Acyloxy Rearrangement-Triggered Regioselective Hydration of ?-Acetoxy-α,β-Alkynoates/Halo Alkynes

Article abstract of DOI:10.1021/acs.joc.0c00061

Herein, we report a simple, efficient, highly regioselective, and broad-scope hydration method that is facilitated by an unusual interception of an electrophilic intermediate by water generated via acetate group participation during [3,3]-acyloxy rearrang

Full text of DOI:10.1021/acs.joc.0c00061

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Article
An [3,3]-Acyloxy Rearrangement-Triggered Regioselective
Hydration of #-Acetoxy-#,#-Alkynoates/Halo Alkynes
Kishor Lahu Mendhekar, Tapas Ranjan Pradhan, and Debendra Kumar Mohapatra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00061 • Publication Date (Web): 10 Mar 2020
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An [3,3]-Acyloxy Rearrangement-Triggered Regioselective Hydration of δ-Acetoxy-α,β-
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Alkynoates/Halo Alkynes
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Kishor L. Mendhekar,a,b Tapas R. Pradhan,a Debendra K. Mohapatraa,b,*
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aDepartment of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, INDIA; mohapatra@iict.res.in
bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh-201 002,
India.
Abstract: Herein, we report a simple, efficient, highly regioselective and broad scope hydration
method that is facilitated by an unusual interception of an electrophilic intermediate by water
generated via acetate group participation during [3,3]-acyloxy rearrangement. Various
carboxylate directing groups including acetate, acrylates, pivalates, benzoate or its derivatives,
and those derived from bioactive natural products were successfully implemented to direct the
regioselective hydration for various functionalized δ-acyloxy-β-ketoesters synthesis. The
reaction pathway was further confirmed by 18O labeling experiments and to the best of our
knowledge, this is the first report of hydration through an electrophilic intermediate generated
during [3,3]-acyloxy rearrangement. Synthetic application includes synthesis of modifiable C5-
carbon chain, 5-, 6- and 7-membered heterocycles and natural product diversification.
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INTRODUCTION
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Hydration reaction, a fundamental and straightforward atom economy route for facile
introduction of carbonyl functionality in to alkyne,1 was classically catalyzed by Lewis acidic
Hg(II)-salts in aqueous acidic solution.2 Since this discovery by Kucherovin 1881, many
catalytic variants including ones catalyzed by Fe,3 Pd,4 Ru,5 Rh,6 Co,7 Ir,8 Sn-W,9 Pt,10 Ag,11
Au12 and Bronsted-acids13 have been developed with each individual method having its’ own
advantages. While most of these studies have mainly focused on hydration of terminal alkynes,
studies to employ unsymmetrical internal alkynes for forming synthons of chemically distinctly
reactive functionalities are limited. For instance, the Au-catalyzed regioselective hydration of
alkynoates,14 complementary to classical base mediated15 and Ti-Claisen condensations,16
provides a reliable method for generating β-keto esters which is still under developed.
Hammond’s report14a (only applied for one substrate) on Au-(III)-catalyzed hydration is the only
example except our recent study14b on neighboring acyloxy-assisted hydration for broad scope
synthesis γ-acetoxy β-ketoesters.
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Owing to the propensity of β-keto esters or its related derivatives as valuable synthons in
synthetic organic chemistry (Scheme 1A),17,15c-e discovery of a method that open a route to
further modifiable unit containing β-keto esters is highly desirable. More importantly, the δ-
hydroxy or acyloxy functionalized intermediates can be easily and selectively manipulated to
structural units present in various potent biologically active natural products having polyhydroxy
functional groups.18 The yet known conventional processes to synthesize δ-hydroxy β-keto esters
are either mediated by strong bases by intercepting the dienolate anion intermediate19 or acid
mediated vinylogous aldol reactions of Chan’s diene20 with an aldehyde (Scheme 1B). While the
former being problematic to substrates having α-chiral aldehydes, the later process is non-atom
economy. Thus, we assumed that an easily accessible δ-hydroxy-α,β-alkynoate can become a
suitable precursor to δ-hydroxy β-keto ester through hydration at distal carbon (β-carbon) of
alkynoate. Inspired by Nolan’s research work based on tandem alkoxylation/intramolecular
interception of oxygen nucleophile (Scheme 1C, left),21 it was anticipated that the use of water
can provide a protocol to regioselectively synthesize open chain β-keto ester (Scheme 1C, right)
through preventing the ring closing event. Considering the relatively difficultness in forming a
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six-membered lactone in compared to its five-membered analogue, the hydration was attempted
under the similar conditions replacing the alcohol with 3 equiv. of water. Unfortunately, the
reaction did not provide the expected hydration product.22 It was therefore surmised that the
catalytic inactivation and competitive cyclization pathways could be suppressed by harnessing
the electronic bias in the form of carboxylate, a recently revealed solution by our research group
for regioselective hydration of alkynoates.14b Intrigued by this finding and our recent success
exploiting carbonyl assisted hydration of alkyne functionality,14b,23 we decided to investigate
whether the yet unknown precedent,24 but highly feasible event of [3,3]-acyloxy rearrangement-
triggered electrophilic intermediate25 A and could be utilized for nucleophilic interception by
water. This regioselectivity likely arises from the thermodynamic stability of six membered ring
size as well as alkyne polarity (i.e. obvious electrophilic nature of β-carbon). Subsequent proto-
deauration and rearrangement-tautomerization would enable to provide a racemization free and
atom economy method for the regiocontrolled synthesis of δ-functionalized β-ketoester (Scheme
1D).
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Scheme 1. Previous Precedents Idealizing Current Reaction Discovery
RESULTS AND DISCUSSION
Keeping the above hypothesis in mind, we initiated the study with a primary δ-acetoxy-α,β-
alkynoate 1a (Table 1). The initial attempt to hydrate 1a under conditions identical to those
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employed in our previous alkyne hydration gave the desired β-ketoester (2a) in 31% and 67%
isolated yield, albeit full conversion of 1a was observed (entries 1 and 2). Furthermore, no
improvement in yield of the hydration products by changing Au-catalysts (entries 3-7) including
Hammond’s hydration conditions (entry 8) led us to study the effect of counter ions,26 whose
crucial role has been displayed in our previous findings on hydration reactions.14b,23b Though the
product isolated from all these conditions is with perfect regioselectivity (entries 9-11), the yield
improvement was still a problematic issue and a maximum of 57% of the hydration product was
obtained from AgNTf2 (entry 10). To our delight, this issue was addressed through solvent
screening (entries 13-16): use of chlorinated solvent (dichloromethane, entry 14) was found to
provide an optimum yield (93%) of 2a because in low dielectric constant solvent, catalyst with
lower gold affinity counter anion, like SbF6⁻, shows higher reactivity.26a,c,d,e As expected, no
reaction was observed in absence of Au(I)-catalyst (entry 16).
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Table 1. Optimization of Reaction Conditionsa
Time
(h)
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yield
2a (%)b
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entrya
Au-cat.
Ag-cat
solvent
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PPh3AuCl
PPh3AuCl
(IPr)AuCl
(IPr)AuCl
AuCl
AgOTf
AgSbF6
AgSbF6
AgOTf
AgOTf
----
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
EtOH/H2O
Dioxane
Dioxane
Dioxane
CH3NO2
(CH2)2Cl2
CH2Cl2
CH3CN
67c
3c
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traced
traced
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trace
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AuCl3
NaAuCl4
NaAuCl4
PPh3AuCl
PPh3AuCl
PPh3AuCl
PPh3AuCl
PPh3AuCl
PPh3AuCl
PPh3AuCl
----
----
----
9e
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AgBF4
AgNTf2
AgPF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
CH2Cl2
trace
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aUnless otherwise mentioned, all reactions were carried out using 0.1 mmol of 1a using 1 mol%
of each Au-and Ag-catalyst, and 1.5 equiv of H2O in 0.3 M solvent without exclusion of air at rt.
bIsolated yield. cReaction was performed using 5 mol% of each of the catalyst. dWith recovery of
starting material. eReaction was attempted at 80 ºC. W = With. W/O = Without.
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With an effective optimal conditions as obtained from Table 1 (entry 14), the scope of
regioselective hydration was examined for 17 different δ-acetoxy-α,β-alkynoates (Scheme 2).
Alkynoates 1 containing aryl and aliphatic groups not only in the δ-position but also in the
alkyne terminated ester unit were found to be viable substrates. These also include primary,
secondary and tertiary carboxylates. Both methyl and benzyl esters of secondary alkynoates (1b
and 1c) were transformed to the desired ketoesters (2b and 2c) in comparable yields. In addition
to the neutral substrates, the substituted δ-positioned aryl group possessing both electron-
withdrawing (−Br and −F) and -donating groups (−Me) at para (1d−1g) smoothly reacted to
provide the corresponding hydration products 2d−2g. This methodology could also be applied to
tertiary carboxylates bearing halogenated aryl ring containing the bromo group either in ortho,
meta or para-positions (2h−2j), addition to the neutral substrates, the substituted δ-positioned
aryl group possessing both electron-withdrawing (−Br and −F) and -donating groups (−Me) at
para- (1d−1g) smoothly thus allowing access to Pd- or Cu-catalyzed post functionalization.
Alkynoate with straight chain alkyl group also gave similar yield of the δ-acetoxy-β-ketoester
product (2k). Recognizing the relatively neutral conditions, base or acid-sensitive functional
groups were well tolerated, including OAc-protected chlorohydrin (2l), and benzyl and silyl
protected alcohols (2m−2r). It is of note that, the thus formed keto esters comprising many C−O
functionalities, which due to owing to the different groups can be employed as versatile
synthons.18
We next investigated the behavior of various carboxylate directing groups towards the
reactivity and regioselectivity of the hydration reaction under the standardized conditions
(Scheme 3A). The directing group not only includes secondary (−OPiv, 3a) and α,β-unsaturated
(acrylate, 3b) aliphatic carboxylates, but also various electronically different aryl carboxylates
(3c−f): in all cases though the regioselectivity was maintained, the later substrates requires little
longer time (up to 4 h) with slightly diminished yield (not less than 15%) maybe due to steric
effects. Notably, O-hydroxy benzoate could also be the directing group and did not alter the
reaction pathway to deliver the corresponding hydration product 4g.
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Scheme 2. Substrate Scope of the Hydration for 1º, 2º and 3º δ-Acetoxy Alkynoatesa,b
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aUnless otherwise noted, all reactions were performed with 0.2 mmol of 1, under the optimized conditions
obtained in entry 14 of table 1. bIsolated yields. cThe reaction was also performed in 4 mmol scale and the
product 2g was isolated in identical yield and regioselectivity.
Finally, when both the Me- and Et-alkynoates (3h and 3i) carrying bulky tertiary benzoate along
with a neighboring bulky silyl ether (−OTBDPS) group were tested; the expected selectivity was
observed leading to similar yield of the β-hydration products (81% for 4h and 83% for 4i). It is
worth mentioning that the chiral substrate 1p proceeded with retention of chirality (See
experimental section for details). Examining the hydration with other functional groups
(−OPMB, −OBoc, −OTHP and −OMe) instead of carboxylate directing group (not shown here in
Scheme 3A) was unfruitful, confirming the role of a neighboring carbonyl group as critical
element in the current hydration reaction.
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With an aim to give not only the broad generality but also to identify the crucial elements
behind the current hydration, the ester functionality on alkyne terminus was replaced with halo (-
Cl, −Br, 3j and 3k), −H (3l), phenyl (3m and 3n), keto (3o), and alkyl (3p, 3q) group (Scheme
3B). While δ-acetoxy halo alkynes (4j and 4k) were readily participated in the reaction with
similar regioselectivity,27 the aryl terminated homopropargylic carboxylates (3m and 3n) gave
the corresponding benzylic oxidation products (4m and 4n) presumably due to electronic effect
of aryl ring.28,12b It is worth mentioning that the terminal carboxylate (3l) and alkynone (3o)
proceeded without giving the desired hydration products under the standard conditions, although
similar type of hydration through 1,2-acyloxy transposition for the later type of alkynes have
recently been successful.14b,24 Though such contrasting behavior of keto functionality with
respect to ester is unexplainable, a plausible reason for terminal and aryl alkynes may be ascribed
to their weaker electron withdrawing ability, thereby causing trace conversion for the former and
reversal selectivity for the later. Not surprisingly, δ-acetoxy propargylic alkane (3p and 3q) did
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o
not show any activity in the current hydration reaction conditions; however, heating at 50 C led
to the formation of non-separable regioisomeric mixture of products (4p:4p' = 1:2 and 4q:4q'=
1:2) in moderate yield after 12 h. When the standard conditions was employed for 1p in presence
of other O-nucleophile (for example MeOH, Scheme 3C), deacylated β-ketoester 2p' (72%) was
observed as a major product along with the formation of 18% of the regular hydration product
2p, which was presumably due to the sequential hydration-deacylation reaction. To validate this
result, the hydration of hydroxyl-precursor of 1p was performed under the standard conditions;
no formation of the desired δ-hydroxy-β-ketoester 2p' rules out the alkyne-acetalization/
hydrolysis process.23b,29 All the above results ensured us the presence of an electron withdrawing
ester group is indispensable as it makes the β-carbon more electrophilic, which in turn facilitate
the hydration through [3,3]-acyloxy rearrangement-triggered electrophilic intermediate.
Scheme 3. Effects of Different Directing Groupsa,b
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a Unless otherwise noted, reaction was performed with 0.2 mmol of 1, under the optimized conditions.
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d
Isolated yields. The reaction at 50 ºC ended up with complex mixtures, No traces of the desired
hydration product was detected in crude 1H NMR of the reaction mixture under standard conditions. e Full
conversion was achieved after 12 h when reaction was heated at 50 ºC.
Scheme 4. Synthetic Applications (Synthetic Transformations and Natural Product
Diversification)a,b,c
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b
aAll reactions were performed in 0.2 mmol scale under the conditions described here. Isolated yield.
cReagents and conditions: For 5a, AgSbF6 (0.1 equiv), H2O (5 equiv), CH2Cl2, rt. For 5b, K2CO3 (1.5
o
o
equiv), MeOH, 0 C−rt, 15 min. For 5c, NaBH4 (0.5 equiv), THF: MeOH (1:1), 0 C−rt. For 5d,
o
o
NH2OH.HCl (1.5 equiv), EtOH, 70 C. For 5e, benzene-1,2-diamine (1.1 equiv.), EtOH, 70 C. For 5f,
NH2CONH2 (1.5 equiv), 3-nitrobenzaldehyde (1.2 equiv), pTSA (0.1 equiv), MeOH, reflux. For 5g,
b
standard conditions as described in entry 14 of table 1, 2 h. dr was confirmed to be >49:1, which means
there is no detection of other diasteromer in NMR.
Inspired by the beneficial and differential reactivity of the δ-acetoxy-β-keto ester, various
synthetic manipulations for the synthesis of further modifiable C5-builiding blocks were
commenced (Scheme 4A−C). Gratifyingly, acid catalyzed deacylation of hindered acetate (from
2h), base mediated elimination of secondary acetate (from 2g) and chemoselective reduction of
keto and ester functionalities (in 2a) provided an easy access to δ-hydroxy-β-ketoester 5b, γ,δ-
conjugated β-ketoester 5b and mono-protected triol derivative 5c. By weddings the differential
electrophilicity of ketoesters to the ubiquitous reactivity of bis-nucleophiles, cyclocondensation
could be employed to construct functionalized heterocycles (Scheme 4D). For instance,
condensation with hydroxyl amine allowed the expedient preparation of 5-oxo-4,5-
dihydroisoxazoline derivative 5d containing protected 1,2-diol unit. Notably, 1,2-diamine was
cyclized to benzodiazepine 5e with concomitant cleavage of primary acetyl group. Moreover, a
three component coupling with aldehyde and urea allowed rapid access to fashionable
tetrahydropyrimidinone heterocycle 5f with the elimination of OAc-functionality. Finally, the
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remarkable chemoselectivity achieved through the modification of complex natural product 5g in
presence of silyl ether and olefinic unit, further attribute to the potential utility of the current
hydration reaction (Scheme 4E). It is of note that the natural product is itself the directing group
in the form of carboxylate.
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To propose a mechanism for the regioselective hydration, at first, we analyzed the
experimental results obtained during scope study (Scheme 1A). Restricted or reversal selectivity
in hydration for substrates having H, alkyl or Phenyl group, acclaimed the requirement of
suitable electron- withdrawing functionality (such as ester and halo) which possibly favors the β-
selective hydration through traditional polarity induction pathway as proposed by Hammond et
al.14a However, complicated reaction results from the hydration of free or protected δ-hydroxy
alkynoates is inconsistent with the aforementioned fact that is only responsible to affect the
hydration. In contradiction, the success of hydration for carboxylate directing group led us to
investigate an alternative assisted reaction pathway via [3,3]-rearrangement-triggered
electrophilic intermediate, which is yet unprecedented though similar type of 5-exo-dig-
cyclization-enabled hydration has been reported by us14b,23 and other group.24 To support this
18
rearrangement triggered hydration, isotope labelling experiment using OH2 was conducted for
2g. The absence of isotopic oxygen in the elimination product 5b as revealed by HRMS (ESI-
TOF) {241.0841 [M + Na]+}, proving our initial assumption of oxygen transposition process for
hydration reaction through [3,3]-acyloxy rearrangement-triggered electrophilic intermediate (top,
Scheme 5B). One would also imagine the feasibility of hydration at β-position of alkynoate with
the assistance of alkynoate-carbonyl via a 4-endo-dig process. However, this process does not
seem to operate because of the following reason; no detection of labelled oxygen in HRMS (ESI-
TOF) of the deacylation product 2g' (m/z = 259.0946 [M + Na]+, down, Scheme 5B) obtained
from isotopic labelled hydration product 18O-2g. Moreover, no detection of α-ketoester via 3-
exo-dig cyclization process completely rules out the assistance of alkynoate ester-carbonyl group
(Scheme 5C). Taking into account these experimental observations and our previous mechanistic
investigation,14b,23 a plausible mechanistic pathway for the hydration reaction is depicted in
Scheme 5D. It initiates with the formation of Au-coordinated complex A. Consequently, an
intramolecular [3,3]-acyloxy rearrangement process via 6-exo-dig cyclization forms an
electrophilic six-membered cyclic intermediate B. This species undergo nucleophilic addition of
water molecule to form the intermediate C that involves a protodeauration process to regenerate
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the Au(I)-catalyst for the next catalytic cycle. Finally, [1,3]-proton rearrangement and keto-enol
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tautomerization furnish the hydration product 2g.
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Scheme 5. Experimental Mechanistic Observations and Plausible Mechanism for the Assisted
Hydration.a
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aSee experimental section for the details of experimental procedure.
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CONCLUSIONS
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A new strategy to synthesize various δ-acetoxy-β-ketoesters has been developed for the first
time trough hydration of [3,3]-acyloxy rearrangement-triggered electrophilic intermediate in
presence of Au(I)-catalyst. The optimized conditions also worked well with halo terminated
carboxylates in providing excellent yields of the corresponding hydration products with complete
regioselectivity. The critical importance of neighboring directing groups as well as alkyne
terminating units has been recognized to affect such hydration. The synthetic potential was
demonstrated in the preparation of modifiable C5-building blocks, heterocycles of varied ring
size and late stage modification of natural product. A reasonable mechanism for the current
assisted hydration has also been deduced from the results of isotope labeling (with 18OH2)
experiment.
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EXPERIMENTAL SECTION
General Information: All reactions were carried out under ambient atmosphere, unless otherwise
stated. All starting materials and reagents were obtained from commercial producers and are
used without further purification. Solvents were generally used as supplied by the manufacturer
except THF (THF was freshly distilled over sodium and benzophenone under inert atmosphere).
Column chromatography was carried out by using silica gel (100–200 mesh) unless otherwise
mentioned. Analytical thin layer chromatography (TLC) was run on Merck silica gel 60 F254
pre-coated plates (250 μm thickness). Oil bath was used for the reactions performed in heating
conditions. Melting points were determined using a Stuart SMP3 apparatus. Infrared spectra
were recorded in CHCl3/neat (as mentioned) and reported in wave number (cm-1). Mass spectral
data were obtained using MS (EI, ESI and APCI) HRMS mass spectrometers. HPLC was
performed on JASCO HPLC systems consisting of the following; detector, 875-UV or UV-970,
measured at 210 nm and 254 nm; column, ATLANTIS C18 (4.6 × 150 mm, 5μ) and LUX
AMISOSE (4.6 × 250 mm, 5μ); mobile phase, acetonitrile, water, isopropanol and hexane; flow
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rate, 1 mL/min. H NMR spectra were recorded in 300, 400, 500, F NMR spectra in 377, and
13C{1H} NMR spectra in 75, 100, 125 MHz using CDCl3 solution. Chemical shifts are in ppm
downfield from tetramethylsilane and coupling constants (J) are reported in hertz (Hz). The
following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad.
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(A) General procedure for the synthesis of δ-arylated homopropargylic alcohol (P-1): For
details, see the supporting information for general scheme employed in the synthesis of hydration
precursors.
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(a) General Procedure for Propargylation of Aromatic Aldehyde and Ketones (P-1a):
Propargyl bromide (2.4 mL 80 wt% in toluene, 15.0 mmol) was added on the activated zinc (3.6
g, 50.0 mmol) in THF (15 mL) at room temperature to generate the Zn-ylide. To this resulting
ylide suspension, the respective aldehyde/ketone (10.0 mmol) in THF was added at room
temperature followed by saturated aqueous NH4Cl solution (10 mL). After completion of the
reaction (as monitored by TLC), it was filtered through a pad of Celite. The organic layer was
separated and the aqueous layer extracted with ethyl acetate (2 × 15 mL). The combined organic
layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under
reduced pressure to get the crude homo-propargylic alcohol (The crude yield of the alkynol was
up to 75%).
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(b) General Procedure for Synthesis of THP Ether (P-1b): To the solution of homo-propargyl
alcohol (6 mmol) in CH2Cl2 (10 mL), 2-H-3,4-dihydropyran (1.2 mL, 15.0 mmol) and catalytic
amount of CSA (26 mg, 1.2 mmol) were added at 0 °C under nitrogen atmosphere and the
reaction mixture was stirred for 1 h at room temperature. After complete consumption of starting
material (as indicated by TLC), the reaction mixture was quenched with saturated aqueous
NaHCO3 solution (20 mL). The organic layer was separated and the aqueous layer was further
extracted with CH2Cl2 (2 × 15 mL). The combined organic layer was washed with brine (30 mL),
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude
product was purified by silica gel column chromatography to obtain the THP ether derivatives
(Yield of the THP ether was up to 80%).
(c) General Procedure for Synthesis of Alkynoates (P-1c): To a solution of terminal alkyne
(5.0 mmol) in THF (5 mL), LHMDS (5 mL, 1 M in toluene, 5.0 mmol) was added dropwise
using a syringe at −78 °C under nitrogen atmosphere and the reaction mixture was stirred at this
temperature for 45 min. Then a solution ethyl chloroformate/methyl chloroformate (10.0 mmol)
in THF (2 mL) was added dropwise to the above dark yellow ylide solution. Then the reaction
mixture was slowly warmed to room temperature and continued to stir until the complete
consumption of starting alkyne (as indicated by TLC). The reaction was quenched by adding
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saturated aqueous NH4Cl solution (10 mL) and diluted with ethyl acetate (15 mL). The organic
layer was separated and the aqueous layer extracted with ethyl acetate (3 × 15 mL). The
combined organic layer were washed with brine (30 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure to get the crude product (The crude yield of the THP ether
protected alkynoate was up o 90%).
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(d) General Procedure for the Deprotection of THP-Protecting Group (P-1d): To a
methanolic solution of the above crude THP ether (2 mmol), was added catalytic amount of CSA
(9 mg, 0.4 mmol) at 0 ºC and the reaction mixture was allowed to stir at room temperature for 1
h. After complete consumption of the starting material (as indicated by TLC), the reaction was
quenched with saturated NaHCO3 (10 mL) solution and the solvent was evaporated under
reduced pressure. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined
organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The obtained crude product was purified by silica gel column
chromatography (The isolated yield of the alcohol was up to 80%).
(B) General Procedure for the Preparation of δ-Alkylated Homo Propargyl Alcohol (P-2):
To a stirred solution of ethyl propiolate (0.6 mL, 6.0 mmol) in THF (5 mL) at−78 ºC, LHMDS (6
mL, 1 M in toluene, 6.0 mmol) was added dropwise using a syringe under nitrogen atmosphere
and was stirred for 45 min maintaining the same temperature. The solution of respective epoxide
(5.0 mmol) in THF (5 mL) followed by BF3.OEt2 (1.7 mL, 5.5 mmol) were added dropwise to
this ylide solution. The above reaction mixture was slowly warmed to room temperature and
continued to stir until completion of the reaction (as indicated by TLC). The reaction was
quenched with saturated aqueous NH4Cl solution (5 mL) and diluted with ethyl acetate (15 mL).
The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 × 15 mL).
The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4
and concentrated under reduced pressure to get the crude homo propargyl alcohol (The isolated
yield of the ring-opening product was up to 80%).
(C) General Procedure for Acetylation, Benzoylation and Pivaloylation of Homo Propargyl
Alcohol (P-3): To a solution of the crude homo-propargyl alcohol (1.0 mmol) obtained from
procedure P1 or P2 in anhydrous CH2Cl2 (5 mL), triethylamine (1.5 mmol) followed by acetic
anhydride (1.5 mmol)/benzoyl chloride (1.2 mmol/pivaloyl chloride (1.2 mmol) were added
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dropwise under nitrogen atmosphere at 0 °C. The catalytic amount of DMAP was added into the
reaction mixture. The resultant mixture was stirred at room temperature till complete
consumption of the starting material (as indicated by TLC). The reaction quenched with water (5
mL) and diluted with CH2Cl2 (10 mL). The organic layer was separated and the aqueous layer
extracted with CH2Cl2 (2 × 10 mL). The collected organic layer was washed with brine solution
(15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude oil
was purified by silica gel column chromatography to get the acetylated hydration precursor (The
isolated yield of the acetate protected hydration precursor was up to 95%).
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(D) General Procedure for the Synthesis of Hydration Precursor Obtained via Acid-
Alcohol Coupling (P-4): To a stirred solution of alcohol (1 mmol) in anhydrous CH2Cl2 (10
mL), were added DCC (1.5 mmol), carboxylic acid (1.2 mmol) and DMAP (0.2 mmol)
sequentially at room temperature and stirred under nitrogen atmosphere for 3 h. After complete
consumption of the starting material (as indicated by TLC), the reaction was quenched with
saturated NaHCO3 solution (10 mL). The organic layer was separated and aqueous layer
extracted with CH2Cl2 (2 × 10 mL). The combined organic layer was washed with brine (20 mL),
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude
product was purified by silica gel column chromatography (The isolated yield of the
esterification product was up to 85%).
Experimental Procedure and Analytical Data for Hydration Precursors:
Methyl 5-acetoxypent-2-ynoate (1a): Following the general procedure P-1 and P-3, 1a (230
mg, 53% yield over 4 steps) was obtained from 3-butyne-1-ol (180 mg, 2.57 mmol) as a
colorless liquid; Rf 0.5 (9:1 hexane/EtOAc); IR (neat) νmax 2956, 2243, 1715, 1437, 1227, 1074,
1041, 753 cm−1; 1H NMR (500 MHz, CDCl3) δ 4.22 (t, J = 6.6 Hz, 2H), 3.77 (s, 3H), 2.69 (t, J =
6.6 Hz, 2H), 2.09 (s, 3H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ 170.6, 153.8, 84.9, 73.9, 60.9,
52.6, 20.7, 19.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C8H10O4Na 193.0478; Found
193.0484.
Methyl 5-acetoxy-5-phenylpent-2-ynoate (1b): Following the general procedure P-1 and P-3,
1b (90 mg, 37% yield over 5 steps) was obtained as a colorless liquid starting from benzaldehyde
(106 mg, 1.0 mmol); Rf 0.5 (19:1 hexane/EtOAc); IR (neat) νmax 3031, 2956, 2335, 2244, 1718,
1441, 1373, 1264, 1034, 759, 705 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.45 – 7.29 (m, 5H), 5.96
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– 5.84 (m, 1H), 3.74 (s, 3H), 2.89 (qd, J = 17.2, 6.4 Hz, 2H), 2.12 (s, 3H) ppm; C{1H} NMR
(125 MHz, CDCl3) δ 169.7, 153.7, 138.3, 128.5, 126.3, 84.2, 74.6, 72.5, 52.5, 26.7, 20.9 ppm;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H14O4Na 269.0784; Found 269.0790.
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1c (120 mg, 37% yield over 5 steps) was obtained as a colorless liquid starting from
benzaldehyde (160 mg, 1.0 mmol); Rf 0.6 (19:1 hexane/EtOAc); IR (neat) νmax 3039, 2954, 2242,
1717, 1498, 1449, 1374, 1240, 1075, 1033, 754, 702 cm–1;1H NMR (400 MHz, CDCl3) δ 7.40 –
7.29 (m, 10H), 5.91 (t, J = 6.4 Hz, 1H), 5.16 (s, 2H), 2.87 (qd, J = 17.2, 6.4 Hz, 2H), 2.10 (s, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 153.1, 138.3, 134.9, 128.6, 128.5, 128.4, 126.3,
84.5, 74.8, 72.6, 67.5, 26.8, 21.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H18O4Na
345.1097; Found 345.1096.
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Methyl 5-acetoxy-5-(4-bromophenyl)pent-2-ynoate (1d): Following the general procedure P-1
and P-3, 1d (150 mg, 39% yield over 5 steps) was obtained as a light yellow coloured liquid
starting from 4-bromobenzaldehyde (221 mg, 1.20 mmol); Rf 0.6 (19:1 hexane/EtOAc); IR (neat)
νmax 2925, 2856, 2245, 1718, 1490, 1438, 1373, 1263, 1077, 1040, 824, 756 cm–1; 1H NMR (400
MHz, CDCl3) δ 7.50 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 5.86 (t, J = 6.4 Hz, 1H), 3.75
(s, 3H), 2.93 – 2.81 (m, 2H), 2.12 (s, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 153.9,
141.0, 131.7, 127.4, 122.0, 85.4, 74.8, 71.2, 52.7, 29.5 ppm; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C14H13O4NaBr 346.9895; Found 346.9904.
Ethyl 5-acetoxy-5-(4-bromophenyl)pent-2-ynoate (1e): Following the general procedure P-1
and P-3, 1e (136 mg, 36% yield over 5 steps) was obtained as a light yellow coloured liquid
starting from 4-bromobenzaldehyde (200 mg, 1.09 mmol); Rf 0.6 (19:1 hexane/EtOAc); IR (neat)
νmax 2927, 2858, 2242, 1717, 1473, 1433, 1360, 1333, 1262, 1030, 826 cm–1;1H NMR (300 MHz,
CDCl3) δ 7.50 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 5.86 (t, J = 6.4 Hz, 1H), 4.20 (q, J =
13
7.1 Hz, 2H), 2.97 – 2.75 (m, 2H), 2.12 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR
(125 MHz, CDCl3) δ169.7, 153.2, 137.3, 131.7, 128.1, 122.6, 83.1, 75.3, 72.0, 62.0, 26.6, 20.9,
13.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H15O4NaBr 361.0051; Found
361.0068.
Methyl 5-acetoxy-5-(4-fluorophenyl)pent-2-ynoate (1f): Following the general procedure P-1
and P-3, 1f (201 mg, 39% yield over 5 steps) was obtained as a colorless liquid starting from 4-
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flourobenzaldehyde (240 mg, 1.94 mmol); Rf 0.5 (9:1 hexane/EtOAc); IR (neat) νmax 2926, 2857,
2359, 2245, 1718, 1610, 1514, 1430, 1373, 1263, 1033, 839 cm–1; 1H NMR (500 MHz, CDCl3) δ
7.36 (dd, J = 8.7, 5.3 Hz, 2H), 7.06 (t, J = 8.7 Hz, 2H), 5.89 (t, J = 6.4 Hz, 1H), 3.75 (s, 3H),
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2.87 (qd, J = 17.2, 6.4 Hz, 2H), 2.11 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ169.7,
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162.7 (d, J = 247.4 Hz), 153.7, 134.1 (d, J = 2.7 Hz), 128.2 (d, J = 8.3 Hz), 115.6 (d, J = 21.6
19
Hz) 83.8, 74.9, 71.9, 52.7, 26.7, 21.0 ppm; F NMR (377 MHz, CDCl3) δ −113.0 ppm; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C14H13O4FNa 287.0696; Found 287.0694.
Methyl 5-acetoxy-5-(p-tolyl)pent-2-ynoate (1g): Following the general procedure P-1 and P-3,
1g (1.4 g, 32% yield over 5 steps) was obtained as a light yellow coloured liquid starting from 4-
methylbenzaldehyde (2.0 g, 16.67 mmol); Rf 0.4 (9:1 hexane/EtOAc); IR (neat) νmax 2931, 2859,
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1746, 1634, 1585, 1471, 1386, 1219, 1020, 848 cm–1; 1H NMR H NMR (400 MHz, CDCl3) δ
7.26 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 5.89 (t, J = 6.5 Hz, 1H), 3.74 (s, 3H), 2.87 (qd,
J = 17.2, 6.5 Hz, 2H), 2.34 (s, 3H), 2.10 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.8,
153.8, 138.5, 135.4, 129.3, 126.3, 84.4, 74.6, 72.5, 52.6, 26.7, 21.1, 21.0 ppm; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C15H16O4Na 283.0946; Found 283.0948.
Ethyl 5-acetoxy-5-(2-bromophenyl)hex-2-ynoate (1h): Following the general procedure P-1
and P-3, 1h (142 mg, 35% yield over 5 steps) was obtained as a light yellow coloured liquid
starting 1-(2-bromophenyl)ethan-1-one (230 mg, 1.16 mmol); Rf 0.6 (19:1 hexane/EtOAc); IR
(neat) νmax 2976, 2342, 1740, 1648, 1427, 1371, 1317, 1243, 1058, 1030, 761 cm–1;1H NMR
(400 MHz, CDCl3) δ 7.58 (dd, J = 7.9, 1.3 Hz, 1H), 7.44 (dd, J = 8.0, 1.6 Hz, 1H), 7.34 – 7.30
(m, 1H), 7.13 (td, J = 7.7, 1.6 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.40 (d, J = 17.1 Hz, 1H), 3.29
(d, J = 17.1 Hz, 1H), 2.11 (s, 3H), 2.04 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 169.1, 153.2, 139.8, 135.4, 129.2, 128.1, 127.3, 119.4, 83.7, 80.9, 75.6, 61.8,
30.2, 24.6, 21.3, 13.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H17O4NaBr
375.0208; Found 375.0208.
Methyl 5-acetoxy-5-(3-bromophenyl)hex-2-ynoate (1i): Following the general procedure P-1
and P-3, 1i (107 mg, 31% yield over 5 steps) was obtained as a light yellow colored liquid
starting from 1-(3-bromophenyl)ethan-1-one (200 mg, 1.01 mmol); Rf 0.5 (9:1 hexane/EtOAc);
IR (neat) νmax 2988, 2350, 2243, 1715, 1566, 1470, 1425, 1373, 1254, 1078, 1017, 784, 760, 699
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 1.8 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.27 (dt, J =
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7.9, 1.4 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 3.75 (s, 3H), 3.17 (d, J = 17.1 Hz, 1H), 3.04 (d, J =
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17.1 Hz, 1H), 2.10 (s, 3H), 1.89 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 169.3 153.6,
145.1, 130.8, 129.9, 127.7, 123.1, 122.6, 83.8, 80.4, 75.4, 52.6, 32.3, 25.3, 21.8 ppm; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C15H15O4NaBr 361.0051; Found 361.0058.
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Methyl 5-acetoxy-5-(4-bromophenyl)hex-2-ynoate (1j): Following the general procedure P-1
and P-3, 1j (107 mg, 33% yield over 5 steps) was obtained as a light yellow coloured liquid
starting from 1-(4-bromophenyl)ethan-1-one (190 mg, 0.97 mmol); Rf 0.6 (9:1 hexane/EtOAc);
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IR (neat) νmax 2978, 2856, 2323, 1717, 1471, 1437, 1370, 1327, 1244, 1028, 827, 647 cm−1; H
NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H), 3.10
(dd, J = 40.8, 17.1 Hz, 2H), 2.09 (s, 3H), 1.90 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
169.4, 153.7, 141.9, 131.6, 126.3, 126.3, 126.2, 121.8, 84.0, 80.7, 75.5, 52.7, 32.4, 25.3, 21.9
ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H15O4NaBr 361.0051; Found
361.0056.361.0051, found: 361.0056.
Methyl 5-acetoxydodec-2-ynoate (1k): Following the general procedure P-2 and P-3, 1k (149
mg, 71% yield over 2 steps) was obtained as a light yellow colored liquid starting from (R)-2-
heptyloxirane (110 mg, 0.78 mmol); Rf 0.6 (19:1 hexane/EtOAc); IR (neat) νmax 2931, 2862,
2244, 1732, 1445, 1375, 1255, 1078, 1034, 754 cm–1; 1H NMR (400 MHz, CDCl3) δ4.99 – 4.91
(m, 1H), 3.76 (s, 3H), 2.70 – 2.56 (m, 2H), 2.07 (s, 3H), 1.72 – 1.64 (m, 2H), 1.35 – 1.23 (m,
13
10H), 0.88 (t, J = 6.8 Hz, 3H) ppm; C NMR (100 MHz, CDCl3) δ 170.4, 153.8, 84.6, 74.5,
70.7, 52.5, 33.0, 31.6, 29.1, 29.0, 25.1, 24.0, 22.5, 20.9, 14.0 ppm; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C15H25O4 269.1753; Found 269.1765.
Ethyl (R)-5-acetoxy-6-chlorohex-2-ynoate (1l): Following the general procedure P-2 and P-3,
1l (163 mg, 70% yield over 2 steps) was obtained as a colorless liquid starting from (R)-2-
(chloromethyl)oxirane (92 mg, 1.0 mmol); Rf 0.4 (17:3 hexane/EtOAc); IR (neat) νmax 2925,
2244, 1750, 1714, 1437, 1376, 1259, 1078, 1042, 801, 757 cm–1; 1H NMR (500 MHz, CDCl3) δ
5.17 – 5.10 (m, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.78 – 3.70 (m, 2H), 2.87 – 2.76 (m, 2H), 2.12 (s,
3H), 1.31 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 153.1, 82.3, 75.3,
69.8, 62.0, 43.9, 21.7, 20.7, 13.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C10H13O4NaCl 255.0400; Found 255.0411.
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Ethyl 5-acetoxy-7-(benzyloxy)hept-2-ynoate (1m): Following the general procedure P-2 and
P-3, 1m (520 mg, 73 % yield over 2 steps) was obtained as a light yellow coloured liquid starting
from 2-(2-(benzyloxy)ethyl)oxirane (400 mg, 2.25 mmol); Rf 0.5 (17:3 hexane/EtOAc); IR
(neat) νmax 2926, 2861, 2243, 1719, 1452, 1373, 1254, 1086, 1028, 802, 750, 602 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.38 – 7.24 (m, 5H), 5.17 – 5.09 (m, 1H), 4.48 (q, J = 11.9 Hz, 2H), 4.21 (q,
J = 7.1 Hz, 2H), 3.56 – 3.48 (m, 2H), 2.74 (dd, J = 17.4, 5.7 Hz, 1H), 2.64 (dd, J = 17.4, 5.1 Hz,
1H), 2.02 (s, 3H), 2.02 – 1.97 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (125 MHz,
CDCl3) δ 170.3, 153.4, 138.1, 128.4, 127.7, 127.6, 84.05, 75.0, 73.0, 68.5, 65.9, 61.9, 33.2, 24.3,
21.0, 14.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H22O5Na 341.1365; Found
341.1369.
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Methyl 5-acetoxy-7-(benzyloxy)hept-2-ynoate (1n): Following the general procedure P-2 and
P-3, 1n (110 mg, 71% yield over 2 steps) was obtained as a light yellow coloured liquid starting
from 2-(2-(benzyloxy)ethyl)oxirane (90 mg , 0.51 mmol); Rf 0.4 (17:3 hexane/EtOAc); IR
1
(neat): νmax 2928, 2242, 1736, 1720, 1442, 1336, 1259, 1033, 704cm−1; H NMR (400 MHz,
CDCl3) δ 7.32 (m, 5H), 5.17 – 5.10 (m, 1H), 4.48 (q, J = 11.9 Hz, 2H), 3.76 (s, 3H), 3.56 – 3.48
(m, 2H), 2.74 (dd, J = 17.5, 5.7 Hz, 1H), 2.64 (dd, J = 17.5, 5.2 Hz, 1H), 2.02 (s, 3H), 1.99 (t, J =
6.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 170.4, 153.8, 138.0, 128.4, 127.7, 127.7, 84.6,
74.7, 73.0, 68.5, 65.9, 52.6, 33.2, 21.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C17H20O5Na 327.1208; Found 327.1213.
Ethyl 5-acetoxy-6-(benzyloxy)hex-2-ynoate (1o): Following the general procedure P-2 and P-
3, 1o (323 mg, 73% yield over 2 steps) was obtained as a light yellow coloured liquid 2-
((benzyloxy)methyl)oxirane (240 mg, 1.46 mmol); Rf 0.4 (17:3 hexane/EtOAc); IR (neat): νmax
1
2933, 2869, 2240, 1742, 1599, 1490, 1447, 1370, 1230, 1097, 1021, 755, 695 cm–1; H NMR
(400 MHz, CDCl3) δ 7.39 – 7.26 (m, 5H), 5.15 – 5.07 (m, 1H), 4.56 (q, J = 12.1 Hz, 2H), 4.21
(q, J = 7.1 Hz, 2H), 3.64 (qd, J = 10.4, 4.9 Hz, 2H), 2.75 (qd, J = 17.3, 6.1 Hz, 2H), 2.09 (s, 3H),
13
1.30 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 170.2, 153.3, 137.6, 128.4,
127.8, 127.6, 83.7, 74.8, 73.4, 69.6, 69.3, 61.9, 21.1, 21.0, 14.0 ppm; HRMS (ESI-TOF) m/z: [M
+ Na]+ Calcd for C17H20O5Na 327.1208; Found 327.1209.
Ethyl (R)-5-acetoxy-6-((tert-butyldiphenylsilyl)oxy)hex-2-ynoate (1p): Following the general
procedure P-2 and P-3, 1p (456 mg, 75% yield over 2 steps) (er 72:18) was obtained as a
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colorless liquid starting from (R)-tert-butyl(oxiran-2-ylmethoxy)diphenylsilane (420 mg, 1.35
mmol); Rf 0.5 (9:1 hexane/EtOAc); IR (neat): νmax 2943, 2864, 2243, 1717, 1666, 1437, 1374,
1250, 1098, 800, 703 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.68 – 7.63 (m, 4H), 7.46 – 7.37 (m,
6H), 5.08 – 5.03 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.82 (dd, J = 10.9, 4.8 Hz, 1H), 3.78 (dd, J =
10.9, 5.0 Hz, 1H), 2.79 (qd, J = 17.2, 6.1 Hz, 2H), 2.04 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.05 (s,
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9H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 170.2, 153.4, 135.6, 135.5, 132.9, 129.8, 127.8,
84.1, 74.7, 71.1, 63.4, 61.9, 26.7, 20.9, 20.8, 19.3, 14.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C26H32O5SiNa 475.1917; Found 475.1923.
Methyl 5-acetoxy-6-((tert-butyldiphenylsilyl)oxy)-5-methylhex-2-ynoate (1q): Following the
general procedure P-2 and P-3, 1q (464 mg, 74% yield over 2 steps) was obtained as a colorless
liquid starting from tert-butyl((2-methyloxiran-2-yl)methoxy)diphenylsilane (450 mg, 1.38
mmol); Rf 0.6 (9:1 hexane/EtOAc); IR (neat): νmax 3064, 2940, 2863, 2241, 1716, 1457, 1373,
1262, 1104, 1028, 815, 703 cm–1; H NMR (400 MHz, CDCl3) δ 7.69 – 7.63 (m, 4H), 7.46 –
1
7.36 (m, 6H), 3.95 (d, J = 10.3 Hz, 1H), 3.76 (s, 3H), 3.72 (d, J = 10.3 Hz, 1H), 3.07 (s, 2H),
2.00 (s, 3H), 1.55 (s, 3H), 1.06 (s, 9H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 170.1, 153.8,
13
135.5, 132.9, 132.8, 129.8, 127.7, 85.1, 81.7, 74.6, 66.5, 26.7, 26.0, 22.0, 20.8, 19.3 ppm; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C26H32O5SiNa 475.1917; Found 475.1921.
Ethyl 5-acetoxy-6-((tert-butyldiphenylsilyl)oxy)-5-methylhex-2-ynoate (1r): Following the
general procedure P-2 and P-3, 1r (266 mg, 74% yield over two steps) was obtained as a
colorless liquid starting from tert-butyl((2-methyloxiran-2-yl)methoxy)diphenylsilane (250 mg,
0.77 mmol); Rf 0.6 (9:1 hexane/EtOAc); IR (neat): νmax 2943, 2864, 2240, 1717, 1465, 1431,
1374, 1248, 1108, 817, 749, 704 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 7.9, 1.4 Hz,
4H), 7.45 – 7.37 (m, 6H), 4.22 (q, J = 7.1 Hz, 2H), 3.95 (d, J = 10.3 Hz, 1H), 3.72 (d, J = 10.3
Hz, 1H), 3.10 – 3.02 (m, 2H), 2.00 (s, 3H), 1.55 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.06 (s, 9H)
ppm; C{1H} NMR (100 MHz) δ 170.2, 153.4, 135.6, 133.0, 132.9, 129.8, 127.7, 84.6, 81.8,
75.0, 66.5, 61.8, 26.7, 26.1, 22.0, 20.8, 19.3, 14.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
13
for C27H34O5SiNa 489.2073; Found 489.2079.
Ethyl 6-(benzyloxy)-5-(pivaloyloxy)hex-2-ynoate (3a): Following the general procedure P-2
and P-3, 3a (470 mg, 72% yield over 2 steps) was obtained as a yellow coloured liquid starting
from 2-((benzyloxy)methyl)oxirane (310 mg, 1.89 mmol); Rf 0.6 (9:1 hexane/EtOAc); IR (neat):
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νmax2973, 2242, 1714, 1469, 1368, 1253, 1150, 1078, 746, 699 cm−1; 1H NMR (400MHz,
CDCl3) δ 7.38 – 7.25 (m, 5H), 5.15 – 5.07 (m, 1H), 4.60 – 4.52 (m, 2H), 4.21 (q, J = 7.1 Hz,
2H), 3.63 (qd, J = 10.4, 5.1 Hz, 2H), 2.75 (qd, J = 17.3, 6.0 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H),
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1.22 (s, 9H) ppm; C{1H} NMR (100 MHz) δ 177.7, 153.4, 137.7, 128.4, 127.7, 127.6, 84.0,
74.7, 73.4, 69.6, 69.2, 61.8, 38.8, 27.1, 21.2, 14.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
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for C20H26O5 Na 369.1678; Found 369.1676.
Methyl 5-(acryloyloxy)dodec-2-ynoate (3b): Following the general procedure P-2 and P-4, 3b
(230 mg, 73% yield over 2 steps) was obtained as a light yellow colored liquid starting from 2-
heptyloxirane (160 mg, 1.13 mmol); Rf 0.7 (19:1 hexane/EtOAc); IR (neat): νmax 2930, 2862,
2244, 1723, 1444, 1416, 1439, 1261, 1189, 1071, 983, 810, 755 cm−1; H NMR (500 MHz,
1
CDCl3) δ 6.43 (dd, J = 17.3, 1.3 Hz, 1H), 6.13 (dd, J = 17.3, 10.4 Hz, 1H), 5.86 (dd, J = 10.4, 1.3
Hz, 1H), 5.06 – 5.00 (m, 1H), 3.76 (s, 3H), 2.73 – 2.62 (m, 2H), 1.77 – 1.67 (m, 2H), 1.38 – 1.23
(m, 10H), 0.88 (t, J = 7.0 Hz, 3H) ppm; 13C{1H} NMR (100 MHz) δ 165.5, 153.8, 131.2, 128.2,
84.6, 74.6, 71.0, 52.6, 33.0, 31.7, 29.2, 29.0, 25.1, 24.1, 22.6, 14.0 ppm; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C16H24O4Na 303.1572; Found 303.1578.
1-(4-Fluorophenyl)-5-methoxy-5-oxopent-3-yn-1-yl benzoate (3c): Following the general
procedure P-2 and P-3, 3c (80 mg, 31% yield over 5 steps) was obtained from 4-
florobenzaldehyde (100 mg, 0.80 mmol) as a light yellow coloured liquid; Rf 0.6 (19:1
hexane/EtOAc); IR (neat): νmax 2934, 2856, 2244, 1744, 1639, 1599, 1486, 1447, 1259, 1086,
1029, 814 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.04 (m, 2H), 7.64 – 7.54 (m, 1H), 7.51 –
7.41 (m, 4H), 7.08 (t, J = 8.7 Hz, 2H), 6.13 (t, J = 6.3 Hz, 1H), 3.73 (s, 3H), 3.06 (dd, J = 17.2,
6.2 Hz, 1H), 2.99 (dd, J = 17.2, 6.4 Hz, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 165.3,
162.7 (d, J = 247.5 Hz), 153.7, 134.2 (d, J = 2.7 Hz), 129.7, 129.6, 128.5, 128.2 (d, J = 8.3 Hz),
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115.6 (d, J = 21.7 Hz), 83.7, 75.1, 72.5, 52.6, 26.9 ppm; F NMR (377 MHz, CDCl3) δ -112.9
ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H15O4NaF 349.0852; Found 349.0854.
1-Chloro-6-ethoxy-6-oxohex-4-yn-2-yl benzoate (3d): Following the general procedure P-2
and P-3, 3d (342 mg, 71% yield over 2 steps) was obtained as a light yellow coloured liquid
starting from 2-(chloromethyl)oxirane (150 mg, 1.63 mmol); Rf 0.5 (9:1 hexane/EtOAc); IR
(neat): νmax 2924, 2860, 2358, 2243, 1720, 1450, 1364, 1263, 1101, 1025, 823, 712 cm−1; H
1
NMR (500 MHz, CDCl3) δ 8.09 – 8.04 (m, 2H), 7.60 (dd, J = 10.7, 4.2 Hz, 1H), 7.46 (t, J = 7.8
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Hz, 2H), 5.42 – 5.35 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.89 (d, J = 5.0 Hz, 2H), 2.96 (d, J = 5.7
Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3), δ 165.4, 153.2, 133.5,
129.9, 129.2, 128.5, 82.3, 75.5, 70.3, 62.1, 44.0, 21.8, 14.0 ppm; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C15H16O4Cl 295.0737; Found 295.0746.
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1-Ethoxy-1-oxododec-2-yn-5-yl 4-methoxybenzoate (3e): Following the general procedure P-2
and P-4, 3e (310 mg, 72% yield over 2 steps) was obtained as a yellow coloured liquid starting
from 2-heptyloxirane (165 mg, 1.16); Rf 0.5 (9:1 hexane/EtOAc); IR (neat): νmax 2930, 2861,
1
2241, 1716, 1611, 1511, 1460, 1367, 1262, 1173, 1032, 854, 767 cm−1; H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 5.23 – 5.10 (m, 1H), 4.21 (q, J = 7.1
Hz, 2H), 3.86 (s, 3H), 2.79 – 2.70 (m, 2H), 1.90 – 1.75 (m, 2H), 1.45 – 1.22 (m, 14H), 1.29 (t, J
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= 7.1 Hz, 5H), 0.87 (t, J = 6.9 Hz, 3H) ppm; C{1H} NMR (125 MHz, CDCl3) δ 165.6, 163.4,
153.4, 131.6, 122.4, 113.5, 84.3, 74.9, 71.0, 61.8, 55.3, 33.1, 31.6, 29.2, 29.0, 25.1, 24.2, 22.5,
14.0, 13.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H30O5Na 397.1991; Found
397.1990.
1-Methoxy-1-oxododec-2-yn-5-yl 4-bromobenzoate (3f): Following the general procedure P-2
and P-4, 3f (291 mg, 71% yield over 2 steps) was obtained as a light yellow coloured liquid
starting from 2-heptyloxirane (142 mg, 1.0 mmol); Rf 0.6 (9:1 hexane/EtOAc); IR (neat): νmax
1
2931, 2861, 2255, 2243, 1723, 1592, 1444, 1266, 1105, 1020,805, 758 cm−1; H NMR (400
MHz, CDCl3) δ 7.91 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 5.24 – 5.14 (m, 1H), 3.76 (s,
3H), 2.84 – 2.69 (m, 2H), 1.91 – 1.75 (m, 2H), 1.42 – 1.23 (m, 10H), 0.87 (t, J = 6.9 Hz, 3H)
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ppm; C{1H} NMR (100 MHz, CDCl3) δ 165.2, 153.8, 131.74, 131.2, 128.9, 128.3, 84.4, 74.8,
71.8, 52.7, 33.1, 31.7, 29.2, 29.1, 25.2, 24.2, 22.6, 14.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C20H25O4NaBr 431.0834; Found 431.0836.
1-Ethoxy-1-oxododec-2-yn-5-yl 2-hydroxybenzoate (3g): Following the general procedure P-2
and P-4, 3g (101 mg, 74% yield over 2 steps) was obtained as a light yellow coloured liquid
starting from 2-heptyloxirane (55 mg, 0.38 mmol); Rf 0.4 (17:3 hexane/EtOAc); IR (neat): νmax
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2930, 2862, 2243, 1715, 1677, 1477, 1373, 1297, 1253, 1215, 1128, 1082, 758, 708 cm−1; H
NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 7.86 (dd, J = 8.0, 1.7 Hz, 1H), 7.47 (ddd, J = 8.7, 7.3,
1.7 Hz, 1H), 6.98 (dd, J = 8.4, 1.0 Hz, 1H), 6.89 (ddd, J = 8.2, 7.3, 1.1 Hz, 1H), 5.23 (dd, J =
13.2, 5.5 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.77 (dd, J = 5.6, 0.7 Hz, 2H), 1.91 – 1.77 (m, 2H),
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1.45 – 1.23 (m, 14H), 0.93 – 0.82 (m, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.5,
161.8, 153.3, 135.9, 129.9, 119.2, 117.6, 112.2, 83.6, 75.2, 72.0, 61.9, 33.1, 31.7, 29.2, 29.0,
25.1, 24.2, 22.6, 14.0, 13.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H28O5Na
383.1834; Found 383.1837.
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1-(tert-Butyldiphenylsilyloxy)-6-methoxy-2-methyl-6-oxohex-4-yn-2-yl
benzoate
(3h):
Following the general procedure P-2 and P-3, 3h (301 mg, 76% yield over 2 steps) was obtained
as a light yellow coloured liquid starting from tert-butyl((2-methyloxiran-2-yl)methoxy)
diphenylsilane (250 mg, 0.77 mmol); Rf 0.7 (97:3 hexane/EtOAc); IR (neat): νmax 2948, 2866,
1
2238, 1718, 1654, 1419, 1258, 703 cm–1; H NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 8.3, 1.3
Hz, 2H), 7.67 (M, 4H), 7.56 – 7.52 (m, 1H), 7.44 – 7.33 (m, 8H), 4.13 (d, J = 10.4 Hz, 1H), 3.90
(d, J = 10.4 Hz, 1H), 3.74 (s, 3H), 3.25 (d, J = 17.1 Hz, 1H), 3.18 (d, J = 17.1 Hz, 1H), 1.69 (s,
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3H), 1.04 (s, 9H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 165.5, 153.8, 135.6, 134.8, 132.9,
130.9, 129.8, 129.6, 128.2, 127.8, 127.7, 85.1, 82.5, 74.8, 66.5, 52.5, 26.7, 20.8, 19.3 ppm;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C31H34O5NaSi 537.2073; Found 537.2076.
1-(tert-Butyldiphenylsilyloxy)-6-ethoxy-2-methyl-6-oxohex-4-yn-2-yl
benzoate
(3i):
Following the general procedure P-2 and P-3, 3i (320 mg, 79% yield over 2 steps) was obtained
as a light yellow coloured liquid starting from tert-butyl((2-methyloxiran-2-yl)methoxy)
diphenylsilane (250 mg, 0.77 mmol); Rf 0.4 (97:3 hexane/EtOAc); IR (neat): νmax 2947, 2865,
2246, 1719, 1667, 1429, 1251, 1108, 800, 707 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J =
8.0 Hz, 4H), 7.67 (t, J = 5.7 Hz, 8H), 7.54 (t, J = 7.4 Hz, 2H), 7.45 – 7.33 (m, 16H), 4.19 (q, J =
7.1 Hz, 4H), 4.14 (d, J = 10.4 Hz, 2H), 3.90 (d, J = 10.4 Hz, 2H), 3.21 (q, J = 17.1 Hz, 4H), 1.70
13
(s, 6H), 1.27 (t, J = 7.1 Hz, 7H), 1.04 (s, 18H) ppm; C{1H} NMR (75 MHz, CDCl3) δ 165.5,
153.4, 135.6, 132.9, 132.8, 131.0, 129.8, 129.6, 128.2, 127.7, 84.6, 82.5, 75.2, 66.6, 61.7, 26.7,
26.6, 20.8, 19.3, 14.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C32H36O5NaSi
551.2230; Found 551.2231.
2-(2-Bromophenyl)-5-chloropent-4-yn-2-yl acetate (3j): NCS (200 mg, 0.6 mmol ) and
AgOAc (9 mg, 0.05 mmol ) were added in the solution of 2-((2-(2-bromophenyl)pent-4-yn-2-
yl)oxy)tetrahydro-2H-pyran (161 mg, 0.5 mmol) in acetone (2.5 mL) and the solution was heated
to reflux for overnight. After the completion of reaction (indicated by TLC) the mixture was
poured onto ice, and resulting aqueous layer was extracted with hexane (3 × 10 mL). The
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combined organic layers were washed with brine, dried over anhydrous Na2SO4 and the solvent
was removed under reduced pressure. The crude oil was used for the next step. By following
procedure P-1d and P-3, 3j (80 mg, 51% yield over 3 steps) was obtained as a light yellow
coloured liquid; Rf 0.6 (19:1 hexane/EtOAc); IR (neat): νmax 2936, 2249, 1743, 1466, 1433,
1240, 1169, 1084, 1023, 960, 761 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 7.9, 1.3 Hz,
1H), 7.42 (dd, J = 8.0, 1.7 Hz, 1H), 7.34–7.28 (m, 1H), 7.11 (ddd, J = 7.9, 7.4, 1.7 Hz, 1H), 3.17
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(s, 2H), 2.10 (s, 3H), 2.00 (s, 3H) ppm; C{1H} NMR (75 MHz, CDCl3) δ 170.6, 153.8, 84.9,
73.9, 60.9, 52.6, 20.7, 19.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H12O2ClBrNa
336.9607; Found 336.9622.
4-Bromobut-3-ynyl acetate (3k): To a stirred solution of but-3-yn-1-ol (350 mg, 6.25 mmol) in
acetone, silver nitrate (1.06 g, 6.25 mmol) and NBS (1.67 g, 1.5 mmol) were added at room
temperature under inert atmosphere and stirred for 6 h. After the completion of reaction
(monitoring by TLC), hexane was added and filtered through a pad of Celite. The organic
solvent was evaporated under reduce pressure and crude was protected by following the
procedure P-3 to yield 3k (800 mg, 67% yield over 2 steps) as a yellow coloured liquid; The
analytical data is in complete agreement with those reported in the literature.30 Rf 0.5 (19:1
1
hexane/EtOAc); IR (neat) νmax 2928, 2243, 1720, 1379, 1248, 1045 cm−1; H NMR (400 MHz,
CDCl3) δ 4.16 (t, J = 6.8 Hz, 2H), 2.55 (t, J = 6.8 Hz, 2H), 2.08 (s, 3H) ppm; 13C{1H} NMR (125
MHz, CDCl3) δ 170.7, 76.0, 61.9, 40.0, 20.8, 20.1 ppm.
1-((tert-Butyldiphenylsilyl)oxy)-5-phenylpent-4-yn-2-yl acetate (3m): Following the general
procedure P-2 and P-3, 3m (152 mg, 77% yield over 2 steps) as a light yellow coloured liquid
was obtained starting from tert-butyl(oxiran-2-ylmethoxy)diphenylsilane (140 mg, 0.45 mmol);
Rf 0.5 (9:1 hexane/EtOAc); IR (neat): νmax 3061, 2946, 2864, 2249, 1740, 1429, 1373, 1235,
1
1107, 1052, 750, 699 cm−1; H NMR (400 MHz, CDCl3) δ 7.72–7.66 (m, 4H), 7.44–7.25 (m,
11H), 5.19–5.07 (m, 1H), 3.95–3.83 (m, 2H), 2.88 (ddd, J = 16.8, 6.7, 1.3 Hz, 1H), 2.79 (ddd, J
13
= 16.9, 5.8, 1.3 Hz, 1H), 2.06 (s, 3H), 1.07 (s, 9H) ppm; C{1H} NMR (100 MHz, CDCl3) δ
170.4, 135.6, 135.5, 133.2, 133.2, 131.6, 129.7, 128.2, 127.8, 127.7, 85.0, 82.4, 72.3, 63.7, 26.7,
21.4, 21.1, 19.3 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C29H32O3NaSi 479.2018;
Found 479.2021.
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1-(Benzyloxy)-5-(4-fluorophenyl)pent-4-yn-2-yl acetate (3n): Following the general procedure
P-2 and P-3, 3n (270 mg, 68% yield over 2 steps) as a light yellow coloured liquid was obtained
starting from 2-((benzyloxy)methyl)oxirane (200 mg, 1.22 mmol); Rf 0.5 (9:1 hexane/EtOAc);
IR (neat): νmax 2926, 2223, 1745, 1499, 1365, 1263, 1011, 816, 687 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.39 – 7.24 (m, 7H), 6.97 (t, J = 8.7 Hz, 2H), 5.22 – 5.14 (m, 1H), 4.59 (q, J = 12.2 Hz,
2H), 3.72 (dd, J = 9.2, 3.7 Hz, 1H), 3.68 (dd, J = 9.1, 3.1 Hz, 1H), 2.78 (qd, J = 16.9, 6.4 Hz,
2H), 2.10 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 162.2 (d, J = 248.9 Hz),
137.8, 133.4 (d, J = 8.1 Hz), 128.4, 127.7, 127.6, 119.4 (d, J = 3.0 Hz), 115.4 (d, J = 22.0 Hz),
84.5, 81.4, 73.3, 70.8, 69.7, 21.7, 21.1 ppm; 19F NMR (377 MHz, CDCl3) δ −111.6 ppm; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H20O3F 327.1396; Found 327.1392.
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1-(Benzyloxy)non-4-yn-2-yl acetate (3p): Following the general procedure P-2 and P-3, 3p
(380 mg, 72% yield over 2 steps) as a light yellow coloured liquid was obtained starting from 2-
((benzyloxy)methyl)oxirane (300, 1.83 mmol); Rf 0.4 (9:1 hexane/EtOAc); IR (neat): νmax 2943,
1
2236, 1715, 1466, 1381, 1265, 759, 693 cm−1; H NMR (400 MHz, CDCl3) δ 7.37 – 7.26 (m,
5H), 5.11 – 5.02 (m, 4.8 Hz, 1H), 4.56 (q, J = 12.2 Hz, 2H), 3.65 (d, J = 4.8 Hz, 2H), 2.62 – 2.43
(m, 2H), 2.15 – 2.09 (m, 2H), 2.08 (s, 3H), 1.48 – 1.32 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δ 170.4, 137.9, 128.3, 127.6, 82.5, 74.7, 73.2, 71.2, 69.8, 30.9,
21.8, 21.1, 18.3, 13.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H24O3Na 311.1623;
Found 311.1616.
1-(Benzyloxy)-5-cyclohexylpent-4-yn-2-yl acetate (3q): Following the general procedure P-2
and P-3, 3q (362 mg, 73% yield over 2 steps) as a light yellow coloured liquid was obtained
starting from 2-((benzyloxy)methyl)oxirane (260 mg, 1.59 mmol); Rf 0.4 (9:1 hexane/EtOAc);
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IR (neat): νmax 2961, 2865, 2248, 1736, 1433, 1363, 1255, 1063, 750, 691 cm−1; H NMR (500
MHz, CDCl3) δ 7.36 – 7.27 (m, 5H), 5.11 – 5.05 (m, 1H), 4.56 (q, J = 12.2 Hz, 2H), 3.65 (d, J =
4.8 Hz, 2H), 2.56 (ddd, J = 16.6, 7.1, 2.2 Hz, 1H), 2.50 (ddd, J = 16.6, 5.9, 2.2 Hz, 1H), 2.30 (s,
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1H), 2.08 (s, 3H), 1.75 – 1.62 (m, 4H), 1.52 – 1.45 (m, 1H), 1.40 – 1.23 (m, 5H) ppm; C{1H}
NMR (125 MHz, CDCl3) δ 170.4, 137.9, 128.3, 127.6, 86.8, 74.7, 73.2, 71.3, 69.8, 32.8, 28.9,
25.9, 24.8, 21.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H26O3Na 337.1780; Found
337.1774.
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Ethyl (R)-6-((tert-butyldiphenylsilyl)oxy)-5-((6-(((3S,8S,9S,10R,13R,14S,17R)-10,13-dimeth-
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yl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradeca-
hydro-1H-
5l5-cyclopenta[a]phenanthren-3-yl)oxy)hexanoyl)oxy)hex-2-ynoate (5ʹ): Following the
general procedure P-2 and P-4, 5ʹ (240 mg, 69% yield over 2 steps) was obtained as a yellow
coloured liquid starting from (R)-tert-butyl(oxiran-2-ylmethoxy)diphenylsilane (122 mg, 0.39
mmol); Rf 0.6 (17:3 hexane/EtOAc); IR (neat): νmax 2938, 2865, 2358, 2241, 1709, 1649, 1459,
1378, 1257, 1105,2, 789, 706 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.72 – 7.62 (m, 4H), 7.41 (m,
6H), 5.34 (s, 1H), 5.12 – 5.00 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.87 – 3.73 (m, 2H), 3.43 (t, J =
6.5 Hz, 2H), 3.18 – 3.04 (m, 1H), 2.78 (qd, J = 17.2, 6.1 Hz, 2H), 2.25 (m, 4H), 2.09 – 1.78 (m,
6H), 1.67 – 1.45 (m, 7H), 1.44 – 1.23 (m, 14H), 1.19 – 1.09 (m, 5H), 1.06 (d, J = 5.4 Hz, 12H),
0.99 (s, 4H), 0.91 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.6 Hz, 6H), 0.68 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 172.8, 153.4, 141.1, 135.5, 135.5, 134.8, 133.0, 132.9, 129.8, 129.6, 127.8,
127.7, 121.4, 84.1, 79.0, 74.7, 70.9, 67.7, 63.5, 61.9, 56.8, 56.2, 50.2, 42.3, 39.8, 39.5, 39.2, 37.3,
36.9, 36.2, 35.8, 34.2, 31.9, 31.9, 29.8, 28.5, 28.2, 28.0, 26.7, 26.5, 25.8, 24.7, 24.3, 23.8, 22.8,
22.6, 21.1, 20.8, 19.4, 19.2, 18.7, 14.0, 11.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C57H84O6NaSi 915.5935; Found 915.5927.
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Experimental Procedure and Analytical Data for Hydration Products:
General procedure for hydration (P-5): To the stirred solution of δ-acetoxy ɑ,β-alkynoate (0.2
mmol) in CH2Cl2 (2 mL), Ph3PAuCl (1 mg, 0.0002 mmol) and AgSbF6 (0.7 mg, 0.0002 mmol)
were added and the reaction mixture stirred at ambient temperature. Distilled water (1.5 mmol)
was added to the above reaction mixture at the same temperature and the resulting reaction
mixture was stirred in open air flask for the respective time shown in manuscript. After
completion of the reaction (monitored by TLC), the solvent was evaporated under reduced
pressure and the crude residue was purified by silica gel column chromatography.
Methyl 5-acetoxy-3-oxopentanoate (2a): Following the general procedure P-5, 2a (35 mg,
93%) was obtained as a colorless liquid starting from 1a (34 mg, 0.2 mmol) Rf 0.3 (17:3
hexane/EtOAc); 1H NMR (400 MHz, CDCl3) δ 4.34 (t, J = 6.2 Hz, 2H), 3.75 (s, 3H), 3.50 (s,
2H), 2.90 (t, J = 6.2 Hz, 2H), 2.04 (s, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 199.7,
170.8, 167.2, 58.8, 52.4, 49.1, 41.5, 20.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C8H12O5Na 211.0582; Found 211.0597.
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Methyl 5-acetoxy-3-oxo-5-phenylpentanoate (2b): Following the general procedure P-5, 2b
(49 mg, 93%) was obtained as a colorless liquid starting from 1b (50 mg, 0.2 mmol); Rf 0.3 (9:1
hexane/EtOAc); IR (neat): νmax 2927, 2865, 1737, 1529, 1459, 1375, 1252, 1030, 801, 713 cm–1;
1H NMR (400 MHz, CDCl3) δ 7.37 – 7.29 (m, 5H), 6.19 (dd, J = 8.6, 4.8 Hz, 1H), 3.72 (s, 3H),
3.47 (d, J = 15.6 Hz, 1H), 3.43 (d, J = 15.7 Hz, 1H), 3.22 (dd, J = 17.0, 8.7 Hz, 1H), 2.98 (dd, J
= 17.0, 4.8 Hz, 1H), 2.04 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 198.7, 169.7, 167.1,
139.3, 128.7, 128.6, 128.3, 126.4, 126.3, 71.2, 52.4, 49.4, 49.0, 21.0 ppm; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C14H16O5Na 287.0895; Found 287.0905.
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Benzyl 5-acetoxy-3-oxo-5-phenylpentanoate (2c): Following the general procedure P-5, 2c (55
mg, 81%) was obtained as a colorless liquid starting from 1c (64 mg, 0.20 mmol); Rf 0.4 (19:1
hexane/EtOAc); IR (neat): νmax 2936, 1735, 1599, 1530, 1464, 1330, 1258, 1031, 709 cm–1; 1H
NMR (500 MHz, CDCl3) δ 7.37 – 7.29 (m, 5H), 6.19 (dd, J = 8.6, 4.8 Hz, 1H), 3.72 (s, 3H), 3.47
(d, J = 15.6 Hz, 1H), 3.43 (d, J = 15.7 Hz, 1H), 3.22 (dd, J = 17.0, 8.7 Hz, 1H), 2.98 (dd, J =
13
17.0, 4.8 Hz, 1H), 2.04 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 198.7, 169.7, 167.1,
139.3, 128.6, 128.6, 128.3, 126.4, 126.3, 71.2, 52.4, 49.4, 49.0, 21.0 ppm; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C20H20O5Na 363.1203; Found 363.1222.
Methyl 5-acetoxy-5-(4-bromophenyl)-3-oxopentanoate (2d): Following the general procedure
P-5, 2d (65 mg, 95%) was obtained as a colorless liquid starting from 1d (64 mg, 0.2 mmol); IR
(neat): νmax 2956, 2853, 1745, 1651, 1599, 1447, 1409, 1335, 1251, 1150, 1029, 810 cm–1; 1H
NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.13 (dd, J = 8.3,
5.1 Hz, 1H), 3.72 (s, 3H), 3.45 (d, J = 0.5 Hz, 2H), 3.21 (dd, J = 17.2, 8.4 Hz, 1H), 2.96 (dd, J =
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17.2, 5.1 Hz, 1H), 2.04 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 198.5, 169.7, 167.1,
138.4, 131.8, 128.2, 128.1, 122.3, 70.60, 52.5, 49.3, 48.7, 21.0 ppm; HRMS (ESI-TOF) m/z: [M
+ Na]+ Calcd for C14H15O5NaBr 365.0001; Found 365.0006.
Ethyl 5-acetoxy-5-(4-bromophenyl)-3-oxopentanoate (2e): Following the general procedure
P-5, 2e (66 mg, 93%) was obtained as a colorless liquid starting from 1e (70 mg, 0.2 mmol); Rf
0.4 (9:1 hexane/EtOAc); IR (neat): νmax 2967, 2853, 1747, 1495, 1436, 1370, 1330, 1241, 1023,
825, 645 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H),
6.14 (dd, J = 8.3, 5.1 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.45 (d, J = 15.6 Hz, 1H), 3.41 (d, J =
15.6 Hz, 1H), 3.22 (dd, J = 17.3, 8.4 Hz, 1H), 2.97 (dd, J = 17.3, 5.1 Hz, 1H), 2.04 (s, 3H), 1.26
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(t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (125 MHz, CDCl3) δ 198.6, 169.6, 166.6, 138.4, 131.8,
128.2, 128.1, 122.3, 70.6, 61.6, 49.6, 48.7, 21.0, 14.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C15H17O5NaBr 379.0157; Found 379.0179.
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Methyl 5-acetoxy-5-(4-fluorophenyl)-3-oxopentanoate (2f): Following the general procedure
P-5, 2f (51 mg, 90%) was obtained as a colorless liquid starting from 1f (53 mg, 0.2 mmol); Rf
0.3 (9:1 hexane/EtOAc); IR (neat): νmax 2924, 2858, 1747, 1658, 1604, 1515, 1445, 1374, 1326,
1238, 1160, 1095, 1030, 840 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.34 (dd, J = 8.7, 5.3 Hz, 2H),
7.03 (t, J = 8.7 Hz, 2H), 6.17 (dd, J = 8.3, 5.1 Hz, 1H), 3.72 (s, 3H), 3.47 (d, J = 15.7 Hz, 1H),
3.43 (d, J = 15.7 Hz, 1H), 3.22 (dd, J = 17.1, 8.4 Hz, 1H), 2.98 (dd, J = 17.1, 5.1 Hz, 1H), 2.03
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(s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 198.6, 169.7, 167.1, 162.5 (d, J = 247.1 Hz),
135.1 (d, J = 2.8 Hz), 128.4 (d, J = 8.3 Hz), 115.5 (d, J = 21.7 Hz), 70.6, 52.4, 49.3, 48.9, 21.0
ppm; F NMR (377 MHz, CDCl3) δ −113.4 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
19
C14H15O5FNa 305.0801; Found 305.0799.
Methyl 5-acetoxy-3-oxo-5-(p-tolyl)pentanoate (2g): Following the general procedure P-5, 2g
(49 mg, 88%) was obtained as a colorless liquid starting from 1g (52 mg, 0.2 mmol); Rf 0.2 (9:1
hexane/EtOAc); IR (neat): νmax 2942, 1727, 1440, 1372, 1320, 1235, 1092, 1023, 818 cm–1;
1HNMR (500 MHz, CDCl3) δ 7.24 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 6.15 (dd, J =
8.6, 4.9 Hz, 1H), 3.72 (s, 3H), 3.47 (d, J = 15.7 Hz, 1H), 3.43 (d, J = 15.6 Hz, 1H), 3.21 (dd, J =
16.9, 8.6 Hz, 1H), 2.96 (dd, J = 16.9, 4.9 Hz, 1H), 2.33 (s, 3H), 2.02 (s, 3H) ppm; 13C{1H} NMR
(75 MHz, CDCl3) δ 198.8, 169.7, 167.1, 138.1, 136.2, 129.2, 126.4, 71.1, 52.3, 49.3, 48.9, 21.1,
21.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H18O5Na 301.1052; Found 301.1060.
Ethyl 5-acetoxy-5-(2-bromophenyl)-3-oxohexanoate (2h): Following the general procedure P-
5, 2h (66 mg, 89%) was obtained as a colorless liquid starting from 1h (71 mg, 0.2 mmol); Rf 0.4
(19:1 hexane/EtOAc); IR (neat): νmax 2988, 1740, 1645, 1428, 1371, 1316, 1242, 1160, 1030,
761 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 7.9, 1.3 Hz, 1H), 7.48 (dd, J = 8.0, 1.6 Hz,
1H), 7.35 – 7.28 (m, 1H), 7.16 – 7.09 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.64 (d, J = 15.2 Hz,
1H), 3.46 (d, J = 15.8 Hz, 1H), 3.39 (d, J = 15.8 Hz, 1H), 3.34 (d, J = 15.2 Hz, 1H), 2.09 (s, 3H),
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2.07 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 199.5, 169.0,
166.8, 140.4, 135.4, 129.2, 128.6, 127.5, 119.5, 81.3, 61.4, 50.8, 50.7, 24.3, 21.6, 14.1 ppm;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H19O5NaBr 393.0314; Found 393.0313.
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