4.56 (m, 6H),
4.42 (d, J¼11.5 Hz, 1H), 4.20e4.11 (m, 1H), 4.09e4.04 (m, 1H),
4.02e3.97 (m, 1H), 3.95e3.90 (m, 1H), 3.75 (dd, J¼9.75, 3.75 Hz,
1H), 3.63 (dd, J¼9.75, 5.25 Hz, 1H), 3.00 (br s, 1H); 13C NMR
4.3.3. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-[2-(4-bromophenyl)quinolin-
4-yl]-
D
-arabinitol (9c). Isolated in 64% yield as a colorless oil; ½a D22
ꢃ
þ39.0 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.24 (br s,1H), 8.11
(s, 1H), 8.05e7.97 (m, 3H), 7.74 (t, J¼7.3 Hz, 1H), 7.64 (d, J¼8.5 Hz,
2H), 7.44e7.32 (m, 14H), 7.29e7.26 (m, 2H), 7.09 (t, J¼7.5 Hz, 1H),
7.01e6.96 (m, 2H), 6.86 (d, J¼7.0 Hz, 2H), 5.64 (d, J¼2.0 Hz, 1H),
4.67e4.56 (m, 6H), 4.43 (d, J¼11.5 Hz,1H), 4.14e4.04 (m, 2H), 4.03 (s,
1H), 3.93 (m, 1H), 3.76 (dd, J¼9.75, 3.75 Hz, 1H), 3.67 (dd, J¼9.75,
(126 MHz, CDCl3):
d 161.5, 159.6, 156.4, 146.1, 145.0, 144.9, 139.5,
138.3, 138.2, 137.4, 137.1, 133.34, 133.27, 129.7, 129.1, 128.82, 128.79,
128.7, 128.4, 128.36, 128.32, 128.2, 128.1, 127.9, 127.8, 126.2, 126.1,
119.7, 119.5, 119.3, 107.2, 107.0, 81.3, 77.8, 77.6, 75.0, 74.1, 73.7, 72.1,
5.0 Hz,1H), 3.03 (br s,1H); 13C NMR (126 MHz, CDCl3):
d 155.7,138.4,
138.3,137.4,137.3,132.2,130.8,129.8,129.5,128.9,128.8,128.7,128.6,
128.4, 128.3, 128.2, 128.17, 128.09, 128.03, 127.95, 127.9, 126.8, 125.6,
123.1,118.2, 81.8, 78.0, 77.5, 75.1, 74.0, 73.8, 72.1, 71.9, 71.3; IR (NaCl):
3567, 3030, 2868, 1958, 1596, 1073, 698 cmꢀ1; HRMS calcd for
C48H45BrNOþ5 [MþHþ]: 794.2476, found 794.2504.
71.9, 71.2; IR (NaCl): 3419, 2927, 2360, 1724, 1625, 1073, 697 cmꢀ1
;
HRMS calcd for C48H45FNOþ5 [MþHþ]: 734.3276, found 734.3300.
4.3.8. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-(6-bromo-2-phenyl quinolin-
4-yl)-
D
-arabinitol (9h). Isolated in 38% yield as a colorless oil; ½a D22
ꢃ
þ59.8 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.30 (s, 1H),
4.3.4. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-[2-(4-cyanophenyl)quinolin-
8.17e8.06 (m, 4H), 7.80 (dd, J¼9.0, 2.0 Hz, 1H), 7.57e7.49 (m, 3H),
7.40e7.28 (m, 15H), 7.06 (t, J¼7.25 Hz, 1H), 6.98 (t, J¼7.25 Hz, 2H),
6.85 (d, J¼7.5 Hz, 2H), 5.53 (d, J¼2.5 Hz, 1H), 4.70e4.62 (m, 3H),
4.61e4.55 (m, 3H), 4.43 (d, J¼11.5 Hz, 1H), 4.16e4.08 (m, 2H),
3.99e3.96 (m, 1H), 3.93e3.89 (m, 1H), 3.74 (dd, J¼9.75, 3.75 Hz,
1H), 3.63 (dd, J¼9.75, 5.25 Hz, 1H), 3.04 (s, 1H); 13C NMR (126 MHz,
4-yl]-
D
-arabinitol (9d). Isolated in 43% yield as a colorless oil; ½a D22
ꢃ
þ56.3 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
8.25 (d, J¼8.5 Hz,
d
1H), 8.20 (d, J¼8.0 Hz, 2H), 8.14 (s, 1H), 8.05 (d, J¼8.0 Hz, 1H),
7.82e7.74 (m, 3H), 7.44 (t, J¼7.5 Hz, 1H), 7.40e7.32 (m, 13H), 7.28
(m, 2H), 7.07 (t, J¼7.25 Hz, 1H), 6.97 (t, J¼7.5 Hz, 2H), 6.84 (d,

9280
P.H. Dobbelaar, C.H. Marzabadi / Tetrahedron 67 (2011) 9273e9282
CDCl3):
d
157.3, 147.6, 144.7, 139.3, 138.3, 137.4, 137.1, 132.9, 132.6,
1724, 1598, 1450, 1073, 737, 698 cmꢀ1; HRMS calcd for C40H37FNOþ4
129.9, 129.1, 128.79, 128.75, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0,
127.9, 126.8, 125.7, 120.6, 119.5, 81.4, 77.5, 77.3, 74.9, 73.9, 73.8, 72.2,
71.9, 71.3; IR (NaCl): 3442, 2927, 2091, 1643, 1072, 697 cmꢀ1; HRMS
calcd for C48H45BrNOþ5 [MþHþ]: 794.2476, found 794.2513.
[MþHþ]: 614.2706, found 614.2707.
4.3.13. (2R,3R,4S)-1,3,4-Tris(benzyloxy)-4-[2-(4-methoxyphenyl)qui-
nolin-4-yl]butan-2-ol (11f). Isolated in 44% yield as a colorless
oil;½a 2D2
ꢃ
ꢀ31.9 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.25e8.23
4.3.9. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-[2-phenyl-6-(trifluoromethyl)
(m, 2H), 8.18 (d, J¼9.0 Hz, 2H), 7.95 (d, J¼8.5 Hz,1H), 7.75 (t, J¼7.5 Hz,
1H), 7.46 (t, J¼7.25 Hz, 1H), 7.39e7.33 (m, 10H), 7.08e7.06 (m, 3H),
6.98 (t, J¼7.5 Hz, 2H), 6.76 (d, J¼7.5 Hz, 2H), 5.67 (s, 1H), 4.74 (d,
J¼12.0 Hz, 1H), 4.55 (s, 2H), 4.40 (d, J¼12.0 Hz, 1H), 4.16 (s, 1H), 4.08
(d, J¼10.5 Hz,1H), 3.94 (s, 3H), 3.85 (m, 1H), 3.74e3.68 (m, 3H), 2.68
quinolin-4-yl]- -arabinitol (9j). Isolated in 18% yield as a colorless
D
oil; ½a 2D2
ꢃ
þ47.0 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.49 (s,
1H), 8.31 (d, J¼8.5 Hz, 1H), 8.20 (s, 1H), 8.17e8.14 (m, 2H),
7.91e7.87 (m, 1H), 7.57e7.52 (m, 3H), 7.40e7.29 (m, 13H),
7.27e7.24 (m, 2H), 7.02 (t, J¼7.25 Hz, 1H), 6.93 (t, J¼7.5 Hz, 2H),
6.81 (d, J¼7.5 Hz, 2H), 5.58 (d, J¼2.5 Hz, 1H), 4.73e4.49 (m, 6H),
4.43 (d, J¼11.5 Hz, 1H), 4.20e4.14 (m, 1H), 4.10e4.05 (m, 1H),
4.01e3.97 (m, 1H), 3.89e3.84 (m, 1H), 3.70 (dd, J¼9.75, 3.5 Hz, 1H),
3.58 (dd, J¼9.75, 5.5 Hz, 1H), 2.99 (d, J¼4.5 Hz, 1H); 13C NMR
(br s, 1H); 13C NMR (126 MHz, CDCl3):
d 161.1, 156.7, 148.8, 145.0,
138.0, 137.6, 137.0, 132.4, 130.8, 129.4, 129.3, 129.0, 128.82, 128.78,
128.7, 128.4, 128.3, 128.27, 128.24, 127.9, 126.3, 125.3, 122.7, 118.0,
114.4, 80.7, 75.4, 74.8, 73.8, 72.1, 71.3, 70.2, 55.7; IR (NaCl): 3450,
3033, 2927, 1723, 1599, 1453, 1072, 737, 698 cmꢀ1; HRMS calcd for
C41H40NOþ5 [MþHþ]: 626.2906, found 626.2918.
(126 MHz, CDCl3):
d 159.0, 150.0, 146.6, 139.1, 138.3, 138.2, 137.3,
137.0, 132.0, 130.2, 129.2, 128.8, 128.7, 128.6, 128.4, 128.2, 128.1,
128.04, 127.98, 127.9, 125.1, 124.7, 121.6, 119.8, 81.2, 77.5, 77.3, 77.0,
74.9, 73.9, 73.7, 72.3, 71.5; IR (NaCl): 3555, 2927, 1727, 1274, 1073,
698 cmꢀ1; HRMS calcd for C49H45F3NO5þ [MþHþ]: 784.3244, found
784.3267.
4.3.14. (2R,3R,4S)-1,3,4-Tris(benzyloxy)-4-[6-fluoro-2-
phenylquinolin-4-yl]butan-2-ol (11g). Isolated in 49% yield as a col-
orless oil; ½a 2D2
ꢃ
ꢀ21.3 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d
8.28e8.21 (m, 2H), 8.16 (d, J¼7.0 Hz, 2H), 7.63 (d, J¼9.0 Hz, 1H),
7.58e7.48 (m, 5H), 7.40e7.31 (m, 9H), 7.05 (t, J¼7.5 Hz, 1H), 6.96 (t,
J¼7.5 Hz, 2H), 6.74 (d, J¼7.5 Hz, 2H), 5.51 (s, 1H), 4.70 (d, J¼12.0 Hz,
1H), 4.62e4.51 (m, 2H), 4.39 (d, J¼12.0 Hz, 1H), 4.28e4.23 (m, 1H),
4.18e4.12 (m, 1H), 3.82e3.65 (m, 4H); 13C NMR (126 MHz, CDCl3):
4.3.10. (1R)-1,2,3,5-Tetra-O-benzyl-1-C-(6-methoxy-2-phenyl)quino-
lin-4-yl]- -arabinitol (9k). Isolated in 56% yield as a colorless oil;
D
½
a 2D2
ꢃ
þ56.0 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.21e8.13 (m,
4H), 7.54 (t, J¼7.5 Hz, 2H), 7.53e7.47 (m, 1H), 7.45e7.33 (m, 15H),
7.28e7.24 (m, 2H), 7.14 (t, J¼7.25 Hz,1H), 7.07 (t, J¼7.25 Hz, 2H), 6.99
(d, J¼7.0 Hz, 2H), 5.58 (d, J¼3.0 Hz, 1H), 4.70e4.54 (m, 6H), 4.43 (d,
J¼11.5 Hz, 1H), 4.31e4.23 (m, 1H), 4.14e4.07 (m, 2H), 3.90e3.84 (m,
1H), 3.74 (dd, J¼9.5, 3.5 Hz,1H), 3.69e3.64 (m, 4H), 3.00 (d, J¼4.0 Hz,
d 161.6, 159.6, 156.5, 145.9, 145.1, 145.0, 139.4, 137.8, 137.4, 136.8,
133.3, 133.2, 129.7, 129.1, 128.9, 128.8, 128.7, 128.5, 128.3, 128.25,
128.21, 127.9, 127.8, 126.2, 126.1, 119.8,119.6, 119.2,106.9,106.7, 80.5,
76.0, 74.7, 73.9, 72.3, 71.1, 70.1; IR (NaCl): 3461, 3031, 2925, 2363,
1723, 1623, 1496, 1072, 738, 697 cmꢀ1; HRMS calcd for C40H37FNOþ4
[MþHþ]: 614.2706, found 614.2731.
1H); 13C NMR (126 MHz, CDCl3):
d 158.0, 154.8, 145.1, 143.8, 139.9,
138.6, 138.3, 137.7, 137.6, 132.3, 129.2, 129.04, 128.96, 128.8, 128.7,
128.6, 128.32, 128.29, 128.2, 128.1, 128.0, 127.9, 127.7, 126.7, 122.0,
119.0, 101.9, 81.9, 77.7, 77.6, 77.1, 75.4, 73.7, 72.2, 71.7, 71.5, 55.6; IR
(NaCl): 3418, 2930, 2015,1622,1497,1073, 697 cmꢀ1; HRMS calcd for
C49H48NOþ6 [MþHþ]: 746.3476, found 746.3508.
4.3.15. (5R)-1,2,3,5-Tetra-O-benzyl-5-C-(2-phenylquinolin-4-yl)-D-
arabinitol (13a). Isolated in 51% yield as a colorless oil; ½a D22
ꢀ6.9 (c
ꢃ
1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.34 (s,1H), 8.22 (s,1H), 8.16
(d, J¼6.5 Hz, 2H), 8.03 (s,1H), 7.79 (t, J¼7.5 Hz,1H), 7.58e7.48 (m, 4H),
7.40e7.27 (m, 13H), 7.20 (d, J¼6.5 Hz, 2H), 7.08 (t, J¼7.5 Hz,1H), 6.99
(t, J¼7.5 Hz, 2H), 6.90 (d, J¼7.0 Hz, 2H), 5.56 (s,1H), 4.70(d, J¼12.0 Hz,
1H), 4.58 (d, J¼12.0 Hz, 1H), 4.51 (d, J¼12.0 Hz, 1H), 4.46e4.42 (m,
2H), 4.34e4.22 (m, 3H), 4.09e4.07 (m, 2H), 3.83e3.76 (m, 1H),
3.68e3.63 (m, 1H), 3.58e3.53 (m, 1H), 2.56 (br s, 1H); 13C NMR
4.3.11. (2R,3R,4S)-1,3,4-Tris(benzyloxy)-4-(2-phenylquinolin-4-yl)
butan-2-ol (11a). Isolated in 57% yield as a colorless oil; ½a D22
ꢀ44.9
ꢃ
(c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.31e8.27 (m, 2H), 8.21
(d, J¼7.5 Hz, 2H), 7.98 (d, J¼8.0 Hz, 2H), 7.78 (t, J¼7 Hz, 1H),
7.59e7.47 (m, 4H), 7.61e7.14 (m, 10H), 7.07 (t, J¼7.5 Hz, 1H), 6.98 (t,
J¼7.5 Hz, 2H), 6.76 (d, J¼7.0 Hz, 2H), 5.69 (s, 1H), 4.75 (d, J¼12.0 Hz,
1H), 4.56 (s, 2H), 4.41 (d, J¼12.0 Hz, 1H), 4.31e4.27 (m, 1H), 4.11 (d,
J¼11.0 Hz, 1H), 3.86 (d, J¼7.5 Hz, 1H,), 3.77e3.65 (m, 3H), 2.70 (s,
(126 MHz, CDCl3): d 156.9,138.2,138.1,137.6,137.0,130.6,129.9,129.1,
128.80,128.77, 128.74, 128.7, 128.3,128.25,128.19,128.1, 128.0,127.9,
127.0, 125.6, 122.9, 118.6, 80.4, 78.0, 77.3, 75.4, 74.3, 73.5, 71.7, 71.6,
69.5; IR (NaCl): 3674, 2835, 2364, 2015, 1724, 1598, 1073, 697 cmꢀ1
;
1H); 13C NMR (126 MHz, CDCl3):
d
157.2, 148.8, 145.3, 139.8, 138.0,
HRMS calcd for C48H46NOþ5 [MþHþ]: 716.3371, found 716.3405.
137.6, 137.0, 131.0, 129.7, 129.5, 129.3, 129.1, 129.08, 129.02, 128.84,
128.81, 128.79, 128.7, 128.5, 128.3, 128.2, 128.0, 127.9, 126.7, 125.6,
122.8, 118.5, 80.7, 75.5, 74.8, 73.8, 72.2, 71.3, 70.2; IR (NaCl): 3449,
3027, 2983, 1723, 1597, 1484, 1075, 745, 696 cmꢀ1; HRMS calcd for
C40H38NOþ4 [MþHþ]: 596.2801, found 596.2812.
4.3.16. (5R)-1,3,4,5-Tetra-O-benzyl-5-C-[2-(4-fluorophenyl)quinolin-
4-yl]-
D
-arabinitol (13b). Isolated in 48% yield as a colorless oil; ½a D22
ꢃ
ꢀ6.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d
8.27 (d, J¼8.5 Hz,
1H), 8.15e8.06 (m, 3H), 8.02 (s, 1H), 7.78 (t, J¼7.75 Hz, 1H), 7.53 (t,
J¼7.75 Hz, 1H), 7.40e7.27 (m, 13H), 7.23e7.16 (m, 4H), 7.08 (t,
J¼7.0 Hz, 1H), 7.00 (t, J¼7.5 Hz, 2H), 6.89 (d, J¼7.5 Hz, 2H), 5.56 (s,
1H), 4.67 (d, J¼12.0 Hz, 1H), 4.58 (d, J¼12.0 Hz, 1H), 4.55e4.39 (m,
3H), 4.33e4.27 (m, 2H), 4.27e4.21 (m, 1H), 4.13e4.03 (m, 2H),
3.75e3.71 (m, 1H), 3.67e3.64 (m, 1H), 3.58e3.55 (m, 1H), 2.55 (br s,
4.3.12. (2R,3R,4S)-1,3,4-Tris(benzyloxy)-4-[2-(4-fluorophenyl)quino-
lin-4-yl]butan-2-ol (11b). Isolated in 47% yield as a colorless oil;
½
a 2D2
ꢃ
ꢀ43.0 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d 8.26 (d,
J¼8.5 Hz, 1H), 8.21 (s, 1H), 8.19e8.16 (m, 2H), 7.97 (d, J¼8.5 Hz, 1H),
7.80 (t, J¼7.5 Hz, 1H), 7.50 (t, J¼7.5 Hz, 1H), 7.40e7.33 (m, 9H), 7.21
(t, J¼8.5 Hz, 2H), 7.08 (t, J¼7.5 Hz, 2H), 6.98 (t, J¼7.5 Hz, 2H), 6.74 (d,
J¼7.5 Hz, 2H), 5.69 (s, 1H), 4.74 (d, J¼11.5 Hz, 1H), 4.56 (s, 2H), 4.41
(d, J¼12.0 Hz, 1H), 4.31e4.27 (m, 1H), 4.12 (d, J¼11.0 Hz, 1H), 3.84
(dd, J¼7.75, 1.75 Hz, 1H), 3.7e3.68 (m, 3H), 2.68 (s, 1H); 13C NMR
1H); 13C NMR (126 MHz, CDCl3):
d 165.2, 163.2, 155.8, 138.2, 137.6,
137.1, 130.7, 129.9, 128.8, 128.74, 128.69, 128.6, 128.3, 128.25, 128.19,
128.1, 128.0, 127.9, 127.0, 125.5, 123.6, 118.2, 116.1, 115.9, 80.5, 78.0,
77.3, 75.4, 74.4, 73.6, 71.8, 71.6, 69.5; IR (NaCl): 3549, 2915, 2360,
1725, 1503, 1080, 697 cmꢀ1; HRMS calcd for C48H45FNOþ5 [MþHþ]:
734.3276, found 734.3306.
(126 MHz, CDCl3):
d 165.1, 163.1, 156.1, 148.7, 145.5, 137.9, 137.6,
137.0, 136.0, 130.9, 129.85, 129.78, 129.7, 129.0, 128.83, 127.9, 128.6,
128.5, 128.3, 128.2, 128.0, 126.8, 125.4, 122.7, 118.1, 116.1, 115.9, 80.7,
75.4, 74.8, 73.8, 72.2, 71.3, 70.1; IR (NaCl): 3448, 3030, 2962, 2360,
4.3.17. (5R)-1,3,4,5-Tetra-O-benzyl-5-C-(6-fluoro-2-phenylquinolin-
4-yl)-
D
-arabinitol (13g). Isolated in 45% yield as a colorless oil; ½a D22
ꢃ

P.H. Dobbelaar, C.H. Marzabadi / Tetrahedron 67 (2011) 9273e9282
9281
ꢀ5.4 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d
8.25e8.21 (m, 1H),
7.60 (t, J¼7.25 Hz, 1H), 7.56 (t, J¼7.5 Hz, 2H), 7.50 (t, J¼7.25 Hz, 1H),
5.99 (s, 1H), 4.00e3.95 (m, 1H), 3.88 (dd, J¼11.5, 3.5 Hz, 1H), 3.78 (d,
J¼9.0 Hz, 1H), 3.70 (dd, J¼11.5, 5.5 Hz, 1H); 13C NMR (126 MHz,
8.18 (s, 1H), 8.14e8.10 (m, 2H), 7.67 (br s, 1H), 7.55e7.49 (m, 4H),
7.40e7.27 (m, 13H), 7.19 (d, J¼7.0 Hz, 2H), 7.07 (t, J¼6.75 Hz, 1H),
7.00 (t, J¼7.5 Hz, 2H), 6.91 (d, J¼7.0 Hz, 2H), 5.36 (s, 1H), 4.65 (d,
J¼12.0 Hz, 1H), 4.56 (d, J¼12.0 Hz, 1H), 4.51 (d, J¼12.0 Hz, 1H),
4.47e4.42 (m, 2H), 4.28e4.21 (m, 3H), 4.07 (d, J¼7.5 Hz, 1H), 4.00
(d, J¼9.0 Hz, 1H), 3.81 (d, J¼10.5 Hz, 1H), 3.66e3.62 (m, 1H),
3.57e3.53 (m, 1H), 2.58e2.54 (m, 1H); 13C NMR (126 MHz, CDCl3):
CD3OD): d 157.6, 150.8, 148.0, 140.0, 129.3, 129.3, 128.7, 127.7, 126.3,
124.8, 123.1, 117.7, 73.8, 72.0, 67.6, 64.0; IR (NaCl): 3632, 2821, 1794,
1599, 1553, 1505, 1415, 1027, 697 cmꢀ1; HRMS calcd for C19H20NOþ4
[MþHþ]: 326.1392, found 326.1402.
d
156.4, 146.1, 144.7, 139.4, 138.2, 138.1, 137.5, 137.0, 133.42, 133.38,
4.4.4. (5R)-5-C-(2-Phenylquinolin-4-yl)-D-arabinitol (16a). Isolated
129.7, 129.1, 128.81, 128.76, 128.7, 128.4, 128.2, 128.1, 128.08, 128.02,
127.7, 119.9, 119.6, 119.1, 82.2, 80.3, 77.9, 75.4, 74.3, 73.5, 71.7, 71.6,
in 60% yield as a white solid; mp 158e162 ꢁC; ½a D22
ꢀ4.8 (c 0.5,
ꢃ
CH3OH); 1H NMR (500 MHz, CD3OD):
d 8.29 (s, 1H), 8.20 (d,
69.4; IR (NaCl): 3543, 2913, 2360, 1724, 1524, 1073, 697 cmꢀ1
;
J¼8.0 Hz, 1H), 8.17e8.14 (m, 3H), 7.76 (t, J¼8.25 Hz, 1H), 7.62e7.54
HRMS calcd for C48H45FNOþ5 [MþHþ]: 734.3276, found 734.3307.
(m, 3H), 7.52e7.48 (m, 1H), 6.01 (s, 1H), 4.01e3.92 (m, 3H),
3.74e3.70 (m, 2H); 13C NMR (126 MHz, CD3OD):
d 157.6, 151.2,
4.4. Representative example of the general procedure for the
preparation of perhydroxylated open-ring glycosylidene-
derived quinolines
148.0, 140.0, 129.3, 129.2, 128.7, 127.8, 126.3, 124.8, 123.2, 117.7,
115.3, 72.9, 70.7, 70.6, 67.5, 64.0; IR (NaCl): 3630, 2823, 1795, 1599,
1555, 1415, 1027, 697 cmꢀ1; HRMS calcd for C20H22NOþ5 [MþHþ]:
356.1492, found 356.1506.
To
a solution of perbenzylated intermediate 9a (70 mg;
0.098 mmol) in dichloromethane (2.0 mL) at ꢀ78 ꢁC was added
BCl3 (1 M in hexane; 0.39 mL; 0.39 mmol). The reaction was stirred
at ꢀ78 ꢁC under an atmosphere of nitrogen. After 1 h, additional
BCl3 (1 M in hexane; 0.195 mL; 0.195 mmol) was introduced, and
the reaction was maintained at ꢀ78 ꢁC for 1 h. The reaction was
quenched with the addition of methanol (2.0 mL). The crude ma-
terial was concentrated in vacuo. The residue was coevaporated
twice with methanol, and then purified with a mass directed re-
verse phase preparative HPLC system. The following chromato-
graphic conditions were used: (a) column: Waters XbridgeC-18,
Acknowledgements
P.H.D. gratefully acknowledges Merck Research Laboratories,
Rahway, NJ for financial support. P.H.D. also thanks the following
scientists from Merck Research Laboratories: Dr. George A. Doss
and Dr. Mikhail Reibarkh for their assistance with NMR experi-
ments, Dr. R. Scott Hoerrner for assistance with high pressure
hydrogenolysis experiments, Dr. Charles W. Ross III and Kithsiri B.
Herath for HRMS analysis, Eric C. Streckfuss for chromatography
suggestions, Dorothy A. Levorse for salt stoichiometry analysis, and
Dr. Vincent J. Colandrea for useful conversations. P.H.D. expresses
gratitude to Prof. David W. C. MacMillan of Princeton University for
insightful discussions of mechanistic principles. The authors rec-
ognize the National Cancer Institute for testing compounds in the
60 human tumor cell line screen.
30ꢂ75 mm, 5
mm; (b) flow rate: 50 mL/min; (c) mobile phase:
A¼waterþammonium hydroxide (pH 10), B¼acetonitrile; (d) mo-
bile phase method: time¼0 min, A¼98, B¼2; time¼11 min, A¼65,
B¼35; time¼11.2 min, A¼0, B¼100; time¼14.2 min, A¼98, B¼2;
time¼15 min, A¼98, B¼2. The resulting fractions that contained the
desired compound 14a were lyophilized.
Supplementary data
4.4.1. (1R)-1C-(2-Phenylquinolin-4-yl)- -arabinitol (14a). Isolated
D
in 69% yield as a white solid; mp 178e180 ꢁC; ½a D22
þ22.3 (c 1.0,
ꢃ
Characterization data and 1H and 13C NMR spectra. Supple-
mentary data associated with this article can be found, in the online
version, at doi:10.1016/j.tet.2011.09.077.
CH3OH); 1H NMR (500 MHz, CD3OD):
d
8.34 (d, J¼8.0 Hz, 1H), 8.21
(s, 1H), 8.17e8.13 (m, 3H), 7.77 (t, J¼7.75 Hz, 1H), 7.61 (t, J¼7.75 Hz,
1H), 7.56 (t, J¼7.5 Hz, 2H), 7.53e7.48 (m, 1H), 5.73 (d, J¼5.0 Hz, 1H),
4.24 (dd, J¼5.0, 2.0 Hz, 1H), 3.78e3.72 (m, 2H), 3.60e3.55 (m, 1H),
References and notes
3.52 (dd, J¼8.0, 1.5 Hz, 1H); 13C NMR (126 MHz, CD3OD):
d 157.6,
1. Varki, A. Glycobiology 1993, 3, 97.
2. Witczak, Z. J. Curr. Med. Chem. 1995, 1, 392.
3. Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt, W.; Kunz, H. Angew. Chem.,
Int. Ed. 1998, 37, 2503.
150.0, 148.1, 139.7, 129.6, 129.5, 129.1, 128.7, 127.7, 126.4, 125.3,
123.8, 118.2, 72.9, 72.5, 71.9, 71.7, 63.6; IR (NaCl): 3631, 2822, 1794,
1599, 1554, 1415, 1027, 697 cmꢀ1; HRMS calcd for C20H22NOþ5
[MþHþ]: 356.1492, found 356.1496.
4. Pessin, J. E.; Bell, G. I. Annu. Rev. Physiol. 1992, 54, 911.
5. Musser, J. H.; Anderson, M. B.; Fugedi, P. Pharm. News 1996, 3, 11.
6. Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocyles and Health In
Heterocycles in Life and Society; John Wiley: Chichester, UK, 1997; pp 135e164.
7. For a review, see: Campoli-Richards, D. M.; Monk, J. P.; Price, A.; Benfield, P.;
Todd, P. A.; Ward, A. Drug 1988, 35, 373.
8. For a review, see: North, D. S.; Fish, D. N.; Redington, J. J. Pharmacotherapy 1998,
18, 915.
9. (a) Kumar, S.; Bawa, S.; Gupta, H. Mini-Rev. Med. Chem. 2009, 9, 1648; (b) Byler,
K. G.; Wang, C.; Setzer, W. N. J. Mol. Model. 2009, 15, 1417.
10. For reviews, see: (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
52, 15031; (b) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem. 2008, 12, 1116.
11. For references and reviews, see the citations within the corresponding organic
name reaction entries:The Merck Index: An Encyclopedia of Chemicals, Drugs, and
Biologicals, 14th ed; O’Neil, M. J., Heckelman, P. E., Koch, C. B., Roman, K. J., Eds.;;
Merck: Whitehouse Station, NJ, USA, 2006.
12. (a) Nakajima, M.; Itoi, K.; Takamatsu, Y.; Kinoshita, T.; Okazaki, T.; Kawakubo,
K.; Shindo, M.; Honma, T.; Tohjigamori, M.; Haneishi, T. J. Antibiot. 1991, 44, 293;
(b) Haruyama, H.; Takayama, T.; Kinoshita, T.; Kondo, M.; Nakajima, M.; Ha-
neishi, T. J. Chem. Soc., Perkin Trans. 1 1991, 1637.
Compounds 14b, 15a, and 16a were prepared in a manner
analogous to 14a.
4.4.2. (1R)-1C-[2-(4-Fluorophenyl)quinolin-4-yl]-D-arabinitol
(14b). Isolated in 63% yield as a white solid; mp 188e189 ꢁC; ½a D22
ꢃ
þ22.0 (c 0.5, CH3OH); 1H NMR (CD3OD):
d
8.32 (d, J¼8.5 Hz, 1H),
8.23e8.17 (m, 3H), 8.13 (d, J¼8.5 Hz, 1H), 7.76 (t, J¼7.25 Hz, 1H), 7.60
(t, J¼7.5 Hz, 1H), 7.29 (t, J¼8.75 Hz, 2H), 5.72 (d, J¼5.0 Hz, 1H), 4.24
(dd, J¼5.0, 2.0 Hz, 1H), 3.78e3.72 (m, 2H), 3.58 (dd, J¼8.0, 2.0 Hz,
1H), 3.53e3.50 (m, 1H); 13C NMR (126 MHz, CD3OD):
d 156.4, 149.7,
148.3, 129.8, 129.7, 129.6, 129.3, 126.4, 125.2, 123.8, 117.8, 115.5,
115.3, 72.9, 72.4, 71.9, 71.6, 63.6; IR (NaCl): 3630, 2820, 1793, 1598,
1554, 1503, 1412, 1027, 697 cmꢀ1; HRMS calcd for C20H21FNOþ5
[MþHþ]: 374.1404, found 374.1417.
13. (a) Bichard, C. J. F.; Mitchell, E. P.; Wormald, M. R.; Watson, K. A.; Johnson, L. N.;
Zographos, S. E.; Koutra, D. D.; Oikonomakos, N. G.; Fleet, G. W. J. Tetrahedron
Lett. 1995, 36, 2145; (b) Osz, E.; Szilagyi, L.; Somsak, L.; Benyei, A. Tetrahedron
1999, 55, 2419.
4.4.3. (1S,2S,3R)-1-(2-Phenylquinolin-4-yl)-butane-1,2,3,4-tetrol
€
ꢀ
ꢀ
ꢀ
(15a). Isolated in 64% yield as a white solid; mp 175e176 ꢁC; ½a D22
ꢃ
ꢀ16.6 (c 0.5, CH3OH); 1H NMR (500 MHz, CD3OD):
d 8.28 (s, 1H),
14. Li, W.; Zhang, Z.-W.; Wang, S.-X.; Ren, S.-M.; Jiang, T. Chem. Biol. Drug Des. 2009,
74, 80.
8.18 (d, J¼8.50 Hz, 1H), 8.15 (d, J¼8.5 Hz, 3H), 7.76 (t, J¼7.25 Hz, 1H),

9282
P.H. Dobbelaar, C.H. Marzabadi / Tetrahedron 67 (2011) 9273e9282
15. Liu, H.-M.; Liu, F.-W.; Zou, D.-P.; Dai, G.-F. Bioorg. Med. Chem. Lett. 2005, 15, 1821.
16. (a) Povarov, L. S.; Mikhailov, B. M. Russ. Chem. Bull. 1963, 12, 871; (b) Povarov, L.
S.; Grigos, V. I.; Mikhailov, B. M. Russ. Chem. Bull. 1963, 12, 1878; (c) Povarov, L.
S.; Grigos, V. I.; Karakhanov, R. A.; Mikhailov, B. M. Russ. Chem. Bull. 1965, 14,
344; (d) Povarov, L. S.; Grigos, V. I.; Mikhailov, B. M. Russ. Chem. Bull. 1966, 15,
120.
17. For reviews, see: (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656; (b) Glushkov,
V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2008, 77, 137; (c) Kouznetsov, V. V. Tet-
rahedron 2009, 65, 2721.
18. (a) Dobbelaar, P. H.; Marzabadi, C. H. Tetrahedron Lett. 2010, 51, 201; (b) Dob-
belaar, P. H.; Marzabadi, C. H. Presented at the 238th National Meeting of the
American Chemical Society, Washington, D.C., Aug 16e20, 2009; Paper ORGN
709. (c) Marzabadi, C. H.; Dobbelaar, P. H.; Konchalski, K.; Brogden, K. N. Pre-
sented at the 238th National Meeting of the American Chemical Society,
Washington, D.C., Aug 16e20, 2009; Paper CARB 26.
19. exo-Glycals were synthesized in two steps. DesseMartin periodinane oxidation
of the free anomeric alcohol of the commercially available benzyl-protected
sugar followed by lactone olefination with Tebbe reagent gave the required
exo-glycal. For the lactone synthesis experimental procedure, see: Csuk, R.;
Dorr, P. J. Carbohydr. Chem. 1995, 14, 35; for the olefin synthesis experimental
procedure, see: RajanBabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51, 5458.
20. Benzanilines were purchased commercially or synthesized according to pub-
lished literature. For a representative experimental procedure, see: Bigelow, L.
A.; Eatough, H. Org. Synth. 1928, 8, 22.
Ondrus, V. Arkivoc 2005, v, 147; (d) Alves, M. J.; Azoia, N. G.; Fortes, A. G. Tet-
rahedron 2007, 63, 727; (e) Mayr, H.; Ofial, A. R.; Sauer, J.; Schmied, B. Eur. J. Org.
Chem. 2000, 2013.
23. The isolation of a hydrated pre-cyclization intermediate provides evidence to
suggest that the mechanism of this particular reaction occurs as a stepwise
process rather than a concerted one. This anomeric alcohol is formed when the
imine carbon of the benzaniline is added to the C2 carbon of the vinyl ether,
and water is added to the C1 carbon of the vinyl ether.
24. Similar
a
-facial selectivity has been reported for other addition reactions for
€
exo-glycals; see: (a) Colinas, P. A.; Jager, V.; Lieberknecht, A.; Bravo, R. D. Tet-
rahedron Lett. 2003, 44, 1071; (b) Enderlin, G.; Taillefumier, C.; Didierjean, C.;
Chapleur, Y. Tetrahedron: Asymmetry 2005, 16, 2459; (c) Taillefumier, C.;
Chapleur, Y. Chem. Rev. 2004, 104, 263.
25. We desired to apply the Boltzmann Distribution to RM1 calculations that were
performed for the spiroanellated stereoisomers. A correlation could not be
made, however, because the calculated energy difference between 8Major and
8Minor was less than the standard error of the model.
26. Sc(OTf)3 has recently been shown to promote pyranoside ring opening re-
actions. See: Qin, H.-L.; Lowe, J. T.; Panek, J. S. J. Am. Chem. Soc. 2007, 129, 38.
27. Hanessian, S.; Liak, T. J.; Vanasse, B. Synthesis 1981, 396.
28. Bieg, T.; Szeja, W. Synthesis 1985, 76.
29. Rodebaugh, R.; Debenham, J. S.; Fraser-Reid, B. Tetrahedron Lett. 1996, 37, 5477.
30. Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989, 111, 1923.
31. Shoemaker, R. H. Nat. Rev. Cancer 2006, 6, 813 We thank the National Cancer
Institute for evaluating our compounds. For a thorough description of the assay
protocol, visit the following websites: http://dtp.nci.nih.gov/branches/btb/
onedose_interp.html and http://dtp.nci.nih.gov/branches/btb/ivclsp.html.
32. The monohydrochloride 14a HCl Salt was easily formed in quantitative yield by
treatment of 14a with excess hydrogen chloride in diethyl ether (1 M solution).
The salt stoichiometry was determined by potentiometric titration to be 1:1.
21. In these experiments, exo-glycal (1.0 equiv), benzaniline (1.0 equiv), and cata-
lyst (0.2 equiv) were stirred in MeCN overnight at room temperature. The re-
actions were monitored by HPLC/MS.
22. (a) Hermitage, S.; Jay, D.; Whiting, A. Tetrahedron Lett. 2002, 43, 9633; (b)
Hermitage, S.; Howard, J. A. K.; Jay, D. A.; Pritchard, R. G.; Probert, M. R.;
Whiting, A. Org. Biomol. Chem. 2004, 2, 2451; (c) Beifuss, U.; Ledderhose, S.;