A mild route to α-alkoxyacetylenes mediated by Lewis acids and synthetic routes to 10-, 11-, and 12-membered ring enediyne carbocycles

Article abstract of DOI:10.1560/7J4F-D8BG-3FQR-E3TD

The condensation of silyl substituted acetylenes with dimethoxy acetals via a modified "Mukaiyama-type reaction" to afford α-alkoxyacetylenes is described. These propargylic ethers 17-21 were synthesized from the reaction of aluminum or zinc acetylides with acetals mediated by Lewis acids. In appropriate cases, when a second acetal was present in the initial acyclic product (24), a subsequent intramolecular acetal-ene (Prins) cyclization ensued to afford the silylalkylidenealkoxycyclopentane (25). Enediyne species were unreactive under these conditions, even in an intramolecular case. Routes to 11-and 12-membered carbocyclic enediyne compounds (43, 44) were developed via an intramolecular pinacol coupling of the dialdehydes 39 with sammarium diodide/HMPA. The requisite double bond was introduced using the thiocarbonate expulsion method with trimethyl phosphite. A route to the highly substituted 10-membered ring enediyne 50 is also described based on the use of an isopropylidene acetal tether control group to facilitate an intramolecular chromium (II)/nickel (II)-mediated coupling of the iodoacetylene aldehyde 49.

Full text of DOI:10.1560/7J4F-D8BG-3FQR-E3TD

A Mild Route to α-Alkoxyacetylenes Mediated by Lewis Acids and Synthetic
Routes to 10-, 11-, and 12-Membered Ring Enediyne Carbocycles
BOGDAN M. COMANITA,† MATTHEW A. HEUFT, TANYA RIETVELD, AND ALEX G. FALLIS*
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, K1N 6N5, Canada
(Received 30 July 2000 and in revised form 9 November 2000)
Abstract. The condensation of silyl substituted acetylenes with dimethoxy ac-
etals via a modified “Mukaiyama-type reaction” to afford α-alkoxyacetylenes is
described. These propargylic ethers 17–21 were synthesized from the reaction of
aluminum or zinc acetylides with acetals mediated by Lewis acids. In appropriate
cases, when a second acetal was present in the initial acyclic product (24), a
subsequent intramolecular acetal-ene (Prins) cyclization ensued to afford the
silylalkylidenealkoxycyclopentane (25). Enediyne species were unreactive under
these conditions, even in an intramolecular case. Routes to 11- and 12-membered
carbocyclic enediyne compounds (43, 44) were developed via an intramolecular
pinacol coupling of the dialdehydes 39 with sammarium diodide/HMPA. The requi-
site double bond was introduced using the thiocarbonate expulsion method with
trimethyl phosphite. A route to the highly substituted 10-membered ring enediyne 50
is also described based on the use of an isopropylidene acetal tether control group to
facilitate an intramolecular chromium (II)/nickel (II)-mediated coupling of the iodo-
acetylene aldehyde 49.
INTRODUCTION
In part, this study was motivated by our interest in
Acetylenes represent a well-studied functional group constructing bicyclic enediyne systems (taxcamycins)
recognized for their synthetic versatility due to the cross that would combine aspects of the important
section of reactions in which they participate.1 The cur- pharmacophores found in the enediyne and taxoid natu-
rent interest in natural products, such as calicheamicin ral product families. It was anticipated that suitable
and esperamicin2 (Fig. 1), has generated considerable functionality should facilitate tubulin binding, and
synthetic activity. Similarily, in related areas, the con- cycloaromatization would induce cell damage. We have
struction of acetylenic bridged annulenes, cyclophanes, previously synthesized various 10-, 11-, and 12-mem-
and carbon networks has provided novel molecular ar- bered ring systems related to 1 and 2 (Fig. 1).6 Unfortu-
rays.3 In particular, cobalt trimerizations,4 the use of nately, the bicyclo[7.3.1]trideca-4,9-dien-2,6-diyne
tin- and palladium-based coupling methods, and compound 2 with the docetaxel (Taxotere) side chain
enediyne syntheses has stimulated the development of attached lacked the desired biological activity.6d Conse-
methods to introduce triple bonds under mild condi- quently, we sought a mild, direct route to acetylene
tions, particularly for carbocyclic systems that contain building blocks and simple cyclic enediynes in which
enediyne units.5 Historically, the most direct route for the secondary alcohols could be differentiated.
the preparation of propargyl alcohols has been the direct
A variety of milder metal acetylides have been exam-
condensation of metal acetylides (usually Li and MgX) ined and compared to alkoxides for use in sensitive
with carbonyl systems. However, for mutifunctionalized systems to avoid the undesirable side reactions that may
compounds these methods are often not appropriate.
accompany strongly basic conditions. Among an exten-
This paper is dedicated to Professor Raymond U. Lemieux on †Present address: Brantford Chemical Ltd., Brantford,
the occassion of his 80th birthday and the receipt of the Wolf Ontario, Canada.
Prize. Presented with respect and gratitude for his contribu- *Authortowhomcorrespondenceshouldbeaddressed. E-mail:
tions to organic chemistry and our friendship.
afallis@science.uottawa.ca
Israel Journal of Chemistry
Vol. 40
2000 pp. 241–253

242
knowledge gained from this investigation has been em-
ployed in a direct synthesis of an analogue of 9 based on
an acetal “tether control” strategy.
LEWIS ACID-MEDIATED ADDITIONS OF
SILYLACETYLENES TO ACETALS
Table 1 summarizes the results for several experiments.
The standard procedure involved treatment of the silyl
acetylenes (11 or 12) with n-butyllithium at 0 °C, fol-
lowed by the addition of either zinc chloride or alumi-
num trichloride to generate the metal complexes. Subse-
quently, the acetal (13 to 16) was added, and, in the case
of the zinc chloride reaction, this was followed by one
equivalent of boron trifluoride etherate. In the absence
of additional Lewis acid, no product was formed. In the
case of dimethoxy acetals derived from stable aldehydes
(Entries a,b), the yields were 81% and 53%, respec-
tively. 1,3-Propandial (malonaldehyde) is difficult to
manipulate, especially in the presence of base. How-
ever, as Entries c–f indicate, the (bis)dimethyl acetal 15
reacted under various conditions to give modest yields
of the methoxy ethers 19 or 20. The greater steric bulk
of the ethoxy group in 16 had minimal effect on the
yield and the triethyl ether 21 was isolated in 27% yield.
In the case of Entry f, two equivalents of acetylide were
added, but only mono addition to give 20 was observed.
Thus acid-sensitive molecules can be prepared under
these conditions and retain functionality for further syn-
thetic manipulation.
In principle, it should be possible to conduct double
addition to these bis-acetal systems under appropriate
conditions, although as noted with the substrates above,
this was not observed. In order to investigate this poten-
tial, excess bis-trimethylacetylene 22 was combined
with the masked 1,4-butanedial (2,5-dimethoxytetra-
hydrofuran 23) in the presence of titanium tetrachloride
in the expectation that the product would be the
disilyldiyne 26 (Scheme 3). However 26 was not de-
tected, but instead the initially formed mono adduct 24
was isolated, accompanied by a small amount of a sec-
Fig. 1. Taxamycins (taxoid-enediyne hybrids).
sive list aluminum-,7 boron-,8 cerium-,9 chromium-,10
manganese-,11 tin-,12 and vanadium-based13 protocols
are representative. Often these methods require a large
excess of the acetylide and enolization can be a signifi-
cant problem, particularly when enediyne anions are
added to aldehydes. In these cases, the addition of ce-
rium trichloride to form the cerium acetylide in situ is
beneficial.9b The synthetic utility and mild conditions of
Mukaiyama-type reactions involving silyl enol ethers or
allylsilanes with acetals under Lewis acid condition are
well established.14 This implied that the condensation of
zinc or aluminum silyl acetylides with methoxy acetals
could be mediated with Lewis acids, as outlined in
Scheme 1. Thus the condensation of 3 with 4 was ex-
pected to provide 6 via the intermediacy of 5. This is the
case, and we have developed a simple procedure to
afford α-propargylmethyl ethers directly under mild
conditions.
Unfortunately, this protocol failed with combina-
tions related to 7 and 8. However, both the 11- and 12-
membered ring systems related to 9 have been prepared
via a pinacol coupling sequence as described below. The
Scheme 1. General route to α-propargyl ethers.
Scheme 2. Possible routes to carbocyclic enediynes.
Scheme 3. Preparation of 24 and cyclopentane 25.
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Table 1. Results of Lewis acid-mediated silylacetylide addition to acetals
entry acetylene substrate method
product
yield
A = 1 equiv n-BuLi, 0 °C, ether, 1 equiv ZnCl2, 1 eq. BF3(EtO)2, 30 min.
B = 1 equiv n-BuLi, 0 °C, hexanes, 1 equiv AlCl3, CH2Cl2, 30 min.
C = 2 equiv n-BuLi, 0 °C, hexanes, 2 equiv AlCl3, CH2Ci2, 30 min.
ond product. Further experimentation established that
exposure of 24 to additional titanium chloride induced
an intramolecular reaction which afforded a cyclic prod-
uct in 82% yield. This material lacked triple bonds and
its spectroscopic features satisfied the cyclopentene-
ether structure 25. Consistent with this assignment, the
1H NMR spectrum contained a broad singlet at d
5.90 ppm for the vinyl hydrogen and the 13C NMR
spectrum displayed a signal for an sp2 hybridized carbon
at d 158.3 ppm, typical of an exocyclic double bond.
Scheme 4. Oxonium ion-ene reaction to 25.
A likely mechanism for this cyclization is illustrated
in Scheme 4. Cyclization to 25 may arise from the initial
loss of methanol from acetal 24 to form the oxonium ion oxocycles from vinylsilane acetals by a related intramo-
A. This sets the stage for rearrangement via an intramo- lecular acetal-ene reactions initiated by SnCl4 at –15 °C.
lecular acetal-ene reaction pathway to B. Subsequent
Irrespective of the experimental method, these
addition of methanol afforded the methyloxymethyl silylacetylide condensations are synthetically equiva-
ether 25. Thus this cyclization belongs to the family of lent although the nature of the zinc and aluminum
intramolecular acetal-ene or Prins reactions (when free acetylide complexes may differ. The zinc acetylide is
carbonyl is involved). Previous examples with acetals less nucleophilic and behaves more like a tightly held
and alkenes have been shown to involve methoxy- organozinc anion. Thus additional Lewis acid, such as
carbonyl cations15 and Overman and coworkers16 have borontrifluoride etherate, is required for the reaction to
utilized related cyclizations for the synthesis of proceed.
Comanita et al. / Routes to α-Alkoxyacetylenes and Enediyne Carbocycles

244
APPROACHES TO 10-MEMBERED RINGS
Several attempts to extend these zinc and aluminum
PINACOL-BASED ROUTE TO 11- AND
12-MEMBERED RINGS
condensation protocols, described in Table 1, to the tri- The investigations above imply that for effective in-
i-propylsilyl-3-ene-1,5-diyne building block 8 with ac- tramolecular reactions to these ring systems, the precur-
etals failed. This is probably a consequence of the re- sor must possess a more rigid geometry, in which re-
duced nucleophilicity present in these extended π-sys- stricted rotation will facilitate the interaction of the reac-
tems. However, given the planar nature of the enediyne tive centers. Pinacol coupling of dialdehydes, similar to
chromophore, it seemed possible that an intramolecular structure 9 in Scheme 2, has been used by Myers and
reaction to form a 10-membered ring was feasible. We Dragovich18 to prepare an unsubstituted 10-membered
suspected the cyclodecene system should form more ring in which the coupling step afforded the expected
easily due to the limited conformational mobility of the α-hydroxycyclodecendiyne ketone in 32% yield with
alkyl component compared to the larger ring homo- VCl3·3THF/Zn. Nicolaou and coworkers19 have also
logues. These experiments are outlined in Scheme 5. synthesized 10-membered carbocyclic enediyne rings
The silyl acetylene 24 prepared above was treated with which contained dimethyl functionality adjacent to the
base to remove the trimethylsilyl group to afford the aldehydes. However, we are not aware of any syntheses
acetylene-acetal 27. This was coupled with vinyl chlo- of the high homologues related to 11- and 12-membered
ride 28 using the palladium/copper-mediated conditions rings by this procedure.
we have employed previously.6 The silyl-substituted
This approach is outlined in Scheme 6 and requires
enediyne 29 was reacted with titanium tetrachloride as the synthesis of the acetylenic aldehydes 39, in which
described earlier, but neither this method nor related the rigid linear orientation of the triple bonds should
reactions with the free acetylene system 30 gave any of assist the cyclization reaction. Small conjugated alkynals
the desired carbocycle 31. Further modification of 29 are not ideal intermediates as they have a tendency to be
afforded the two aldehydes 32 and 33, but these mol- unstable, are often difficult to manipulate, and are some-
ecules also failed to undergo intramolecular condensa- times explosive. However, with these higher molecular
tion under fluoride ion or basic conditions with lithium weight compounds, this was not the case.
diisopropyl amide, for which there is literature prece-
In a parallel series of reactions, the appropriate acyl
dent.17 A referee has kindly suggested that the back chloride was coupled with bis-trimethysilyl acetylene
reaction, retrocyclization to afford starting material, (22) in the presence of aluminum trichloride to provide
may be favored in these systems and account for these the diketones 36. Reduction of the ketones to the corre-
observations. In previous research we have established sponding alcohols 37 was readily accomplished with
that the chromium(II)/nickel(II)-mediated intramolecu- sodium borohydride and cerium trichloride in methanol.
lar reaction often succeeds where other methods fail.6 The trimethylsilyl groups were removed under phase
Unfortunately in this series, we were unable to synthe- transfer conditions with sodium hydroxide and the pro-
size the iodo-aldehyde 34 to examine this alternative.
tection of the secondary alcohols as their t-butyldi-
methylsilyl ethers was effected with the silyl chloride
and imidazole in yields of 90% or better.
In order to introduce the aldehyde functionality, di-
rect condensation of the dilithioacetylides, derived from
38, were reacted with paraformaldehyde, followed by
Dess–Martin periodinane oxidation to the aldehydes 39.
The direct condensation with dimethylformamide fol-
lowed by hydrolysis was also investigated, but this was
less satisfactory than the two-step procedure. A series of
pinacol coupling conditions were examined and in each
case samarium iodide/HMPA was the best reagent, as
summarized in Table 2. Under these conditions (Entries
a and b), the cyclizations proceeded smoothly to provide
40a and 40b in yields of 84% and 74%, respectively.
The use of vanadium trichloride tris(tetrahydrofuran)
complex in dichloromethane at 21 °C for 3 h gave a
diminished yield of 35% for 40b, and the vanadium
reagents also failed completely in the case of the 11-
membered ring (Entry e). Titanium reagents have a
Scheme 5. Attempted intramolecular acetal coupling.
Israel Journal of Chemistry
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245
Table 2. Pinacol couplings
entry
reagent
ring size
compound
yield
a
b
c
d
e
f
SmI2/HMPA
SmI2/HMPA
SmI2
SmI2
VCl3·3THF/Zn
VCl3·3THF/Zn
11
12
11
12
11
12
40a
40b
40a
40b
40a
40b
84%
74%
21%
52%
0
35%
(a) CS2, AlCl3, 0 °C, 30 min, 66%, 90%; (b) NaBH4, CeCl3,
MeOH, 0 °C, 57%, 88%; (c) NaOH, BnEt3NCl, CH3CN, 0 °C,
0.5 h; t-BuMe2SiCl, Imidazole, THF, 21 °C, 15 h, 90%, 95%;
(d) n-BuLi, THF, (CHO)2, –78–21 °C, 15 h, 82%, 84%; (e)
Dess-Martin peiodinane CH2Cl2, 21 °C, 15 min, 87%, 93%; (f)
Sml2, THF, HMPA, –78–21 °C, 84%, 74%; (g) DMAP, ClC =
SCl, CH2Cl2, –10 °C, 30 min, 66%, 71%; (h) (MeO)3P, 55 °C,
5 d, 9%; (i) (MeO)3P, 45 °C, 24 h, 75%.
Unsuccessful titanium reagents: TiCl3/K, TiCl4/Zn, TiCl4/
Mg(Hg), CpTiCl3/LiAlH4, TiCl3/LiAlH4, TiCl3/Zn-Cu.
trimethylphosphite. The best procedure was to conduct
the reaction for 4 h at 55 °C to produce a 9% yield of 43.
The yield was reduced to 2% upon direct thermolysis. In
contrast, the 12-membered ring system 44 was formed
in 75% yield when the reaction was conducted at 45 °C
for 24 h. The low yield encountered in the case of the
11-membered ring is likely a consequence of the unfa-
vorable geometry and increased ring strain that results
from introduction of further unsaturation into the
enediyne ring. An attempt to modify the nature of the
acetylene geometry was examined, through the prepara-
tion of the bis-hexacarbonyl cobalt derivative of 41, but
the desired introduction of the double bond was not
observed. Nevertheless, this route has provided the de-
sired compounds 43 and 44.
ACETAL-CONTROLLED ROUTE TO A
10-MEMBERED RING
Scheme 6. Pinacol route to 11- and 12-membered rings.
The knowledge gained above has been extended to the
synthesis of functionalized 10-member rings. It is an-
reputation for being particularly useful for this type of ticipated that appropriate combinations of a biological
transformation,20 but as the list at the bottom of the table recognition agent and an endiyne will afford com-
indicates, none of the reaction combinations listed gave pounds with medicinal potential. We have designed
any of the desired product.
antiestrogen-enediyne hybrid species that will possess
The successful synthesis of the diols, which were a both an anti-estrogenic and cytotoxic component. They
1:1 cis/trans mixture in each case, set the stage for will be linked together by a chain that would be hydro-
introduction of the double bonds using the thio- lyzed after administration, as illustrated in the general
carbonate procedure of Corey and Winter.21 Treatment concept outlined in Scheme 7. For the enediyne compo-
of the diols 40 independently with thiophosgene pro- nent, a stable molecule is required during the synthesis,
vided the thiocarbonates 41 and 42, respectively. Elimi- but the cyclodecenediyne should contain a trigger de-
nation to form 43 proved particularly troublesome, as at vice in order to induce cycloaromatization in the range
40 °C only starting material was recovered and com- of 35–40 °C. A model to explore the potential of this
plete decomposition occurred at 70 °C in the presence of concept has been developed based on a route that em-
Comanita et al. / Routes to α-Alkoxyacetylenes and Enediyne Carbocycles

246
Introduction of the iodine substituent by quenching the
lithium acetylide with iodine provided 48 and set the
stage for the preparation of the iodo-aldehyde 49 by
Dess–Martin periodinane oxidation in 91% yield. Con-
sistent with our previous experience,6 the chromium
mediated condensation produced variable yields, and in
the best case the reaction was conducted at room tem-
perature (21 °C), with excess chromium dichloride and
a catalytic amount of nickel dichloride to afford the
desired compound 50 in 71% yield (average 57%).
Scheme 7. Antiestrogen-enediyne hybrids.
ploys an isopropylidene acetal tether control group. This
principle has proved very useful in our intramolecular
Diels–Alder studies directed toward paclitaxel and re-
lated natural products.22
CONCLUSIONS
This basic strategy for the synthesis of the enediyne
50 is outlined in Scheme 8. The known acetal 46 was
derived from diethyl tartrate.23 The acetal will act as a
control group to facilitate the 10-membered ring cy-
clization. In addition, upon deprotection, the useful
functionality is restored. In addition, the strain inherent
in the trans isopropylidene moiety should inhibit
Bergman cyclization initially, but allow the required
close acetylene contact required upon hydrolysis to the
diol. Eventually the enediyne will be linked to a steroi-
dal or a tamoxifen mimic, which is known to interact
with the breast cancer receptor. As illustrated, the
enediyne component 8 was condensed with the alde-
hyde 45 and the resulting secondary alcohol 46a (3:1
ratio) protected as its benzyl ether. The silyl groups
were removed with tetrabutylammonium fluoride in
THF to provide the acetylene-alcohol 47 in 96% yield.
In summary, these investigations provide a direct route
to simple alkoxypropargylic systems, from sensitive
substrates, under mild Lewis acid conditions without
excess reactant. Selection of the appropriate substitution
pattern provides direct access to trisubstituted cyclo-
pentene systems. A pinacol-based coupling route has
been developed to 11- and 12-membered enediyne
carbocycles, and this has been extended to a highly
substituted 10-membered ring based on an acetal tether
control strategy employing chromium/nickel-mediated
cyclization.
EXPERIMENTAL
General
Melting points were determined in capillary tubes with a
Thomas–Hoover unit-melt apparatus and are uncorrected. In-
frared (IR) spectra were recorded on a Bomem Michelson 100
FTIR spectrometer. Proton magnetic resonance spectra
(1H NMR) were measured at 200 MHz with a Varian Gemini
spectrometer, at 300 MHz with a Varian XL-300 spectrom-
eter, or at 500 MHz with a Brüker AMX500 spectrometer in
deuterochloroform, unless otherwise stated. Carbon magnetic
resonance spectra (13C NMR) were measured at 50 MHz
(Varian Gemini), at 75 MHz (Varian XL-300), or at 125 MHz
(Brüker). The residual CHCl3 signal was used as an internal
1
reference, CDCl3 H; δ 7.24 ppm; 13C; δ 77.0 ppm. Chemical
shifts are reported in ppm downfield from trimethylsilane (δ
scale). The multiplicity, coupling constants (Hz), and number
of protons are indicated in parentheses. Mass spectra (MS)
were determined on a V.G. micromass 7070 HS instrument
using an ionization energy of 70 eV. Elemental analyses were
conducted by M-H-W Laboratories, Phoenix, AZ, USA. The
purity of all title compounds was judged to be >95% as deter-
mined by a combination of GC-MS, 1H NMR, and 13C NMR
analyses.
Unless otherwise stated, all nonaqueous reactions were
performed under an atmosphere of nitrogen in flame-dried
glassware equipped with a magnetic stirring bar and a rubber
septum. Standard inert atmosphere techniques were used in
handling all air- and moisture-sensitive reagents. Reactions
were monitored by analytical thin layer chromatography
(TLC) using commercial aluminum sheets precoated (0.2 mm
Scheme 8. Acetal-controlled route to cyclodecaenediyne 50.
Israel Journal of Chemistry
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2000

247
layer thickness) with silica gel 60 F254 (E. Merck). Product replaced with methylene dichloride (10 mL). Malondial-
purification employed flash column chromatography using E. dehyde tetramethylacetal (15) (0.6 mL, 3.6 mmol) was added
Merck silica gel 60 (230–400 mesh). Solutions in organic and the reaction was stirred for 16 h at 0 °C. The reaction was
solvents were dried over anhydrous magnesium sulfate and quenched with water, extracted with ether, and washed with
stripped of solvents with a Büchi rotatory evaporator con- 10% aqueous potassium sodium tartrate solution until the
nected to a water aspirator. Trace solvents were removed on a organic phase was clear. The organic phase was dried
vacuum pump. All compounds were stored at –15 °C in vials (MgSO4). The mixture was filtered, concentrated, and
flushed with nitrogen.
chromatographed (ether/petroleum ether, 1:5) to afford 20
Petroleum ether refers to a mixture of hydrocarbons with a (37%, 0.4 g).
boiling range of 30–60 °C. Anhydrous diethyl ether (ether)
Method C. Triisopropylsilylacetylene (12) (0.26 mL,
and anhydrous tetrahydrofuran (THF) were distilled from ben-
zophenone/sodium. Dry benzene, toluene, dichloromethane
(CH2Cl2), and triethylamine were distilled from calcium hy-
dride, and ethanol was distilled from lithium aluminum hy-
dride. Commercial starting materials were purchased from
Aldrich Chemical Company unless otherwise indicated.
1.2 mmol) was dissolved in hexane (2 mL), cooled to 0 °C, and
n-butyllithium (0.47 mL, 4.4 mmol, 2.5 M solution in hex-
anes) was added. After stirring for 15 min, the solution was
transferred via cannula into aluminum trichloride (0.072 g,
0.54 mmol) and stirred for an additional 30 min. The solvent
was evaporated under a stream of nitrogen and the solvent
replaced with methylene dichloride (3 mL). Malondialdehyde
tetramethylacetal (15) (0.09 mL, 0.54 mmol) was added and
the reaction was stirred for 16 h at 0 °C, followed by further
stirring for 24 h at 21 °C. The reaction was quenched with
water, extracted with ether, and washed with 10% aqueous
potassium sodium tartrate solution until the organic phase was
clear. The organic phase was dried (MgSO4). The mixture was
filtered, concentrated, and chromatographed (ether/petroleum
1-Trimethylsilyl-4-phenyl-3-methoxy-1-butyne (17)
Trimethysilylacetylene (11) (0.7 mL, 5 mmol) was dis-
solved in ether (12.5 mL) cooled to 0 °C, n-butyllithium (2.25
mL, 5.6 mmol, 2.5 M solution of in hexanes) was added,
followed in 15 min by zinc dichloride (5.5 mL, 5.5 mmol, 1M
solution in ether). The reaction was stirred for 30 min, and
phenylacetaldehyde dimethylacetal (13) (0.9 g, 5.4 mmol) was
added, followed immediately by boron trifluoride etherate
(0.93 mL, 6.2 mmol). The reaction was quenched after 4 h
with methanol, washed with saturated aqueous sodium bicar-
bonate, brine, and dried (MgSO4). The mixture was filtered,
concentrated, and chromatographed (ether/petroleum ether,
1:5) to afford 17 (81%, 0.96 g). 1H NMR (200 MHz, CDCl3) δ
7.2 (m, 5H), 4.1 (t, J = 6.7 Hz, 1H), 3.4 (s, 3H), 3.0 (m, 2H),
0.1 (s, 9H); 13C NMR (200 MHz, CDCl3) δ –0.1, 42.0, 56.5,
72.6, 91.5, 103.8, 126.5, 128.1, 128.2, 129.4, 129.7, 137.2; IR
(NaCl, neat) 3061, 3028, 2954, 2865, 2169, 1694, 1601; MS
232 (M+, 0.6), 217 (M+-Me 16), 141 (100); HRMS (EI): calcd
for C13H17OSi (M+-Me) 217.1048, found 217.1038.
1
ether, 1:5) to afford 20 (33%, 0.06 g). H NMR (200 MHz,
CDCl3) δ 4.6 (t, J = 5.9 Hz, 1H), 4.0 (t, J = 6.7 Hz, 1H), 3.4 (s,
3H), 3.3 (s, 6H), 1.7-2.1 (m, 2H), 1.0 (s, 21H); 13C NMR (200
MHz, CDCl3) δ 11.1, 18.5, 39.1, 53.1, 53.6, 56.2, 68.2, 87.1,
102.0, 105.7; IR (NaCl, neat) 2908, 2167, 1731, 1457, 1378,
1071 cm–1; MS 283 (M+-OMe, 1.9), 271 (M+-iPr, 16), 213 (92),
105 (100); HRMS (EI): calcd for C14H27O3Si (M+-i-Pr)
271.1729, found 271.1718.
1-Triisopropylsilyl-3-methoxy-3-(3′-cyclohexenyl)-1-
1
propyne (18). Method A. 18 (54%, 0.29 g). H NMR (200
MHz, CDCl3) δ 5.6 (bs, 2H), 3.84 and 3.82 (2d, J = 4 .0 Hz,
J = 4.4 Hz, 1H), 3.4 (s, 3H), 1.8–2.2 (7H), 1.1 (bs, 21H); 13
C
General Methods for Silylacetylene Addition
NMR (200 MHz, CDCl3) δ 11.2, 18.6, 22.7, 24.4, 24.8, 24.9,
27.2, 27.6, 38.7, 56.5, 75.8, 76.0, 87.4, 105.2, 105.3, 125.9,
126.1, 126.8, 127.0; IR (NaCl, neat) 3023, 2946, 2858, 2165,
1457, cm–1; MS 305 (M+-H, 0.3), 291 (M+-Me, 12), 263 (M+-
iPr, 23), 75 (100); HRMS (EI): calcd for C18H31OSi (M+-Me)
291.2144, found 291.2178.
5-Triisopropylsilyl-3-methoxy-4-pentyn-1-al dimethyl ac-
etal (20). Method A. Triisopropylsilylacetylene (12) (0.515
mL, 2.3 mmol) was dissolved in ether (4 mL), cooled to 0 °C,
n-butyllithium (1.012 mL, 2.5 mmol, 2.5 M solution in hex-
ane) was added, followed 15 min later by zinc dichloride (2.5
mL, 2.5 mmol, 1 M solution in ether). The reaction was stirred
for 30 min, malondialdehyde tetramethylacetal (15) (0.46 g,
2.5 mmol) was added, followed by borontrifluoride etherate
(0.31 mL, 2.5 mmol). The reaction was quenched after 16 h
with methanol, washed with saturated aqueous sodium bicar-
bonate, brine, and dried (MgSO4). The mixture was filtered
concentrated and chromatographed (ether/petroleum ether,
1:5) to afford 20 (18%, 0.128 g).
5-Trimethylsilyl-3-methoxy-4-pentyne-1-al dimethyl ac-
etal (19). Method A. 19 (23%, 0.128 g). 1H NMR (200 MHz,
CDCl3) δ 4.54 (t, J = 5.9 Hz, 1H), 4.0 (t, J = 6.4 Hz, 1H), 3.4 (s,
3H), 3.3 (s, 6H), 1.8–2.1 (m, 2H), 0.1 (s, 9H); 13C NMR (200
MHz, CDCl3) δ –0.1, 38.7, 52.9, 53.3, 56.3, 68.1, 90.9, 101.6,
103.7; IR (NaCl, neat) 2940, 2828, 2170, 1455, 1380 cm–1; MS
215 (M+-Me, 0.6), 200 (M+-2Me, 1), 199 (M+-OMe, 3), 141
(19), 75 (100); HRMS (EI): calcd for C10H19O3Si (M+-Me)
215.1103, found 215.1115.
Method B. Triisopropylsilylacetylene (12) (0.9 mL,
4 mmol) was dissolved in hexane (8 mL), cooled to 0 °C, and
n-butyllithium (1.78 mL, 4.4 mmol, 2.5 M solution in hex-
anes) was added. After stirring for 15 min, the solution was (21). Method B. 21 (27%, 0.063 g). H NMR (200 MHz,
transferred via cannula into aluminum trichloride (0.49 g, CDCl3) δ 4.7 (t, 3J =5.9Hz, 1H), 4.1(t, J = 6.5 Hz, 1H), 3.4 (m,
3.7 mmol) and stirred for an additional 30 min. The solvent 6H), 1.7–2.1 (m, 2H), 1.2 (t, J = 7 Hz, 9H), 1.0 (s, 21H);
was evaporated under a stream of nitrogen and the solvent 13C NMR (200 MHz, CDCl3) δ 11.1, 15.1, 15.3, 18.6, 40.3, 61.5,
5-Triisopropylsilyl-3-ethoxy-4-pentyne-1-al diethyl acetal
1
Comanita et al. / Routes to α-Alkoxyacetylenes and Enediyne Carbocycles

248
62.1, 64.0, 66.5, 100.3, 106.6; IR (NaCl, neat) 2913, 2166, 1458, (54%, 0.7 g). 1H NMR (200 MHz, CDCl3) δ 4.3 (m, 1H), 3.9
1367, 1078 cm–1; MS 313 (M+-i-Pr, 19), 241 (100); HRMS (EI): (m, 1H), 3.3 (s, 3H), 3.2 (s, 6H), 2.4 (d, J = 2.0 Hz, 1H), 1.7 (m,
calcd for C17H33O3Si (M+-i-Pr) 313.2199, found 313.2204.
4H); 13C NMR (200 MHz, CDCl3) δ 27.9, 30.4, 52.6, 56.3,
70.5, 73.9, 82.2, 104.0; IR (NaCl, neat) 3273, 2935, 2828,
2109, 1453, 1092 cm–1; MS-EI 172 (0.03), 171 (0.3), 141
(2.2), 109 (24.7), 75 (100); HRMS (EI): calcd for C8H13O2,
(M+-MeO)found 141.09344.
4-Methoxy-6-trimethylsilyl-5-hexynal dimethylacetal (24).
2,5-Dimethoxytetrahyrofuran (23) (0.330 mL, 2.5 mmol) was
dissolved in methylene chloride (10 mL), bis-(trimethylsilyl)
acetylene (22) (0.56 mL, 2.5 mmol) was added, the reaction
cooled to –78 °C, and treated with titanium tetrachloride
(Z)-4-Methoxy-10-trimethylsilyl-7-decene-5,9-diyne-1-al
(0.375 mL, 1M solution in methylene chloride). The reaction dimethyl acetal (29). Trimethylsilylacetylene (11) (3 mL, 21
was stirred for 30 min, quenched with excess methanol, and mmol), cis-dichloroethylene (3 mL, 42 mmol), and n-buty-
warmed to room temperature (21 °C). The solution was lamine (10 mL, 100 mmol) were dissolved in ether (50 mL).
washed with aqueous 10% HCl, water, and dried (MgSO4). Tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) and
The organic phase was filtered, concentrated, and chroma- copper iodide (0.4 g, 2.2 mmol) were added and the reaction
tographed (ether/petroleum ether, 1:4) to afford 24 (51%, was stirred under nitrogen for 15 h. The reaction mixture was
0.310 g). 1H NMR (200 MHz, CDCl3) δ 4.3–4.4 (m, 1H), 3.9– concentrated, petroleum ether added (50 mL), filtered through
4.0 (m, 1H), 3.3 (s, 3H), 3.2 (s. 6H), 1.6–1.8 (m, 4H), 0.1 (s, a plug of Celite®, reconcentrated, and chromatographed (ether/
9H); 13C NMR (200 MHz, CDCl3) δ –0.1. 27.9, 30.4, 52.5, petroleum ether, 1:9) to afford the pure enyne (28) (57%, 2.0
56.3, 71.1, 90.6, 104.0, ; IR (NaCl) 2950, 2856, 2169, 1727, g). The alkyne (27) (0.172 g, 1 mmol), eneyne (28) (0.16 g, 1
1453, 1250 cm–1; MS 244 (0.1), 229 (0.3), 198(3.6), 182 (5.4), mmol), and n-butylamine (1 mL, 10 mmol) were dissolved in
154 (12.7), 141 (20.2), 75(100); HRMS (EI): calcd for (M+-) ether (10 mL). Tetrakis(triphenylphosphine)palladium (0.05
C11H21O3Si (M+-Me) 229.1260, found 229.1250.
g, 0.05 mmol) and copper iodide (0.04 g, 0.21 mmol) were
added and stirring continued for 15 h. Ether (50 mL) was
added to the reaction mixture, filtered through a plug of
Celite®, concentrated and chromatographed (ether/petroleum
ether, 1:4) to afford enediyne 29 (40%, 0.120 g). 1H NMR (200
MHz, CDCl3) δ 5.8 (m, 2H), 4.4 (m, 1H), 4.1 (m, 1H), 3.4 (s,
3H), 3.3 (s, 6H), 1.7 (m, 4H), 0.1 (s, 9H); 13C NMR (200 MHz,
CDCl3) δ –0.3, 28.0, 30.4, 30.5, 52.6, 56.5, 71.2, 83.3, 95.8,
101.8, 102.9, 104.1, 119.8, 110.0; IR (NaCl, neat)2954, 2858,
2827, 2145, 1453, 1251, 1093 cm–1; MS-EI 293 (0.04), 279
(0.17), 263 (5.22), 191 (26.8), 159 (17.2), 89 (27.3), 75 (100);
HRMS (EI): calcd for C15H23O2Si (M+-MeO) 263.1467, found
263.1467.
1-Trimethysilyl-3-methoxymethyloxy-6-methoxy-1-
cyclohexene (25). Acetal (24) (0.110 g, 0.45 mmol) was
dissolved in methylene chloride, (10 mL) bis-(trimethylsilyl)
acetylene (22) (0.3 mL, 1.3 mmol, 1.3 equiv), was added, the
reaction cooled to –78 °C, and treated with titanium tetrachlo-
ride (0.7 mL, 1M solution in methylene chloride). The reaction
was stirred for 30 min, quenched with excess methanol, and
warmed to 21 °C. The solution was washed with aqueous 10%
HCl, water, and dried (MgSO4). The organic phase was fil-
tered, concentrated, and chromatographed (ether/petroleum
1
ether, 1:6) to afford 25 (82%, 0.091 g). H NMR (200 MHz,
CDCl3) δ 5.9 (bs, 1H), 4.71 and 4.64 (AB, J = 6.5 Hz, 2H),
4.1–4.2 (m, 1H), 4.0–4.1 (m, 1H), 3.3 (s, 3H), 3.2 (s, 3H), 1.6–
(Z)-4-Methoxy-7-decene-5,9-diyne-1-al dimethyl acetal
1.9 (m, 4H), 0.9 (s, 9H);13C NMR (200 MHz, CDCl3) δ –0.4, (30). The enediyne (29) (1.4 g, 4.7 mmol) was dissolved in
27.5, 29.4, 55.2, 55.3, 79.57, 79.63, 94.6, 130.4, 158.3; IR THF (4 mL) and added to THF/methanol (10 mL:28 mL)
(NaCl)2952, 2820, 1727, 1637, 1452, 1355, 1247, 1149 cm–1; solution containing potassium carbonate (1 g). The reaction
MS 229 (0.5), 199 (7.1), 182 (14.3), 167 (24.9), 89 (100); MS- was stirred for 2.5 h and ether (25 mL) and water (5 mL)
FAB 555 (0.1), 497(0.2), 459 (1.5), 73.1 (100); HRMS (EI): added. The organic phase was dried (MgSO4), filtered, con-
calcd for C11H21O3Si 229.1260, found 229.1252.
centrated, and chromatographed (ether/petroleum ether, 1:4)
to afford acetal 30 (87%). 1H NMR (200 MHz, CDCl3) δ 5.9
(dd, J = 11 Hz, J = 0.75 Hz, 1H), 5.75 (dd, J = 11 Hz, J = 2.2
Hz, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.4 (s, 3H), 3.2 (s, 6H), 1.7
(m, 5H); 13C NMR (200 MHz, CDCl3) δ 27.9, 30.3, 52.5, 56.3,
71.1, 80.5, 82.8, 84.8, 95.3, 103.9, 118.8, 121.0; IR (NaCl,
neat) 3271, 2937, 2828, 1453, 1387, 1336 cm–1; MS-EI 191
(4.6), 161 (3.9), 159 (13.8),128 (20), 75 (100); HRMS (EI):
calcd for C13H18O3 191.1072, found 191.1061.
4-Methoxy-5-hexyne-1-al dimethyl acetal (27). 2,5-
Dimethoxytetrahydrofuran (23) (0.990 mL, 7.5 mmol) and
bis-trimethylsilylacetylene (22) (1.68 mL, mmol) were dis-
solved in methylene chloride (30 mL), cooled to –78 °C, and
titanium tetrachloride (11.25 mL 1M solution in methylene
chloride) was added. The reaction was stirred for 30 min,
quenched with excess methanol, and warmed to 21 °C. The
solution was washed with aqueous 10% HCl, water, dried
(MgSO4), filtered, and concentrated to afford 25 (1.85 g). This
(Z)-4-Methoxy-10-trimethylsilyl-7-decene-5,9-diyne-1-al
material was dissolved in acetonitrile (10 mL), TEBA (32). Dimethylacetal (29) (0.080 g, 0.27 mmol) was dissolved
(0.35 mmol) was added, followed by 12 M sodium hydroxide in dry acetone (3 mL) and p-toluenesulphonic acid (3 mg). The
solution (2 mL), and stirred at 0 °C for 45 min. The reaction reaction was stirred for 15 h and chloroform added (25 mL).
was quenched with a 1:1 mixture of water and ether (60 mL), The organic phase was washed with water, brine, and dried
the organic phase was washed with water, brine, and dried (MgSO4). The organic phase was filtered, concentrated, and
(MgSO4). The organic phase was filtered, concentrated, and chromatographed (ether/petroleum ether, 1:9) to afford alde-
chromatographed (ether/petroleum ether, 1:19) to afford 27 hyde 32 (63%, 0.042 g). 1H NMR (200 MHz, CDCl3) δ 9.8 (bs,
Israel Journal of Chemistry
40
2000

249
1H), 5.8 (s, 2H), 4.2 (t, 1H), 3.4 (s, 3H), 2.6 (t, 2H), 2.1 (m, tored by TLC and quenched with 10% hydrochloric acid. The
2H), 0.18 (s, 9H); 13C NMR (200 MHz, CDCl3) δ –0.2, 28.1, reaction was concentrated under vacuum, extracted with ethyl
39.5, 56.6, 70.4, 83.8, 94.9, 101.7, 103.1, 119.6, 120.2, 201.5; acetate (3 × 50 mL), the organic phase was extracted with
IR (NaCl, neat) 2950.5, 2825, 2144, 1725, 1446, 1390, 1251, brine. The organic phase was dried (MgSO4), filtered, concen-
1098 cm–1; MS-EI 248 (0.9), 220 (1.2), 191 (11.5)159.0 (10.9), trated, and chromatographed (ether/petroleum ether, 1:2) to
115.1 (11.8)84.0 (100); HRMS (EI): calcd for C14H20O2Si, afford 37a (57%, 3.9 g). 1H NMR (200 MHz, CDCl3) δ 4.26
248.1232, found 248. 1219.
(m, 2H), 2.5 (bs, 2H), 1.4–1.7 (m, 6H), 0.02 (s, 18H); 13C
NMR (200 MHz, CDCl3) δ –0.1, 20.7, 37.0, 62.4, 89.22,
106.8; IR (NaCl) 3359, 2943, 2172, 1397, 1326, 1251 cm–1.
(Z)-4-Methoxy-7-decene-5,9-diyne-1-al (33). Enediyne
(32) (0.11 g, 0.44 mmol) and acetic anhydride (0.084 mL,
0.88 mmol) were dissolved in acetonitrile (2 mL), cesium
fluoride (0.23 g, 1.54 mmol) and sodium bicarbonate (0.037 g)
were added and the reaction was stirred for 3 h. The reaction
mixture was filtered through silica gel, concentrated, and
chromatographed (ether/petroleum ether, 1:7) to afford the
endiyne 33 (89%, 0.069 g). Note: For consistent results, the
CsF should be dried under vacuum for 2 h at 100 °C, acetoni-
trile refluxed over calcium hydride and distilled, and acetic
anhydride refluxed with quinoline and distilled. 1H NMR (200
MHz, CDCl3) δ 9.8 (bs, 1H), 5.9 (d, J = 11 Hz, 1H), 5.75(d, J =
11 Hz, 1H), 4.1 (m, 1H), 3.4 (s, 3H), 2.6 (t, 2H), 2.1 (m, 2H),
1.8 (s, 1H); 13C NMR (200 MHz, CDCl3) δ 28.4, 39.3, 56.4,
71.1, 80.3, 82.6, 84.9, 95.7 118.5, 121.4, 201.2; IR (NaCl,
neat) 3275, 2938, 2825, 1724, 1097 cm–1.
1,10-Ditrimethylsilyl-1,9-decadiyne-3,8-diol (37b). The
parallel reaction with diketone 36b (6.3 g, 20.7 mmol) af-
forded 37b (88%, 6.2 g). 1H NMR (200 MHz, CDCl3) δ 4.23 (t,
J = 6.4 Hz, 2H), 2.1 (bs, 2H), 1.55 (m, 4H), 1.37 (m, 4H), 0.04
(s, 18H); 13C NMR (200 MHz, CDCl3) δ –0.12, 24.7, 37.4,
62.6, 89.3, 106.8; IR (NaCl) 3350, 2919, 2171, 1411, 1251,
1036, 855 cm–1.
3,7-Di(t-butyldimethylsilyloxy)-1,9-ditrimethylsilyl-1,8-
nonadiyne (38a). A sodium hydroxide solution (12 M, 36%
W/W, d = 1.39 g/mL, 24 mL, 288 mmol) was added dropwise
to a cold (0 °C), stirred solution containing 1,9-ditri-
methylsilyl-1,8-decadiyne-3,7-diol (37a) (8.27 g, 28.3 mmol),
benzyltriethylammonium chloride (0.3 g) in acetonitrile (25
mL) for 30 min. The reaction mixture was diluted with ether,
washed with water, brine, dried (MgSO4), filtered, concen-
trated, to give the diacetylene (4 g, 26.7 mmol). This material
and imidazole (9.5 g, 140.4 mmole) were dissolved in tetrahy-
drofuran (20 mL), a THF solution (20 mL) containing tert-
butyldimethylsilylchloride (9.75 g, 65 mmol) was added. The
reaction stirred for 15 h, petroleum ether and 1M hydrochloric
acid added, and the organic phase was washed with aqueous
saturated sodium bicarbonate and brine. The organic extracts
were filtered, concentrated, and chromatographed (ether/pe-
troleum ether, 1:30) to afford 38a (90%, 9.1 g). 1H NMR (200
MHz, CDCl3) δ 4.3 (m, 2H), 2.3 (d, J = 2.1 Hz, 2H), 1.4-1.8
6H), 0.9 (s, 18H), 0.09 (d, 12H); 13C NMR (200 MHz, CDCl3)
δ –5.0, –4.5, 18.1, 21.0, 25.8, 38.2, 62.6, 72.1, 85.5; IR (NaCl)
3303, 2910, 1467 cm–1; MS 380 (0.05), 323 (17.4), 147 (79.6),
73 (100); HRMS (EI): calcd for C17H31O2Si2 (M+-t-Bu)
323.1862, found 323.1858.
3,7-Dioxo-1,9-ditrimethylsilyl-1,8-nonadiyne (36a). A so-
lution of glutaryl chloride (35a) (2.94 mL, 23 mmol) and bis-
trimethylsilylacetylene (22) (10.39 mL, 46 mmol) in carbon
disulfide (10 mL) was added via syringe pump (30 minutes) to
a stirred suspension of aluminum trichloride (6.14 g, 46 mmol)
in carbon disulfide (50 mL) at 0 °C. The reaction was stirred
for 30 min and the resulting brown suspension was poured
over crushed ice, and the organic phase was washed (4×) with
10% hydrochloric acid, followed by brine, dried (MgSO4),
filtered, concentrated, and chromatographed (ether/petroleum
1
ether, 1:4) to afford 36a (66%, 4.4 g). H NMR (200 MHz,
CDCl3) δ 2.5 (t, J = 7.1 Hz, 4H), 1.8 (qv, J = 7.1 Hz, 2H), 0.08
(s, 18H); 13C NMR (200 MHz, CDCl3) δ –0.08, 17.6, 43.8,
43.9, 98.14, 101.7, 186.5; IR (NaCl) 2919, 2900.8, 2150.2,
1677.3, 1253. 1108, 860.9 cm–1; MS 277.1 (16.2), 167.1
(18.6), 125 (100), 97 (41.1), 73 (59); HRMS (EI): calcd for
C14H21O2Si2 277.1080, found 277.1091; Anal. Calcd for
C12H24O2Si2: C, 61.58; H, 8.26. Found: C, 61.42; H, 8.25.
3,8-Di(t-butyldimethylsilyloxy)-1,10-ditrimethylsilyl-1,9-
decadiyne (38b).
A parallel reaction with 1,10-
3,8-Dioxo-1,10-ditrimethylsilyl-1,9-decadiyne (36b). A
parallel reaction with adipoyl chloride (35b) (3.36 mL, 23
mmol) gave 36b as a yellow liquid (90%, 6.3 g) 1H NMR (200
ditrimethylsilyl-1,9-decadiyne-3,8-diol (37b) (4.8 g, 15.5
mmol) gave 38b (95%, 5.8 g). 1H NMR (200 MHz, CDCl3) δ
4.23 (dt, J = 6 Hz, J = 2 Hz, 2H), 2.26 (d, J = 2 Hz, 2H), 1.6 (m,
4H), 1.3 (m, 4H), 0.8 (s, 18 H), 0.0 (2s, 12 H); 13C NMR (200
MHz, CDCl3) δ –5.1, –4.5, 18.2, 24.7, 25.7, 38.5, 62.6, 71.9,
85.6; IR (NaCl) 3307, 2943, 2859, 1467, 1361, 1254, 1081, 841,
779 cm–1; MS 337 (11), 263 (7.5), 243 (8.1), 189 (12.2), 169
(11.3), 147 (100), 131 (14.6), 91 (14.3), 73 (83); HRMS (EI):
calcd for C18H33O2Si2 337.2019, found 337.2052; Anal. Calcd
for C22H42O2Si2: C, 66.94; H, 10.72. Found: C, 66.79; H, 10.84.
MHz, CDCl3) δ 2.44 (m, 4H), 1.55 (m, 4H), 0.1 (s, 18H); 13
C
NMR (200 MHz, CDCl3) δ –0.8, 22.9, 44.7, 97.8, 101.8, 187;
IR (NaCl) cm–1 2943, 2150, 2092, 1676, 1407, 1357, 1252,
1109, 1045, 859, 762 cm–1; MS 291 (13), 263 (2.6), 193(2.4),
173 (4.2), 155(8.7), 140 (15.7), 125 (93.7), 97 (41,6), 73 (100);
HRMS (EI): calcd for C15H23O2Si2 291.1236, found 291.1219.
1,9-Ditrimethylsilyl-1,8-nonadiyne-3,7-diol (37a). The
diketone 36a (4.4 g, 14.95 mmol) was dissolved in methanol
(500 mL), cerium trichloride heptahydrate (51 g, 138 mmol)
4,8-Di(t-butyldimethylsilyloxy)-2,9-diyne-1,11-
was added and the reaction stirred for 10 min. The solution undecadiol. The diyne (38a) (5.5 g, 14.5 mmol) was dissolved
was cooled to 0 °C, sodium borohydride (6.96 g, 184 mmol) in tetrahydrofuran (100 mL), cooled to –78 °C and n-butylli-
was added in portions portionwise, and the reaction was moni- thium (13 mL, 33 mmol, 2.5 M solution in hexanes)was added
Comanita et al. / Routes to α-Alkoxyacetylenes and Enediyne Carbocycles

250
dropwise. After 15 min, paraformaldehyde (4.3 g, 145 mmol) added. The organic phase was washed with brine and dried
(previously dried under water aspirator vacuum for two hours (MgSO4). The solution was filtered, concentrated, and
at 80°C) was added, the bath removed, the reaction mixture chromatographed (ether/petroleum ether, 1:2.5) to yield 40a
1
stirred for 15 h at 21 °C. Saturated ammonium chloride solu- (84%, 0.081 g). H NMR (200 MHz, CDCl3) δ 4.3–4.5 (bs,
tion was added followed by ether and the extracts washed with 4H), 2.7–2.9 (bs, 1H), 2.5–2.7 (bs, 1H), 1.5–2.0 (m, 6H), 0.8
brine. The organic extracts were dried (MgSO4), filtered, con- (s, 18H), 0.08 (d. 12H); 13C NMR (200 MHz, CDCl3) δ –5.0,
centrated, and chromatographed (ether/petroleum ether, 1:5) –4.9, –4.6, –4.3, 18.2, 19.7, 20.1, 25.8, 37.0, 63.4, 63.5, 68.0,
to afford the diol (82%, 5.2 g). 1H NMR (200 MHz, CDCl3) δ 68.1, 82.8, 89.6; IR (NaCl) 3363, 2910, 1466 cm–1; Anal. Calcd
4.3 (m, 2H), 4.2 (s, 4H), 2.7–2.9 (bs, 2H), 1.5-1.8 (m, 6H), 0.8 for C23H42O4Si2: C, 62.96; H 9.64. Found: C 63.32; H 9.75.
(s, 18H), 0.06 (d, 6H); 13C NMR (200 MHz, CDCl3) δ –5.0,
5,10-Di(t-butyldimethylsilyloxy)-3,11-cyclododecadiyne-
–4.5, 18.1, 20.7, 20.9, 25.7, 38.0, 50.8, 62.9, 82.5, 86.9; IR
1,2-diol (40b). The parallel method with dialdehyde 39b
(NaCl) 3344, 2942, 2858, 1466 cm–1; MS 422.8 (M+-H2O,
1
(0.1 g, 0.22 mmol) afforded the diol 40b (74%, 0.074 g). H
2.5), 382.9 (M+-t-Bu, 1.7), 364.9 (4.1), 291 (100).
NMR (200 MHz, CDCl3) δ 4.4–4.7 (m, 4H), 2.5–2.8 (m, 2H),
1.6–1.9 (m, 8H), .95 (bs, 18H), 0.15 (bs, 12 H); 13C NMR (200
MHz, CDCl3) δ –5.0, –4.9, –4.5, 18.21, 23.1, 23.3, 23.6 23.7,
25.8, 36.3, 36.4, 36.7, 62.7, 62.8, 63.04, 63.2, 67.1, 67.2, 81.7,
81.8, 89.0, 89.1; IR (NaCl) 3373, 2942, 2858, 1254, 1075.7,
842.2 cm–1; Anal. Calcd for C24H44O4Si2: C, 63.66; H 9.79.
Found: C 63.80; H 9.81.
4,9-Di(t-butyldimethylsilyloxy)-2,10-diyne-1,12-
dodecadiol. A parallel reaction with diyne (38b) (1.8 g, 4.5
mmol) afforded the corresponding diol (84%, 1.7 g). 1H NMR
(200 MHz, CDCl3) δ 4.25–4.4 (m, 2H), 4.2 (s, 4H), 2.3–2.5
(bs, 2H), 1.5–1.7 (m, 4H), 1.3–1.5 (m, 4H), 0.8 (s, 18H), 0.07
(d, 6H); 13C NMR (200 MHz, CDCl3) δ –5.0, –4.5, 18.2, 24.7,
25.8, 38.4, 50.9, 62.8, 82.2, 87.3; IR (NaCl) 3355, 2909,
1468.9 cm–1.
Alternative method: Vanadium trichloride tris(tetrahydro-
furan) complex (0.144 g, 0.38 mmol) and zinc (0.014 g,
0.21 mmol) were suspended in methylene chloride (5 mL) and
stirred for 15 min until the solution turned dark green color.
Dialdehyde (39b) (0.05 g, 0.11 mmol) in methylene chloride
(1 mL) was added dropwise and stirred for 3 h. Aqueous
sodium tartrate 10% w/v was added and the reaction mixture
extracted with dichloromethane. The combined extracts were
washed with saturated aqueous sodium bicarbonate, and dried
(MgSO4). The solution was filtered, concentrated, and
chromatographed (ether/petroleum ether, 1:2) to yield 41b
(35%, 0.018 g).
4,8-Di(t-butyldimethylsilyloxy)-2,9-diyne-1,11-undecadial
(39a). Dess-Martin reagent (3.7 g, 8.8 mmol) was added to the
diol (1.8 g, 4 mmol) in methylene chloride (200 mL) and after
15 min, ether (200 mL) was added. The reaction was concen-
trated to ~20 mL and additional ether (300 mL) added fol-
lowed by a 1:1 mixture of 1 M sodium thiosulphate and 1 M
sodium bicarbonate aqueous solution The reaction was stirred
until two clear phases separated. The organic phase was
washed with brine, back extracted with ether, and dried
(MgSO4). The solution was filtered, concentrated, and
chromatographed (ether/petroleum ether, 1:20) to yield 39a
(87%, 1.5 g). 1H NMR (200 MHz, CDCl3) δ 9.2 (s, 2 H), 4.5 (t,
J = 6.1 Hz, 2 H), 1.5–1.7 (m, 6H), 0.8 (s, 18 H), 0.07 (d, 12 H);
13C NMR (200 MHz, CDCl3) δ –5.2, –4.7, 18.0, 20.6, 25.6,
37.1, 62.4, 83.6, 97.2, 176.4; IR (NaCl) 2943, 2858, 2215,
1671, 1467 cm–1; MS-CI (M-1)+, 421; MS-EI 421, 407, 379.
Bicyclo[9.3.0]-3,8-di(t-butyldimethylsilyloxy)-13-thiono-
12,14-dioxa-2,9-tetradecadiyne (41). A methylene dichloride
solution (2 mL) containing the diol (40a) (0.1 g, 0.22 mmol)
and 4-dimethylaminopyridine (0.064 g, 0.53 mmol) was
cooled to –10 °C and thiophosgene (0.02mL, 0.26 mmol)
added dropwise. After 30 min, silica gel (0.4 g) was added, the
reaction was concentrated and chromatographed (ether/petro-
leum ether, 1:20) to afford 43 (66%, 0.074 g). 1H NMR (200
MHz, CDCl3) δ 5.39 (J = 11.3, J = 2.24, 1H), 5.31–5.36 (m,
2H), 5.26 (J = 11.3, J = 1.3, 1H), 1.6–2.0 (m, 6H), 0.9 (d, 18H),
0.07 (d, 12 H); 13C NMR (200 MHz, CDCl3) δ –5.1, –5.0, –4.8,
–4.7, 18.1, 18.6, 18.9, 19.2, 25.7, 38.4, 38.6, 38.9, 63.3, 63.5,
75.0, 75.1, 75.9, 76.0, 100.0, 100.2, 189.3; IR (NaCl) 2910,
2222, 1842, 1465 cm–1; MS 423, (9.4), 363.2 (3.5), 231 (13.5),
147 (25.9), 73 (100); HRMS (EI): calcd for C20H31O4Si2S
423.1498, found 423.1472.
4,9-Di(t-butyldimethylsilyloxy)-2,10-diyne-1,12-
dodecadial (39b). A parallel reaction with the b diol (2.3 g,
5 mmol) gave 39b (93%, 2.1 g). 1H NMR (200 MHz, CDCl3) δ
9.2 (s, 2H), 4.5 (t, J = 6.4 Hz, 2H), 1.6–1.8 (m, 4H), 1.3–1.5
(m, 4H), 0.9 (s, 9H), 0.09 (d, J = 6 Hz, 6H); 13C NMR (200
MHz, CDCl3) δ –5.2, –4.7, 18.1, 24.5, 25.6, 37.5, 62.5, 83.5,
97.5, 176.5; IR (NaCl) 2909, 2215, 1671.6, 1467, 1388 cm–1.
5,9-Di(t-butyldimethylsilyloxy)-3,10-cycloundecadiyne-
1,2-diol (40a). Dialdehyde (39a) (0.1 g, 0.22 mmol) was dis-
solved in tetrahydrofuran (3 mL) in a nitrogen atmosphere and
frozen in liquid nitrogen. Three freeze–thaw cycles were con-
Bicyclo[10.3.0]-3,10-di(t-butyldimethylsilyloxy)-14-
ducted. In a separate flask, dry HMPA (1 mL) and tetrahydro- thiono-13,15-dioxa-2,10-tetradecadiyne (42). A parallel reac-
furan (4 mL) were degassed by the same freeze–thaw proce- tion with diol 40b (0.170 g, 0.37 mmol) afforded 42 (71%,
1
dure. Samarium diiodide (8.8 mL, 0.88 mmol, 0.1M solution 0.129 g). H NMR (500 MHz, CDCl3) δ 5.2–5.4 (2H), (5.35
in tetrahydrofuran was added to the HMPA solution to give a (dd, J = 11.4Hz, J = 2.4Hz, 1H), 5.29 (bs, 2H), 5.24 (dd, J =
dark purple solution which was cooled to –78 °C. The de- 11.4Hz, J = 1.1Hz, 1H), 4.5 (m, 1H), 4.4 (m, 1H), 1.4–1.8 (m,
gassed dialdehyde solution was injected by syringe pump over 8H), 0.87 (bs, 18 H), 0.09 and 0.07(s, 12H); 13C NMR (500
1 h and the reaction was quenched with 1 M hydrochloric acid. MHz, CDCl3) δ –5.1, –4.7, 18.1, 23.7, 23.8, 23.9, 24.2, 25.7,
Ether and aqueous 10% sodium thiosulfate solution were 25.8, 37.0, 37.4, 37.6, 62.6, 62.7, 62.9, 63.0, 74.0, 74.1, 74.3,
Israel Journal of Chemistry
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251
74.5, 75.5, 75.6, 97.9, 98.0, 189.5; IR (NaCl) 2911, 2234,
(2S, 3S, 7Z)-4-Benzyloxy-1-hydroxy-2,3-O-isopro-
1843, 1465 cm–1; MS 437 (4.5), 73 (100); HRMS (EI): calcd pylidenedec-7-en-5,9-diyne-(9-tri-isopropylsilyl)-2,3-diol
for C21H33O4Si2S 437.1655, found 437.1622.
(46b). Alcohol 46a (9.342 g, 18.4 mmol) was transfered via
canula to an ice cold (0 °C) solution of NaH (60% suspension
in mineral oil, 25 mg, 0.62 mmol) which was previously
washed with pentane (3 × 45 mL) prior to the addition of THF
(10 mL). The resulting brown solution was stirred for 20 min
at 0 °C followed by the dropwise addition (syringe) of benzyl
bromide (3.462 g, 20.24 mmol). The reaction was allowed to
warm to 21 °C and stirred for 17 h. Water (50 mL) and ether
(50 mL) were added to the orange-brown solution and the
mixture stirred for further 2 h. The aqueous and organic phases
were separated. The aqueous fraction was extracted with ether
(3 × 20 mL). The organic extracts were washed with brine and
dried (MgSO4). The solution was filtered, concentrated, and
chromatographed (ether/petroleum ether, 1:20) to afford 46b
(88%, 7.90 g) as a colorless oil and recovered starting mate-
rial, 46a (1.7 g). 1H NMR (500 MHz, CDCl3) δ 0.09 (s, 6H),
0.97 (s, 9H), 1.05–1.11 (m, 3H), 1.15 (d, 18H, J = 6.5 Hz),
1.46 (s, 6H), 3.83-3.86 (m, 1H), 3.99-4.02 (m, 1H), 4.40 (d,
1H, J = 3.2 Hz), 4.40–4.50 (m, 1H), 4.53 (d, 1H, J = 11.7 Hz),
4.59 (d, 1H, J = 2.9 Hz), 4.93 (d, 1H, J = 11.7 Hz), 4.89–5.55
(m, 2H), 7.06–7.34 (m, 5H); 13C NMR (125 MHz, CDCl3) δ
–5.2, –5.1, 11.6, 18.9, 26.1, 27.3, 27.7, 64.5, 71.2, 71.4, 78.9,
79.6, 85.1, 94.3, 100.1, 104.4, 110.0, 119.7, 120.6, 127.9,
128.0, 128.2, 128.5, 138.2.
7,11-Di(t-butyldimethylsilyloxy)-3-ene-1,5-cyclounde-
cadiyne (43). Thionocarbonate (41) (0.120 g, 0.25 mmol) was
heated in trimethylphosphite at 55 °C for 3 days. The reaction
mixture was concentrated, petroleum ether and aqueous satu-
rated sodium bicarbonate were added. The organic phase was
dried(MgSO4), filtered, concentrated, and chromatographed
(ether/petroleum ether, 1:20) to yield enediyne 43 (9%, 0.009
g). 1H NMR (200 MHz, CDCl3) δ 5.8 (s, 2H), 4.6–4.8 (m, 2H),
1.6–1.9 (m, 6H), 0.8 (s, 18H), 0.1 (s, 12H); 13C NMR (200
MHz, CDCl3) δ –5.0, –4.6, 18.4, 20.1, 25.8, 37.2, 63.4, 82.1,
98.2, 120.3; IR (NaCl) 2950, 2850, 1468, 1339 cm–1; MS
347.1 (12.6), 271 (7.9), 215 (25), 141 (41), 73 (100); HRMS
(EI): calcd for C19H31O2Si2, 347.1862, found 347.1858.
7,12-Di(t-butyldimethylsilyloxy)-3-ene-1,5-cyclo-
dodecadiyne (44). Thionocarbonate (42) (1 g, 2 mmol) was
dissolved in trimethylphosphite (20 mL) and heated at 45 °C
for 24 h. The reaction mixture was concentrated, petroleum
ether and aqueous saturated sodium bicarbonate were added.
The organic phase was dried(MgSO4), filtered, concentrated,
and chromatographed (ether/petroleum ether, 1:20) to yield
enediyne 44 (75%, 0.62 g). 1H NMR (200 MHz, CDCl3) δ 5.8
(s, 2H), 4.6 (m, 2H), 1.6–1.9 (m, 8H), 0.9 (s, 18 H), 0.08 and
0.1 (2s, 12H); 13C NMR (200 MHz, CDCl3) δ –4.9, –4.5, 18.3,
23.8, 24.3, 25.8, 36.7, 36.8, 63.6, 64.0, 82.9, 98.5, 98.7, 120.6;
IR (NaCl) 2810, 2234, 1468, 1337 cm–1; MS 361 (12.6), 229
(28), 155 (30.6), 73 (100); HRMS (EI): calcd for C20H33O2Si2
361.2019, found 361.2038.
(2S, 3S, 7Z)-4-Benzyloxy-1-hydroxy-2,3-O-isopro-
pylidenedec-7-en-5,9-diyne-2,3-diol (47). t-Butyl ammonium
fluoride (1M in THF, 3.59 mL, 3.59 mmol) was added to THF
(15 mL) at –78 °C containing 46b (1.023 g, 1.171 mmol). The
reaction was stirred at –78 °C for 2 h, for a further 2 h at 0 °C,
water was added, and stirring was continued for a further 20
min. Ether (2 mL) was added, the aqueous fraction which was
extracted with ether (3 × 15 mL). The organic extracts were
washed with brine and dried (MgSO4). The solution was fil-
tered, concentrated, and chromatographed (ether/petroleum
ether, 1:1) to afford 47 (93%, 519 mg) as a colorless oil. IR
(neat) 3459, 3285, 3033, 2987, 2910, 2096, 1496, 1455, 1377,
1248, 1215, 1165, 1060, 906, 854 cm–1; 1H NMR (500 MHz,
C6D6) δ 1.34 (s, 3H), 1.37 (s, 3H), 1.88 (br s, 1H), 2.97 (s, 1H),
3.70–3.81 (m, 2H), 4.16–4.28 (m, 2H), 4.40–4.43 (m, 1H),
4.48 (d, 1H, J = 11.8 Hz), 4.84 (d, 1H, J = 11.8 Hz), 5.35 (d,
1H, J = 11.0 Hz), 5.44 (d, 1H, J = 11.0 Hz), 7.05–7.32 (m, 5H);
13C NMR (125 MHz, C6D6)δ 27.0, 27.4, 63.2, 70.4, 71.2, 79.1,
79.6, 81.0, 84.9, 85.7, 93.8, 109.8, 119.8, 120.9, 127.8, 128.0,
128.2, 128.8, 137.8; HRMS (EI): calcd for C19H19O4 (M+-Me)
311.1283, found 311.1271.
(2S, 3S, 7Z)-4-Hydroxy-1-tert-butyldimethylsilyloxy-2,3-
O-isopropylidenedec-7-en-(9-tri-isopropylsilyl)-5-9-diyne-
2,3-diol (46a). n-Butyllithium (2.56 M in THF, 11.47 mL,
29.36 mmol) was added slowly to a cold (–78 °C) solution of
1-(triisopropylsilyl)-3-hexen-1,5-diyne (8) (6.500g,
27.96 mmol) in THF (100 mL). The initial yellow solution
turned dark brown. The reaction was stirred for 20 min and a
solution of freshly distilled 45 (3.837 g, 13.98 mmol) in THF
(15 mL) was added dropwise. The reaction was stirred at –78 °C
for an additional 30 min and warmed to 0 °C. Water (50 mL)
and ether (50 mL) were added and the phases were separated.
The aqueous fraction was extracted with ether (3 × 50 mL).
The organic extracts were washed with brine and dried
(MgSO4). The solution was filtered, concentrated, and
chromatographed (ether/petroleum ether, 1:10 to 1:5) to afford
46a (86%, 6.1 g) as an orange oil. IR (neat) 3435, 2942, 2864,
2361, 2339, 1464, 1379, 1252, 1142, 1083, 1018, 882, 837 cm–1;
1H NMR (500 MHz, CDCl3) δ 0.05 (s, 3H), 0.05 (s, 3H), 0.93
(2S, 3S, 7Z)-4-Benzyloxy-1-hydroxy-2,3-O-isopro-
(s, 9H), 1.05–1.14 (m, 3H), 1.17 (d, 18H, J = 6.4 Hz), 1.39 (s, pylidenedec-7-en-5,9-diyne-9-iodo-2,3-diol (48). n-Butyl-
3H), 1.41 (s, 3H), 2.47 (d, 1H, J = 5.2 Hz), 3.80 (dd, 1H, J = lithium (2.56 M in hexanes, 0.29 mL, 0.74 mmol) was added
10.8, 4.3 Hz), 3.83 (dd, 1H, J = 10.8, 4.3 Hz), 4.14–4.25 (m, via syringe to a –78 °C solution of diisopropylamine (78 mg,
2H), 4.70 (ddd, 1H, J = 5.0, 5.0, 1.7 Hz), 5.47 (d, 1H, J = 11.1 0.77 mmol) in THF (10 mL). The reaction was stirred for 5
Hz), 5.51 (d, 1H, J = 11.1 Hz); 13C NMR (125 MHz, CDCl3)δ min at –78 °C, warmed to 0 °C for 20 min and the solution
–5.4, –5.3, 11.6, 18.9, 26.1, 27.2, 27.5, 64.1, 64.4, 75.0, 80.5, recooled to –78 °C. A solution of 47 (115 mg, 0.35 mmol) in
83.9, 95.8, 99.9, 104.4, 109.9, 120.0, 120.5; HRMS (EI): calcd THF (1 mL) was added and stirring was continued for 1 h.
for C27H47O4Si2 (M+-Me) 491.3015, found 491.3001.
Iodine (89.5 mg, 0.35 mmol) addition produced an orange-
Comanita et al. / Routes to α-Alkoxyacetylenes and Enediyne Carbocycles

252
brown solution The reaction was stirred at –78 °C for a further Engineering Research Council of Canada (NSERC) and the
6.5 h, 1 h at 0 °C, and saturated aqueous Na2SO3 (5 mL) was Canadian Breast Cancer Research Initiative (NCI, Canada),
added. After stirring for 20 min, ether (5 mL) was added and for financial support of this research. Preliminary experiments
the organic and aqueous phases were separated. The aqueous by Y.-F. Lu are appreciated and M.A. Heuft and T. Rietveld
fraction was extracted with ether (3 × 3 mL). The organic thank NSERC for Graduate Scholarships.
extracts were washed with brine and dried (MgSO4). The
solution was filtered, concentrated, and chromatographed
REFERENCES AND NOTES
(ether/petroleum ether, 3:10) to afford 48 (93%, 147 mg) as a
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Chemistry of Acetylenes; Marcel Dekker, Inc.: New
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(s, 3H), 2.20 (br s, 1H), 3.69–3.87 (m, 2H), 4.17–4.24 (m, 2H),
4.40 (d, 1H, J = 3.7 Hz), 4.51 (d, 1H, J = 11.7 Hz), 4.87 (d, 1H,
J = 11.7 Hz), 5.37 (d, 1H, J = 10.9 Hz), 5.47 (d, 1H, J = 10.9
(2) Borders, D.B.; Doyle, T.W., Eds. Enediyne Antibiotics
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27.5, 63.2, 70.5, 71.2, 79.0, 79.8, 85.0, 92.0, 94.0, 109.9,
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(2S, 3S, 7Z)-4-Benzyloxy-1-formyl-2,3-O-isopro-
pylidenedec-7-en-5,9-diyne-2,3-diol (49). Sodium bicarbon-
ate (2.2115g, 26.3 mmol) and Dess-Martin periodinane
(2.3524g, 5.55 mmol) were added to a solution of 48 (2.3847g,
5.27 mmol) in CH2Cl2 (100 mL) and stirred at 21 °C for 1 h. A
1:1 mixture of NaCO3 (aqueous, saturated)/NaS2O3 (aqueous
saturated) (60 mL) was added and stirring continued for 20
min. Ether (40 mL) was added and the phases were separated.
The aqueous fraction was extracted with ether (3 × 30 mL).
The organic extracts were washed with brine and dried
(MgSO4). The solution was filtered, concentrated, and
chromatographed (ether/petroleum ether, 3:2) to afford 49
(91%, 2.165 g) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ
1.19 (s, 3H), 1.38 (s, 3H), 4.32–4.46 (m, 3H), 4.49 (d, 1H, J =
11.8 Hz), 4.86 (d, 1H, J = 11.8 Hz), 5.34 (d, 1H, J = 10.8 Hz),
5.44 (d, 1H, J = 10.9 Hz), 7.07–7.40 (m, 5H), 9.50 (d, 1H, J =
1.5 Hz); 13C NMR (125 MHz, CDCl3)d 26.6, 27.0, 70.3, 71.1,
78.8, 82.5, 82.7, 85.4, 92.0, 93.2, 112.3, 121.0, 121.1, 128.0,
128.3, 128.4, 128.5, 128.6, 137.8, 198.6.
(2S, 3S, 7Z)-4-Benzyloxy-1-hydroxy-2,3-O-isopro-
pylidenecyclodec-7-en-5,9-diyne-9-iodo-2,3-diol (50). A so-
lution of aldehyde 49 (40.0 mg, 0.09 mmol) in THF (2 mL)
was added to a suspension of NiCl2 (3.6 mg, 0.03 mmol) and
CrCl2 (102.5 mg, 0.79 mmol) in THF (5 mL) via syringe and
stirred at 21 °C for 1 h. Ammonium chloride (aq, sat. 3 mL) was
added and stirring continued for 20 min. Ether (5 ≤mL) was
added, the aqueous fraction was extrated with ether (3 × 10 mL).
The organic extracts were washed with brine and dried
(MgSO4). The solution was filtered, concentrated, and
chromatographed (ether/petroleum ether, 1:4) to afford 50
(57%, 12.5 mg) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ
1.39 (s, 3H), 1.53 (s, 3H), 1.94 (br d, 1H, J = 3.0 Hz), 4.38 (d, 1H,
J = 11.7 Hz), 4.52 (dd, 1H, J = 1.8, 1.8 Hz), 4.65 (br s, 1H), 4.73
(d, 1H, J = 11.7 Hz), 4.89 (dd, 1H, J = 5.6, 2.0 Hz), 4.95 (dd, 1H,
J = 5.6, 2.2 Hz), 5.44 (d, 1H, J = 2.5 Hz), 5.45 (d, 1H, 2.5 Hz),
7.04–7.30 (m, 5H); 13C NMR (125 MHz, CDCl3)δ 27.7, 28.1,
63.4, 70.8, 72.0, 80.6, 80.8, 86.7, 87.8, 98.7, 99.6, 111.2,
124.7, 125.2, 127.8, 128.0, 128.2, 128.3, 128.6, 137.9. HRMS
(EI): calcd for C19H17O4 (M+-Me 309.1127, found 309.1119.
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Acknowledgment. We are grateful to the Natural Sciences and
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