Metal-catalyzed cycloisomerization and tandem oxycyclization/hydroxylation of alkynols: Synthesis of nonfused, spiranic and fused oxabicyclic β-lactams

Article abstract of DOI:10.1002/ejoc.201000710

2-Azetidinone-tethered alkynols, readily prepared from the corresponding aldehydes or ketones, were used as starting materials for the oxycyclization reaction catalyzed by precious metals. AgOAc exclusively affords dihydrofurans, methylenetetrahydrofurans, or methylenetetrahydro-2H-pyrans through specific 5-endo, 5-exo, or 6-exo pathways, respectively. Interestingly, in the presence of a catalytic amount: of Pt^II or Au^III salts, cyclization reactions occurred preferentially through a tandem oxycyclization/hydroxylation of alkynols to afford a variety of nonfused, spiranic and fused oxabicyclic β-lactams in moderate to high yields. Besides, it has been observed that the tandem gold-catalyzed cycloetherification/hydroxylation of a methoxymethyl alkynyl ether can be accomplished.

Full text of DOI:10.1002/ejoc.201000710

FULL PAPER
DOI: 10.1002/ejoc.201000710
Metal-Catalyzed Cycloisomerization and Tandem Oxycyclization/
Hydroxylation of Alkynols: Synthesis of Nonfused, Spiranic and Fused
Oxabicyclic β-Lactams
Benito Alcaide,*[a] Pedro Almendros,*[b] Teresa Martínez del Campo,[a] and
Rocío Carrascosa[a]
Keywords: Alkynes / Cyclization / Gold / Lactams / Platinum
2-Azetidinone-tethered alkynols, readily prepared from the
corresponding aldehydes or ketones, were used as starting
materials for the oxycyclization reaction catalyzed by pre-
cious metals. AgOAc exclusively affords dihydrofurans,
methylenetetrahydrofurans, or methylenetetrahydro-2H-pyr-
ans through specific 5-endo, 5-exo, or 6-exo pathways,
respectively. Interestingly, in the presence of a catalytic
amount of PtII or AuIII salts, cyclization reactions occurred
preferentially through a tandem oxycyclization/hydroxyl-
ation of alkynols to afford a variety of nonfused, spiranic and
fused oxabicyclic β-lactams in moderate to high yields. Be-
sides, it has been observed that the tandem gold-catalyzed
cycloetherification/hydroxylation of a methoxymethyl alk-
ynyl ether can be accomplished.
Introduction
Results and Discussion
Precursors for the nonfused and spiranic oxacycles,
homopropargylic alcohols 2a–c and 5a–c, were made start-
ing from 4-oxoazetidine-2-carbaldehydes 1a–c (Scheme 1)
and azetidine-2,3-diones 4a–c (Scheme 2) through regio-
The structural motifs of tetrahydrofuran and pyran are
present in a wide variety of natural products and biolo-
gically relevant compounds. Therefore, the development of
synthetic methods for their construction has attracted much
attention.[1] Among the possibilities, transition-metal-
assisted intramolecular addition of oxygen nucleophiles
across a carbon–carbon triple bond is intriguing from the
point of view of regioselectivity as well as it being one of
the most rapid and convenient methods for the preparation
of oxacycles.[2] However, relatively few methods for the con-
struction of tetrahydrofuran- or pyran-based β-lactams are
available.[3] The highly selective properties of metals would
seem to recommend their application to the preparation of
highly functionalized β-lactams. Our combined interest in
the area of β-lactams and the synthetic use of metals[4] led
us to explore metal-mediated alkynol cyclization strategies
for developing a novel and versatile entry to diversely func-
tionalized nonfused, spiranic and fused oxabicyclic β-lac-
tams as an alternative to existing methodologies.
Scheme 1. Zinc-mediated Barbier-type carbonyl propargylation of
aldehydes 1 followed by Sonogashira functionalization. Synthesis
of alkynyl-β-lactams 2 and 3. Reagents and conditions: (i) Zn,
THF, NH4Cl (aq. sat.), room temp., 2a: 12 h; 2b: 9 h; 2c: 10 h.
(ii) PhI, Pd(PPh3)2Cl2 (1 mol-%), CuI (2 mol-%), Et3N, MeCN,
room temp., 3a: 48 h; 3b: 22 h; 3c: 30 h. PMP = 4-MeOC6H4.
[a] Grupo de Lactamas y Heterociclos Bioactivos, Departamento
de Química Orgánica I, Unidad Asociada al CSIC, Facultad de
Química, Universidad Complutense de Madrid,
28040 Madrid, Spain
Fax: +34-91-39444103
E-mail: alcaideb@quim.ucm.es
Scheme 2. Zinc-mediated Barbier-type carbonyl propargylation of
ketones 4 followed by Sonogashira functionalization. Synthesis of
alkynyl-β-lactams 5 and 6. Reagents and conditions: (i) Zn, THF,
NH4Cl (aq. sat.), room temp., 5a: 12 h; 5b: 24 h; 5c: 20 h. (ii) PhI,
Pd(PPh3)2Cl2 (1 mol-%), CuI (2 mol-%), Et3N, MeCN, room temp.,
6a: 19 h; 6b: 19 h; 6c: 23 h. PMP = 4-MeOC6H4. Diox = (S)-2,2-
dimethyl-1,3-dioxolan-4-yl. Tol = 4-MeC6H4.
[b] Instituto de Química Orgánica General, Consejo Superior de
Investigaciones Científicas, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-91-5644853
E-mail: Palmendrosb@iqog.csic.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000710.
View this journal online at
wileyonlinelibrary.com
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Nonfused, Spiranic and Fused Oxabicyclic β-Lactams
Scheme 3. Preparation of alkynols 9 and 10. Reagents and conditions: (i) THF, –78 °C, 1.5 h. (ii) nBuLi, THF, –78 °C, 5 h. (iii) (a)
Me2SO4, NaOH, TBAI, DCM/H2O, room temp., 3 h; (b) HCl (conc.), iPrOH/THF (1:1), room temp., 24 h. PMP = 4-MeOC6H4. MOM
= MeOCH2. TBAI = tetrabutylammonium iodide.
and stereocontrolled zinc-mediated Barbier-type carbonyl– sion of alkynols 3 into tetrahydrofuryl hemiacetals 14,
propargylation reaction in aqueous media.[5] Terminal al- water is required, and it probably comes from the trace
kynes 2 and 5 were functionalized as their corresponding amounts of water present in the solvent or the catalyst. Ad-
phenyl alkynols 3 and 6 by treatment with iodobenzene un- ditionally, it should be noted that PTSA has water in it and
der Sonogashira conditions (Schemes 1 and 2). Precursors the monohydrate is actually employed. Another difference
for the fused oxacycles, alkynols 9 and 10, were prepared between silver and gold/platinum catalysis is that the reac-
by the diastereoselective addition of magnesium or lithium tion conditions are basic for the silver catalysts, whereas the
acetylides to carbaldehyde 1d,[6] followed by protecting reaction conditions are acidic for the gold and platinum
group manipulation (Scheme 3). Starting alkynol 11 was catalysts, making further hydration highly likely. Qualitative
prepared by selective transformations of the hydroxy groups homonuclear NOE difference spectra allowed us to assign
of compound 2c, whereas phenyl alkynol 12 was available the stereochemistry at the newly formed stereocenter of
from precursor 11 and iodobenzene by using the Sonoga- tetrahydrofuryl hemiacetals 14.
shira protocol (Scheme 4).
Scheme 4. Preparation of alkynols 11 and 12. Reagents and con-
ditions: (i) (a) MOMCl, Hünig’s base, CH2Cl2, reflux, 12 h; (b)
NaOMe, MeOH, 0 °C, 5 h. (ii) PhI, Pd(PPh3)2Cl2 (1 mol-%),
CuI (2 mol-%), Et3N, MeCN, room temp., 19 h. PMP = 4-MeO-
C6H4. MOM = MeOCH2.
Our investigations began with alkynols 2a and 3a as
model substrates. Attempts to cyclize 2a by using gold or
platinum catalysts failed. However, reaction of terminal alk-
ynol 2a with silver acetate in the presence of triethylamine
afforded 2-azetidinone-tethered dihydrofuran 13a in a rea-
sonable 70% yield. The stage was thus set for the metal-
Scheme 5. Cycloetherification of 2-azetidinone-tethered homopro-
pargylic alcohols 2 and 3. Synthesis of nonfused tetrahydrofuryl
β-lactams 13 and 14. Reagents and conditions: (i) AgOAc, Et3N,
catalyzed cycloetherification reaction of phenyl alkynol 3a.
acetone, room temp., 13a: 48 h; 13b: 40 h. (ii) AuCl3 (5 mol-%),
Conversion into the corresponding dihydrofuran could not
be satisfied with silver promoters. Nicely, we found that un-
der the appropriate reactions conditions AuCl3 and
[PtCl2(CH2=CH2)]2 could be excellent catalyst for this pur-
pose. Extrapolation of the cycloetherification reaction to
the rest of alkynols 2 and 3 was easily achieved (Scheme 5).
PTSA (10 mol-%), CH2Cl2, room temp., 14a: 6 h; 14b: 5 h; 14c:
6 h. (iii) [PtCl2(CH2=CH2)]2 (1 mol-%), TDMPP (2 mol-%),
CH2Cl2, room temp., 14a: 5 h; 14b: 2.5 h; 14c: 3 h. PMP = 4-MeO-
C6H4. PTSA = p-toluenesulfonic acid. TDMPP = tris(2,6-dimeth-
oxyphenyl)phosphane.
A possible pathway for the gold- or platinum-catalyzed
Examples in Scheme 5 show that tetrahydrofuryl hemiacet- achievement of 2-azetidinone-tethered tetrahydrofuryl hemi-
als 14a–c are accessible as single isomers in good yields acetals 14 may initially involve the formation of π complex
through the gold- or particularly platinum-catalyzed tan- 15 through coordination of the gold or platinum chlorides
dem oxycyclization/hydroxylation reaction of 2-azetidi- to the triple bond of phenyl alkynols 3. Next, 5-endo oxy-
none-tethered homopropargylic alcohols. For the conver- metalation forms intermediates 16. Enol vinylmetal species
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B. Alcaide, P. Almendros, T. Martínez del Campo, R. Carrascosa
FULL PAPER
16 did not evolve through demetalation and proton transfer,
generating dihydrofuran 17 and releasing the metal catalyst.
By contrast, rearrangement (phosphane-catalyzed for Pt
and Brønsted acid catalyzed for Au) of species 16 generate
isomeric metalaoxocarbeniums 18, enhancing the electro-
philicity of the alkene moiety. Subsequent nucleophilic at-
tack of water to the benzylic position from the less hindered
face would form ate complex 19. Demetalation linked to
proton transfer liberate adduct 14 with concomitant regen-
eration of the PtII or AuIII species (Scheme 6).
Scheme 7. PtII-catalyzed tandem oxycyclization/hydroxylation reac-
tion of alkynol 3b. Reagents and conditions: (i) [PtCl2(CH2=
CH2)]2 (1 mol-%), TDMPP (2 mol-%), D2O (2 equiv.), CH2Cl2,
room temp., 2.5 h. TDMPP = tris(2,6-dimethoxyphenyl)phos-
phane.
To determine whether the conclusions with homoprop-
argylic alcohols 2 and 3 could be extrapolated to other alk-
ynols, we examined the series of tertiary carbinols 5a–c and
6a–c. Under similar conditions, except the use of heat for
Pt, spiranic β-lactams 20a–c and 21a–c were obtained as
single isomers in good yields (Scheme 8). One problem of
electrophilic metal catalysis is functional group compatibil-
ity in the presence of acid-sensitive protecting groups. The
gold-catalyzed hydroalkoxylation reaction of alkynol 6a
was troublesome because of the acid lability of the aceto-
nide moiety, indicating a better functional group compati-
bility of PtII-based catalyst as compared to the AuIII cata-
lyst.
Scheme 6. Mechanistic explanation for the metal-catalyzed tandem
oxycyclization/hydroxylation of homopropargylic alcohols 3.
With the aim of trapping the organometal intermediate
to confirm the mechanism of this reaction, we performed
deuterium labeling studies with deuterium oxide. When the
platinum-catalyzed tandem oxycyclization/hydroxylation of
homopropargylic alcohol 3b was carried out in the presence
of two equivalents of D2O, adduct 14b with additional deu-
terium incorporation at the C4 tetrahydrofuran carbon
(80% D) was achieved (Scheme 7). The fact that the plati-
num-catalyzed conversion of alkynol 3b into tetrahydro-
furyl hemiacetal 14b in the presence of two equivalents of
D2O afforded [4-D]-14b, as judged by the decrease of the
Scheme 8. Cycloetherification of 2-azetidinone-tethered homoprop-
argylic alcohols 5 and 6. Synthesis of spiranic tetrahydrofuryl β-
lactams 20–22. Reagents and conditions: (i) AgOAc, Et3N, acetone,
room temp., 20a: 48 h; 20b: 72 h; 20c: 72 h. (ii) AuCl3 (5 mol-%),
PTSA (10 mol-%), CH2Cl2, room temp., 21a: 48 h; 21b: 72 h; 21c:
48 h. (iii) [PtCl2(CH2=CH2)]2 (1 mol-%), TDMPP (2 mol-%),
CH2Cl2, sealed tube, 21a: 27 h, 50 °C; 21b: 48 h, 95 °C; 21c: 48 h,
95 °C. PMP = 4-MeOC6H4. Diox = (S)-2,2-dimethyl-1,3-dioxolan-
4-yl. Tol = 4-MeC6H4. PTSA = p-toluenesulfonic acid. TDMPP =
tris(2,6-dimethoxyphenyl)phosphane.
1
peak at δ = 3.14 ppm in the H NMR spectrum, which is
the signal of the H4 proton of the five-membered ring on
the
4-(5-hydroxy-5-phenyltetrahydrofuran-2-yl)-3-meth-
To further probe the scope of these transformations, we
oxyazetidin-2-one (14b), suggests that deuteriolysis of the tested the tolerance of the noble metal-catalyzed heterocy-
carbon–platinum bond in species 19 had occurred. Along clization reactions of alkynols to the fused bicyclic version.
with the clarification of the reaction mechanism, we should Gratifyingly, treatment of 2-azetidinone-tethered bishomo-
point out at the same time that, although metal-catalyzed propargylic alcohol 9 with silver acetate provided tetra-
cycloisomerization reactions of alkynes are well known in hydrofuran 23 (Scheme 9); nucleophilic attack took place at
alkynols, tandem oxycyclization/hydroxylation is not an the internal alkyne carbon through a 5-exo-dig hydroalkox-
easy task and still remains a real challenge.
ylation. Similarly, under PtII catalysis, 9 afforded bicycle 23.
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Nonfused, Spiranic and Fused Oxabicyclic β-Lactams
We also examined the catalytic activity of AuCl3 for the
reaction of 9. Alkynol 9 was exposed to our initially dis-
closed conditions for substrates 3 and 6. Nicely, desired
cycloetherification/hydroxylation product 24 was obtained
in good yield. Interestingly, the gold-catalyzed reaction of
25 possessing a (methoxymethyl)oxy moiety instead of the
free hydroxy group also proceeded smoothly to give cycliza-
tion product 24, albeit in lower yield (Scheme 9). Notably,
the observed regioselectivity (5-exo cyclization) was not af-
fected by the nature of the metal or the presence of a pro-
tective group at the hydroxy moiety. Phenyl alkynol 10 does
not react efficiently under these conditions.
Scheme 10. Cycloetherification of 2-azetidinone-tethered trishomo-
propargylic alcohols 11 and 12. Synthesis of fused pyranyl β-lact-
ams 26–28 and nonfused tetrahydrofuryl β-lactam 29. Reagents
and conditions: (i) AgOAc, Et3N, acetone, room temp., 96 h.
(ii) [PtCl2(CH2=CH2)]2 (1 mol-%), TDMPP (2 mol-%), CH2Cl2,
room temp., 27: 4 h; 29: 7 h. (iii) AuCl3 (5 mol-%), PTSA (10 mol-
%), CH2Cl2, room temp., 6 h. MOM = MeOCH2. PTSA = p-tolu-
enesulfonic acid. TDMPP = tris(2,6-dimethoxyphenyl)phosphane.
Scheme 9. Cycloetherification of 2-azetidinone-tethered bishomo-
propargylic alcohol 9 and bishomopropargylic ether 25. Synthesis
of fused tetrahydrofuryl β-lactams 23 and 24. Reagents and
conditions: (i) AgOAc, Et3N, acetone, room temp., 2 h.
(ii) [PtCl2(CH2=CH2)]2 (1 mol-%), TDMPP (2 mol-%), CH2Cl2,
room temp., 3.5 h. (iii) AuCl3 (5 mol-%), PTSA (10 mol-%),
CH2Cl2, room temp., from 9: 5.5 h; from 25: 12 h. (iv) Me2SO4,
NaOH, TBAI, DCM/H2O, room temp., 3 h. PMP = 4-MeOC6H4.
tially involve the formation of π complex 30 through coor-
dination of the gold trichloride to the alkyne moiety
(Scheme 11). Next, it could be presumed that initially
PTSA
= p-toluenesulfonic acid. TDMPP = tris(2,6-dimeth-
oxyphenyl)phosphane. MOM = MeOCH2.
These metal-catalyzed oxycyclizations were successfully
extended to trishomopropargylic alcohol 11. The results of
these studies are shown in Scheme 10. The nature of the
catalyst system greatly influences the reactivity, but the
same regioselectivity was still exhibited. Whereas AgI gave
6-exo-dig cyclization product 26, PtII afforded isomeric bi-
cycle 27, and AuIII yielded oxycyclization/hydroxylation ad-
duct 28 with concomitant MOM cleavage. By contrast, the
presence of a phenyl substituent at the terminal alkyne car-
bon showed a substantial effect on the reactivity. Thus,
phenyl alkynol 12 favors the formation of nonfused tetra-
hydrofuran 29 through a 5-endo-dig oxycyclization/hydrox-
ylation sequence under platinum catalysis, whereas AuCl3
afforded a complex mixture.
The stereochemistry of the hemiacetal stereocenters in
fused bicycles 24 and 28 was determined by qualitative
homonuclear NOE difference spectra. The total diastereo-
selectivity for tetrahydrofuran 24 and tetrahydropyran 28
could be explained by attack of water to the alkenemetal
complex from the less hindered face (opposite to the β-lac-
tam ring).
Scheme 11. Mechanistic explanation for the gold-catalyzed tandem
oxycyclization/hydroxylation of bishomopropargylic methoxy-
A conceivable mechanism for the achievement of bicyclic
tetrahydrofuran 24 from methoxymethyl ether 25 may ini- methyl ether 25.
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B. Alcaide, P. Almendros, T. Martínez del Campo, R. Carrascosa
4:1) gave (+)-13a (35 mg, 70%) as a colorless oil. [α]2D0 = +68.7 (c
FULL PAPER
formed alkynegold complex 30 undergoes regioselective in-
tramolecular attack (5-exo vs. 6-endo oxyauration) by the
(methoxymethyl)oxy group, giving rise to vinylgold inter-
mediate 31, which after elimination of methoxymethanol
would then isomerize to metalaoxocarbenium species 32.
Probably, the water molecule in the third step of the cata-
lytic cycle comes from the trace amounts of water present
in the solvent or the catalyst. Subsequent nucleophilic at-
tack of water from the less hindered face of intermediate 32
1
= 2.8, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.56 and
6.87 (d, J = 9.0 Hz, each 2 H, ArH), 6.33 (dd, J = 4.4, 2.5 Hz, 1
H, =CH), 4.98 (dd, J = 5.1, 2.4 Hz, 1 H, =CH), 4.81 (dd, J = 18.5,
8.5 Hz, 1 H, OCH), 4.61 (d, J = 5.4 Hz, 1 H, H3), 4.34 (dd, J =
9.0, 5.4 Hz, 1 H, H4), 3.79 (s, 3 H, OMe), 3.63 (s, 3 H, OMe), 2.88
(ddt, J = 15.6, 10.1, 2.4 Hz, 1 H, CHH), 2.40 (ddt, J = 15.8, 8.2,
2.4 Hz, 1 H, CHH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
165.2, 156.5, 144.7, 131.1, 119.7, 114.0, 99.8, 82.3, 82.1, 61.2, 59.5,
55.4, 32.9 ppm. IR (CHCl ): ν = 1745 cm–1. HRMS (ESI): calcd.
˜
3
would form ate complex 33. Deauration and proton trans- for C15H17NO4 [M]+ 275.1158; found 275.1154.
fer liberate adduct 24 with concomitant regeneration of the
Nonfused Dihydrofuran (–)-13b: From alkynol (+)-2b (55 mg,
AuIII species. In an independent experiment, we did not ob-
tain hydroxytetrahydrofuran 24 through the AuCl3-cata-
lyzed reaction of methylenetetrahydrofuran 23 (obtained
from alkynol 9 by using silver acetate), which should follow
Markovnikov-type water addition, which strongly discards
its role as an intermediate in the gold-catalyzed oxycycli-
zation/hydroxylation sequence.
0.22 mmol). Chromatography of the residue (hexanes/ethyl acetate,
3:1) gave (–)-13b (32 mg, 56%) as a colorless oil. [α]2D0 = –8.3 (c =
1
0.3, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.30 (m, 5
H, ArH), 6.27 (q, J = 2.4 Hz, 1 H, =CH), 4.89 (dd, J = 5.1, 2.4 Hz,
1 H, =CH), 4.83 and 4.21 (d, J = 14.9 Hz, each 1 H, NCHH), 4.74
(m, 1 H, OCH), 4.45 (d, J = 4.9 Hz, 1 H, H3), 3.62 (dd, J = 9.0,
4.9 Hz, 1 H, H4), 3.56 (s, 3 H, OMe), 2.78 (ddt, J = 15.9, 10.3,
2.2 Hz, 1 H, CHH), 2.20 (ddt, J = 15.6, 7.1, 2.4 Hz, 1 H,
CHH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 167.5, 144.7,
139.8, 128.7, 128.6, 128.4, 127.6, 99.4, 83.1, 81.9, 59.3, 45.1,
32.6 ppm. IR (CHCl ): ν = 1743 cm–1. MS (ESI): m/z (%) = 260
Conclusions
˜
3
(100) [M + H]+, 259 (23) [M]+.
In conclusion, we have developed efficient catalyst sys-
tems based on precious metal salts for the asymmetric syn-
thesis of a variety of nonfused, spiranic and fused oxa-
bicyclic β-lactams.[7] Silver exclusively affords cycloisomer-
ization products, whereas the presence of a catalytic amount
of platinum or gold salts favors the formation of tandem
oxycyclization/hydroxylation adducts. At the present time,
the application of these protocols to the preparation of
other types of heterocyclic compounds is ongoing in our
group.
Spirocyclic Dihydrofuran (+)-20a: From alkynol (+)-5a (44 mg,
0.13 mmol). Chromatography of the residue (hexanes/ethyl acetate,
2:1) gave (+)-20a (25 mg, 57%) as a pale-yellow solid. M.p. 155–
156 °C. [α]2D0 = +9.1 (c = 0.4, CHCl3). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.71 and 6.89 (d, J = 9.2 Hz, each 2 H, ArH), 6.32 and
5.10 (q, J = 2.7 Hz, each 1 H, CH=CH), 4.42 (m, 1 H, CHO), 4.22
(dd, J = 9.0, 7.0 Hz, 1 H, CHHO), 4.03 (d, J = 8.5 Hz, 1 H, H4),
3.81 (s, 3 H, OMe), 3.66 (dd, J = 9.0, 6.0 Hz, 1 H, CHHO), 3.25
and 2.91 (dt, J = 16.6, 2.2 Hz, each 1 H, =CHCHH), 1.55 and 1.35
(s, each 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
165.0, 156.6, 131.1, 119.8, 114.4, 114.0, 110.0, 100.1, 91.1, 76.8,
72.3, 68.0, 55.5, 26.7, 25.6, 24.7 ppm. IR (CHCl ): ν = 1746 cm–1.
˜
3
MS (EI): m/z (%) = 331 (61) [M]+, 149 (100) [M – 182]+.
C18H21NO5 (331.4): calcd. C 65.24, H 6.39, N 4.23; found C 65.37,
H 6.34, N 4.20.
Experimental Section
1
General Methods: H and 13C NMR spectra were recorded with a
Bruker AMX-500, Bruker Avance-300, Varian VRX-300S, or
Bruker AC-200 instrument. NMR spectra were recorded in CDCl3
solutions, except otherwise stated. Chemical shifts are given in ppm
relative to TMS (1H, 0.0 ppm) or CDCl3 (13C, 76.9 ppm). Low-
and high-resolution mass spectra were taken with an Agilent 6520
Accurate-Mass QTOF LC–MS spectrometer by using the electronic
impact (EI) or electrospray modes (ESI) unless otherwise stated.
IR spectra were recorded with a Bruker Tensor 27 spectrometer.
All commercially available compounds were used without further
purification.
Spirocyclic Dihydrofuran (؎)-20b: From alkynol (Ϯ)-5b (70 mg,
0.21 mmol). Chromatography of the residue (hexanes/ethyl acetate,
2:1) gave (Ϯ)-20b (31 mg, 45%) as a yellow solid. M.p. 143–144 °C.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.31 and 6.81 (d, J =
9.2 Hz, each 2 H, ArH), 7.19 (s, 4 H, ArH), 6.11 and 5.02 (q, J =
2.4 Hz, each 1 H, CH=CH), 4.97 (s, 1 H, H4), 3.76 (s, 3 H, OMe),
3.33 and 3.04 (dt, J = 16.1, 2.4 Hz, each 1 H, =CHCHH), 2.36 (s,
3 H, Me) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 165.5,
156.4, 144.9, 138.3, 130.7, 129.3, 127.4, 119.0, 114.3, 99.3, 93.3,
77.2, 72.0, 55.4, 35.5, 21.3 ppm. IR (CHCl ): ν = 1747 cm–1. MS
˜
3
General Procedure for the Silver-Promoted Cyclization of α-, β-, or
γ-Alkynol 2, 5, or 11: Silver acetate (0.29 mmol) and triethylamine
(0.23 mmol) were sequentially added to a stirred solution of alky-
nol 2, 5, or 11 (0.23 mmol) in acetone (1.5 mL). The reaction mix-
ture was stirred at room temperature protected from sunlight until
disappearance of the starting material (TLC). The mixture was fil-
tered through a pad of Celite before the filtrate was extracted with
ethyl acetate (4ϫ5 mL). The organic extract was washed with
brine, dried (MgSO4), and concentrated under reduced pressure.
Chromatography of the residue (hexanes/ethyl acetate) gave analyt-
ically pure 13, 20, or 26.
(EI): m/z (%) = 321 (34) [M]+, 172 (100) [M – 149]+. C20H19NO3
(321.4): calcd. C 74.75, H 5.96, N 4.36; found C 74.61, H 6.01, N
4.40.
Spirocyclic Dihydrofuran (؎)-20c: From alkynol (Ϯ)-5c (69 mg,
0.22 mmol), Chromatography of the residue (hexanes/ethyl acetate,
2:1) gave (Ϯ)-20c (45 mg, 69%) as a yellow solid. M.p. 172–173 °C.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.51 (m, 1 H, HetH), 7.42
(m, 1 H, HetH), 7.36 and 6.83 (d, J = 9.2 Hz, each 2 H, ArH),
6.43 (m, 1 H, HetH), 6.23 and 5.03 (q, J = 2.4 Hz, each 1 H,
CH=CH), 4.95 (s, 1 H, H4), 3.77 (s, 3 H, OMe), 3.31 and 2.98 (dt,
J = 16.3, 2.4 Hz, each 1 H, =CHCHH) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 164.8, 156.5, 144.9, 143.5, 141.5, 130.6, 119.6,
Nonfused Dihydrofuran (+)-13a: From alkynol (+)-2a (50 mg,
0.18 mmol). Chromatography of the residue (hexanes/ethyl acetate,
118.9, 114.3, 109.9, 99.4, 93.1, 64.5, 55.4, 35.1 ppm. IR (CHCl ): ν
˜
3
4916
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4912–4919

Nonfused, Spiranic and Fused Oxabicyclic β-Lactams
= 1745 cm–1. MS (EI): m/z (%) = 297 (51) [M]+, 148 (100) [M –
149]+. C17H15NO4 (297.3): calcd. C 68.68, H 5.09, N 4.71; found
C 68.55, H 5.03, N 4.74.
25 °C): δ = 200.6, 165.3, 164.7, 164.1, 135.6, 133.4, 132.2, 128.9,
128.6, 128.5, 128.1, 127.9, 124.0, 113.9, 74.2, 71.4, 61.2, 55.5, 46.0,
35.0, 25.7 ppm. IR (CHCl ): ν = 3352, 1744, 1722 cm–1. MS (ESI):
˜
3
m/z (%) = 474 (100) [M + H]+, 473 (17) [M]+.
Fused Methylenetetrahydropyran (+)-26: From alkynol (+)-11
(50 mg, 0.15 mmol). Chromatography of the residue (hexanes/ethyl
Preparation of Spirocycles (+)-21a and (+)-22: From alkynol (+)-6a
(34 mg, 0.084 mmol). Chromatography of the residue (hexanes/
ethyl acetate, 3:1) afforded less-polar (+)-22 (7 mg, 20%) and more-
polar (+)-21a (18 mg, 50%).
acetate, 3:1) gave (+)-26 (30 mg, 69%) as a colorless oil. [α]2D0
=
+8.0 (c = 0.6, CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C): δ =
7.34 (m, 5 H, ArH), 5.05 (d, J = 5.1 Hz, 1 H, H3), 4.59 (dd, J =
15.9, 6.9 Hz, 1 H, OCHH), 4.49 and 4.31 (d, J = 14.9 Hz, each 1
H, NCHH), 4.43 (m, 1 H, OCH), 3.99 (br. s, 1 H, H4), 3.81 (m, 2
H, =CHH), 3.33 (s, 3 H, OMe), 2.51 (m, 2 H, CHH) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 167.4, 153.3, 134.8, 129.1,
128.5, 128.3, 95.6, 90.6, 78.0, 69.4, 55.7, 54.7, 45.0, 28.2 ppm. IR
Spirocyclic Hemiacetal (+)-21a: Colorless oil. [α]2D0 = +7.3 (c = 0.4,
CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 8.00 (m, 2 H,
ArH), 7.58 and 6.87 (d, J = 9.2 Hz, each 2 H, ArH), 7.52 (m, 3 H,
ArH), 5.03 (br. s, 1 H, OH), 4.46 (dd, J = 13.2, 6.6 Hz, 1 H, OCH),
4.32 (dd, J = 8.7, 6.7 Hz, 1 H, OCHH), 4.07 (d, J = 6.6 Hz, 1 H,
H4), 3.85 (m, 1 H, OCHH), 3.80 (s, 3 H, OMe), 3.46 (m, 2 H,
CHHCOH), 2.36 (m, 2 H, CHHCH2O), 1.47 and 1.35 (s, each 3
H, Me) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 201.4, 168.4,
156.6, 133.7, 131.1, 128.7, 128.3, 119.9, 114.1, 109.8, 83.8, 76.6,
(CHCl ): ν = 1744 cm–1. HRMS (ESI): calcd. for C H NO
˜
3
16 19
4
[M]+ 289.1314; found 289.1310.
General Procedure for the Platinum-Catalyzed Cyclization of α-, β-
, or γ-Alkynol 3, 6, 9, or 11: [PtCl2(CH2=CH2)]2 (0.01 mmol) and
tris(2,6-dimethoxyphenyl)phosphane (0.02 mmol) were sequentially
added to a stirred solution of alkynol 3, 6, 9, or 11 (1.0 mmol)
in dichloromethane (1.0 mL) under an atmosphere of argon. The
resulting mixture was stirred at room temperature until disappear-
ance of the starting material (TLC). The reaction was then
quenched with brine (1.0 mL), the mixture was extracted with ethyl
acetate (3ϫ5 mL), and the combined extract was washed with
brine (2ϫ). The organic layer was dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue (ethyl acet-
ate/hexanes) gave analytically pure adduct 14, 21–23, or 27.
67.6, 66.8, 55.5, 33.4, 30.2, 26.5, 25.1 ppm. IR (CHCl ): ν = 3352,
˜
3
1747 cm–1. HRMS (ESI): calcd. for C24H27NO6 [M]+ 425.1838;
found 425.1834.
Spirocyclic Dihydrofuran (+)-22: Colorless oil. [α]2D0 = +8.0 (c = 0.4,
CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.74 and 6.90 (d,
J = 9.2 Hz, each 2 H, ArH), 7.54 (m, 2 H, ArH), 7.36 (m, 3 H,
ArH), 5.46 (t, J = 2.8 Hz, 1 H, =CH), 4.54 (m, 1 H, OCH), 4.14
(dd, J = 9.0, 6.8 Hz, 1 H, OCHH), 4.10 (d, J = 8.8 Hz, 1 H, H4),
4.08 (s, 3 H, OMe), 3.67 (dd, J = 9.0, 6.1 Hz, 1 H, OCHH), 3.48
and 3.10 (dd, J = 17.1, 2.7 Hz, each 1 H, =CHCHH), 1.54 and
1.34 (s, each 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 165.1, 154.9, 133.8, 131.1, 128.7, 128.4, 128.3, 125.1, 119.8, 114.0,
110.2, 94.3, 91.3, 83.8, 77.1, 72.6, 66.6, 55.5, 36.9, 26.7, 24.8 ppm.
Nonfused Hemiacetal (+)-14a: From alkynol (–)-3a (40 mg,
0.11 mmol). Chromatography of the residue (hexanes/ethyl acetate,
2:1) gave (+)-14a (39 mg, 94%) as a colorless oil. [α]2D0 = +16.2 (c
1
= 0.6, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.95 (dd,
IR (CHCl ): ν = 1744 cm–1. HRMS (ESI): calcd. for C H NO
˜
3
24 25
5
J = 8.0, 1.5 Hz, 2 H, ArH), 7.49 (m, 3 H, ArH), 7.42 and 6.88 (d,
J = 9.3 Hz, each 2 H, ArH), 4.65 (d, J = 5.4 Hz, 1 H, H3), 4.36
(dd, J = 5.4, 3.7 Hz, 1 H, H4), 4.11 (m, 1 H, OCH), 3.79 (s, 3 H,
3H), 3.67 (s, 3 H, 3H), 3.18 (t, J = 6.7 Hz, 2 H, CHH), 2.84 (dd, J
= 4.1, 1.3 Hz, 1 H, OH), 2.01 (m, 2 H, CHH) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 200.2, 165.1, 156.8, 133.1, 130.7,
128.6, 128.0, 120.4, 119.7, 114.3, 82.9, 70.3, 61.0, 59.8, 55.5, 35.0,
[M]+ 407.1733; found 407.1730.
Fused Methylenetetrahydrofuran (+)-23: From alkynol (+)-9
(24 mg, 0.09 mmol). Chromatography of the residue (hexanes/ethyl
acetate, 3:1) gave (+)-23 (17 mg, 71%) as a colorless oil. [α]2D0
=
1
+71.8 (c = 0.5, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ =
7.38 and 6.91 (d, J = 9.0 Hz, each 2 H, ArH), 5.40 (dd, J = 4.1,
0.5 Hz, 1 H, H3), 4.94 and 4.42 (d, J = 2.2 Hz, each 1 H, =CHH),
4.49 (d, J = 3.7 Hz, 1 H, H4), 4.24 (s, 1 H, OCH), 3.81 (s, 3 H,
OMe), 3.43 (s, 3 H, OMe) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 161.6, 158.3, 156.8, 130.0, 118.2, 114.7, 94.5, 86.4, 77.8,
28.3 ppm. IR (CHCl ): ν = 3347, 1744 cm–1. HRMS (ESI): calcd.
˜
3
for C21H23NO5 [M]+ 369.1576; found 369.1580.
Nonfused Hemiacetal (+)-14b: From alkynol (+)-3b (50 mg,
0.16 mmol). Chromatography of the residue (hexanes/ethyl acetate,
2:1) gave (+)-14b (42 mg, 74%) as a colorless oil. [α]2D0 = +37.0 (c
60.1, 56.3, 55.5 ppm. IR (CHCl ): ν = 1743 cm–1. HRMS (ESI):
˜
3
calcd. for C14H15NO4 [M]+ 261.1001; found 261.1003.
1
= 1.8, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.96 (dd,
Fused Dihydropyran (+)-27: From alkynol (+)-11 (53 mg,
0.16 mmol). Chromatography of the residue (hexanes/ethyl acetate,
2:1) gave (+)-27 (28 mg, 60%) as a colorless oil. [α]2D0 = +32.0 (c =
J = 8.1, 1.5 Hz, 2 H, ArH), 7.44 (m, 8 H, ArH), 4.84 and 4.27 (d,
J = 15.1 Hz, each 1 H, NCHH), 4.49 (d, J = 5.1 Hz, 1 H, H3),
3.88 (m, 1 H, OCH), 3.61 (m, 4 H, OMe + H4), 3.14 (dt, J = 6.8,
2.9 Hz, 2 H, CHH), 2.74 (d, J = 3.7 Hz, 1 H, OH), 1.90 (m, 2 H,
CHH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 200.2, 167.8,
136.8, 135.6, 133.2, 128.9, 128.6, 128.3, 128.0, 127.8, 83.5, 70.2,
1
0.3, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.31 (m, 5
H, ArH), 5.11 (d, J = 4.9 Hz, 1 H, H3), 4.87 (dt, J = 6.1, 1.2 Hz,
1 H, =CH), 4.60 and 4.47 (d, J = 7.0 Hz, each 1 H, OCHH), 4.59
and 4.25 (d, J = 14.8 Hz, each 1 H, NCHH), 4.03 (d, J = 6.1 Hz,
1 H, OCH), 3.92 (dt, J = 4.9, 1.5 Hz, 1 H, H4), 3.27 (s, 3 H, Me),
1.86 (d, J = 0.7 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 164.8, 154.8, 134.9, 128.8, 128.4, 128.2, 120.9, 94.5,
60.6, 59.5, 45.6, 35.1, 28.4 ppm. IR (CHCl ): ν = 3350, 1745 cm–1.
˜
3
MS (ESI): m/z (%) = 354 (100) [M + H]+, 353 (11) [M]+.
Nonfused Hemiacetal (+)-14c: From alkynol (+)-3c (26 mg,
0.06 mmol). Chromatography of the residue (hexanes/ethyl acetate,
3:1) gave (+)-14c (18 mg, 65%) as a colorless oil. [α]2D0 = +17.8 (c
78.4, 64.7, 57.2, 55.4, 44.4, 20.2 ppm. IR (CHCl ): ν = 1745 cm–1.
˜
3
HRMS (ESI): calcd. for C16H19NO4 [M]+ 289.1314; found
1
= 0.4, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 8.02 and
289.1318.
6.92 (d, J = 9.0 Hz, each 2 H, ArH), 7.84 (dd, J = 8.3, 1.4 Hz, 2
H, ArH), 7.45 (m, 8 H, ArH), 6.10 (d, J = 4.9 Hz, 1 H, H3), 4.85 General Procedure for the Gold-Catalyzed Cyclization of α-, β-, or
and 4.47 (d, J = 14.9 Hz, each 1 H, NCHH), 3.95 (m, 1 H, OCH), γ-Alkynol 3, 6, 9, or 11: AuCl3 (0.05 mmol) and p-toluenesulfonic
3.88 (s, 3 H, OMe), 3.76 (dd, J = 6.8, 5.0 Hz, 1 H, H4), 3.04 (td, J acid (0.10 mmol) were sequentially added to a stirred solution of
= 6.3, 1.7 Hz, 2 H, CHH), 2.83 (d, J = 4.4 Hz, 1 H, OH), 1.80 (dd, alkynol 3, 6, 9, or 11 (1.0 mmol) in dichloromethane (1.0 mL) un-
J = 12.2, 6.0 Hz, 2 H, CHH) ppm. 13C NMR (75 MHz, CDCl3, der an atmosphere of argon. The resulting mixture was stirred at
Eur. J. Org. Chem. 2010, 4912–4919
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4917

B. Alcaide, P. Almendros, T. Martínez del Campo, R. Carrascosa
FULL PAPER
room temperature until disappearance of the starting material
(TLC). The reaction was then quenched with brine (1.0 mL), the
mixture was extracted with ethyl acetate (3ϫ5 mL), and the com-
bined extracts were washed with brine (2ϫ). The organic layer was
dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue (ethyl acetate/hexanes) gave analyt-
ically pure adduct 21, 24, or 28.
Acknowledgments
We would like to thank the Dirección General de Investigación-
Ministerio de Ciencia e Innovación (DGI-MICINN) (Project
CTQ2009-09318), Universidad Complutense-Banco Santander
Central Hispano (UCM-BSCH) (Grant GR58/08), and Comun-
idad Autónoma de Madrid (CAM) (Project S2009/PPQ-1752) for
financial support. T.M.C. and R.C. thank the MICINN for predoc-
toral grants.
Spirocyclic Hemiacetal (؎)-21b: From alkynol (Ϯ)-6b (29 mg,
0.07 mmol). Chromatography of the residue (hexanes/ethyl acetate,
3:1) gave (Ϯ)-21b (20 mg, 67%) as a yellow oil. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 8.00 (m, 2 H, ArH), 7.52 (m, 3 H,
ArH), 7.29 and 6.81 (d, J = 9.0 Hz, each 2 H, ArH), 7.20 (m, 5 H,
ArH), 5.07 (s, 1 H, H4), 3.76 (s, 3 H, OMe), 3.46 (td, J = 7.1,
1.7 Hz, 2 H, CHHCOH), 3.08 (br. s, 1 H, OH), 2.52 (m, 2 H,
CHHCH2CO), 2.36 (s, 3 H, 3 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 200.2, 167.4, 156.3, 138.8, 136.6, 133.3, 130.7, 129.9,
128.6, 128.2, 127.1, 118.9, 114.4, 85.3, 68.1, 55.4, 33.1, 30.0,
[1] For recent reviews on tetrahydrofuran rings, see: a) J. P. Wolfe,
M. B. Hay, Tetrahedron 2007, 63, 261; b) X.-L. Hou, Z. Yang,
K.-S. Yeung, H. N. C. Wong in Progress in Heterocyclic Chem-
istry (Eds.: G. W. Gribble, J. A. Joule), Elsevier, Oxford, 2005,
vol. 17, pp. 142–171; c) M. Saleem, H. J. Kim, M. S. Ali, Y. S.
Lee, Nat. Prod. Rep. 2005, 22, 696; for recent reviews on pyran
rings, see: d) P. A. Clarke, S. Santos, Eur. J. Org. Chem. 2006,
2045; e) J. D. Hepworth, B. M. Heron in Progress in Heterocy-
clic Chemistry (Eds.: G. W. Gribble, J. A. Joule), Elsevier, Ox-
ford, 2005, vol. 17, pp. 362–388.
21.2 ppm. IR (CHCl ): ν = 3351, 1746 cm–1. MS (ESI): m/z (%) =
˜
3
416 (100) [M + H]+, 415 (9) [M]+.
[2] For reviews on the construction of heterocycles by alkyne acti-
vation, see: a) Y. Yamamoto, I. D. Gridnev, N. T. Patil, T. Jin,
Chem. Commun. 2009, 5075; b) S. F. Kirsch, Synthesis 2008,
3183; for selected examples, see: c) S. Belot, K. A. Vogt, C.
Besnard, N. Krause, A. Alexakis, Angew. Chem. 2009, 121,
9085; Angew. Chem. Int. Ed. 2009, 48, 8923; d) A. S. K.
Hashmi, A. M. Schuster, F. Rominger, Angew. Chem. 2009,
121, 8396; Angew. Chem. Int. Ed. 2009, 48, 8247; e) J. Bar-
luenga, A. Fernández, A. Diéguez, F. Rodríguez, F. J. Fañanás,
Chem. Eur. J. 2009, 15, 11660; f) Y. K. Chung, G. C. Fu, An-
gew. Chem. 2009, 121, 2259; Angew. Chem. Int. Ed. 2009, 48,
2225; g) V. Belting, N. Krause, Org. Biomol. Chem. 2009, 7,
1221; h) J. Barluenga, A. Mendoza, F. Rodríguez, F. J.
Fañanás, Angew. Chem. 2009, 121, 1672; Angew. Chem. Int. Ed.
2009, 48, 1644; i) S. Y. Seo, X. Yu, T. J. Marks, J. Am. Chem.
Soc. 2009, 131, 263; j) J. Meng, Y.-L. Zhao, C.-Q. Ren, Y. Li,
Z. Li, Q. Liu, Chem. Eur. J. 2009, 15, 1830; k) A. Aponik, C.-
Y. Li, J. A. Palmes, Org. Lett. 2009, 11, 121; l) M. Schuler, F.
Silva, C. Bobbio, A. Tessier, V. Gouverneur, Angew. Chem.
2008, 120, 8045; Angew. Chem. Int. Ed. 2008, 47, 7927; m) J.
Barluenga, A. Mendoza, F. Rodríguez, F. J. Fañanás, Chem.
Eur. J. 2008, 14, 10892; n) L.-Z. Dai, M. Shi, Chem. Eur. J.
2008, 14, 7011; o) J. Barluenga, A. Fernández, A. Satrústegui,
A. Diégez, F. Rodríguez, F. J. Fañanás, Chem. Eur. J. 2008, 14,
4153; p) C. V. Ramana, R. Mallik, R. G. Gonnade, Tetrahedron
2008, 64, 219; q) S. Arimitsu, G. B. Hammond, J. Org. Chem.
2007, 72, 8559; r) H. Harkat, J.-M. Weibel, P. Pale, Tetrahedron
Lett. 2007, 48, 1439; s) E. Genin, S. Antoniotti, V. Michelet,
J.-P. Genêt, Angew. Chem. 2005, 117, 5029; Angew. Chem. Int.
Ed. 2005, 44, 4949; t) V. Belting, N. Krause, Org. Lett. 2006,
8, 4489; u) B. Liu, J. K. De Brabander, Org. Lett. 2006, 8, 4907;
v) M. H. Davidson, F. E. McDonald, Org. Lett. 2004, 6, 1601;
w) B. M. Trost, Y. H. Rhee, J. Am. Chem. Soc. 2003, 125, 7482;
x) P. Wipf, T. H. Graham, J. Org. Chem. 2003, 68, 8798; y) P.
Pale, J. Chuche, Eur. J. Org. Chem. 2000, 1019; z) F. E. McDon-
ald, Chem. Eur. J. 1999, 5, 3103.
Spirocyclic Hemiacetal (؎)-21c: From alkynol (Ϯ)-6c (39 mg,
0.10 mmol). Chromatography of the residue (hexanes/ethyl acetate,
2:1) gave (Ϯ)-21c (20 mg, 50%) as a yellow oil. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 8.01 (m, 2 H, ArH), 7.60 (m, 1 H,
HetH), 7.56 (t, J = 1.4 Hz, 1 H, HetH), 7.47 (m, 3 H, ArH), 7.34
and 6.83 (d, J = 9.0 Hz, each 2 H, ArH), 6.41 (m, 1 H, HetH),
5.07 (s, 1 H, H4), 3.78 (s, 3 H, OMe), 3.45 (m, 2 H, CHHCOH),
2.49 (m, 2 H, CHHCH2CO) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 200.4, 167.2, 156.4, 144.2, 141.5, 136.5, 133.4, 130.6,
128.7, 128.2, 118.8, 114.4, 109.6, 85.0, 61.2, 55.4, 33.1, 29.6 ppm.
IR (CHCl ): ν = 3354, 1747 cm–1. MS (ESI): m/z (%) = 392 (100)
˜
3
[M + H]+, 391 (5) [M]+.
Fused Hemiacetal (+)-24: From alkynol (+)-9 (24 mg, 0.09 mmol).
Chromatography of the residue (hexanes/ethyl acetate, 2:1) gave
(+)-24 (15 mg, 59%) as a colorless oil. [α]2D0 = +19.8 (c = 0.8,
CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.35 and 6.90 (d,
J = 9.0 Hz, each 2 H, ArH), 5.27 (d, J = 4.0 Hz, 1 H, H3), 4.43
(d, J = 4.0 Hz, 1 H, H4), 3.80 (s, 3 H, OMe), 3.71 (s, 1 H, OCH),
3.55 (s, 3 H, OMe), 1.58 (s, 3 H, Me) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 206.9, 164.8, 156.4, 131.0, 118.0, 114.6, 85.1,
82.7, 60.3, 58.4, 55.5, 16.3 ppm. IR (CHCl ): ν = 3350, 1748 cm–1.
˜
3
HRMS (ESI): calcd. for C14H17NO5 [M]+ 279.1107; found
279.1111.
Fused Hemiacetal (+)-28: From alkynol (+)-11 (26 mg,
0.08 mmol).Chromatography of the residue (hexanes/ethyl acetate,
2:1) gave (+)-28 (19 mg, 81%) as a colorless oil. [α]2D0 = +9.8 (c =
1
0.3, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.30 (m, 5
H, ArH), 5.11 (d, J = 5.1 Hz, 1 H, H3), 5.09 (d, J = 6.6 Hz, 1 H,
OH), 4.79 (d, J = 6.8 Hz, 1 H, OH), 4.46 and 4.31 (d, J = 14.9 Hz,
each 1 H, NCHH), 4.07 (m, 1 H, OHCH), 3.93 (dt, J = 5.1, 1.3 Hz,
1 H, H4), 2.03 (ddd, J = 14.0, 4.2, 1.5 Hz, 1 H, CHH), 1.84 (ddd,
J = 14.0, 1.9, 1.0 Hz, 1 H, CHH), 1.43 (s, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 206.5, 166.7, 129.1, 128.5, 128.4,
[3] For selected examples, see: a) Z. Zhang, Q. Zhang, Z. Ni, Q.
Liu, Chem. Commun. 2010, 46, 1269; b) E. Leemans, M.
D’hooghe, Y. Dejaegher, K. W. Törnroos, N. De Kimpe, Eur.
J. Org. Chem. 2010, 352; c) A. Al-Harrasi, F. Pfrengle, V. Prisy-
azhnyuk, S. Yekta, P. Koósˇ, H.-U. Reissig, Chem. Eur. J. 2009,
15, 11632; d) A. Kozioł, B. Furman, J. Frelek, M. Woz´nica, E.
Altieri, M. Chmielewski, J. Org. Chem. 2009, 74, 5687; e) P.
Del Buttero, G. Molteni, A. Papagni, T. Pilati, Tetrahedron:
Asymmetry 2005, 16, 971.
[4] See, for instance: a) B. Alcaide, P. Almendros, A. Luna, M. R.
Torres, Adv. Synth. Catal. 2010, 352, 621; b) B. Alcaide, P. Al-
mendros, T. Martínez del Campo, M. T. Quirós, Chem. Eur. J.
2009, 15, 3344; c) B. Alcaide, P. Almendros, R. Carrascosa, T.
128.2, 84.1, 65.2, 55.1, 44.6, 28.0, 9.5 ppm. IR (CHCl ): ν = 3347,
˜
3
1745 cm–1. MS (ESI): m/z (%) = 264 (100) [M + H]+, 263 (5)
[M]+.
Supporting Information (see footnote on the first page of this arti-
cle): Compound characterization data and experimental procedures
for compounds 2a–c, 3a–c, 5a–c, 6a–c, 7–12, and 25 in addition to
copies of the NMR spectra for all new compounds.
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Received: May 18, 2010
Published Online: July 13, 2010
Eur. J. Org. Chem. 2010, 4912–4919
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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