Hybrids of sugars and aromatics: A Pd-catalyzed modular approach to chromans and isochromans

Article abstract of DOI:10.1016/j.bmc.2010.03.004

Herein we describe the synthesis of highly substituted chromans and isochromans using carbohydrates as starting materials. The key step of our synthetic approach is the annelation of the benzene moiety via a highly efficient Pd-catalyzed domino reaction. This powerful approach led to a small library of highly substituted chromans and isochromans by making use of a variety of different diynes and bromoglycals. We investigated several Pd-catalysts in order to improve the yields and to enlarge the scope of the domino reaction. Furthermore, we elucidated the mechanistic picture of the reaction with isotope-labelling experiments. Most probably the reaction proceeds via an oxidative addition followed by two carbopalladation steps and a final cyclization reaction.

Full text of DOI:10.1016/j.bmc.2010.03.004

Bioorganic & Medicinal Chemistry 18 (2010) 3656–3667
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Hybrids of sugars and aromatics: A Pd-catalyzed modular approach to chromans
and isochromans
Markus Leibeling a, Dennis C. Koester a, Martin Pawliczek a, Daniel Kratzert b, Birger Dittrich b,
Daniel B. Werz a,
*
a Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
b Institut für Anorganische Chemie, Georg-August-Universität Göttingen, Tammannstr. 4, 37077 Göttingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we describe the synthesis of highly substituted chromans and isochromans using carbohydrates
as starting materials. The key step of our synthetic approach is the annelation of the benzene moiety via a
highly efficient Pd-catalyzed domino reaction. This powerful approach led to a small library of highly
substituted chromans and isochromans by making use of a variety of different diynes and bromoglycals.
We investigated several Pd-catalysts in order to improve the yields and to enlarge the scope of the dom-
ino reaction. Furthermore, we elucidated the mechanistic picture of the reaction with isotope-labelling
experiments. Most probably the reaction proceeds via an oxidative addition followed by two carbopalla-
dation steps and a final cyclization reaction.
Received 15 January 2010
Revised 2 March 2010
Accepted 4 March 2010
Available online 10 March 2010
Keywords:
Carbohydrates
Domino reactions
Chromans
Ó 2010 Elsevier Ltd. All rights reserved.
Isochromans
Palladium
CH3
1. Introduction
HO
CH3
CH3
CH3
CH3
Chroman and isochroman motifs are widespread elements in
natural products and have attracted much attention from a wide
area of science including natural product chemistry as well as
medicinal and synthetic organic chemistry. Chroman-derived nat-
ural products possess a broad array of biological activities such as
antimicrobial, antiviral, antiproliferative, sex pheromone, antitu-
mor and central nervous system activity.1 Probably the most prom-
inent example of such a biologically active compound with a
H3C
O
CH3
CH3
1
CH3
H3C
O
O
OH
N
H3C
NC
OH
HO
H3C
chroman core is the vitamin E family [a-tocopherol (1)] (Fig. 1),
CH3
CH3
which consists of eight naturally occurring compounds differing
in the aliphatic side chain and the residues of the aromatic core
leading to varying biological activity.2 A representative example
of a synthetic pharmaceutical agent with a chroman scaffold is
cromakalin (2), a potent activator of ATP-dependent potassium
channels that is known to induce apoptosis.3 Also a plethora of nat-
ural products show the chroman core such as the potent anti-HIV
agent daurichromenic acid (3), which was isolated from Rhododen-
dron dauricum (Fig. 1). Its remarkable EC50 value of 5.67 ng/mL and
the therapeutic index (TI) of 3710 encouraged a lot of synthetic or-
ganic chemists to establish a total synthesis.4
O
O
CH3
3
2
Figure 1. Examples for chroman systems with biological activity. The chroman core
is shown in bold.
mens asymmetric transition metal- and organocatalyzed coupling
reactions especially stand out.5 Three of the most straightforward
syntheses to build up the chroman framework are highlighted as
follows.
The first example deals with an organocatalytic domino oxa-Mi-
chael-Michael reaction.6 The reaction between 2-hydroxy cinna-
Among the numerous different synthetic strategies developed
for the synthesis of chromans, chromens, isochromans and isochro-
maldehyde
4 and a nitroolefin 5 discloses access to highly
functionalized chromans containing multiple stereogenic centers
(Scheme 1). As catalyst the chiral diphenylprolinol TMS ether (6)
revealed to be the one of choice.
* Corresponding author. Tel.: +49 551 393251; fax: +49 551 399476.
E-mail address: dwerz@gwdg.de (D.B. Werz).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.03.004

M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
3657
Ph
Ph
OTMS
OMe
O
H
N
O
CHO
NO2
N
H
N
6
CHO
+
N
H
NO2
NaOAc
CHCl3, rt
O
O
OH
O
R
X
R
X
4
5
15
Figure 2. Hybrid 15 of sugar and benzodiazepine.
7
up to 85% yield,
98 % ee and 10:1 dr
Scheme 1. Organocatalytic oxa-Michael–Michael domino reaction.
As part of our ongoing studies on the facile modification of car-
bohydrates,10 we gained interest in the synthesis of carbohydrate-
derived chromans. We envisioned high structural diversity due to
the sugar moiety bearing a high density of functional groups and
chiral information. Furthermore, we anticipated biological activity
against several protein targets on accounts of earlier studies, which
were able to demonstrate that aromatic systems grafted to saccha-
rides show significant carbohydrate–protein interactions.11
On the basis of the biosynthetic mechanism assembling the
chroman skeleton that leads via a Friedel–Crafts-type allylation
of a phenolic core with an allylic pyrophosphate and subsequent
cyclization of the resulting O-allylated intermediate, one may as-
sume that the cyclocoupling of phenols with allylic alcohols is a
viable method to access chromans. Indeed, Yamamoto et al. re-
ported a formal [3+3]-cyclocoupling catalyzed by a molybdenum
complex and chloranil leading to various chromans in moderate
to good yields (Scheme 2).7
2. Results and discussion
At the beginning of the century the groups of Trost, Helmchen
and Pfaltz have demonstrated that Pd-catalyzed asymmetric allylic
alkylations (AAA) are powerful tools in organic synthesis.8 Espe-
cially Trost et al. elucidated an intermolecular AAA of phenols with
allyl carbonates for the synthesis of chiral chromans (Scheme 3).
Unfortunately this approach lacks two aspects, namely the regio-
and enantioselectivity. To address these issues an intramolecular
AAA of phenol allyl carbonates was used. Best results were
achieved by utilizing the Trost ligand 14.
Most of the previous chroman and isochroman syntheses anne-
late a pyrane moiety to an aromatic system. In contrast, our ap-
proach creates the benzene moiety starting from
a pyrane
derivative. In this paper, we report the full details of this highly
efficient procedure to access chromans and isochromans of type
16 and 20 by utilizing an appropriately substituted 2-bromoglycal
(17 or 21, respectively) as starting material of the domino reaction
(Scheme 4).12 Our method allows the facile introduction of defined
stereocenters on the pyrane unit. The latter is easily accessible
from monosaccharides of type 25 in a few steps. For the creation
of the benzene moiety an intramolecular Pd-catalyzed domino
In recent years the design and the synthesis of new molecular
platforms which are hybrids of two scaffolds have attracted much
attention.9 Chimeric frameworks such as 15 (Fig. 2) that are hy-
brids of benzodiazepins and b-D-glucopyranose have been synthe-
sized to explore receptor space accessible neither to pyranoside
nor to benzodiazepine scaffolds when applied individually. The
continuing efforts in this field of medicinal chemistry should gain
much importance in the near future due to commonly appearing
resistances of bacteria against a variety of pharmaceuticals.
Chroman
R'
O
Isochroman
O
O
(RO)n
X
X
(AcO) n
R'
O
OH
[CpMo(CO)3]2
20
16
o-chloranil
+
R3
PhCl
R1
OH
O
R1
R2
R3
R2
150 ºC, mw, 1 h
R'
O
O
8
9
10
Br
O
X
(RO)n
X
Scheme 2. [3+3]-Cyclocoupling of phenols with allylic alcohol.
Br
n
(AcO)
O
R'
21
17
[Pd],
R3
R3
R2
R2
R1
OH
R1
*LPd
12
R'
L* (14)
HO
+
OH
O
O
LG
(RO)n
(AcO)n
X
+
X
11
Br
Br
Hal
OH
OAc
R'
23
19
22
18
O
O
NH HN
O
R3
OH
R2
(AcO)n
O
OH
OH
O
R1
Ph2P
PPh2
OAc
24
HO
13
14
OH
LG = leaving group
L* = chiral ligand
25
Scheme 3. Intramolecular allylic alkylation (AAA) to access chiral chromans of
type 13.
Scheme 4. Retrosynthetic analysis of chromans 16 and isochromans 20 leading to
monosaccharides of type 25 as starting materials.

3658
M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
reaction13 was used that employs a diyne chain attached to the
pyrane core. Such a procedure allows the synthesis of heavily func-
tionalized chroman and isochroman derivatives that are difficult to
obtain by other routes. The target molecules may be regarded as
hybrids between carbohydrates and aromatic compounds.
We began our studies for the synthesis of chromans by preparing
a variety of 2-bromoglycals of type 18, which are easily accessible
from the corresponding peracetylated glycals (Scheme 5). The latter
are either commercially available or can be synthesized from the na-
tive sugars (not shown). As carbohydrate precursors we used the
by a chromatographic separation of the different regioisomers 37a
and 37b was performed.
Recently, Bergman developed a highly enantioselective ap-
proach for the synthesis of kumarans15 and we became interested
in testing the notion whether we could also use five-membered
bromoglycals as starting material for our domino method. How-
ever, efforts to synthesize 2-bromo-D-arabinal in furanoside form
were in vain. Although there is literature evidence for the synthesis
of the five-membered peracetylated arabinal 40 by starting from
arabinose 39, we did not succeed in preparing this compound. A
closer look to our experiments gives the idea that this literature
from the 1930s regarding the topic of selective synthesis of per-
acetylated five-membered arabinal is highly doubtable.16 Simple
analytical techniques to distinguish between five- and six-mem-
bered glycals were embryonic in these days. We were only able
to isolate the six-membered arabinal 41 by using this procedure
(Scheme 6). The latter could be converted to the corresponding
bromoarabinal 42.
Townsend reported the preparation of a persilylated furano-
side-arabinal 44,17 but our attempts to subject 44 to our bromina-
tion–elimination sequence lacked any success. The removal of the
silyl groups—either with fluoride or under acidic conditions—fur-
nished a furane derivative.18
hexoses
D-glucose, D-galactose and L-rhamnose as well as the pen-
tose -arabinose. A bromination–elimination sequence afforded
D
the peracetylated bromoglycals 27, 31, and 35, respectively, in mod-
erate yields. Saponification furnished the corresponding deprotec-
ted bromoglycals 28,14 32, and 36. In the case of bromoglucal 28
(Scheme 5a) selective protection of the 4- and the 6-hydroxyl groups
can be achieved by making use of the isopropylidene protecting
group, whereas an analogous procedure led in the galactose series
to protection of the 3- and 4-hydroxyl groups. Therefore, we utilized
the benzylidene protecting group yielding the desired product 33 in
68%. A selective benzylation of one hydroxyl group of bromorham-
nal 36 proved to be difficult; thus, a random benzylation followed
To prepare a variety of diynes we started from the commercially
available 1,6-heptadiyne (47). The major challenge was the desym-
metrization of the symmetric structure in good yields. To address
this problem either a chain elongation by one methylene unit uti-
lizing n-BuLi/paraformaldehyde or a Sonogashira monocoupling
with phenyl iodide was employed.19 The sequence starting with
the chain elongation by paraformaldehyde proved to be more effi-
cient for the syntheses of the respective diynes. The elongated
propargylic alcohol is either subjected to an Appel reaction yield-
ing the bisalkyne 46 or its terminal triple bond can be further func-
tionalized to give 45, 48 and 49a/49b (Scheme 7).
The synthesis of the propargylic iodide 50 with an oxygen atom
in the tether commences with 2-butyne diol (51). The same start-
ing material led via a double Appel reaction and nucleophilic sub-
stitution over two steps to the propargylic bromide 54 with
geminal ester moieties (Scheme 8). Five steps were necessary to
obtain the alkynyl cyanide 56—a pseudodiyne—from propargylic
alcohol 55 (Scheme 8).
(a)
OAc
OAc
O
O
1) Br2, CH2Cl2, rt
2) DBU, DMSO, rt
NaOMe
MeOH
AcO
AcO
Br
OAc
OAc
27 (68%)
26
OH
O
O
Me2C(OMe)2
p-TsOH
O
DMF,
0 ºC
HO
Br
O
Br
OH
OH
29 (78%)
28 (85%)
(b)
OAc
OAc
O
O
NaOMe
1) Br2, CH2Cl2, rt
2) DBU, DMSO, rt
MeOH
AcO
AcO
Br
OAc
OAc
31 (35%)
30
OH
O
OH
HO
O
O
PhCH(OMe)2
p-TsOH
HO
OH
O
DMF,
60 ºC
39
HO
Br
Ph
O
O
Br
OH
OH
33 (68%)
32 (88%)
O
O
AcO
(c)
AcO
O
AcO
NaOMe
MeOH
1) Br2, CH2Cl2, rt
2) DBU, DMSO, rt
AcO
OAc
AcO
Br
40
41
OAc
OAc
1) Br2, CH2Cl2, rt
2) DBU, DMSO, rt
34
35 (73%)
O
O
O
O
O
NaH, BnBr
DMF, 0 ºC
TIPSO
+
Br HO
RO
Br
TIPSO
BnO
Br
HO
Br
OR
OH
37a (19%)
Scheme 5. Synthesis of 2-bromoglycals.
OBn
OH
44
42 (R = Ac)
43 (R = H)
NaOMe,
MeOH
36 (75%)
37b (6%)
Scheme 6. Synthesis of bromoarabinals 42–43.

M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
3659
R'
O
1) NaH, 0 ºC, 1h
2) 19, rt, 20 h
(RO)n
+
X
Br
Ph
45
Hal
I
I
OH
46
19
18
n-BuLi, 1 h, -78 ºC
1) n-BuLi, 1 h, -78 ºC
(CH2O)n, 20 h, rt, THF
2) PPh3, I2, imidazole
1 h, Et2O, MeCN
1)
(CH2O)n, 20 h, rt, THF
R'
O
2) PhI, CuI, Pd(PPh3)2Cl2,
20 h, rt, NEt3
3) PPh3, I2, imidazole
1 h, Et2O, MeCN
X
(RO)n
57% (over 2 steps)
Br
O
45% (over 3 steps)
17
47
1) n-BuLi, 1 h, -78 ºC
(CH2O)n, 20 h, rt, THF
2) imidazole, TBSCl,
20 h, 50 ºC, DMF
Scheme 9. Attachment of diynes 19 to bromoglycals 18 to afford the domino
precursors 17.
1) n-BuLi, 1 h, -78 ºC
(CH2O)n, 20 h, rt, THF
2) n-BuLi, 1 h, -78 ºC
TBSCl, 16 h, rt
HCl, 16 h, rt THF
3) PPh3, I2, imidazole
1 h, Et2O, MeCN
3) n-BuLi, 1 h, -78 ºC
MeI, 20 h, rt, THF
cyclization sequence we screened several catalytic systems as
shown in Table 1 for the domino product 16c using precursor
17c as a test substrate. Utilizing 10 mol % of Pd2(dba)3 and
4.0 equiv of HN(i-Pr)2 in DMF/MeCN/NMP (8:8:1) and stirring the
reaction mixture for 30 min at 120 °C under microwave irradiation,
we observed no conversion. Changing the catalytic system to
Pd(OAc)2 and davephos, the desired product was obtained in 56%
yield. With the use of 6.0 equiv of HN(i-Pr)2 and Pd(dppf)Cl2 as cat-
4) AcOH, TBAF,
20 h, rt, THF
5) PPh3, I2, imidazole
1 h, Et2O, MeCN
37% (over 3 steps)
37% (over 5 steps (49a))
36% (over 5 steps (49b))
CH3
49a
CD3
TBS
I
48
I
I
Table 1
49b
Optimization of the domino sequence using different catalytic systems for the
synthesis of 16c
Scheme 7. Synthesis of the different propargylic iodides.
Entry Reagents
Yield (%)
1
Pd2(dba)3 (10 mol %), HN(i-Pr)2 (4.0 equiv), DMF/
MeCN/NMP (8:8:1), 30 min, 120 °C (mw)
Starting
material
With several propargylic halides of type 19 in hand the attach-
ment of the diyne to the remaining 3-hydroxyl group of the bromo-
glycals was performed by using the typical reaction conditions for
propargylic substitution reactions (Scheme 9). In order to investi-
gate the scope of the Pd-catalyzed domino reaction a variety of dif-
ferent coupling products were prepared (Table 2) from propargylic
halides of type 19 (Scheme 9) through alkylation of the remaining
3-hydroxyl group of bromoglycals 18.
2
Pd(OAc)2 (10 mol %), davephos (20 mol %), HN(i-Pr)2
(4.0 equiv), DMF/MeCN/NMP (8:8:1), 30 min, 120 °C
(mw)
56
3
4
Pd(dppf)Cl2 (10 mol %), HN(i-Pr)2 (6.0 equiv), DMF/
MeCN/NMP (8:8:1), 30 min, 120 °C (mw)
72
92
Pd(PPh3)4 (10 mol %), HN(i-Pr)2 (4.0 equiv), DMF/
MeCN/NMP (8:8:1), 30 min, 120 °C (mw)
NMP = N-methyl-2-pyrrolidone; davephos = 2-dicyclohexylphosphino-20-(N,N-dime-
thylamino)biphenyl.
In order to optimize the reaction conditions for the desired
domino reaction (Table 2) consisting of a Heck-carbopalladation–
CO2Me
CO2Me
Br
1) KOH,
MeO2C CO2Me
2 h, rt, DMSO
OH
Br
O
2) PPh3, I2, imidazole
2 h, rt, Et2O, MeCN
Ph
PPh3, Br2
53
NaH, 20 h, rt
THF
1 h, rt
MeCN
83%
(18% over 2 steps)
.
OH
Ph
Br
Br
44%
I
50
51
52
54
1) DHP, p-TsOH, 16 h, rt, DCM
2) n-BuLi, 1 h, -78 ºC
Cl
Br
OH
1 h, -5 ºC, 20 h, 75 ºC
3) NaCN, 20 h, 55 ºC, DMSO
4) p-TsOH, 24 h, rt, MeOH
5) PPh3, I2, imidazole, 2 h, rt,
Et2O, MeCN
N
I
55
56
(40% over 5 steps)
Scheme 8. Synthesis of the different propargylic diynes.

3660
M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
Table 2
Carbohydrate diyne derivatives 17, chroman products 16, deprotected chromans 38 and yield of the domino sequence and deprotection, respectively
R'
R'
R'
O
O
O
Pd(PPh3)4
HN(iPr)2
Deprotection
(Hydrolysis or
hydrogenolysis)
X
X
X
(HO)n
(RO)n
(RO)n
DMF, MeCN,
Br
NMP
O
O
O
120 ºC, mw
17
16
38
Starting material
Product
Yield (%)a
O
70
87
RO
RO
O
O
Br
O
O
O
17a
16a (R,R = CMe2)
38a (R = H)
Ph
O
Ph
O
Quant.
83
O
O
RO
Br
Br
O
RO
O
17b
O
16b (R,R = CMe2)
38b (R = H)
Me
O
Me
O
92
88
RO
O
O
RO
O
17c
O
16c (R,R = CMe2)
38c (R = H)
Ph
O
Ph
O
86
33
CO2Me
CO2Me
O
RO
CO2Me
CO2Me
Br
RO
O
O
16d (R,R = CMe2)
17d
38d (R = H)
O
52
99
RO
O
O
O
O
O
O
RO
Br
O
O
O
O
O
16e (R,R = CMe2)
17e
38e (R = H)
N
—
O
No reaction
Br
O
17f
Me3Si
O
SiMe3
92
O
RO
Br
RO
O
O
17g
16g (R,R = CMe2)
Me
RO
O
98
Me
O
Br
17h
BnO
O
O
16h (R = Bn)
25b
—
Me
RO
O
Me
O
O
O
Br
BnO
O
O
16i (R = Bn)
17i
38i (R = H)

M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
3661
Table 2 (continued)
Starting material
Ph
Product
Yield (%)a
Ph
81
75
Me
O
Me
RO
O
Br
BnO
O
17j
O
16j (R = Bn)
38j (R = H)
Ph
O
Ph
O
88
89
Me
Me
RO
CO2Me
CO2Me
CO2Me
CO2Me
Br
BnO
O
O
16k (R = Bn)
17k
38k (R = H)
O
67
68
RO
O
O
RO
Br
Br
Ph
Ph
HO
O
O
O
16l (R,R = CHPh)
17l
38l (R = H)
Ph
O
Ph
O
75
57
O
RO
O
O
RO
O
17m
O
16m (R,R = CHPh)
38m (R = H)
38b
O
HO
Br
O
16n
O
17n
Ph
O
Ph
56b
76
O
Br
17o
BnO
RO
O
O
16o (R = Bn)
38o (R = H)
a
The first value is the yield of the domino reaction; the second value is the yield of the deprotection.
The yield is given for a two-step procedure starting from 2-bromoglycal and diynyl halide.
b
alyst precursor the yield was improved to 72%. It has not escaped
our notice that more equivalents of base are necessary for a better
yield using PdII catalysts. However, the best results could be
observed using 10 mol % of Pd(PPh3)4 and 4.0 equiv of HN(i-Pr)2
(entry 4).
In order to regenerate the native hydroxyl group pattern of
the corresponding carbohydrates we deprotected the chromans
16a–16o. The deprotection reactions were carried out under acidic
conditions for removal of isopropylidene whereas hydrogenolysis
was applied for the cleavage of benzyl moieties. With these efforts
we were able to create hydroxylated chromans 38a–38o, which
are hardly accessible by other routes.
Due to the similar basic conditions of the domino reaction com-
pared to a Pd-catalyzed propargylic substitution we became inter-
ested in testing the notion whether the complete synthesis from
18 and 19 to 16 could be streamlined in a one-pot operation. Since
attempts to perform the diyne attachment by a Pd-catalyzed propar-
gylic substitution—which is well known for soft nucleophiles22—did
not afford the coupling product, we tried several other approaches
for a one-pot domino sequence. Surprisingly, a non-sequential
procedure proved to be the most successful. Thus, all reagents—
the protected bromoglycal 29, the diynyl halide 46, sodium hydride
and the Pd catalyst—were added at the same time and the micro-
wave irradiation was started leading in 42% to the desired product
16a. A consolidated view of all these factors indicates that the
one-pot procedure turned out to be a considerable alternative to
the conventional two-step procedure.
With the optimized reaction conditions in hand, scope and lim-
itations of the reaction were investigated by employing different
coupling products varying in the diyne chain as well as in the sugar
core. The results are summarized in Table 2. The reaction generally
proceeds in moderate to excellent yield (25% to quantitative yield)
tolerating a broad range of functional groups in the diyne chain.
Terminal phenyl moieties, hydrogen atoms, methyl and silyl units
as well as ethers and esters as part of the tether were tolerated.
Such a silyl group may give access to hydroxy-substituted chro-
mans via Fleming–Tamao oxidation.20 Summarizing the results
one can conclude that oxygen heteroatoms in the tether decrease
the yield (see 16e and 16i) whereas geminal ester functionalities
seem to have no influence (see 16d and 16k). However, attempts
to extend this reaction to a pseudodiyne, the nitrile 17f that would
afford a pyridine moiety attached to the sugar core were in vain.
This might be due to the higher stability of the CN
p-bond com-
pared to the CC -bond, which might lead to a -complex with
p
r
the Pd-species. In the literature only rare examples are known in
which Pd-species insert in a CN bond to create pyridine-like
structures.21
To elucidate the mechanistic picture of the domino reaction we
synthesized a deuterium-labelled bromoglycal 17c(D3). Relying
upon our results it is supposed that the domino reaction is initiated

3662
M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
by the oxidative addition of the Pd0 species into the C–Br bond of
the respective bromoglycal to furnish intermediate 57c(D3). Two
intramolecular carbopalladation reactions of the Pd-species to
the triple bonds generate triene 59c(D3) (Scheme 10). The final
cyclization step affording the benzene unit may be regarded as
HO
Br
O
.
BF3 Et2O (1.0 eq)
AcO
+
OAc
CH2Cl2, 20 h, rt
OAc
R
electrocyclic 6
p electron ring-closure followed by the subsequent
27 (Glc)
31 (Gal)
23a (R = H)
23b (R = Ph)
release of the catalytic species. A Heck-type transformation would
also lead to the desired product; however an anti-dehydropallada-
tion—due to the resulting aromatization possible, but rarely ob-
served—would have to occur.
O
O
O
O
Br
Pd(PPh3)4
To answer the question whether the final ring-closure or a
hypothetical b-hydride elimination is faster the product distribu-
tion of the reaction using the deuterated congener was analyzed.
If a b-hydride elimination takes place leading to the intermediates
61c(HD2) and 62c(HD2), respectively, followed by a cyclization one
will observe a displacement of one deuterium atom by hydrogen
(Scheme 10). However, we observed no scrambling (no occurrence
of 16c(HD2)) leading to the assumption that the cyclization step via
AcO
AcO
HN(i-Pr)2
DMF, MeCN,
NMP
AcO
R
AcO
R
120 ºC, mw
21a (Glc, R = Ph)
20a (Glc, R = Ph)
65%
20b (Gal, R = H) 20%
20c (Gal, R = Ph)
41%
48%
21b (Gal, R = H) 63%
57%
21c (Gal, R = Ph)
Scheme 11. Synthesis of the isochromans 20a–20c.
60c(D3) to 16c(D3) is faster than
elimination.
a hypothetical b-hydride
Two of the starting materials, the deprotected 2-bromoglucal
(28)14 as well as the deprotected 2-bromogalactal (32), could be
crystallographically characterized. The molecular structure shows
the typical half-chair form of six-membered alkenes as depicted
for the bromogalactal 32 in Figure 3. It is interesting to note that
the photochemical behavior of the two bromoglycal crystals was
completely different. Whereas the colorless crystals of 28 were
highly light-sensitive and got dark brown after several days, the
colorless crystals of 2-bromogalactal were stable in sunlight for
months. Indeed, a careful look at the solid-state structure of the
crystals may give a hint for their different behavior. In the struc-
ture of 28 we found close intermolecular contacts (3.64 Å) between
bromine centers being shorter than the sum of the van der Waals
radii (3.7 Å)25 as depicted in Figure 4, whereas in the solid-state
structure of 32 no such interaction is observed. Only in the first
case elemental bromine can be formed by light-induced cleavage
Encouraged by the results shown above, we tried to extend our
domino approach to the preparation of isochromans. We looked for
a possibility to build up the precursors in an easy and modular
manner. Starting from 2-bromoglucal 27, 2-bromogalactal 31 and
diynols of type 23 we were able to make use of a Lewis-acid pro-
moted Ferrier reaction resulting in a shift of the C@C double bond
in the six-membered ring (Scheme 11).23 We tried different
amounts of BF3-etherate. It turned out that stoichiometric amounts
of Lewis acid at room temperature and a long reaction time (20 h)
are essential for a successful reaction.24 In all cases the
a-anomer
was the major product and only traces of the b-anomer were de-
tected that could easily be removed by silica gel column chroma-
tography. Appling the same conditions as used in the synthesis of
the chromans 16 the yields of the analogous domino reaction
affording the isochromans 20a–20c were poorer than for 16.
O
O
O
O
O
O
Pd(PPh3)4
to 16c(HD2)
R
HN(iPr)2
DMF, MeCN,
NMP
O
O
Br
CD3
O
O
O
120 ºC, mw
O
H
16c(D3)
CD2
17c(D3)
(R = CD3)
to 16c(D3)
- PdHBrLn
O
16c(HD2)
(R = CHD2)
O
O
62c(HD2)
- PdDBrLn
CD2
O
O
O
C
O
O
O
O
O
O
H
PdLnBr
CD3
- PdDBrLn
PdLn
Br
61c(HD2)
O
O
O
O
O
O
60c(D3)
O
CD3
O
PdLnBr
CD3
57c(D3)
Br
PdLn
CD3
58c(D3)
59c(D3)
Scheme 10. Proposed mechanism for the annelation of the benzene unit to the sugar core shown for the synthesis of 16c(D3).

M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
4. Experimental
3663
4.1. General experimental
All solvents were distilled before use unless otherwise stated.
Air and moisture sensitive reactions were carried out in oven-dried
or flame-dried glassware, septum-capped under atmospheric pres-
sure of argon. Commercially available compounds were used with-
out further purification. Proton (1H) and carbon (13C) NMR spectra
were recorded on a 300, 500 or 600 MHz instrument using the
residual signals from CHCl3, d 7.26 ppm and d 77.0 ppm, and meth-
anol, d 4.87 ppm and d 49.2 ppm, as internal references for 1H and
13C, respectively. ESI-HRMS mass spectrometry was carried out on
a FTICR instrument. IR spectra were measured on conventional
spectrometer. UV spectra were measured with a common photom-
eter. Optical rotations were measured at 20 °C using a common
optical rotation instrument. HClO4–SiO2 was prepared according
to literature methods.28 Analytical data of chromans and precur-
sors not provided in this Experimental are given in our recent
communication.12a
Figure 3. X-ray structure (ellipsoids drawn at 50% probability level) of the 2-
bromogalactal (32).
4.2. General procedure for the deacetylation of 2-bromoglycals
The peracetylated bromoglycal (10.0 mmol, 1.0 equiv) was dis-
solved in methanol (50 mL). A sodium methoxide solution (0.50 M
in methanol, 7.00 mmol, 0.7 equiv) was slowly added until pH
P12. The reaction was stirred for 3 h at rt. Then the reaction solu-
tion was neutralized by the addition of Amberlite IR-120 (H+). The
solution was filtered and the solvent was removed by rotary evap-
oration. The residue was purified by silica gel column chromatog-
raphy (DCM/MeOH) to afford the desired compound as a white
solid.
Analytical Data of 32: yield: 88%. Rf: 0.16 (DCM/MeOH = 8:1).
a
= +61.2 (c 0.52, MeOH). 1H NMR (300 MHz, CD3OD): d = 3.27–
3.34 (m, 1H), 3.73 (dd, J = 5.2, 11.8 Hz, 1H), 3.82 (dd, J = 6.7,
11.8 Hz, 1H), 3.98–4.02 (m, 1H), 4.05 (d, J = 2.1 Hz, 1H), 4.27
(ddd, J = 1.6, 2.1, 4.6 Hz, 1H), 4.85 (sbr, 2H), 6.64 (d, J = 1.6 Hz,
1H). 13C NMR (125 MHz, CD3OD): d = 61.7, 67.8, 68.3, 79.7, 104.1,
144.8. IR (KBr):
m
(cmꢀ1) = 3503, 3320, 3167, 3069, 1645, 1348,
1175. UV (MeOH): kmax (lg e) [nm] = 217 (3.77). MS (ESI): m/z
(%) = 247.0 (100) [M+Na]+. HRMS (ESI): m/z calcd for [MꢀH]ꢀ:
224.9611; found: 224.9592.
Figure 4. Packing of 2-bromoglucal (28) in the solid state showing close Br–Br
interactions (dashed lines).
Analytical Data of 36: yield: 75%. Rf: 0.38 (DCM/MeOH = 10:1).
a
= ꢀ43.8 (c 0.89, MeOH). 1H NMR (300 MHz, CD3OD): d = 1.32
of the weak C–Br bond, whereas the discrete Br atoms in 32 cannot
lead to any dimerisation. Intermolecular interactions between neu-
tral halogen centers have been addressed in the literature.26 These
closed-shell interactions have at first been interpreted in terms of
donor–acceptor interactions, however, later it was shown that
electron correlation effects play a considerable role.27
(d, J = 6.5 Hz, 3H), 3.42 (dd, J = 9.1, 6.5 Hz, 1H), 3.83–3.94 (m, 1H),
4.00 (dd, J = 6.5, 1.2 Hz, 1H), 4.88 (sbr, 2H), 6.60 (d, J = 1.2 Hz, 1H).
13C NMR (75 MHz, CD3OD): d = 17.3, 73.5, 76.1, 76.9, 103.6,
145.0. IR (KBr):
(CH3CN): kmax (lg
m
e
(cmꢀ1) = 3002, 2363, 2330, 1777, 1265. UV
) [nm] = 216.0 (3.29). MS (ESI): m/z (%) = 209.0
(100) [M+H]+. HRMS (ESI): m/z calcd for [M+H]+: 208.9642; found:
208.9648.
3. Conclusion
Analytical Data of 43: yield: 70%. Rf: 0.06 (pentane/EtOAc 5:1).
a
= +125.0 (c 0.2, MeOH). 1H NMR (300 MHz, CD3OD): d = 3.30
In conclusion, we have successfully developed a highly efficient
synthetic route to heavily substituted chromans and isochromanes
via a Pd-catalyzed domino approach. We have demonstrated the
versatility of this approach by using numerous monosaccharides
with their rich stereochemistry and a variety of diynes differing
in the tether. Our synthetic strategy allows the generation of com-
plex oligocyclic structures with little effort. We were able to
engender a high structural diversity, which provides access to a
variety of carbohydrate-aromatic hybrids. Furthermore, the biolog-
ical activity of many chromans suggests an exciting adventure into
the realms of drug discovery. Our synthetic approach provides a
facile access to novel molecular entities for explorations in chem-
ical biology.
(mc, 1H), 3.74 (mc, 1H), 3.89 (mc, 2H), 4.12 (dd, J = 1.4, 4.0 Hz,
1H), 6.66 (s, 1H). 13C NMR (125 MHz, CD3OD): d = 65.5, 67.9,
69.5, 100.8, 146.0. IR (film):
m
(cmꢀ1) = 2914, 1633, 1466, 1370.
UV (MeOH): kmax (lg e) [nm] = 289.0 (2.81). MS (ESI): m/z
(%) = 195.4 (96) [M+H]+. HRMS (ESI): m/z calcd for [MꢀH]ꢀ:
192.9501; found: 192.9515.
4.3. General procedure for the chroman domino precursors
The bromoglycal (1.50 mmol, 1.0 equiv) was dissolved in DMF
(40 mL) and cooled to 0 °C, NaH (60% in mineral oil, 1.50 mmol,
1.0 equiv) was added and the solution was allowed to warm to

3664
M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
rt. The propargylic halide (1.65 mmol, 1.1 equiv), dissolved in DMF
(15 mL), was added to the reaction mixture at 0 °C and stirred over
night at rt. The reaction was stopped by the addition of water. The
aqueous layer was extracted three times with EtOAc. The com-
bined organic layers were washed with water and brine, dried over
Na2SO4, the solvent was removed by rotary evaporation and the
residue was purified by silica gel column chromatography (pen-
tane/EtOAc) to afford the desired compound as a yellow oil.
AnalyticalData of 17c: yield:77%. Rf: 0.32 (hexane/EtOAc = 10:1).
at rt and stopped by the addition of saturated NaHCO3 solution.
The aqueous layer was extracted three times with EtOAc. The com-
bined organic layers were washed with water and dried over
Na2SO4. The solvent was removed by rotary evaporation and the
residue was purified by silica gel column chromatography (tolu-
ene/acetone) to afford the desired compound as a yellow oil.
Analytical Data of 21b: yield: 63%. Rf: 0.46 (toluene/ace-
tone = 10:1).
a
= ꢀ83.1 (c 0.35, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 1.72 (tt, J = 7.0, 7.1 Hz, 2H), 1.95 (t, J = 2.6 Hz, 1H), 2.05 (s, 3H),
2.07 (s, 3H), 2.30 (dt, J = 2.6, 7.1 Hz, 2H), 2.36 (tt, J = 2.2, 7.0 Hz,
2H), 4.17–4.21 (m, J = 6.4 Hz, 3H), 4.30 (t, J = 2.2 Hz, 2H), 5.02 (dd,
J = 2.7, 6.1 Hz, 1H), 5.26 (s, 1H), 6.42 (d, J = 6.1 Hz, 1H). 13C NMR
(125 MHz, CDCl3): d = 17.6, 17.9, 20.8, 20.8, 27.4, 55.8, 62.2, 64.8,
66.4, 69.0, 75.1, 83.3, 87.1, 95.0, 97.2, 126.8, 169.9, 170.3. IR (film):
a
= +74.0 (c 0.15, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3H),
1.51 (s, 3H), 1.67 (tt, J = 7.2, 7.2 Hz, 2H), 1.76 (t, J = 2.7 Hz, 3H), 2.23
(qt, J = 2.7, 7.2 Hz, 2H), 2.33 (tt, J = 2.3, 7.2 Hz, 2H), 3.74–3.86 (m, 2H),
3.87–3.98 (m, 1H), 3.99–4.08 (m, 1H), 4.20 (dd, J = 1.6, 7.2 Hz, 1H),
4.32 (td, J = 2.3, 15.0 Hz, 1H), 4.40 (td, J = 2.3, 15.0 Hz, 1H), 6.60 (d,
J = 1.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): d = 3.6, 18.0, 18.1, 19.1,
28.1, 29.0, 59.2, 61.4, 70.4, 72.8, 75.6, 76.1, 76.4, 78.2, 86.4, 99.6,
m
(cmꢀ1) = 2939, 2357, 1748, 1651. UV (CH3CN): kmax (lg
e)
[nm] = 199.5 (4.10). MS (ESI): m/z (%) = 435.0 (100) [M+Na]+. HRMS
(ESI): m/z calcd for [M+Na]+: 435.0414; found: 435.0414.
100.8, 144.8. IR (film):
kmax (lg
m
(cmꢀ1) = 2371, 1634, 1172. UV (CH3CN):
e
) [nm] = 215.5 (3.85). MS (ESI): m/z (%) = 405.1 (100)
Analytical Data of 21c: yield: 57%. Rf: 0.42 (pentane/EtOAc = 3:1).
[M+Na]+. HRMS (ESI): m/z calcd for [M+Na]+: 405.0672; found:
405.0667.
a
= ꢀ76.5 (c 0.26, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.81 (tt,
J = 7.0, 7.1 Hz, 2H), 2.06 (s, 3H), 2.08 (s, 3H), 2.42 (tt, J = 2.1, 7.0 Hz,
2H), 2.53 (t, J = 7.1 Hz, 2H), 4.20 (d, J = 6.6 Hz, 2H), 4.33 (m, 2H),
4.36 (dd, J = 2.6, 6.6 Hz, 1H), 5.03 (dd, J = 2.6, 5.8 Hz, 1H), 5.29 (s,
1H), 6.43 (d, J = 5.8 Hz, 1H), 7.23–7.40 (m, 5H). 13C NMR (125 MHz,
CDCl3): d = 18.1, 18.7, 20.8, 20.8, 27.7, 55.8, 62.2, 64.9, 66.4, 75.1,
81.3, 87.3, 88.9, 95.0, 126.7, 127.5, 128.9, 128.1, 128.1, 131.4,
Analytical Data of 17e: yield: 62%. Rf: 0.16 (hexane/
EtOAc = 10:1).
a
= +76.0 (c 0.48, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 1.40 (s, 3H), 1.50 (s, 3H), 2.43 (t, J = 2.5 Hz, 1H), 3.73–3.84
(m, 2H), 3.87–3.96 (m, 1H), 3.98–4.08 (m, 1H), 4.20 (dd, J = 1.6,
7.2 Hz, 1H), 4.25 (d, J = 2.5 Hz, 2H), 4.30 (t, J = 1.9 Hz, 2H), 4.39 (td,
J = 1.9, 15.6 Hz, 1H), 4.47 (td, J = 1.9, 15.6 Hz, 1H), 6.60 (d,
J = 1.7 Hz, 1H). 13C NMR (125 MHz, CDCl3): d = 19.1, 29.0, 56.5,
56.8, 58.8, 61.3, 70.3, 72.8, 75.0, 75.9, 78.9, 81.6, 83.0, 99.6, 100.4,
169.9, 170.3. IR (film):
kmax (lg
m
(cmꢀ1) = 3021, 1746, 1372. UV (CH3CN):
e
) [nm] = 202.0 (4.53), 239.0 (4.20), 249.5 (4.17), 271.5
(3.04), 278.0 (2.94). MS (ESI): m/z (%) = 511.07 (98) [M+Na]+. HRMS
(ESI): m/z calcd for [M+Na]+: 511.0732; found: 511.0727.
145.0. IR (film):
(CH3CN): kmax (lg
m
(cmꢀ1) = 3289, 3079, 2994, 2116, 1631, 1376. UV
e
) [nm] = 216.0 (3.86). MS (ESI): m/z (%) = 393.0
(100) [M+Na]+. HRMS (ESI): m/z calcd for [M+Na]+: 393.0308; found:
393.0294.
4.5. General procedure for the domino reaction leading to
chromans and isochromans
Analytical Data of 17j: yield: 71%. Rf: 0.46 (hexane/EtOAc = 8:1).
a
= ꢀ27.8 (c 0.23, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.32 (d,
The alkylated bromoglycal (0.10 mmol, 1.0 equiv) was dissolved
J = 6.8 Hz, 3H), 1.77 (tt, J = 7.1, 7.2 Hz, 2H), 2.37 (tt, J = 2.3, 7.2 Hz,
2H), 2.50 (t, J = 7.1 Hz, 2H), 3.63 (dd, J = 4.7, 6.6 Hz, 1H), 4.10–
4.22 (m, 2H), 4.34 (t, J = 2.3 Hz, 2H), 4.68 (d, J = 11.8 Hz, 1H), 4.84
(d, J = 11.8 Hz, 1H), 6.61 (d, J = 1.2 Hz, 1H), 7.17–7.43 (m, 10 H).
13C NMR (125 MHz, CDCl3): d = 16.6, 18.1, 18.7, 27.8, 58.5, 73.2,
73.8, 76.6, 77.2, 78.7, 81.3, 86.5, 88.6, 98.4, 123.7, 127.6, 127.8,
127.9, 128.1, 128.4, 131.5, 137.6, 144.2. IR (film):
3062, 2935, 2235, 1725, 1490, 1266. UV (CH3CN): kmax (lg
[nm] = 238.5 (4.29), 250.0 (4.23), 271.0 (3.42), 278.0 (3.36). MS
(ESI): m/z (%) = 501.1 (100) [M+Na]+. HRMS (ESI): m/z calcd for
[M+Na]+: 501.1036; found: 501.1019, [M+Na]+ (ESI-HRMS).
Analytical Data of 17l: yield: 77%. Rf: 0.17 (hexane/EtOAc = 4:1).
in
a
mixture of DMF/MeCN/NMP (1.0 mL, 1.0 mL, 0.15 mL).
mol, 0.1 equiv) and diisopropylamine (0.40 mmol,
Pd(PPh3)4 (10
l
4.0 equiv) were added. The reaction was stirred in the microwave
for 30 min at 120 °C. The absorption level was set as very high
and the prestirring time at 10 s. The reaction was stopped by the
addition of brine. The aqueous layer was extracted three times
with EtOAc. The combined organic layers were washed with water
and brine, dried over Na2SO4, the solvent was removed by rotary
evaporation and the residue was purified by silica gel column chro-
matography (pentane/EtOAc) to afford the desired compound as a
white solid.
m
(cmꢀ1) =
e
)
Analytical Data of 16c: yield: 92%. Rf: 0.32 (hexane/EtOAc = 6:1).
a
= +181.9 (c 0.16, CHCl3). 1H NMR (600 MHz, CDCl3): d = 1.72 (tt,
a
= +37.1 (c 0.14, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.47 (s,
J = 7.0, 7.0 Hz, 2H), 1.96 (t, J = 2.6 Hz, 1H), 2.30 (dt, J = 2.6, 7.0 Hz,
2H), 2.36 (tt, J = 2.2, 7.0 Hz, 2H), 3.98–4.01 (m, 1H), 4.04 (dd,
J = 1.5, 12.5 Hz, 1H), 4.33 (dd, J = 1.5, 12.5 Hz, 1H), 4.36 (td, J = 2.2,
15.9 Hz, 1H), 4.40 (td, J = 2.2, 15.9 Hz, 1H), 4.44 (dd, J = 1.2, 5.0 Hz,
1H), 4.54 (dd, J = 1.2, 5.0 Hz, 1H), 5.63 (s, 1H), 6.73 (d, J = 1.9 Hz,
1H), 7.29–7.38 (m, 3H), 7.49–7.51 (m, 2H). 13C NMR (125 MHz,
CDCl3): d = 17.6, 17.9, 27.4, 57.3, 69.0, 69.0, 69.3, 70.4, 72.0, 76.3,
3H), 1.51 (s, 3H), 2.00–2.16 (m, 5H), 2.60–2.87 (m, 4H), 3.88–4.02
(m, 3H), 4.10–4.22 (m, 1H), 4.79 (dd, J = 2.6, 12.9 Hz, 1H), 5.02 (d,
J = 10.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): d = 11.6, 19.0, 25.6,
29.0, 30.6, 31.5, 62.4, 70.2, 72.6, 72.8, 79.2, 99.7, 117.9, 121.4,
129.2, 133.9, 146.3, 147.5. IR (KBr):
m
(cmꢀ1) = 2997, 2953, 2896,
1610, 1476. UV (CH3CN): kmax (lg e) [nm] = 206.5 (4.61), 284.0
(3.29). MS (ESI): m/z (%) = 325.2 (45) [M+Na]+. HRMS (ESI): m/z
calcd for [M+Na]+: 325.1410; found: 325.1408.
83.3, 86.5, 98.8, 101.3, 126.2, 128.1, 129.0, 137.2, 144.4. IR (film):
m
)
(cmꢀ1) = 3292, 2935, 2360, 1642, 1358. UV (CH3CN): kmax (lg
e
Analytical Data of 16g: yield: 92%. Rf: 0.61 (hexane/EtOAc = 6:1).
[nm] = 208.0 (4.11), 255.0 (2.65), 261.0 (2.57), 266.5 (2.44). MS
(ESI): m/z (%) = 439.1 (100) [M+Na]+. HRMS (ESI): m/z calcd for
[M+Na]+: 439.0515; found: 439.0516.
a
= 23.9 (c 0.44, CHCl3). 1H NMR (300 MHz, CDCl3): d = 0.28 (s, 9H),
1.47 (s, 3H), 1.51 (s, 3H), 2.05 (tt, J = 7.3 Hz, 2H), 2.67 (dt, J = 4.0,
7.3 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H), 3.89–3.98 (m, 3H), 4.05–4.15
(m, 1H), 4.82 (dd, J = 2.3, 12.9 Hz, 1H), 4.99–5.06 (m, 2H). 13C NMR
(125 MHz, CDCl3): d = 1.3, 19.0, 25.9, 29.0, 29.6, 34.5, 62.3, 70.0,
72.4, 72.9, 79.4, 99.7, 118.5, 120.6, 129.5, 133.4, 153.1, 154.4. IR
4.4. General procedure for isochroman domino precursors
The peracetylated bromoglycal (0.30 mmol, 1.0 equiv) and the
corresponding propargylic alcohol (0.30 mmol, 1.0 equiv) were dis-
solved in dry dichloromethane (5 mL). After the addition of BF3-
etherate (0.30 mmol, 1.0 equiv), the reaction was stirred over night
(film): m e)
(cmꢀ1) = 2953, 2361, 1618, 1593. UV (CH3CN): kmax (lg
[nm] = 209.5 (4.50), 289.5 (3.44), 295.0 (3.44). MS (ESI): m/z
(%) = 383.2 (100) [M+Na]+. HRMS (ESI): m/z calcd for [M+Na]+:
383.1649; found: 383.1651.

M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
3665
Analytical Data of 16h: yield: 98%. Rf: 0.47 (hexane/EtOAc = 8:1).
= ꢀ121.3 (c 0.23, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.49 (d,
solution (0.5 mL) the pH value was set to pH 3. The mixture was
stirred for 24 h at 40–50 °C. The reaction was stopped by the addi-
tion of saturated NaHCO3 solution. The aqueous layer was ex-
tracted three times with EtOAc. The combined organic layers
were washed with water and dried over Na2SO4. The solvent was
removed by rotary evaporation and the residue was purified by sil-
ica gel column chromatography (pentane/EtOAc) to afford the de-
sired compound as a white solid.
a
J = 6.4 Hz, 3H), 1.99–2.16 (m, 2H), 2.62–2.72 (m, 2H), 2.84 (t,
J = 9.4 Hz, 2H), 3.38 (dd, J = 8.1, 9.3 Hz, 1H), 4.14 (qd, J = 6.4, 9.3 Hz,
1H), 4.71 (d, J = 11.9 Hz, 1H), 4.84 (dd, J = 1.4, 11.9 Hz, 1H), 4.96–
5.14 (m, 3H, 3-H), 6.52 (s, 1H), 7.22–7.43 (m, 5H). 13C NMR
(125 MHz, CDCl3): d = 18.4, 26.1, 30.1, 32.8, 72.6, 72.8, 74.9, 79.8,
82.9, 108.2, 127.5, 127.8, 128.2, 138.2, 121.7, 128.3, 136.5, 147.6,
149.9. IR (KBr):
(lg
m
(cmꢀ1) = 2845, 1622, 1467, 1112. UV (CH3CN): kmax
Analytical Data of 38b: yield: 83%. Rf: 0.12 (hexane/
e
) [nm] = 206.0 (4.66), 287.0 (3.52). MS (ESI): m/z (%) = 345.1
EtOAc = 1:1). a
= +18.3 (c 0.06, CHCl3). 1H NMR (300 MHz, CDCl3):
(100) [M+Na]+. HRMS (ESI): m/z calcd for [M+Na]+: 345.1461; found:
345.1457.
d = 2.02 (tt, J = 7.1, 7.7 Hz, 2H), 2.53 (sbr, 1H), 2.69–2.82 (m, 4H),
3.90 (d, J = 3.4 Hz, 2H), 3.93–3.99 (m, 2H), 4.46 (sbr, 1H), 4.86 (d,
10.8 Hz, 1H), 5.03–5.09 (m, 2H), 7.21–7.44 (m, 5H). 13C NMR
(125 MHz, CDCl3): d = 26.4, 30.7, 32.7, 61.9, 69.5, 73.0, 79.3, 82.3,
121.7, 123.2, 129.6, 135.1, 135.9, 146.1, 146.5, 126.9, 128.0,
Analytical Data of 16l: yield: 75%. Rf: 0.09 (hexane/EtOAc = 4:1).
a
= ꢀ145.0 (c 0.10, CHCl3). 1H NMR (600 MHz, CDCl3): d = 1.90–
2.16 (m, 2H), 2.61–3.02 (m, 4H), 4.03–4.06 (m, 1H), 4.10–4.17
(m, 1H), 4.47 (dd, J = 1.7, 12.3 Hz, 1H), 4.62 (dd, J = 1.1, 3.5 Hz,
1H), 4.97 (dd, J = 1.8, 12.1 Hz, 1H), 5.15 (dd, J = 2.6, 12.1 Hz, 1H),
5.24 (m, 1H), 5.64 (s, 1H), 7.24–7.32 (m, 5H), 7.35–7.43 (m, 2H),
7.46–7.51 (m, 2H), 7.65–7.73 (m, 1H). 13C NMR (125 MHz, CDCl3):
d = 26.2, 30.7, 32.9, 69.3, 70.0, 72.4, 73.6, 77.7, 101.3, 120.0, 122.8,
129.2, 134.4, 136.0, 137.6, 145.7, 146.5, 126.6, 126.7, 127.9, 128.1,
129.7. IR (KBr):
kmax (lg
m
(cmꢀ1) = 2929, 2360, 1628, 1417. UV (CH3CN):
e
) [nm] = 206.0 (4.44), 250.0 (3.96), 291.0 (3.52). MS
(ESI): m/z (%) = 347.2 (58) [M+Na]+. HRMS (ESI): m/z calcd for
[M+Na]+: 347.1254; found: 347.1255.
Analytical Data of 38c: yield: 88%. Rf: 0.13 (hexane/EtOAc = 1:1).
a
= +31.0 (c 0.10, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.24 (sbr
,
129.0, 129.9. IR (KBr):
m
(cmꢀ1) = 2328, 1733, 1652, 1327. UV
1H), 1.96–2.15 (m, 5H), 2.55–2.86 (m, 4H), 3.80–3.81 (m, 1H),
3.94–4.08 (m, 3H), 4.16 (sbr, 1H), 4.80 (d, J = 11.1 Hz, 1H), 4.95–
5.10 (m, 2H). 13C NMR (125 MHz, CDCl3): d = 11.6, 25.6, 30.6, 31.4,
62.2, 69.8, 72.9, 79.0, 82.2, 117.8, 120.8, 128.8, 133.0, 146.2, 147.5.
(CH3CN): kmax (lg ) [nm] = 204.5 (4.65), 224.0 (4.34), 250.0
e
(4.04), 290.5 (3.59). MS (ESI): m/z (%) = 435.2 (100) [M+Na]+. HRMS
(ESI): m/z calcd for [M+Na]+: 435.1567; found: 435.1568.
Analytical Data of 20a: yield: 65%. Rf: 0.24 (pentane/EtOAc 3:1).
IR (KBr):
(lg e) [nm] = 207.0 (4.56), 284.0 (3.33). MS (ESI): m/z (%) = 285.1
m
(cmꢀ1) = 2921, 2843, 1615, 1102. UV (CH3CN): kmax
a
= +29.2 (c 0.24, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.26 (s,
3H), 1.90–2.03 (m, 2H), 2.07 (s, 3H), 2.39–2.51 (m, 1H), 2.76–2.92
(m, 3H), 3.90–3.97 (m, 1H), 4.22 (dd, J = 3.2, 12.1 Hz, 1H), 4.36 (dd,
J = 5.3, 12.1 Hz, 1H), 5.10 (dd, J = 1.9, 12.7 Hz, 1H), 5.21 (d,
J = 12.7 Hz, 1H), 6.12 (d, J = 6.6 Hz, 1H), 6.32 (s, 1H), 7.25–7.73 (m,
5H). 13C NMR (125 MHz, CDCl3): d = 19.7, 20.9, 25.5, 31.2, 32.3,
62.7, 65.7, 72.6, 76.5, 100.8, 126.0, 127.0, 128.9, 132.7, 134.5,
(100) [M+Na]+. HRMS (ESI): m/z calcd for [M+Na]+: 285.1097; found:
285.1099.
4.7. General procedure for the deprotection of
based chromans
L-rhamnose
134.9, 137.1, 139.0, 146.4, 169.9, 170.6. IR (film):
m
(cmꢀ1) = 2930,
) [nm] = 205.5 (4.56),
The protected chroman (50 lmol, 1.0 equiv) was dissolved in
1742, 1437, 1371. UV (CH3CN): kmax (lg
e
methanol (3 mL) and dichloromethane (1.0 mL). Pd(OH)2/C (Pearl-
man’s Catalyst) (5 mg) was added to the reaction mixture. Then a
hydrogen atmosphere was generated in the reaction reservoir.
The mixture was stirred over night at rt. The solvent was removed
by rotary evaporation and the residue was purified by silica gel col-
umn chromatography (pentane/EtOAc) to afford the desired com-
pound as a white solid.
317.0 (3.04). MS (ESI): m/z (%) = 431.1 (100) [M+Na]+. HRMS (ESI):
m/z calcd for [M+Na]+: 431.1471; found: 431.1465.
Analytical Data of 20b: yield: 20%. Rf: 0.10 (toluene/ace-
tone = 4:1).
a
= ꢀ58.2 (c 0.73, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 2.06 (s, 3H), 2.06 (s, 3H), 2.03–2.18 (m, 2H), 2.70–2.85 (m, 2H),
2.85–2.99 (m, 2H), 3.89 (dt, J = 1.6, 6.6 Hz, 1H), 4.34 (d, J = 6.6 Hz,
2H), 4.98 (d, J = 12.6 Hz, 1H), 5.13 (d, J = 12.6 Hz, 1H), 5.70 (d,
J = 1.6 Hz, 1H), 6.44 (s, 1H), 7.26 (s, 1H). 13C NMR (125 MHz, CDCl3):
d = 20.9, 21.0, 25.6, 30.8, 32.6, 62.8, 67.5, 71.8, 73.9, 101.4, 122.1,
Analytical Data of 38c: yield: 89%. Rf: 0.18 (hexane/EtOAc = 1:1).
a
= ꢀ12.4 (c 0.17, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.42 (d,
J = 6.2 Hz, 3H), 3.05 (d, J = 3.3 Hz, 1H), 3.33–3.53 (m, 4H), 3.53–
3.66 (m, 1H), 3.68 (s, 3H), 3.71 (s, 3H), 3.98–4.09 (m, 1H), 4.86
(d, J = 12.0 Hz, 1H), 4.97 (d, J = 8.3 Hz, 1H), 5.08 (d, J = 12.0 Hz,
1H), 7.26–7.44 (m, 5H). 13C NMR (125 MHz, CDCl3): d = 17.7,
38.3, 40.2, 53.0, 53.0, 60.8, 72.7, 73.9, 76.0, 82.3, 122.9, 123.0,
124.8, 135.1, 135.1, 141.3, 147.4, 127.0, 128.0, 129.7, 171.7,
127.8, 134.8, 135.3, 139.1, 146.8, 170.1, 170.5. IR (KBr):
m
(cmꢀ1) =
e) [nm] = 204.5
2954, 1742, 1436, 1230. UV (CH3CN): kmax (lg
(4.58). MS (ESI): m/z (%) = 355.1 (100) [M+Na]+. HRMS (ESI): m/z
calcd for [M+Na]+: 355.1152; found: 355.1162.
Analytical Data of 20c: yield: 41%. Rf: 0.20 (pentane/EtOAc = 3:1).
a
= ꢀ25.4 (c 0.24, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.99 (s, 3H),
171.7. IR (KBr): m
(cmꢀ1) = 2956, 1736, 1630, 1271. UV (CH3CN):
2.01 (s, 3H), 2.02–2.15 (m, 2H), 2.68–2.81 (m, 2H), 2.83–2.92 (m, 2H),
3.92 (td, J = 1.6, 5.5 Hz, 1H), 4.18 (d, J = 5.5 Hz, 1H), 4.20 (d, J = 3.9 Hz,
1H), 5.05 (d, J = 12.6 Hz, 1H), 5.19 (d, J = 12.6 Hz, 1H), 5.78 (d,
J = 1.6 Hz, 1H), 6.58 (s, 1H), 7.30–7.75 (m, 5H). 13C NMR (125 MHz,
CDCl3): d = 20.9, 20.9, 25.6, 31.4, 32.5, 63.4, 65.6, 72.0, 75.0, 101.7,
126.3, 127.6, 128.2, 130.4, 133.8, 135.5, 136.2, 136.9, 138.9, 145.4,
kmax (lg e) [nm] = 206.5 (4.42), 288.5 (3.52). MS (ESI): m/z
(%) = 447.1 (100) [M+Na]+. HRMS (ESI): m/z calcd for [M+Na]+:
447.1414; found: 447.1425.
4.8. General procedure for the deprotection of
based chromans
D-galactose
168.9, 170.5. IR (film):
m
(cmꢀ1) = 2364, 1747, 1372, 1224. UV
(CH3CN): kmax (lg
e
) [nm] = 206.5 (4.58). MS (ESI): m/z (%) = 431.1
Chroman (40 lmol, 1.0 equiv) was dissolved in acetonitrile
(100) [M+Na]+. HRMS (ESI): m/z calcd for [M+Na]+: 431.1471; found:
(2 mL) and HClO4–SiO2 (10 mg) was added. The mixture was stir-
red over night at rt. The reaction was stopped by the addition of
saturated NaHCO3 solution. The aqueous layer was extracted three
times with EtOAc. The combined organic layers were washed with
water and dried over Na2SO4. The solvent was removed by rotary
evaporation and the residue was purified by silica gel column chro-
matography (pentane/EtOAc) to afford the desired compound as a
white solid.
431.1465.
4.6. General procedure for the deprotection of
chromans
D-glucose based
The protected chroman (60
methanol (5 mL) and water (0.5 mL). By addition of a 0.1 M HCl
lmol, 1.0 equiv) was suspended in

3666
M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
Table 3
and experimental details for the X-ray measurements are listed
in Table 3. CCDC-759503 and -757984 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Crystal data and structure refinement for bromoglycals 2814 and 32
Compound
28
32
CCDC number
Empirical formula
Formula weight
Crystal system
Space group
Temperature (K)
Wavelength (pm)
Unit cell dimensions
a (Å)
759503
C6H9BrO4
225.04
Monoclinic
C2
757984
C6H9BrO4
225.04
Orthorhombic
P212121
100(2)
Acknowledgements
100(2)
154.178
71.073
We are grateful to the Deutsche Forschungsgemeinschaft (DFG)
and the Fonds der Chemischen Industrie (FCI) for financial support
(Emmy Noether Fellowship as well as Liebig Fellowship to D.B.W.).
D.C.K. thanks the Studienstiftung des deutschen Volkes and the
Fonds der Chemischen Industrie (FCI) for an undergraduate and a
Ph.D. fellowship, respectively. We are grateful to Professor Dietmar
Stalke for providing access to X-ray facilities. We thank Professor
Lutz F. Tietze (University of Göttingen) for helpful discussions
and generous support of our work.
25.0428(11)
4.7361(2)
6.7198(2)
90
4.7279(5)
11.5640(11)
13.9128(14)
90
b (Å)
c (Å)
a
(°)
b (°)
94.5086(18)
90
90
90
c
(°)
Z
4
4
Volume (Å3)
794.54(5)
1.881
760.66(13)
1.965
Dcalc (g/cm3)
l
(mmꢀ1
)
6.827
5.366
Max./min. transmission
h range for data coll. (°)
Index ranges
0.3851/0.1890
3.54–71.15
ꢀ30 ꢁ h ꢁ 30
ꢀ4 ꢁ k ꢁ 5
ꢀ8 ꢁ l ꢁ 8
5790
1280
1274/1/104
0.0434
1.126
0.0481
0.1326
0.12(5)
0.4550/0.6652
2.29–27.31
ꢀ6 ꢁ h ꢁ 6
ꢀ14 ꢁ k ꢁ 14
ꢀ17 ꢁ l ꢁ 17
13,579
1707
1707/9/127
0.0226
1.11
0.0119
0.0319
0.014(6)
0.388/ꢀ0.206
References and notes
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Independent reflections
Data/restraints/parameters
Rint
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R1(F) [I > 2
r
(I)]
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Analytical Data of 38l: yield: 68%. Rf: 0.08 (hexane/EtOAc = 1:1).
= +14.0 (c 0.15, CH2Cl2). 1H NMR (300 MHz, DMSO-d6): d = 1.92–
a
2.07 (m, 2H), 2.67 (t, J = 7.3 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 3.70 (d,
J = 7.4 Hz, 2H), 3.99–4.05 (m, 2H), 4.18 (dd, J = 3.5, 3.5 Hz, 1H),
4.69–4.77 (m, 1H), 4.79–4.88 (m, 1H), 4.94–5.02 (m, 2H), 6.44 (s,
1H). 13C NMR (125 MHz, DMSO-d6): d = 25.5, 29.4, 32.3, 60.4,
62.5, 72.0, 78.3, 78.6, 107.3, 121.3, 127.7, 136.4, 145.7, 149.9. IR
(KBr):
m e)
(cmꢀ1) = 2927, 1750, 1622, 1468. UV (CH3CN): kmax (lg
[nm] = 205.5 (4.35), 225.0 (3.71), 286.5 (3.28). MS (ESI): m/z
(%) = 271.1 (100) [M+Na]+. HRMS (ESI): m/z calcd for [M+Na]+:
271.0941; found: 271.0941.
5. X-ray investigations
The data for 2814 and 32 were collected from shock-cooled crys-
tals at 100 K mounted with inert oil on glass fibers.29 The data of 28
was collected on a Bruker Smart 6000-Cu rotating anode with
INCOATEC Helios mirror optics. The data of 32 was collected on a
Bruker TXS-Mo rotating anode with D8 goniometer and INCOATEC
Helios mirror optics. Both were equipped with a low-temperature
30
device. The data was integrated with SAINT
,
and an empirical
31
absorption correction with SADABS was applied. Both structures
were solved by direct methods (SHELXS-97)32 and refined by full-ma-
trix least-squares methods against F2 (SHELXL-97).32 The correctness
of the absolute structures was successfully determined by the Flack
x parameter (zero within 3 esd’s) during the refinement.33
All non-hydrogen atoms were refined with anisotropic displace-
ment parameters. The hydrogen atoms were refined isotropically
on calculated positions using a riding model with their Uiso values
constrained to 1.5 times the Ueq of their pivot atoms for terminal
sp3 carbon atoms and 1.2 times for all other carbon atoms. Crystal-
lographic data (excluding structure factors) for the structures re-
ported in this paper have been deposited with the Cambridge
Crystallographic Data Centre. The CCDC numbers, crystal data
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M. Leibeling et al. / Bioorg. Med. Chem. 18 (2010) 3656–3667
3667
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