Novel olefin-phosphorus hybrid and diene ligands derived from carbohydrates

Article abstract of DOI:10.1055/s-0030-1258190

Starting from readily available monosaccharides d-glucose and d-arabinose, a family of novel chiral diene and olefin-phosphinite hybrid ligands has been designed. These ligands were prepared by attaching phosphinite or allylic donor sites onto unsaturated carbohydrate scaffolds. In rhodium(I)-catalysed conjugate addition of boronic acids to enones, the olefin-phosphinite hybrids gave products in up to 99% ee and above, whereas the dienes only led to modest enantioselectivity. However, by shifting the allylic donor sites from position 4 of the pyranose to the anomeric centre, an unexpected reversal of the stereoinduction process was observed. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258190

3248
SPECIAL TOPIC
Novel Olefin–Phosphorus Hybrid and Diene Ligands Derived from
Carbohydrates
O
lefin–Phosphoru
o
s
H
ybrid and
l
Diene
g
L
igands er Grugel, Tobias Minuth, Mike M. K. Boysen*
Institute of Organic Chemistry, Gottfried Wilhelm Leibniz University of Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: mike.boysen@oci.uni-hannover.de
Received 30 April 2010
who prepared ligand 7 containing a 5H-dibenzo[a,d]cy-
Abstract: Starting from readily available monosaccharides D-glu-
cloheptene scaffold9 and only shortly afterwards, Hayashi
cose and D-arabinose, a family of novel chiral diene and olefin–
phosphinite hybrid ligands has been designed. These ligands were
prepared by attaching phosphinite or allylic donor sites onto unsat-
et al. introduced norbornene-derived hybrid ligand 8.10
Later, Widhalm11 and Carreira12 used chiral binaphthyl
urated carbohydrate scaffolds. In rhodium(I)-catalysed conjugate scaffolds for the preparation of ligands 9 and 10, respec-
tively, while Stepnicka13 and Bolm14 reported planar-
addition of boronic acids to enones, the olefin–phosphinite hybrids
gave products in up to 99% ee and above, whereas the dienes only
led to modest enantioselectivity. However, by shifting the allylic
chiral ligands 11 and 12.
donor sites from position 4 of the pyranose to the anomeric centre,
an unexpected reversal of the stereoinduction process was observed.
diene ligands
MeO
R1
Key words: carbohydrates, ligand design, asymmetric catalysis,
rhodium, boron
R1
R1
R1
R1
i-Bu
R1 = Bn, allyl
1
2
3
R1 = Ph, Bn
R1 = Ph, Bn
As target structures in both natural product chemistry and
medicinal chemistry are generally optically pure chiral
compounds, stereoselective preparation of chiral building
blocks is of great importance in modern organic synthesis.
Asymmetric catalysis using chiral metal complexes is a
very efficient tool for the preparation of chiral materials
and thus the development of novel chiral ligands is an ac-
tive research field. Scaffolds containing olefinic donor
centres are a very recent and particularly exciting addition
to the choice of chiral ligands available for stereoselective
synthesis.1 While simple olefin ligands only lead to very
labile complexes, chiral chelators with two olefinic donor
sites or containing one olefinic donor in combination with
a second donor centre make excellent steering ligands for
catalysis, creating a unique chiral environment around the
metal centre. Figure 1 shows examples of chiral olefin
ligands. The earliest ligands were rigid bicyclic dienes: In
2003, Hayashi et al. reported the use of bicyclo[2.2.1]hep-
tadienes 1 as the first chiral olefin ligands that were suc-
cessful in conjugate addition reactions;2 concurrently,
Carreira et al. introduced the use of compounds of type 3,
which were based on carvone, in allylic displacement re-
actions.4 The following year, Hayashi’s group prepared
bicyclo[2.2.2]octadiene ligands 2.3 More recently,
Laschat,5 as well as Xu and Lin,6 independently reported
the use of bicyclo[3.3.0]octadienes 4, while Hayashi et al.
designed a-phellandrene-derived ligand 5,7 and Hu et al.
explored simple aliphatic diene 6.8 The first example of a
hybrid ligand containing one olefinic and one phospho-
rus-based donor was published by Grützmacher et al.,
R1
H
i-Pr
OH
OH
OH
H
4
R1
5
6
R1 = Ph, Bn
olefin–phosphorus hybrid ligands
PPh2
Ph
PPh2
Ph
P
O
Ph
8
9
7
Ph
Ph
O
O
PPh2
CO
N
P
Fe PPh2
Re
OC
OC
10
11
12
Figure 1 Selected examples of diene and olefin–phosphorus hybrid
ligands
The most important application of chiral olefin ligands is
the rhodium(I)-catalysed conjugate addition of boronic
acids to enones and acrylic ester substrates (the Hayashi–
Miyaura reaction).15,16 High enantioselectivities in these
transformations have been achieved by Hayashi et al. with
dienes 1 and 2, as well as with hybrid ligand 8, and by
Carreira et al. who employed ligands of type 3. Despite
their utility in asymmetric synthesis, the application of
SYNTHESIS 2010, No. 19, pp 3248–3258
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Advanced online publication: 05.08.2010
DOI: 10.1055/s-0030-1258190; Art ID: C03810SS
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Olefin–Phosphorus Hybrid and Diene Ligands
3249
OAc
many olefin ligands is hampered by one serious draw-
back: With the exception of Carreira’s and Hayashi’s di-
ene ligands 3 and 5, which are derived from the terpenes
carvone and a-phellandrene, respectively, most structures
shown in Figure 1 are prepared as racemates and require
subsequent enantiomeric resolution by preparative HPLC,
making their synthesis a laborious process.
OH
1) Ac2O, NaOAc
O
O
AcO
AcO
HO
HO
2) HBr, HOAc
79% over 2 steps
AcO
OH
OH
Br
14
13
D-glucose
Zn, CuSO4
HOAc
72%
Carbohydrates are the most abundant substances in the
chiral pool and are readily available in enantiomerically
pure form. The first successful carbohydrate-based com-
plex ligands were prepared over 30 years ago by reaction
of monosaccharide diols with diphenyl chlorophosphine
to yield diphosphinites.17,18 However, the great potential
of carbohydrates as starting materials for the design and
development of novel chiral ligands has only started to be
recognised fairly recently.19
EtOH
BF3⋅OEt2
O
O
OEt
CH2Cl2
AcO
AcO
commercially
available
81%
AcO
AcO
16
15
OAc
D-glucal
1) MeOH–H2O–Et3N
(9:6:1)
85% over
2 steps
2) TrCl, pyridine
O
OEt
O
OEt
Ph2PCl, Et3N
THF
As part of our ongoing research programme on the design
of carbohydrate complex ligands,20 we envisioned the use
of novel olefin ligands based on simple monosaccharides
for two reasons: Firstly, a number of unsaturated
monosaccharide derivatives are either easily accessible in
just a few simple synthetic steps or are commercially
available. Secondly, the remaining hydroxy functions can
be used for the introduction of additional donor sites, for
example, by formation of phosphinites, as in the synthesis
of the first carbohydrate ligands,17 or by attachment of
olefin residues, for example, by etherification with allylic
halides.
TrO
TrO
HO
70%
O
17
Ph2P
18
gluco-enoPhos
Scheme 1 Preparation of olefin–phosphinite hybrid ligand gluco-
enoPhos (18) from D-glucose.
Table 1 Rhodium(I)-Catalysed Asymmetric 1,4-Addtion of Phe-
nylboronic Acid (20) to Enones and Unsaturated Lactones (19) with
Ligand gluco-enoPhos (18)21
The preparation of the first example of a carbohydrate-
based olefin–phosphinite hybrid ligand is shown in
Scheme 1.21 Our synthetic route started from commercial-
ly available ethyl-4,6-di-O-acetyl-2,3-dideoxy-a-D-eryth-
ro-hex-2-enopyranose (16; 25.00 €/g, Sigma–Aldrich),
which can also be easily prepared from D-glucose (13):
Per-acetylation22 of 13, followed by transformation into
glucosyl bromide 1423 and subsequent treatment with zinc
in acetic acid, yields acetylated D-glucal 15,24 which can,
in turn, be transformed into hex-2-enopyranose 1625
through a Ferrier rearrangement26 as a key step. In the case
of D-glucal, this reaction usually proceeds with good se-
lectivity for the a-anomer. Base-mediated deprotection27
of 16 with subsequent 6-O-tritylation,28 yielded alcohol
17. The desired ligand gluco-enoPhos (18) was obtained
by treatment of 17 with diphenyl chlorophosphine under
conditions described by Uemura and Ohe for the prepara-
tion of carbohydrate-based oxazoline–phosphinite hybrid
ligands.29 Thus, the novel ligand can be prepared in enan-
tiomerically pure form and good yield in only three steps
from commercially available hex-2-enopyranose 16, or in
seven steps from D-glucose 13.21
O
O
Ph-B(OH)2 (20)
gluco-enoPhos (18) (3.3 mol%)
[RhCl(H2C=CH2)2]2 (1.5 mol%)
∗
KOH, dioxane–H2O
Ph
19
21
Entry
1
Substrate
Product
Yield (%)a ee (%)
O
O
80
82
>99b
(R)
Ph
19a
21a
O
O
2
99b
(R)
Ph
19b
O
21b
O
O
3
4
O
48
90
94b
52c
(R)
Ph
19c
21c
The results obtained with novel olefin hybrid ligand 18 in
the Hayashi–Miyaura reaction of enone substrates 19a–d
with phenylboronic acid (20) are summarised in
Table 1.21 Under conditions described previously,30 2-cy-
clohexen-1-one (19a) gave the corresponding 1,4-addition
product 21a in high yield and excellent stereoselectivity
of 99% ee (entry 1). Smaller cyclic enone 19b was con-
O
Ph
O
(S)
21d
a Isolated yield after chromatography.
19d
b Determined by HPLC analysis on a chiral column.
c Determined by 1H NMR analysis with Rh2[R-(+)-MTPA]4 as chiral
complexing reagent (dirhodium method).31
Synthesis 2010, No. 19, 3248–3258 © Thieme Stuttgart · New York

3250
H. Grugel et al.
SPECIAL TOPIC
verted with a similarly excellent result (entry 2), and un- both D- and L-enantiomers of pentose saccharide arabi-
saturated lactone 19c gave product 21c in moderate yield nose are commercially available at low cost. Therefore,
and high stereoselectivity (entry 3). Acyclic enones such we decided to prepare D-arabinose congeners of our
as 19d are challenging substrates in asymmetric 1,4-addi- glucose-based diene and hybrid ligands.
tions. Unlike cyclic substrates, they have great conforma-
The synthetic route towards arabinose-based olefin
tional flexibility, especially if they do not have sterically
ligands shown in Scheme 3 is analogous to that used for
demanding substituents on their termini, which may oth-
the corresponding glucose derivatives. Per-acetylation34
erwise favour a certain conformation. Using hybrid ligand
of D-arabinose, followed by treatment with hydrogen bro-
18, acyclic 1,4-addition product 21d was obtained in high
mide, gave arabinosyl bromide 27,35 which was trans-
yield and a moderate stereoselectivity of 52% ee (entry 4),
formed into D-arabinal36 by reductive elimination. Unlike
which, for this substrate, is still a promising first result.
D-glucal, which usually gives good a-selectivity in Ferrier
Encouraged by these first excellent results, we set out to reactions (a/b ratio 10:1 or better), D-arabinal may yield
explore carbohydrate-based diene ligands. Inspired by di- rearrangement products as anomeric mixtures, necessitat-
olefin ligand 6, reported by Hu,8 and olefin–phosphine hy- ing tedious chromatographic separation and leading to di-
brid ligand 9, designed by Widhalm,11 both with aliphatic minished yields.37 To avoid this problem, we performed
olefin moieties as donor sites, we planned to introduce al- the rearrangement reaction with triethyl silane as the nu-
lylic residues into the carbohydrate scaffolds. Simple cleophile, which led to anhydro-compound 29 in excellent
Williamson etherification of unsaturated pyranose alcohol yield.38 Base-mediated deprotection27 gave alcohol 30 as
17 with allyl bromide and cinnamyl bromide yielded di- a key intermediate, which was transformed into olefin–
ene ligands 22 and 23, respectively. An even more phosphinite hybrid 31 by treatment with diphenyl chloro-
straightforward access to glucose-based dienes can be phosphine,29 and diene 32 by alkylation with allyl bro-
achieved through the Ferrier rearrangement: Treatment of mide.
acetylated glucal 15 with allyl alcohol or allyl trimethylsi-
lane in the presence of Lewis acid catalysts yielded O-glu-
cosidic diene 2432 and C-glucosidic diene 2533 in a total of
only four steps from D-glucose. All new diene ligands 22–
25 were obtained in excellent yields (Scheme 2).
Br
OH
OH
1) Ac2O, NaOAc
2) HBr, HOAc
O
O
OAc
57% over 2 steps
OH
OAc
HO
AcO
27
26
D-arabinose
R1
NaH, DMF
Br
O
OEt
O
OEt
Zn, CuSO4
HOAc
60%
TrO
TrO
HO
O
Et3SiH
BF3⋅OEt2
O
O
17
R1
22 90%
23
CH2Cl2
94%
R
1 = H
AcO
AcO
R
1 = Ph
93%
29
OAc
28
D-arabinal
MeOH–H2O–Et3N
(9:6:1)
OH
74%
FeCl3, CH2Cl2
O
O
AcO
AcO
Br
87%
Ph2PCl
Et3N, THF
O
O
O
O
NaH, DMF
92%
AcO
24
85%
O
HO
O
AcO
15
30
PPh2
31
OAc
TMS
O
32
SnCl4, CH2Cl2
AcO
AcO
Scheme 3 Preparation of olefin–phosphinite hybrid ligand 31 and
diene ligand 32 from D-arabinose (26)
98%
25
Scheme 2 Synthesis of glucose-based diene ligands 22 and 23 from
hex-2,3-enopyranose 17 by Williamson ether synthesis, and dienes 24
and 25 from D-glucal 15 via Ferrier rearrangement
All new diene ligands 22–25 and 32 and new olefin–phos-
phinite 31 were subsequently evaluated in the rhodium(I)-
catalysed conjugate addition of phenylboronic acid (20) to
2-cyclohexen-1-one (19a); Table 2 summarises the re-
sults. While all ligands promoted the 1,4-addition, their
efficiency regarding product yield and stereoinduction
proved to be strikingly different. 4-O-Allyl-substituted
gluco-ligand 22 gave product 21a in fair yield, while
ligand 23, with the more bulky 4-O-cinnamyl residue, led
to a severely reduced yield. Unfortunately, both ligands
To access both enantiomeric products of any asymmetri-
cally catalysed process, both enantiomers of the catalyst
ligand have to be available. This presents a challenge
when carbohydrates are used as ligand precursors because
the L-enantiomers of these natural products are often pro-
hibitively expensive and sometimes even unavailable.
While this problem certainly arises in the case of glucose,
Synthesis 2010, No. 19, 3248–3258 © Thieme Stuttgart · New York

SPECIAL TOPIC
Olefin–Phosphorus Hybrid and Diene Ligands
3251
produced essentially racemates (entries 2 and 3). Switch- structurally simplified analogues of glucose-derived hy-
ing the allylic substituent from the 4-position to the ano- brid (18) and diene 22. Results obtained using these
meric centre (position 1) in O-glucoside diene 24 and C- ligands should therefore give some indications of whether
glucoside diene 25 led to a curious result (entries 4 and 5). the anomeric ethoxy residue and the trityloxy methyl
While both ligands promoted the 1,4-addition in only low group, which are missing in these arabino ligands and
to moderate yields and modest stereoselectivity, they both which are most likely not involved in the coordination of
led to the formation of ent-21a — the enantiomer of the the rhodium centre, have any impact on the stereodiffer-
products obtained with 4-O-phosphinite gluco-enoPhos entiation process. Entry 6 shows that arabinose olefin–
(18; entry 1) and 4-O-allylic ligands 22 and 23 (entries 2 phosphinite hybrid 31 is an efficient ligand in terms of
and 3). Arabinose-based hybrid ligand 31 and diene 32 are yield (92%), while the addition product 21a was obtained
Table 2 Evaluation of D-Glucose-Based Dienes 22–25, D-Arabinose-Derived Diene 32 and Hybrid Ligand 31 in the Conjugate Addition of
Phenylboronic Acid (20) to Enone 19a
O
O
Ph-B(OH)2 (20)
ligand (3.3 mol%)
[RhCl(H2C=CH2)2]2 (1.5 mol%)
∗
KOH, dioxane–H2O
Ph
19a
21a
Entry
Ligand
Product
Yield (%)a
80
ee (%)b
>99
O
O
OEt
OEt
O
TrO
1
2
O
(R)
Ph2P
Ph
21a
18
O
TrO
77
27
2
O
O
(R)
Ph
21a
22
O
OEt
O
TrO
3
racemic
(R)
Ph
Ph
21a
23
O
O
O
AcO
4
5
6
14
44
92
9
17
76
(S)
AcO
Ph
24
ent-21a
O
O
AcO
AcO
(S)
Ph
25
ent-21a
O
O
O
(R)
PPh2
Ph
21a
31
O
O
7
81
24
O
(R)
Ph
21a
32
a Isolated yield after chromatography.
b Determined by HPLC analysis on a chiral column.
Synthesis 2010, No. 19, 3248–3258 © Thieme Stuttgart · New York

3252
H. Grugel et al.
SPECIAL TOPIC
enantiomers
pseudo enantiomers
in only 76% ee as opposed to the >99% ee achieved with
gluco-enoPhos (18; entry 1). The simplified arabinose
ligand is therefore clearly inferior to its glucose counter-
part. Arabinose-based 4-O-allyl ligand 32 gave the ex-
pected product 21a in good yield and 24% ee.
A
B
ent-A
O
O
O
4
4
O
O
O
O
O
O
O
1
1
1
O
O
O
The findings can be summarised as follows: Carbohy-
drate-based olefin–phosphinite hybrid ligands (com-
pounds 18 and 31) are efficient ligands for the asymmetric
Hayashi–Miyaura reaction, promoting the reaction in high
yields and with fair to excellent enantioselectivity. Diene
ligands derived from carbohydrates give the 1,4-addition
products in highly variable yields, depending on the na-
ture and position of the allylic substituent in the carbohy-
drate scaffold. 4-O-Allyl-modified gluco and arabino
ligands 22 and 32 promote the reaction in high yields, but
while 22 produces 21a essentially racemically, 32 gives a
modest enantioselectivity of 24% ee, which is the best re-
sult for all the tested carbohydrate diene ligands. Ligand
24, containing a bulky 4-O-cinnamyl residue, leads to low
yield and no stereoselectivity, while the anomeric O-allyl
and C-allyl glucosides 24 and 25 switch the direction of
the stereoinduction process, even if both show only very
modest efficiency in the 1,4-addition reaction.
O
O
D-gluco
L-gluco
D-gluco
O
O
O
modified at position 4
modified at position 1
O
O
O
OEt
AcO
AcO
TrO
O
24
18
Ph2P
O
OEt
O
TrO
AcO
AcO
22
23
R
R
1 = H
1 = Ph
O
25
R1
Figure 2 Enantiomeric D-gluco and L-gluco scaffolds with modifi-
cation at the 4-position (structures A and ent-A) and pseudo-enantio-
meric D-gluco scaffold with modification at the 1-position (structure
B)
The surprising reversal of the stereoinduction mediated by
ligands 24 and 25 can be rationalised when a careful com-
parison is made between structures with phosphorus or
olefin donor sites at the 4-position and at the anomeric
centre (Figure 2). The D-gluco scaffold A and L-gluco
scaffold ent-A, with modification at the 4-position, are
enantiomeric and therefore true mirror images. Shifting
the modification to the anomeric centre (position 1) re-
sults in D-gluco scaffold B. When structure B is compared
to A, it becomes apparent that, with respect to the relative
position of the modifications, B may be regarded as a
pseudo mirror image of A when both the immediate sur-
rounding and the remaining stereocentres are disregarded.
Therefore, O-glucosidic and C-glucosidic diene ligands
24 and 25 are pseudo-enantiomeric to 4-O-modified ole-
fin–phoshinite hybrid 18 and dienes 22 and 23, even
though all are derived from D-glucose. The application of
pseudo-enantiomeric complex ligands or chiral auxiliaries
in asymmetric synthesis has considerable precedence, es-
pecially for stereodirecting agents derived from carbohy-
drates.39,40 Compounds 24 and 25 show that this strategy
also works for carbohydrate-derived olefin ligands, even
though their level of enantioselectivity is only modest.
decrease in stereoselectivity, therefore, the preparation of
olefin hybrid ligands from arabinose appears less attrac-
tive, even though this monosaccharide is available in both
enantiomeric forms at low price. Diene ligands prepared
by introduction of allylic residues into carbohydrate scaf-
folds do not lead to high levels of enantioselectivity. The
reversal of the stereoinduction connected to the shift of
the second donor site from position 4 to position 1 under-
lines the potential of the pseudo-enantiomeric approach
for carbohydrate-based ligands. Further experiments on
more efficient pseudo-enantiomeric ligands are currently
in progress.
Anhydrous solvents were obtained by distillation over appropriate
drying reagents under a nitrogen atmosphere (CH2Cl2 was distilled
over CaH2, THF was distilled over sodium/benzophenone ketyl),
were purchased in dried form from commercial sources (DMF and
pyridine from ACROS), or were taken from a solvent purification
system (M. Braun Group, toluene). The petroleum ether (PE) used
was that boiling in the range 40–60 °C. All reactions involving air-
and moisture-sensitive reagents were carried out under a nitrogen
atmosphere (glove box and/or Schlenk techniques). Reactions were
monitored by TLC on 60 F254 aluminium plates (Merck) with de-
tection by UV light and/or charring with 10% sulfuric acid in EtOH,
or a mixture of cerium(IV) sulfate and molybdophosphoric acid in
8% sulfuric acid. Flash chromatography was performed on Merck
silica (grain size 40–63 mm). NMR spectra were recorded with an
AVS 400 instrument (Bruker) at 400 MHz (1H), 100 MHz (13C) and
161.9 MHz (31P). CDCl3 was used as solvent and NMR spectra were
In summary, we have prepared a family of novel carbohy-
drate diene and olefin–phosphinite hybrid ligands em-
ploying readily available monosaccharides D-glucose and
D-arabinose as starting materials. With gluco-enoPhos
(18), we have introduced the first olefin–phosphorus hy-
brid ligand based on an enantiomerically pure compound
from the chiral pool. It can be prepared either from com-
mercially available hex-2-enopyranose (16) in three steps
or from bulk material D-glucose in seven straightforward
high-yielding steps and offers high levels of enantioselec-
tivity in the Hayashi–Miyaura reaction. The application of
its arabinose-based counterpart 31 leads to a significant
1
referenced against the residual solvent peak (d = 7.24 ppm for H
and d = 77.0 ppm for 13C). Chemical shifts (d) are given in ppm,
coupling constants (J) are given in Hz. Electrospray mass (ESI)
spectra were recorded with a Micromass LCT device (Waters), in-
jection into the HPLC instrument (Waters) was performed in loop
modus. Determination of enantiomeric excesses by HPLC analysis
was performed on chiral stationary phases with Chiralpak AD-H, or
Chiralcel OD-H, and Chiralcel OB-H columns purchased from
Synthesis 2010, No. 19, 3248–3258 © Thieme Stuttgart · New York

SPECIAL TOPIC
Olefin–Phosphorus Hybrid and Diene Ligands
3253
DAICEL Co., Ltd. Determination of enantiomeric excesses by 1H
NMR analysis was performed with Rh2[R-(+)-MTPA]4 as a chiral
complexing reagent (dirhodium method).31 Optical rotations were
recorded with a Perkin–Elmer 451 instrument at r.t.: wavelength
589.3 nm (sodium D line), cell length 1 dm, solvent and sample con-
centration (in 10 mg/mL) are given with the individual experiment.
stirred at 0 °C for 30 min and then at r.t. for 16 h. The mixture was
filtered over Celite and the filter cake was washed with H2O (2 × 30
mL). CH2Cl2 (350 mL) was added to the filtrate and, after phase
separation, the organic layer was washed with sat. aq NaHCO3
(2 × 200 mL) and with H2O (2 × 50 mL), dried over Na2SO4, fil-
tered and concentrated in vacuo. Purification by flash chromatogra-
phy on silica gel (PE–EtOAc, 1:1) gave 15.
2,3,4,6-Tetra-O-acetyl-a-D-glucopyranosylbromide (14)
20
Yield: 6.30 g (23.14 mmol, 79%); colourless oil; [a]D +21.2 (c
NaOAc (30.00 g) was suspended in Ac2O (420 mL) and the result-
ing mixture was heated to reflux for 20 min. The heating bath was
removed and D-glucose (13; 60.00 g, 333.22 mmol) was added in
small portions, keeping the reaction mixture just at reflux tempera-
ture. Subsequently, the mixture was stirred for an additional 15 min
under heating and, after cooling to r.t., it was poured onto crushed
ice (1.6 L). After keeping mixture in the refrigerator at 4 °C for 3 h,
the resulting precipitate was filtered and washed with ice-water
(2.50 L) and cold EtOH (200 mL). After drying under reduced pres-
sure, the crude product was recrystallised from EtOH (600 mL) to
yield 1,2,3,4,6-penta-O-acetyl-b-D-glucopyranoside.
1.10, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.99 (s, 3 H, CH3), 2.02 (s, 3 H,
CH3), 2.04 (s, 3 H, CH3), 4.15 (dd, J = 11.9, 3.0 Hz, 1 H, H-6¢), 4.20
(ddd ~ td, J = 5.8, 3.0 Hz, 1 H, H-5), 4.35 (dd, J = 5.8, 4.9 Hz, 1 H,
H-6), 4.79 (dd, J = 6.1, 3.0 Hz, 1 H, H-2), 5.17 (dd, J = 7.5, 5.8 Hz,
1 H, H-4), 5.28–5.31 (m, 1 H, H-3), 6.43 (d, J = 6.1 Hz, 1 H, H-1).
13C NMR (100 MHz, CDCl3): d = 20.6 (CH3), 20.7 (CH3), 20.9
(CH3), 61.2 (C-6, CH2), 67.0 (C-4, CH), 67.3 (C-3, CH), 73.8 (C-5,
CH), 98.9 (C-2, CH), 145.4 (C-1, CH), 169.4 (CH3CO), 170.3
(CH3CO), 170.4 (CH3CO).
Yield: 122.87 g (314.78 mmol, 95%); colourless solid; [a]D20 +6.41
(c 0.80, CHCl3).
HRMS (ESI+): m/z [M + Na] calcd for C12H16O7Na: 295.2788;
found: 295.2779.
1H NMR (400 MHz, CDCl3): d = 1.98 (s, 3 H, CH3), 2.00 (s, 6 H,
CH3), 2.05 (s, 3 H, CH3), 2.08 (s, 3 H, CH3), 3.80 (ddd ~ td, J = 9.9,
4.4, 2.3 Hz, 1 H, H-5), 4.08 (dd, J = 2.3, 12.6 Hz, 1 H, H-6¢), 4.26
(dd, J = 4.4, 12.6 Hz, 1 H, H-6), 5.07–5.12 (m, 2 H, H-2, H-4), 5.22
(dd ~ t, J = 9.2, 9.5 Hz, 1 H, H-3), 5.68 (d, J = 8.2 Hz, 1 H, H-1).
13C NMR (100 MHz, CDCl3): d = 20.5 (CH3), 20.5 (CH3), 20.7
(CH3), 20.8 (CH3), 61.3 (C-6, CH2), 67.6 (C-2, CH), 70.1 (C-4,
CH), 72.6 (C-3, CH), 72.7 (C-5, CH), 91.6 (C-1, CH), 168.9
(COCH3), 169.2 (COCH3), 169.3 (COCH3), 170.0 (COCH3), 170.5
(COCH3).
Ethyl 4,6-Di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyra-
noside (16)
Triacetyl glucal 15 (1.20 g, 4.41 mmol) was stirred in anhydrous
CH2Cl2 (10 mL) under a nitrogen atmosphere at 0 °C. Absolute
EtOH (1.29 mL, 22.05 mmol) was added, followed by dropwise ad-
dition of BF3·OEt2 (810 mg, 5.73 mmol). After stirring at r.t. for 3 h,
the reaction was quenched with sat. aq NaHCO3 (2 × 10 mL) and di-
luted with CH2Cl2 (20 mL). The phases were separated and the
aqueous layer was extracted with CH2Cl2 (20 mL). The combined
organic layers were washed with brine (10 mL), dried over Na2SO4,
filtered and concentrated in vacuo. Purification by flash chromatog-
raphy on silica gel (PE–EtOAc, 8:1) afforded 16.
HRMS (ESI+): m/z [M + Na] calcd for C16H22NO11Na: 413.3290;
found: 413.3301.
The pentaacetate described above (60.00 g, 153.71 mmol) was dis-
solved in a solution of HBr in AcOH (33% HBr, 240 mL). Ac2O (24
mL) was added and the mixture was stirred until the reaction
reached completion (reaction monitored by TLC: toluene–EtOAc,
1:1). Subsequently, CH2Cl2 (600 mL) was added and the mixture
was poured onto ice (200 mL). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3 × 200 mL). The com-
bined organic layers were washed with sat. aq NaHCO3 (2 × 500
mL), dried over Na2SO4, filtered and concentrated in vacuo. The
precipitate was dissolved in refluxing Et2O and crystallized by ad-
dition of PE to give 14.
Yield: 920 mg (3.56 mmol, 81%); colourless foam; [a]D20 +130.4 (c
1.07, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.22 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 2.05 (s, 3 H, CH3), 2.06 (s, 3 H, CH3), 3.51–3.59 (m,
1 H, OCH2CH3), 3.76–3.84 (m, 1 H, OCH2CH3), 4.08 (ddd, J = 9.2,
5.1, 2.1 Hz, 1 H, H-5), 4.15 (dd, J = 12.0, 2.4 Hz, 1 H, H-6¢), 4.22
(dd, J = 12.0, 5.1 Hz, 1 H, H-6), 5.01 (d ~ br s, 1 H, H-1), 5.24–5.31
(m, 1 H, H-4), 5.82 (ddd ~ dt, J = 10.2, 2.0 Hz, 1 H, H-2), 5.83–
5.87 (m, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = 15.3 (OCH2CH3, CH3), 20.7
(COCH3, CH3), 20.9 (COCH3, CH3), 63.0 (C-6, CH2), 64.3
(OCH2CH3, CH2), 65.3 (C-4, CH), 66.8 (C-5, CH), 94.2 (C-1, CH),
127.9 (C-2, CH), 129.0 (C-3, CH), 170.3 (CH3CO, C), 170.8
(CH3CO, C).
Yield: 52.51 g (128.07 mmol, 83%); colourless solid; [a]D20 +181 (c
1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.01 (s, 3 H, CH3), 2.02 (s, 3 H,
CH3), 2.07 (s, 3 H, CH3), 2.07 (s, 3 H, CH3), 4.1 (dd, J = 2.1,
12.6 Hz, 1 H, H-6¢), 4.26 (ddd, J = 10.2, 4.1, 1.7 Hz, 1 H, H-5), 4.30
(dd, J = 3.8, 12.3 Hz, 1 H, H-6), 4.80 (dd, J = 4.1, 10.2 Hz, 1 H, H-
2), 5.13 (dd ~ t, J = 9.6, 9.9 Hz, 1 H, H-4), 5.53 (dd ~ t, J = 9.9,
9.6 Hz, 1 H, H-3), 6.58 (d, J = 3.8 Hz, 1 H, H-1).
13C NMR (100 MHz, CDCl3): d = 20.5 (CH3), 20.6 (CH3), 20.6
(CH3), 20.6 (CH3), 60.9 (C-6, CH2), 67.1 (C-4, CH), 70.1 (C-3,
CH), 70.6 (C-2, CH), 72.1 (C-5, CH), 86.5 (C-1, CH), 169.42
(COCH3), 169.76 (COCH3), 169.81 (COCH3), 170.46 (COCH3).
HRMS (ESI+): m/z [M + Na] calcd C12H16O7Na: 295.2788; found:
295.2789.
Ethyl 2,3-Dideoxy-6-O-trityl-a-D-erythro-hex-2-enopyranoside
(17)
Hex-2-enopyranoside 16 (1.00 g, 3.87 mmol) was dissolved in
MeOH–H2O–Et3N (9:6:1, 32 mL) and stirred at r.t. for 3 h. Solvent
evaporation under reduced pressure and column chromatography on
silica gel (PE–EtOAc, 1:1) yielded ethyl 2,3-dideoxy-a-D-erythro-
hex-2-enopyranoside.
HRMS (ESI+): m/z [M + Na] calcd for C14H20O9BrNa: 434.1890;
found: 434.1859.
Yield: 640 mg (3.67 mmol, 95%); colourless foam; [a]D20 +61.8 (c
1.10, CHCl3).
3,4,6-Tri-O-acetyl-D-glucal (15)
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 2.67 (br s, 1 H, 6-OH), 3.09 (br s, 1 H, 4-OH), 3.48–
3.56 (m, 1 H, OCH2CH3), 3.67 (ddd ~ td, J = 8.8, 4.1, 2.7 Hz, 1 H,
H-5), 3.75–3.88 (m, 3 H, H-6, H-6¢, OCH2CH3), 4.12–4.14 (m, 1 H,
Glucosyl bromide 14 (12.00 g, 29.18 mmol) was dissolved in
AcOH (190 mL). After cooling to 0 °C, a solution of CuSO4·5H2O
(3.39 g, 13.58 mmol) in H2O (20 mL) then zinc dust (36.00 g,
550.38 mmol) were added to the reaction mixture. The mixture was
Synthesis 2010, No. 19, 3248–3258 © Thieme Stuttgart · New York

3254
H. Grugel et al.
SPECIAL TOPIC
H-4), 4.95 (d, J = 2.3 Hz, 1 H, H-1), 5.71 (ddd, J = 1.7, 2.3, 10.2 Hz,
1 H, H-2), 5.92 (dd, J = 10.2, 1.3 Hz, 1 H, H-3).
Ethyl 4-O-Allyl-2,3-dideoxy-6-O-trityl-a-D-erythro-hex-2-
enopyranoside (22)
Alcohol 17 (500 mg, 1.20 mmol) was stirred in anhydrous DMF (15
mL) under nitrogen at 0 °C. After addition of NaH (60% suspension
in paraffin oil, 72 mg, 1.80 mmol) the mixture was stirred for
30 min at the same temperature. Allyl bromide (160 mL,
1.80 mmol) was added and the mixture was stirred at r.t. for an ad-
ditional 3 h. Upon completion, H2O (10 mL) and CH2Cl2 (20 mL)
were added and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (3 × 30 mL) and the organic layers were
combined and washed with H2O (3 × 30 mL), dried over Na2SO4,
filtered and concentrated in vacuo. Purification by flash chromatog-
raphy on silica gel (PE–EtOAc, 6:1) afforded 22.
13C NMR (100 MHz, CDCl3): d = 15.2 (OCH2CH3, CH3), 62.5 (C-
6, CH2), 64.0 (OCH2CH3, CH2), 64.1 (C-4, CH), 71.4 (C-5, CH),
94.1 (C-1, CH), 126.2 (C-2, CH), 133.5 (C-3, CH).
HRMS (ESI+): m/z [M + Na] calcd for C8H14O4: 197.0779; found:
197.0784.
The diol described above (740 mg, 4.02 mmol) was dissolved in an-
hydrous pyridine (50 mL). The solution was cooled to 0 °C and tri-
tyl chloride (1.68 g, 6.03 mmol) was added. The reaction mixture
was stirred at r.t. for 24 h then poured into H2O (50 mL). The aque-
ous layer was extracted with EtOAc (3 × 50 mL) and the combined
organic layers were washed with brine (30 mL), dried over Na2SO4
and concentrated under reduced pressure. Column chromatography
on silica gel (PE–EtOAc, 4:1) gave 17.
Yield: 491 mg (107.60 mmol, 90%); colourless oil; [a]D20 +53.8 (c
0.89, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 3.22 (dd, J = 10.0, 5.1 Hz, 1 H, H-6¢), 3.43 (dd,
J = 10.0, 1.9 Hz, 1 H, H-6), 3.62 (dq, J = 9.6, 7.1 Hz, 1 H,
OCH2CH3), 3.82 (dddd ~ ddt, J = 12.7, 5.6, 1.4 Hz, 1 H, CH2allyl),
3.91–4.02 (m, 3 H, H-5, OCH2CH3, CH2allyl), 4.06 (ddd, J = 9.4,
3.0, 1.6 Hz, 1 H, H-4), 5.00–5.20 (m, 3 H, =CH2, H-1), 5.68
(dddd ~ ddt, J = 17.2, 10.4, 5.6 Hz, 1 H, CH2CH=CH2), 5.80 (ddd,
J = 10.2, 2.6, 2.0 Hz, 1 H, H-2), 6.04 (d, J = 10.2 Hz, 1 H, H-3),
7.21–7.35 (m, 9 H, PhH), 7.49–7.55 (m, 6 H, PhH).
13C NMR (100 MHz, CDCl3): d = 15.3 (OCH2CH3), 63.1 (C-6,
CH2), 63.6 (OCH2CH3), 69.5 (C-5, CH), 70.0 (OCH2CH=), 70.6 (C-
4, CH), 86.3 (OCPh3), 94.2 (C-1, CH), 117.0 (=CH2), 126.7 (C-2,
CH), 126.9 (ArC, C), 127.7 (ArC, CH), 127.7 (ArC, CH), 127.9
(ArC, C), 128.8 (ArC, CH), 128.8 (ArC, CH), 131.3 (C-3, CH),
134.6 (CH2CH=CH2), 144.1 (ArC).
20
Yield: 1.49 g (3.58 mmol, 89%); colourless foam; [a]D –3.5 (c
1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.25 (t, J = 7.1 Hz, 3 H, CH2CH3),
2.31 (br s, 1 H, 4-OH), 3.37 (dd, J = 9.5, 5.1 Hz, 1 H, H-6¢), 3.46
(dd, J = 5.8, 9.5 Hz, 1 H, H-6), 3.59–3.51 (m, 1 H, OCH2CH3), 3.86
(ddd ~ td, J = 9.2, 5.8, 5.1 Hz, 1 H, H-5), 3.90–3.93 (m, 1 H,
OCH2CH3), 4.08–4.12 (m, 1 H, H-4), 4.97 (d, J = 2.3 Hz, 1 H, H-1),
5.74 (ddd ~ td, J = 1.7, 2.3, 10.2 Hz, 1 H, H-2), 5.90 (ddd ~ td,
J = 1.7, 10.2 Hz, 1 H, H-3), 7.22–7.26 (m, 3 H, PhH), 7.29–7.33 (m,
6 H, PhH), 7.45–7.48 (m, 6 H, PhH).
13C NMR (100 MHz, CDCl3): d = 15.3 (OCH2CH3), 63.8
(OCH2CH3), 65.0 (C-6, CH2), 66.2 (C-4, CH), 70.0 (C-5, CH), 87.2
(O-CPh3, C), 93.9 (C-1, CH), 126.2 (C-2, CH), 127.1 (ArC, CH),
127.9 (ArC, CH), 128.6 (ArC, CH), 132.9 (ArC, C), 143.6 (C-3,
CH).
HRMS (ESI+): m/z [M + Na] calcd for C30H32O4Na: 479.2198;
found: 479.2197.
HRMS (ESI+): m/z [M + H] calcd for C27H29O4: 417.2066; found:
417.2060.
Ethyl 4-O-Cinnamyl-2,3-dideoxy-6-O-trityl-a-D-erythro-hex-2-
enopyranoside (23)
Ethyl 2,3-Dideoxy-4-O-diphenylphosphino-6-O-trityl-a-D-
erythro-hex-2-enpyranoside (gluco-enoPhos; 18)
Alcohol 17 (300 mg, 720 mmol) was stirred in anhydrous DMF (10
mL) under a nitrogen atmosphere at 0 °C. After addition of NaH
(60% suspension in paraffin oil, 72 mg, 1.80 mmol) the mixture
was stirred for 30 min at the same temperature. Cinnamyl bromide
(213 mg, 1.08 mmol) was added and the mixture was stirred at r.t.
for an additional 3 h. After addition of H2O (10 mL) and CH2Cl2 (20
mL), the phases were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layer was washed
with H2O (3 × 20 mL) and dried over Na2SO4, filtered and concen-
trated in vacuo. Purification by flash chromatography (PE–EtOAc,
6:1) gave 23.
Under a nitrogen atmosphere, alcohol 17 (250 mg, 600 mmol) and a
catalytic amount of DMAP were dissolved in anhydrous, degassed
THF–Et3N (1:1 v/v, 2 mL). To this solution, diphenyl chlorophos-
phine (150 mg, 660 mmol) was added and the mixture was stirred at
r.t. for 15 min. The solvent was evaporated and the residue was pu-
rified by column chromatography on silica gel (degassed PE–
EtOAc, 6:1) to yield 18. When a solution of 18 was kept under at-
mospheric conditions, it rapidly oxidised to the corresponding phos-
phinate. Therefore 18 should be stored under a nitrogen atmosphere.
20
Yield: 250 mg (420 mmol, 70%); colourless foam; [a]D +95.8 (c
1.00, CHCl3).
Yield: 376 mg (706.40 mmol, 98%); colourless foam; [a]D20 +37.8
(c 0.82, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.32 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 3.14 (dd, J = 6.8, 9.9 Hz, 1 H, H-6¢), 3.41 (dd, J = 1.7,
9.9 Hz, 1 H, H-6), 3.59–3.67 (m, 1 H, OCH2CH3), 4.02–4.10 (m,
1 H, OCH2CH3), 4.23 (ddd ~ td, J = 1.7, 6.8, 9.5 Hz, 1 H, H-5),
4.38–4.42 (m, 1 H, H-4), 5.06 (d, J = 2.0 Hz, 1 H, H-1), 5.75 (ddd
~ td, J = 1.7, 2.0, 10.2 Hz, 1 H, H-2), 5.92 (dd, J = 10.2, 1.7 Hz,
1 H, H-3), 7.11–7.14 (m, 3 H, PhH), 7.18–7.26 (m, 10 H, PhH),
7.29–7.32 (m, 3 H, PhH), 7.37–7.47 (m, 9 H, PhH).
1H NMR (400 MHz, CDCl3): d = 1.24 (t, J = 7.1 Hz, 3 H, CH3), 3.18
(dd, J = 10.1, 5.1 Hz, 1 H, H-6¢), 3.42 (dd, J = 10.1, 1.8 Hz, 1 H, H-
6), 3.54–3.61 (m, 1 H, OCH2CH3), 3.89–3.98 (m, 3 H, H-5,
OCH2alkenyl, OCH2CH3), 4.04–4.11 (m, 2 H, H-4, OCH2alkenyl),
5.05 (s, 1 H, H-1), 5.73–5.79 (m, 1 H, H-2), 5.95–6.04 (m, 2 H, H-
3, CH=CHPh), 6.37 (d, J = 15.9 Hz, 1 H, CHPh), 7.15–7.28 (m,
12 H, PhH), 7.43–7.50 (m, 8 H, PhH).
13C NMR (100 MHz, CDCl3): d = 15.4 (OCH2CH3). 63.2 (C-6,
CH2), 63.7 (OCH2CH3), 69.6 (C-5, CH), 69.7 (OCH2CH=), 70.6 (C-
4, CH), 86.3 (OCPh3), 94.2 (C-1, CH), 125.9 (C-2, CH), 126.5
(ArC, CH), 126.8 (ArC, CH), 126.9 (ArC, CH), 127.3 (ArC, C),
127.6 (ArC, C), 127.7 (ArC, CH), 127.9 (ArC, CH), 128.5
(CH2CH=CH2Ph), 128.6 (ArC, CH), 128.8 (ArC, CH), 131.5 (C-3,
CH), 132.4 (ArC, C), 136.6 (ArC, C), 144.1 (CH2-CH=CH2).
13C NMR (100 MHz, CDCl3): d = 15.3 (OCH2CH3), 63.5 (CH2, C-
6), 63.8 (OCH2CH3), 70.5 (C-5, CH), 72.2 (C-4, CH), 86.4
(OCPh3), 93.9 (C-1, CH), 126.8 (C-2, CH), 127.9 (ArC, CH), 128.1
(ArC, CH), 128.2 (ArC, CH), 128.8 (ArC, CH), 129.2 (ArC, CH),
130.1 (ArC, CH), 130.4 (ArC, CH), 132.0 (C-3, CH), 141.5 (C,
ArC), 142.4 (ArC, C), 144.1 (ArC, C).
31P NMR (161.9 MHz, CDCl3): d = 113.3 (OPPh2).
HRMS (ESI+): m/z [M + Na] calcd for C36H36O4Na: 555.2511;
found: 555.2516.
HRMS (ESI+): m/z [M + Na] calcd for C39H37O4PNa: 623.2299;
found: 623.2322.
Synthesis 2010, No. 19, 3248–3258 © Thieme Stuttgart · New York

SPECIAL TOPIC
Olefin–Phosphorus Hybrid and Diene Ligands
3255
Allyl-4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyra-
noside (24)
concentrated in vacuo to give 1,2,3,4-tetra-O-acetyl-D-arabinopyra-
noside.
Tri-O-acetyl glucal 15 (5.00 g, 18.37 mmol) and allyl alcohol (1.38
mL, 20.21 mmol) were dissolved in CH2Cl2 (100 mL) at r.t. under a
nitrogen atmosphere. After addition of a suspension of anhydrous
FeCl3 (29 mg, 179 mmol) in CH2Cl2 (2 mL), the resulting mixture
was stirred for 30 min. The reaction was stopped by addition of sat.
aq NaHCO3 (20 mL), the phases were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined organ-
ic layers were dried over Na2SO4, filtered and concentrated in vac-
uo. Purification by flash chromatography on silica gel (PE–EtOAc,
3:1) afforded 24 as a mixture of anomers (a/b 10:1, 4.32 g, 16.00
mmol, 87%) as a colourless oil. The pure a-anomer (3.76 g, 13.92
mmol, 76%) could be separated as a colourless solid.
20
Yield: 39.60 g (124.40 mmol, 93%); colourless crystals; [a]D
–117.1 (c 0.89, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.00 (s, 6 H, CH3), 2.13 (s, 3 H,
CH3), 2.13 (s, 3 H, CH3), 3.80 (dd, J = 13.2, 2.0 Hz, 1 H, H-5), 4.04
(dd, J = 13.1, 0.7 Hz, 1 H, H-5¢), 5.32–5.38 (m, 3 H, H-2, H-3, H-
4), 6.32 (d, J = 3.1 Hz, 1 H, H-1).
13C NMR (100 MHz, CDCl3): d = 20.5 (CH3), 20.7 (CH3), 20.9
(CH3), 20.9 (CH3), 62.7 (C-5, CH2), 66.6 (C-2, CH), 67.0 (C-3,
CH), 68.4 (C-4, CH), 90.1 (C-1, CH), 169.1 (COCH3), 169.8
(COCH3), 170.1 (COCH3), 170.3 (COCH3).
HRMS (ESI+): m/z [M + Na] calcd for C13H18O9Na: 341.0849;
[a]D20 +106.8 (c 1.00, CHCl3).
found: 341.0851.
1H NMR (400 MHz, CDCl3): d = 2.04 (s, 3 H, CH3), 2.06 (s, 3 H,
CH3), 4.01–4.06 (m, 1 H, OCH2), 4.07–4.10 (m, 1 H, H-5), 4.14
(dd, J = 12.1, 2.4 Hz, 1 H, H-6¢), 4.19–4.25 (m, 2 H, OCH2, H-6),
5.04 (d, J = 1.8 Hz, 1 H, H-1), 5.16 (ddd, J = 10.4, 2.8, 1.3 Hz, 1 H,
allyl CH2), 5.25 (ddd, J = 10.7, 3.1, 1.5 Hz, 1 H, allyl CH2), 5.29 (m,
1 H, H-4), 5.80 (ddd, J = 10.2, 2.5, 1.8 Hz, 1 H, H-2), 5.83–5.95 (m,
2 H, allylCH, H-3).
13C NMR (100 MHz, CDCl3): d = 20.8 (CH3), 20.9 (CH3), 62.9 (C-
6, CH2), 65.2 (C-4, CH), 66.9 (C-5, CH), 66.2 (OCH2), 93.6 (C-1,
CH), 117.5 (CH=CH2), 127.7 (C-2, CH), 129.2 (C-3, CH), 134.1
(CH2CH=CH2), 170.2 (COCH3), 170.7 (COCH3).
Tetraacetyl arabinose (25.00 g, 78.56 mmol) was dissolved at r.t. in
a solution of HBr in AcOH (33% HBr, 130 mL). Ac2O (13 mL) was
added and the reaction mixture was stirred at r.t. overnight. CH2Cl2
(200 mL) was added and the reaction mixture was poured onto ice
(300 mL). After phase separation, the aqueous layer was extracted
with CH2Cl2 (2 × 250 mL) and the combined organic layers were
washed with sat. aq NaHCO3 (400 mL), dried over Na2SO4, filtered
and concentrated in vacuo. The residue was dissolved in Et2O (50
mL), cooled to 4 °C and crystallized by addition of PE to give 27.
Yield: 16.20 g (47.77 mmol, 61%); colourless solid; [a]D20 –327.0
(c 1.27, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.01 (s, 3 H, CH3), 2.09 (s, 3 H,
CH3), 2.13 (s, 3 H, CH3), 3.91 (dd, J = 13.4, 1.7 Hz, 1 H, H-5¢), 4.18
(d, J = 13.4 Hz, 1 H, H-5), 5.06 (ddd, J = 11.6, 3.8, 1.4 Hz, 1 H, H-
2), 5.35–5.40 (m, 2 H, H-3, H-4), 6.67 (d, J = 3.8 Hz, 1 H, H-1).
13C NMR (100 MHz, CDCl3): d = 20.6 (CH3), 20.7 (CH3), 20.8
(CH3), 64.7 (C-5, CH2), 67.9, 67.8, 67.6 (C-2, C-3, C-4, CH), 89.6
(C-1, CH), 169.8 (COCH3), 170.0 (COCH3), 170.0 (COCH3).
HRMS (ESI+): m/z [M + Na] calcd for C13H18O6Na: 293.1001;
found: 293.1005.
Allyl 4,6-Di-O-acetyl-1,2,3-trideoxy-a-D-erythro-hex-2-enopyr-
anoside (25)
Tri-O-acetyl glucal (15; 500 mg, 1.84 mmol) and allyltrimethylsi-
lane (321 mL, 2.02 mmol) were dissolved in anhydrous CH2Cl2 (15
mL) under an argon atmosphere. The mixture was cooled to –20 °C,
SnCl4 (43 mL, 367 mmol) was added and the mixture was stirred at
–20 °C overnight. The reaction was quenched by adding sat. aq
NaHCO3 (20 mL), then CH2Cl2 (15 mL) was added and the phases
were separated. The organic layer was dried over Na2SO4, filtered
and concentrated in vacuo. Purification by flash chromatography on
silica gel (PE–EtOAc, 4:1) afforded 25.
HRMS (ESI+): m/z [M + Na] calcd for C11H15O7Na: 282.2218;
found: 282.2682.
3,4-Di-O-acetyl-D-arabinal (28)
Arabinosyl bromide 27 (6.00 g, 17.69 mmol) was dissolved in
AcOH (90 mL). After cooling to 0 °C, CuSO4·5H2O (1.21 g,
4.85 mmol) in H2O (10 mL) and then Zn dust (11.31 g,
173.00 mmol) were added. After stirring for 1 h at 0 °C, CH2Cl2
(100 mL) was added and the mixture was then filtered through
Celite. The phases were separated and the aqueous layer was ex-
tracted with CH2Cl2 (20 mL). The combined organic layers were
washed with sat. aq NaHCO3 (2 × 80 mL) and H2O (100 mL), dried
over Na2SO4 and concentrated in vacuo. Purification by flash chro-
matography on silica gel (PE–EtOAc, 9:1→4:1) gave 28.
Yield: 456 mg (1.79 mmol, 98%); colourless syrup; [a]D20 +64.4 (c
1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.06 (s, 6 H, CH3), 2.30 (ddd,
J = 14.2, 7.1, 6.0 Hz, 1 H, CH2CH=CH2), 2.44 (ddd, J = 14.6, 7.9,
6.8 Hz, 1 H, CH2CH=CH2), 3.93 (td, J = 6.5, 3.5 Hz, 1 H, H-5),
4.13 (dd, J = 11.9, 3.5 Hz, 1 H, H-6¢), 4.21 (dd, J = 11.8, 6.6 Hz,
1 H, H-6), 4.26 (ddd, J = 8.1, 5.2, 2.3 Hz, 1 H, H-4), 5.07–5.14 (m,
3 H, H-1, =CH2), 5.75–5.87 (m, 2 H, CH=CH2, H-2), 5.90 (ddd,
J = 10.4, 2.4, 1.6 Hz, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = 20.8 (CH3), 21.1 (CH3), 37.9
(CH2CH=CH2), 62.9 (C-6, CH2), 65.0 (C-4, CH), 69.8 (C-5, CH),
71.4 (C-1, CH), 117.6 (=CH2), 123.70 (C-2, CH), 132.81 (C-3, CH),
133.97 (CH=CH2), 170.4 (COCH3), 170.8 (COCH3).
Yield: 2.34 g (11.69 mmol, 60%); colourless solid; [a]D20 +81.7 (c
1.28, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.02 (s, 3 H, CH3), 2.03 (s, 3 H,
CH3), 3.97–3.91 (m, 2 H, H-5¢, H-5), 4.80 (dd, J = 6.0, 5.1 Hz, 1 H,
H-2), 5.14 (ddd ~ dt, J = 9.4, 4.2 Hz, 1 H, H-4), 5.37–5.41 (m, 1 H,
H-3), 6.45 (dd, J = 6.0, 0.6 Hz, 1 H, H-1).
13C NMR (100 MHz, CDCl3): d = 20.7 (CH3), 21.1 (CH3), 62.8 (C-
5, CH2), 62.8 (C-4, CH), 65.9 (C-3, CH), 97.4 (C-2, CH), 147.7 (C-
1, CH), 169.9 (COCH3), 170.5 (COCH3).
HRMS (ESI+): m/z [M + Na] calcd for C13H18O5Na: 277.1052;
found: 277.1051.
2,3,4-Tri-O-acetyl-b-D-arabinopyranosylbromide (27)
HRMS (ESI+): m/z [M + Na] calcd for C9H12O5Na: 223.0582;
found: 223.0582.
D-Arabinose (26; 20.00 g, 133.00 mmol) was suspended in pyridine
(400 mL) at 0 °C. A catalytic amount of DMAP and Ac2O (200.00
mL, 2.13 mol) were added and the resulting mixture was stirred at
r.t. overnight. The mixture was concentrated in vacuo and the resi-
due was dissolved in toluene. The organic phase was washed with
aq HCl (1 M, 3 × 150 mL), H2O (2 × 100 mL), brine (50 mL), and
4-O-Acetyl-1,5-anhydro-2,3-dideoxy-D-glycero-pent-2-enitol
(29)
Diacetyl arabinal 28 (2.80 g, 14.00 mmol) was dissolved in anhy-
drous CH2Cl2 (15 mL) under a nitrogen atmosphere. Triethylsilane
Synthesis 2010, No. 19, 3248–3258 © Thieme Stuttgart · New York

3256
H. Grugel et al.
SPECIAL TOPIC
(2.68 mL, 16.8 mmol) was added and the resulting mixture was
stirred at r.t. for 5 min. BF3·OEt2 (1.76 mL, 14.00 mmol) was added
dropwise and the reaction mixture was stirred for an additional
30 min. The reaction was quenched by addition of sat. aq NaHCO3
(20 mL), the phases were separated and the organic layer was
washed with H2O (15 mL), dried over Na2SO4, filtered and concen-
trated in vacuo. Purification by flash chromatography on silica gel
(PE–EtOAc, 5:1) gave 29.
4-O-Allyl-1,5-anhydro-2,3-dideoxy-D-glycero-pent-2-enitol (32)
Under a nitrogen atmosphere, alcohol 30 (300 mg, 3.00 mmol) was
dissolved in anhydrous DMF (10 mL). After cooling to 0 °C, NaH
(60% suspension in paraffin oil, 300 mg, 7.50 mmol) was added
and the mixture was stirred at the same temperature for 30 min. Al-
lyl bromide (389 mL, 4.50 mmol) was added and the mixture was
stirred at r.t. for an additional 3 h. After addition of H2O (10 mL)
and CH2Cl2 (20 mL), the phases were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined organ-
ic layer was washed with H2O (3 × 20 mL) and dried over NaSO4,
filtered and concentrated in vacuo. Purification by flash chromatog-
raphy (PE–EtOAc, 6:1) gave 32.
20
Yield: 1.87 g (13.20 mmol, 94%); colourless oil; [a]D +172.2 (c
1.02, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.1 (s, 3 H, CH3), 3.77 (dd,
J = 12.4, 3.2 Hz, 1 H, H-5¢), 3.90 (ddd, J = 12.5, 2.6, 1.0 Hz, 1 H,
H-5), 4.06 (dddd ~ dq, J = 17.0, 2.1 Hz, 1 H, H-1¢), 4.20 (dddd,
J = 17.0, 3.2, 2.0, 1.1 Hz, 1 H, H-1), 5.06 (ddd, J = 4.5, 2.2, 0.9 Hz,
1 H, H-4), 5.87–5.93 (m, 1 H, H-3), 6.01–6.09 (m, 1 H, H-2).
13C NMR (100 MHz, CDCl3): d = 21.2 (CH3), 64.8 (C-4, CH), 65.0
(C-1, CH2), 67.7 (C-5, CH2), 122.4 (C-3, CH), 132.2 (C-2, CH),
170.7 (COCH3).
20
Yield: 386 mg (2.75 mmol, 92%); colourless oil; [a]D +92.0 (c
0.94, CHCl3).
1H NMR (400 MHz, CDCl3): d = 3.79 (dd, J = 3.9, 1.3 Hz, 1 H),
3.81–3.92 (m, 1 H), 3.95–4.10 (m, 3 H), 4.11–4.20 (m, 1 H), 5.17–
5.32 (m, 2 H, =CH2), 5.83–6.03 (m, 3 H, H-2, H-3, OCH2CH=CH2).
13C NMR (100 MHz, CDCl3): d = 65.2 (C-1, CH2), 67.8 (OCH2),
68.9 (C-4, CH), 69.6 (C-6, CH2), 117.1 (=CH2), 124.7 (C-2, CH),
130.1 (C-3, CH), 134.9 (CH=CH2).
1,5-Anhydro-2,3-dideoxy-D-glycero-pent-2-enitol (30)
Acetate 29 (1.50 g, 10.55 mmol) was dissolved in a mixture of
MeOH (60 mL) and H2O (40 mL). Et3N (6 mL) was added and the
mixture was stirred at r.t. for 30 min. Subsequently, the mixture was
concentrated in vacuo and the crude material was purified by flash
chromatography (EtOAc) to give 30.
Catalytic Asymmetric 1,4-Addition of Phenylboronic Acid (20)
to Enones 19; General Procedure
In a glove box, [Rh(C2H4)2Cl]2 (3.6 mg, 18 mmol Rh) and the re-
spective ligand (20 mmol) were placed into a flame-dried Schlenk
flask. Under a nitrogen atmosphere, degassed 1,4-dioxane (2 mL)
was added and the solution was stirred at r.t. for 15 min. Aq KOH
(1.5 M, 0.30 mL, 450 mmol KOH) was added and the mixture was
stirred at r.t. for an additional 15 min. Then, first the enone compo-
nent 19 (600 mmol) and second phenylboronic acid (20; 120 mg,
900 mmol) were added as solids. To completely dissolve the solids,
an additional portion of 1,4-dioxane (1.5 mL) was added and the re-
sulting mixture was stirred at 30 °C for 16 h. The mixture was then
filtered through a silica pad with Et2O, the solvent was removed un-
der reduced pressure and the residue was purified by flash chroma-
tography on silica gel to yield the desired 1,4-addition products.
20
Yield: 780 mg (7.81 mmol, 74%); colourless oil; [a]D +169.9 (c
0.88, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.09 (s, 1 H, OH), 3.72 (dd,
J = 11.8, 3.0 Hz, 1 H, H-5¢), 3.82 (ddd, J = 11.8, 2.8, 0.9 Hz, 1 H,
H-5), 3.95 (ddd ~ tt, J = 5.8, 3.1 Hz, 1 H, H-4), 4.03 (dq, J = 16.7,
1.9 Hz, 1 H, H-1¢), 4.09–4.17 (m, 1 H, H-1), 5.87–5.92 (m, 1 H, H-
2), 5.96 (ddtd, J = 10.1, 4.1, 2.0, 1.1 Hz, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = 62.6 (C-4, CH), 65.3 (C-1, CH2),
70.8 (C-5, CH2), 126.6 (C-3, CH), 129.8 (C-2, CH).
1,5-Anhydro-4-O-diphenylphosphino-2,3-dideoxy-D-glycero-
pent-2-enitol (31)
The experiments listed below were performed with ligand gluco-
enoPhos (18).
Under a nitrogen atmosphere, alcohol 30 (200 mg, 2.00 mmol) was
dissolved in a mixture of anhydrous THF–Et3N (3:2 v/v, 5 mL).
Diphenyl chlorophosphine (43 mL, 2.39 mmol) was added dropwise
at r.t. and the resulting mixture was subsequently stirred for 30 min.
After concentration in vacuo, the residue was purified by flash chro-
matography on silica gel (degassed PE–EtOAc, 10:1) to give 31.
When a solution of 31 was kept under atmospheric conditions, it
rapidly oxidised to the corresponding phosphinate. Therefore 31
should be stored under a nitrogen atmosphere.
3-(R)-Phenylcyclohexanone (21a)
Purified on silica gel (PE–Et2O, 10:1).
Yield: 83 mg (480 mmol, 80%); [a]D20 +20.9 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.76–1.91 (m, 2 H), 2.07–2.19 (m,
2 H), 2.35–2.62 (m, 4 H), 2.98–3.07 (m, 1 H), 7.22–7.36 (m, 5 H,
PhH).
13C NMR (100 MHz, CDCl3): d = 25.5, 32.7, 41.1, 44.7, 48.9, 126.5,
126.6, 128.6, 144.3, 210.9.
20
Yield: 480 mg (1.69 mmol, 85%); colourless oil; [a]D +64.9 (c
1.00, CHCl3).
The enantiomeric excess was determined with a Chiralcel OD-H
column (hexane–2-propanol, 99.0:1.0); flow rate 0.5 mL/min;
wavelength 240 nm; retention times: tR = 28.5 min (minor, S),
31.1 min (major, R).
1H NMR (400 MHz, CDCl3): d = 3.80 (dd, J = 11.7, 4.9 Hz, 1 H, H-
5¢), 3.87 (dd, J = 11.7, 4.1 Hz, 1 H, H-5), 4.04 (ddd ~ dq, J = 6.4,
2.4 Hz, 1 H, H-1¢), 4.18 (ddd, J = 16.2, 3.5, 1.7 Hz, 1 H, H-1), 4.37–
4.46 (m, 1 H, H-4), 5.89–5.99 (m, 2 H, H-2, H-3), 7.31–7.54 (m,
10 H, PhH).
3-(R)-Phenylcyclopentanone (21b)
Purified on silica gel (PE–Et2O, 10:1).
Yield: 79 mg (490 mmol, 82%); [a]D20 +87.3 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.91–2.02 (m, 1 H), 2.23–2.48 (m,
4 H), 2.65 (dd, J = 7.5, 18.1 Hz, 1 H), 3.35–3.44 (m, 1 H), 7.20–
7.24 (m, 2 H, PhH), 7.30–7.37 (m, 3 H, PhH).
13C NMR (100 MHz, CDCl3): d = 65.1 (C-1, CH2), 69.1 (C-5, CH2),
70.6 (C-4, CH), 125.8 (C-2, CH), 128.3 (CH, ArC), 128.2 (CH,
ArC), 129.2 (CH, ArC), 129.8 (C-3, CH), 130.2 (CH, ArC), 130.4
(CH, ArC), 131.5 (ArC, C).
31P NMR (161.9 MHz, CDCl3): d = 111.21 (OPPh2).
HRMS (ESI+): m/z [M + H] calcd for C17H18O2P: 285.1044; found:
285.1043.
13C NMR (100 MHz, CDCl3): d = 31.1, 38.6, 42.2, 45.7, 126.7,
126.7, 128.6, 143.0, 218.4.
The enantiomeric excess was determined with a Chiralcel OB-H
column (hexane–2-propanol, 99.5:0.5); flow rate 1.0 mL/min;
Synthesis 2010, No. 19, 3248–3258 © Thieme Stuttgart · New York

SPECIAL TOPIC
Olefin–Phosphorus Hybrid and Diene Ligands
3257
wavelength 240 nm; retention times: tR = 26.2 min (minor, S),
26.9 min (major, R).
(6) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am.
Chem. Soc. 2007, 129, 5336.
(7) Okamoto, K.; Hayashi, T.; Rawal, V. H. Org. Lett. 2008, 10,
4387.
4-(R)-Phenyltetrahydro-2H-pyran-2-one (21c)
Purified on silica gel (PE–Et2O, 1:1).
Yield: 51 mg (290 mmol, 48%); [a]D20 +20.9 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.76–1.91 (m, 2 H), 2.07–2.19 (m,
2 H), 2.35–2.62 (m, 4 H), 2.98–3.07 (m, 1 H), 7.22–7.36 (m, 5 H,
PhH).
(8) Hu, X.; Zhuang, M.; Du, H. Org. Lett. 2009, 11, 4744.
(9) (a) Deblon, S.; Grützmacher, H.; Schönberg, H. WO 03/
048175 A1, 2003. (b) Maire, P.; Maire, P.; Deblon, S.;
Breher, F.; Geier, J.; Böhler, C.; Rüegger, H.; Schönberg, H.;
Grützmacher, H. Chem. Eur. J. 2004, 10, 4198. (c) Piras,
E.; Läng, F.; Rüegger, H.; Stein, D.; Wörle, M.;
Grützmacher, H. Chem. Eur. J. 2006, 12, 5849.
(10) (a) Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.;
Hayashi, T. Angew. Chem. Int. Ed. 2005, 44, 4611.
(b) Duan, W.-L.; Iwamura, H.; Shintani, R.; Hayashi, T.
J. Am. Chem. Soc. 2007, 129, 2130.
13C NMR (100 MHz, CDCl3): d = 30.2, 37.3, 37.4, 68.5, 126.3,
127.1, 128.9, 142.7, 170.6.
The enantiomeric excess was determined with a Chiralpak AD-H
column (hexane–2-propanol, 95.0:5.0); flow rate 0.7 mL/min; re-
tention times: tR = 38.1 min (minor, S), 45.0 min (major, R).
(11) Kasák, P.; Arion, V. B.; Widhalm, M. Tetrahedron:
Asymmetry 2006, 17, 3084.
(12) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M.
Angew. Chem. Int. Ed. 2007, 46, 3139.
4-(S)-Phenylpentan-2-one (21d)
In a glove box, [Rh(C2H4)2Cl]2 (10 mg, 51 mmol Rh) and ligand 18
(35 mg, 56 mmol) were placed into a flame-dried Schlenk flask. Un-
der a nitrogen atmosphere, degassed 1,4-dioxane (2 mL) was added
and the solution was stirred at r.t. for 15 min. Aq KOH (1.0 M, 0.90
mL, 0.89 mmol KOH) was added and the mixture was stirred at r.t.
for an additional 15 min. 3-Penten-2-one (19d; 156 mg, 1.78 mmol)
and phenylboronic acid (20; 435 mg, 3.57 mmol) were added and
the reaction mixture was stirred for 5 h at 50 °C. The reaction was
quenched with sat. aq NH4Cl (5 mL) and the aqueous layer was ex-
tracted with Et2O (3 × 25 mL). The solvent was removed under vac-
uum and the residue was purified by flash chromatography on silica
gel (PE–EtOAc, 10:1) to yield 21d.
(13) (a) Stepnicka, P.; Cisarova, I. Inorg. Chem. 2006, 45, 8785.
(b) Stepnicka, P.; Lamac, M.; Cisarova, I. J. Organomet.
Chem. 2008, 693, 446.
(14) Stemmler, R. T.; Bolm, C. Synlett 2007, 1365.
(15) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.;
Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579.
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see: (a) Casalnuovo, A. L.; RajanBabu, T. V.; Ayers, T. A.;
Warren, T. H. J. Am. Chem. Soc. 1994, 116, 9869.
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Carbon Compounds, 2nd ed, 2nd Suppl., Vol. 1E/F/G;
Sainsbury, M., Ed.; Elsevier: Amsterdam, 1993, Chap. 23b,
273. (b) Diéguez, M.; Pàmies, O.; Claver, C. Chem. Rev.
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390.
20
Yield: 258 mg (1.59 mmol, 90%); colourless oil; [a]D +18.1 (c
1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.29 (d, J = 7.1 Hz, 2 H), 2.08 (s,
3 H), 2.65–2.81 (m, 2 H), 3.30–3.36 (m, 1 H), 7.19–7.33 (m, 5 H,
PhH).
13C NMR (100 MHz, CDCl3): d = 21.9, 30.5, 35.4, 51.9, 126.2,
126.7, 128.5, 146.1, 207.7.
The enantiomeric excess was determined by 1H NMR with Rh2[R-
(+)-MTPA]4 as chiral complexing reagent (dirhodium method).31
Acknowledgment
Generous financial support of this work by the German Research
Foundation (DFG) and the Volkswagen Foundation is gratefully
acknowledged.
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Synthesis 2010, No. 19, 3248–3258 © Thieme Stuttgart · New York