Intermolecular twofold carbopalladation/cyclization sequence to access chromans and isochromans from carbohydrates

Article abstract of DOI:10.1002/chem.201101917

Fuse it! An intermolecular Pd-catalyzed domino process leading to chromans and isochromans is reported (see scheme). A bromoglycal derived from monosaccharides and two alkyne units set the stage for the benzene annelation. Copyright

Full text of DOI:10.1002/chem.201101917

DOI: 10.1002/chem.201101917
Intermolecular Twofold Carbopalladation/Cyclization Sequence to Access
Chromans and Isochromans from Carbohydrates
Markus Leibeling,[a] Bastian Milde,[a] Daniel Kratzert,[b] Dietmar Stalke,[b] and
Daniel B. Werz*[a]
Dedicated to Professor Rolf Gleiter on the occasion of his 75th birthday
Due to vanishing petrochemical resources, the quest to
find new pathways for efficient chemical synthesis from re-
newable feedstock has been intensified.[1] So far, major ef-
forts have been achieved in the preparation of non-petrole-
um derived chemicals such as furfural from hemicellulose-
rich biomass.[2] Advances using terpenes such as linalool as a
starting material for alternative high-density fuels were also
effectuated.[3] For the last decade the spotlight in green
chemistry has been on biomass-derived energy sources and
the development of novel and more efficient catalytic pro-
cesses.[4] However, almost all fine chemicals are still derived
from fossil resources. According to the technology roadmap
of the U.S. Department of Energy for plant-based renewable
resources in 1999, at least 10% of the fine chemicals should
be based on non-fossil origin by 2020.[5] Recently, a report
Scheme 1. Retrosynthetic analysis of highly substituted chromans (left)
and isochromans (right) leading to bromoglycals and two alkyne units.
was published that makes use of terpene feedstock by con-
verting it into polyketide architectures[6] and our group dis-
closed metal-catalyzed synthetic routes to spiroketals,[7]
C-glycosides,[8] as well as chroman-type structures[9] starting
from carbohydrates.
The starting material is a 2-bromoglycal that can be easily
derived from the native monosaccharide in several
steps.[10,15] This six-membered ring can be employed either
to give chroman- or isochroman-type structures. In the
former case, an alkynyl chain is attached to C3, in the latter
to C1. Propargylic bromides are utilized for chroman syn-
thesis, whereas the corresponding propargylic alcohols are
employed in a Ferrier reaction[16] to afford the starting mate-
rials for isochromans. The latter transformation consists of a
Lewis acid-catalyzed SN2’ reaction of peracetylated or per-
benzoylated bromoglycals resulting in a shift of the C=C
double bond in the six-membered ring to give the corre-
sponding 2-bromoglycals with an alkyne chain attached to
the anomeric position. In all cases, the a anomer was the
major product; the b anomer was detected only in minor
amount (a/b=ꢀ8:1) and could easily be separated by
column chromatography.
In contrast to our earlier studies, which showed limita-
tions with respect to the substitution pattern due to the use
of an intramolecular domino reaction,[9,10] our results for a
much more flexible intermolecular variant are described in
this report. The general idea is depicted in Scheme 1. In
contrast to many other chroman and isochroman syntheses,
which are confined to the annelation of the pyran moiety to
the benzene ring,[11] our approach enables a synthesis of the
aromatic core through a domino sequence consisting of a
twofold carbopalladation followed by subsequent cycliza-
tion.[12,13,14]
[a] M. Leibeling, B. Milde, Dr. D. B. Werz
Institut fꢁr Organische und Biomolekulare Chemie
Georg-August-Universitꢂt Gçttingen, Tammannstr. 2
37077 Gçttingen (Germany)
Fax : (+49)551-399476
E-mail: dwerz@gwdg.de
During our ongoing efforts on the intermolecular assem-
bly of chromans and isochromans, we screened various pal-
ladium sources, ligands, bases, ratios of starting materials,
but also the concentration of the reaction mixture. The cata-
[b] D. Kratzert, Prof. Dr. D. Stalke
Institut fꢁr Anorganische Chemie
Georg-August-Universitꢂt Gçttingen,
Tammannstr. 4, 37077 Gçttingen (Germany)
lysts PdCATHUNGERTNN(NUG OAc)2, PdAHCTUNGTRE(NGUNN PPh3)4, and PdACHTNUGTERN(NUGN dppf)Cl2 were employed;
however, improved catalytic yields were observed when Fuꢀs
salt ([(tBu)3PH]BF4) was added to the reaction mixture pro-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101917.
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Chem. Eur. J. 2011, 17, 9888 – 9892

COMMUNICATION
viding a sterically hindered ligand with a strongly s-donating
phosphorus atom.[17] This ligand proved to be superior to
the previously used triphenylphosphine ligands. In our study,
we finally found the equivalents of alkyne 2a and the con-
centration of the reaction mixture to be the predominant ef-
fects on the yield of the reaction. The best results were ac-
complished with a 20-fold excess of alkyne 2a, but also a
lower amount of alkyne 2a provided the desired product
(Table 1). A lower concentration also proved to be benefi-
spective bromoglycal. Intramolecular carbopalladation of
the adjacent alkyne unit gives a diene system that reacts in a
second intermolecular carbopalladation with alkyne II to
afford a 1,3,5-triene. The final cyclization step generating
the benzene unit may be regarded either as disrotatory elec-
À
trocyclic 6p-electron ring-closure or as C H activation (for
a detailed reaction mechanism, see Supporting Informa-
tion).
Only (trimethylsilyl)acetylene (2d) was tolerated as un-
symmetrically substituted alkyne of type II. Notably, only
regioisomer 3d was found in moderate yield whereas the
other regioisomer could not be detected. The use of phenyl-
acetylene or 1-hexyne led only to traces of the desired prod-
ucts. The intermolecular carbopalladation occurs at the less
hindered position of the terminal alkyne; thus, the silyl
moiety is located adjacent to the pyran ring. Experiments
with electron-poor alkynes such as acetylene carboxylic
esters proved to be unsuccessful illustrating the electrophilic
attack of the Pd species to the triple bond.
Table 1. Optimization of the Pd-catalyzed intermolecular domino pro-
ACHTUNGTRENNUNG
cess.[a]
Catalyst
[10 mol%]
Ligand
Base
2a
[equiv]
c (1b)
[mmolLÀ1
]
Yield
[%]
G
[20 mol%] [4.0 equiv]
G
U
Similar experiments were performed with 1-alkynyl-sub-
stituted 2-bromoglycals 5a–5c. The respective isochromans
6a–6e were obtained in yields of 40–56% (Table 3).
Deprotection reactions provided chromans and isochro-
mans with free hydroxyls. Isopropylidene was removed by
the action of acid and benzylidene protecting groups were
cleaved under acidic conditions or by hydrogenolysis
(Table 2). The acidic cleavage of isopropylidene also result-
ed in the removal of the TMS group adjacent to the pyran
moiety in 3b and 3d. We rationalized this behavior by a sta-
bilization of a positive charge in the ortho position (com-
pound 8) due to the neighboring oxygen atom of the pyran
ring (Scheme 2). In this way, the chroman 4d could be ob-
tained in 91% yield.
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dppf)Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
(PPh3)4
11 Pd(PPh3)4
12 Pd(PPh3)4
N
PPh3
–
NBu3
2.0
3.0
50
35
35
35
35
35
35
35
60
20
10
10
0
HN
HN
HN
U
23
36
44
49
14
37
50
43
54
66
65[b]
[c]
[c]
[c]
[c]
[c]
[c]
[c]
[c]
[c]
[c]
P
P
P
P
P
P
P
P
P
P
G
10.0
20.0
20.0
20.0
20.0
20.0
20.0
20.0
20.0
20.0
E
N
Cs2CO3
Cs2CO3
K2CO3
CsF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
10 Pd
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] General conditions: DMF/MeCN/NMP=8:8:1, 2 h, 1208C, microwave
irradiation (mw). [b] 15 h, 1208C, no microwave irradiation.
[c] [(tBu)3PH]BF4 was employed.
cial. In highly concentrated reaction mixtures even traces of
the respective cyclooctatetraene derivatives were found.
With an optimized catalytic system in hand (DMF/MeCN/
NMP=8:8:1; PdACHTUNGTRENNUNG(PPh3)4, [(tBu)3PH]BF4, Cs2CO3 or HN-
ACHTUNGTRENNUNG
tion), we investigated the scope of the intermolecular
domino process.
2-Bromoglycals derived from glucose and galactose with
different alkynes attached to the sugar core were investigat-
ed (alkyne I with R=H, Me, Ph). As coupling partners, in-
ternal and terminal alkynes (alkyne II) such as 3-hexyne
(2a), bis(trimethylsilyl)acetylene (2b), tolane (2c) and (tri-
methylsilyl)acetylene (2d) were employed (Table 2).[18]
Notably, even highly sterically encumbered alkynes II
such as 2b and 2c were successfully converted. Alkynes I
with a sterically demanding substituent were found to be
difficult substrates in the intermolecular domino reaction.
With 3-hexyne we were able to isolate the desired product
3g in only low yield (14%); using the same substrate and
tolane as alkyne II product formation could not be ob-
served.
Scheme 2. Acidic cleavage of the TMS group adjacent to the pyran
moiety leading to chroman 4d.
The saponification of the ester groups in isochromans 6a–
6e proved not to be possible with the commonly employed
sodium methoxide in methanol. The strongly basic condi-
tions also led to the abstraction of the slightly acidic anome-
ric proton resulting in decomposition of the desired product.
Milder conditions utilizing potassium carbonate gave rise to
the corresponding free hydroxyl groups in good to excellent
yields (48–92%). In some cases, such as in 7a and 7e, a
We suppose that the domino sequence is initiated by an
0
À
oxidative addition of the Pd into the C Br bond of the re-
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9889

D. B. Werz et al.
Table 2. Monoalkynylated 2-bromoglycals 1a–1e, alkynes II 2a–2d, chromans 3a–3j, deprotected chromans 4a–4j and corresponding yields of the
domino sequence and the deprotection.
Starting materials
Product
Yield
[%][a]
Starting materials
Product
Yield
[%][a]
57
72
27
100
57
98
14
–
25
79
65
38
27
91
69
78
66
73
60
88
[a] The first value is the yield of the domino reaction; the second value is the yield of the deprotection.
slight anomeric isomerization was noticed (a/b=ꢀ10:1 and
a/b=ꢀ4:1, respectively, Table 3).
The structure of deprotected isochroman 7d could also be
confirmed by X-ray crystallography. The absolute configura-
tion of the anomeric stereocenter that was obtained by the
diastereoselective Ferrier reaction was approved. In addi-
tion, it revealed a strongly distorted conformation of the
corresponding pyran unit (Figure 1).
In conclusion, we have developed a convenient and gener-
al entry to carbohydrate-based chromans and isochromans
by using an intermolecular Pd-catalyzed domino reaction in
À
which three C C bonds and two rings are formed. Starting
materials are easily accessible monoalkynyl substituted
2-bromoglycals and terminal or internal alkynes being
added in excess to the reaction mixture. We believe that the
structural diversity of these carbohydrate derivatives will be
useful in exploring differential avidity properties with chro-
man- and isochroman-binding enzymes.
Figure 1. The structure of deprotected isochroman 7d, depicted with an-
AHCTUNGERTGiNNUN sotropic displacement parameters at the 50% probability level.
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Intermolecular Twofold Carbopalladation/Cyclization
COMMUNICATION
Table 3. Monoalkynylated 2-bromoglycals 5a–5c, alkynes II 2a–2b, iso-
chromans 6a–6e, deprotected isochromans 7a–7e and corresponding
yields of the domino sequence and the deprotection.
stirred in a microwave reactor for 2 h at 1208C. 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, and dried over Na2SO4. The solvent was removed by rotary
evaporation and the residue was purified by silica gel column chromatog-
raphy (pentane/EtOAc) to afford chroman 3 or isochroman 6, respective-
ly, as a colorless to slightly yellow solid.
For the X-ray crystal structure of 7d a single crystal was mounted with
inert oil on a glass fiber.[19a] The data were collected at 100 K on a
Bruker Smart Apex II with mirror optics. Data reduction was obtained
from SAINT,[19b] and an empirical absorption correction with SA-
DABS[19c] was applied. The structure was solved by direct methods
(SHELXS-97)[19d] and refined by full-matrix least-squares methods
against F2 (SHELXL-97).[19d] The absolute structures was successfully de-
termined by the Flack x parameter (zero within 3 esdꢀs) during the refi-
nement.[19e] All non-hydrogen atoms were refined with anisotropic dis-
placement parameters. The hydrogen atoms were refined isotropically on
calculated positions using a riding model with their Uiso values constrain-
ed to 1.5 times the Ueq of their pivot atoms for terminal sp3 carbon atoms
and 1.2 times for all other carbon atoms. Crystallographic data (excluding
structure factors) for the structures reported in this paper have been de-
posited with the Cambridge Crystallographic Data Centre.[20]
Starting materials
Product
Yield
[%][a]
40
81[b]
54
84
Acknowledgements
We are grateful to the Deutsche Forschungsgemeinschaft (Emmy Noeth-
er Fellowship to D.B.W.), the Fonds der Chemischen Industrie, the
DNRF-funded Centre of Materials Crystallography, and the State of
Lower Saxony (Ph.D. Fellowship of the CaSuS Program to M.L.). Fur-
thermore, we thank Prof. Dr. Lutz F. Tietze for helpful discussions and
generous support of our work.
40
78
Keywords: carbohydrates · chromans · cyclization · domino
reactions · palladium
52
92
[1] a) J. Szekely, R. Laudise, J. Mater. Res. 1995, 10, 485–486; b) P.
Tundo, A. Perosa, F. Zecchini, Methods and Reagents for Green
Chemistry: An Introduction, Wiley-VCH, New York, 2007.
[2] J. B. Binder, J. J. Blank, A. V. Cefali, R. T. Raines, ChemSusChem
2010, 3, 1268–1272.
[3] H. A. Meylemans, R. L. Quintana, B. R. Goldsmith, B. G. Harvey,
ChemSusChem 2011, 4, 465–469.
[4] J. H. Clark, D. J. Macquarrie, J. Mater. Chem. 2009, 19, 8512–8514.
[5] A. K. Mohanty, M. Misra, L. T. Drzal, J. Polym. Environ. 2002, 10,
19–26.
56
48[c]
[6] P. Winter, C. Vaxelaire, C. Heinz, M. Christmann, Chem. Commun.
2011, 47, 394–396.
[7] a) C. Brand, G. Rauch, M. Zanoni, B. Dittrich, D. B. Werz, J. Org.
Chem. 2009, 74, 8779–8786; b) D. C. Koester, A. Holkenbrink, D. B.
Werz, Synthesis 2010, 3217–3242.
[8] D. C. Koester, M. Leibeling, R. Neufeld, D. B. Werz, Org. Lett. 2010,
12, 3934–3937.
[9] a) M. Leibeling, D. C. Koester, M. Pawliczek, S. C. Schild, D. B.
Werz, Nat. Chem. Biol. 2010, 6, 199–201; b) D. W. Young, Nat.
Chem. Biol. 2010, 6, 174–175.
[10] M. Leibeling, D. C. Koester, M. Pawliczek, D. Kratzert, B. Dittrich,
D. B. Werz, Bioorg. Med. Chem. 2010, 18, 3656–3667.
[11] For recent examples of chroman syntheses, see: a) L. Zu, S. Zhang,
H. Xie, W. Wang, Org. Lett. 2009, 11, 1627–1630; b) Y. Yamamoto,
K. Itonaga, Org. Lett. 2009, 11, 717–720; c) B. M. Trost, H. C. Shen,
L. Dong, J.-P. Surivet, C. Sylvain, J. Am. Chem. Soc. 2004, 126,
11966–11983.
[a] The first value is the yield of the domino reaction; the second value is
the yield of the deprotection. [b] Partial isomerization of the anomeric
stereocenter (a/b=ꢀ10:1). [c] Partial decomposition and isomerization
of the anomeric stereocenter (a/b=ꢀ4:1).
Experimental Section
General procedure: The alkynylated bromoglycal 1 or 5 (0.20 mmol, 1.0
equiv), respectively, and alkyne II (4.0 mmol, 20.0 equiv) were dissolved
in a mixture of DMF/MeCN/NMP (9.0 mL, 9.0 mL, 1.2 mL). PdACTHUNTRGNE(UNG PPh3)4
(20 mmol, 0.1 equiv), [(tBu)3PH]BF4 (40 mmol, 0.2 equiv) and diisopropyl-
amine or Cs2CO3 (0.80 mmol, 4.0 equiv) were added. The reaction was
Chem. Eur. J. 2011, 17, 9888 – 9892
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9891

D. B. Werz et al.
[12] For a general overview of domino reactions, see: a) L. F. Tietze, G.
Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis,
Wiley-VCH, Weinheim, Germany, 2006; b) L. F. Tietze, Chem. Rev.
1996, 96, 115–136; c) V. Gevorgyan, U. Radhakrishnan, A. Takeda,
M. Rubina, M. Rubin, Y. Yamamoto, J. Org. Chem. 2001, 66, 2835–
2841.
[13] For other examples of Pd-mediated domino processes, see: a) F. E.
Meyer, A. de Meijere, Synlett 1991, 777–778; b) L. F. Tietze, A.
Dꢁfert, F. Lotz, L. Sçlter, K. Oum, T. Lenzer, T. Beck, R. Herbst-
Irmer, J. Am. Chem. Soc. 2009, 131, 17879–17884; c) R. C. Larock,
M. J. Doty, Q. Tian, J. M. Zenner, J. Org. Chem. 1997, 62, 7536–
Nieger, S. Brꢂse, Org. Biomol. Chem. 2011, 9, 3136–3138; e) H. A.
Wegner, S. Ahles, M. Neuburger, Chem. Eur. J. 2008, 14, 11310–
11313.
[15] K. Yoshimoto, H. Kawabata, N. Nakamichi, M. Hayashi, Chem.
Lett. 2001, 30, 934–935.
[16] R. J. Ferrier, W. G. Overend, A. E. Ryan, J. Chem. Soc. 1962, 3667–
3670.
[17] M. R. Netherton, G. C. Fu, Org. Lett. 2001, 3, 4295–4298.
[18] R. Gleiter, D. B. Werz, Chem. Rev. 2010, 110, 4447–4488.
[19] a) T. Kottke, D. Stalke, J. Appl. Crystallogr. 1993, 26, 615; b) Bruker,
SAINT V7.68A, Bruker AXS Inc., Madison (WI, USA), 2005;
c) G. M. Sheldrick, SADABS 2008/2, Gçttingen, 2008; d) G. M.
Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112–122; e) H. D.
Flack, Acta Crystallogr. Sect. A 1983, 39, 876–881.
[20] The crystal data and experimental details for the X-ray measure-
ments are listed in the Supporting Information. CCDC-830678 con-
tains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ˇ
7537; d) J. Cvengros, J. Schꢁtte, N. Schlçrer, J.-M. Neudçrfl, H.-G.
Schmalz, Angew. Chem. 2009, 121, 6264–6267; Angew. Chem. Int.
Ed. 2009, 48, 6148–6151; e) Y. Hu, H. Yao, Y. Sun, J. Wan, X. Lin,
T. Zhu, Chem. Eur. J. 2010, 16, 7635–7641; f) J. Petrignet, A.
Budhar, G. Blond, J. Suffert, Angew. Chem. 2011, 123, 3343–3347;
Angew. Chem. Int. Ed. 2011, 50, 3285–3289.
[14] For other examples of domino reactions, see: a) D. Enders, M. R. M.
Hꢁttl, C. Grondal, G. Raabe, Nature 2006, 441, 861–863; b) T.
Saget, N. Cramer, Angew. Chem. 2010, 122, 9146–9149; Angew.
Chem. Int. Ed. 2010, 49, 8962–8965; c) M. Rueping, K. L. Haack, W.
Ieawsuwan, H. Sundꢄn, M. Blanco, F. R. Schoepke, Chem.
Commun. 2011, 47, 3828–3830; d) E. Bourcet, M. C. Brçhmer, M.
Received: June 21, 2011
Published online: August 2, 2011
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Chem. Eur. J. 2011, 17, 9888 – 9892