Asymmetric synthesis of carbocycles: Use of intramolecular conjugate displacement

Article abstract of DOI:10.1039/c3ob40115d

Intramolecular conjugate displacement (ICD), the process illustrated in eqn (1), has been applied to the Morita-Baylis-Hillman adducts formed from (5S)-5-(l-menthyloxy)-2(5H)-furanone and aldehydes that are substituted in the γ- or δ-position by geminal phenylthio groups. When the initial Morita-Baylis-Hillman alcohols are acetylated and oxidized to geminal sulfones, deprotonation causes ring closure by ICD (2.5→2.6). Hydrogenation, DIBAL-H reduction and desulfonylation releases an optically pure carbocycle. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40115d

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Asymmetric synthesis of carbocycles: use of
intramolecular conjugate displacement†
Cite this: Org. Biomol. Chem., 2013, 11,
3128
Dinesh T. Sreedharan and Derrick L. J. Clive*
Intramolecular conjugate displacement (ICD), the process illustrated in eqn (1), has been applied to the
Morita–Baylis–Hillman adducts formed from (5S)-5-(L-menthyloxy)-2(5H)-furanone and aldehydes that
are substituted in the γ- or δ-position by geminal phenylthio groups. When the initial Morita–Baylis–
Hillman alcohols are acetylated and oxidized to geminal sulfones, deprotonation causes ring closure by
ICD (2.5→2.6). Hydrogenation, DIBAL-H reduction and desulfonylation releases an optically pure
carbocycle.
Received 19th January 2013,
Accepted 6th March 2013
DOI: 10.1039/c3ob40115d
www.rsc.org/obc
Introduction
The process summarized by eqn (1), which has been named
intramolecular conjugate displacement (ICD),1 is an effective
method for making rings in which the nucleophilic atom X is
N,1,2 S3 or C.4 The subunit represented by atoms 1–3 (see eqn
(1)) is more reactive than the corresponding Michael acceptor
in which the leaving group (OAc) is absent,5 and the cycliza-
tion proceeds under mild conditions and does not require the
use of transition metal catalysts. Publications from this labora-
tory have illustrated the ICD process for the construction of
both heterocycles1–3 and carbocycles4 of various ring sizes and
the method was used as a key step in the total synthesis of
the marine alkaloid halichlorine6 and also to prepare7 an
advanced polycyclic model of the fungal metabolites
CP-225,917 and CP-263,114.
Scheme 1 Asymmetric ICD for amines.
ð1Þ
Scheme 1 which illustrates the route for a particular example.
In this procedure, the chiral auxiliary can be removed at the
end of the sequence by reduction with DIBAL-H so as to
release an optically pure amine (e.g. 1.6).
We have now examined the corresponding asymmetric
process for making carbocycles, based on the related approach
that is illustrated in Scheme 2.
Where the nucleophile is nitrogen it was possible to
develop a general asymmetric version2 based on the use
of L-menthol (1) as a chiral auxiliary. The approach is shown in
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
E-mail: derrick.clive@ualberta.ca; Fax: +1 (780) 492 8231; Tel: +1 (780) 492 3251
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, X-ray data, cif files, ORTEP diagrams and copies of NMR spectra. CCDC
Results and discussion
As indicated in Scheme 2, the starting materials are a chiral
lactone, usually containing a chiral auxiliary unit such as a
menthyloxy group (e.g. as in 2.1), and an aldehyde which
920139, 920140, 920141, 920142 and 920143 for 5l, 9.2, 9.4, 9c and 9g. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3ob40115d
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Scheme 4 Preparation of aldehyde 8.
Scheme 2 Principle of the all-carbon asymmetric ICD.
carries geminal phenylthio groups in the position γ or δ to the
carbonyl carbon. The lactones we have used are 1.1,8 2.1 [as a
mixture of C(2) epimers],2 2, and 3.9 Except for 2, these are
known compounds readily accessible by the literature
methods; each was optically pure, except for 2, which was
racemic and was used as a mixture of C(2) epimers. The
material was prepared by phenylselenation of the parent
lactone 4 (LDA, PhSeCl); both enantiomers of that lactone are
known.10 The enantiomers of 1.1, 2.1 and 3 are accessible by
using D-menthol.
Scheme 5 Preparation of aldehyde 9.
The aldehydes we examined are 5–13. Of these, 5,4 7,4 and 104
are known and were made by the reported methods. The other
aldehydes are accessible by straightforward reactions, as
summarized in Schemes 3–8.
Aldehyde 6 was made (Scheme 3) from commercially available
3-chloropropionaldehyde diethyl acetal by exchanging the
ethoxy groups for p-fluorophenylthio groups, followed by chlor-
ide displacement with cyanide and then DIBAL-H reduction.
Scheme 3 Preparation of aldehyde 6.
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the known14 geminal dibromide 6.2. This was subjected to
double nucleophilic displacement with PhSNa, and the route
was completed by ester reduction and oxidation with
SO3·pyridine.
The mono phenylthio compound 12 was available from
phthalide (7.1) by ring opening with PhSNa,15 carboxyl
reduction16 and oxidation (Scheme 7).
Aldehyde 13 was made (Scheme 8) from aldehyde 11 by
Wittig olefination with Ph3PvCH(OMe) and acid hydrolysis.
Condensation of the chiral lactones with the
aldehydes
Scheme 6 Preparation of aldehyde 11.
We used two methods for condensing the aldehydes with the
chiral lactones. The aliphatic aldehydes 5–7 and 10 reacted
smoothly with the anion generated by deprotonation of the
selenium-containing lactone 2.1; surprisingly, reaction by the
Jauch method17 (condensation with 1.1 in the presence of
PhSeLi) did not work well and the yield was much lower. In
contrast, the aromatic aldehydes reacted better by the Jauch
method than with the deprotonated selenium-containing
lactone. We found that the best conditions for using 2.1 called
for adding an LDA solution slowly to a solution of the lactone
in THF at −78 °C. The mixture was stirred for ca. 1 h, and then
a solution of the aldehyde was added dropwise. If 2.1 is added
to LDA, extensive deselenation occurs; however, with the opti-
mized procedure, yields close to 70% were reproducibly
obtained. In a few experiments the similar use of (Me3Si)2NK
was also examined but the yields were lower.
Scheme 7 Preparation of aldehyde 12.
Oxidative removal of the selenium generates the required
α,β-unsaturated lactone system and leads to two alcohols epi-
meric at the hydroxyl-bearing carbon. The fact that two diaster-
eoisomers are formed is inconsequential, however. During
oxidative removal of the selenium the phenylthio groups are
converted into phenylsulfonyl groups. This feature makes the
use of phenylthio groups in the starting aldehydes especially
convenient because the presence of a very acidic hydrogen at
an earlier stage would interfere in the reaction of the carba-
nion with the aldehyde.18
Scheme 8 Preparation of aldehyde 13.
Aldehyde 8 was made from commercial 2-(bromomethyl)-
benzonitrile (4.1, Scheme 4) by converting the nitrile to an
aldehyde, according to a literature procedure.11 We note that
the stipulated use of hydrobromic acid in the workup of this
reduction is crucial to avoid loss of the benzylic bromine. The
aldehyde was then protected by acetalization, and the resulting
bromide (4.3) was used to alkylate the anion derived from bis
(phenylthio)methane. Finally, acetal hydrolysis released alde-
hyde 8.
Condensation in the presence of PhSeLi gives only a single
isomer to which we assign the indicated stereochemistry (see
Table 1, entries v, vi, viii) by analogy with earlier results17a,c
and the structure determination by X-ray analysis of 9c (see
entry vi). In those cases where we used PhSeLi, oxidation of
the phenylthio groups to the sulfone level was done by treating
the alcohols or their acetates with MCPBA.
In most cases, the epimeric alcohols formed in the initial
condensation could be separated by chromatography, and
each was either treated with MCPBA and acetylated, or acetyl-
ated and then oxidized.
The same sequence used for 8 was applied12,13 (Scheme 5)
to make 9 from the fluorobromide 5.2, itself prepared in one
step by free radical bromination12 of commercial 2-methyl-5-
fluorobenzonitrile (5.1).
Benzylic bromination was also used (Scheme 6) in the syn-
thesis of 11 from methyl o-methylbenzoate (6.1) by way of
The lactone 3, in which the double bond carries a methyl
substituent was deprotonated with LDA and condensed with
aldehydes 5 and 9; in both cases reaction occurred at the
α-position to the lactone carbonyl (Table 2).
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Table 1 Formation of the Morita–Baylis–Hillman alcohols and acetates
a Z = SO2Ph, Z′ = SO2C6H4F-p (entry ii). b Corrected for recovered aldehyde.
In those cases where we obtained two separable isomers of
the ICD precursors (Table 2, entries i–iv), both gave the identi-
cal ICD product. This indicates that attack of the intermediate
carbanion on the β-carbon of the unsaturated lactone unit
occurs smoothly both syn and anti to the acetate leaving group,
and that the stereochemistry at the newly-formed asymmetric
Ring closure by intramolecular conjugate
displacement
We used Cs2CO3 in THF at 0 °C to room temperature to induce
the ICD process, as these conditions had previously been
found to work well.4
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Table 2 Formation of the Morita–Baylis–Hillman alcohols from lactone 3
Table 3 Ring closure by intramolecular conjugate displacement
a More polar (5i) 10%, less polar (5i′) 12%, mixture of both 40%.
b More polar isomer.
center is not controlled by the stereochemistry at the acetoxy-
bearing carbon.
Six- and seven-membered rings are generated easily
(70–99% yield), but when we attempted to form an eight-
membered ring, conjugate displacement did not occur and
the main pathway appeared to be the result of elimination
of the acetate (Table 3, entry vii). Seven-membered rings
fused onto a benzene ring are easily formed and very
high yields were obtained in those cases (entries v and vi)
where the carbanionic center is two carbons from the
benzene ring. When the carbanionic center is benzylic (see
entry viii), we did not isolate any of the expected ICD
product; likewise, the corresponding experiment in the
nitrogen series (cf. Scheme 1) was also unsuccessful.19 We
suspected that possibly the bulk of the two sulfone groups
was preventing cyclization and so we examined the ICD
precursor 14, made from aldehyde 12 (see Experimental
section), but this also did not appear to cyclize. In a further
attempt to effect cyclization of a benzylic carbanion, we pre-
pared the ICD precursor 15 from aldehyde 13 (see Experimen-
tal section); however, that did not cyclize either and
we conclude that a nucleophilic benzylic position (either
as a carbanion or as an aniline19) is not suitable for ICD
reactions. The possibility that other acidifying groups might
not be subject to this problem, was explored briefly, but
our attempts to prepare an ICD precursor using the ester 1620
or the malonate 174 were unsuccessful: with the ester, the
initial adduct underwent spontaneous lactonization and with
the malonate, the presence of the acidic hydrogen prevented
carbanion addition, even when the carbanion was used in
excess.
a Z = SO2Ph, Z′ = SO2C6H4F-p (entry ii). b From acetate derived from
more polar alcohol. c From acetate derived from less polar alcohol.
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A limitation to the ICD process is that substitution at the
carbon being attacked is not tolerated and we found that com-
pounds 5k, 5k′ and 9f (Table 2) failed to undergo the ICD
closure; they were recovered unchanged at room temperature,
and the ICD pathway was not followed at
temperature.
a higher
Stereochemistry of the ICD adducts
In the case of the fluorine-substituted ICD product 9g the
stereochemistry at the newly-created stereogenic center was
established by X-ray analysis. By analogy, we assign the same
stereochemistry to 8d. The coupling constant for the signal of
the acetal hydrogen (O–CH–O) of 9g at δ 6.46 was <1 Hz and
the value for 8d (δ 6.53) was 1 Hz.
For compound 7f, the acetal signal at δ 6.78 is a doublet
with J = 1.3 Hz, a value consistent only with the indicated
stereochemistry.
Scheme 9 Removal of the chiral auxiliary.
Assignment of stereochemistry to 5l, 6d and 5m was impor-
tant because in the nitrogen series (cf. Scheme 1) formation
of a six-membered ring resulted in an anomalous stereo-
chemistry. In that case the nitrogen nucleophile approached
from the same face as the auxiliary group R*O – an unexpected
outcome that was conclusively established by single crystal
X-ray analysis of the ICD product. In the present work we were
able to obtain satisfactory crystals of 5l, and X-ray analysis
established the indicated stereochemistry. The other two
examples (6d and 5m) are assigned by analogy. Evidently, the
factors responsible for the anomalous outcome in the nitrogen
series for production of a 6-membered ring (nitrogen adds syn
to the R*O group) do not operate in the present all-carbon
series or else the steric bulk of the two sulfone groups is the
controlling factor.
confirmed the structure. Mechanistically, the formation of 9.2
must have occurred by conjugate reduction of the unsaturated
carbonyl system to generate an enolate equivalent (Scheme 10)
which displaced the geminal bis(sulfone) unit (10.1→10.2)
and reformed an unsaturated lactone that was again reduced,
initially to a lactol (10.2→10.3) and then to a diol. Finally,
mono-desulfonylation21 gave 9.2. Periodic analysis of the
DIBAL-H reaction mixture by high resolution electrospray
mass spectrometry revealed the generation of substances with
molecular formulas corresponding to the intermediates 10.2
and 10.3. The circumstances in which displacements of the
Removal of the chiral auxiliary
In the nitrogen series, where the nucleophile for the ICD is
nitrogen (Scheme 1), the auxiliary was easily removed2 by
reduction with DIBAL-H (1.5→1.6); however, in the present all-
carbon series this process was initially troublesome. We used
the ICD product 9g as a test case and found that treatment
with DIBAL-H (Scheme 9) opened the ring that had been
formed by the ICD, and the resulting product (9.1) was then
treated with Na(Hg) to afford (64%) the diol 9.2. This com-
pound was crystalline and single crystal X-ray analysis
Scheme 10 Formation of 9.2.
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type 10.1→10.2 are observed must be rare as a search of the A portion (1.81 mL, 0.37 mmol LDA) of this stock solution was
Reaxys database served to identify only
precedent.22
a
single close added dropwise (over ca. 10 min, added manually by syringe)
to a stirred and cooled (−78 °C) solution of lactone 2.1
When we sought to remove the sulfone groups of 9g (120 mg, 0.302 mmol) in THF (4 mL). Stirring at −78 °C was
before lactone reduction we found that elimination of one continued for 45 min and then HMPA (0.5 mL) was added
sulfone group occurred (9g→9.3); presumably, the electron- dropwise. Stirring was continued for 5 min, and then a solu-
withdrawing sulfone groups acidified the allylic C(7) hydrogen tion of aldehyde 54 (139 mg, 0.48 mmol) in THF (2 mL) was
sufficiently to permit elimination23 in the basic reaction added at a fast dropwise rate. Stirring at −78 °C was continued
medium.
for 20–30 min (tlc control, silica, Et2O–hexane, disappearance
Once these characteristics of 9g were established we found of aldehyde monitored). Then saturated aqueous NH4Cl
that stereoselective hydrogenation over Pearlman’s catalyst (ca. 3 mL) was added and the mixture was extracted with Et2O.
(9g→9.4) and DIBAL-H reduction, followed by desulfonylation The combined organic extracts were dried (Na2SO4) and evap-
[6% Na(Hg), Na2HPO4, MeOH, 0 °C to room temperature], gave orated. Flash chromatography of the residue over silica gel (2 ×
the desired hydrocarbon 9.6. The stereochemistry of the inter- 15 cm), using 30% Et2O–hexane, gave 5a and 5a′ as separable
mediate hydrogenation product 9.4 was assigned by single isomers: more polar 5a (88 mg, 43%) and less polar 5b (66 mg,
crystal X-ray analysis.
31%), each as an oil.
The more polar alcohol 5a had: FTIR νmax (CDCl3, cast)/
cm−1 3367, 3072, 3058, 2953, 2923, 2868, 1762, 1582, 1477,
1455, 1438; 1H NMR (500 MHz, CDCl3) δ 7.60–7.58 (m, 2 H),
7.49–7.44 (m, 4 H), 7.39–7.27 (m, 7 H), 7.25–7.21 (m, 2 H), 5.68
(d, J = 5.9 Hz, 1 H), 4.43 (t, J = 6.5 Hz, 1 H), 3.63–3.56 (m, 2 H),
2.91 (dd, J = 14.6, 6.4 Hz, 1 H), 2.60–2.50 (m, 1 H), 2.20–2.03
(m, 3 H), 2.02–1.93 (m, 2 H), 1.80–1.65 (m, 3 H), 1.56–1.48 (m,
1 H), 1.44–1.36 (m, 1 H), 1.31–1.21 (m, 1 H), 1.06–0.75 (m, 12
H); 13C NMR (125 MHz, CDCl3) δ 176.8 (s), 138.0 (d), 134.1 (s),
134.0 (s), 132.7 (d), 132.5 (d), 129.7 (d), 128.9 (d), 128.9 (d),
127.7 (d), 127.7 (d), 125.4 (s), 97.8 (d), 77.3 (d), 71.4 (d), 57.8
(d), 50.0 (s), 47.7 (d), 39.4 (t), 34.8 (t), 34.3 (t), 32.8 (t), 31.4 (d),
28.2 (t), 24.9 (d), 22.7 (t), 22.2 (q), 21.1 (q), 15.4 (q); exact mass
(electrospray) calcd for C36H44NaO4S278Se (M + Na) 705.1755,
found 705.1755.
Conclusion
Our experiments show that the asymmetric ICD process can be
used to prepare optically pure six- and seven-membered carbo-
cycles that carry functionality suitable for further elaboration.
A limitation is that the nucleophilic carbon must not be
benzylic (see entry viii of Table 3) and the acceptor double
bond should be unsubstituted (cf. Table 2). The method works
well, especially for benzo-fused carbocycles, and either enan-
tiomer is accessible because both enantiomers of the chiral
auxiliary are readily available. The aldehyde components
required are made by simple reactions, at least in the examples
we have studied.
The less polar alcohol 5a′ had: FTIR νmax (CDCl3, cast)/cm−1
3495, 3057, 3018, 2953, 2923, 2868, 1763, 1582, 1476, 1454,
1438; 1H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 8.1, 1.2 Hz,
2 H), 7.44–7.41 (m, 5 H), 7.34–7.25 (m, 8 H), 5.67 (dd, J = 6.5,
1.3 Hz, 1 H), 4.40 (t, J = 6.5 Hz, 1 H), 3.59–3.54 (m, 2 H), 2.86
(br s, 1 H), 2.71 (dd, J = 15.3, 6.5 Hz, 1 H), 2.48–2.42 (m, 1 H),
2.17–2.07 (m, 2 H), 2.05–1.98 (m, 1 H), 1.91–1.81 (m, 2 H),
1.70–1.62 (m, 3 H), 1.43–1.34 (m, 1 H), 1.30–1.22 (m, 1 H),
1.06–0.76 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 175.1 (s),
138.1 (d), 133.9 (s), 133.9 (s), 132.8 (d), 132.8 (d), 129.9 (d),
129.1 (d), 128.9 (d), 127.7 (d), 127.7 (d), 125.9 (s), 97.8 (d), 77.4
(d), 71.9 (d), 58.0 (d), 53.1 (s), 47.8 (d), 39.5 (t), 36.7 (t), 34.3 (t),
32.7 (t), 31.4 (d), 28.7 (t), 25.0 (d), 22.8 (t), 22.2 (q), 21.1 (q),
15.6 (q); exact mass (electrospray) m/z calcd for
C36H44NaO4S280Se (M + Na) 707.1740, found 707.1727.
Experimental
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 and transferred by syringe or
cannula. The symbols s, d, t and q used for 13C NMR spectra
indicate zero, one, two, or three attached hydrogens, respect-
ively, the assignments being made by from APT spectra. Solu-
tions were evaporated under water pump vacuum and the
residue was then kept under oil pump vacuum. Electrospray
ionization was used for mass spectra. For high resolution
spectra an orthogonal time of flight analyzer was used and a
quadrupole analyzer for low resolution spectra.
(5R)-3-[4,4-Bis(benzenesulfonyl)-1-hydroxybutyl]-5-{[(1R,2S,5R)-
5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-3-(pheylselanyl)-2,5-
dihydrofuran-2-one (5b, 5b′)
(5R)-3-[1-Hydroxy-4,4-bis(phenylsulfanyl)butyl]-5-{[(1R,2S,5R)-
5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-3-(pheylselanyl)-
oxolan-2-one (5a, 5a′)
Use of 5a′. MCPBA (70%, 309 mg, 1.25 mmol) was added to
a stirred and cooled (0 °C) solution of 5a′ (43 mg, 0.062 mmol)
A stock solution of LDA was prepared as follows: BuLi (2.5 M in CH2Cl2 (4 mL). The ice bath was left in place but not
in hexanes, 0.75 mL, 1.89 mmol) was added to a stirred and recharged and stirring was continued for 12 h. The reaction
cooled (−78 °C) solution of i-Pr2NH (0.30 mL, 1.88 mmol) in mixture was quenched with a mixture of saturated aqueous
THF (8 mL), and stirring was continued for 30 min at −78 °C. NaHCO3 (2 mL) and saturated aqueous Na2S2O3 (2 mL) and
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extracted with CH2Cl2. The combined organic extracts were evaporated. Flash chromatography of the residue over silica gel
washed with water and brine, dried (Na2SO4) and evaporated. (1 × 15 cm), using 50% EtOAc–hexane, gave 5c′ (31 mg, 91%)
Flash chromatography of the residue over silica gel (1 × as a colorless foam: FTIR νmax (neat)/cm−1 3067, 2955, 2926,
15 cm), using 30% EtOAc–hexane, gave 5b′ (32.4 mg, 88%) as a 2870, 1766, 1653, 1584, 1478, 1448; 1H NMR (500 MHz, CDCl3)
colorless oil: FTIR νmax (CDCl3, cast)/cm−1 3516, 3067, 2955, δ 7.93–7.90 (m, 4 H), 7.71–7.68 (m, 2 H), 7.59–7.55 (m, 4 H),
2925, 2870, 1761, 1584, 1448; 1H NMR (500 MHz, CDCl3) 6.94 (t, J = 1.2 Hz, 1 H), 6.00 (s, 1 H), 5.61–5.59 (m, 1 H), 4.50
δ 7.95–7.93 (m, 4 H), 7.71–7.67 (m, 2 H), 7.59–7.55 (m, 4 H), (dd, J = 6.0, 5.0 Hz, 1 H), 3.61 (td, J = 10.7, 4.3 Hz, 1 H),
6.96 (s, 1 H), 5.99 (s, 1 H), 4.77 (t, J = 5.6 Hz, 1 H), 4.52–4.50 2.30–2.08 (m, 9 H), 1.69–1.63 (m, 2 H), 1.43–1.37 (m, 1 H),
(m, 1 H), 3.63 (td, J = 10.7, 4.3 Hz, 1 H), 2.68 (br s, 1 H), 2.35 1.27–1.21 (m, 1 H), 1.02–0.78 (m, 12 H); 13C NMR (100 MHz,
(q, J = 6.5 Hz, 2 H), 2.17–2.07 (m, 3 H), 2.01–1.94 (m, 1 H), CDCl3) δ 169.9 (s), 168.9 (s), 145.4 (d), 137.9 (s), 137.9 (s), 136.1
1.69–1.64 (m, 2 H), 1.44–1.36 (m, 1 H), 1.28–1.22 (m, 1 H), (s), 134.9 (d), 134.9 (d), 129.8 (d), 129.9 (d), 129.4 (d), 99.3 (d),
1.06–0.77 (m, 12 H); 13C NMR (175 MHz, CDCl3) δ 170.2 (s), 82.9 (d), 79.5 (d), 67.5 (d), 47.9 (d), 40.7 (t), 34.4 (t), 31.7 (q),
143.9 (d), 139.0 (s), 137.7 (s), 137.7 (s), 134.7 (d), 134.6 (d), 30.5 (t), 25.4 (d), 23.3 (t), 22.4 (d), 21.2 (t), 21.1 (q), 21.1 (q),
129.7 (d), 129.6 (d), 129.2 (d), 129.2 (d), 99.4 (d), 82.7 (d), 79.4 15.9 (q); exact mass (electrospray) m/z calcd for C32H40NaO9S2
(d), 66.6 (d), 47.7 (d), 40.4 (t), 34.2 (t), 32.3 (t), 31.5 (d), 25.3 (d), (M + Na) 655.2006, found 655.1999.
23.1 (t), 22.2 (q), 21.9 (t), 20.9 (q), 15.8 (q); exact mass (electro-
spray) m/z calcd for C30H38NaO8S2 (M + Na) 613.1900, found stirred solution of 5b (44 mg, 0.07 mmol) in CH2Cl2 (2 mL).
613.1892. The mixture was then cooled to 0 °C, and AcCl (0.026 mL,
Use of 5b. DMAP (0.8 mg, 0.007 mmol) was added to a
Use of 5a. MCPBA (70%, 382 mg, 1.55 mmol) was added to 0.37 mmol) and pyridine (0.042 mL, 0.52 mmol) were added
a stirred and cooled (0 °C) solution of 5a (53 mg, 0.077 mmol) sequentially. The ice bath was left in place but not recharged
in CH2Cl2 (4 mL). The ice bath was left in place but not and stirring was continued for 3 h, during which time the cold
recharged and stirring was continued for 12 h. The reaction bath reached room temperature. The reaction mixture was
mixture was quenched with a mixture of saturated aqueous quenched with saturated aqueous CuSO4 (2 mL) and water
NaHCO3 (2 mL) and saturated aqueous Na2S2O3 (2 mL) and (5 mL), and extracted with CH2Cl2 (2 × 10 mL). The combined
extracted with CH2Cl2. The combined organic extracts were organic extracts were washed with brine, dried (MgSO4) and
washed with water and brine, dried (Na2SO4) and evaporated. evaporated. Flash chromatography of the residue over silica gel
Flash chromatography of the residue over silica gel (1 × (1 × 15 cm), using 50% EtOAc–hexane, gave 5c (42 mg, 90%) as
15 cm), using 40% EtOAc–hexane, gave 5b (39.0 mg, 86%) as a a colorless foam: FTIR νmax (neat)/cm−1 3066, 2955, 2926,
colorless oil: FTIR νmax (CDCl3, cast)/cm−1 3513, 3097, 3067, 2870, 1766, 1653, 1584, 1448; 1H NMR (500 MHz, CDCl3)
2955, 2925, 2870, 1760, 1584, 1448; 1H NMR (500 MHz, CDCl3) δ 7.95–7.92 (m, 4 H), 7.71–7.68 (m, 2 H), 7.59–7.55 (m, 4 H),
δ 7.95–7.94 (m, 4 H), 7.71–7.68 (m, 2 H), 7.57 (t, J = 7.6 Hz, 6.90 (t, J = 1.1 Hz, 1 H), 5.97 (s, 1 H), 5.52–5.50 (m, 1 H), 4.51
4 H), 6.94 (t, J = 1.4 Hz, 1 H), 5.99 (t, J = 1.1 Hz, 1 H), 4.75 (t, J = (t, J = 5.4 Hz, 1 H), 3.63 (td, J = 10.7, 4.3 Hz, 1 H), 2.30–2.22 (m,
5.5 Hz, 1 H), 4.50–4.48 (m, 1 H), 3.63 (td, J = 10.7, 4.3 Hz, 1 H), 3 H), 2.16–2.10 (m, 6 H), 1.70–1.64 (m, 2 H), 1.44–1.37 (m, 1
2.86 (br s, 1 H), 2.44–2.32 (m, 2 H), 2.17–2.07 (m, 3 H), H), 1.29–1.23 (m, 1 H), 1.06–0.78 (m, 12 H); 13C NMR
2.03–1.96 (m, 1 H), 1.70–1.64 (m, 2 H), 1.45–1.36 (m, 1 H), (100 MHz, CDCl3) δ 169.7 (s), 168.6 (s), 144.7 (d), 137.7 (s),
1.28–1.23 (m, 1 H), 1.06–0.78 (m, 12 H); 13C NMR (125 MHz, 137.6 (s), 135.9 (s), 134.7 (d), 134.6 (d), 129.6 (d), 129.6 (d),
CDCl3) δ 170.4 (s,), 143.5 (d), 138.8 (s), 137.7 (s), 137.7 (s), 129.1 (d), 99.0 (d), 82.5 (d), 79.6 (d), 67.2 (d), 47.7 (d), 40.5 (t),
134.6 (d), 134.6 (d), 129.6 (d), 129.6 (d), 129.1 (d), 129.1 (d), 34.1 (t), 31.5 (q), 30.6 (t), 25.2 (d), 23.1 (t), 22.2 (d), 21.3 (t),
99.4 (d), 82.7 (d), 79.5 (d), 66.4 (d), 47.7 (d), 40.4 (t), 34.2 (t), 20.9 (q), 20.8 (q), 15.7 (q); exact mass (electrospray) m/z calcd
32.4 (t), 31.5 (d), 25.2 (d), 23.1 (t), 22.2 (q), 22.0 (t), 20.9 (q), for C32H40NaO9S2 (M + Na) 655.2006, found 655.2001.
15.8 (q); exact mass (electrospray) m/z calcd for C30H38NaO8S2
(3R,3aR)-4,4-Bis(benzenesulfonyl)-3-{[(1R,2S,5R)-5-methyl-2-
(propan-2-yl)cyclohexyl]oxy}-1,3,3a,4,5,6-hexahydro-2-
(M + Na) 613.1900, found 613.1891.
4,4-Bis(benzenesulfonyl)-1-[(5R)-5-{[(1R,2S,5R)-5-methyl-2-
(propan-2-yl)cyclohexyl]oxy}-2-oxo-2,5-dihydrofuran-3-yl]butyl
acetate (5c, 5c′)
benzofuran-1-one (5l)
Use of 5c′. Cs2CO3 (77.3 mg, 0.23 mmol) was added to a
stirred and cooled (0 °C) solution of 5c′ (30 mg, 0.047 mmol)
Use of 5b′. DMAP (ca. 1 mg, 0.01 mmol) was added to a in THF (3 mL). The ice bath was left in place but not recharged
stirred solution of 5b′ (32 mg, 0.05 mmol) in CH2Cl2 (3 mL). and stirring was continued for 2 h. The reaction mixture was
The mixture was then cooled to 0 °C, and AcCl (0.02 mL, quenched with saturated aqueous NH4Cl (2 mL) and extracted
0.27 mmol) and pyridine (0.04 mL, 0.37 mmol) were added with EtOAc (20 mL). The combined organic extracts were
sequentially. The ice bath was left in place but not recharged washed with water and brine, dried (Na2SO4) and evaporated.
and stirring was continued for 3 h, during which time the cold Flash chromatography of the residue over silica gel (1 ×
bath reached room temperature. The reaction mixture was 15 cm), using 50% EtOAc–hexane, gave 5l (23.5 mg, 87%) as a
quenched with saturated aqueous CuSO4 (2 mL) and water single diastereoisomer.
(5 mL), and extracted with CH2Cl2 (2 × 10 mL). The combined
Use of 5c. Cs2CO3 (61 mg, 0.19 mmol) was added to a
organic extracts were washed with brine, dried (MgSO4) and stirred and cooled (0 °C) solution of 5c (24 mg, 0.037 mmol) in
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THF (3 mL). The ice bath was left in place but not recharged in CH2Cl2 (5 mL). The ice bath was left in place but not
and stirring was continued for 2 h. The reaction mixture was recharged and stirring was continued for 4 h. The reaction
quenched with saturated aqueous NH4Cl (2 mL) and extracted mixture was quenched with a mixture of saturated aqueous
with EtOAc (20 mL). The combined organic extracts were NaHCO3 (2 mL) and saturated aqueous Na2S2O3 (2 mL), and
washed with water and brine, dried (Na2SO4) and evaporated. extracted with CH2Cl2. The combined organic extracts were
Flash chromatography of the residue over silica gel (1 × washed with water and brine, dried (Na2SO4) and evaporated.
15 cm), using 50% EtOAc–hexane, gave 5l (23.5 mg, 82%) as a Flash chromatography of the residue over silica gel (1 ×
single diastereoisomer: FTIR νmax (neat)/cm−1 3066, 2954, 15 cm), using 40% Et2O–hexane, gave 6b′ (48 mg, 56%) as a
1
2927, 2869, 1768, 1692, 1583, 1478, 1448; H NMR (500 MHz, colorless oil: FTIR νmax (CDCl3, cast)/cm−1 3510, 3107, 2956,
1
CDCl3) δ 8.15–8.07 (m, 4 H), 7.76–7.70 (m, 2 H), 7.63–7.54 (m, 2926, 2871, 1761, 1591, 1493, 1456, 1406; H NMR (500 MHz,
4 H), 6.84 (q, J = 3.6 Hz, 1 H), 6.54 (d, J = 4.5 Hz, 1 H), 3.78 (td, CDCl3) δ 8.04–8.01 (m, 4 H), 7.31–7.28 (m, 4 H), 7.01 (t, J =
J = 10.7, 4.1 Hz, 1 H), 3.25 (dt, J = 7.6, 3.7 Hz, 1 H), 2.71–2.56 1.4 Hz, 1 H), 6.04 (s, 1 H), 4.80 (t, J = 5.7 Hz, 1 H), 4.58 (m,
(m, 2 H), 2.44–2.37 (m, 1 H), 2.27–2.18 (m, 2 H), 1.91 (ddd, J = 1 H), 3.67 (td, J = 10.7, 4.3 Hz, 1 H), 2.37–2.32 (m, 2 H),
14.6, 9.0, 7.6 Hz, 1 H), 1.70–1.67 (m, 2 H), 1.44–1.35 (m, 2 H), 2.23–2.00 (m, 4 H), 1.73–1.66 (m, 2 H), 1.47–1.41 (m, 1 H),
1.11–0.85 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 165.9 (s), 1.31–1.24 (m, 2 H), 1.07–0.82 (m, 12 H); 13C NMR (125 MHz,
1
138.7 (s), 135.3 (s), 135.1 (d), 135.0 (d), 134.7 (d), 131.9 (d), CDCl3) δ 170.2 (s), 166.5 (CF, JCF = 258.7 Hz), 143.9 (d), 139.1
3
3
131.3 (d), 129.0 (d), 128.7 (d), 126.6 (s), 98.7 (d), 87.5 (s), 77.1 (s), 133.5 (s), 132.8 (CCCF, JCF = 10.2 Hz), 132.8 (CCCF, JCF
=
(d), 48.1 (d), 46.4 (d), 38.3 (t), 34.3 (t), 31.4 (d), 27.9 (t), 25.7 (d), 10.2 Hz), 116.6 (CCF, 2JCF = 22.9 Hz), 99.4 (d), 82.9 (d), 79.5 (d),
24.3 (t), 23.3 (t), 22.3 (q), 21.0 (q), 15.9 (q); exact mass (electro- 66.7 (d), 47.8 (d), 40.4 (t), 34.2 (t), 32.2 (t), 31.5 (d), 25.3 (d),
spray) m/z calcd for C30H36NaO7S2 (M + Na) 595.1795, found 23.1 (t), 22.2 (q), 22.1 (t), 20.9 (q), 15.8 (q); exact mass (electro-
595.1788.
spray) m/z calcd for C30H36F2NaO8S2 (M + Na) 649.1712, found
For X-ray analysis crystals of 5l were grown by slow vapor 649.1701.
diffusion of hexanes into a solution of the compound in
CH2Cl2: mp 210–212 °C.
Use of 6a. MCPBA (70%, 960 mg, 3.89 mmol) was added to
a stirred and cooled (0 °C) solution of 6a (187 mg, 0.26 mmol)
in CH2Cl2 (5 mL). The ice bath was left in place but not
recharged and stirring was continued for 3 h. The reaction
mixture was quenched with a mixture of saturated aqueous
NaHCO3 (2 mL) and saturated aqueous Na2S2O3 (2 mL), and
(5R)-3-{4,4-Bis[(4-fluorophenyl)sulfanyl]-1-hydroxybutyl}-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-3-
(phenylselanyl)oxolan-2-one (6a, 6a′)
A solution of LDA was prepared as follows: BuLi (2.5 M in extracted with CH2Cl2. The combined organic extracts were
hexanes, 2.58 mL, 6.45 mmol) was added to a stirred and washed with water and brine, dried (Na2SO4) and evaporated.
cooled (−78 °C) solution of i-Pr2NH (0.98 mL, 7 mmol) in THF Flash chromatography of the residue over silica gel (1 ×
(20 mL), and stirring was continued for 30 min at −78 °C. A 15 cm), using 50% Et2O–hexane, gave 6b (101 mg, 62%) as a
portion (4.71 mL) of this stock solution was then taken up into colorless oil: FTIR νmax (CDCl3, cast)/cm−1 3514, 3107, 2956,
1
a syringe and added dropwise (over ca. 10 min, added manu- 2926, 2871, 1760, 1591, 1493, 1456, 1406; H NMR (500 MHz,
ally by syringe) to a stirred and cooled (−78 °C) solution of CDCl3) δ 8.05–8.02 (m, 4 H), 7.32–7.28 (m, 4 H), 6.98 (t, J =
lactone 2.1 (427 mg, 1.078 mmol) in THF (3 mL). Stirring at 1.4 Hz, 1 H), 6.04 (t, J = 1.2 Hz, 1 H), 4.78 (t, J = 5.7 Hz, 1 H),
−78 °C was continued for 45 min and then HMPA (1 mL) was 4.57 (dt, J = 8.6, 1.6 Hz, 1 H), 3.67 (dt, J = 10.7, 5.3 Hz, 1 H),
added dropwise. Stirring was continued for 5 min and then a 2.42–2.32 (m, 2 H), 2.23–2.02 (m, 4 H), 1.73–1.68 (m, 2 H),
solution of aldehyde 6 (524 mg, 1.61 mmol) in THF (2 mL) was 1.45–1.40 (m, 1 H), 1.32–1.24 (m, 2 H), 1.07–0.81 (m, 12 H); 13
C
1
added at a fast dropwise rate. Stirring at −78 °C was continued NMR (125 MHz, CDCl3) δ 170.4 (s), 166.5 (CF, JCF = 258.6 Hz),
3
for 20–30 min (tlc control, disappearance of aldehyde moni- 143.6 (d), 138.8 (s), 133.5 (s), 132.8 (CCCF, JCF = 10.1 Hz),
2
tored). Then saturated aqueous NH4Cl (5 mL) was added and 116.6 (CCF, JCF = 23.0 Hz), 99.4 (d), 82.9 (d), 79.6 (d), 66.4 (d),
the mixture was extracted with Et2O. The combined organic 47.7 (d), 40.4 (t), 34.2 (t), 32.4 (t), 31.5 (d), 25.3 (q), 23.1 (t),
extracts were dried (Na2SO4) and evaporated. Flash chromato- 20.9 (q), 15.8 (q); exact mass (electrospray) m/z calcd for
graphy of the residue over silica gel (4 × 15 cm), using 40% C30H36F2NaO8S2 (M + Na) 649.1712, found 649.1710.
Et2O–hexane gave two diastereoisomers which were partially
4,4-Bis[(4-fluorobenzene)sulfonyl]-1-[(5R)-5-{[(1R,2S,5R)-5-
separated [more polar isomer 6a (187 mg, 26%); less polar
methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-2,5-dihydrofuran-
3-yl]butyl acetate (6c, 6c′)
isomer 6a′ (200 mg, 28%)] as oils. Neither isomer was pure
and so the material was used without characterization for the
next step.
Use of 6b′. DMAP (ca. 1 mg, 0.01 mmol) was added to a
stirred solution of 6b′ (50 mg, 0.079 mmol) in CH2Cl2 (2 mL).
The mixture was then cooled to 0 °C, and AcCl (0.028 mL,
0.39 mmol) and pyridine (0.046 mL, 0.55 mmol) were added
sequentially. The ice bath was left in place but not recharged
(5R)-3-{4,4-Bis[(4-fluorobenzene)sulfonyl]-1-hydroxybutyl}-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2,5-
dihydrofuran-2-one (6b, 6b′)
Use of 6a′. MCPBA (70%, 512 mg, 2.08 mmol) was added to and stirring was continued for 3 h, during which time the cold
a stirred and cooled (0 °C) solution of 6a′ (100 mg, 0.14 mmol) bath reached room temperature. The reaction mixture was
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quenched with saturated aqueous CuSO4 (2 mL) and water Flash chromatography of the residue over silica gel (1 ×
(5 mL), and extracted with CH2Cl2 (2 × 10 mL). The combined 15 cm), using 50% EtOAc–hexane, gave 6d (14 mg, 78%).
organic extracts were washed with brine, dried (MgSO4) and
Use of 6c. Cs2CO3 (44 mg, 0.13 mmol) was added to a
evaporated. Flash chromatography of the residue over silica gel stirred and cooled (0 °C) solution of 6c (18 mg, 0.026 mmol) in
(1 × 15 cm), using 30% EtOAc–hexane, gave 6c′ (38 mg, 72%) THF (2 mL). The ice bath was left in place but not recharged
as a colorless foam: FTIR νmax (CDCl3, cast)/cm−1 3106, 2956, and stirring was continued for 2 h. The reaction mixture was
1
2926, 2871, 1765, 1591, 1493, 1456, 1406; H NMR (500 MHz, quenched with saturated aqueous NH4Cl (2 mL) and extracted
CDCl3) δ 8.03–8.00 (m, 4 H), 7.32–7.28 (m, 4 H), 6.99 (t, J = with EtOAc (20 mL). The combined organic extracts were
1.3 Hz, 1 H), 6.04 (s, 1 H), 5.66–5.63 (m, 1 H), 4.54 (dd, J = 6.2, washed with water and brine, dried (Na2SO4) and evaporated.
5.1 Hz, 1 H), 3.66 (td, J = 10.7, 4.3 Hz, 1 H), 2.35–2.09 (m, 9 H), Flash chromatography of the residue over silica gel (1 ×
1.75–1.68 (m, 2 H), 1.46–1.44 (m, 1 H), 1.31–1.24 (m, 1 H), 15 cm), using 50% EtOAc–hexane, gave 6d (11 mg, 70%): FTIR
1.06–0.81 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 169.7 (s), νmax (CDCl3, cast)/cm−1 3106, 2955, 2927, 2870, 1769, 1692,
1
1
168.8 (s), 166.5 (CF, JCF = 258.8 Hz), 145.2 (d), 135.8 (s), 133.4 1590, 1493, 1456, 1406; H NMR (500 MHz, CDCl3) δ 8.17–8.08
2
3
(CCF, JCF = 17.3 Hz), 132.7 (CCCF, JCF = 10.2 Hz), 116.6 (CCF, (m, 4 H), 7.31–7.20 (m, 4 H), 6.88 (q, J = 3.7 Hz, 1 H), 6.47 (d,
2JCF = 23.9 Hz), 99.1 (s), 82.8 (s), 79.4 (s), 67.1 (s), 47.7 (s), 40.4 J = 4.5 Hz, 1 H), 3.76 (td, J = 10.7, 4.1 Hz, 1 H), 3.20 (dt, J = 7.7,
(t), 34.2 (t), 31.5 (q), 30.3 (t), 25.2 (d), 23.1 (t), 22.2 (d), 21.1 (d), 3.7 Hz, 1 H), 2.75–2.66 (m, 1 H), 2.57 (ddd, J = 14.6, 6.6,
20.9 (q), 20.9 (q), 15.7 (d); exact mass (electrospray) m/z calcd 2.1 Hz, 1 H), 2.49–2.42 (m, 1 H), 2.23–2.14 (m, 2 H), 1.91 (ddd,
for C32H38F2NaO9S2 (M + Na) 691.1818, found 691.1809.
J = 14.7, 9.0, 7.3 Hz, 1 H), 1.71–1.67 (m, 2 H), 1.43–1.29 (m, 2
Use of 6b. DMAP (1.2 mg, 0.01 mmol) was added to a H), 1.08–0.82 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 166.7
1
3
stirred solution of 6b (35 mg, 0.05 mmol) in CH2Cl2 (2 mL). (CF, JCF = 258.3 Hz), 165.7 (s), 135.01 (CCCF, JCF = 4.2 Hz),
The solution was then cooled to 0 °C, and AcCl (0.019 mL, 135.0 (s), 134.5 (d), 134.4 (d), 131.1 (CCCCF, JCF = 3.4 Hz),
4
2
2
0.28 mmol) and pyridine (0.031 mL, 0.39 mmol) were added 126.5 (s), 116.5 (CCF, JCF, J = 22.7 Hz), 116.2 (CCF, JCF = 22.8
sequentially. The ice bath was left in place but not recharged Hz), 98.5 (d), 87.8 (s), 76.5 (d), 48.2 (d), 46.5 (d), 38.4 (t), 34.3
and stirring was continued for 3 h, during which time the cold (t), 31.4 (d), 28.0 (t), 25.8 (d), 24.3 (t), 23.3 (t), 22.4 (q), 21.1
bath reached room temperature. The reaction mixture was (q), 16.0 (q); exact mass (electrospray) m/z calcd for
quenched with saturated aqueous CuSO4 (2 mL) and water C30H34F2NaO7S2 (M + Na) 631.1606, found 631.1600.
(5 mL), and extracted with CH2Cl2 (2 × 10 mL). The combined
5-Butyl-3-[1-hydroxy-4,4-bis(phenylsulfanyl)butyl]-3-
(phenylselanyl)oxolan-2-one (5d, 5d′)
organic extracts were washed with brine, dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel
(1 × 15 cm), using 30% EtOAc–hexane, gave 6c (25 mg, 68%) as A stock solution of LDA was prepared as follows: BuLi (2.5 M
a colorless foam: FTIR νmax (CDCl3, cast)/cm−1 3106, 2956, in hexanes, 0.63 mL, 1.59 mmol) was added to a stirred and
1
2926, 2871, 1767, 1591, 1493, 1456, 1406; H NMR (500 MHz, cooled (−78 °C) solution of i-Pr2NH (0.24 mL, 1.73 mmol) in
CDCl3) δ 8.04–7.99 (m, 4 H), 7.31–7.27 (m, 4 H), 6.93 (t, J = THF (20 mL), and stirring was continued for 30 min at −78 °C.
1.3 Hz, 1 H), 6.01 (t, J = 1.2 Hz, 1 H), 5.57–5.54 (m, 1 H), 4.54 A portion (2.1 mL, 0.15 mmol LDA) of this stock solution was
(ddd, J = 6.5, 4.7, 2.0 Hz, 1 H), 3.67 (td, J = 10.7, 4.3 Hz, 1 H), added dropwise (over ca. 10 min, added manually by syringe)
2.34–2.10 (m, 9 H), 1.70–1.67 (m, 2 H), 1.45–1.41 (m, 1 H), to a stirred and cooled (−78 °C) solution of lactone 2 (43 mg,
1.31–1.25 (m, 1 H), 1.09–0.82 (m, 12 H); 13C NMR (125 MHz, 0.145 mmol) in THF (4 mL). Stirring at −78 °C was continued
CDCl3) δ 169.8 (s), 168.7 (s), 166.47 (CF, 1JCF = 258.7 Hz), 144.8 for 45 min and then HMPA (0.4 mL) was added dropwise. Stir-
4
3
(d), 135.9 (s), 133.4 (CCCCF, JCF = 3.3 Hz), 132.8 (CCCF, JCF
=
=
ring was continued for 5 min and then a solution of aldehyde
3
2
5.2 Hz), 132.8 (CCCF, JCF = 5.2 Hz), 116.6 (CCF, JCF
54 (41.6 mg, 0.148 mmol) in THF (2 mL) was added at a fast
22.9 Hz), 99.1 (d), 82.8 (d), 79.7 (d), 67.1 (d), 47.7 (d), 40.5 (t), dropwise rate. Stirring at −78 °C was continued for 20–30 min
34.1 (t), 31.5 (t), 30.6 (t), 25.3 (d), 23.1 (t), 22.2 (d), 21.3 (t), 20.9 (tlc control, silica, Et2O–hexane, disappearance of aldehyde
(q), 20.8 (q), 15.7 (q); exact mass (electrospray) m/z calcd for monitored). Then saturated aqueous NH4Cl (ca. 3 mL) was
C32H38F2NaO9S2 (M + Na) 691.1818, found 691.1804.
added and the mixture was extracted with Et2O. The combined
organic extracts were dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (2 × 15 cm),
using 30% Et2O–hexane, gave the less polar isomer 5d′ (32 mg,
36%) and the more polar isomer 5d (26 mg, 32%) (57.6 mg in
all, 68%) as oils.
(3R,3aR)-4,4-Bis[(4-fluorobenzene)sulfonyl]-3-{[(1R,2S,5R)-5-
methyl-2-(propan-2-yl)cyclohexyl]oxy}-1,3,3a,4,5,6-hexahydro-2-
benzofuran-1-one (6d)
Use of 6c′. Cs2CO3 (49 mg, 0.15 mmol) was added to a
The more polar alcohol 5d had: FTIR νmax (CDCl3, cast)/
stirred and cooled (0 °C) solution of 6c′ (20 mg, 0.03 mmol) in cm−1 3459, 3057, 2954, 2930, 2861, 1753, 1582, 1476, 1438; H
THF (2 mL). The ice bath was left in place but not recharged NMR (500 MHz, CDCl3) δ 7.62–7.60 (m, 2 H), 7.50–7.46 (m, 4
and stirring was continued for 3 h. The reaction mixture was H), 7.39 (ddt, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.34–7.24 (m, 8 H),
quenched with saturated aqueous NH4Cl (2 mL) and extracted 4.48–4.40 (m, 2 H), 3.71 (dd, J = 10.7, 1.5 Hz, 1 H), 2.85 (dd, J =
with EtOAc (20 mL). The combined organic extracts were 14.4, 8.9 Hz, 1 H), 2.49 (dddd, J = 13.9, 10.2, 5.6, 1.8 Hz, 1 H),
washed with water and brine, dried (Na2SO4) and evaporated. 2.18–2.11 (m, 2 H), 1.88–1.73 (m, 3 H), 1.66–1.58 (m, 1 H),
1
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1.53–1.26 (m, 5 H), 0.90 (t, J = 7.1 Hz, 3 H); 13C NMR washed with brine, dried (MgSO4) and evaporated. Flash
(125 MHz, CDCl3) δ 177.5 (s), 137.9 (d), 134.1 (s), 134.0 (s), chromatography of the residue over silica gel (1 × 15 cm),
132.8 (d), 132.6 (d), 129.9 (d), 129.1 (d), 128.9 (d), 127.8 (d), using 50% EtOAc–hexane, gave 5f (45 mg, 90%) as a colorless
127.8 (d), 125.6 (s), 78.3 (d), 72.5 (d), 57.9 (d), 52.8 (s), 35.7 (t), oil: FTIR νmax (CDCl3, cast)/cm−1 3068, 2958, 2933, 2873, 1753,
1
33.5 (t), 32.7 (t), 28.8 (t), 27.7 (t), 22.3 (t), 13.9 (q); exact mass 1584, 1479, 1448; H NMR (500 MHz, CDCl3) δ 7.96–7.93 (m,
(electrospray) calcd for C30H34NaO3S278Se (M + Na) 607.1021, 4 H), 7.72 (td, J = 7.5, 0.7 Hz, 2 H), 7.61–7.57 (m, 4 H), 7.25 (t,
found 607.1024.
J = 1.4 Hz, 1 H), 5.58–5.56 (m, 1 H), 4.96 (t, J = 6.5 Hz, 1 H),
The less polar alcohol 5d′ had: FTIR νmax (CDCl3, cast)/cm−1 4.56 (t, J = 5.4 Hz, 1 H), 2.34–2.17 (m, 4 H), 2.11 (s, 3 H),
1
3477, 3057, 2955, 2931, 2861, 1753, 1582, 1476, 1438; H NMR 1.79–1.72 (m, 1 H), 1.69–1.62 (m, 1 H), 1.47–1.35 (m, 4 H), 0.93
(500 MHz, CDCl3) δ 7.66 (dt, J = 8.1, 1.5 Hz, 2 H), 7.51–7.41 (m, (t, J = 7.0 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 170.8 (s),
5 H), 7.36–7.23 (m, 8 H), 4.44 (t, J = 6.5 Hz, 1 H), 4.39–4.34 (m, 169.8 (s), 150.8 (d), 137.8 (s), 137.6 (s), 134.7 (d), 134.7 (d),
1 H), 3.68 (dd, J = 9.9, 2.0 Hz, 1 H), 2.92 (br s, 1 H), 2.67 (dd, 132.1 (s), 129.5 (d), 129.5 (d), 129.2 (d), 82.6 (d), 81.7 (d), 67.6
J = 14.8, 8.6 Hz, 1 H), 2.19–2.12 (m, 1 H), 1.98–1.85 (m, 3 H), (d), 32.9 (t), 30.3 (t), 27.1 (t), 22.4 (t), 21.1 (t), 20.9 (q), 13.8 (q);
1.80–1.75 (m, 1 H), 1.65–1.58 (m, 1 H), 1.43–1.18 (m, 5 H), 0.88 exact mass (electrospray) m/z calcd for C26H30NaO8S2 (M + Na)
(t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 176.6 (s), 557.1274, found 557.1268.
138.0 (d), 133.9 (s), 133.9 (s), 132.8 (d), 132.8 (d), 129.9 (d),
128.9 (d), 128.9 (d), 127.8 (d), 127.7 (d), 126.0 (s), 78.2 (d), 72.9
(d), 58.0 (d), 55.4 (s), 35.6 (t), 35.3 (t), 32.8 (t), 29.4 (t), 27.4 (t),
1-[5-Butyl-2-oxo-3-(phenylselanyl)oxolan-3-yl]-4,4-bis-
(phenylsulfanyl)butyl acetate (5g′)
22.3 (t), 13.9 (q); exact mass (electrospray) calcd for
C30H34NaO3S278Se (M + Na) 607.1021, found 607.1024.
Use of 5d′. DMAP (ca. 1 mg, 0.01 mmol) was added to a
stirred solution of 5d′ (35 mg, 0.06 mmol) in CH2Cl2 (2 mL).
The mixture was then cooled to 0 °C and AcCl (0.022 mL,
0.29 mmol) and pyridine (0.039 mL, 0.48 mmol) were added
sequentially. The ice bath was left in place but not recharged
3-[4,4-Bis(benzenesulfonyl)-1-hydroxybutyl]-5-butyl-2,5-
dihydrofuran-2-one (5e)
Use of 5d. MCPBA (70%, 288 mg, 1.67 mmol) was added to and stirring was continued for 3 h, during which time the cold
a stirred and cooled (0 °C) solution of 5d (49 mg, 0.083 mmol) bath reached room temperature. The reaction mixture was
in CH2Cl2 (4 mL). The ice bath was left in place but not quenched with saturated CuSO4 (2 mL) and water (5 mL), and
recharged and stirring was continued for 12 h. The mixture extracted with CH2Cl2 (2 × 10 mL). The combined organic
was quenched with a mixture of saturated aqueous NaHCO3 extracts were washed with brine, dried (MgSO4) and evapor-
(2 mL) and saturated aqueous Na2S2O3 (2 mL), and extracted ated. Flash chromatography of the residue over silica gel
with CH2Cl2. The combined organic extracts were washed with (1 × 15 cm), using 50% Et2O–hexane, gave 5g′ (32 mg, 86%) as
water and brine, dried (Na2SO4) and evaporated. Flash chrom- a colorless oil: FTIR νmax (CDCl3, cast)/cm−1 3058, 2956, 2932,
atography of the residue over silica gel (1 × 15 cm), using 50% 2861, 1761, 1582, 1477, 1439; 1H NMR (500 MHz, CDCl3)
EtOAc–hexane, gave 5e (34 mg, 84%) as a colorless oil: FTIR δ 7.65–7.63 (m, 2 H), 7.48–7.40 (m, 5 H), 7.35–7.28 (m, 8 H),
νmax (CDCl3, cast)/cm−1 3513, 3067, 2957, 2931, 2872, 1745, 5.26 (dd, J = 10.5, 2.6 Hz, 1 H), 4.38 (dd, J = 7.5, 6.1 Hz, 1 H),
1
1584, 1479, 1448; H NMR (400 MHz, CDCl3) δ 7.96–7.94 (m, 4.28–4.23 (m, 1 H), 2.55 (dd, J = 14.7, 8.0 Hz, 1 H), 2.22–2.07
4 H), 7.72–7.68 (m, 2 H), 7.57 (t, J = 7.7 Hz, 4 H), 4.96–4.92 (m, (m, 2 H), 2.01 (dd, J = 14.7, 6.7 Hz, 1 H), 1.95 (s, 3 H),
1 H), 4.81–4.78 (m, 1 H), 4.52–4.50 (m, 1 H), 2.91 (br s, 1 H), 1.88–1.72 (m, 2 H), 1.51–1.43 (m, 1 H), 1.30–1.14 (m, 5 H), 0.85
2.36 (q, J = 6.5 Hz, 2 H), 2.19–2.11 (m, 1 H), 2.06–1.96 (m, 1 H), (t, J = 7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 174.8 (s),
1.77–1.60 (m, 2 H), 1.45–1.33 (m, 4 H), 0.91 (t, J = 7.0 Hz, 3 H); 170.2 (s), 138.0 (d), 133.6 (s), 133.5 (s), 133.2 (d), 133.0 (d),
13C NMR (125 MHz, CDCl3) δ 172.4 (s), 149.3 (d), 137.7 (s), 129.9 (d), 129.3 (d), 128.9 (d), 127.9 (d), 127.9 (d), 126.2 (s),
137.7 (s), 135.3 (s), 134.6 (d), 129.6 (d), 129.6 (d), 129.2 (d), 78.1 (d), 74.8 (d), 57.5 (d), 53.2 (s), 37.3 (t), 35.4 (t), 31.9 (t),
129.2 (d), 82.7 (d), 82.0 (d), 66.6 (d), 32.9 (t), 32.5 (t), 27.1 (t), 28.6 (t), 27.2 (t), 22.3 (t), 20.7 (q), 13.8 (q); exact mass (electro-
22.4 (t), 21.9 (t), 13.8 (q); exact mass (electrospray) m/z calcd spray) calcd for C32H36NaO4S278Se (M + Na) 649.1127, found
for C24H28NaO7S2 (M + Na) 515.1169, found 515.1164.
649.1133.
4,4-Bis(benzenesulfonyl)-1-(5-butyl-2-oxo-2,5-dihydrofuran-3-
yl)butyl acetate (5f)
4,4-Bis(benzenesulfonyl)-1-(5-butyl-2-oxo-2,5-dihydrofuran-
3-yl)butyl acetate (5h′)
Use of 5e. DMAP (1.1 mg, 0.01 mmol) was added to a stirred
Use of 5g′. MCPBA (70%, 112 mg, 0.45 mmol) was added to
solution of 5e (45 mg, 0.09 mmol) in CH2Cl2 (3 mL). The a stirred and cooled (0 °C) solution of 5g′ (19 mg, 0.030 mmol)
mixture was then cooled to 0 °C and AcCl (0.033 mL, in CH2Cl2 (4 mL). The ice bath was left in place but not
0.46 mmol) and pyridine (0.051 mL, 0.64 mmol) were added recharged and stirring was continued for 12 h. The reaction
sequentially. The ice bath was left in place but not recharged mixture was quenched with a mixture of saturated aqueous
and stirring was continued for 3 h, during which time the cold NaHCO3 (2 mL) and saturated aqueous Na2S2O3 (2 mL), and
bath reached room temperature. The mixture was quenched extracted with CH2Cl2. The combined organic extracts were
with saturated CuSO4 (2 mL) and water (5 mL), and extracted washed with water and brine, dried (Na2SO4) and evaporated.
with CH2Cl2 (2 × 10 mL). The combined organic extracts were Flash chromatography of the residue over silica gel (1 ×
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15 cm), using 50% EtOAc–hexane, gave 5h′ (18 mg, 86%) as a dropwise (over ca. 10 min, added manually by syringe) to a
colorless oil: FTIR νmax (CDCl3, cast)/cm−1 3069, 2958, 2932, stirred and cooled (−78 °C) solution of lactone 2.1 (120 mg,
1
2873, 1753, 1584, 1448; H NMR (500 MHz, CDCl3) δ 7.95–7.91 0.30 mmol) in THF (2 mL). Stirring at −78 °C was continued
(m, 4 H), 7.72–7.68 (m, 2 H), 7.59–7.56 (m, 4 H), 7.24 (t, J = for 45 min and then HMPA (0.4 mL) was added dropwise. Stir-
1.4 Hz, 1 H), 5.56–5.54 (m, 1 H), 4.94 (ddt, J = 7.4, 5.6, 1.7 Hz, ring was continued for 5 min and then a solution of aldehyde
1 H), 4.52 (td, J = 5.5, 3.5 Hz, 1 H), 2.31–2.17 (m, 4 H), 2.10 (s, 74 (165 mg, 0.55 mmol) in THF (1 mL) was added at a fast
3 H), 1.76–1.60 (m, 2 H), 1.46–1.33 (m, 4 H), 0.92 (t, J = 7.1 Hz, dropwise rate. Stirring at −78 °C was continued for 20–30 min
3 H); 13C NMR (125 MHz, CDCl3) δ 170.8 (s), 169.8 (s), 150.7 (tlc control, silica, 40% Et2O–hexane, disappearance of alde-
(d), 137.7 (s), 137.6 (s), 134.7 (d), 134.6 (d), 132.2 (s), 129.6 (d), hyde monitored). Then saturated aqueous NH4Cl (3 mL) was
129.5 (d), 129.2 (d), 82.6 (d), 81.6 (d), 67.6 (d), 32.9 (t), 30.4 (t), added and the mixture was extracted with Et2O. The combined
27.1 (t), 22.4 (t), 21.1 (t), 20.9 (q), 13.8 (q); exact mass (electro- organic extracts were dried (Na2SO4) and evaporated. Flash
spray) m/z calcd for C26H30NaO8S2 (M + Na) 557.1274, found chromatography of the residue over silica gel (2 × 15 cm),
557.1280.
using 40% Et2O–hexane, gave 7a and 7a′ (150 mg, 70%) as an
oil that was a mixture of diastereoisomers [more polar isomer
7a, 73 mg, 34%; less polar isomer 7a′, 77 mg (not pure), ca.
36%]. Only the more polar isomer 7a could be separated in
(3S,3aR)-rel-4,4-Bis(benzenesulfonyl)-3-butyl-1,3,3a,4,5,6-
hexahydro-2-benzofuran-1-one (5m)
Use of 5h′. Cs2CO3 (115 mg, 0.36 mmol) was tipped into a pure form, and the crude less polar isomer 7a′ (containing
stirred and cooled (−15 °C) solution of 5h′ (38 mg, some 2.1) was acetylated and then purified.
0.034 mmol) in dry THF (2 mL), and stirring at −15 °C was
The more polar alcohol 7a had: FTIR νmax (CDCl3, cast)/
continued for 2 h. The mixture was quenched with saturated cm−1 3457, 3073, 3058, 2951, 2923, 2868, 1763, 1582, 1477,
aqueous NH4Cl (2 mL) and extracted with EtOAc (20 mL). The 1455, 1438; 1H NMR (500 MHz, CDCl3) δ 7.63–7.61 (m, 2 H),
combined organic extracts were washed with water and brine, 7.47–7.39 (m, 5 H), 7.34–7.27 (m, 8 H), 5.67 (d, J = 5.9 Hz, 1 H),
dried (Na2SO4) and evaporated. Flash chromatography of the 4.38 (t, J = 6.5 Hz, 1 H), 3.64 (dd, J = 10.4, 0.2 Hz, 1 H), 3.58 (td,
residue over silica gel (1 × 15 cm), using 50% EtOAc–hexane, J = 10.7, 4.1 Hz, 1 H), 2.88 (dd, J = 14.5, 6.4 Hz, 1 H), 2.51 (dtd,
gave 5m (30 mg, 91%).
Use of 5f. Cs2CO3 (91.5 mg, 0.28 mmol) was added to a H), 1.85–1.75 (m, 2 H), 1.70–1.65 (m, 2 H), 1.60–1.51 (m, 2 H),
stirred and cooled (0 °C) solution of 5f (30 mg, 0.056 mmol) in 1.44–1.36 (m, 1 H), 1.30–1.19 (m, 2 H), 1.06–0.79 (m, 12 H); 13
J = 14.0, 7.0, 2.7 Hz, 1 H), 2.20–2.11 (m, 2 H), 1.99–1.90 (m, 2
C
THF (2 mL). The ice bath was left in place but not recharged NMR (125 MHz, CDCl3) δ 176.9 (s), 137.9 (d), 134.17 (s), 134.14
and stirring was continued for 2 h. The mixture was quenched (s), 132.80 (d), 132.77 (d), 129.8 (d), 129.00 (d), 128.9 (d), 128.9
with saturated aqueous NH4Cl (2 mL) and extracted with (d), 127.8 (d), 125.6 (s), 97.8 (d), 77.3 (d), 71.5 (d), 58.4 (d), 50.2
EtOAc (20 mL). The combined organic extracts were washed (q), 47.8 (t), 39.5 (t), 35.4 (t), 35.0 (t), 34.4 (t), 31.4 (s), 30.1 (t),
with water and brine, dried (Na2SO4) and evaporated. Flash 25.0 (d), 23.9 (t), 22.7 (t), 22.3 (q), 21.1 (q), 15.5 (q); exact mass
chromatography of the residue over silica gel (1 × 15 cm), (electrospray) m/z calcd for C37H46NaO4S278Se (M
using 50% EtOAc–hexane, gave 5m (23 mg, 88%): FTIR νmax 719.1911, found 719.1901.
(CDCl3, cast)/cm−1 3067, 3021, 2958, 2930, 2871, 1760, 1690,
+ Na)
1
(5R)-3-[5,5-Bis(benzenesulfonyl)-1-hydroxypentyl]-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2,5-
dihydrofuran-2-one (7b)
1583, 1477, 1467, 1448; H NMR (500 MHz, CDCl3) δ 8.04 (d,
J = 7.6 Hz, 2 H), 7.89 (d, J = 7.7 Hz, 2 H), 7.76 (t, J = 7.5 Hz,
1 H), 7.71 (t, J = 7.5 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 2 H), 7.56 (t, J =
7.9 Hz, 2 H), 6.75 (q, J = 3.3 Hz, 1 H), 4.93 (t, J = 8.3 Hz, 1 H),
Use of 7a. MCPBA (70%, 232 mg, 0.94 mmol) was added to
3.61 (dq, J = 6.3, 3.1 Hz, 1 H), 2.49–2.35 (m, 4 H), 2.30–2.24 (m, a stirred and cooled (0 °C) solution of 7a (33 mg, 0.047 mmol)
1 H), 1.68–1.60 (m, 1 H), 1.54–1.45 (m, 1 H), 1.44–1.25 (m, 3 in CH2Cl2 (3 mL). The ice bath was left in place but not
H), 0.90 (t, J = 7.2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 167.3 recharged and stirring was continued for 12 h. The reaction
(s), 138.4 (s), 136.6 (s), 136.0 (d), 135.3 (d), 135.0 (d), 131.7 (d), mixture was quenched with a mixture of saturated aqueous
130.7 (d), 129.1 (d), 128.9 (d), 126.2 (s), 89.7 (s), 79.9 (d), 43.6 NaHCO3 (2 mL) and saturated aqueous Na2S2O3 (2 mL), and
(d), 35.8 (t), 27.8 (t), 27.3 (t), 24.4 (t), 22.0 (t), 13.9 (q); exact extracted with CH2Cl2 (2 × 10 mL). The combined organic
mass (electrospray) m/z calcd for C24H26NaO6S2 (M + Na) extracts were washed with water and brine, dried (Na2SO4) and
497.1063, found 497.1058.
evaporated. Flash chromatography of the residue over silica gel
(1 × 15 cm), using 50% EtOAc–hexane, gave 7b (25.0 mg, 88%)
as a colorless oil: FTIR νmax (CDCl3, cast)/cm−1 3518, 3097,
2956, 2925, 2870, 1760, 1584, 1448; 1H NMR (500 MHz, CDCl3)
δ 7.95 (d, J = 7.5 Hz, 4 H), 7.70 (t, J = 7.4 Hz, 2 H), 7.58 (t, J =
(5R)-3-[1-Hydroxy-5,5-bis(phenylsulfanyl)pentyl]-5-{[(1R,2S,5R)-
5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-3-(phenylselanyl)-
oxolan-2-one (7a, 7a′)
A solution of LDA was prepared as follows: BuLi (2.5 M in 7.8 Hz, 4 H), 6.90 (t, J = 1.2 Hz, 1 H), 6.00 (s, 1 H), 4.47–4.44
hexanes, 0.15 mL, 0.38 mmol) was added to a stirred and (m, 2 H), 3.64 (td, J = 10.7, 4.3 Hz, 1 H), 2.61 (br s, 1 H), 2.23
cooled (−78 °C) solution of i-Pr2NH (0.06 mL, 0.42 mmol) in (q, J = 6.6 Hz, 2 H), 2.14–2.08 (m, 2 H), 1.85–1.72 (m, 3 H),
THF (2 mL), and stirring was continued for 30 min at −78 °C. 1.69–1.60 (m, 3 H), 1.45–1.37 (m, 1 H), 1.28–1.23 (m, 1 H),
This LDA solution was then taken up into a syringe and added 1.06–0.78 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 170.5 (s),
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143.2 (d), 139.5 (s), 137.8 (s), 137.7 (s), 134.6 (d), 129.6 (d), 9.7, 2.7 Hz, 1 H), 4.31 (t, J = 6.8 Hz, 1 H), 3.52 (td, J = 10.7,
129.6 (d), 129.2 (d), 99.3 (d), 83.2 (d), 79.4 (d), 66.1 (d), 47.7 4.2 Hz, 1 H), 2.67 (dd, J = 15.3, 6.5 Hz, 1 H), 2.32–2.25 (m,
(d), 40.4 (t), 34.2 (t), 34.1 (t), 31.5 (d), 25.3 (d), 25.1 (t), 23.7 (t), 1 H), 2.14–2.03 (m, 5 H), 1.89–1.76 (m, 2 H), 1.69–1.56 (m,
23.1 (t), 22.2 (q), 20.9 (q), 15.8 (q); exact mass (electrospray) 6 H), 1.40–1.34 (m, 1 H), 1.26–1.19 (m, 1 H), 1.04–0.78 (m, 12
m/z calcd for C31H40NaO8S2 (M
627.2049.
+
Na) 627.2057, found H); 13C NMR (125 MHz, CDCl3) δ 173.4 (s), 170.2 (s), 138.2 (d),
134.1 (s), 134.2 (s), 132.8 (d), 132.8 (d), 129.8 (d), 129.0 (d),
128.9 (d), 128.9 (d), 127.7 (d), 127.7 (d), 126.3 (s), 97.8 (d), 77.5
5,5-Bis(benzenesulfonyl)-1-[(5R)-5-{[(1R,2S,5R)-5-methyl-2-
(propan-2-yl)cyclohexyl]oxy}-2-oxo-2,5-dihydrofuran-3-yl]pentyl
acetate (7c)
(d), 74.6 (d), 58.1 (d), 51.1 (s), 47.7 (d), 39.5 (t), 38.0 (t), 35.6 (t),
34.3 (t), 31.4 (q), 30.4 (t), 24.9 (d), 23.6 (t), 22.8 (t), 22.3 (d),
21.1 (q), 20.9 (q), 15.6 (q); exact mass (electrospray) m/z calcd
DMAP (1.3 mg, 0.01 mmol) was added to a stirred solution of for C39H48NaO5S280Se (M + Na) 761.2018, found 761.2016.
crude 7b (65 mg, 0.107 mmol) in CH2Cl2 (3 mL). The mixture
was then cooled to 0 °C, and AcCl (0.038 mL, 0.53 mmol) and
pyridine (0.069 mL, 0.72 mmol) were added sequentially. The
ice bath was left in place but not recharged and stirring was
5,5-Bis(benzenesulfonyl)-1-[(5R)-5-{[(1R,2S,5R)-5-methyl-2-
(propan-2-yl)cyclohexyl]oxy}-2-oxo-2,5-dihydrofuran-3-yl]pentyl
acetate (7e′)
continued for 3 h, during which time the cold bath reached MCPBA (70%, 266 mg, 1.08 mmol) was added to a stirred and
room temperature. The reaction mixture was quenched with cooled (0 °C) solution of 7d′ (40 mg, 0.054 mmol) in CH2Cl2
saturated aqueous CuSO4 (2 mL) and water (5 mL), and (3 mL). The ice bath was left in place but not recharged and
extracted with CH2Cl2 (2 × 20 mL). The combined organic stirring was continued for 12 h. The mixture was quenched
extracts were washed with brine, dried (MgSO4) and evapor- with a mixture of saturated aqueous NaHCO3 (2 mL) and satu-
ated. Flash chromatography of the residue over silica gel (1 × rated aqueous Na2S2O3 (2 mL), and extracted with CH2Cl2. The
15 cm), using 50% EtOAc–hexane, gave 7c (64.6 mg, 93%) as a combined organic extracts were washed with water and brine,
colorless foam: FTIR νmax (CDCl3, cast)/cm−1 3067, 2955, 2926, dried (Na2SO4) and evaporated. Flash chromatography of the
1
2870, 1766, 1584, 1448; H NMR (500 MHz, CDCl3) δ 7.95–7.93 residue over silica gel (1 × 15 cm), using 40% EtOAc–hexane,
(m, 4 H), 7.70 (td, J = 7.5, 0.5 Hz, 2 H), 7.60–7.56 (m, 4 H), 6.86 gave 7e′ (28.9 mg, 83%) as a colorless foam: FTIR νmax (CDCl3,
1
(t, J = 1.4 Hz, 1 H), 5.97 (t, J = 1.3 Hz, 1 H), 5.51–5.49 (m, 1 H), cast)/cm−1 3096, 3067, 2955, 2926, 2870, 1766, 1584, 1448; H
4.39 (t, J = 5.7 Hz, 1 H), 3.63 (td, J = 10.7, 4.3 Hz, 1 H), NMR (500 MHz, CDCl3) δ 7.94–7.92 (m, 4 H), 7.70 (tq, J = 7.5,
2.21–2.16 (m, 2 H), 2.14–2.09 (m, 5 H), 1.88–1.81 (m, 1 H), 1.6 Hz, 2 H), 7.60–7.56 (m, 4 H), 6.92 (t, J = 1.3 Hz, 1 H), 6.01
1.77–1.63 (m, 5 H), 1.44–1.36 (m, 1 H), 1.28–1.21 (m, 1 H), (s, 1 H), 5.60–5.58 (m, 1 H), 4.40 (t, J = 5.7 Hz, 1 H), 3.62 (td, J
1.06–0.79 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 169.7 (s), = 10.7, 4.2 Hz, 1 H), 2.25–2.08 (m, 7 H), 1.87–1.75 (m, 2 H),
168.8 (s), 144.3 (d), 137.8 (s), 137.7 (s), 136.6 (s), 134.6 (d), 1.69–1.62 (m, 4 H), 1.44–1.36 (m, 1 H), 1.27–1.22 (m, 1 H),
129.6 (d), 129.2 (d), 98.9 (d), 83.1 (d), 79.5 (d), 67.8 (d), 47.7 1.06–0.78 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 169.7 (s),
(d), 40.5 (t), 34.2 (t), 31.8 (t), 31.5 (d), 25.3 (d), 25.1 (t), 23.4 (t), 168.9 (s), 144.9 (d), 137.8 (s), 137.7 (s), 136.3 (d), 134.6 (d),
23.1 (t), 22.2 (d), 20.9 (q), 20.8 (q), 15.8 (q); exact mass (electro- 129.6 (d), 129.2 (d), 99.0 (d), 83.0 (d), 79.2 (d), 67.9 (d), 47.7
spray) m/z calcd for C33H42NaO9S2 (M + Na) 669.2162, found (d), 40.5 (t), 34.2 (t), 31.5 (q), 31.4 (t), 25.2 (d), 25.1 (t), 23.1 (t),
669.2154.
23.1 (t), 22.2 (d), 20.9 (q), 20.9 (q), 15.7 (q); exact mass (electro-
spray) m/z calcd for C33H42NaO9S2 (M + Na) 669.2162, found
669.2153.
5,5-Bis(benzenesulfonyl)-1-[(5R)-5-{[(1R,2S,5R)-5-methyl-2-
(propan-2-yl)cyclohexyl]oxy}-2-oxo-3-(phenylselanyl)oxolan-3-
yl]pentyl acetate (7d′)
(3R,3aR)-4,4-Bis(benzenesulfonyl)-3-{[(1R,2S,5R)-5-methyl-2-
(propan-2-yl)cyclohexyl]oxy}-1H,3H,3aH,4H,5H,6H,7H-
cyclohepta[c]furan-1-one (7f)
Use of 7a′. DMAP (1.4 mg, 0.01 mmol) was added to a
stirred solution of 7a′ (40 mg, 0.057 mmol) in CH2Cl2 (3 mL).
The mixture was then cooled to 0 °C, and Ac2O (0.028 mL,
Use of 7e′. Cs2CO3 (55 mg, 0.17 mmol) was added to a
0.29 mmol) and Et3N (0.048 mL, 0.343 mmol) were added stirred and cooled (0 °C) solution of 7e′ (22 mg, 0.034 mmol)
sequentially. The ice bath was left in place but not recharged in THF (2 mL). The ice bath was left in place but not recharged
and stirring was continued for 3 h, during which time the cold and stirring was continued for 2 h. The mixture was quenched
bath reached room temperature. The reaction mixture was with saturated aqueous NH4Cl (2 mL) and extracted with
quenched with saturated aqueous NH4Cl (2 mL) and water EtOAc (20 mL). The combined organic extracts were washed
(5 mL), and extracted with CH2Cl2 (2 × 20 mL). The combined with water and brine, dried (Na2SO4) and evaporated. Flash
organic extracts were washed with brine, dried (MgSO4) and chromatography of the residue over silica gel (1 × 15 cm),
evaporated. Flash chromatography of the residue over silica gel using 50% EtOAc–hexane, gave 7f (17.9 mg, 90%).
(1 × 15 cm), using 30% Et2O–hexane, gave 7d′ (35.4 mg, 84%)
Use of 7c. Cs2CO3 (121 mg, 0.37 mmol) was added to a
as a colorless oil: FTIR νmax (CDCl3, cast)/cm−1 3058, 2952, stirred and cooled (0 °C) solution of 7c (48 mg, 0.074 mmol) in
2924, 2868, 1766, 1746, 1582, 1477, 1455, 1438; 1H NMR THF (4 mL). The ice bath was left in place but not recharged
(500 MHz, CDCl3) δ 7.66–7.64 (m, 2 H), 7.44–7.40 (m, 5 H), and stirring was continued for 2 h. The mixture was quenched
7.35–7.27 (m, 8 H), 5.60 (dd, J = 6.5, 2.6 Hz, 1 H), 5.22 (dd, J = with saturated aqueous NH4Cl (2 mL) and extracted with
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EtOAc (20 mL). The combined organic extracts were washed (3 mL). The ice bath was left in place but not recharged and
with water and brine, dried (Na2SO4) and evaporated. Flash stirring was continued for 12 h. The reaction mixture was
chromatography of the residue over silica gel (1 × 15 cm), quenched with a mixture of saturated aqueous NaHCO3 (2 mL)
using 50% EtOAc–hexane, gave 7f (38 mg, 88%): FTIR νmax and saturated aqueous Na2S2O3 (2 mL), and extracted with
(CDCl3, cast)/cm−1 3066, 2955, 2927, 2870, 1766, 1682, 1583, CH2Cl2. The combined organic extracts were washed with
1
1448; H NMR (500 MHz, CDCl3) δ 8.16 (dd, J = 8.4, 1.0 Hz, 2 water and brine, dried (Na2SO4) and evaporated. Flash chrom-
H), 7.98–7.97 (m, 2 H), 7.76–7.69 (m, 2 H), 7.60 (dt, J = 11.4, atography of the residue over silica gel (1 × 15 cm), using 60%
7.9 Hz, 4 H), 6.78 (br signal including d, J = 1.3 Hz, 2 H), 3.88 Et2O–hexane, gave 8b (50 mg, 96%) as a colorless oil: FTIR
(t, J = 1.7 Hz, 1 H), 3.74 (td, J = 10.7, 4.1 Hz, 1 H), 2.45–2.32 (m, νmax (CDCl3, cast)/cm−1 3497, 3065, 2955, 2925, 2870, 1757,
1
1 H), 2.26–2.16 (m, 3 H), 2.13–2.07 (m, 1 H), 1.71–1.65 (m, 2 1584, 1491, 1479, 1448; H NMR (500 MHz, CDCl3) δ 7.88–7.86
H), 1.45–1.37 (m, 1 H), 1.34–1.16 (m, 3 H), 1.09–0.82 (m, 12 H), (m, 2 H), 7.75–7.73 (m, 2 H), 7.67–7.64 (m, 1 H), 7.61–7.57 (m,
0.56–0.47 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 168.8 (s), 1 H), 7.53–7.50 (m, 2 H), 7.45–7.42 (m, 2 H), 7.27–7.17 (m, 4
138.3 (d), 137.5 (s), 136.2 (s), 135.2 (d), 134.8 (d), 132.0 (d), H), 7.07 (t, J = 1.5 Hz, 1 H), 6.05 (t, J = 1.4 Hz, 1 H), 5.89 (t, J =
131.1 (d), 129.7 (d), 128.6 (d), 125.8 (s), 96.9 (d), 91.1 (s), 76.6 1.7 Hz, 1 H), 5.40 (dd, J = 7.9, 4.2 Hz, 1 H), 3.87–3.74 (m, 2 H),
(d), 48.2 (d), 46.3 (d), 39.0 (t), 34.4 (t), 31.8 (t), 31.5 (t), 31.5 (d), 3.64 (td, J = 10.7, 4.2 Hz, 1 H), 3.08 (d, J = 3.8 Hz, 1 H),
25.5 (d), 23.3 (t), 22.3 (q), 21.0 (q), 18.4 (t), 15.8 (q); exact mass 2.14–2.03 (m, 2 H), 1.70–1.64 (m, 2 H), 1.42–1.35 (m, 1 H),
(electrospray) m/z calcd for C31H38NaO7S2 (M + Na) 609.1951, 1.30–1.24 (m, 1 H), 1.05–0.76 (m, 12 H); 13C NMR (125 MHz,
found 609.1942.
CDCl3) δ 169.9 (s), 143.9 (d), 1396 (s), 138.6 (s), 138.2 (s), 137.7
(s), 134.6 (d), 134.3 (d), 134.1 (s), 131.3 (d), 129.6 (d), 129.1 (d),
129.1 (d), 128.9 (d), 128.7 (d), 128.2 (d), 127.9 (d), 99.5 (d), 84.4
(d), 79.4 (d), 65.7 (d), 47.7 (d), 40.4 (t), 34.2 (t), 31.5 (d), 28.2 (t),
25.6 (d), 23.4 (t), 22.2 (q), 20.8 (q), 16.1 (q); exact mass (electro-
(5R)-3-[(S)-{2-[2,2-Bis(phenylsulfanyl)ethyl]phenyl}(hydroxy)-
methyl]-5-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-
2,5-dihydrofuran-2-one (8a)
BuLi (2.5 M in hexane, 0.941 mL, 0.255 mmol) was added spray) m/z calcd for C35H40NaO8S2 (M + Na) 675.2057, found
dropwise to a stirred and cooled (−20 °C) solution of PhSeSePh 675.2049.
(721 mg, 2.312 mmol) in THF (4 mL). After 10 min, the
mixture was cooled to −45 °C, a mixture of 1.1 (275.0 mg,
1.156 mmol) and 8 (289 mg, 0.8257 mmol) in THF (9 mL) was
added dropwise, and stirring was continued for 8 h at −45 °C.
(S)-{2-[2,2-Bis(benzenesulfonyl)ethyl]phenyl}[(5R)-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-2,5-
dihydrofuran-3-yl]methyl acetate (8c)
Then BnBr (0.28 mL, 2.312 mmol) and Bu4NI (30.4 mg, DMAP (1.8 mg, 0.015 mmol) was added to a stirred solution of
0.0825 mmol) were added and stirring was continued for 8b (50 mg, 0.09 mmol) in CH2Cl2 (2 mL). The mixture was
another 8 h at −45 °C to −20 °C. The mixture was quenched then cooled to 0 °C, and AcCl (0.033 mL, 0.46 mmol) and pyri-
with saturated aqueous NH4Cl (3 mL) and extracted with Et2O. dine (0.049 mL, 0.61 mmol) were added sequentially. The ice
The combined organic extracts were washed with brine, dried bath was left in place but not recharged and stirring was con-
(MgSO4) and evaporated. Flash chromatography of the residue tinued for 3 h, during which time the cold bath reached room
over silica gel (2 × 15 cm), using 2 : 3 Et2O–hexanes, gave 8a temperature. The reaction mixture was quenched with satu-
[(223 mg, 46%, or 71% corrected for recovered 1.1 (85 mg)] as rated aqueous CuSO4 (2 mL) and water (5 mL), and extracted
an oil: FTIR νmax (CDCl3, cast)/cm−1 3439, 3059, 2955, 2925, with CH2Cl2 (2 × 10 mL). The combined organic extracts were
2897, 1765, 1582, 1480, 1450, 1439; 1H NMR (500 MHz, CDCl3) washed with brine, dried (MgSO4) and evaporated. Flash
δ 7.44–7.25 (m, 14 H), 6.70 (t, J = 1.4 Hz, 1 H), 5.99 (s, 1 H), chromatography of the residue over silica gel (1 × 15 cm),
5.51 (s, 1 H), 4.62 (dd, J = 7.8, 6.7 Hz, 1 H), 3.65 (td, J = 10.7, using 60% Et2O–hexane, gave 8c (49 mg, 93%) as a colorless
4.3 Hz, 1 H), 3.35–3.26 (m, 2 H), 2.98 (s, 1 H), 2.13–2.09 (m, 2 foam: FTIR νmax (CDCl3, cast)/cm−1 3065, 2955, 2926, 2870,
H), 1.72–1.65 (m, 2 H), 1.44–1.39 (m, 1 H), 1.31–1.24 (m, 1 H), 1764, 1585, 1493, 1480, 1448; 1H NMR (500 MHz, CDCl3)
1.09–0.81 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 170.1 (s), δ 7.96–7.89 (m, 3 H), 7.61–7.58 (m, 2 H), 7.49–7.46 (m, 4 H),
144.2 (d), 139.4 (s), 137.9 (s), 135.7 (s), 134.0 (s), 133.9 (s), 7.42 (dd, J = 7.6, 1.1 Hz, 1 H), 7.28–7.18 (m, 3 H), 7.13 (t, J =
133.3 (d), 132.9 (d), 131.5 (d), 130.9 (d), 129.0 (d), 129.0 (d), 1.4 Hz, 1 H), 6.82 (t, J = 1.7 Hz, 1 H), 6.21 (t, J = 5.8 Hz, 1 H),
128.4 (d), 128.1 (d), 128.0 (d), 127.9 (d), 127.5 (d), 99.2 (d), 79.3 6.03 (t, J = 1.4 Hz, 1 H), 4.05 (dd, J = 15.8, 5.7 Hz, 1 H), 3.88
(d), 65.6 (d), 60.2 (d), 47.7 (d), 40.4 (t), 39.2 (t), 34.2 (t), 31.5 (d), (dd, J = 15.8, 5.9 Hz, 1 H), 3.63 (td, J = 10.6, 4.3 Hz, 1 H),
25.5 (d), 23.3 (s), 22.2 (q), 20.8 (q), 15.9 (q); exact mass (electro- 2.13–2.03 (m, 5 H), 1.69–1.64 (m, 2 H), 1.42–1.36 (m, 1 H),
spray) m/z calcd for C35H40NaO4S2 (M + Na) 611.2260, found 1.32–1.20 (m, 2 H), 1.03–0.76 (m, 12 H); 13C NMR (125 MHz,
611.2258.
CDCl3) δ 169.4 (s), 168.6 (s), 144.4 (d), 138.3 (s), 138.1 (s), 137.1
(s), 135.2 (s), 134.3 (s), 134.1 (d), 134.1 (d), 133.4 (d), 128.7 (d),
128.7 (d), 128.6 (d), 128.2 (d), 127.6 (d), 99.2 (d), 81.6 (d), 79.4
(d), 67.2 (d), 47.7 (d), 40.5 (t), 34.2 (t), 31.5 (d), 28.7 (t), 25.4 (d),
23.3 (t), 22.2 (d), 20.9 (q), 20.8 (q), 15.9 (q); exact mass (electro-
(5R)-3-[(S)-{2-[2,2-Bis(benzenesulfonyl)ethyl]phenyl}(hydroxy)-
methyl]-5-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-
2,5-dihydrofuran-2-one (8b)
MCPBA (70%, 197 mg, 0.79 mmol) was added to a stirred and spray) m/z calcd for C37H42NaO9S2 (M + Na) 717.2162, found
cooled (0 °C) solution of 8a (47 mg, 0.079 mmol) in CH2Cl2 717.2150.
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(6R,7R)-8,8-Bis(benzenesulfonyl)-6-{[(1R,2S,5R)-5-methyl-2-
(propan-2-yl)cyclohexyloxy}-5-oxatricyclo[8.4.0.03,7]tetradeca-1-
(14),2,10,12-tetraen-4-one (8d)
131.2 (s), 129.1 (d), 129.1 (d), 128.2 (CCCF, 3JCF = 7.1 Hz), 115.4
(CCF, 2JCF = 21.3 Hz), 114.1 (CCF, 2JCF = 22.5 Hz), 99.2 (d), 79.4
(d), 65.2 (d), 60.4 (d), 47.7 (d), 40.3 (t), 38.5 (t), 34.2 (t), 31.5 (d),
25.5 (d), 23.3 (t), 22.2 (q), 20.8 (q), 15.9 (q); exact mass (electro-
spray) m/z calcd for C35H39FNaO4S2 (M + Na) 629.2166, found
629.2163.
Cs2CO3 (56.3 mg, 0.17 mmol) was added to a stirred and
cooled (0 °C) solution of 8c (26 mg, 0.035 mmol) in THF
(1.5 mL). The ice bath was left in place but not recharged and
stirring was continued for 1 h, by which time the temperature
had reached 5 °C. The mixture was quenched with saturated
aqueous NH4Cl (2 mL) and extracted with EtOAc (20 mL). The
combined organic extracts were washed with water and brine,
dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (1 × 15 cm), using 60% Et2O–hexane,
gave 8d (21 mg, 95%) whose 1H NMR spectrum indicted the
presence of ca. 2% of an impurity: FTIR νmax (CDCl3, cast)/
(S)-{2-[2,2-Bis(phenylsulfanyl)ethyl]-5-fluorophenyl}[(5R)-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-2,5-
dihydrofuran-3-yl]methyl acetate (9b)
DMAP (5.5 mg, 0.045 mmol) was added to a stirred solution of
9a (274 mg, 0.45 mmol) in CH2Cl2 (5 mL). The mixture was
then cooled to 0 °C, and AcCl (0.19 mL, 2.71 mmol) and pyri-
dine (0.29 mL, 3.61 mmol) were added sequentially. The ice
bath was left in place but not recharged and stirring was con-
tinued for 3 h, during which time the cold bath reached room
temperature. The reaction mixture was quenched with satu-
rated aqueous CuSO4 (5 mL) and water (5 mL), and extracted
with CH2Cl2 (2 × 20 mL). The combined organic extracts were
washed with brine, dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (1 × 15 cm),
using 40% Et2O–hexane, gave 9b (292 mg, 99%) as a colorless
foam: FTIR νmax (CDCl3, cast)/cm−1 3060, 2956, 2925, 2870,
1
cm−1 3065, 2955, 2926, 2869, 1769, 1660, 1583, 1478, 1448; H
NMR (500 MHz, CDCl3) δ 8.17–8.08 (m, 3 H), 7.76 (tt, J = 7.5,
1.4 Hz, 1 H), 7.70–7.53 (m, 6 H), 7.33–7.26 (m, 2 H), 7.10 (td,
J = 7.4, 1.6 Hz, 1 H), 6.98–6.95 (m, 1 H), 6.54 (d, J = 1.1 Hz,
1 H), 3.68–3.62 (m, 2 H), 3.53 (d, J = 14.9 Hz, 1 H), 3.05 (d, J =
14.9 Hz, 1 H), 2.05–1.96 (m, 2 H), 1.67–1.61 (m, 3 H), 1.35–1.28
(m, 1 H), 1.18–1.12 (m, 1 H), 1.05–0.72 (m, 11 H), 0.52 (q, J =
11.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 168.6 (s), 137.5 (s),
137.2 (s), 136.8 (d), 135.7 (s), 135.1 (d), 134.9 (d), 133.7 (s),
133.1 (d), 132.2 (d), 132.1 (d), 130.2 (d), 129.2 (d), 129.1 (d),
128.8 (s), 128.7 (d), 127.8 (d), 102.8 (s), 96.6 (d), 76.1 (d), 48.8
(d), 47.7 (d), 38.4 (t), 37.7 (t), 34.4 (t), 31.3 (d), 25.3 (d), 23.1 (t),
22.3 (q), 20.9 (q), 15.7 (q); exact mass (electrospray) m/z calcd
for C35H38NaO7S2 (M + Na) 657.1951, found 657.1949.
1
1774, 1612, 1592, 1500, 1479, 1456, 1439; H NMR (500 MHz,
CDCl3) δ 7.47–7.45 (m, 2 H), 7.39–7.37 (m, 2 H), 7.29–7.23 (m,
7 H), 7.02–6.94 (m, 2 H), 6.65 (t, J = 1.4 Hz, 1 H), 6.42 (d, J =
1.2 Hz, 1 H), 5.95 (t, J = 1.1 Hz, 1 H), 4.88 (t, J = 7.3 Hz, 1 H),
3.60 (td, J = 10.7, 4.2 Hz, 1 H), 3.27 (d, J = 7.4 Hz, 2 H),
2.11–2.03 (m, 5 H), 1.69–1.63 (m, 2 H), 1.41–1.36 (m, 1 H),
1.26–1.20 (m, 1 H), 1.04–0.77 (m, 12 H); 13C NMR (125 MHz,
(4R)-2-[(S)-{2-[2,2-Bis(phenylsulfanyl)ethyl]-5-fluorophenyl}-
(hydroxy)methyl]-4-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)-
cyclohexyl]oxy}cyclopent-2-en-1-one (9a)
BuLi (2.5 M in hexane, 0.17 mL, 0.42 mmol) was added drop- 128.9 (d), 128.0 (d), 127.7 (d), 115.7 (CCF, 2JCF = 21.1 Hz), 114.5
1
CDCl3) δ 169.0 (s), 167.9 (s), 162.0 (CF, JCF = 246.6 Hz), 145.9
(d), 137.0 (s), 137.0 (s), 136.5 (s), 134.0 (s), 133.8 (d), 133.7 (d),
133.7 (s), 133.4 (d), 132.7 (d), 131.9 (s), 131.9 (s), 129.0 (d),
2
wise to a stirred and cooled (−20 °C) solution of PhSeSePh (CCF, JCF = 22.7 Hz), 98.6 (d), 79.4 (d), 66.0 (d), 58.0 (d), 47.7
(130.6 mg, 0.42 mmol) in THF (6 mL). After 10 min, the (d), 40.4 (t), 38.7 (t), 34.2 (t), 31.5 (q), 25.4 (d), 23.3 (t), 22.2 (d),
mixture was cooled to −60 °C and a mixture of 1.1 (166 mg, 20.8 (q), 20.8 (q), 15.9 (q); exact mass (electrospray) m/z calcd
0.697 mmol) and 9 (385 mg, 1.05 mmol) in THF (6 mL) was for C37H41FNaO5S2 (M + Na) 671.2272, found 671.2261.
added dropwise. Stirring was continued for 8 h, during which
(S)-{2-[2,2-Bis(benzenesulfonyl)ethyl]-5-fluorophenyl}[(5R)-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-2,5-
dihydrofuran-3-yl]methyl acetate (9c)
time the temperature of the cold bath rose to −20 °C. The reac-
tion mixture was then quenched with saturated aqueous
NH4Cl (3 mL) and extracted with Et2O. The combined organic
extracts were washed with brine, dried (MgSO4) and evapor- MCPBA (70%, 1.37 g, 5.54 mmol) was added to a stirred and
ated. Flash chromatography of the residue over silica gel (2 × cooled (0 °C) solution of 9b (360 mg, 0.55 mmol) in CH2Cl2
15 cm), using 30% Et2O–hexanes, gave 9a (371 mg, 88%) as an (8 mL). The ice bath was left in place but not recharged and
oil: FTIR νmax (CDCl3, cast)/cm−1 3460, 3060, 2955, 2925, 2870, stirring was continued for 7 h. The reaction mixture was
1
1766, 1612, 1590, 1497, 1479, 1455, 1439; H NMR (500 MHz, quenched with a mixture of saturated aqueous NaHCO3 (2 mL)
CDCl3) δ 7.45–7.43 (m, 2 H), 7.37–7.20 m, 9 H), 7.10 (dd, J = and saturated aqueous Na2S2O3 (2 mL), and extracted with
9.8, 2.7 Hz, 1 H), 6.97 (td, J = 8.2, 2.7 Hz, 1 H), 6.66 (s, 1 H), CH2Cl2. The combined organic extracts were washed with
6.00 (s, 1 H), 5.43 (s, 1 H), 4.53 (t, J = 7.2 Hz, 1 H), 3.66 (td, J = water and brine, dried (Na2SO4) and evaporated. Flash chrom-
10.7, 4.2 Hz, 1 H), 3.24 (dd, J = 7.0, 5.0 Hz, 2 H), 3.08 (d, J = atography of the residue over silica gel (2 × 15 cm), using 60%
2.8 Hz, 1 H), 2.14–2.07 (m, 2 H), 1.70 (dq, J = 10.0, 3.5 Hz, Et2O–hexane, gave 9c (383 mg, 96%) as a solid: FTIR νmax
2 H), 1.45–1.40 (m, 1 H), 1.32–1.26 (m, 1 H), 1.06–0.79 (m, 12 (CDCl3, cast)/cm−1 3066, 2956, 2927, 2871, 1764, 1613, 1593,
1
1
H); 13C NMR (125 MHz, CDCl3) δ 170.0 (s), 162.1 (CF, JCF
=
1502, 1479, 1448; H NMR (500 MHz, CDCl3) δ 7.95–7.91 (m, 4
246.6 Hz), 144.4 (d), 140.2 (s), 140.1 (s), 138.9 (s), 133.9 (s), H), 7.62 (td, J = 7.5, 0.9 Hz, 2 H), 7.52–7.48 (m, 4 H), 7.43 (dd,
133.8 (s), 133.3 (d), 133.2 (d), 133.1 (d), 133.0 (d), 131.3 (s), J = 8.6, 5.7 Hz, 1 H), 7.18 (t, J = 1.4 Hz, 1 H), 6.98–6.90
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(m, 2 H), 6.81 (d, J = 1.5 Hz, 1 H), 6.19 (t, J = 5.7 Hz, 1 H), 6.05 7.5 Hz, 2 H), 7.97 (d, J = 7.4 Hz, 2 H), 7.75 (t, J = 7.5 Hz, 1 H),
(s, 1 H), 4.00 (dd, J = 15.9, 5.7 Hz, 1 H), 3.88 (dd, J = 15.9, 7.69 (t, J = 7.5 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 2 H), 7.57 (t, J =
5.7 Hz, 1 H), 3.64 (td, J = 10.7, 4.2 Hz, 1 H), 2.13–2.03 (m, 5 H), 7.8 Hz, 2 H), 6.91 (dd, J = 8.7, 2.5 Hz, 1 H), 6.58 (s, 1 H), 6.54
1.70–1.65 (m, 2 H), 1.42–1.37 (m, 1 H), 1.31–1.25 (m, 1 H), (td, J = 8.4, 2.6 Hz, 1 H), 6.42 (dd, J = 8.3, 5.6 Hz, 1 H), 3.75 (d,
1.07–0.77 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ 169.4 (s), J = 16.3 Hz, 1 H), 3.53 (td, J = 10.7, 4.0 Hz, 1 H), 3.38 (t, J =
1
168.6 (s), 162.3 (CF, JCF = 247.3 Hz), 144.7 (d), 138.1 (s), 138.0 13.0 Hz, 1 H), 3.31–3.25 (m, 1 H), 3.18–3.11 (m, 2 H), 3.04 (d,
(s), 137.6 (s), 137.5 (s), 136.7 (s), 135.4 (d), 135.4 (d), 134.2 (d), J = 9.2 Hz, 1 H), 2.00–1.93 (m, 2 H), 1.65–1.60 (m, 2 H),
130.3 (s), 130.3 (s), 129.8 (d), 129.7 (d), 128.8 (d), 128.8 (d), 1.34–1.21 (m, 1 H), 1.15–1.10 (m, 1 H), 0.99–0.75 (m, 11 H),
2
2
115.9 (CCF, JCF = 21.0 Hz), 114.2 (CCF, JCF = 22.7 Hz), 99.3 0.56 (q, J = 11.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 175.3
1
(d), 81.5 (d), 79.6 (d), 67.0 (d), 47.7 (d), 40.5 (t), 34.2 (t), 31.5 (s), 162.3 (CF, JCF = 248.2 Hz), 141.3 (s), 141.2 (s), 137.6 (s),
(q), 28.1 (t), 25.5 (d), 23.4 (t), 22.2 (d), 20.9 (q), 20.8 (q), 16.0 136.8 (s), 135.2 (d), 135.1 (d), 132.8 (d), 132.4 (d), 132.3 (d),
(q); exact mass (electrospray) m/z calcd for C37H41FNaO9S2 131.8 (d), 129.6 (d), 128.6 (d), 126.6 (s), 126.6 (s), 115.1 (CCF,
2
(M + Na) 735.2068, found 735.2057.
2JCF = 21.8 Hz), 113.3 (CCF, JCF = 21.2 Hz), 97.6 (d), 87.9 (s),
76.2 (d), 48.3 (d), 47.9 (d), 41.8 (d), 38.9 (t), 35.3 (t), 34.4 (t),
31.3 (d), 30.4 (t), 25.5 (d), 22.8 (t), 22.2 (q), 21.1 (q), 15.3 (q);
exact mass (electrospray) m/z calcd for C35H39FNaO7S2
(M + Na) 677.2013, found 677.2008.
(6R,7R)-8,8-Bis(benzenesulfonyl)-13-fluoro-6-{[(1R,2S,5R)-5-
methyl-2-(propan-2-yl)cyclohexyl]oxy}-5-oxatricyclo[8.4.0.03,7]-
tetradeca-1(14),2,10,12-tetraen-4-one (9g)
Cs2CO3 (876 mg, 2.69 mmol) was added to a stirred and
cooled (0 °C) solution of 9c (383 mg, 0.54 mmol) in THF
(10 mL) and stirring at 0 °C was continued for 20 min. The
(7R,8S)-6,6-Bis(benzenesulfonyl)-2-fluoro-8-(hydroxymethyl)-
6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl]methanol (9.5)
cold bath was removed and stirring was continued for 1 h. The DIBAL-H (1 M in PhMe, 1.5 mL, 1.53 mmol) was added manu-
mixture was quenched with saturated aqueous NH4Cl (2 mL) ally dropwise over 5 min. by syringe to a stirred and cooled
and extracted with CH2Cl2 (3 × 20 mL). The combined organic (0 °C) solution of 9.4 (50 mg, 0.076 mmol) in PhMe (4 mL).
extracts were washed with water and brine, dried (Na2SO4) and After the addition stirring at 0 °C was continued for 1 h. The
evaporated. Flash chromatography of the residue over silica gel cold bath was removed and stirring was continued for 8 h. The
(1 × 15 cm), using 60% Et2O–hexane, gave 9g (348 mg, 99%) as mixture was quenched with MeOH (0.052 mL, 1.52 mmol),
a solid: mp 135–137 °C; FTIR νmax (CDCl3, cast)/cm−1 3069, water (0.028 mL, 1.52 mmol) and NaF24 (64 mg, 1.52 mmol).
1
2955, 2927, 2869, 1770, 1668, 1581, 1502, 1494, 1479, 1448; H The mixture was diluted with EtOAc (20 mL), stirred vigorously
NMR (500 MHz, CDCl3) δ 8.14–8.12 (m, 2 H), 8.07–8.05 (m, 2 at room temperature for 1 h, and then filtered through a pad
H), 7.75 (tt, J = 7.5, 1.4 Hz, 1 H), 7.67 (tt, J = 7.5, 1.4 Hz, 1 H), of Celite, using Et2O as a rinse. Evaporation of the filtrate and
7.62–7.59 (m, 3 H), 7.56–7.53 (m, 2 H), 7.00–6.94 (m, 2 H), 6.79 flash chromatography of the residue over silica gel (1 × 15 cm),
(td, J = 8.3, 2.7 Hz, 1 H), 6.46 (d, J = 1.0 Hz, 1 H), 3.63–3.58 (m, using 80% EtOAc–hexane, gave 9.5 (32 mg, 82%) as an oil:
2 H), 3.45 (d, J = 15.0 Hz, 1 H), 3.04 (d, J = 15.0 Hz, 1 H), FTIR νmax (CDCl3, cast)/cm−1 3354, 3103, 3068, 2928, 1613,
1
1.98–1.92 (m, 2 H), 1.65–1.58 (m, 2 H), 1.33–1.25 (m, 1 H), 1584, 1502, 1477, 1448; H NMR (500 MHz, CDCl3) δ 8.05 (d,
1.15–1.09 (m, 1 H), 1.02–0.73 (m, 11 H), 0.44 (q, J = 11.7 Hz, 1 J = 7.7 Hz, 2 H), 7.72–7.68 (m, 3 H), 7.62 (tt, J = 7.5, 1.1 Hz,
1
H); 13C NMR (125 MHz, CDCl3) δ 168.3 (s), 161.9 (CF, JCF
=
1 H), 7.57 (t, J = 7.9 Hz, 2 H), 7.40 (t, J = 8.0 Hz, 2 H), 6.75 (dd,
249.0 Hz), 137.5 (s), 137.0 (s), 135.6 (d), 135.2 (d), 135.1 (d), J = 9.5, 2.7 Hz, 1 H), 6.60 (td, J = 8.2, 2.6 Hz, 1 H), 6.36 (s, 1 H),
134.9 (d), 134.8 (d), 132.2 (d), 132.1 (d), 130.2 (s), 129.5 (s), 4.31 (dd, J = 12.0, 4.1 Hz, 1 H), 4.23–4.18 (m, 1 H), 3.89 (d, J =
2
129.3 (d), 128.8 (d), 116.5 (CCF, JCF = 22.1 Hz), 116.1 (CCF, 16.4 Hz, 1 H), 3.74–3.69 (m, 1 H), 3.60–3.56 (m, 1 H), 3.46 (dd,
2JCF = 21.4 Hz), 102.7 (s), 96.5 (d), 76.0 (d), 48.8 (d), 47.7 (d), J = 16.6, 11.5 Hz, 1 H), 3.38–3.30 (m, 2 H), 3.19 (br s, 1 H),
38.3 (t), 37.0 (t), 34.4 (t), 31.3 (t), 25.4 (d), 23.2 (t), 22.3 (q), 20.9 2.42–2.34 (m, 3 H); 13C NMR (125 MHz, CDCl3) δ 162.0 (CF,
(q), 15.7 (q); exact mass (electrospray) m/z calcd for 1JCF = 247.3 Hz), 142.6 (s), 142.5 (s), 138.5 (s), 137.1 (s), 134.9
C35H37FNaO7S2 (M + Na) 675.1857, found 675.1854.
(d), 134.7 (d), 134.6 (d), 134.4 (d), 132.0 (d), 131.5 (d), 128.9 (d),
128.2 (d), 126.6 (s), 116.3 (CCF, 2JCF = 21.1 Hz), 112.6 (CCF, 2JCF
= 21.1 Hz), 97.8 (s), 64.9 (t), 59.4 (t), 45.7 (d), 39.5 (d), 36.2 (t),
33.2 (t); exact mass (electrospray) m/z calcd for C25H25FNaO6S2
(M + Na) 527.0969, found 527.0965.
(3S,6R,7R)-8,8-Bis(benzenesulfonyl)-13-fluoro-6-{[(1R,2S,5R)-5-
methyl-2-(propan-2-yl)cyclohexyl]oxy}-5-oxatricyclo[8.4.0.03,7]-
tetradeca-1(14),10,12-trien-4-one (9.4)
10% Pd(OH)2-charcoal (50 mg) was added to a solution of 9g
(100 mg, 0.153 mmol) in EtOAc (10 mL) and AcOH (1 mL). The
mixture was hydrogenated in a Parr apparatus (50 psi) at room
[(7R,8S)-2-Fluoro-8-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-
benzo[7]annulen-7-yl]methanol (9.6)
temperature for 36 h and then filtered through a pad of Celite, 6% Na(Hg) (300 mg) and Na2HPO4 (56 mg, 0.396 mmol) were
using EtOAc (50 mL) as a rinse. Evaporation of the filtrate and added to a stirred and cooled (0 °C) solution of 9.5 (20 mg,
flash chromatography of the residue over silica gel (1 × 15 cm), 0.039 mmol) in MeOH (5 mL), and stirring at 0 °C was conti-
using 80% EtOAc–hexane, gave 9.4 (100 mg, 100%): FTIR νmax nued for 30 min. The ice bath was removed and stirring was
(CDCl3, cast)/cm−1 3067, 2955, 2927, 2870, 1790, 1613, 1595, continued for 2 h. The mixture was quenched with water
1583, 1498, 1447; 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = (2 mL) and the MeOH was evaporated under reduced pressure.
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Organic & Biomolecular Chemistry
The residue was extracted with EtOAc (20 mL) and the com-
bined organic extracts were washed with water and brine,
dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (1 × 15 cm), using 100% EtOAc, gave 9.6
8 (a) J. C. de Jong, F. van Bolhuis and B. L. Feringa, Tetra-
hedron: Asymmetry, 1991, 2, 1247–1262; (b) O. M. Moradei
and L. A. Paquette, Org. Synth., 2003, 80, 66–74.
9 G. Grossmann and U. Séquin, Synlett, 2001, 278–280.
(7 mg, 79%) as an oil: FTIR νmax (CDCl3, cast)/cm−1 3315, 10 E.g. (a) G. C. Paddon-Jones, C. J. Moore, D. J. Brecknell,
1
2926, 2881, 1611, 1592, 1498, 1443, 1422; H NMR (500 MHz,
CDCl3) δ 7.02 (dd, J = 8.1, 5.9 Hz, 1 H), 6.82–6.76 (m, 2 H),
3.70–3.64 (m, 2 H), 3.42 (dd, J = 10.9, 4.6 Hz, 1 H), 3.31 (dd, J =
10.6, 8.6 Hz, 1 H), 2.89–2.85 (m, 2 H), 2.82–2.72 (m, 2 H),
W. A. König and W. Kitching, Tetrahedron Lett., 1997, 38,
3479–3482; (b) Y. Shimotori and T. Miyakoshi, Synth.
Commun., 2009, 39, 1570–1582; (c) A. Habel and W. Boland,
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2.33–2.29 (m, 1 H), 2.11–2.05 (m, 1 H), 1.76–1.71 (m, 1 H), 11 X.-X. Zhang and S. J. Lippard, J. Org. Chem., 2000, 65,
1.53–1.44 (m, 1 H), 1.26 (s, 1 H), 0.89–0.86 (m, 1 H); 13C NMR
5298–5305.
1
(125 MHz, CDCl3) δ 161.2 (CF, JCF = 243.5 Hz), 141.0 (CCCF, 12 B. N. Naidu, J. Banville, F. Beaulieu, T. P. Connolly,
3JCF = 7.9 Hz), 138.1 (CCCCF, 4JCF = 3.3 Hz), 130.0 (CCCF, 3JCF
=
M. R. Krystal, J. D. Matiskella, C. Ouellet, S. Plamondon,
R. Remillard, M. E. Sorenson, Y. Ueda and M. A. Walker,
US Patent 2005/0267105 A1, 2005.
8.0 Hz), 116.5 (CCF, 2JCF = 20.9 Hz), 112.6 (CCF, 2JCF = 20.5 Hz),
66.6 (t), 62.4 (t), 47.4 (d), 39.5 (d), 38.3 (t), 34.1 (t), 26.4 (t);
exact mass (electrospray) m/z calcd for C13H17FNaO2 (M + Na) 13 B. Devadas, S. J. Hartmann, R. F. Heier, K. D. Jerome,
247.1105, found 247.1102.
S. A. Kolodziej, J. P. Mathias, M. B. Norton, M. A. Promo,
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3144 | Org. Biomol. Chem., 2013, 11, 3128–3144
This journal is © The Royal Society of Chemistry 2013