Formation of Enol Ethers by Radical Decarboxylation of α-Alkoxy β-Phenylthio Acids

Article abstract of DOI:10.1021/acs.joc.9b02042

Enol ethers are formed by radical decarboxylation of α-alkoxy β-phenylthio acids via the corresponding Barton esters. The phenylthio acids were usually made by the known regioselective reaction of α,β-epoxy acids with PhSH in the presence of InCl₃, followed by O-alkylation of the resulting alcohol. In one case, thiol addition to an α,β-unsaturated ethoxymethyl ester was used.

Full text of DOI:10.1021/acs.joc.9b02042

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Article
Formation of Enol Ethers by Radical
Decarboxylation of #-Alkoxy #-Phenylthio Acids
Ashokkumar Palanivel, Sidra Mubeen, Thomas Warner, Nayeem Ahmed, and Derrick L. J. Clive
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02042 • Publication Date (Web): 28 Aug 2019
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Formation of Enol Ethers by Radical Decarboxylation of -Alkoxy -
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Phenylthio Acids
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Ashokkumar Palanivel, Sidra Mubeen, Thomas Warner, Nayeem Ahmed, and Derrick L. J.
Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
derrick.clive@ualberta.ca
ABSTRACT
Enol ethers are formed by radical decarboxylation of -alkoxy -phenylthio acids via the
corresponding Barton esters. The phenylthio acids were usually made by the known
regioselective reaction of ,-epoxy acids with PhSH in the presence of InCl3, followed by O-
alkylation of the resulting alcohol. In one case thiol addition to an ,-unsaturated ethoxymethyl
ester was used.
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INTRODUCTION
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In connection with synthetic work related to the anticancer antibiotic MPC1001,1 which
contains a cyclic enol ether substructure, we needed to prepare an alcohol that was functionalized
in a way that would allow etherification of the hydroxyl and, at a later stage, formation under
mild conditions of an enol ether, along the lines expressed by (eq 1).
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This requirement resulted from our present approach to MPC1001 which is based on
cyclization of an alcohol onto a -amino enone by addition-elimination, followed by introduction
of a double bond (eq 2).
Procedures for making enol ethers were reviewed several years ago2 but recent
publications have provided a number of more modern examples. Apart from methods that
involve transfer of a vinyl group to an alcohol,3 or elaboration of an existing simple enol ether,4
the classical preparation is the acid- or Lewis acid-catalyzed elimination of an alcohol from an
acetal.5 A very versatile route is the Birch reduction or palladium-mediated reduction of vinyl
phosphate ethers, which are available from esters and lactones.6 Another powerful method is the
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methylenation of an ester carbonyl with the Tebbe or Petasis reagents.7 This procedure can be
combined with ring-closing metathesis to afford cyclic enol ethers.8 Reaction of aldehydes and
ketones with Wittig or Horner-Wadsworth-Emmons reagents carrying an alkoxy group also give
enol ethers.9 Similarly, the Peterson olefination, using -alkoxysilanes10 and the Julia
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olefination with -alkoxysulfones11 both serve to generate enol ethers.
A number of elimination processes are known in which a saturated ether bearing suitable
groups at either or both the  and  positions are converted into enol ethers by base treatment12
or by reduction.13 Selenoxide fragmentation has also been used to convert a saturated ether into
an enol ether.1, 14
An approach involving a different principle is the isomerization of allyl ethers to enol
ethers, a process that has sometimes been combined with initial ring-closing metathesis of allyl
ethers.15 Acetylenic ethers, on semihydrogenation, give enol ethers,16 and acetylenes can
undergo monoaddition of an alcohol in a process promoted by a metal salt.17
Michael addition of an alcohol to an ,-acetylenic ester has been used to generate enol
ethers,18 and there are also a number of metal-mediated cross-coupling procedures for forming a
C—O bond between a vinyl halide, triflate or boronic acid or by CH activation.19
RESULTS AND DISCUSSION
None of the existing methods appeared to be appropriate for our needs and so we have
explored the process summarized in Scheme 1. The key step of our approach is radical
fragmentation of the Barton ester 1c, our working hypothesis being that radical decarboxylation
(1c1d) would be followed by rapid expulsion20 of a thiyl radical. In connection with this
Scheme we can find only one report21 of the collapse of a Barton ester made from a carboxylic
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SCHEME 1. Principle of the present enol ether synthesis
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acid carrying a -thio substituent (eq 3). In that case two disulfides were isolated in yields of
18% and 33%. Evidently, ethylene must have been released, but to establish if the yield of olefin
can be synthetically useful, we first added thiophenol to the unsaturated ester 2a (Scheme 2),
hydrolyzed the adduct to the parent acid 2b, and then formed the Barton ester 2c by DCC-
mediated coupling with N-hydroxypyridine-2(1H)-thione. Exposure of the Barton ester to
daylight for about 15 min resulted in smooth collapse to dec-1-ene which was isolated in 85%
yield.
SCHEME 2. Simple test of the planned radical fragmentation
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With the efficiency of alkene formation established, two -phenylthio -hydroxy acids
were generated from epoxy acids using a literature procedure (Scheme 3). The precursors to the
phenylthio compounds were the epoxy acids 3f and 3g, and both were made as shown in Scheme
3 by the sequence of Horner-Wadsworth-Emmons olefination, ester hydrolysis and epoxidation22
with Oxone. Each of these steps proceeded without incident and the regioselective epoxide
opening with PhSH in the presence of InCl323 (3f3h, 3g3i) under the reported23 conditions
SCHEME 3. Synthesis of -hydroxy -phenylthio acids
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was also satisfactory. The intermediate olefinic acids 3d and 3e were isolated stereochemically
pure in 78% and 82% yield, respectively by hydrolysis of their methyl esters and, as expected,
the subsequent hydroxy phenylthio acids 3h (85%) and 3i (66%) were each a single
stereoisomer.
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The next step was the O-alkylation of the secondary hydroxyl. In the case of 4a (Scheme
4), deprotonation of 3h with BuLi (2 equiv) and addition of Me2SO4 was found to give the
desired product (67%). For the other examples we examined a variety of conditions and
established that satisfactory results could be obtained by treating the hydroxy acids 3h and 3i
with 1.95 equiv (not 1 equiv) of NaH at 0 °C, adding the alkylating agent at 0 °C and allowing
the mixture to warm to room temperature. In two cases (3h4b; 3h4c), the mixture was
refluxed after adding the alkylating agent. During alkylation of the hydroxyl we did not observe
formation of any alkyl ester and little, if any, must have been formed.24 We also prepared the O-
silylated compounds 4d and 4f (Scheme 4) and only in these cases was the whole sequence of
hydroxyl deprotonation and protection done at 0 °C to room temperature, a modification needed
in order to minimize carboxyl silylation.
SCHEME 4. Conversion of -hydroxy -phenylthio acids to enol ethers
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Each of the acids 4a-f was converted into its Barton ester and, for this purpose, we found
(based on experiments with 4e) that the use of DCC in the presence of DMAP for coupling the
acid with N-hydroxypyridine-2(1H)-thione gave better yields than experiments run in the
absence of DMAP.25 We also tried reaction of the sodium salt of N-hydroxypyridine-2(1H)-
thione with the acid chloride25 derived from 4b, but the yield was poor. Each of the Barton
esters underwent very rapid reaction when a solution in a mixture of EtOAc and hexane was
exposed to daylight; the process appeared to be complete within 15 min, leading to the Z/E enol
ethers 4aa–4ff in yields of 62-79%. In our first photolysis (formation of 2d) we irradiated a
dichloromethane solution, but in the experiments with 4a-f we found it convenient to generate
the Barton ester in CH2Cl2 (radical decarboxylation has been reported in this solvent26) and to
pass the reaction mixture through a short column of silica gel, using EtOAc-hexane (all done
with protection from light), and the eluate was then exposed to daylight directly without
evaporating the solvent.
We next applied the above method to a cyclic system and, after a number of preliminary
experiments in which we explored routes to 7-membered oxygen heterocycles,27 we chose the
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phenylthio acid 5c as a suitable starting material (Scheme 5). Our intention was to add PhSH to
the corresponding unsaturated acid 5a which we expected to be available by hydrolysis of ester
5b. Alternatively, we could add the thiol to the ester and do the hydrolysis as the second step.
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SCHEME 5. Planned route to a cyclic model -phenylthio acid
We decided to use a general cyclization method developed by Moody and Taylor28 to prepare the
keto ester 6d (Scheme 6) and convert that into the desired acid 5a or ester 5b. To this end
coumarin was hydrogenated over Pd/C in AcOH29 (6a6b) and the product was mixed with
EtO2CCHN2 and treated with LDA, following the literature procedure.28 This experiment gave
SCHEME 6. First approach to a cyclic -phenylthio acid
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the reported diazo compound 6c which underwent the desired cyclization (6c6d) in refluxing
benzene in the presence of catalytic Rh2(OAc)4.28 This sequence worked well on a multigram
scale.
Reduction of the ketone carbonyl of 6d, which existed as a mixture of keto enol
tautomers, was initially troublesome. We tried NaBH4/CeCl3.7H2O, L-Selectride, DIBAL-H and
Pd/C but eventually found that the use of 0.5 mole NaBH4 per mole 6d in EtOH at –78 °C
worked satisfactorily and gave the expected hydroxy esters 6e as an inconsequential mixture of
epimers (78%). The alcohols were easily tosylated and we next sought to displace the tosyloxy
group by treatment with PhSNa. Surprisingly, the product (72%) was the unsaturated ester 5b.
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This compound was subsequently obtained by treatment of the tosylate with DBU (84%). The
phenylthio group could then be added by exposure of the unsaturated ester to a 10:1 mixture of
PhSH and PhSLi,30 conditions that provide a powerful nucleophile (PhS–) as well as a source of
protons (PhSH). Unfortunately, the resulting phenylthio ester 6g could not be hydrolyzed to
form acid 5a without extensive elimination of the PhS group. Evidently, a more easily
removable protecting group for the carboxyl was required.
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SCHEME 7. Formation of a cyclic -phenylthio acid and conversion to cyclic enol ether
Ester 5b was hydrolyzed to acid 5a (Scheme 7). We were unable to add PhSH to the
acid31 and so the acid was protected (88%) by treatment with EtOCH2Cl in DMF in the presence
of Et3N (5a7a).32 Although esters of the type RCOOCH2OR' are often not stable to silica
gel,33 compound 7a could be subjected to standard flash chromatography over silica gel.
Addition of thiophenol, again using a 10:1 mixture of PhSH and PhSLi,30 proceeded without
incident and we obtained directly the desired phenylthio acid 5c. We did not establish the point
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(which could be during the reaction, during aqueous acidic workup, or on exposure to silica gel)
that the EtOCH2 group was lost in the formation of 5c. With that acid in hand, we made the
Barton esters 7b and found that they behaved in the same way as our other examples, giving 7c
in 64% yield over the two steps from acid 5c. The efficiency is probably higher as the oxepine is
fairly volatile6b but we did not determine the yield by a method involving an internal standard.6b
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Because of the difficulty in hydrolyzing the phenylthio ester 6g, we considered a related
process that would more easily accommodate ester hydrolysis. The plan (Scheme 8) was to
effect conjugate addition of a PhMe2Si group34 to 5b in the expectation, based on extensive
precedent,35 that base hydrolysis of the product 8a would afford the -silyl acid 8b. Several -
silyl acids, made by totally different routes, have been oxidized electrochemically36 or with
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Pb(OAc)4 to alkenes. However, this plan was thwarted by the fact that ester 5b does not
undergo conjugate addition of a PhMe2Si group from a cuprate34, 38 or an organocopper reagent
under conditions that are successful with unsaturated esters that are not also enol ethers.34, 38, 39
SCHEME 8. Attempted formation of a -silyl acid
CONCLUSION
Barton esters derived from -alkoxy--phenylthio acids decompose within 15 to 30 min on
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exposure to visible light to afford enol ethers. The parent -phenylthio carboxylic acids are
available either by way of regioselective opening of ,-epoxy acids with PhSH in the presence
of InCl3, or by conjugate addition of PhSLi in the presence of PhSH to ethoxymethyl esters of -
alkoxy ,-unsaturated acids. The use of the ethoxymethyl ester instead of an ethyl ester is
crucial to allow ester hydrolysis without loss of the PhS group.
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EXPERIMENTAL SECTION
Solvents used for chromatography were distilled before use. Commercial thin layer
chromatography plates (silica gel, Merck 60F-254) were used.
Silica gel for flash
chromatography was Merck type 60 (230−400 mesh). Dry solvents were prepared under an inert
atmosphere (N2) and transferred by syringe or cannula. The symbols s, d, t, and q used for
13C{1H} NMR spectra indicate zero, one, two, or three attached hydrogens, respectively, the
assignments being made from APT spectra. Solutions were evaporated under water pump
vacuum, and the residue was then kept under oil pump vacuum. High resolution electrospray
mass spectrometric analyses were done with an orthogonal time-of-flight analyzer, and electron
ionization mass spectra were measured with a double-focusing sector mass spectrometer.
Methyl (2E)-Undec-2-enoate (2a).40 NaH (60%w/w in oil, 2.18 g, 0.054 mol) was
suspended in THF (75 mL) (N2 atmosphere). Methyl diethylphosphonoacetate (10 mL, 54
mmol) was added dropwise over 5 min and stirring at room temperature was continued for ca 15
min. Nonanal (8.4 mL, 49 mmol) was then added dropwise and stirring was continued for 2 h.
The solution was diluted with Et2O (75 mL), and washed with saturated aqueous NaHCO3 (50
mL) and brine (50 mL). The combined organic extracts were dried (MgSO4) and evaporated.
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Flash chromatography of the residue over silica gel (5.0  20 cm), using 15:1 hexane-EtOAc,
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afforded 2a as a colorless oil (7.7 g, 80%): H NMR (400 MHz, CDCl3)  0.90 (t, J = 7.0 Hz, 3
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H), 1.28–1.33 (m, 10 H), 1.45–1.48 (m, 2 H), 2.20 (qd, J = 7.6, 1.6 Hz, 2 H), 3.74 (s, 3 H), 5.83
(dt, J = 15.7, 1.7 Hz, 1 H), 6.97 (dt, J = 15.6, 7.1 Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3) 
14.1, 22.6, 28.0, 29.14, 29.19, 29.35, 31.8, 32.2, 51.4, 120.8, 149.8, 167.2.
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rac-3-(Phenylsulfanyl)undecanoic acid (2b). (a) rac-Methyl 3-(Phenylsulfanyl)-
undecanoate. The following experiment was modeled on a general literature procedure.41 Ester
2a (1.0 g, 5 mmol) was dissolved in THF (5 mL) (N2 atmosphere) and PhSH (2.6 mL, 25 mmol)
was added dropwise to the solution, followed by Et3N (0.70 mL, 5 mmol). The slightly yellow
solution was stirred at room temperature for ca 20 h, diluted with Et2O (20 mL), washed with 5%
hydrochloric acid (20 mL), water (20 mL), and brine (20 mL). The combined organic extracts
were dried (MgSO4) and evaporated. Flash chromatography of the residue over silica gel (3.0 
15.0 cm), using 50:1 hexane-EtOAc, afforded rac-methyl 3-(phenylsulfanyl)undecanoate as a
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colorless oil (1.4 g, 98%): H NMR (400 MHz, CDCl3)  0.88 (t, J = 7.1 Hz, 3 H), 1.20–1.33
(m, 10 H), 1.45–1.65 (m, 4 H), 2.56 (ddd, J = 27.6, 15.6, 6.9 Hz, 2 H), 3.47 (ddd, J = 14.4, 7.3,
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5.6 Hz, 1 H), 3.66 (s, 3 H), 7.25–7.37 (m, 3 H), 7.43–7.45 (m, 2 H); C{1H} NMR (100 MHz,
CDCl3)  14.1, 22.6, 26.8, 29.2, 29.3, 29.4, 31.8, 34.6, 40.4, 45.1, 51.7, 127.3, 128.9, 132.9,
134.0, 172.1; exact mass (ESI) m/z calcd for C18H28NaO2S (M + Na)+ 331.1702, found 331.1703.
(b) rac-3-(Phenylsulfanyl)undecanoic acid (2b). rac-Methyl 3-(phenylsulfanyl)undec-
anoate (1.0 g, 3.2 mmol) was covered with hydrochloric acid (6 M, 20 mL) and the mixture was
refluxed for 5 days, cooled and extracted with CH2Cl2 (3 x 20 mL). The combined organic
extracts were dried (MgSO4) and evaporated. Flash chromatography of the residue over silica
gel (3.0 cm  15 cm), using 9:1 hexane-EtOAc containing 0.1%v/v AcOH, afforded 2b as a
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colorless oil (0.76 g, 80%): H NMR (400 MHz, CDCl3)  0.89 (t, J = 7.1 Hz, 3 H), 1.20–1.36
(m, 10 H), 1.40–1.70 (m, 4 H), 2.60 (ddd, J = 27.7, 16.1, 6.8 Hz, 2 H), 3.46 (ddd, J = 14.4, 7.3,
7.3 Hz, 1 H), 7.24–7.33 (m, 3 H), 7.43–7.47 (m, 2 H), 10.4 (br s, 1 H), (OH signal not observed);
13C{1H} NMR (100 MHz, CDCl3)  14.1, 22.6, 26.8, 29.2, 29.3, 29.4, 31.8, 34.5, 40.3, 44.8,
127.5, 128.9, 133.0, 133.7, 177.6; exact mass (ESI) m/z calcd for C17H25O2S (M – H)– 293.1581,
found 293.1577.
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Dec-1-ene (2d).42 A general literature procedure43 was followed to prepare the
intermediate Barton ester. Acid 2b (0.057 g, 0.19 mmol) was dissolved in CH2Cl2 (2 mL) and
the flask was wrapped with aluminum foil. The solution was cooled to 0 °C (ice bath) and DCC
(0.041 g, 0.19 mmol) and 1-N-hydroxypyridine-2(1H)-thione (0.025 g, 0.19 mmol) were added.
The ice bath was removed and stirring was continued for 4 h. A pad of silica gel (2  4 cm) was
prepared in a foil-wrapped chromatography column and the reaction mixture was passed through
it using 4:1 hexane-EtOAc. The yellow fractions were exposed to sunlight and, once colorless
(ca 15 min), were combined and evaporated. Flash chromatography of the residue over silica gel
(Pasteur pipette, 0.5  4.0 cm), using hexane, gave 2d (0.027 g, 85%) as a colorless oil: 1H
NMR (400 MHz, CDCl3)  0.89 (t, J = 7.0 Hz, 3 H), 1.27–1.32 (m, 10 H), 1.34–1.40 (m, 2 H),
2.03 (q, J = 7.6 Hz, 2 H), 4.91–5.02 (m, 2 H), 5.81 (ddt, J = 10.3, 6.8, 6.7, 1 H); 13C{1H} NMR
(100 MHz, CDCl3)  14.1, 22.7, 29.0, 29.2, 29.3, 29.5, 31.9, 33.8, 114.1, 139.3.
(2E)-Undec-2-enoic acid (3d).44 Ester 2a (1.0 g, 5.0 mmol) was dissolved in acetone (90
mL), and an aqueous solution of LiOH (1.0 M, 50 mL) was added dropwise. Stirring was
continued for 24 h and the acetone was evaporated. The residue was covered with Et2O (100
mL) and the mixture was shaken with 10% aqueous NaHCO3 (2 x 50 mL). The combined
aqueous phases were acidified using concentrated hydrochloric acid (5 mL) and extracted with
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Et2O (3 x 25 mL). The combined organic extracts were dried (MgSO4) and evaporated to afford
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3d as a colorless oil (0.70 g, 78%): H NMR (400 MHz, CDCl3)  0.91 (t, J = 7.0 Hz, 3 H),
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1.23–1.39 (m, 10 H), 1.42–1.52 (m, 2 H), 2.21–2.27 (m, 2 H), 5.83 (dt, J = 15.6, 1.0 Hz, 1 H),
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7.09 (dt, J = 15.6, 7.0 Hz, 1 H), (OH signal not observed); C{1H} NMR (100 MHz, CDCl3) 
14.1 (q), 22.6 (t), 27.9 (t), 29.1 (t), 29.2 (t), 29.3 (t), 31.8 (t), 32.3 (t), 120.7 (d), 152.4 (d), 172.0
(s).
rac-Trans-3-Octyloxirane-2-carboxylic acid (3f).45 A literature procedure22 for
epoxidation was followed. Acid 3d (5.60 g, 30.4 mmol) was dissolved in a mixture of acetone
(10 mL) and water (10 mL). Solid NaHCO3 (10.2 g, 122 mmol) was added and a solution of
Oxone (20.0 g, 64 mmol) and Na2EDTA (10 mg) in water (90 mL) was added over 2 h by
syringe pump. The reaction mixture was stirred for a further 2 h, before being cooled to 0 °C
and quenched with 10% aqueous H2SO4. The mixture was extracted with EtOAc (3 x 25 mL),
and the combined organic extracts were dried (MgSO4) and evaporated to afford pure 3f as
1
colorless crystals (4.56 g, 75%): H NMR (400 MHz, CDCl3)  0.90 (t, J = 7.0 Hz, 3 H), 1.23–
1.40 (m, 10 H), 1.42–1.53 (m, 2 H), 1.59–1.68 (m, 2 H), 3.21 (ddd, J = 6.2, 4.9, 2.0 Hz, 1 H),
3.28 (s, 1 H), (OH signal not observed); C{1H} NMR (100 MHz, CDCl3)  14.1, 22.6, 25.6,
13
29.1, 29.2, 29.4, 31.4, 31.8, 52.6, 59.1, 174.1.
rac-(2R,3S)-2-Hydroxy-3-(phenylsulfanyl)undecanoic acid (3h).
The general
procedure reported by Fringuelli et. al.23 was followed. The pH of a mixture of PhSH (2.35 mL,
23 mmol), InCl3 (0.46 g, 2.1 mmol) and water (45 mL) was carefully adjusted to 4.0 using an
aqueous solution of NaOH (0.5 M). The mixture was stirred and heated at 35 °C (oil bath) and a
solution of epoxy acid 3f (4.2 g, 20.9 mmol) in acetone (1 mL) was added at a fast dropwise rate.
The solution was stirred for an additional 2 h at 35 °C, after which it was cooled to 0 °C and
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quenched with 10% aqueous H2SO4. The resulting mixture was extracted with EtOAc (3  10
mL) and the combined organic extracts were washed with brine (10 mL), dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (5.0  20 cm), using 3:2 PhMe-
EtOAc containing 0.01%v/v AcOH, afforded 3h as a colorless oil (5.51 g, 85%): FTIR (film)
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3433, 2927, 2855, 1724, 1584, 1466, 1439, 1231, 1128, 1097, 1025, 747, 692 cm–1; H NMR
(400 MHz, CDCl3)  0.88–0.91 (m, 3 H), 1.22–1.40 (m, 11 H), 1.42–1.47 (m, 1 H), 1.60–1.66
(m, 2 H), 3.58 (ddd, J = 8.4, 5.7, 2.9 Hz, 1 H), 4.33 (d, J = 2.9 Hz, 1 H), 7.27–7.35 (m, 3 H),
7.48–7.50 (m, 2 H), (CO2H signal not observed); 13C{1H} NMR (100 MHz, CDCl3)  14.1, 22.7,
27.4, 29.17, 29.21, 29.27, 29.3, 31.8, 53.2, 72.0, 127.7, 129.3, 132.2, 133.7, 175.8; exact mass
(ESI) m/z calcd for C17H25O3S (M – H)– 309.1530, found 309.1532.
rac-(2R,3S)-2-Methoxy-3-(phenylsulfanyl)undecanoic acid (4a). Freshly titrated n-
BuLi (2.1 M in hexane, 0.44 mL, 0.917 mmol) was added dropwise to a stirred and cooled (–78
°C) solution of 3h (0.135 g, 0.437 mmol) in THF (5 mL). Stirring was continued for 10 min and
freshly distilled Me2SO4 (0.09 mL, 0.917 mmol) was added dropwise. The cold bath was left in
place, but not recharged, and stirring was continued for 20 h during which the mixture reached
room temperature. An aqueous solution of NH4OH (5%w/v, 10 mL) was added and stirring was
continued for 10 min. The mixture was quenched with 10% aqueous hydrochloric acid (50 mL)
and extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (3.0  15 cm), using 4:1 PhMe-
EtOAc containing 0.01%v/v AcOH, afforded 4a as a colorless oil (0.096 g, 67%): FTIR (film)
2956, 2926, 2855, 1716, 1465, 1261, 1105, 798, 747 cm–1; 1H NMR (400 MHz, CDCl3)  0.89 (t,
J = 7.0 Hz, 3 H), 1.20–1.38 (m, 10 H), 1.41–1.47 (m, 1 H), 1.60–1.75 (m, 3 H), 3.49–3.53 (s, 3 H
and m, 1 H), 3.89 (d, J = 3.9 Hz, 1 H), 7.23–7.28 (m, 1 H), 7.30–7.38 (m, 2 H), 7.45–7.50 (m, 2
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H), (OH signal not observed); C{1H} NMR (100 MHz, CDCl3)  14.1 (q), 22.7 (t), 27.2 (t),
29.21 (t), 29.30 (t), 29.36 (t), 29.47 (t), 31.8 (t), 51.3 (d), 60.0 (q), 82.5 (d), 127.2 (d), 129.1 (d),
131.9 (d), 134.7 (s), 174.9 (s); exact mass (ESI) m/z calcd for C18H27O3S (M – H)– 323.1686,
found 323.1688.
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(Z)-1-Methoxydec-1-ene and (E)-1-Methoxydec-1-ene (4aa).46 Acid 4a (0.080 g, 0.25
mmol) was dissolved in CH2Cl2 (2 mL) and the flask was wrapped with aluminum foil. The
solution was cooled to 0 °C (ice bath) and DCC (0.053 g, 0.26 mmol) and N-hydroxypyridine-
2(1H)-thione (0.031 g, 0.25 mmol) were added. The ice bath was removed and stirring was
continued for 4 h. A pad of silica gel (1.5  4 cm) was prepared in a foil-wrapped
chromatography column and the reaction mixture was passed through it using 4:1 hexane-EtOAc
(subdued laboratory lighting). The yellow fractions were exposed to sunlight for 15 min and,
once colorless, were combined and evaporated. Flash chromatography of the residue over silica
gel (1.5  10 cm), using 100:1 hexane-EtOAc afforded 4aa (0.026 g, 62%) as a colorless oil that
was a mixture of isomers: FTIR (film) 2955, 2855, 1725, 1656, 1465, 1261, 1126, 1108, 1026,
933, 803, 739, 700 cm–1; 1H NMR (400 MHz, CDCl3)  0.90 (t, J = 7.0 Hz, 3 H, both isomers),
1.22–1.39 (m, 12 H, both isomers), 1.90–1.95 (m, 2 H, major isomer), 2.03–2.10 (m, 2 H, minor
isomer), 3.52 (s, 3 H, major isomer), 3.59 (s, 3 H, minor isomer), 4.35 (dt, J = 7.3, 6.5 Hz, 1 H,
minor isomer), 4.74 (dt, J = 14.7, 7.3 Hz, 1 H, major isomer), 5.88 (dt, J = 6.2, 1.2 Hz, 1 H,
minor isomer), 6.29 (dt, J = 12.6, 1.2 Hz, 1 H, major isomer); 13C{1H} NMR (100 MHz, CDCl3)
 14.1 (q), 22.7 (t), 23.9 (t), 27.7 (t), 29.0 (t), 29.30 (t), 29.31 (t), 29.33 (t), 29.47 (t), 29.48 (t),
29.9 (t), 30.8 (t), 30.9 (t), 31.90 (t), 31.91 (t), 55.9 (q), 59.5 (q), 103.3 (d), 107.2 (d), 145.9 (d),
146.9 (d); exact mass (EI) m/z calcd for C11H22O (M)+ 170.1671, found 170.1672.
rac-(2R,3S)-3-(Phenylsulfanyl)-2-(prop-2-en-1-yl)undecanoic acid (4b). Acid 3h
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(0.157 g, 0.51 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0 °C. NaH
(60%w/w in oil, 0.04 g, 0.99 mmol) was added as a solid and the mixture was stirred for 15 min
at 0 °C. The ice bath was removed and stirring was continued for 1 h, during which the mixture
reached room temperature. Freshly distilled allyl bromide (0.044 mL, 0.53 mmol) was added
and the reaction mixture was then refluxed for 8 h. The mixture was cooled, quenched with 5%
hydrochloric acid (30 mL), and extracted with EtOAc (3 x 15 mL). The combined organic
extracts were dried (MgSO4) and evaporated. Flash chromatography of the residue over silica
gel (3.0  15 cm), using 3:1 hexane-EtOAc, followed by 1:1 hexane-EtOAc, afforded 4b as a
colorless oil (0.12 g, 67%): FTIR (film) 2956, 2926, 2856, 1716, 1466, 1439, 1260, 1095, 1025,
928, 798, 747, 692 cm–1; 1H NMR (400 MHz, CDCl3)  0.89 (t, J = 7.0 Hz, 3 H), 1.27–1.31 (m,
10 H), 1.43–1.49 (m, 1 H), 1.60–1.72 (m, 3 H), 3.55 (ddd, J = 9.6, 4.0, 4.0 Hz, 1 H), 4.07 (d, J =
4.0 Hz, 1 H), 4.15 (dddd, J = 12.5, 5.8, 1.3, 1.3 Hz, 2 H), 5.20–5.28 (m, 2 H), 5.90 (ddt, J = 17.2,
10.3, 5.9 Hz, 2 H), 7.21–7.28 (m, 1 H), 7.30–7.37 (m, 2 H), 7.44–7.47 (m, 2 H), (OH signal not
observed); 13C{1H} NMR (100 MHz, CDCl3)  14.1 (q), 22.7 (t), 27.2 (t), 29.2 (t), 29.3 (t), 29.4
(t), 29.6 (t), 31.8 (t), 51.3 (d), 73.2 (t), 79.7 (d), 118.8 (s), 127.1 (d), 129.1 (d), 131.6 (d), 133.2
(d), 134.9 (t), 174.6 (s); exact mass (ESI) m/z calcd for C20H29O3S (M – H)– 349.1843, found
349.1843.
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(1Z)-1-(Propen-1-yloxy)dec-1-ene and (1Z)-1-(Propen-1-yloxy)dec-1-ene (4bb). Acid
4b (0.099 g, 0.28 mmol) was dissolved in CH2Cl2 (2 mL) and the flask was wrapped with
aluminum foil. The solution was cooled to 0 °C (ice bath) and DCC (0.061 g, 0.29 mmol) and
N-hydroxypyridine-2(1H)-thione (0.037 g, 0.29 mmol) were added. The ice bath was removed
and stirring was continued for 4 h. A pad of silica gel (2  4 cm) was prepared in a foil-wrapped
chromatography column and the reaction mixture was passed through it using 4:1 hexane-EtOAc
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(subdued laboratory lighting. The yellow fractions were exposed to sunlight and, once colorless
(ca 15 min), were combined and evaporated. Flash chromatography of the residue over silica gel
(1.5  10 cm), using 100:1 hexane-EtOAc, afforded 4bb (0.040 g, 73%) as a colorless oil which
was a mixture of isomers: FTIR (film) 2956, 2926, 2856, 1716, 1466, 1439, 1260, 1095, 1025,
928, 798, 747, 692 cm–1; 1H NMR (400 MHz, CDCl3)  0.89 (t, J = 7.0 Hz, 3 H, both isomers),
1.27–1.37 (m, 12 H, both isomers), 1.89–1.94 (m, 2 H, major isomer), 2.07–2.13 (m, 2 H, minor
isomer), 4.19 (dt, J = 5.4, 1.5 Hz, 1 H, major isomer), 4.26 (dt, J = 5.4, 1.5 Hz, 1 H, minor
isomer), 4.39 (dt, J = 7.3, 6.5 Hz, 1 H, minor isomer), 4.83 (dt, J = 12.4, 7.2 Hz, 1 H, major
isomer), 5.20–5.24 (m, 2 H, minor isomer), 5.29–5.35 (m, 2 H, major isomer), 5.88–6.01 (m, 3
H, one H of minor isomer and two other H of both isomers), 6.22 (dt, J = 12.6, 1.2 Hz, 1 H,
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major isomer); C{1H} NMR (100 MHz, CDCl3)  14.1 (q), 22.7 (t), 24.0 (t), 27.7 (t), 29.0 (t),
29.32 (t), 29.33 (t), 29.34 (t), 29.4 (t), 29.5 (t), 29.8 (t), 30.7 (t), 31.91 (t), 31.93 (t), 70.1 (t), 72.5
(t), 105.2 (d), 107.6 (d), 117.1 (t), 117.3 (t), 133.8 (d), 134.2 (d), 144.2 (d), 145.5 (d); exact mass
(EI) m/z calcd for C13H24O (M)+ 196.1827, found 196.1828.
rac-(2R,3S)-2-(Benzyloxy)-3-(phenylsulfanyl)undecanoic acid (4c). Acid 3h (0.157 g,
0.51 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0 °C. NaH (60%w/w
in oil, 0.04 g, 0.99 mmol) was added and the mixture and stirred for 15 min at 0 °C. The ice bath
was removed and stirring was continued for 1 h during which the mixture reached room
temperature. Freshly distilled BnBr (0.063 mL, 0.53 mmol) was added and the reaction mixture
was refluxed for 8 h. The mixture was cooled, quenched with 5% hydrochloric acid (30 mL),
and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (3.0  15 cm), using 3:1 hexane-
EtOAc, followed by 1:1 hexane-EtOAc, afforded 4c as a colorless oil (0.12 g, 67%): FTIR
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(film) 3061, 2926, 2855, 1717, 1497, 1455, 1439, 1280, 1244, 1139, 1106, 1026, 744, 695 cm–1;
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1H NMR (400 MHz, CDCl3)  0.92 (t, J = 7.0 Hz, 3 H), 1.31–1.37 (m, 10 H), 1.41–1.56 (m, 1
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H), 1.67–1.81 (m, 3 H), 3.63 (ddd, J = 9.5, 4.0, 4.0 Hz, 1 H), 4.19 (d, J = 4.0 Hz, 1 H), 4.69 (AB
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q, J = 11.4, 
= 37.1 Hz, 2 H), 7.27–7.47 (m, 10 H), (OH signal not observed); C{1H}
AB
NMR (100 MHz, CDCl3) (two signals coincide)  14.1 (q), 22.7 (t), 27.2 (t), 29.2 (t), 29.3 (t),
29.4 (t), 29.7 (t), 31.9 (t), 51.6 (d), 74.2 (t), 80.0 (d), 127.2 (d), 128.2 (d), 128.5 (d), 129.1 (d),
131.8 (d), 134.9 (s), 136.7 (s), 174.6 (s); exact mass (ESI) m/z calcd for C24H31O3S (M – H)–
399.1999, found 399.1998.
{[(1Z)-Dec-1-en-1-yloxy]methyl}benzene
and
{[(1E)-Dec-1-en-1-yloxy]methyl}-
benzene (4cc).47 Acid 4c (0.105 g, 0.26 mmol) was dissolved in CH2Cl2 (2.5 mL) and the flask
was wrapped with aluminum foil. The solution was cooled to 0 °C (ice bath) and DCC (0.081 g,
0.39 mmol), N-hydroxypyridine-2(1H)-thione (0.040 g, 0.31 mmol), and DMAP (0.048, 0.39
mmol) were added. The ice bath was removed and stirring was continued for 4 h. A pad of
silica gel (2  4 cm) was prepared in a foil-wrapped chromatography column and the reaction
mixture was passed through it using 4:1 hexane-EtOAc (subdued laboratory lighting). The
yellow fractions were exposed to sunlight and, once colorless (ca 15 min), were combined and
evaporated. Flash chromatography of the residue over silica gel (1.5  10 cm), using 100:1
hexane-EtOAc, afforded 4cc (0.042 g, 65%) as a colorless oil which was a mixture of isomers:
FTIR (film) 3033, 2956, 2925, 2854, 1665, 1654, 1455, 1378, 1154, 1132, 1099, 931, 734, 696
cm–1; 1H NMR (400 MHz, CDCl3)  0.89 (t, J = 7.2 Hz, 3 H, both isomers), 1.28–1.35 (m, 12 H,
both isomers), 1.91–1.96 (m, 2 H, minor isomer), 2.10–2.16 (m, 2 H, major isomer), 4.41 (dt, J =
7.3, 6.2 Hz, 1 H, major isomer), 4.73 (s, 2 H, minor isomer), 4.81 (s, 2 H, major isomer), 4.91
(dt, J = 12.6, 7.4 Hz, 1 H, minor isomer), 6.02 (dt, J = 6.2, 1.5 Hz, 1 H, major isomer), 6.33 (dt, J
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= 12.6, 1.5 Hz, 1 H, minor isomer), 7.28–7.38 (m, 5 H, both isomers); 13C{1H} NMR (100 MHz,
CDCl3)  14.1 (q), 22.7 (t), 24.1 (t), 27.8 (t), 29.0 (t), 29.30 (t), 29.33 (t), 29.35 (t), 29.50 (t),
29.51 (t), 29.8 (t), 30.7 (t), 31.91 (t), 31.93 (t), 71.1 (t), 73.5 (t), 105.4 (d), 108.1 (d), 127.3 (d),
127.5 (d), 127.7 (d), 127.8 (d), 128.42 (d), 128.45 (d), 137.4 (s), 137.9 (s), 144.4 (d), 145.8 (d);
exact mass (EI) m/z calcd for C17H26O (M)+ 246.1984, found 246.1985.
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rac-(2R,3S)-2-[(tert-Butyldiphenylsilyl)oxy]-3-(phenylsulfanyl)undecanoic acid (4d).
Acid 3h (0.270 g, 0.87 mmol) was dissolved in THF (8 mL) and the reaction mixture was cooled
to 0 °C. NaH (60%w/w in oil, 0.04 g, 0.99 mmol) was added and the mixture was stirred for 15
min at 0 °C, and then cooled to –78 °C. Freshly distilled t-BuPh2SiCl (0.22 mL, 0.87 mmol) was
added dropwise. The cold bath was removed and stirring was continued for 2 h during which the
mixture reached room temperature. The mixture was quenched with 5% hydrochloric acid (30
mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel (3.0  15 cm), using 3:1
hexane-EtOAc, followed by 1:1 hexane-EtOAc, afforded 4d as a colorless oil (0.30 g, 63%):
FTIR (film) 3073, 3051, 2955, 2930, 2857, 1723, 1588, 1472, 1439, 1428, 1148, 1113, 823, 739,
1
701 cm–1; H NMR (400 MHz, CDCl3)  0.90 (t, J = 7.1 Hz, 3 H), 1.09 (s, 9 H), 1.19–1.38 (m,
11 H), 1.40–1.49 (m, 1 H), 1.54–1.64 (m, 1 H), 1.65–1.79 (m, 1 H), 3.24 (ddd, J = 9.4, 4.8, 3.4
Hz, 1 H), 4.42 (d, J = 3.4 Hz, 1 H), 7.19–7.26 (m, 5 H), 7.30–7.38 (4 H), 7.39–7.45 (m, 2 H),
13
7.55–7.65 (m, 4 H), (OH signal not observed); C{1H} NMR (100 MHz, CDCl3)  14.1 (q),
19.4 (s), 22.6 (t), 26.9 (q), 27.2 (t), 29.18 (t), 29.22 (t), 29.36 (t), 30.6 (t), 31.8 (t), 53.3 (d), 75.7
(d), 126.8 (d), 127.67 (d), 127.70 (d), 128.9 (d), 130.07 (d), 130.10 (d), 131.4 (d), 132.08 (s),
132.15 (s), 135.3 (s), 135.9 (d), 136.1 (d), 173.7 (s); exact mass (ESI) m/z calcd for C33H43O3SSi
(M – H)– 547.2708, found 547.2707.
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tert-Butyl[(1Z)-dec-1-en-1-yloxy]diphenylsilane
and
tert-Butyl[(1E)-dec-1-en-1-
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yloxy]diphenylsilane (4dd).48 Acid 4d (0.123 g, 0.23 mmol) was dissolved in CH2Cl2 (2.5 mL)
and the flask was wrapped with aluminum foil. The solution was cooled to 0 °C (ice bath) and
DCC (0.070 g, 0.34 mmol), N-hydroxypyridine-2(1H)-thione (0.034 g, 0.27 mmol), and DMAP
(0.041, 0.34 mmol) were added. The ice bath was removed and stirring was continued for 4 h.
A pad of silica gel (2  4 cm) was prepared in a foil-wrapped chromatography column and the
reaction mixture was passed through it using 4:1 hexane-EtOAc (subdued laboratory lighting).
The yellow fractions were exposed to sunlight and, once colorless (ca 15 min), were combined
and evaporated. Flash chromatography of the residue over silica gel (1.5  10 cm), using 100:1
hexane-EtOAc, afforded 4dd (0.060 g, 67%) as a colorless oil which was a mixture of isomers:
FTIR (film) 3072, 3000, 2927, 2856, 1657, 1464, 1428, 1259, 1114, 1095, 823, 740, 710, 700
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cm–1; H NMR (400 MHz, CDCl3)  0.88 (two overlapping t, J = 7.2 Hz, 3 H, both isomers),
1.06 (s, 9 H, minor isomer), 1.08 (s, 9 H, major isomer), 1.21–1.42 (m, 12 H, both isomers),
1.78–1.81 (m, 2 H, minor isomer), 2.21–2.25 (m, 2 H, major isomer), 4.45 (dt, J = 7.3, 5.9 Hz, 1
H, major isomer), 5.05 (dt, J = 11.9, 7.3 Hz, 1 H, minor isomer), 6.18 (dt, J = 5.8, 1.6 Hz, 1 H,
major isomer), 6.22 (dt, J = 12.0, 1.2 Hz, 1 H, minor isomer), 7.38–7.49 (m, 6 H, both isomers),
7.69–7.74 (m, 4 H, both isomers); 13C{1H} NMR (100 MHz, CDCl3)  14.09 (q), 14.11 (q), 19.2
(s), 19.3 (s), 22.66 (t), 22.69 (t), 23.8 (t), 26.55 (q), 26.57 (q), 27.2 (t), 28.9 (t), 29.3 (t), 29.36 (t),
29.40 (t), 29.42 (t), 29.54 (t), 29.7 (t), 30.3 (t), 31.87 (t), 31.92 (t), 110.7 (d), 112.0 (d), 127.66
(d), 127.70 (d), 129.7 (d), 129.8 (d), 133.0 (s), 133.1 (s), 135.4 (d), 135.5 (d), 138.7 (d), 140.2
(d); exact mass (EI) m/z calcd for C26H38OSi (M)+ 394.2692, found 394.2695.
Methyl (2E)-5-Phenylpent-2-enoate (3c).49 Methyl diethylphosphonoacetate (2.8 mL,
15.2 mmol) was added dropwise over 5 min to a stirred suspension of NaH (60%w/w in oil, 0.61
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g, 15.2 mmol) in THF (20 mL) (N2 atmosphere). Stirring at room temperature was continued for
ca 15 min and hydrocinnamaldehyde (1.8 mL, 14 mmol) was then added dropwise. Stirring was
continued for 2 h and the solution was diluted with Et2O (75 mL) and washed with saturated
aqueous NaHCO3 (50 mL) and brine (50 mL). The combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the residue over silica gel (5.0  20 cm),
using 15:1 hexane-EtOAc, afforded 3c as a colorless oil (2.64 g, 91%): 1H NMR (400 MHz,
CDCl3)  2.54–2.57 (m, 2 H), 2.78–2.82 (m, 2 H), 3.75 (s, 3 H), 5.87 (dt, J = 15.7, 1.6 Hz, 1 H),
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7.03 (dt, J = 15.7, 6.8 Hz, 1 H), 7.19–7.23 (m, 3 H), 7.30–7.32 (m, 2 H); C{1H} NMR (100
MHz, CDCl3)  33.9 (t), 34.4 (t), 51.4 (q), 121.5 (d), 126.2 (d), 128.3 (d), 128.5 (d), 140.8 (s),
148.4 (d), 167.0 (s).
(2E)-5-Phenylpent-2-enoic acid (3e).50 Ester 3c (2.64 g, 13.9 mmol) was dissolved in
acetone (270 mL), and an aqueous solution of LiOH (1.0 M, 132 mL, 13.2 mmol) was added
dropwise. Stirring was continued for 24 h and the acetone was evaporated. The residue was
partitioned between Et2O (100 mL) and 10% aqueous NaHCO3 (2 x 50 mL). The combined
aqueous base solutions were acidified using concentrated hydrochloric acid (5 mL) and extracted
with Et2O (3 x 25 mL). The combined organic extracts were dried (MgSO4) and evaporated to
1
afford 3e as a colorless oil (2.01 g, 82%): H NMR (400 MHz, CDCl3)  2.57–2.60 (m, 2 H),
2.80–2.83 (m, 2 H), 5.87 (dt, J = 15.7, 1.5 Hz, 1 H), 7.16 (dt, J = 15.7, 6.8 Hz, 1 H), 7.19–7.28
13
(m, 3 H), 7.30–7.38 (m, 2 H), (OH signal not observed); C{1H} NMR (100 MHz, CDCl3) 
34.0 (t), 34.2 (t), 121.3 (d), 126.3 (d), 128.3 (d), 128.5 (d), 140.6 (s), 151.0 (d), 172.0 (s).
rac-Trans-3-(2-Phenylethyl)oxirane-2-carboxylic acid (3g).51 Acid 3e (1.23 g, 6.98
mmol) was dissolved in a mixture of acetone (5 mL) and water (5 mL). Solid NaHCO3 (2.34 g,
27.9 mmol) was added and a solution of Oxone (4.51 g, 14.6 mmol) and Na2EDTA (10 mg) in
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water (50 mL) was added over 2 h by syringe pump. The reaction mixture was stirred for a
further 2 h, before being cooled to 0 °C and quenched with 10% aqueous H2SO4. The mixture
was extracted with EtOAc (3 x 25 mL), and the combined organic extracts were dried (MgSO4)
and evaporated to afford pure 3g as a colorless oil (1.18 g, 88%): FTIR (film) 3062, 3027, 2929,
1723, 1496, 1454, 1250, 900, 752, 700 cm–1; 1H NMR (400 MHz, CDCl3)  1.90–2.04 (m, 2 H),
2.78–2.90 (m, 2 H), 3.26–3.28 (m, 2 H) 7.20–7.26 (m, 3 H), 7.31–7.35 (m, 2 H) 10.2 (br s, 1 H);
13C{1H} NMR (100 MHz, CDCl3)  31.9 (t), 33.2 (t), 52.6 (d), 58.4 (d), 126.4 (d), 128.3 (d),
128.7 (d), 140.3 (s), 174.8 (s); exact mass (ESI) m/z calcd for C11H11O3 (M – H)– 191.0714,
found 191.0713.
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rac-(2R,3S)-2-Hydroxy-5-phenyl-3-(phenylsulfanyl)pentanoic acid (3i). The pH of a
mixture of PhSH (0.9 mL, 8.6 mmol), InCl3 (0.17 g, 0.78 mmol) and water (20 mL) was adjusted
to 4.0 using an aqueous solution of NaOH (0.5 M). The mixture was stirred and heated at 35 °C
(oil bath) and a solution of epoxy acid 3g (1.5 g, 7.8 mmol) in acetone (1 mL) was added at a fast
dropwise rate. The solution was stirred for an additional 2 h at 35 °C, after which it was cooled
to 0 °C and quenched with 10% aqueous H2SO4. The resulting mixture was extracted with
EtOAc (3  10 mL) and the combined organic extracts were washed with brine (10 mL), dried
(MgSO4) and evaporated. Flash chromatography of the residue over silica gel (5.0  20 cm),
using 3:2 PhMe-EtOAc containing 0.01%v/v AcOH, afforded 3i as a colorless oil (1.55 g, 66%):
FTIR (film) 3413, 3048, 2927, 2860, 1725, 1583, 1454, 1438, 1261, 1099, 1078, 1024, 739, 691
1
cm–1; H NMR (400 MHz, CDCl3)  1.94–2.01 (m, 2 H), 2.77 (dt, J = 14.0, 8.5, 8.3 Hz, 1 H),
2.98–3.00 (m, 1 H), 3.53 (ddd, J = 8.1, 7.0, 3.0 Hz, 1 H), 4.33 (d, J = 3.0 Hz, 1 H), 7.18–7.23 (m,
13
3 H), 7.25–7.33 (m, 5 H), 7.42–7.49 (m, 2 H), (both OH signals not observed); C{1H} NMR
(100 MHz, CDCl3)  31.0 (t), 33.3 (t), 52.4 (d), 72.4 (d), 126.2 (d), 127.6 (d), 128.5 (d), 128.6
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(d), 129.3 (d), 132.2 (d), 133.8 (s), 140.9 (s), 176.3 (s); exact mass (ESI) m/z calcd for C17H17O3S
5
6
(M – H)– 301.0904, found 301.0896.
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rac-(2R,3S)-5-Phenyl-3-(phenylsulfanyl)-2-(propen-1-yloxy)pentanoic acid (4e).
Acid 3i (0.269 g, 0.89 mmol) was dissolved in THF (20 mL) and the solution was cooled to 0 °C.
NaH (60%w/w in oil, 0.04 g, 0.99 mmol) was added and the mixture was stirred for 15 min at 0
°C. The ice bath was removed and stirring was continued for 1 h during which the mixture
reached room temperature. Freshly distilled allyl bromide (0.077 mL, 0.94 mmol) was added
and the mixture was refluxed for 8 h. The mixture was cooled, quenched with 5% hydrochloric
acid (30 mL), and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the residue over silica gel (3.0  15 cm),
using 3:1 hexane-EtOAc, followed by 1:1 hexane-EtOAc, afforded 4e as a colorless oil (0.28 g,
91%): FTIR (film) 3061, 3027, 2927, 1719, 1583, 1481, 1439, 1243, 1127, 1083, 1026, 996,
930, 746, 700 cm–1; 1H NMR (400 MHz, CDCl3)  1.90–2.10 (m, 2 H), 2.76 (ddd, J = 13.8, 9.5,
7.2 Hz, 1 H), 3.02 (ddd, J = 13.8, 9.5, 4.9 Hz, 1 H), 3.55 (ddd, J = 9.5, 4.0, 4.0 Hz, 1 H), 4.09 (d,
J = 4.0 Hz, 1 H), 4.12 (ddt, J = 12.4, 5.9, 1.0 Hz, 1 H), 4.21 (ddt, J = 12.4, 5.9, 1.0 Hz, 1 H),
5.19–5.29 (m, 2 H), 5.88 (ddt, J = 17.2, 10.4, 5.9 Hz, 1 H), 7.18–7.21 (m, 3 H), 7.22–7.33 (m, 5
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H), 7.41–7.47 (m, 2 H), (OH signal not observed); C{1H} NMR (100 MHz, CDCl3)  31.4,
33.2, 50.7, 73.2, 79.9, 118.8, 126.0, 127.3, 128.4, 128.5, 129.2, 131.8, 133.2, 134.5, 141.1,
173.9; exact mass (ESI) m/z calcd for C20H21O3S (M – H)– 341.1217, found 341.1223.
[(3Z)-4-(Prop-2-en-1-yloxy)but-3-en-1-yl]benzene and [(3Z)-4-(Prop-2-en-1-yloxy)-
but-3-en-1-yl]benzene (4ee).52 Acid 4e (0.030 g, 0.09 mmol) was dissolved in CH2Cl2 (2 mL)
and the flask was wrapped with aluminum foil. The solution was cooled to 0 °C (ice bath) and
DCC (0.027 g, 0.13 mmol), N-hydroxypyridine-2(1H)-thione (0.013 g, 0.11 mmol), and DMAP
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(0.016 g, 0.13 mmol) were added. The ice bath was removed and stirring was continued for 4 h.
A pad of silica gel (1.5  4 cm) was prepared in a foil-wrapped chromatography column and the
reaction mixture was passed through it using 4:1 hexane-EtOAc (subdued laboratory lighting).
The yellow fractions were exposed to sunlight and, once colorless (ca 15 min), were combined
and evaporated. Flash chromatography of the residue over silica gel (1.5  10 cm), using 100:1
hexane-EtOAc, afforded 4ee (0.013 g, 79%) as a colorless oil which was a mixture of isomers:
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1
FTIR (film) 2959, 2927, 2855, 1723, 1463, 1265, 1126, 805, 742 cm–1; H NMR (700 MHz,
CDCl3)  2.29 (q, J = 7.4 Hz, 2 H, minor isomer), 2.41 (q, J = 7.5 Hz, 2 H, major isomer), 2.64
(t, J = 7.9 Hz, 2 H, minor isomer), 2.67 (t, J = 7.9 Hz, 2 H, major isomer), 4.15 (d, J = 5.4 Hz, 2
H, minor isomer), 4.25 (d, J = 5.3 Hz, 2 H, major isomer), 4.40 (q, J = 6.8 Hz, 1 H, major
isomer), 4.83 (dt, J = 12.5, 7.4 Hz, 1 H, minor isomer), 5.17–5.21 (m, 2 H, minor isomer), 5.25–
5.30 (m, 2 H, major isomer), 5.85–5.90 (m, 1 H, both isomers), 5.93 (d, J = 6.2 Hz, 1 H, major
isomer), 6.22 (d, J = 12.5 Hz, 1 H, minor isomer), 7.15–7.20 (m, 3 H, both isomers), 7.25–7.28
13
(m, 2 H, both isomers); C{1H} NMR (100 MHz, CDCl3)  25.7 (t), 29.8 (t), 35.9 (t), 37.3 (t),
70.1 (t), 72.5 (t), 104.1 (d), 106.3 (d), 117.1 (t), 117.3 (t), 125.6 (d), 125.8 (d), 128.20 (d), 128.24
(d), 128.48 (d), 128.50 (d), 133.6 (d), 134.1 (d), 141.9 (s), 142.3 (s), 144.8 (d), 146.1 (d).
rac-(2R,3S)-2-[(tert-Butyldiphenylsilyl)oxy]-5-phenyl-3-(phenylsulfanyl)pentanoic
acid (4f). Acid 3i (0.309 g, 1.02 mmol) was dissolved in THF (25 mL) and the solution was
cooled to 0 °C. NaH (60%w/w in oil, 0.08 g, 1.99 mmol) was added and the mixture and stirred
for 15 min at 0 °C, and then cooled to –78 °C. Freshly distilled t-BuPh2SiCl (0.28 mL, 1.07
mmol) was added dropwise. The cold bath was removed and stirring was continued for 2 h,
during which the mixture reached room temperature. The mixture was quenched with 5%
hydrochloric acid (30 mL), and extracted with EtOAc (3 x 15 mL). The combined organic
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extracts were dried (MgSO4) and evaporated. Flash chromatography of the residue over silica
gel (3.0  15 cm), using 10:1 hexane-EtOAc, followed by 4:1 hexane-EtOAc, afforded 4f as a
colorless oil (0.271 g, 49%): FTIR (film) 3071.9, 2932, 2894, 2858, 1722, 1454, 1428, 1138,
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1
1113, 822, 739, 700 cm–1; H NMR (400 MHz, CDCl3)  1.09 (s, 9 H), 1.88–2.00 (m, 1 H),
2.06–2.15 (m, 1 H), 2.62–2.71 (ddd, J =13.8, 9.5, 7.2 Hz, 1 H), 2.83–2.92 (ddd, J = 13.8, 9.5, 4.9
Hz, 1 H), 3.34 (ddd, J = 9.5, 4.0, 4.0 Hz, 1 H), 4.42 (d, J = 3.6 Hz, 1 H), 7.11–7.64 (m, 20 H),
13
(OH signal not observed); C{1H} NMR (100 MHz, CDCl3)  19.5 (s), 27.0 (q), 32.0 (t), 33.2
(t), 52.5 (d), 75.7 (d), 126.0 (d), 126.9 (d), 127.65 (d), 127.67 (d), 128.41 (d), 128.46 (d), 128.9
(d), 130.03 (d), 130.06 (d), 131.6 (d), 132.3 (s), 134.9 (s), 136.0 (d), 136.1 (d), 141.2 (s), 174.5
(s); exact mass (ESI) m/z calcd for C33H35O3SSi (M – H)– 539.2082, found 539.2091.
tert-Butyldiphenyl{[(1Z)-4-phenylbut-1-en-1-yl)silane and tert-Butyldiphenyl{[(1E)-
4-phenylbut-1-en-1yl)silane (4ff). Acid 4f (0.109 g, 0.20 mmol) was dissolved in CH2Cl2 (4
mL) and the flask was wrapped with aluminum foil. The solution was cooled to 0 °C (ice bath)
and DCC (0.062 g, 0.30 mmol), N-hydroxypyridine-2(1H)-thione (0.031 g, 0.24 mmol), and
DMAP (0.037, 0.30 mmol) were added. The ice bath was removed and stirring was continued
for 4 h. A pad of silica gel (2  4 cm) was prepared in a foil-wrapped chromatography column
and the reaction mixture was passed through it using 4:1 hexane-EtOAc (subdued laboratory
lighting). The yellow fractions were exposed to sunlight and, once colorless (ca 15 min), were
combined and evaporated. Flash chromatography of the residue over silica gel (1.5  10 cm),
using 100:1 hexane-EtOAc, afforded 4ff (0.0601 g, 78%) as a colorless oil which was a mixture
of isomers: FTIR (film) 3028, 3000, 2931, 2858, 1657, 1428, 1262, 1114, 1030, 823, 741, 711,
700 cm–1; H NMR (400 MHz, CDCl3)  1.07 (s, 9 H, minor isomer), 1.12 (s, 9 H, major
1
isomer), 2.16–2.19 (m, 2 H, minor isomer), 2.57–2.64 (m, 2 H, both isomers), 2.74–2.79 (m, 2 H,
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major isomer), 4.53 (dt, J = 7.3, 5.9 Hz, 1 H, major isomer), 5.15 (dt, J = 11.9, 7.3 Hz, 1 H,
minor isomer), 6.21 (dt, J = 5.9, 1.6 Hz, 1 H, major isomer), 6.26 (dt, J = 11.9, 1.6 Hz, 1 H,
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minor isomer), 7.12–7.49 (m, 11 H, both isomers), 7.66–7.69 (m, 4 H, both isomers); C{1H}
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NMR (100 MHz, CDCl3)  19.3 (s), 25.8 (t), 26.6 (q), 35.9 (t), 109.5 (d), 125.7 (d), 127.72 (d),
127.77 (d), 127.78 (d), 127.784 (d), 128.2 (d), 128.5 (d), 129.9 (d), 133.0 (s), 135.40 (d), 135.49
(d), 139.4 (d), 142.5 (s); exact mass calcd (EI) m/z for C26H30OSi 386.2066, found 386.2075.
3,4-Dihydro-2H-1-benzopyran-2-one (6b).29 10%Pd/C (729 mg) was added to a stirred
solution of 6a (10 g, 68.42 mmol) in AcOH (200 mL) and the mixture was stirred under H2
(balloon) for 2 days and then filtered through a pad of Celite (w  h = 5  4 cm), using EtOAc as
a rinse. The solvent was evaporated and the residue was taken up in Et2O. The resulting
solution was washed with saturated aqueous NaHCO3, dried (MgSO4) and evaporated to give 6b
1
(9.1 g, 90%) which was pure enough for the next step. The material had: H NMR (500 MHz,
CDCl3)  2.75–2.79 (m, 2 H), 2.97–3.01 (m, 2 H), 7.01–7.10 (m, 2 H), 7.18–7.28 (m, 2 H);
13C{1H} NMR (125 MHz, CDCl3)  23.7 (t), 29.2 (t), 117.0 (d), 122.7 (s), 124.4 (d), 128.1 (d),
128.3 (d), 152.0 (s), 168.7 (s).
Ethyl 2-diazo-5-(2-hydroxyphenyl)-3-oxopentanoate (6c).28 A stock solution of LDA
was made by addition of BuLi (2.5 M, 8 mL, 20.24 mmol) to a stirred and cooled (–78 °C)
solution of i-Pr2NH (2.83 mL, 20.24 mmol) in THF (50 mL). Stirring was continued for 30 min
at –78 °C and the whole solution was taken up into a syringe and added at a fast dropwise rate to
a stirred and cooled (–78 °C) solution of 6b (2 g, 13.49 mmol) and EtO2CCHN2 (2.12 mL, 20.24
mmol) in THF (40 mL). Stirring at –78 °C was continued for 5 h and then a solution of AcOH
(4 mL) in Et2O (16 mL) was added rapidly. The cold bath was removed and stirring was
continued for 15 min at which point the mixture had reached room temperature. Water (40 mL)
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Page 29 of 46
The Journal of Organic Chemistry
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was added and the mixture was extracted with CH2Cl2. The combined organic extracts were
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dried (MgSO4) and evaporated. Flash chromatography of the residue over silica gel (4  20 cm),
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using 1:3 EtOAc-hexane, gave 6c (2.0 g, 57%) as a yellow oil: H NMR (500 MHz, CDCl3) 
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1.30 (t, J = 7.0 Hz, 3 H), 2.90 (t, J = 6.5 Hz, 2 H), 3.20 (t, J = 6.5 Hz, 2 H), 4.30 (q, J = 7.0 Hz,
2 H), 6.85–6.92 (m, 2 H), 7.10–7.28 (m, 2 H), 7.71 (br s, 1 H); 13C{1H} NMR (125 MHz,
CDCl3)  14.3 (q), 24.1 (t), 42.2 (t), 61.8 (t), 117.4 (d), 120.6 (d), 127.1 (s), 128.1 (d), 130.6 (d),
154.5 (s), 161.2 (s), 194.3 (s). The carbon bearing the N2-group was not visible due to
quadrupole coupling and relaxation effects.
Ethyl 3-oxo-2,3,4,5-tetrahydro-1-benzoxepine-2-carboxylate (6d).28 A solution of 6c
(2.0 g, 7.62 mmol) in dry PhH (200 mL) was added over 45 min (syringe pump) to a stirred and
refluxing suspension of Rh2(OAc)4 (68 mg, 0.15 mmol) in PhH (200 mL). Refluxing was
continued for 1 h after the addition, and the mixture was then cooled and filtered through a pad
of Celite, using EtOAc as a rinse. Evaporation of the filtrate and flash chromatography of the
residue over silica gel (4  20 cm), using 1:3 EtOAc-hexane, gave 6d (1.1 g, 61%) as an oil
which was a 2:1 keto-enol mixture: 1H NMR (500 MHz, CDCl3)  1.30 (t, J = 7.5 Hz, 3 H,
keto), 1.42 (t, J = 7.5 Hz, 1.7 H, enol), 2.71–2.78 (m, 2 H), 3.00–3.07 (m, 2 H), 3.13–3.19 (m, 1
H), 3.22–3.28 (m, 1 H), 4.29 (q, J = 7.0 Hz, 2 H), 4.34 (q, J = 7.0 Hz, 1 H), 4.97 (s, 1 H), 7.06–
7.12 (m, 2 H), 7.14–7.19 (m, 4 H), (OH signal not observed); 13C{1H} NMR (125 MHz, CDCl3)
 14.0 (q), 14.3 (q), 26.7 (t), 27.2 (t), 31.1 (t), 40.0 (t), 61.2 (t), 62.0 (t), 86.3 (d), 120.4 (d), 122.0
(d), 124.7 (d), 124.9 (d), 127.3 (s), 127.5 (d), 128.1 (d), 130.0 (d), 130.4 (s), 130.5 (d), 133.0 (s),
156.3 (s), 160.0 (s), 165.3 (s), 165.4 (s), 169.3 (s).
Ethyl 3-hydroxy-2,3,4,5-tetrahydro-1-benzoxepine-2-carboxylate (6e).53 NaBH4 (80
mg, 2.11 mmol) was added in one lot to a stirred and cooled (–78 °C) solution of 6d (1.00 g, 4.23
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