Ring-closing alkyne metathesis in the synthesis of alkyne-linked glycoamino acids

Article abstract of DOI:10.1055/s-2007-990920

Synthesis of alkyne-linked glycoamino acids via ring-closing alkyne metathesis is investigated. Two different strategies are described to attach alkynylamino acids to an alkynyl sugar, either via a linker at O-4 or at O-9 of the alkynyl sugar. Ring-closing alkyne metathesis of the O-4 linked diynes failed to proceed, but alkyne-linked glycoamino acids of different chain length were effectively synthesized via attachment at O-9. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990920

LETTER
111
Ring-Closing Alkyne Metathesis in the Synthesis of Alkyne-Linked
Glycoamino Acids
Synthesis of
A
t
lkyne-
a
inke
d
G
ly
n
coamino
A
cids Groothuys, S. (Bas) A. M. W. van den Broek, Brian H. M. Kuijpers, Maarten IJsselstijn, Floris L. van Delft,*
Floris P. J. T. Rutjes*
Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax +31(24)3653393; E-mail: F.Rutjes@science.ru.nl
Received 9 October 2008
Schrock et al.,8 a catalyst that operates under fairly mild
conditions, sometimes ambient temperature, and effects
up to several hundred catalytic turnovers per minute.
Abstract: Synthesis of alkyne-linked glycoamino acids via ring-
closing alkyne metathesis is investigated. Two different strategies
are described to attach alkynylamino acids to an alkynyl sugar, ei-
ther via a linker at O-4 or at O-9 of the alkynyl sugar. Ring-closing
alkyne metathesis of the O-4 linked diynes failed to proceed, but
alkyne-linked glycoamino acids of different chain length were ef-
fectively synthesized via attachment at O-9.
In the past decade, ring-closing alkyne metathesis
(RCAM) has been regularly applied in the total synthesis
of natural products.9 In a collaborative effort, we have also
shown that RCAM can be successfully applied in the syn-
thesis of diaminosuberic acid derivatives, with an all-car-
bon chain mimicking the natural cystine bridge.10 Along
the same line, we showed11 that conformationally restrict-
ed b-turn peptide mimetics can be obtained by performing
RCAM on a dialkyne-containing linear peptide, an ap-
proach later adapted by Liskamp et al.12 in the synthesis of
a mimic of the lantibiotic nisin Z.
Key words: alkynes, glycopeptides, ring-closing alkyne metathe-
sis, ring closure
Rarely a novel synthetic transformation attained wide ap-
plication in synthetic organic chemistry as rapidly as the
olefin-metathesis reaction for the synthesis of unsaturated
carbo- and heterocycles. In particular, the preparation of
the first efficient metathesis catalyst by Schrock,1 and the
efforts of Grubbs, who developed air-stable catalysts with
much broader functional group compatibility,2 led to an
explosion in number of applications of olefin metathesis
in the mid 1990s.
The examples above demonstrate the versatility of RCAM
for the synthesis of cycloalkynes or Z-configured alkenes.
Based on these observations, we became interested in the
synthesis of alkyne-linked glycoamino acids via RCAM
of alkynyl glucoside 3 and 2-butynyl glycine 4
(Scheme 1). The resulting alkyne-linked glycoamino ac-
ids 1 were projected as chemically and metabolically sta-
ble all-carbon glycopeptide isosteres. Moreover, the
alkyne-linked glycoamino acids can be stereoselectively
reduced, giving selective access to E- or Z-configured alk-
ene-linked derivatives from a common precursor. Similar
C-glycoamino acids have earlier been prepared via olefin
metathesis by Westermann et al.13 However, with longer
chains, mixtures of E- and Z-cycloalkenes were formed
upon ring closure.
A conceptually similar transformation is alkyne metathe-
sis, first reported by Pennella et al. in the late 1960s3 and
applied in the synthesis of organic macrocycles by Fürst-
ner et al.4 The inherent advantages of alkyne over alkene
metathesis reside in the fact that RCAM is particularly
useful for large (>12-membered) rings without high dilu-
tion and cannot lead to E,Z-mixtures. More than that, un-
der the proper conditions the resulting triple bond can be
stereoselectively reduced to a desired E- or Z-olefin.
However, due to the lack of a stable and generally appli-
cable catalyst, alkyne metathesis lags far behind olefin
metathesis in popularity. Often, temperatures as high as
400 °C are required when heterogeneous silica-bound
tungsten oxides are applied. Mortreux and co-workers later
developed5 a soluble Mo(CO)6 catalyst able to perform at
lower temperatures (160 °C), but only internal acetylenes
undergo metathesis, while terminal acetylenes lead exclu-
sively to polymerization.6 Fürstner et al. developed sever-
al molybdenum catalysts of the general type [Mo{N(t-
Bu)(Ar)}3],7 but a major drawback of these complexes is
incompatibility with oxygen, nitrogen, moisture, acidic
protons, and secondary amides. The most widely applica-
ble catalyst [(t-BuO)3WCCMe3] (13) was developed by
Two retrosynthetic disconnections were devised for the
assembly of alkyne-linked glycoamino acid 1 by RCAM
of a 2-propynyl sugar 3 with L-2-butynyl glycine 4
(Scheme 1). In one case, the amino acid is connected at
the former anomeric center of the carbohydrate (C-4 of
glycosylacetylene 2a), in the other case at the former 6-
position (C-9 of 2b).
First, the route of RCAM of diynes linked via C-4 was in-
vestigated. To this end, the known lactone 514 was con-
verted into propynyl glucoside 6 (Scheme 2) by
subjection to nucleophilic addition of the in situ generated
Li-acetylide from 1-bromopropene and two equivalents n-
BuLi.15
It is known that RCAM is suitable for the formation of cy-
cloalkynes of ring size 12 or larger.16 Therefore, a spacer
between the alkynyl sugar and 2-butynyl glycine was pro-
SYNLETT 2008, No. 1, pp 0111–0115
Advanced online publication: 11.12.2007
DOI: 10.1055/s-2007-990920; Art ID: G30907ST
x
x.
x
x.
2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

112
S. Groothuys et al.
LETTER
RO
RO
CO2H
NH2
O
n
RO
RO
1
O
RO
O
linker
NHPG
O
RO
RO
4
O
9
O
n
RO
RO
RO
n
O
O
linker
NHPG
2a
RO
2b
O
RO
RO
O
n
+
BnO
RO
PGHN
CO2H
OH
3
4
Scheme 1 Retrosynthesis
BnO
BnO
BnO
Br
ROH
TMSOTf
O
O
BnO
BnO
n-BuLi
BnO
CH2Cl2, 0 °C
THF, –78 °C
97%
O
BnO
BnO
OH
5
6
BnO
O
R =
OH
7 18%
8 24%
9 33%
O
BnO
BnO
BnO
=
=
OH
OR
OH
Scheme 2 Synthesis of anomeric coupled linkers
1)
2)
Br
BnO
n-BuLi
11
THF, –78 °C
O
BnO
BnO
BocHN
CO2H
O
S
O
O
O
BnO
DCC, DMAP
10
O
OH
5
9
CH2Cl2
89%
THF, –78 °C
3) H2SO4, H2O
52%
BnO
Ot-Bu
O
BnO
BnO
t-BuO
W
C
t-Bu
O
13
Ot-Bu
toluene, 80 °C
BnO
dimer
O
O
12
NHBoc
Scheme 3 Coupling of amino acid to anomeric linker and RCAM
Synlett 2008, No. 1, 111–115 © Thieme Stuttgart · New York

LETTER
Synthesis of Alkyne-Linked Glycoamino Acids
113
jected, connected at the newly generated acetal at C-4 disappearance of starting material and the formation of a
(former C-1 of gluconolactone). Three different diols less lipophilic product. Unfortunately, analysis of the
were investigated as linkers. Firstly, hemiacetal 6 was formed product after workup and silica gel purification
condensed with diethyleneglycol under the action of a showed that only cross-metathesis had occurred, giving
Lewis acid (TMSOTf) in the presence of a drying agent rise to dimer formation.21 Since the ring size of the desired
(MgSO4).17 However, despite the fact that a large excess product (12-ring) is sufficiently large to enable formation
of diethyleneglycol was added (5 equiv), compound 7 of a cycloalkyne (as indicated by Fürstner’s rule),16 an al-
could not be obtained in a yield exceeding 18%, especially ternative explanation for the lack of ring closure may be
due to incomplete conversion and the formation of found in steric hindrance of the tertiary anomeric center in
dimers. The five-fold excess of diethyleneglycol is appar- vicinity to the sugar alkyne.
ently not sufficient to prevent double glycosylation with
carbohydrate 6. A similar result was obtained by addition
of 1,4-benzenedimethanol instead of diethyleneglycol (8,
24%), whereas a slight increase in yield was observed for
ortho-benzenedimethanol to afford the desired glycoside
9 in 33% yield.
Since RCAM of a diyne linked via the anomeric center
was not successful, another strategy was considered to at-
tach 2-butynyl glycine to one of the alcohols of the carbo-
hydrate. An additional advantage of such a strategy is that
a late-stage deoxygenation of the anomeric carbon (C-4)
is avoided. The O-9 position (former O-6) was considered
An alternative mode of introduction of a linker, not in- most amenable for selective deprotection. Thus, the C-4
volving dehydrative condensation with excess diol, en- hemiacetal of 6 was first deoxygenated under the action of
tails nucleophilic attack of 6 at a suitable electrophile. A BF3·OEt2 and Et3SiH yielding stereoselectively the b-con-
suitable approach appeared the application of cyclic sul- figured alkynyl glucoside 14 (Scheme 4).22 Selective re-
fate technology, with the inherent advantage that only sin- moval of the benzyl group at O-9 by acetolysis (H2SO4,
gle addition is possible and a free alcohol is liberated for Ac2O), followed by removal of the resulting acetyl gave
esterification with the amino acid. Thus, 1,2-benzene- the desired glucosyl acetylene 15 with a free primary hy-
dimethanol was converted into cyclic sulfate 1018 as de- droxyl.23 Introduction of the linker was performed under
scribed by O’Brien et al.19 It was reasoned that conversion similar conditions as above, involving deprotonation of
of 6 into a good nucleophile could be effected by deproto- the alcohol by KHMDS in THF, and subsequent addition
nation with a strong base. However, a more direct ap- of cyclic sulfate 10, leading to chain-extended compound
proach was followed, involving addition of cyclic sulfate 16.24 Diimide-mediated esterification of 16 with Boc-pro-
10 to the alkoxide formed in situ by acetylide addition to tected 2-butynyl glycine proceeded uneventfully, afford-
lactone 5 (Scheme 3). Subsequent hydrolysis of O-sulfate ing the RCAM precursor 17 in good yield.25
with sulfuric acid and water proceeded in a one-pot proce-
dure leading to the desired alcohol 9 in 52% overall yield
from lactone 5. Compound 9 was isolated as an a,b-mix-
ture in a ratio of 3:4.
Diyne 17 was now subjected to RCAM as described ear-
lier. Thus, thorough drying and degassing was executed to
avoid premature decomposition of the sensitive catalyst.
Much to our satisfaction, prolonged treatment of 17 with
Next, Boc-protected 2-butynyl glycine 1120 was coupled the tungsten-based RCAM catalyst 13 led to the cyclized
to the free hydroxyl of 9 under the action of DCC and alkyne 18 in 80% yield (entry 1, Table 1).26 The structure
DMAP, leading to diyne 12. Compound 12 is suitably of cycloalkyne 18 was corroborated by NMR and mass
geared for ring-closing alkyne metathesis and was dis- spectral analysis.26 We were interested if the rate of
solved in toluene and degassed before addition of the RCAM depends on the a-configuration of the amino acid.
tungsten-based catalyst 13. After heating the reaction Therefore, racemic 2-butynyl glycine ( )-11 was attached
mixture to 80 °C for 30 minutes, TLC analysis showed the to the carbohydrate derivative 16 and subjected to ring
1) H2SO4,
Ac2O,
–20 °C
BnO
BnO
HO
BnO
BF3·OEt2
Et3SiH
O
O
6
BnO
BnO
2) KCN,
MeOH
63%
MeCN,
CH2Cl2,
0 °C
BnO
14
BnO
15
75%
O
NHBoc
11
1) KHMDS,
THF, –78 °C
OH
O
DCC, DMAP
O
O
CH2Cl2
94%
2) 10, THF,
–78 °C
54%
O
O
BnO
BnO
BnO
BnO
BnO
BnO
17
16
Scheme 4 Synthesis of glucoamino acid 16
Synlett 2008, No. 1, 111–115 © Thieme Stuttgart · New York

114
S. Groothuys et al.
LETTER
Table 1 Synthesis of RCAM Precursors and RCAM Products
Esterificationa
Yield (%)
RCAMb
Yield (%)
O
O
NHBoc
O
O
O
O
NHBoc
NHBoc
NHBoc
94
80
O
O
O
O
O
O
BnO
BnO
BnO
BnO
OBn
OBn
18
17
O
O
NHBoc
O
92
80
O
O
O
BnO
BnO
BnO
BnO
OBn
OBn
20
19
O
O
NHBoc
( )n
O
(92)
(84)
(62)
(29)
O
( )n
O
O
BnO
BnO
BnO
BnO
OBn
OBn
22: n = 2
24: n = 3
21: n = 2
23: n = 3
a Conditions: DCC, DMAP, CH2Cl2.
b Conditions: 13, toluene, 80 °C.
closure. No difference in reaction rate between the two 22, and 24 as versatile isosteres of glycoamino acids is
epimers could be observed, leading to a 1:1 mixture of currently under way.
diastereomeric cycloalkynes 20. Some L-diastereomeric
glycoamino acids were also prepared by applying L-3-
Acknowledgment
pentynyl glycine and L-4-hexynyl glycine20 to the synthet-
SenterNovem (Ministry of Economic Affairs, The Netherlands) is
gratefully acknowledged for providing financial support.
ic sequence of esterification–RCAM (entries 3 and 4, re-
spectively). In both cases, the desired cycloalkynes were
successfully formed, although extension of the amino acid
side chain led to reduced yields, i.e. giving the corre-
sponding cyclic acetylenes from 3-pentynyl glycine and
4-hexynyl glycine in yields of 62% and 29%, respectively.
References and Notes
(1) Schrock, R. R. Nobel lecture. http://nobelprize.org/
nobel_prizes/chemistry/laureates/2005/schrock-lecture.pdf
(accessed 26.10.2007).
(2) Grubbs, R. H. Nobel lecture. http://nobelprize.org/
nobel_prizes/chemistry/laureates/2005/grubbs-lecture.pdf
(accessed 26.10.2007).
(3) Pennella, F.; Banks, R. L.; Bailey, G. C. J. Chem. Soc.,
Chem. Commun. 1968, 1548.
(4) Fürstner, A.; Seidel, G. Angew. Chem. Int. Ed. 1998, 37,
1734.
(5) Mortreux, A.; Blanchar, M. J. Chem. Soc., Chem. Commun.
1974, 786.
(6) Bray, A.; Mortreux, A.; Petit, F.; Petit, M.; Szymanskabuzar,
T. J. Chem. Soc., Chem. Commun. 1993, 197.
(7) Fürstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc.
1999, 121, 9453.
(8) Pedersen, S. F.; Schrock, R. R.; Churchill, M. R.;
Wasserman, H. J. J. Am. Chem. Soc. 1982, 104, 6808.
(9) Fürstner, A.; Davies, P. W. Chem. Commun. 2005, 2307.
In conclusion, acetylene-linked glycoamino acids were
successfully prepared by application of ring-closing
alkyne metathesis. To this end, alkynyl sugars and alkynyl-
amino acids were coupled via a benzenedimethanol link-
er, derived from cyclic sulfate 10. Attachment points for
the amino acid were either the newly formed anomeric
center at C-4 or the primary hydroxyl at C-9. Performing
RCAM on the anomerically linked dialkyne led exclu-
sively to dimerization and failed to yield cycloalkyne
product, presumably due to steric hindrance. Linkage via
O-9, however, before subjection to RCAM proceeded
smoothly for 2-butynyl glycine of different configuration
and chain lengths, leading to the desired glucoamino acids
with ring sizes varying between 15 and 17. Further pro-
cessing of the ring-closed alkynyl glycoamino acids 18,
Synlett 2008, No. 1, 111–115 © Thieme Stuttgart · New York

LETTER
Synthesis of Alkyne-Linked Glycoamino Acids
115
(10) Aguilera, B.; Wolf, L. B.; Nieczypor, P.; Rutjes, F. P. J. T.;
Overkleeft, H. S.; van Hest, J. C. M.; Schoemaker, H. E.;
Wang, B.; Mol, J. C.; Fürstner, A.; Overhand, M.; van der
Marel, G. A.; van Boom, J. H. J. Org. Chem. 2001, 66, 3584.
(11) (a) IJsselstijn, M.; Aguilera, B.; van der Marel, G. A.; van
Boom, J. H.; van Delft, F. L.; Schoemaker, H. E.;
Overkleeft, H. S.; Rutjes, F. P. J. T.; Overhand, M.
Tetrahedron Lett. 2004, 45, 4379. (b) IJsselstijn, M.;
Kaiser, J.; van Delft, F. L.; Schoemaker, H. E.; Rutjes, F. P.
J. T. Amino Acids 2003, 24, 263.
NH4Cl and extracted with EtOAc (2 × 100 mL). The sulfate
was concentrated and redissolved in THF (100 mL).
Afterwards, H2SO4 (0.40 mL) and H2O (0.15 mL) were
added and the reaction was stirred for 4 d. Half of the THF
was evaporated and the reaction mixture was diluted with
EtOAc (200 mL) and washed with H2O (3 × 100 mL), brine,
dried (MgSO4), and evaporated. Purification by flash
chromatography (EtOAc–heptane, 1:2) afforded compound
16 (0.51 g, 54%) as a white solid. Rf = 0.20 (EtOAc–heptane,
1:2). 1H NMR (400 MHz, CDCl3): d = 7.42–7.20 (m, 19 H),
4.98 (d, J = 10.6 Hz, 1 H), 4.90 (d, J = 11.1 Hz, 1 H), 4.84–
4.76 (m, 3 H), 4.66 (d, J = 5.3 Hz, 2 H), 4.61 (d, J = 11.5 Hz,
2 H), 4.53 (d, J = 11.1 Hz, 1 H), 3.99 (dd, J = 2.0, 9.2 Hz, 1
H), 3.72 (dd, J = 2.0, 10.6 Hz, 1 H), 3.63–3.50 (m, 4 H),
3.43–3.40 (m, 1 H), 3.10 (br t, J = 6.1 Hz, 1 H), 1.88 (d,
J = 2.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 140.6,
138.4, 138.0, 138.0, 135.7, 130.2, 129.8, 128.9, 128.4,
128.3, 128.2, 127.9, 127.8, 127.8, 127.7, 127.6, 86.1, 83.0,
82.7, 78.4, 77.8, 76.2, 75.8, 75.5, 75.2, 72.8, 70.3, 69.0, 63.7,
4.2. [a]D20 +6.4 (c 1.0, CHCl3). IR (film): n = 3480, 3062,
3027, 2905, 2868, 2250. HRMS (CI): m/z calcd for C38H41O6
[M + H]: 593.2903; found: 593.2875.
(12) Ghalit, N.; Poot, A. J.; Fürstner, A.; Rijkers, D. T. S.;
Liskamp, R. M. J. Org. Lett. 2005, 7, 2961.
(13) Walter, A.; Westermann, B. Synlett 2000, 1682.
(14) Ali, M. H.; Collins, P. M.; Overend, W. G. Carbohydr. Res.
1990, 205, 428.
(15) Leeuwenburgh, M. A.; Appeldoorn, C. C. M.; van Hooft, P.
A. V.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J.
H. Eur. J. Org. Chem. 2000, 873.
(16) Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem.
Soc. 1999, 121, 11108.
(17) Li, X. L.; Ohtake, H.; Takahashi, H.; Ikegami, S.
Tetrahedron 2001, 57, 4297.
(18) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30,
655.
(19) O’Brien, M. K.; Sledeski, A. W.; Truesdale, L. K.
Tetrahedron Lett. 1997, 38, 509.
(20) Wolf, L. B.; Sonke, T.; Tjen, K. C. M. F.; Kaptein, B.;
Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.
Adv. Synth. Catal. 2001, 343, 662.
(25) A solution of 2-butynyl glycine 11 (18 mg, 79 mmol) and
alcohol 16 (34 mg, 56 mmol) in CH2Cl2 (1 mL) was stirred at
0 °C. Then, DMAP (0.7 mg, 6 mol) and DCC (15 mg, 73
mmol) in CH2Cl2 (1 mL) were added and the reaction was
stirred overnight at r.t. The reaction mixture was filtered and
the residue was washed with CH2Cl2. The organic layer was
evaporated. Flash chromatography afforded dialkyne 17 (42
mg, 94%) as a white solid. Rf = 0.43 (EtOAc–heptane, 1:2).
1H NMR (400 MHz, CDCl3): d = 7.41–7.12 (m, 19 H), 5.34–
5.25 (m, 3 H), 5.00 (d, J = 10.6 Hz, 1 H), 4.91 (d, J = 11.0
Hz, 1 H), 4.82–4.79 (m, 3 H), 4.64 (d, J = 12.4 Hz, 2 H), 4.50
(d, J = 10.8 Hz, 1 H), 4.45–4.42 (m, 1 H), 4.00 (dd, J = 1.7,
9.2 Hz, 1 H), 3.73 (d, J = 10.8 Hz, 1 H), 3.67 (dd, J = 4.5,
10.8 Hz, 1 H), 3.63–3.53 (m, 3 H), 3.43 (dd, J = 2.9, 9.2 Hz,
1 H), 2.72–2.56 (m, 2 H), 1.88 (d, J = 1.8 Hz, 3 H), 1.67 (t,
J = 2.2 Hz, 3 H), 1.44 (s, 9 H). 13C NMR (75 MHz, CDCl3):
d = 170.5, 154.9, 138.4, 138.1, 137.9, 136.4, 133.7, 129.3,
129.0, 128.3, 128.3, 128.1, 127.9, 127.8, 127.8, 127.7,
127.7, 127.6, 86.1, 82.7, 82.7, 80.1, 79.4, 78.9, 78.0, 76.6,
75.8, 75.5, 75.2, 73.2, 71.1, 70.2, 69.3, 64.9, 52.6, 28.6, 23.4,
4.2, 3.9. [a]D20 +6.6 (c 0.8, CHCl3). IR (film): n = 3723,
3425, 3058, 3028, 2967, 2911, 2855, 2250, 1740, 1722. ESI-
HRMS: m/z calcd for C49H55NNaO9 [M + Na]: 824.3775;
found: 824.3774.
(26) Dialkyne 17 (108 mg, 0.135 mmol) was coevaporated with
toluene (2 × 10 mL) and subsequently (t-BuO)3W≡Ct-Bu
(13, 22 mg, 47 mmol) was added. This was dissolved in
toluene (2 mL) and stirred for 30 min at 80 °C. The reaction
was concentrated and purified by flash chromatography
(EtOAc–heptane, 1:4) to yield cyclized product 18 (81 mg,
80%) as a white solid. Rf = 0.43 (EtOAc–heptane, 1:2). 1H
NMR (400 MHz, CDCl3): d = 7.35–7.26 (m, 19 H), 5.34–
5.23 (m, 3 H), 4.94–4.77 (m, 6 H), 4.71 (d, J = 11.7 Hz, 1 H),
4.62–4.58 (m, 2 H), 3.92 (d, J = 9.6 Hz, 2 H), 3.61–3.43 (m,
5 H), 2.96 (d, J = 16.4 Hz, 1 H), 2.56 (ddd, J = 2.1, 5.5, 16.6
Hz, 1 H), 1.39 (s, 9 H). 13C NMR (50 MHz, CDCl3):
d = 171.1, 155.2, 138.5, 138.1, 138.0, 138.0, 137.5, 132.8,
130.2, 128.9, 128.6, 128.6, 128.5, 128.4, 128.2, 128.1,
128.0, 128.0, 127.9, 127.8, 85.9, 82.2, 81.9, 81.4, 80.4, 79.5,
78.3, 75.9, 75.3, 75.3, 71.8, 69.7, 69.3, 65.2, 53.5, 28.4, 23.9.
[a]D20 –30.0 (c 0.26, CHCl3). IR (film): n = 3321, 3062,
3032, 2967, 2907, 2868, 2258, 1701. ESI-HRMS: m/z calcd
for C45H49NNaO9 [M + Na]: 770.3305; found: 770.3366.
(27) Leone, A.; Consiglio, G. Helv. Chim. Acta 2005, 88, 210.
(21) Mass analyses showed the formation of a product with m/z =
1784, which indicates [dimer + Na+].
(22) Tietze, L. F.; Griesbach, U.; Schuberth, I.; Bothe, U.; Marra,
A.; Dondoni, A. Chem. Eur. J. 2003, 9, 1296.
(23) To a solution of 1422 (1.3 g 2.4 mmol) in Ac2O (45 mL),
H2SO4 (5% in Ac2O, 10 mL) was added dropwise at –20 °C.
The reaction was stirred for 10 min. The reaction was
quenched with aq NaOAc, diluted with EtOAc, and washed
with sat. NaHCO3 and brine. The organic phase was dried
(Na2SO4) and concentrated in vacuo. The crude product was
purified by flash chromatography (EtOAc–heptane, 1:5) and
yielded the acetolyzed product (1.0 g, 81%) as a white solid.
To a solution of the acetolyzed product (1.0 g, 1.9 mmol) in
MeOH (40 mL) was added KCN (15 mg, 0.23 mmol). The
reaction was stirred for 24 h. The mixture was neutralized
with basic Amberlyst, filtrated, and evaporated. The mixture
was redissolved in EtOAc and washed with NH4Cl, dried
(MgSO4), and evaporated. Purification by flash chromatog-
raphy (EtOAc–heptane, 1:2) yielded 15 as a white solid
(0.75 g, 1.6 mmol, 82%). Rf = 0.30 (EtOAc–heptane, 1:2).
1H NMR (400 MHz, CDCl3): d = 7.37–7.24 (m, 15 H), 4.99
(d, J = 10.6 Hz, 1 H), 4.92 (d, J = 11.1 Hz, 1 H), 4.87–4.80
(m, 3 H), 4.65 (d, J = 10.9 Hz, 1 H), 4.05 (dd, J = 1.6, 9.5 Hz,
1 H), 3.87 (dd, J = 2.3, 12.0 Hz, 1 H), 3.70–3.50 (m, 4 H),
3.35–3.31 (m, 1 H), 2.05 (br s, 1 H), 1.88 (d, J = 1.2 Hz, 3
H). 13C NMR (50 MHz, CDCl3): d = 138.6, 138.2, 138.0,
128.6, 128.5, 128.3, 128.1, 128.0, 128.0, 127.9, 127.8, 86.0,
83.0, 82.8, 79.4, 77.6, 76.5, 75.8, 75.6, 75.3, 70.1, 62.1, 3.9.
[a]D20 –8.25 (c 0.63, CHCl3). IR (neat): n = 3373, 3036,
2902, 2859, 2245. HRMS (CI): m/z calcd for C30H33O5
[M + H]: 473.2328; found: 473.2331.
(24) Compound 15 (0.76 g, 1.6 mmol) was dissolved in anhyd
THF (50 mL) and cooled to –78 °C. Then, KHMDS (0.5 M
in toluene, 4.8 mL, 2.4 mmol) was added and stirred for 30
min at –78 °C. Cyclic sulfate 10 (0.64 g, 3.2 mmol)19,27 was
added. The temperature was raised overnight to r.t. After
stirring for 20 h, the reaction mixture was poured into aq sat.
Synlett 2008, No. 1, 111–115 © Thieme Stuttgart · New York

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