Sonogashira couplings of halo- and epoxy-halo-exo-glycals: Concise entry to carbohydrate-derived enynes

Article abstract of DOI:10.1002/ejoc.201000170

Furanose- and pyranose-derived mono- and dihalo-exo-glycals undergo Sonogashira coupling reactions in the presence of Pd catalysts to give carbohydrate-derived enynes in a completely stereoselective manner. On the other hand, a furanose-derived 2, 3-anhydrohalo-exo-glycal, available from D-mannose in five steps, undergoes Pd⁰-catalyzed Sonogashira coupling, leading to 2-deoxyenynes.

Full text of DOI:10.1002/ejoc.201000170

FULL PAPER
DOI: 10.1002/ejoc.201000170
Sonogashira Couplings of Halo- and Epoxy-Halo-exo-Glycals: Concise Entry
to Carbohydrate-Derived Enynes
Ana M. Gómez,*[a] Aitor Barrio,[a] Ana Pedregosa,[a] Clara Uriel,[a] Serafín Valverde,[a] and
J. Cristóbal López*[a]
Keywords: Carbohydrates / Glycals / Palladium / Cross-coupling / Enynes
Furanose- and pyranose-derived mono- and dihalo-exo-gly-
cals undergo Sonogashira coupling reactions in the presence
of Pd catalysts to give carbohydrate-derived enynes in a com-
pletely stereoselective manner. On the other hand, a fu-
ranose-derived 2,3-anhydrohalo-exo-glycal, available from
-mannose in five steps, undergoes Pd0-catalyzed Sonoga-
shira coupling, leading to 2-deoxyenynes.
D
(Scheme 1b)[13] and by Julia-type olefination of sugar
lactones.[14] More recently, a highly versatile Ramberg–
Backlund convergent approach has been described
(Scheme 1c).[6a,15] Other strategies also used in the prepara-
tion of substituted exo-glycals involve elimination of a leav-
ing group located at C-1Ј on a C-glycoside (Scheme 1d)[16]
or at the anomeric position in ketose-related derivatives
(Scheme 1e; X = OR,[17] X = Cl[18]), SN1Ј substitution on a
vinyl ketose (Scheme 1e; R = CH2, X = OH),[19] ring-
closing olefin metathesis on exo-glycals (Scheme 1f),[20] and
[2,3] Wittig rearrangement of propargyl ketosides
(Scheme 1g).[21]
Introduction
Much of the rich chemistry of carbohydrates emanates
from transformations at the anomeric (hemiacetal) center.[1]
The advent of unsaturated anomeric derivatives [e.g., endo-
and exo-glycals, 1 (R = H) and 2, respectively] has added
new avenues for additional synthetic transformations.[2] In
this context, the less studied exo-glycals (2,5- or 2,6-anhy-
dro-1-deoxyhex-1-enitols or -hept-1-enitols, e.g., 2), are now
well-recognized unsaturated carbohydrate derivatives fre-
quently used as intermediates in transformations leading to
carbohydrate mimetics or to complex molecules.[3,4] More
recently, substituted exo-glycals (e.g., 3)[5] that display ad-
ditional substituent(s) at the exocyclic carbon atom, while
maintaining the enol ether functionality, have also emerged
as valuable substrates in synthetic[6] and biological investi-
gations.[7] The olefinic substituent(s) allow(s) easy retrosyn-
thetic correlation with biologically relevant C-glycosides
(e.g. 4),[8] whereas the enol ether moiety permits the incor-
poration of additional functionality into the carbohydrate
entity (Figure 1).[9,10]
Figure 1. Glycal (1), exo-glycal (2), substituted exo-glycal (3), and
C-glycoside (4).
Synthetic strategies to substituted exo-glycals 3[11] have
been addressed by Wittig-type olefination of either glycosyl
phosphonium salts (Scheme 1a)[12] or sugar lactones
Scheme 1. Strategies for the synthesis of substituted exo-glycals.
[a] Instituto de Química Orgánica General, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-915644853
Our group has been interested in the synthesis of unsatu-
rated anomeric derivatives (i.e., 1–3), and we have reported
novel synthetic entries to glycals (1, R = H)[22] and C-1
E-mail: anagomez@iqog.csic.es
clopez@iqog.csic.es
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Sonogashira Couplings of Halo- and Epoxy-Halo-exo-Glycals
glycals (1, R = = CRЈRЈЈRЈЈЈ).[23] More recently, we have olefination of 2,3:5,6-di-O-isopropylidene--mannono-1,4-
been involved in the design of synthetic routes to substi- lactone,[36] according to methodologies developed by the
tuted exo-glycals (3)[24] on the basis of cross-coupling reac- group of Chapleur,[37] led to dihalo-exo-glycals 12[38] and
tions of halo-exo-glycals (Scheme 1h). In this context, we 13.[39]
have explored the Suzuki[25] and Stille[26] cross-coupling
These substrates were selected to (1) compare the behav-
reactions of monohalo-exo-glycals (Scheme 1h; X = Br, I; ior of pyranoid (5–7) and furanoid (8–13) derivatives,
Y = H). (2) study the influence of the halogen (Br vs. I) in the reac-
In this manuscript, we report in full our studies regarding tivity (e.g., 8b and 9a vs. 8c and 9b), (3) evaluate the effect
the Sonogashira cross-coupling reaction[27] of mono- of the stereochemistry of the alkenyl halide (10b vs. 11) in
halo-,[28] dihalo-, and epoxy-halo-exo-glycals aimed at the the reactivity of these substrates, and (4) assess the reactiv-
preparation of carbohydrate-derived enynes,[29] enediynes, ity and/or chemoselectivity in dihalogenated derivatives 12
and functionalized enynes, respectively.
and 13 (Br vs. Cl).
On the other hand, as alkynes we have employed aryl,
trimethylsilyl, and alkyl derivatives 14–16 (Figure 3).
Results and Discussion
Synthesis of the Precursors
The precursors for these studies were pyranoid iodo-exo-
glycals 5–7 and furanosidic halo-exo-glycals 8–13 (Fig-
ure 2). Pyranoid (Z)-iodo-exo-glycals 5–7 were prepared
from the corresponding aldonolactones[30–32] by methylen-
ation (Petasis reagent)[33] followed by stereoselective iodin-
Figure 3. Alkynes employed in the Sonogashira cross-coupling re-
actions.
ation[25a] with iodonium dicollidinium triflate (IDCT).[34] Sonogashira Cross-Coupling Reaction of Pyranoid
Furanoid exo-glycals 8b and 8c were prepared by stereose- Derivatives
lective bromination (Br2, Et3N, 8b) or iodination (IDCT,
We first explored the reaction of -glucopyranose-de-
8c) of the corresponding epoxy-exo-glycal (8a, X = H).[25b]
rived alkenyl iodides 5 with alkynes 14–16 in the presence
Furanoid diacetates 9 were prepared from halo-exo-glycals
of different catalysts and bases (Table 1).
8b,c by oxirane ring opening [THF/H2O (3:1), Bu4NOH,
The stereochemistry of the resulting enynes was assigned
reflux][25b] followed by acetylation (Ac2O, pyridine). (Z)-
on the basis of mechanistic grounds, as the cross-coupling
Halo-exo-glycal 10b was prepared stereoselectively from
takes place with retention of configuration at the alkene[27]
exo-glycal 10a[17d] (Br2, Et3N). On the other hand, bromi-
and was further proved in the case of compound 17 by an
nation of 10 with tetra-n-butylammonium tribromide
observed NOESY between 1Ј-H and 2-H (see Table 1, En-
(nBu4NBr3)[35] rather than Br2 resulted in the formation of
try i).
a 6:1 isomeric mixture of 10b and 11, from which (E)-
The use of a PdII catalyst under Sonogashira–Hagihara
bromo-exo-glycal 11 could be isolated. Finally, Wittig-type
conditions[40] [Pd(PPh3)2Cl2, CuI] in different solvents
(Table 1, Entries ii–iv, vii, and viii) did not lead to appreci-
able amounts of coupled products. Consequently, the use of
Pd0[41,42] was next attempted [Pd(PPh3)4, CuI, base] and
was found to facilitate the formation of the sought enynes
(Table 1, Entries i, v, vi, and ix–xi). Concerning the base
employed, although piperidine led to good yields of enynes
(Table 1, Entries i, v, and ix) a faster reaction was observed
when diethylamine was used (Table 1, Entries vi, x, and xi).
As expected, methyl- and benzyl-protected derivatives 5a
and 5b displayed similar behavior in the Sonogashira cross-
coupling reaction (Table 1, Entries x and xi).
These optimized reaction conditions were successfully
applied to pyranose-derived galacto- and manno-iodo-exo-
glycals 6 and 7, respectively (Table 2). Thus, the Sonoga-
shira cross-coupling reactions were carried out in Et2NH
(10 mL/mmol) in the presence of CuI (0.1 equiv.) and
Pd(PPh3)4 (0.05 equiv.) at room temperature. In all cases,
the reaction took place smoothly to afford the desired
enynes in good to excellent yields (Table 2, Entries i–vi).
Finally, according to the results outlined in Tables 1 and
2, gluco-, manno-, and galacto-pyranose derivatives all dis-
Figure 2. Halogenated exo-glycals 5–13.
Eur. J. Org. Chem. 2010, 2910–2920
played similar behavior, which seems to indicate that there
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A. M. Gómez, A. Barrio, A. Pedregosa, C. Uriel, S. Valverde, J. C. López
FULL PAPER
Table 1. Sonogashira cross-coupling reaction of halo-exo-glycals 5a
and 5b with alkynes 14–16.
Table 2. The Pd(PPh3)4-catalyzed Sonogashira cross-coupling reac-
tion of iodo-exo-glycals 6 and 7 with alkynes 14–16 in the presence
of CuI in diethylamine as solvent at room temperature.
[a] exo-Glycal 5a (90%) was recovered. [b] exo-Glycal 5a (43%) was
recovered.
agreement with the higher reactivity of the former to palla-
dium(0) oxidative addition. (2) No appreciable effect due to
the orientation and nature of the protecting groups was ob-
served in the outcome of the reaction (Table 3, compare
Entries i, iii, and v with Entries vii–ix). (3) Z and E isomers
10b and 11 behaved similarly in terms of observed yield and
reaction times, although the slightly higher reactivity found
for the Z isomer could be ascribed to their different steric
environments (Table 3, compare Entries vii, viii, and ix with
Entries x, xi, and xii). (4) Higher yields and shorter reaction
times were observed for alkynes 14 and 15 when compared
to less reactive aliphatic alkyne 16.
[a] exo-Glycal 5a (90%) was recovered. [b] exo-Glycal 5a (43%) was
recovered.
is little or no effect on the reaction rates or yields caused
by the stereochemistry of the substituents in the pyranose
ring.
Sonogashira Cross-Coupling Reactions on Dihalogenated
Substrates
Sonogashira Cross-Coupling Reactions of Furanoid
Derivatives
Enediyne derivatives[43] could be easily accessed through
Furanoid halo-exo-glycals 9a,b, 10b, and 11 proved to be Sonogashira coupling[27] from readily available dihaloge-
more reactive than the corresponding pyranosyl derivatives. nated derivatives 12 and 13.[33,35,36,44] On the other hand,
Thus, the coupling with furanose derivatives could be car- we were also interested in evaluating the reactivity of the
ried out under standard Sonogashira–Hagihara conditions two bromine atoms in our substrates. In this context, the
[Pd(PPh3)2Cl2, Et2NH, CuI, THF],[40] and the results are Pd-catalyzed highly trans-selective monosubstitution of 1,1-
displayed in Table 3.
dihalo-1-alkenes had attracted considerable attention since
On the basis of these results, some conclusions could be the pioneer work of Minato et al.[45] More recently, trans-
drawn: (1) Alkenyl furanosyl iodides gave only slightly bet- stereoselective cross-coupling reactions have been attained
ter yields than the corresponding alkenyl bromides (Table 3, on monosubstituted 1,1-dibromo-1-alkenes in Negishi,[46]
compare Entries i and ii, iii and iv; v and vi), which is in Suzuki,[47] Stille,[48] and Sonogashira[49] cross-couplings.
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Sonogashira Couplings of Halo- and Epoxy-Halo-exo-Glycals
Table 3. The Pd(PPh3)4-catalyzed Sonogashira cross-coupling reac-
tion of furanoid halo-exo-glycals 9a, 9b, 10b, and 11 with alkynes
14–16 in the presence of CuI with diethylamine as solvent at room
temperature.
Table 4. The Pd(PPh3)4-catalyzed Sonogashira cross-coupling reac-
tion of dihalo-exo-glycals 12 and 13 with alkynes 14–16 in the pres-
ence of CuI with diethylamine as solvent at room temperature.
[a] Unassigned Z/E mixture (4:1). [b] Only one major isomer could
be identified. [c] exo-Glycal 12 (10%) was recovered. [d] Unas-
signed isomeric Z/E mixture (1.1:1). [e] exo-Glycal 12 (43%) was
recovered.
On the other hand, dichloro-exo-glycal 13 did not un-
dergo Sonogashira cross-coupling under the various reac-
tion conditions attempted. These results are in agreement
with the lower reactivity of alkenyl chlorides when com-
pared to bromides or iodides[50] and to recent results re-
ported by the group of Chapleur.[44]
Sonogashira Cross-Coupling on a Furanose-Derived 2,3-
Anhydrohalo-exo-glycal
We have recently described a three-component assembly
of bromoalkenyl allylic oxirane 8b with amines and boronic
acids to furnish exo-glycal derivatives 28 (Scheme 2a).[51] In
this context, we speculated about a related transformation
of compound 8b involving a Sonogashira cross-coupling re-
action, rather than a Suzuki coupling, which could generate
a highly functionalized enyne, that is, 30 (Scheme 2b).
Compound 8b possesses two reactive sites for palladium-
[a] exo-Glycal 10b (16%) was recovered. [b] exo-Glycal 11 (44%)
was recovered.
The reaction of 1Ј,1Ј-dibromo-exo-glycal 12 with alkynes
14–16 (Table 4) took place smoothly under conditions sim- mediated reactions: the allylic oxirane and the alkenyl bro-
ilar to those previously employed with the furanosidic exo- mide. The transformation depicted in Scheme 2a suppos-
glycals (see Table 3). We were pleased to observe that the edly occurs by uncatalyzed, thermal oxirane opening fol-
reaction of 12 with the less reactive aliphatic alkyne 16 lowed by Suzuki cross-coupling of the alkenyl bromide.
could be stopped at the monosubstitution stage to give 26c
Because the Sonogashira cross-coupling reaction takes
as a 1.1:1 unassigned isomeric mixture of Z/E isomers place at room temperature rather than at 60 °C (and be-
(Table 4, Entry iii). More reactive alkynes 14 and 15, how- cause no appreciable nucleophilic opening of epoxide 8b
ever, gave mixtures of enynes and enediynes 26 and 27, with amines had been observed at room temperature) a dif-
respectively (Table 4, Entries i and ii). Enynes 26a and 26b ferent reaction course could be anticipated for the transfor-
were also obtained as unidentified Z/E isomeric mixtures. mation proposed in Scheme 1b. Accordingly, we had envis-
Accordingly, we have been unable to assign a higher reactiv- aged that compound 8b would first undergo Sonogashira
ity to any of the bromine atoms in dibromo-exo-glycal 12.
cross-coupling at the alkenyl bromide followed by genera-
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A. M. Gómez, A. Barrio, A. Pedregosa, C. Uriel, S. Valverde, J. C. López
FULL PAPER
tries i and ii). Likewise, when aliphatic alkyne 16 was em-
ployed, a ≈1:1 mixture of enynes 31c (37%) was obtained,
albeit this time accompanied by 2-deoxy-2-amino derivative
32 (17%; Table 5, Entry iii). These results seemed to indi-
cate that the Sonogashira cross-coupling was taking place
first and that it was followed by the formation π–allyl palla-
dium complex 29; the latter will then explain the formation
of compounds 31a–c as geometric enyne mixtures.[53]
Furthermore, the addition of hydride from a palladium–
hydride species to 29 could be responsible for the formation
of the 2-deoxy, rather than the 2-deoxy-2-amino deriva-
tives.[54]
On the other hand, the presence of an unreacted bromine
atom in amino alcohol 32 (Table 5, Entry iii) was surpris-
ing. Therefore, we carried out several attempts to conduct
Sonogashira couplings with 32 and alkyne 14 that were not
successful.
When the reaction was carried out in the presence of pi-
peridine at 60 °C (Table 5, Entry iv), only amino alcohol 33
Scheme 2. Three-component reaction of haloalkenyl oxirane 8b,
and the proposed three-component reaction of 8b involving a
Sonogashira coupling.
could be isolated. In our hands, all attempts to induce a
Sonogashira cross-coupling in compound 33 have met with
failure.
tion of a π–allyl palladium complex (e.g., 29),[52] which
could then react with the amine (NHR1R2) to give func-
tionalized enynes, for example, 30 (Scheme 1b).
However, instead of desired amino alkynes 30, the reac-
tion of compound 8b with alkynes 14 and 15 [alkyne
(1.1 equiv.), Pd(PPh3)4 (5 mol-%), CuI (10 mol-%), Et2NH
(4 mL/mmol), room temperature] produced a mixture of 2-
deoxyenynes 31a (1.2:1, unassigned Z/E mixture) and 31b
(2:1, unassigned Z/E mixture), respectively (Table 5, En-
Conclusions
Furanose- and pyranose-derived halo-exo-glycals are
useful synthetic intermediates in the preparation of enyne
exo-glycals. The reaction can also be applied to dibromo-
exo-glycals to generate carbohydrate-derived enediynes. Fu-
ranose derivatives undergo the cross-coupling reaction un-
der standard Sonogashira–Hagihara conditions, whereas
pyranose derivatives required the use of Pd0 as a catalyst.
Alkenyl iodides react with alkynes to give slightly better
yields, with shorter reaction times, than the corresponding
bromo derivatives. (E)-Alkenyl bromides display a slightly
higher reactivity than their isomeric (Z) counterparts. How-
ever, this slight reactivity difference does not allow the prep-
aration of a single monosubstituted enyne from the Suzuki
coupling of dihalo-exo-glycals. A highly functionalized fu-
ranose derivative, containing a bromoalkene and an allylic
epoxide, undergoes Sonogashira cross-coupling followed by
hydride transfer to a π–allyl palladium complex to furnish
2-deoxyenynes in fair yields. Finally, a series of 2-deoxy-2-
amino alkenyl bromides derived from furanoses were reluc-
tant to undergo the Sonogashira coupling under reaction
conditions that had proven successful for the transforma-
tion of related non-amino derivatives.
Table 5. Sonogashira cross-coupling reaction of epoxy-bromo-exo-
glycal 8b with alkynes 14–16 in the presence of amines.
Experimental Section
General Remarks: All reactions were performed in dry flasks fitted
with glass stoppers or rubber septa under a positive pressure of
Ar, unless otherwise noted. Air- and moisture-sensitive liquids and
solutions were transferred by syringe or stainless steel cannula. Op-
tical rotations were determined for solutions in chloroform. Flash
column chromatography was performed using 230–400 mesh silica
gel. Thin-layer chromatography was conducted on Kieselgel 60
F254 (Merck). Spots were observed first under UV irradiation
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Sonogashira Couplings of Halo- and Epoxy-Halo-exo-Glycals
(254 nm) then by charring with a solution of 20% aqueous H2SO4
C), 128.5 (2 C), 128.4 (2 C), 128.3 (4 C), 128.1 (2 C), 127.9 (3 C),
(200 mL) in AcOH (800 mL). Anhydrous MgSO4 or Na2SO4 was 127.8 (5 C), 127.7 (4 C), 127.4, 123.9, 93.6, 89.9, 84.2, 83.8, 77.8,
used to dry organic solutions during workup, and evaporation of
the solvents was performed under vacuum using a rotary evapora-
tor. Solvents were dried and purified by using standard methods.
Unless otherwise noted 1H and 13C NMR spectra were recorded
in CDCl3 at 300 and 75 MHz, respectively. Chemical shifts are ex-
pressed in parts per million (δ scale) downfield from tetramethylsil-
ane and are referenced to residual protium in the NMR solvent
(CHCl3: δ = 7.25 ppm).
77.7, 77.6, 73.9, 73.6, 73.3, 71.6, 68.5 ppm. MS (API-ES+): m/z =
637.3 [M + 1]+, 659.3 [M + Na]+. C43H40O5 (636.77): calcd. C
81.11, H 6.33; found C 81.07, H 6.54.
Compound 18: Iodo-exo-glycal 5a (100 mg, 0.15 mmol) and tri-
methylsilylacetylene (15; 22 µL, 0.16 mmol) were treated according
to general method B. After purification by flash chromatography
(hexane/EtOAc, 95:5), compound 18 was obtained as a colorless
oil (88 mg, 91%). In a different experiment, glycal 5a (100 mg,
0.15 mmol) and 15 (22 µL, 0.16 mmol) were treated according to
General Procedure for the Sonogashira Coupling Reaction
general method D to yield compound 18 (81 mg, 84%). [α]2D5
=
Method A: To a thoroughly degassed (argon, 10 min) solution
of halo-exo-glycal in piperidine (10 mL/mmol) was added CuI
(5 mol-%) and Pd(PPh3)2Cl2 (10 mol-%). The reaction mixture was
kept at room temperature with stirring for 5 min. The appropriate
terminal alkyne (1 equiv.) dissolved in piperidine (10 mL/mmol)
was then added by cannula. The reaction was then stirred at room
temperature until complete disappearance of the starting material.
The solution was treated with H2O and extracted with ethyl acetate
(EtOAc). The organic layer was then dried and evaporated to fur-
nish a residue, which was purified by flash chromatography (hex-
ane/EtOAc).
+33.6 (c = 1.2, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.42–
7.19 (m, 20 H, Ph), 5.00 (s, 1 H, 1Ј-H), 4.80–4.51 (m, 8 H, O-CH2-
Ph), 4.18 (ddd, J = 9.7, 3.1, 2.4 Hz, 1 H, 5-H), 3.91 (d, J = 4.1 Hz,
1 H, 2-H), 3.89–3.79 (m, 4 H), 0.18 (s, 9 H, TMS) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.8, 138.3, 138.0, 137.8, 137.4, 128.4 (2
C), 128.3 (2 C), 128.2 (4 C), 127.9 (2 C), 127.8 (7 C), 127.7, 127.6,
127.5, 99.7, 98.7, 89.8, 83.6, 77.6 (2 C), 77.5, 73.8 (2 C), 73.0, 71.4,
68.4, 0.4 (3 C) ppm. MS (API-ES+): m/z = 633.3 [M + 1]+, 655.3
[M + Na]+. C40H44O5Si (632.85): calcd. C 75.91, H 7.01; found C
75.79, H 6.94.
Compound 19: Iodo-exo-glycal 5a (100 mg, 0.15 mmol) and 1-dode-
cyne (16; 37 µL, 0.16 mmol) were treated according to general
method D. After purification by flash chromatography (hexane/
EtOAc, 90:10), compound 19 was obtained as a colorless oil
(103 mg, 98%). [α]2D5 = +54.0 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.45–7.21 (m, 20 H, Ph), 5.03 (br. s, 1 H,
1Ј-H), 4.85–4.56 (m, 8 H, O-CH2-Ph), 4.13 (br. d, J = 9.3 Hz, 1 H,
5-H), 3.96 (d, J = 6.9 Hz, 1 H, 2-H), 3.92–3.80 (m, 4 H), 2.38 (td,
J = 10.2, 3.3 Hz, 2 H), 1.67–1.22 (m, 16 H), 0.94 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.4, 138.4, 138.1,
138.0, 137.6, 128.4 (2 C), 128.3 (2 C), 128.2 (4 C), 127.8 (6 C),
127.7 (4 C), 127.6, 127.5, 94.8, 90.6, 84.0, 78.0, 77.7, 77.6, 74.6,
73.9, 73.6, 73.3, 71.6, 68.5, 31.9, 29.6, 29.5, 29.3, 29.2, 28.9 (2 C),
22.6, 19.8, 14.1 ppm. MS (API-ES+): m/z = 723.5 [M + Na]+.
C47H56O5 (700.49): calcd. C 80.53, H 8.05; found C 80.63, H 7.97.
Method B: To a thoroughly degassed (argon, 10 min) solution of
iodo-exo-glycal (0.1 mmol) in piperidine (10 mL/mmol) was added
successively Pd(PPh3)4 (5mol-%), CuI (0.01 mmol) and the corre-
sponding alkyne (1.1 equiv., 0.11 mmol). The reaction mixture was
then stirred at room temperature until complete disappearance of
the starting material (1–2 h). The solution was diluted with ethyl
acetate and washed successively with saturated NH4Cl and brine.
The organic layer was dried (magnesium sulfate) and evaporated
to furnish a residue, which was purified by flash chromatography
(hexane/EtOAc).
Method C: To a thoroughly degassed (argon, 10 min) solution of
halo-exo-glycal in Et2NH (10 mL/mmol) was added CuI (5 mol-%)
and Pd(PPh3)2Cl2 (10 mol-%). The reaction mixture was kept at
room temperature with stirring for 5 min. The appropriate terminal
alkyne (1 equiv.) dissolved in Et2NH (10 mL/mmol) was then added
by cannula. The reaction was then stirred at room temperature until
complete disappearance of the starting material. The solution was
treated with H2O and extracted with ethyl acetate (EtOAc). The
organic layer was then dried and evaporated to furnish a residue,
which was purified by flash chromatography (hexane/EtOAc).
Compound 20: Iodo-exo-glycal 5b (40 mg, 0.07 mmol) and phenyl-
acetylene (14; 9 µL, 0.08 mmol) were treated according to general
method D. After purification by flash chromatography (hexane/
EtOAc, 95:5), compound 20 was obtained as a colorless oil (21 mg,
90%). [α]2D5 = +33.9 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.43–7.39 (m, 2 H, Ph), 7.29–7.26 (m, 3 H, Ph), 5.11 (s, 1 H,
1Ј-H), 3.97 (m, 1 H, 5-H), 3.79–3.67 (m, 3 H), 3.54 (s, 3 H, OMe),
3.52 (s, 3 H, OMe), 3.51 (s, 3 H, OMe), 3.45 (s, 3 H, OMe), 3.41
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.1, 130.9 (2
C), 127.9 (2 C), 127.4, 123.7, 93.1, 89.2, 84.3, 84.0, 79.5, 78.6, 76.9,
70.9, 59.4, 58.7, 58.2, 57.2 ppm. MS (API-ES+): m/z = 333.0 [M +
1]+, 355.0 [M + Na]+. C19H24O5 (332.16): calcd. C 68.66, H 7.28;
found C 68.49, H 7.44.
Method D: To a thoroughly degassed (argon, 10 min) solution of
iodo-exo-glycal (0.1 mmol) in Et2NH (10 mL/mmol) was added
successively Pd(PPh3)4 (5mol-%), CuI (0.01 mmol), and the corre-
sponding alkyne (1.1 equiv., 0.11 mmol). The reaction was then
stirred at room temperature until complete disappearance of the
starting material (1–2 h). The solution was diluted with ethyl acet-
ate and washed successively with saturated NH4Cl and brine. The
organic layer was dried (magnesium sulfate) and evaporated to fur-
nish a residue, which was purified by flash chromatography (hex-
ane/EtOAc).
Compound 21a: Iodo-exo-glycal 6 (100 mg, 0.15 mmol) and phenyl-
acetylene (14; 18 µL, 0.16 mmol) were treated according to general
method D. After purification by flash chromatography (hexane/
Compound 17: Iodo-exo-glycal 5a (100 mg, 0.15 mmol) and phenyl- EtOAc, 90:10), compound 21a was obtained as a colorless oil
acetylene (14; 18 µL, 0.16 mmol) were treated according to general
method B. After purification by flash chromatography (hexane/
EtOAc 90:10), compound 17 was obtained as a colorless oil (88 mg,
92%). [α]2D5 = +57.5 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
(88 mg, 92%). [α]2D5 = +33.9 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.44–7.23 (m, 25 H, Ph), 5.42 (d, J = 1.5 Hz, 1 H, 1Ј-
H), 4.89 (d, J = 11.7 Hz, 1 H), 4.71–4.55 (m, 6 H, O-CH2-Ph), 4.45
(d, J = 11.7 Hz, 1 H), 4.41 (dd, J = 9.0, 1.0 Hz, 1 H), 4.07 (t, J =
δ = 7.34–7.11 (m, 25 H, Ph), 5.09 (s, 1 H, 1Ј-H), 4.70–4.47 (m, 8 2.0 Hz, 1 H), 3.99 (dt, J = 6.0, 2.0 Hz, 1 H), 3.82–3.70 (m, 2 H),
H, O-CH2-Ph), 4.09 (ddd, J = 10.0, 4.0, 2.0 Hz, 1 H, 5-H), 3.89 (d, 3.68 (dd, J = 9.0, 2.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
J = 4.6 Hz, 1 H, 2-H), 3.89–3.72 (m, 4 H) ppm. 13C NMR
δ = 160.7, 138.3, 138.1, 138.0, 137.8, 131.4 (2 C), 128.4 (2 C), 128.3
(75 MHz, CDCl3): δ = 158.7, 138.3, 138.0, 137.9, 137.4, 131.4 (2 (4 C), 128.1 (2 C), 127.9 (4 C), 127.8 (5 C), 127.7 (3 C), 127.6 (2
Eur. J. Org. Chem. 2010, 2910–2920
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2915

A. M. Gómez, A. Barrio, A. Pedregosa, C. Uriel, S. Valverde, J. C. López
FULL PAPER
C), 127.5, 123.9, 93.6, 90.7, 84.4, 81.6, 78.9, 76.7, 74.3, 74.1, 74.0,
73.5, 72.8, 68.8 ppm. MS (API-ES+): m/z = 659.3 [M + Na]+.
C43H40O5 (636.77): calcd. C 81.11, H 6.33; found C 80.98, H 6.21.
69.0, 0.0 (3 C) ppm. MS (API-ES+): m/z = 633.3 [M + 1]+, 655.3
[M + Na]+. C40H44O5Si (632.85): calcd. C 75.91, H 7.01; found C
75.83, H 6.88.
Compound 21b: Iodo-exo-glycal 6 (100 mg, 0.15 mmol) and tri-
methylsilylacetylene (15; 22 µL, 0.16 mmol) were treated according
to general method D. After purification by flash chromatography
(hexane/EtOAc, 95:5), compound 21b was obtained as a colorless
oil (79 mg, 84%). [α]2D5 = +33.6 (c = 1.2, CHCl3). 1H NMR
Compound 22c: Iodo-exo-glycal 6 (100 mg, 0.15 mmol) and 1-dode-
cyne (16; 36 µL, 0.16 mmol) were treated according to general
method D. After purification by flash chromatography (hexane/
EtOAc, 90:10), compound 22c was obtained as a colorless oil
(100 mg, 95%). [α]2D5 = +14.0 (c = 0.7, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.42–7.19 (m, 20 H, Ph), 5.00 (s, 1 H, 1Ј- (300 MHz, CDCl3): δ = 7.41–7.21 (m, 20 H, Ph), 4.86 (d, J =
H), 4.80–4.51 (m, 8 H, O-CH2-Ph), 4.18 (ddd, J = 9.7, 3.1, 2.4 Hz,
1 H, 5-H), 3.91 (d, J = 4.1 Hz, 1 H, 2-H), 3.89–3.79 (m, 4 H), 0.18
(s, 9 H, TMS) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.8, 138.3,
138.0, 137.8, 137.4, 128.4 (2 C), 128.3 (2 C), 128.2 (4 C), 127.9 (2
C), 127.8 (7 C), 127.7, 127.6, 127.5, 99.7, 98.7, 89.8, 83.6, 77.6 (2
10.8 Hz, 1 H), 4.82 (t, J = 2.1 Hz, 1 H, 1Ј-H), 4.72–4.48 (m, 6 H,
OCH2Ph), 4.35 (d, J = 12.6 Hz, 1 H), 4.19 (t, J = 8.7 Hz, 1 H, 4-
H), 3.95 (d, J = 3.0 Hz, 1 H, 2-H), 3.83 (d, J = 3.6 Hz, 2 H, 2 6-
H), 3.74 (td, J = 8.7, 3.6 Hz, 1 H, 5-H), 3.62 (dd, J = 8.7, 3.0 Hz,
1 H, 3-H), 2.27 (dt, J = 6.9, 2.1 Hz, 2 H), 1.64–1.22 (m, 16 H),
C), 77.5, 73.8 (2 C), 73.0, 71.4, 68.4, 0.4 (3 C) ppm. MS (API-ES+): 0.84 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
m/z = 633.3 [M + 1]+, 655.3 [M + Na]+. C40H44O5Si (632.85): calcd. 159.1, 138.4, 138.2, 138.1, 137.9, 128.4 (2 C), 128.2 (2 C), 128.1 (3
C 75.91, H 7.01; found C 75.81, H 6.90.
C), 127.9 (5 C), 127.8 (3 C), 127.7 (2 C), 127.6, 127.5, 127.4, 94.7,
91.3, 81.5, 78.7, 76.7, 74.7, 74.2 (2 C), 73.7, 73.5, 72.7, 68.6, 31.9,
29.6 (2 C), 29.3, 29.2, 28.9 (2 C), 22.7, 19.7, 14.1 ppm. MS (API-
ES+): m/z = 723.5 [M + Na]+. C47H56O5 (700.49): calcd. C 80.53,
H 8.05; found C 80.32, H 8.13.
Compound 21c: Iodo-exo-glycal 6 (100 mg, 0.15 mmol) and 1-dode-
cyne (16; 36 µL, 0.16 mmol) were treated according to general
method D. After purification by flash chromatography (hexane/
EtOAc, 90:10), compound 21c was obtained as a colorless oil
(88 mg, 86%). [α]2D5 = +44.3 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.35–7.26 (m, 20 H, Ph), 5.25 (ddd, J = 3.9, 2.2,
Compound 23a: Bromo-exo-glycal 9a (57 mg, 0.15 mmol) and phen-
ylacetylene (14; 18 µL, 0.16 mmol) were treated according to gene-
1.6 Hz, 1 H, 1Ј-H), 4.93 (d, J = 11.5 Hz, 1 H), 4.74–4.60 (m, 6 H, ral method D. After purification by flash chromatography (hexane/
O-CH2-Ph), 4.50 (d, J = 11.7 Hz, 1 H), 4.39 (dd, J = 8.8, 1.6 Hz, EtOAc, 60:40), compound 23a was obtained as a colorless oil
1 H, 4-H), 4.12 (t, J = 2.4 Hz, 1 H), 4.00 (dt, J = 6.0, 2.4 Hz, 1 (52 mg, 88%). In a different experiment, iodo-exo-glycal 9b (64 mg,
H), 3.80 (d, J = 6.0 Hz, 2 H, 2 6-H), 3.70 (dd, J = 8.8, 2.4 Hz, 1
0.15 mmol) and 14 (18 µL, 0.16 mmol) were treated according to
H, 3-H), 2.28 (dt, J = 6.9, 2.2 Hz, 2 H), 1.41–1.34 (m, 2 H), 1.25– general method D to afford 23a (55 mg, 91%). [α]2D5 = +31.5 (c =
1.16 (m, 14 H), 0.79 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.1, 138.4, 138.2, 138.1, 137.9, 128.4 (2 C), 128.2 (2
C), 128.1 (3 C), 127.9 (5 C), 127.8 (3 C), 127.7 (2 C), 127.6, 127.5,
127.4, 94.7, 91.3, 81.5, 78.7, 76.7, 74.7, 74.2 (2 C), 73.7, 73.5, 72.7,
68.6, 31.9, 29.6 (2 C), 29.3, 29.2, 28.9 (2 C), 22.7, 19.7, 14.1 ppm.
MS (API-ES+): m/z = 723.5 [M + Na]+. C47H56O5 (700.49): calcd.
C 80.53, H 8.05; found C 80.41, H 8.09.
0.9, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.32 (m, 5 H, Ph),
5.54 (s, 1 H, 2-H), 5.37 (d, J = 4.0 Hz, 1 H, 3-H), 5.17 (s, 1 H, 1Ј-
H), 4.58 (dd, J = 7.9, 4.0 Hz, 1 H, 4-H), 4.37 (ddd, J = 7.8, 5.6,
5.3 Hz, 1 H, 5-H), 4.18 (m, 2 H, 2 6-H), 2.14 (s, 3 H, Me), 2.12 (s,
3 H, Me), 1.47 (s, 3 H, Me), 1.37 (s 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 169.3, 169.2, 161.3, 131.4, 128.3 (2 C), 128.1
(2 C), 123.7, 109.8, 94.7, 85.4, 83.6, 83.3, 75.2, 74.2, 72.4, 67.0,
26.9, 25.4, 20.9, 20.8 ppm. MS (API-ES+): m/z = 423.3 [M +
Na]+, 401.2 [M + 1]+. C22H24O7 (400.42): calcd. C 65.99, H 6.04;
found C 66.14, H 6.17.
1
Compound 22a: Iodo-exo-glycal 7 (100 mg, 0.15 mmol) and phenyl-
acetylene (14; 18 µL, 0.16 mmol) were treated according to general
method D. After purification by flash chromatography (hexane/
EtOAc, 90:10), compound 22a was obtained as a colorless oil
(79 mg, 83%). [α]2D5 = –16.2 (c = 1.0, CHCl3). 1H NMR (300 MHz,
Compound 23b: Bromo-exo-glycal 9a (57 mg, 0.15 mmol) and tri-
methylsilylacetylene (15; 22 µL, 0.16 mmol) were treated according
CDCl3): δ = 7.44–7.24 (m, 25 H, Ph), 5.13 (s, 1 H, 1Ј-H), 4.91 (d, to general method D. After purification by flash chromatography
J = 11.0 Hz, 1 H), 4.81–4.58 (m, 6 H, O-CH2-Ph), 4.46 (d, J =
12.7 Hz, 1 H), 4.24 (t, J = 8.0 Hz, 1 H, 5-H), 4.11 (d, J = 3.0 Hz,
(hexane/EtOAc, 70:30), compound 23b was obtained as a colorless
oil (52 mg, 87%). In a different experiment, iodo-exo-glycal 9b
1 H, 2-H), 3.94–3.88 (m, 3 H), 3.74 (dd, J = 8.0, 3.0 Hz, 1 H, 3- (64 mg, 0.15 mmol) and 15 (22 µL, 0.16 mmol) were treated accord-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.7, 138.3, 138.1,
138.0, 137.8, 131.4 (2 C), 128.4 (2 C), 128.3 (4 C), 128.1 (2 C),
127.9 (3 C), 127.8 (5 C), 127.7 (4 C), 127.6 (2 C), 127.5, 123.9, 93.6,
90.7, 84.4, 81.6, 78.9, 76.7, 74.3, 74.1, 74.0, 73.5, 72.8, 68.8 ppm.
MS (API-ES+): m/z = 637.1 [M + 1]+, 659.2 [M + Na]+. C43H40O5
(636.77): calcd. C 81.11, H 6.33; found C 81.01, H 6.27.
ing to general method D to afford 23b (53.5 mg, 90%). [α]2D5
=
+21.0 (c = 0.15, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.48
(d, J = 1.1 Hz, 1 H, 2-H), 5.33 (dd, J = 3.6, 1.1 Hz, 1 H, 3-H), 4.98
(s, 1 H, 1Ј-H), 4.57 (dd, J = 7.6, 3.6 Hz, 1 H, 4-H), 4.36 (ddd, J =
7.6, 5.8, 5.3 Hz, 1 H, 5-H), 4.15 (m, 2 H, 2 6-H), 2.12 (s, 3 H, Me),
2.09 (s, 3 H, Me), 1.46 (s, 3 H, Me), 1.37 (s 3 H, Me), 0.20 (s, 9 H,
TMS) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.3, 169.1, 162.5,
109.7, 98.9, 85.2, 83.2, 82.2, 75.1, 74.1, 72.3, 66.7, 26.8, 25.5, 20.9
(2 C), 0.2 (3 C) ppm. MS (API-ES+): m/z = 419.0 [M + Na]+, 397
[M + 1]+. C19H28O7Si (396.50): calcd. C 57.55, H 7.12; found C
57.71, H 7.17.
Compound 22b: Iodo-exo-glycal 7 (100 mg, 0.15 mmol) and tri-
methylsilylacetylene (15; 22 µL, 0.16 mmol) were treated according
to general method D. After purification by flash chromatography
(hexane/EtOAc, 95:5), compound 22b was obtained as a colorless
oil (93 mg, 92%). [α]25 = –12.3 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.35–7.15 (m, 20 H, Ph), 4.88 (s, 1 H, 1Ј- Compound 23c: Bromo-exo-glycal 9a (57 mg, 0.15 mmol) and 1-do-
H), 4.81–4.35 (m, 8 H, OCH2Ph), 4.16 (t, J = 8.4 Hz, 1 H, 5-H), decyne (16; 36 µL, 0.16 mmol) were treated according to general
3.96 (d, J = 3.0 Hz, 1 H, 2-H), 3.84–3.80 (m, 3 H), 3.63 (dd, J = method D. After purification by flash chromatography (hexane/
8.4, 3.0 Hz, 1 H, 3-H), 0.14 (s, 9 H, TMS) ppm. 13C NMR
EtOAc, 60:40), compound 23c was obtained as a colorless oil
(75 MHz, CDCl3): δ = 159.5, 138.3, 138.2, 138.0, 137.6, 128.4 (2 (65 mg, 93%). In a different experiment, iodo-exo-glycal 9b (64 mg,
C), 128.3 (2 C), 128.0 (4 C), 127.9 (2 C), 127.8 (7 C), 127.7, 127.6,
127.5, 99.2 (2 C), 93.3, 80.5, 80.0, 74.5, 74.2, 73.6, 73.4, 71.7, 69.8,
0.15 mmol) and 16 (22 µL, 0.16 mmol) were converted into 23c by
following general method D. After workup and purification similar
2916
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2910–2920

Sonogashira Couplings of Halo- and Epoxy-Halo-exo-Glycals
to that above, 23c was obtained (67 mg, 96%). [α]2D5 = +23.4 (c =
0.83, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.45 (s, 1 H, 2-H),
5.29 (d, J = 3.9 Hz, 1 H, 3-H), 4.90 (s, 1 H, 1Ј-H), 4.46 (dd, J =
7.9,3.9 Hz, 1 H, 4-H), 4.32 (ddd, J = 7.9, 6.3, 5.4 Hz, 1 H, 5-H),
(300 MHz, CDCl3): δ = 7.43–7.40 (m, 2 H, Ph), 7.28–7.26 (m, 3 H,
Ph), 5.41 (d, J = 5.8 Hz, 1 H, 2-H), 5.31 (s, 1 H, 1Ј-H), 4.81 (dd,
J = 5.8, 4.1 Hz, 1 H, 3-H), 4.45 (m, 1 H, 5-H), 4.15–4.04 (m, 3 H,
2 6-H and 4-H), 1.48 (s, 3 H, Me), 1.45 (s, 3 H, Me), 1.41 (s, 3 H,
4.12 (m, 2 H, 2 6-H), 2.27 (dt, J = 6.9, 2.1 Hz, 2 H), 2.09 (s, 3 H, Me), 1.38 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ =
Me), 2.06 (s, 3 H, Me), 1.42 (s, 3 H, Me), 1.33 (s, 3 H, Me), 1.11
166.0, 131.1 (2 C), 128.1 (2 C), 127.5, 123.9, 113.5, 109.3, 92.4,
(m, 16 H, 8 CH2), 0.87 (t, J = 6.0 Hz, 3 H, Me) ppm. 13C NMR 85.1, 84.7, 83.3, 79.3, 77.9, 72.9, 66.3, 26.8, 26.5, 25.6, 25.0 ppm.
(75 MHz, CDCl3): δ = 169.5, 169.3, 160.6, 109.8, 96.3, 86.0, 83.0,
75.1, 74.4, 74.3, 72.4, 67.2, 32.1, 29.8 (2 C), 29.5, 29.4, 29.1, 28.9,
27.0, 25.5, 21.9, 21.1, 21.0, 20.0, 14.3 ppm. MS (API-ES+): m/z =
465.6 [M+ H]+. C26H40O7 (464.59): calcd. C 67.22, H 8.68; found
C 67.03, H 8.49.
MS (API-ES+): m/z = 357.2 [M + 1]+. C21H24O5 (356.41): calcd.
C 70.77, H 6.79; found C 57.61, H 6.66.
Compound 25b: Bromo-exo-glycal 11 (50 mg, 0.15 mmol) and tri-
methylsilylacetylene (15; 22 µL, 0.16 mmol) were treated according
to general method D. After purification by flash chromatography
(hexane/EtOAc, 75:25), compound 25b was obtained as a colorless
oil (37 mg, 71%). [α]2D5 = +41.3 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 5.71 (d, J = 1.0 Hz, 1 H, 1Ј-H), 5.14 (dd,
J = 5.9, 1.0 Hz, 1 H, 2-H), 4.80 (dd, J = 5.9, 3.8 Hz, 1 H, 3-H),
4.43 (m, 1 H, 5-H), 4.14–4.02 (m, 3 H, 4-H and 2 6-H), 1.48 (s, 6
H, Me), 1.44 (s, 3 H, 2 Me), 1.38 (s, 3 H, Me), 0.18 (m, 9 H,
TMS) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.6, 113.4, 109.3
(2 C), 99.5, 98.9, 82.8, 79.9, 79.1, 73.0, 66.5, 26.8, 26.5, 25.5, 25.1,
0.0 (3 C) ppm. MS (API-ES+): m/z = 353.2 [M + 1]+. C18H28O5Si
(352.49): calcd. C 61.33, H 8.01; found C 61.22, H 7.94.
Compound 24a: Bromo-exo-glycal 10b (50 mg, 0.15 mmol) and
phenylacetylene (14; 18 µL, 0.16 mmol) were treated according to
general method D. After purification by flash chromatography
(hexane/EtOAc, 80:20), compound 24a was obtained as a colorless
oil (41 mg, 76%). [α]2D5 = +109.0 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.42–7.39 (m, 2 H, Ph), 7.29–7.26 (m, 3 H,
Ph), 5.17 (d, J = 5.6 Hz, 1 H, 2-H), 4.96 (s, 1 H, 1Ј-H), 4.81 (dd,
J = 5.6, 3.7 Hz, 1 H, 3-H), 4.51 (ddd, J = 7.7, 6.0, 4.9 Hz, 1 H, 5-
H), 4.27 (dd, J = 7.7, 3.6 Hz, 1 H, 4-H), 4.20–4.18 (m, 2 H, 2 6-
H), 1.49 (s, 3 H, Me), 1.48 (s, 3 H, Me), 1.40 (s, 6 H, 2 Me) ppm.
13C NMR (75 MHz, CDCl3): δ = 154.8, 131.2 (2 C), 128.2 (2 C),
127.7, 123.9, 114.0, 109.5, 93.7, 84.1, 83.2, 82.3, 80.3, 78.2, 73.1,
66.5, 27.0, 26.9, 26.0, 25.4 ppm. MS (API-ES+): m/z = 357.2 [M +
1]+. C21H24O5 (356.41): calcd. C 70.77, H 6.79; found C 70.94, H
6.81.
Compound 25c: Bromo-exo-glycal 11 (50 mg, 0.15 mmol) and 1-do-
decyne (16; 36 µL, 0.16 mmol) were treated according to general
method D. After stirring for 14 h and purification by flash
chromatography (hexane/EtOAc, 80:20), compound 25c was ob-
tained (19 mg, 31%) followed by recovered starting material 11
(22 mg, 44%). Data for 25c: [α]2D5 = +32.7 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 5.32 (dd, J = 6.0, 1.3 Hz, 1 H, 2-
H), 5.11 (d, J = 1.3 Hz, 1 H, 1Ј-H), 4.78 (dd, J = 6.0, 3.9 Hz, 1 H,
3-H), 4.42 (ddd, J = 7.3, 6.1, 4.6 Hz, 1 H, 5-H), 4.11 (dd, J = 9.0,
6.1 Hz, 1 H, 6a-H), 4.05 (dd, J = 9.0, 4.6 Hz, 1 H, 6b-H), 4.01 (dd,
J = 7.3, 3.9 Hz, 1 H, 4-H), 2.32 (dt, J = 7.1, 2.2 Hz, 2 H), 1.51 (m,
2 H), 1.47 (s, 3 H, Me), 1.44 (s, 3 H, Me), 1.40 (s, 3 H, Me), 1.38
(s, 3 H, Me), 1.25 (m, 14 H), 0.87 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 164.6, 113.4, 109.3, 93.4, 86.1, 83.1,
79.0, 78.0, 74.9, 73.0, 66.4, 31.9, 29.6 (2 C), 29.3, 29.2, 28.9, 28.8,
26.8, 26.4, 25.5, 25.1, 22.6, 19.7, 14.1 ppm. MS (API-ES+): m/z =
437.3 [M + NH4]+. C25H40O5 (420.58): calcd. C 71.39, H 9.59;
found C 71.15, H 9.33.
Compound 24b: Bromo-exo-glycal 10b (50 mg, 0.15 mmol) and tri-
methylsilylacetylene (15; 22 µL, 0.16 mmol) were treated according
to general method D. After purification by flash chromatography
(hexane/EtOAc, 75:25), compound 24b was obtained as a colorless
oil (39 mg, 74%). [α]2D5 = +104.3 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 5.35 (d, J = 0.9 Hz, 1 H, 1Ј-H), 5.14 (dd,
J = 5.7, 0.9 Hz, 1 H, 2-H), 4.89 (dd, J = 5.7, 3.8 Hz, 1 H, 3-H),
4.50 (m, 1 H, 5-H), 4.23–4.18 (m, 3 H, 4-H and 2 6-H), 1.49 (s, 6
H, 2 Me), 1.43 (s, 3 H, Me), 1.42 (s, 3 H, Me), 0.22 (m, 9 H,
TMS) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.4, 114.2, 109.5
(2 C), 99.5, 98.9, 82.8, 79.9, 79.1, 73.0, 66.5, 26.9, 26.8, 25.9, 25.3,
0.1 (3 C) ppm. MS (API-ES+): m/z = 353.2 [M + 1]+. C18H28O5Si
(352.49): calcd. C 61.33, H 8.01; found C 61.51, H 8.12.
Compound 24c: Bromo-exo-glycal 10b (50 mg, 0.15 mmol) and 1-
dodecyne (16; 36 µL, 0.16 mmol) were treated according to general
method D. After stirring for 12 h and purification by flash
chromatography (hexane/EtOAc, 80:20), compound 24c was ob-
tained (38 mg, 60%) followed by recovered starting material 10b
(8 mg, 16%). Data for 24c: [α]2D5 = +107.9 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 5.09 (d, J = 5.6 Hz, 1 H, 2-H), 4.77
(dd, J = 5.6, 3.8 Hz, 1 H, 3-H), 4.73 (m, 1 H, 1Ј-H), 4.47 (ddd, J
= 7.8, 5.8, 4.6 Hz, 1 H, 5-H), 4.18–4.14 (m, 3 H, 2 6-H and 4-H),
2.32 (dt, J = 6.9, 2.2 Hz, 2 H), 1.55–1.49 (m, 2 H), 1.47 (s, 3 H,
Me), 1.46 (s, 3 H, Me), 1.39 (s, 3 H, Me), 1.38 (s, 3 H, Me), 1.26
(m, 14 H), 0.88 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 163.5, 113.7, 109.4, 94.8, 83.0, 82.9, 80.1, 78.2, 74.4,
73.0, 66.5, 31.8, 29.5, 29.4, 29.3, 29.1, 28.8, 28.7, 26.9 (2 C), 25.9,
25.3, 22.6, 19.7, 14.0 ppm. MS (API-ES+): m/z = 421.3 [M + 1]+,
443.2 [M + Na]+. C25H40O5 (420.58): calcd. C 71.39, H 9.59; found
C 71.27, H 9.43.
Compounds 26a and 27a: Bromo-exo-glycal 12 (100 mg, 0.24 mmol)
and phenylacetylene (14; 28 µL, 0.26 mmol) were treated according
to general method D. Purification by flash chromatography (hex-
ane/EtOAc, 90:10) gave compound 27a (28 mg, 24%) followed by
compound 26a as an inseparable 4:1 unassigned Z/E mixture
(41 mg, 39%). MS (API-ES+): m/z = 434.0 [M]+, 436.0 [M + 2].+
Data for 26a, major isomer: 1H NMR (300 MHz, CDCl3): δ =
7.48–7.38 (m, 2 H, Ph), 7.33–7.31 (m, 3 H, Ph), 5.35 (d, J = 5.8 Hz,
1 H, 2-H), 4.88 (dd, J = 5.8, 3.7 Hz, 1 H, 3-H), 4.51 (m, 1 H, 5-
H), 4.24 (dd, J = 7.8, 3.7 Hz, 1 H, 4-H), 4.17 (d, J = 5.1 Hz, 2 H,
2 6-H), 1.49 (s, 3 H, Me), 1.48 (s, 3 H, Me), 1.43 (s, 3 H, Me), 1.41
(s, 3 H, Me) ppm. Selected peaks for 26a, minor isomer: 5.40 (d, J
= 5.8 Hz, 1 H, 2-H), 4.93 (dd, J = 5.8, 3.7 Hz, 1 H, 3-H), 1.51 (s,
3 H, Me) ppm. Data for 27a: 1H NMR (300 MHz, CDCl3): δ =
7.52–7.46 (m, 4 H, Ph), 7.34–7.26 (m, 6 H, Ph), 5.52 (d, J = 5.9 Hz,
1 H, 2-H), 4.89 (dd, J = 5.9, 3.9 Hz, 1 H, 3-H), 4.55 (ddd, J = 7.6,
5.9, 4.6 Hz, 1 H, 5-H), 4.32 (dd, J = 7.6, 3.9 Hz, 1 H, 4-H), 4.22–
Compound 25a: Bromo-exo-glycal 11 (50 mg, 0.15 mmol) and phen- 4.17 (m, 2 H, 2 6-H), 1.51 (s, 3 H, Me), 1.50 (s, 3 H, Me), 1.45 (s,
ylacetylene (14; 18 µL, 0.16 mmol) were treated according to gene-
3 H, Me), 1.42 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ
ral method D. After purification by flash chromatography (hexane/
= 169.2, 131.4 (2 C), 128.2 (6 C), 128.1, 127.9, 123.5, 123.4, 113.8,
EtOAc, 80:20), compound 25b was obtained as a colorless oil 109.6, 93.1, 91.4, 84.3, 83.7, 83.0, 82.5, 80.3, 78.0, 72.9, 66.4, 26.9,
(43 mg, 80%). [α]2D5 = +249.7 (c = 1.0, CHCl3). 1H NMR 26.8, 25.9, 25.3 ppm. MS (API-ES+): m/z = 457.2 [M + 1]+.
Eur. J. Org. Chem. 2010, 2910–2920
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2917

A. M. Gómez, A. Barrio, A. Pedregosa, C. Uriel, S. Valverde, J. C. López
FULL PAPER
C29H28O5 (456.19): calcd. C 76.30, H 6.18; found C 76.41, H 6.33.
Isolated compound 26a could be converted into compound 27a in
50% yield by following general method D.
127.3 (2 C), 109.6, 91.0, 87.0, 86.6, 80.1, 73.0, 70.1, 67.4, 38.3, 26.9,
25.1 ppm. MS (API-ES+): m/z = 301.2 [M + 1]+, 323.1 [M + Na]+.
Data for 31a, minor isomer: 1H NMR (300 MHz, CDCl3): δ = 7.41
(m, 2 H), 7.28 (m, 3 H), 5.31 (s, 1 H, 1Ј-H), 4.95 (br. s., 1 H, 3-H),
4.38 (ddd, J = 8.2, 6.2, 5.1 Hz, 1 H, 5-H), 4.30 (dd, J = 8.2, 6.7 Hz,
1 H, 4-H), 4.18 (dd, J = 8.6, 6.2 Hz, 1 H, 6a-H), 4.04 (dd, J = 8.6,
5.1 Hz, 1 H, 6b-H), 3.30 (d, J = 3.3 Hz, 2 H, 2-H), 1.47 (s, 3 H,
Me), 1.39 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ =
159.5, 131.6 (2 C), 130.9, 128.2 (2 C), 128.1, 109.3, 100.33, 85.9,
83.5, 82.4, 73.6, 72.9, 66.9, 26.9, 25.2, 19.7 ppm. MS (API-ES+):
m/z = 301.0 [M + 1]+, 323.3 [M + Na]+.
Compounds 26b and 27b: Bromo-exo-glycal 12 (100 mg, 0.24 mmol)
and trimethylsilylacetylene (15; 37 µL, 0.26 mmol) were treated ac-
cording to general method D. Purification by flash chromatography
(hexane/EtOAc, 95:5) gave compounds 27b (39 mg, 37%) followed
by compound 26b as an inseparable mixture of Z and E isomers
(38 mg, 37%). Data for 26b, major isomer: 1H NMR (300 MHz,
CDCl3): δ = 5.28 (d, J = 5.7 Hz, 1 H, 2-H), 4.83 (dd, J = 5.7,
3.6 Hz, 1 H, 3-H), 4.47 (m, 1 H, 5-H), 4.23 (dd, J = 7.2, 3.6 Hz, 1
H, 4-H), 4.13 (m, 2 H, 2 6-H), 1.48 (s, 3 H, Me), 1.46 (s, 3 H, Me),
1.41 (s, 3 H, Me), 1.39 (s, 3 H, Me), 0.20 (m, 9 H, TMS) ppm. 13C
NMR (75 MHz, CDCl3): δ = 161.6, 113.8, 109.6, 102.7, 98.4, 83.8,
80.9, 78.2, 72.9, 66.2, 26.9, 26.6, 25.7, 25.4, 0.0 (3 C) ppm. MS
(API-ES+): m/z = 431.1 [M]+, 433.1 [M + 2]+. Data for 27b: 1H
NMR (300 MHz, CDCl3): δ = 5.09 (dd, J = 5.7, 0.9 Hz, 1 H, 2-
H), 4.77 (m, 1 H, 3-H), 4.47 (m, 1 H, 5-H), 4.27 (dd, J = 7.5,
3.9 Hz, 1 H, 4-H), 4.15 (d, J = 5.4 Hz, 2 H, 2 6-H), 1.47 (s, 6 H, 2
Me), 1.40 (s, 3 H, Me), 1.38 (s, 3 H, Me), 0.18 (m, 18 H, TMS)
ppm. MS (API-ES+): m/z = 449.3 [M]+.
Compound 31b: Bromide 8b (100 mg, 0.36 mmol) and trimethyl-
silylacetylene (15; 54 µL, 0.40 mmol) were treated according to the
general procedure. After purification by flash chromatography
(hexane/EtOAc, 80:20), compound 31b was obtained as a 1:1 sepa-
rable but unassigned mixture of compounds 31b. Data for 31b, iso-
mer 1: 1H NMR (300 MHz, CDCl3): δ = 5.94 (br. s, 1 H, 1Ј-H),
4.55 (m, 1 H, 3-H), 4.35 (ddd, J = 8.5, 6.1, 4.6 Hz, 1 H, 5-H), 4.17
(dd, J = 8.8, 6.1 Hz, 1 H, 4-H), 4.12 (dd, J = 8.5, 3.4 Hz, 1 H),
4.01 (dd, J = 8.8, 4.4 Hz, 1 H), 2.97 (t, J = 1.7 Hz, 1 H), 2.94 (dd,
J = 5.1, 2.4 Hz, 1 H, 2b-H), 1.44 (s, 3 H, Me), 1.37 (s, 3 H, Me),
0.17 (s, 9 H, TMS) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.3,
109.9, 102.9, 95.6, 87.3, 80.4, 73.2, 70.3, 67.6, 38.5, 27.1, 25.3, 0.4
(3 C) ppm. MS (API-ES+): m/z = 297.1 [M + 1]+, 319.0 [M + Na]+.
Data for 31b, isomer 2: 1H NMR (300 MHz, CDCl3): δ = 4.55 (m,
2 H, 3-H, 1Ј-H), 4.41 (ddd, J = 8.3, 6.1, 4.9 Hz, 1 H, 5-H), 4.22
(dd, J = 9.0, 6.1 Hz, 1 H, 6a-H), 4.19 (dd, J = 8.3, 3.2 Hz, 1 H, 4-
H), 4.10 (dd, J = 9.0, 4.9 Hz, 1 H, 6b-H), 2.87 (ddd, J = 17.0, 5.4,
2.2 Hz, 1 H, 2a-H), 2.65 (d, J = 17.3 Hz, 1 H, 2b-H), 1.44 (s, 3 H,
Me), 1.38 (s, 3 H, Me), 0.18 (s, 9 H, TMS) ppm. 13C NMR
(75 MHz, CDCl3): δ = 169.3, 109.9, 102.9, 95.6, 87.3, 80.4, 73.2,
70.3, 67.6, 38.5, 27.1, 25.3, 0.4 (3 C) ppm. MS (API-ES+): m/z =
297.1 [M + 1]+.
Compound 26c: Bromo-exo-glycal 12 (100 mg, 0.24 mmol) and 1-
dodecyne (16; 58 µL, 0.26 mmol) were treated according to general
method D. Purification by flash chromatography (hexane/EtOAc,
80:20) gave compounds 26c as an inseparable 1:1 mixture of Z and
E isomers (37 mg, 31%) followed by recovered starting material 12
(32 mg, 30%). Data for 26c: 1H NMR (300 MHz, CDCl3): δ = 5.29
(d, J = 5.9 Hz, 1 H, 2-H), 4.88 (dd, J = 5.9, 3.8 Hz, 0.5 H, 3-H),
4.83 (dd, J = 5.9, 3.8 Hz, 0.5 H, 3-H), 4.47 (ddd, J = 9.1, 5.4,
4.2 Hz, 1 H, 5-H), 4.18–4.09 (m, 3 H), 2.41 (t, J = 6.8 Hz, 2 H),
1.61–1.49 (m, 2 H), 1.48 (s, 3 H, Me), 1.47–1.44 (m, 4 H), 1.42 (s,
3 H), 1.40 (s, 3 H), 1.39 (s, 3 H), 1.26 (br. s, 10 H), 0.88 (t, J =
6.8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.4 (2 C),
113.7,113.6, 109.6 (2 C), 99.0, 96.8, 83.7, 83.6, 80.8, 79.9, 79.4,
79.1, 78.5, 77.2, 75.8, 75.5, 72.9, 66.5 (2 C), 31.9 (2 C), 29.6 (4 C),
29.3 (2 C), 29.1 (2 C), 28.8, 28.7, 28.5, 28.4, 26.9 (2 C), 26.6 (2 C),
25.9, 25.8, 25.3 (2 C), 22.7 (2 C), 19.8 (2 C), 14.1 (2 C) ppm. MS
(API-ES+): m/z = 521.1 [M + Na]+, 523.1 [M + Na + 2]+.
Compound 31c: Bromide 8b (100 mg, 0.36 mmol) and 1-dodecyne
(16; 92 µL, 0.40 mmol) were treated according to the general pro-
cedure. After purification by flash chromatography (hexane/EtOAc,
60:40), compound 31c was obtained as a 1:1 inseparable but unas-
signed mixture of compounds (48 mg, 37%) followed by amino
alcohol 32. Data for 31c: 1H NMR (300 MHz, CDCl3): δ = 5.01
(m, 1 H), 4.59 (m, 1 H), 4.49 (m, 1 H), 4.22 (m, 2 H), 4.17 (dd, J
= 8.5, 4.6 Hz, 1 H, 2-H), 3.02 (m, 1 H), 2.69 (m, 1 H), 1.39 (m, 16
H), 1.37 (s, 3 H, Me), 0.85 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 155.2, 109.6, 106.7, 85.4, 80.7, 79.9, 73.5, 66.9, 60.7,
45.1, 31.9 (2 C), 29.6, 27.1 (2 C), 26.3, 25.5, 24.9, 23.0 (2 C), 14.5
(2 C) ppm. MS (API-ES+): m/z = 365.1 [M + 1]+. Data for 32:
General Procedure for the Preparation of 2-Deoxy Derivatives 31:
To a thoroughly degassed (argon, 10 min) solution of 2,3-anhydro-
bromo-exo-glycal 8b (0.1 mmol) in Et2NH (10 mL/mmol) was
added successively Pd(PPh3)4 (5mol-%) and CuI (0.01 equiv.). The
reaction was then stirred at room temperature for 5 min, after
which time a degassed solution of the corresponding alkyne dis-
solved in Et2NH was added. The reaction mixture was stirred until
TLC showed complete disappearance of the starting material. The
solution was then diluted with ethyl acetate and washed success-
ively with saturated NH4Cl and brine. The organic layer was dried
(magnesium sulfate) and evaporated to furnish a residue, which was
purified by flash chromatography (hexane/EtOAc).
1
[α]2D5 = +45.1 (c = 0.5, CHCl3). H NMR (300 MHz, CDCl3): δ =
5.16 (d, J = 1.2 Hz, 1 H, 1Ј-H), 4.52 (dd, J = 4.6, 2.6 Hz, 1 H, 3-
H), 4.34 (m, 2 H), 4.20 (dd, J = 8.8, 5.7 Hz, 1 H, 6a-H), 4.10 (dd,
J = 8.6, 4.4 Hz, 1 H, 6b-H), 3.82 (dd, J = 2.6, 1.0 Hz, 1 H, 2-H),
3.60 (q, J = 6.9 Hz, 4 H, 2 NEt2), 1.47 (s, 3 H, Me), 1.38 (s, 3 H,
Me), 1.06 (t, J = 6.9 Hz, 6 H, 2 NEt2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 157.1, 109.9, 84.0, 77.1, 73.6, 72.9, 71.0, 67.6, 44.6,
26.9, 25.3, 13.4 ppm. MS (API-ES+): m/z = 351 [M + 1]+.
C14H24BrNO4 (349.2): calcd. C 48.01, H 6.91, N 4.00; found C
48.22, H 6.94, N 3.89.
Compound 31a: Bromide 8b (100 mg, 0.36 mmol) and phenylacetyl-
ene (14; 45 µL, 0.40 mmol) were treated according to the general
procedure. After purification by flash chromatography (hexane/
EtOAc, 60:40), compound 31a was obtained as a 1.2:1 separable
but unassigned mixture of compounds 31a: Data for 31a, major
isomer: H NMR (300 MHz, CDCl3): δ = 7.39 (m, 2 H), 7.27 (m,
Compound 33:[51] [α]2D5 = +4.5 (c = 0.4, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 5.13 (br. s, 1 H, 1Ј-H), 4.53 (dd, J = 4.0,
1.8 Hz, 1 H, 3-H), 4.32 (m, 2 H), 4.19 (dd, J = 8.8, 5.7 Hz, 1 H,
6a-H), 4.06 (dd, J = 8.8, 4.6 Hz, 1 H, 6b-H), 3.47 (br. s, 1 H, 2-H),
2.48 (m, 4 H), 1.55 (m, 6 H), 1.46 (s, 3 H, Me), 1.37 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 156.0, 109.7, 85.1, 78.0, 75.3,
73.1, 72.7, 67.7, 51.8 (2 C), 27.2, 26.4 (2 C), 25.6, 24.5 ppm. MS
1
3 H), 5.14 (br. s, 1 H, 1Ј-H), 4.59 (t, J = 4.3 Hz, 1 H, 3-H), 4.38
(ddd, J = 8.6, 6.2, 4.7 Hz, 1 H, 5-H), 4.19 (dd, J = 8.6, 5.8 Hz, 1
H, 6a-H), 4.16 (dd, J = 8.6, 3.5 Hz, 1 H, 4-H), 4.04 (dd, J = 8.6,
4.7 Hz, 1 H, 6b-H), 3.09 (t, J = 17.9 Hz, 1 H, 2a-H), 2.98 (dd, J =
17.9, 2.7 Hz, 1 H, 2b-H), 1.45 (s, 3 H, Me), 1.37 (s, 3 H, Me) ppm.
13C NMR (75 MHz, CDCl3): δ = 167.7, 130.8 (2 C), 128.2 (2 C),
2918
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2910–2920

Sonogashira Couplings of Halo- and Epoxy-Halo-exo-Glycals
(API-ES+): m/z = 362 [M]+, 364 [M + 2]+. C15H24BrNO4 (361.26):
calcd. C 49.73, H 6.68, Br 22.06, N 3.87; found C 49.56, H 6.64,
Br 21.97, N 3.79.
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Acknowledgments
This research has been supported with funds from the Ministerio
de Ciencia y Tecnología (Grants CTQ-2006-C03 and CTQ2009-
10343) and from the Comunidad de Madrid (Grant S2009/PPQ-
1752). A.P. is thankful to Janssen-Cilag S.A. for financial support.
A.B. is grateful to Consejo Superior de Investigaciones Científicas
(CSIC) for a predoctoral scholarship.
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Published Online: April 15, 2010
2920
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2910–2920