Studies of the synthesis of providencin: Construction and assembly of two major subunits

Article abstract of DOI:10.1021/jo402485h

The northern sector of the cembranoid diterpene providencin containing a tetrasubstituted cyclobutane was synthesized from the bis(acetonide) of D-glucose using dicyclopentadienylzirconium(0)-mediated oxygen abstraction from a furanose. Oxidative scission of the vinyl substituent of this cyclobutane gave an aldehyde, which was reacted with an alkynylstannane to provide an allenol. Cyclization of the derived allenone with silver nitrate led to a cyclobutylfuran comprising the northern subunit of providencin. The southern sector of the cembranoid skeleton containing a trisubstituted iodoalkene attached to an a- phenylselenyl-?-lactone was synthesized from (R)-glycidol. Negishi carbometalation-iodination established the (E)-iodoalkene, and addition of the lithio dianion of phenylselenoacetic acid to a tosylate generated the substituted lactone. The two sectors were joined via stannylation of the furan of the northern component followed by Stille cross-coupling of the furylstannane with the iodoalkene of the southern subunit. Linkage of the two segments was also made at C12-C13 of providencin using intermolecular aldol condensation of the enolate from the selenyl lactone of the southern portion with an acetaldehyde appendage on the cyclobutane of the northern sector. Closure of the providencin macrocycle from these conjoined subunits was unsuccessful.

Full text of DOI:10.1021/jo402485h

Article
pubs.acs.org/joc
Studies of the Synthesis of Providencin: Construction and Assembly
of Two Major Subunits
James D. White* and Somnath Jana
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331-4003, United States
S
* Supporting Information
ABSTRACT: The “northern” sector of the cembranoid
diterpene providencin containing a tetrasubstituted cyclo-
butane was synthesized from the bis(acetonide) of D-glucose
using dicyclopentadienylzirconium(0)-mediated oxygen ab-
straction from a furanose. Oxidative scission of the vinyl
substituent of this cyclobutane gave an aldehyde, which was
reacted with an alkynylstannane to provide an allenol.
Cyclization of the derived allenone with silver nitrate led to
a cyclobutylfuran comprising the northern subunit of
providencin. The “southern” sector of the cembranoid skeleton containing a trisubstituted iodoalkene attached to an α-
phenylselenyl-γ-lactone was synthesized from (R)-glycidol. Negishi carbometalation−iodination established the (E)-iodoalkene,
and addition of the lithio dianion of phenylselenoacetic acid to a tosylate generated the substituted lactone. The two sectors were
joined via stannylation of the furan of the northern component followed by Stille cross-coupling of the furylstannane with the
iodoalkene of the southern subunit. Linkage of the two segments was also made at C12−C13 of providencin using intermolecular
aldol condensation of the enolate from the selenyl lactone of the southern portion with an acetaldehyde appendage on the
cyclobutane of the northern sector. Closure of the providencin macrocycle from these conjoined subunits was unsuccessful.
was tested in a model substrate but gave a cyclobutanol in low
yield.
INTRODUCTION
■
The gorgonian octocorals Pseudopterogorgia kallos and
Pseudopterogorgia bipinnata have proven to be rich sources of
novel diterpenes, including many that bear the structural
signature of a cembranoid origin.1 A subset of this family
comprises the furanocembranoids, exemplified by the kallolides
(e.g., 1)2 and the bipinnatins (e.g., 2),3 where the common
structural motif is a 14-membered macrocycle containing a
2,3,5-trisubstituted furan and a butenolide or epoxidized
butenolide (Figure 1). Unique among this group is providencin
(3), isolated by Rodriguez from P. kallos (Bielschowski)
collected near Old Providence Island in the southwestern
Caribbean sea.4 The gross structure and relative configuration
of providencin were secured through a combination of NMR
experiments and X-ray crystallographic analysis, which revealed
that the molecule contains a tetrasubstituted cyclobutane
embedded in a bicyclo[12.2.0]hexadecane scaffold. These
studies exposed important conformational details of the
macrocyclic ring in providencin but did not establish its
absolute configuration.
Although providencin displays only modest in vitro
bioactivity,4 its novel position within the cembranoid family
has prompted several groups to attempt its synthesis. An
intriguing approach to the cyclobutanol portion of providencin
was conceived by Pattenden on the basis of its proposed
biogenesis, in which a photochemically initiated Norrish type-II
hydrogen abstraction at C2 of bipinnatin E (2) generates
biradical 4, which then closes to 3 (Scheme 1).5 This concept
A different approach to the furanylcyclobutane substructure
of 3 based on a [2 + 2] ketene acetal cycloaddition to fumarate
has been disclosed by Wood,6 but the most extensive studies of
a providencin synthesis have been conducted by Mulzer, who
developed two methods for closing the macrocycle of 3 from a
precyclization substrate containing both a trisubstituted furan
and a modified cyclobutanol.7 These noteworthy accomplish-
ments notwithstanding, a completed synthesis of 3 has thus far
remained elusive.
RESULTS AND DISCUSSION
■
Our initial strategy for the synthesis of providencin envisioned
the formation of the macrocycle from aldehyde 5, which would
house reacting termini at C12 and C13 suitable for an
asymmetric Nozaki−Hiyama−Kishi reaction (Scheme 2).8 The
acquisition of precyclization candidate 5 was programmed from
two components, specifically, a “northern” sector 6 comprising
the furanylcyclobutane moiety of 3 with appendages at C1 of
the cyclobutane and C8 of the furan for fusion to a “southern”
segment containing a suitably functionalized butenolide. Since
the absolute configuration of providencin is unknown, an
arbitrary choice was made that would construct the
tetrasubstituted cyclobutane of 6 asymmetrically using an
Received: November 8, 2013
© XXXX American Chemical Society
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Figure 1. Cembranoid diterpenes from Pseudopterogorgia kallos and Pseudopterogorgia bipinnata.
Scheme 1. Pattenden’s Proposed Biogenesis of Providencin
grace for this approach was the discovery that the cyclo-
butanone of 12 could not be reacted with any of the
conventional methylenating agents to install the C15−C16
exomethylene unit of providencin. This last problem was
thought to be due to steric hindrance by the three substituents
surrounding the ketone of 12, but later success with
methylenation of a related cyclobutanone (vide infra) suggests
a different explanation.
The difficulties encountered with diester 12 prompted us to
revise our route to the macrocycle of 3 by relocating the point
of sector assembly to C6 of the furan in a simplified northern
subunit 13 (Scheme 5). Stille coupling with a haloalkene13
(e.g., 14) or a metal-mediated C−H activation of the furan14
was envisioned for this step. The previously programmed C12−
C13 union of the northern and southern segments would be
retained, but we now favored an aldol-type coupling of lactone
14 with aldehyde 13 for this connection.
The new route to the northern portion of 3 began at
cyclobutane 15 and set a goal that would build the disubstituted
furan of 13 from an aldehyde obtained from oxidative cleavage
of the vinyl substituent of 15. Before the oxidative scission was
attempted, however, a decision was made to replace both the p-
methoxybenzyl and tert-butyldimethylsilyl ethers of 15 with
more robust alcohol protection that could withstand the
reaction conditions planned for later stages of the synthesis,
particularly those envisioned for assembling the core structure
of 3. First, the p-methoxybenzyl ether of 15 was cleaved with
2,3-dichloro-4,5-dicyanobenzoquinone under neutral condi-
tions15 to yield primary alcohol 16, and the latter was exposed
to ethanol containing p-toluenesulfonic acid to provide diol 17
(Scheme 6). Acylation of 17 with trimethylacetyl chloride
afforded pivalate 18, and the remaining secondary alcohol was
acetylated with acetic anhydride in the presence of DMAP to
furnish diester 19. Oxidative cleavage of the vinyl group in 19
with catalytic osmium tetroxide and excess sodium periodate16
led cleanly to aldehyde 20. Treatment of 20 with known
alkynyl bromide 2117 in the presence of stannous chloride and
inexpensive material derived from the chiral pool, specifically, a
bis(acetonide) of D-glucose, 7.9
Our published sequence from 7 to the cyclobutane portion
of 610 is summarized in Scheme 3 and features oxygen
abstraction from tetrahydrofuran 8 by dicyclopentadienylzirco-
nium(0). This method was first reported by Taguchi11 and was
applied subsequently by Paquette to an enantioselective
synthesis of cyclobutanols.12 The presumed mechanism of the
transformation from 8 to cyclobutane 9 is shown in Scheme 4,
where the observed retention of configuration is rationalized in
terms of conformationally favored alkylzirconium complex 10
over the alternative complex 11.
Subsequent steps advanced 9 to furanylcyclobutanone 12, a
potential entry point to the C1−C9 segment of providencin,
but problems that emerged in the course of this sequence made
the route untenable. In particular, attempts at selective
hydrolysis or hydride reduction of the methyl and ethyl esters
in 12 resulted in no chemical differentiation of these functions,
and although continuation of the synthesis could be envisioned
with a different phosphonate for the Horner−Wadsworth−
Emmons olefination of the C7 aldehyde, the aldehyde itself
proved to be a difficult compound to handle. Furthermore, the
C7−C8 double bond generated by olefination of the keto
aldehyde precursor to 12 was produced as a mixture of E and Z
isomers that was inseparable by chromatography. The coup de
Scheme 2. Retrosynthetic Dissection of the Cyclobutylfuran “Northern” Sector of Providencin
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Scheme 3. First-Generation Synthesis of the Cyclobutylfuran Subunit of Providencin
Scheme 4. Mechanism for the Formation of 9 from Tetrahydrofuran 8
Scheme 5. Retrosynthetic Analysis of the Second-Generation
Approach to Providencin
sodium iodide18 produced allenic alcohol 22 as a single
stereoisomer together with a small amount (17% yield) of an
easily separable isomeric alkynyl alcohol. Although the
configuration of the hydroxyl group in 22 was inconsequential
for our purpose, Mosher ester analysis19 of this alcohol
established that it had the S orientation, indicating that attack
by the organostannane formed from 21 had taken place at the si
face of the carbonyl group of 20. Oxidation of 22 with Dess−
Martin periodinane yielded ketone 23, which upon exposure to
conditions described by Marshall20 involving silver nitrate on
silica in a mixture of dichloromethane and hexanes gave furan
24. Selective methanolysis of the acetate in diester 24 led to
alcohol 25, and subsequent oxidation with Ley’s reagent under
C
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Scheme 6. Second-Generation Route to the Cyclobutylfuran Sector of Providencin
catalytic conditions21 afforded cyclobutanone 26. In contrast to
cyclobutanone 12, Wittig olefination of 26 led successfully to
exomethylene-functionalized cyclobutane 27, albeit in modest
yield; alkene 27 was accompanied by a minor quantity (15%
yield) of primary alcohol 28 resulting from base-induced
cleavage of the pivalate. The failure of 12 to undergo
methylenation must now be attributed to substituents on the
furan rather than those on the cyclobutanone.22
Synthesis of the southern component of 3 for linkage to 27
was based on a route published by Pattenden and commenced
from (R)-glycidol (29).23 This epoxide was reacted with
lithiotrimethylacetylene to give 30, which was treated with
methanolic potassium carbonate to afford diol 3124 (Scheme
7). Negishi carbometalation−iodination25 of alkyne 31 led to
(E)-iodoalkene 32 with only a trace of its regioisomer. The
primary alcohol of diol 32 underwent selective tosylation to
provide 33, from which two routes to the southern sector were
pursued. First, 33 was reacted with the lithio anion of
ethoxyacetylene, and the resultant alkyne was treated with
acidic ethanol to furnish γ-lactone 34. However, mono-α-
selenylation of this lactone proceeded in low yield, and 35 was
accompanied by an equal quantity of the α,α′-diselenide. A
more efficient one-pot pathway from 33 to 35 was discovered
when tosylate 33 was reacted with the dilithio dianion of
D
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Scheme 7. Synthesis of the Butenolide Segment of Providencin
Scheme 8. Heck Reaction of Iodoalkene 35 with 28
phenylselenoacetic acid (36)26 and the resultant hydroxy acid
37 was lactonized in situ with p-toluenesulfonic acid in hot
benzene. This gave α-phenylselenyl lactone 35 as the sole
product, formed as a 1.4:1 mixture of stereoisomers at the
selenyl substituent.
The blueprint drafted for uniting the two subunits of
providencin was designed initially around a C−H activation
protocol published by Fagnou, who showed that substitution at
C5 of a furan can be achieved by a catalytic palladium(II)
species, which can lead to efficient coupling with aryl halides.27
However, treatment of furan 27 and iodoalkene 35 with
palladium(II) acetate in a biphasic medium at 60 °C or in N,N-
dimethylacetamide at 100 °C under the conditions described by
Fagnou resulted in extensive decomposition of the starting
materials with no evidence for formation of a coupled product.
The same outcome was observed when alcohol 28, prepared by
reduction of pivalate 27 with diisobutylaluminum hydride, was
tested as a coupling partner with 35. Doucet has published
reaction conditions slightly different from those of Fagnou for
C−H activation of furans and has shown that C5 arylation of a
2,3-disubstituted furan can be achieved in high yield by his
method.28 In the event, application of Doucet’s palladium(II)
acetate-catalyzed furan arylation to pivalate 27 and 35 in the
presence of potassium acetate failed to produce a coupled
product, but when alcohol 28 was invested in this process, a
reaction took place to give conjugated diene 38 as a mixture of
(E,E) and (E,Z) stereoisomers (Scheme 8). This result implies
that a Heck reaction29 of 35 with the exomethylene function of
28 takes precedence over palladium-catalyzed C−H activation
of the furan.
The failure of these furan C−H activation procedures to
promote the desired intermolecular coupling of our two
E
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Scheme 9. Linkage of the Cyclobutylfuran and Butenolide Subunits of Providencin at C12−C13
Scheme 10. Fusion of the Cyclobutylfuran and Butenolide Subunits of Providencin at C6−C7
providencin subunits left open the possibility that intra-
molecular furan C−H activation, where driving force could
accrue from formation of the natural macrocycle, would be
more successful. This idea shifted our focus toward initial C12−
C13 fusion of the northern and southern sectors, and oxidation
of alcohol 28 to aldehyde 39 with Ley’s reagent was the first
step in this direction (Scheme 9). The lithium enolate of 35,
generated at low temperature, was reacted with 39, and the
product was treated in situ with 30% H2O2 to promote
subsequent selenoxide formation and elimination.23 Butenolide
40 was produced from this coupling as a 4:3 mixture of
hydroxyl configurations at C13; however, attempts to close the
macrocycle from 40 using furan C−H activation methods
described above led only to decomposition of the substrate
with no evidence for ring formation.
The foregoing results convinced us that prefunctionalization
at the furan C5 position would be needed if the northern and
southern sectors of 3 were to be merged at this locus.
Pattenden showed in his synthesis of bis(deoxy)lophotoxin that
this could be accomplished through site-selective stannylation
of a furan and that subsequent macrocyclization could be
achieved, though in very low yield, via intramolecular Stille
coupling from a substrate resembling 40.23 Encouraging
precedent for this plan also existed in Trauner’s synthesis of
(−)-bipinnatin J, where a C5-stannylated 2,3-disubstituted
furan underwent efficient intermolecular Stille coupling with an
iodoalkene that can be viewed as a surrogate for 35.30
Following these examples, stannylation of furan 28 was
investigated under a variety of conditions, and these studies
revealed that initial lithiation of 28 could be accomplished only
with sec-butyllithium in the presence of TMEDA. Reaction of
the intermediate C5 lithiofuran with trimethyltin chloride at
low temperature provided unstable stannane 41, which was
reacted directly with 35 in the presence of catalytic tetrakis-
(triphenylphosphine)palladium(0) and copper(I) iodide
(Scheme 10). The coupled product 42 was obtained from
this sequence in acceptable yield based on furan 28. In
principle, access to our macrocyclic target from 42 required
only a C12−C13 connection along lines demonstrated in the
intermolecular enolate condensation of 35 with aldehyde 39.
Unfortunately, oxidation of the primary alcohol of 42 to an
aldehyde for this step was accompanied in all cases by
concomitant oxidation and elimination of the phenylselenyl
substituent, leading to butenolide 43 as the sole product. This
outcome effectively removed any prospect for macrocyclization
from 42 and leaves in doubt a viable route to the core structure
of providencin along lines developed here.
CONCLUSION
■
Two subunits of the cembranoid diterpene providencin have
been prepared, including a sector that houses the heavily
substituted cyclobutylfuran component. The two subunits were
linked at C6 of the furan via Stille cross-coupling of a
F
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1H), 4.26 (t, J = 7.7 Hz, 2H), 5.00−5.08 (m, 2H), 6.00 (ddd, J = 8.6,
10.3, 17.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 11.9 (3C), 17.9
(6C), 32.3, 39.6, 45.7, 62.1, 74.6, 75.3, 115.3, 137.8; EI-HRMS m/z
calcd for C17H35O3Si [M]+ 315.2356, found 315.2328.
stannylated furan with a trisubstituted iodoalkene representing
the “southern” sector of the molecule, and a second connection
between these fragments was made at the C12−C13 bond of
providencin via an intermolecular aldol condensation of an α-
phenylselenyl-γ-lactone with an aldehyde. Combination of
these fusion modes to complete the macrocyclic core of
providencin was not successful.
2-((1R,2R,3R,4R)-2-Hydroxy-3-(triisopropylsilyloxy)-4-
vinylcyclobutyl)ethyl Pivalate (18). To a CH2Cl2 solution (0.8
mL) of 17 (27 mg, 0.085 mmol) at 0 °C were added pyridine (13.8
μL, 0.171 mmol), trimethylacetyl chloride (13.6 μL, 0.11 mmol), and
DMAP (1.04 mg, 0.085 mmol). The mixture was allowed to warm to
room temperature and stirred for 18 h, after which the reaction was
quenched by addition of a satd aqueous NaHCO3 solution (10 mL).
The separated aqueous layer was extracted with CH2Cl2 (2 × 20 mL),
and the combined organic extract was washed with saturated CuSO4
solution, dried (Na2SO4), filtered, and concentrated. The crude
residue was purified by silica gel chromatography (7:93 ethyl acetate/
hexanes) to give 18 (22 mg, 64%) as a colorless oil. Rf 0.66 (8:2
hexanes/ethyl acetate); [α]D25 −86.3 (c 1.0, CHCl3); IR (neat) 3470,
2941, 2859, 1731 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.07 (s, 21H),
1.21 (s, 9H), 1.63−1.73 (m, 1H), 1.96−2.06 (m, 1H), 2.08 (d, J = 2.0
Hz, OH), 2.16−2.23 (m, 1H), 2.67−2.72 (m, 1H), 4.06−4.20 (m,
2H), 4.23−4.31 (m, 2H), 5.00−5.08 (m, 2H), 5.98 (ddd, J = 8.3, 10.1,
17.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 11.9 (3C), 17.8 (6C),
27.2 (3C), 28.1, 36.8, 38.7, 44.9, 63.2, 75.1, 75.3, 115.5, 137.4, 178.7;
CI-HRMS m/z calcd for C22H42O4Si [M + H]+ 399.2930, found
399.2943.
EXPERIMENTAL SECTION
■
General Techniques. All of the reactions requiring anhydrous
conditions were conducted in flame-dried glass apparatus under an
atmosphere of argon. THF, Et2O, CH2Cl2, DMF, benzene, and
acetonitrile were dried by passage through an activated alumina
column under argon. DMSO was distilled from CaH2 at 15 mmHg
and stored over activated 4 Å molecular sieves. Anhydrous MeOH was
freshly distilled from calcium hydride. Preparative chromatographic
separations were performed on silica gel (35−75 μm); reactions were
followed by TLC analysis using silica plates with fluorescent indicator
(254 nm) and visualized with a UV lamp or phosphomolybdic acid.
Commercially available reagents were purchased and used as received
unless stated otherwise. Optical rotations were measured with a
polarimeter using a 1 mL capacity cell with 1 dm path length. Infrared
spectra were recorded using thin films supported on KBr discs or
1
dispersed in KBr pellets. H and 13C NMR spectra were recorded in
2-((1R,2R,3R,4R)-2-Acetoxy-3-(triisopropylsilyloxy)-4-
vinylcyclobutyl)ethyl Pivalate (19). To a CH2Cl2 solution (0.5
mL) of 18 (22 mg, 0.055 mmol) at 0 °C were slowly added pyridine
(13.4 μL, 0.165 mmol), acetic anhydride (15.6 μL, 0.165 mmol), and
DMAP (0.65 mg, 0.085 mmol). The mixture was allowed to warm to
room temperature and stirred for 1 h, and the reaction was quenched
by addition of satd aqueous NaHCO3 solution (5 mL). The separated
aqueous layer was extracted with CH2Cl2 (2 × 20 mL), and the
combined organic extract was washed with satd CuSO4 solution, dried
(Na2SO4), filtered, and concentrated. The crude mixture was purified
by silica gel chromatography (5:95 ethyl acetate/hexanes) to afford 19
(21 mg, 87%) as a colorless oil. Rf 0.51 (9:1 hexanes/ethyl acetate);
[α]2D5 −77.5 (c 1.0, CHCl3); IR (neat) 2945, 2870, 1751, 1729, 1462
Fourier transform mode at the specified field strength on either a 300,
400, or 700 MHz spectrometer. Spectra were obtained on CDCl3
solutions in 5 mm diameter tubes, and chemical shifts are quoted in
parts per million relative to the residual signals of chloroform (δH
=
1
7.26 ppm, δC = 77.0 ppm). Multiplicities in the H NMR spectra are
described as follows: s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, br = broad; coupling constants are reported in hertz.
High-resolution mass spectrometry (HRMS) was performed using a
quadrupole mass analyzer, and the data are reported with ion mass/
charge (m/z) ratios as values in atomic mass units.
2-((1R,2R,3R,4R)-2-(tert-Butyldimethylsilyloxy)-3-(triisopro-
pylsilyloxy)-4-vinylcyclobutyl)ethanol (16). To a stirred solution
of 15 (44.0 mg, 0.08 mmol) in CH2Cl2 (1.0 mL) and pH 7 buffer
(0.05 mL) at 0 °C was added DDQ (22.0 mg, 0.096 mmol). The
solution was stirred at 0 °C for 1 h, after which the mixture was diluted
with pH 7 buffer (50.0 μL). The aqueous layer was separated and
extracted with CH2Cl2 (2 × 10 mL). The combined organic extract
was dried (Na2SO4), filtered, and concentrated in vacuo. The crude
residue was purified by silica gel chromatography (6:94 ethyl acetate/
hexanes) to yield 16 (22.0 mg, 65%) as a pale-yellow oil. Rf 0.43 (9:1
hexanes/ethyl acetate); [α]D22 −39.5 (c 1.0, CHCl3); IR (neat) 3330,
2943, 2863, 1478 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 3H),
0.09 (s, 3H), 0.90 (s, 9H), 1.06 (m, 21H), 1.59−1.68 (m, 1H), 1.86−
1.95 (m, 1H), 2.10−2.19 (m, 1H), 2.65 (t, J = 8.3 Hz, 1H), 3.63−3.74
(m, 2H), 4.22 (dd, J = 6.9, 8.3 Hz, 1H), 4.31 (dd, J = 6.3, 7.5 Hz, 1H),
5.05 (dd, J = 6.3, 7.5 Hz, 1H), 5.05 (dd, J = 9.5, 10.2 Hz, 2H), 6.01
(ddd, J = 8.8, 10.2, 17.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
−4.7, −4.6, 12.1 (3C), 18.0 (6C), 25.9 (3C), 29.7, 32.4, 38.4, 45.1,
61.3, 75.1, 75.6, 115.6, 138.1; CI-HRMS m/z calcd for C23H48O3Si2
[M]+ 428.3164, found 428.3145.
(1R,2R,3R,4R)-2-(2-Hydroxyethyl)-4-(triisopropylsilyloxy)-3-
vinylcyclobutanol (17). To an EtOH (absolute) solution (0.3 mL)
of 16 (24.0 mg, 0.056 mmol) was added p-toluenesulfonic acid (1.0
mg, 0.0056 mmol) at room temperature, and the mixture was stirred
for 4 h. When TLC showed that all the starting material had been
consumed, the reaction was quenched with satd aqueous NaHCO3
solution. The aqueous layer was extracted with EtOAc (3 × 5 mL),
and the combined organic extract was dried over anhydrous Na2SO4,
filtered, and concentrated. The crude oil was purified by silica gel
chromatography (6:4 hexanes/ethyl acetate) to afford 17 (9.0 mg,
53%) as a colorless oil. Rf 0.28 (6:4 hexanes/ethyl acetate); [α]D22
−29.0 (c 0.40, CHCl3); IR (neat) 3302, 2920, 2868, 1455, 1154 cm−1;
1H NMR (400 MHz, CDCl3) δ 1.07 (m, 21H), 1.68−1.75 (m, 1H),
1
cm−1; H NMR (400 MHz, CDCl3) δ 1.04 (s, 21H), 1.19 (s, 9H),
1.58−1.62 (m, 1H), 1.73−1.83 (m, 1H), 2.08 (s, 3H), 2.38 (m, 1H),
2.81 (t, J = 8.5 Hz, 1H), 4.05 (t, J = 6.6 Hz, 2H), 4.48 (dd, J = 6.8, 8.5
Hz, 1H), 5.04−5.14 (m, 3H), 6.01 (ddd, J = 8.4, 10.6, 17.1 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 11.8 (3C), 17.6 (6C), 20.6, 27.1
(3C), 28.2, 35.7, 38.7, 45.3, 62.4, 71.7, 76.1, 116.2, 136.5, 170.2, 178.5;
CI-HRMS m/z calcd for C24H44O5NaSi [M + Na]+ 463.2856, found
463.2842.
2-((1R,2R,3R,4R)-2-Acetoxy-4-formyl-3-(triisopropylsilyloxy)-
cyclobutyl)ethyl Pivalate (20). To a solution of 19 (22 mg, 0.049
mmol) in dioxane/water (3:1, 0.5 mL) were added 2,6-lutidine (11.35
μL, 0.248 mmol), OsO4 (0.05 M in 2-methyl-2-propanol, 50.0 μL,
0.0024 mmol), and NaIO4 (42.0 mg, 0.196 mmol). The reaction
mixture was stirred at room temperature for 2 h and then diluted with
water (10 mL) and CH2Cl2 (10 mL). The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The
combined organic extract was washed with aqueous CuSO4 solution
and brine and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure, and the crude residue was purified by silica gel
chromatography (1:9 ethyl acetate/hexanes) to afford 20 (15.0 mg,
68%) as a pale-brown oil. Rf 0.41 (15:85 hexanes/ethyl acetate); [α]D26
−53.8 (c 1.0, CHCl3); IR (neat) 2944, 2861, 1754, 1724(2) cm−1; 1H
NMR (400 MHz, CDCl3) δ 1.04 (s, 21H), 1.19 (s, 9H), 1.54−1.61
(m, 1H), 1.78−1.86 (m, 1H), 2.09 (s, 3H), 2.90−2.97 (m, 1H), 3.13
(d, J = 9.3 Hz, 1H), 3.97−4.07 (m, 2H), 4.72 (dd, J = 6.8, 9.2 Hz, 1H),
5.24 (dd, J = 6.4, 7.9 Hz, 1H), 9.88 (d, J = 2.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 11.7 (3C), 17.5 (6C), 20.5, 27.1 (3C), 27.2,
30.1, 38.7, 52.5, 62.1, 72.7, 75.7, 169.8, 178.4, 200.7; EI-HRMS m/z
calcd for C23H42O6NaSi [M + Na]+ 465.2648, found 465.2659.
2 - ( ( 1 R , 2 R , 3 R , 4 S ) - 2 - A c e t o x y - 4 - ( ( R ) - 2 - ( ( t e r t -
butyldimethylsilyloxy)methyl)-1-hydroxybuta-2,3-dienyl)-3-
(triisopropylsilyloxy)cyclobutyl)ethyl Pivalate (22). To a sol-
1.93−2.03 (m, 1H), 2.25−2.32 (m, 1H), 2.65 (dt, J = 2.8, 7.9 Hz, 1H),
3.14 (bs, 2OH), 3.63 (ddd, J = 7.8, 11.7, 17.5 Hz, 1H), 3.76−3.83 (m,
G
dx.doi.org/10.1021/jo402485h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ution of 21 (149.0 mg, 0.568 mmol) in 3.0 mL of DMF at room
temperature under argon were added SnCl2 (129.0 mg, 0.68 mmol)
and NaI (102.0 mg, 0.68 mmol), and the resulting mixture was stirred
for 3 h while protected from light in a flask wrapped with aluminum
foil. After the foil was removed, the bright-yellow solution was cooled
to 0 °C, and a solution of 20 (84.0 mg, 0.189 mmol) in 2.0 mL of
DMF was added over a 10 min period. After 30 h of stirring at 0 °C in
the absence of light, the reaction mixture was diluted with Et2O (20
mL) and a satd aqueous solution of NH4Cl (20 mL) while being
vigorously stirred. The separated aqueous layer was extracted with
Et2O (3 × 20 mL), and the combined organic extract was washed with
satd aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and
filtered. The solvent was removed under reduced pressure, and flash
chromatographic purification of the residual oil on silica gel (6:94 ethyl
acetate/hexanes) afforded 22 (61.0 mg, 53%) as a colorless oil. Rf 0.50
(85:15 hexanes/ethyl acetate); [α]2D0 −53.1 (c 1.20, CHCl3); IR (neat)
3540, 2953, 2867, 1960, 1742, 1731, 1458, 1369, 1236, 1151 cm−1; 1H
NMR (400 MHz, CDCl3) δ 0.07 (s, 3H), 0.07 (s, 3H), 0.89 (s, 9H),
1.06 (s, 21H), 1.19 (s, 9H), 1.58−1.67 (m, 1H), 1.76−1.85 (m, 1H),
2.07 (s, 3H), 2.48 (td, J = 2.7, 9.2 Hz, 1H), 2.68 (dd, J = 3.0, 8.5 Hz,
1H), 3.01 (d, J = 3.1 Hz, OH), 3.96 (t, J = 7.3 Hz, 2H), 4.18 (td, J =
2.0, 11.6 Hz, 1H), 4.31 (td, J = 2.0, 11.6 Hz, 1H), 4.62 (dd, J = 6.2, 9.4
Hz, 1H), 4.69 (pentet, J = 2.9 Hz, 1H), 4.91 (qq, J = 2.2, 10.5 Hz, 2H),
5.27 (dd, J = 5.9, 9.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ −5.4,
−5.3, 11.8 (3C), 17.6 (3C), 17.8 (3C), 20.7, 25.8 (3C), 27.1 (3C),
28.9, 29.7, 30.2, 38.6, 44.9, 62.6, 63.1, 66.2, 72.1, 76.5, 78.1, 104.2,
169.8, 178.4, 205.5; CI-HRMS m/z calcd for C33H63O7Si2 [M]+
627.4112, found 627.4088.
2 - ( ( 1 R , 2 R , 3 R , 4 R ) - 2 - A c e t o x y - 4 - ( 2 - ( ( t e r t -
butyldimethylsilyloxy)methyl)buta-2,3-dienoyl)-3-
(triisopropylsilyloxy)cyclobutyl)ethyl Pivalate (23). To a sol-
ution of 22 (61.0 mg, 0.097 mmol) in 1.0 mL of CH2Cl2 at 0 °C was
added NaHCO3 (32.5 mg, 0.38 mmol) followed by Dess−Martin
periodinane (82.5 mg, 0.194 mmol). The slurry was stirred at 0 °C for
1 h and then diluted with CH2Cl2 (5.0 mL). The reaction was
quenched with satd Na2S2O3 solution (15 mL) by stirring the biphasic
mixture vigorously for 20 min. After the layers were separated, the
aqueous phase was extracted with CH2Cl2 (2 × 10 mL), and the
combined organic extract was washed with satd NaHCO3 solution,
water, and brine and dried over Na2SO4. The drying agent was
removed by filtration, and the filtrate was concentrated in vacuo.
Purification of the crude residue by silica gel chromatography (94:6
hexanes/ethyl acetate) provided 23 (59 mg, 97%) as a yellow oil. Rf
0.50 (85:15 hexanes/ethyl acetate); [α]1D8 −14.6 (c 0.98, CHCl3); IR
(neat) 2953, 2863, 1933, 1750, 1731, 1664, 1466, 1369, 1228 cm−1;
1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6H), 0.08 (s, 9H), 1.01 (s,
1H), 3.46 (dd, J = 3.2, 9.1 Hz, 1H), 3.97−4.08 (m, 2H), 4.50 (d, J =
2.9 Hz, 2H), 4.63 (dd, J = 6.6, 8.3 Hz, 1H), 5.52 (dd, J = 6.6, 8.8 Hz,
1H), 6.31 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ −5.2 (2C), 11.8 (3C), 17.5 (3C), 17.6 (3C),
18.3, 20.6, 25.9 (3C), 27.1 (3C), 28.7, 35.0, 38.6, 39.0, 57.2, 62.2, 72.5,
76.2, 110.6, 121.6, 140.9, 147.8, 170.0, 178.3; CI-HRMS m/z calcd for
C33H61O7Si2 [M]+ 625.3955, found 625.3938.
2-((1R,2R,3R,4R)-2-(3-((tert-Butyldimethylsilyloxy)methyl)-
furan-2-yl)-4-hydroxy-3-(triisopropylsilyloxy)cyclobutyl)ethyl
Pivalate (25). To a stirred solution of 24 (38.0 mg, 0.06 mmol) in dry
MeOH (0.6 mL) at 0 °C was added K2CO3 (21.0 mg, 0.152 mmol).
The mixture was stirred at 0 °C for 3 h, and water (10 mL) was added
to the reaction mixture. The separated aqueous layer was extracted
with EtOAc (3 × 20 mL), and the combined organic extract was dried
over anhydrous Na2SO4, filtered, and concentrated. The crude residue
was purified by silica gel chromatography (92:8 hexane/ethyl acetate)
to afford 25 (29.0 mg, 82%) as a colorless oil. Rf 0.68 (8:2 hexanes/
ethyl acetate); [α]2D0 −6.0 (c 1.45, CHCl3); IR (neat) 3466, 2933,
2871, 1734, 1711, 1454 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.08 (s,
3H), 0.09 (s, 3H), 0.95 (s, 30H), 1.20 (s, 9H), 1.72−1.81 (m, 1H),
2.06−2.14 (m, 1H), 2.16 (d, J = 4.7 Hz, 1H), 2.64 (dd, J = 3.6, 8.0 Hz,
1H), 3.34 (dd, J = 6.2, 8.4 Hz, 1H), 4.06−4.22 (m, 2H), 4.44 (dd, J =
6.2, 8.4 Hz, 1H), 4.49 (d, J = 2.0 Hz, 2H), 4.66 (dd, J = 5.7, 9.4 Hz,
1H), 6.32 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 1.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ −5.2 (2C), 11.9 (3C), 17.6 (6C), 25.9 (3C),
27.1 (3C), 28.8, 29.7, 38.6, 57.2, 63.1, 75.3, 76.0, 110.7, 121.3, 121.3,
140.6, 148.7, 178.6; CI-HRMS m/z calcd for C31H58O6Si2Na [M +
Na]+ 605.3670, found 605.3654.
2-((1R,2R,3R)-2-(3-((tert-Butyldimethylsilyloxy)methyl)furan-
2-yl)-4-oxo-3-(triisopropylsilyloxy)cyclobutyl)ethyl Pivalate
(26). To a CH2Cl2 (0.5 mL) solution of 25 (31.0 mg, 0.053 mmol)
were added 4 Å molecular sieves, TPAP (1.86 mg, 0.0052 mmol), and
NMO (18.69 mg, 0.159 mmol). The reaction mixture was stirred at
room temperature for 30 min, after which the suspension was loaded
directly on a silica gel column. The crude mixture was purified by
chromatography (93:7 hexanes/ethyl acetate) to yield 26 (29.0 mg,
94%) as a colorless oil. Rf 0.75 (2:8 hexanes/ethyl acetate); [α]D21
+38.7 (c 1.45, CHCl3); IR (neat) 2957, 2868, 1792, 1733, 1470, 1158
1
cm−1; H NMR (400 MHz, CDCl3) δ 0.10 (s, 6H), 0.93−0.96 (m,
30H), 1.17 (s, 9H), 1.95−2.14 (m, 2H), 3.53−3.59 (m, 1H), 3.69 (dd,
J = 5.9, 9.1 Hz, 1H), 4.13 (t, J = 6.1 Hz, 2H), 4.56 (d, J = 7.0 Hz, 2H),
5.18 (dd, J = 2.9, 9.3 Hz, 1H), 6.32 (d, J = 1.3 Hz, 1H), 7.29 (d, J = 1.3
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ −5.2 (2C), 11.8 (3C), 17.4
(3C), 17.5 (3C), 18.3, 25.9 (3C), 27.1 (3C), 29.9, 36.8, 38.7, 56.2,
57.2, 61.8, 83.2, 110.7, 122.1, 141.3, 147.2, 178.3, 208.4; CI-HRMS m/
z calcd for C31H56O6Si2 [M]+ 580.3615, found 580.3616.
21H), 1.17 (s, 9H), 1.50−1.60 (m, 1H), 1.72−1.81 (m, 1H), 2.06 (s,
3H), 2.78−2.85 (m, 1H), 3.90 (dd, J = 3.2, 9.8 Hz, 1H), 3.97 (t, J = 6.5
Hz, 2H), 4.28 (td, J = 3.6, 13.3 Hz, 1H), 4.44 (td, J = 3.4, 13.3 Hz,
1H), 4.60 (dd, J = 6.5, 9.5 Hz, 1H), 5.24−5.29 (m, 2H), 5.36 (td, J =
3.4, 13.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ −5.4, −5.3, 12.1
(3C), 17.6 (3C), 17.7 (3C), 18.2, 20.5, 25.8 (3C), 27.1 (3C), 27.5,
31.9, 38.6, 48.8, 58.4, 62.2, 72.2, 75.9, 82.1, 112.0, 169.6, 178.3, 197.3,
216.3; CI-HRMS m/z calcd for C33H61O7Si2 [M]+ 625.3956, found
625.3955.
2-((1R,2R,3R)-2-(3-((tert-Butyldimethylsilyloxy)methyl)furan-
2-yl)-4-methylene-3-(triisopropylsilyloxy)cyclobutyl)ethyl Piv-
alate (27) and 2-((1R,2R,3R)-2-(3-((tert-Butyldimethylsilyloxy)-
methyl)furan-2-yl)-4-methylene-3-(triisopropylsilyloxy)-
cyclobutyl)ethanol (28). To a solution of 26 (26.0 mg, 0.044 mmol)
in dry THF (1.0 mL) at 0 °C was added Ph3PCH2 [1.50 mL, 0.179
mmol, 0.119 M in THF, freshly prepared from Ph3PCH3Br (200.0 mg,
0.56 mmol) and n-BuLi (0.17 mL, 0.47 mmol, 2.7 M solution in
hexane) in THF (4.0 mL) at 0 °C], and the mixture was stirred at 0 °C
for 10 min and at room temperature for 45 min. The reaction was
quenched with satd aqueous NH4Cl solution (10 mL), and the
separated aqueous layer was extracted with Et2O (2 × 10 mL). The
combined organic extract was dried (Na2SO4), filtered, and
concentrated, and the crude residue was purified by silica gel
chromatography (3:97 ethyl acetate/hexanes) to give 27 (12.0 mg,
48%) and 28 (3.0 mg, 15%) as colorless oils.
2 - ( ( 1 R , 2 R , 3 R , 4 R ) - 2 - A c e t o x y - 4 - ( 3 - ( ( t e r t -
b u t y l d i m e t h y l s i l y l o x y ) m e t h y l ) f u r a n - 2 - y l ) - 3 -
(triisopropylsilyloxy)cyclobutyl)ethyl Pivalate (24). To a sol-
ution of 23 (54.0 mg, 0.086 mmol) in 3.58 mL of hexane and 0.70 mL
of CH2Cl2 at room temperature was added 73.3 mg of AgNO3 on SiO2
(10 wt.%, 0.043 mmol) in a single portion. The suspension was stirred
at room temperature for 2 h in the absence of light and then diluted
with Et2O and filtered through a short pad of Celite, which was washed
with Et2O (20 mL). The filtrate was concentrated in vacuo, and the
crude mixture was purified by silica gel chromatography (96:4
hexanes/ethyl acetate) to furnish 24 (43.0 mg, 79%) as a pale-yellow
oil. Rf 0.57 (85:15 hexanes/ethyl acetate); [α]1D8 −27.3 (c 1.00,
27: Rf 0.8 (9:1 hexanes/ethyl acetate); [α]1D9 −4.1 (c 0.6, CHCl3);
IR (neat) 2953, 2959, 1725, 1466 cm−1; 1H NMR (400 MHz, CDCl3)
δ 0.08 (s, 3H), 0.09 (s, 3H), 0.95 (m, 30H), 1.18 (s, 9H), 1.94 (dd, J =
6.9, 7.5 Hz, 2H), 3.53 (m, 1H), 3.46 (dd, J = 5.9, 7.8 Hz, 1H), 4.10 (t,
J = 6.7 Hz, 2H), 4.54 (d, J = 2.6 Hz, 2H), 5.03 (s, 1H), 5.08 (m, 1H),
5.22 (s, 1H), 6.33 (d, J = 1.5 Hz, 1H), 7.30 (d, J = 1.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ −5.2 (2C), 12.0 (3C), 17.7 (6C), 25.9
(3C), 27.1 (3C), 29.6, 33.4, 38.6, 41.6, 43.1, 57.3, 62.3, 72.7, 77.1,
1
CHCl3); IR (neat) 2953, 2863, 1746, 1731, 1462, 1365 cm−1; H
NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.92 (s, 30H), 1.17 (s, 9H),
1.67−1.73 (m, 1H), 1.84−1.92 (m, 1H), 2.10 (s, 3H), 2.78−2.85 (m,
H
dx.doi.org/10.1021/jo402485h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
107.3, 110.8, 121.4, 148.8, 154.9, 178.4. CI-HRMS m/z calcd for
C32H58O5Si2 [M]+ 578.3822, found 578.3814.
concentrated. Chromatographic purification of the residue (silica gel,
25:75 ethyl acetate/hexanes) gave 34 (8.0 mg, 57%) as a colorless oil.
Rf 0.4 (6:4 hexanes/ethyl acetate); [α]2D0 −82.8 (c 0.85, CHCl3); IR
28: Rf 0.46 (8:2 hexanes/ethyl acetate); [α]2D3 −18.0 (c 0.4, CHCl3);
1
IR (neat) 3400, 2941, 2863, 1462, 1246 cm−1; H NMR (400 MHz,
1
(neat) 2923, 2851, 1768, 1456, 1174 cm−1; H NMR (400 MHz,
CDCl3) δ 0.10 (s, 3H), 0.11 (s, 3H), 0.95 (s, 30H), 1.72 (t, J = 4.3 Hz,
OH), 1.76−1.85 (m, 1H), 1.90−1.98 (m, 1H), 3.39−3.49 (m, 2H),
3.67 (d, J = 4.3 Hz, 2H), 4.55 (q, J = 1.4, 7.1 Hz, 2H), 5.03 (s, 1H),
5.07 (dd, J = 1.4, 7.1 Hz, 1H), 5.20 (s, 1H), 6.32 (d, J = 1.4 Hz, 1H),
7.30 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ −5.1 (2C),
11.7 (3C), 17.7 (6C), 25.9 (3C), 37.3, 42.6, 43.2, 57.2, 58.8, 61.0, 72.9,
106.8, 111.1, 121.2, 140.8, 149.4, 155.4; EI-HRMS m/z calcd for
C27H50O4Si2 [M]+ 494.3247, found 494.3229.
(S,E)-5-Iodo-4-methylpent-4-ene-1,2-diol (32). To a suspen-
sion of Cp2ZrCl2 (334.4 mg, 1.14 mmol) in DCE (1.0 mL) at room
temperature was added slowly AlMe3 (0.3 mL, 3.12 mmol), and the
mixture was stirred for 15 min. The solution was cooled to 0 °C, and a
solution of 3124 (105.0 mg, 1.04 mmol) in DCE (1.1 mL) was added
via cannula. The mixture was stirred for 41 h at room temperature and
then cooled to −30 °C, and a solution of I2 in Et2O (3.0 mL) was
added. The mixture was stirred for 45 min −30 °C and then allowed to
warm to 0 °C, and the reaction was quenched with satd sodium
potassium tartrate solution (30 mL) and pentane (20 mL). The layers
were separated, and the aqueous layer was extracted with EtOAc (6 ×
30 mL). The combined organic extract was dried (Na2SO4), filtered,
and concentrated, and the crude residue was purified by silica gel
chromatography (55:45 ethyl acetate/hexanes) to give 32 (154 mg,
60%) as a colorless oil. Rf 0.25 (3:7 hexanes/ethyl acetate); [α]D21
−10.4 (c 0.65, CHCl3); IR (neat) 3361, 2921, 2871, 1271, 1151 cm−1;
1H NMR (300 MHz, CDCl3) δ 1.91 (d, J = 0.8 Hz, 3H), 2.39 (dd, J =
CDCl3) δ 1.86−1.90 (m, 1H), 1.92 (d, J = 1.0 Hz, 3H), 2.28−2.38 (m,
1H), 2.51 (dd, J = 8.7, 14.1 Hz, 1H), 2.56 (dd, J = 6.9, 9.5 Hz, 2H),
2.66 (dd, J = 7.2, 14.3 Hz, 1H), 4.63 (m, 1H), 6.11 (q, J = 1.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 24.4, 27.6, 28.5, 44.9, 78.3, 78.6,
142.7, 176.6; EI-HRMS m/z calcd for C8H11O2I [M]+ 265.9804, found
265.9799.
(S,E)-5-(3-Iodo-2-methylallyl)-3-(phenylselenyl)-
dihydrofuran-2(3H)-one (35). To a solution of α-phenylseleno-
acetic acid (36) (4.48 g, 20.74 mmol) in anhydrous THF (20 mL) was
added slowly LiHMDS (45.6 mL, 45.65 mmol, 1 M solution in THF)
at −78 °C. The mixture was stirred at −78 °C for 1 h, and a solution
of 33 (3.18 g, 8.01 mmol) in THF (20 mL) was added. The reaction
mixture was stirred at −78 °C for 30 min and then at 0 °C for 1 h. The
mixture was warmed to room temperature and stirred at room
temperature for 2 h. To the mixture was added 1 N NaOH (85 mL),
and the layers were separated. The organic layer was discarded, and
the aqueous layer was acidified with 1 N HCl (125.0 mL) and
extracted with Et2O (3 × 50 mL). The combined organic extract was
dried (Na2SO4), filtered, and concentrated to give a crude oil.
The oil obtained above was immediately dissolved in dry benzene
(20 mL), and TsOH·H2O (180 mg, 0.94 mmol, 10 mol %) was added
to the solution. The mixture was refluxed for 16 h, and the reaction
was quenched with satd aqueous NaHCO3 solution. The aqueous
layer was extracted with Et2O (2 × 30 mL), and the organic extract
was dried (Na2SO4), filtered, and concentrated. Purification of the
residual oil by silica gel chromatography (15:85 ethyl acetate/
hexanes) gave an inseparable mixture (1.4:1) of stereoisomers 35
(1.82 g, 54% based on 33) as a viscous yellow oil. Rf 0.31 (8:2
8.3, 11.1 Hz, 2H), 3.46 (dd, J = 10.6, 6.9 Hz, 1H), 3.88 (m, 1H), 6.06
(q, J = 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.2, 43.2, 66.2,
69.6, 77.6, 144.6; EI-HRMS m/z calcd for C6H11IO2 [M]+ 241.9804,
found 241.9797.
1
hexanes/ethyl acetate); IR (neat) 2918, 2847, 1767, 1434 cm−1; H
(S,E)-2-Hydroxy-5-iodo-4-methylpent-4-enyl 4-Methylben-
zenesulfonate (33). To a solution of 32 (2.53 g, 10.45 mmol) in
pyridine (25.0 mL) at 0 °C was added p-toluenesulfonyl chloride (2.19
g, 11.50 mmol), and the mixture was stirred at 4 °C for 20 h. After the
reaction was quenched with water (100 mL), the layers were
separated, and the aqueous layer was extracted with EtOAc (4 × 50
mL). The combined organic extract was dried over Na2SO4, filtered,
and concentrated. The crude mixture was purified by silica gel
chromatography (22:88 ethyl acetate/hexanes) to afford 33 (3.18 g,
76%) as a colorless oil. Rf 0.66 (7:3 hexanes/ethyl acetate); [α]1D8 +5.8
(c 0.85, CHCl3); IR (neat) 3517, 2910, 2848, 1361, 1170, 1096, 976
NMR (400 MHz, CDCl3) (major isomer) δ 1.85 (s, 3H), 2.35 (dd, J =
5.4, 7.5 Hz, 2H), 2.45 (dd, J = 5.8, 14.4 Hz, 1H), 2.61 (dd, J = 7.1, 14.2
Hz, 1H), 3.96 (t, J = 5.4 Hz, 1H), 4.40 (m, 1H), 6.06 (s, 1H), 7.40−
7.50 (m, 3H), 7.65−7.75 (2H); (minor isomer) δ 1.83 (d, J = 1.0 Hz,
3H), 1.96 (ddd, J = 7.9, 9.1, 13.7 Hz, 1H), 2.29−2.36 (m, 1H), 2.48
(dd, J = 7.1, 14.4 Hz, 1H), 2.75 (ddd, J = 6.7, 9.4, 13.7 Hz, 1H), 4.02
(t, J = 9.3 Hz, 1H), 4.55−4.65 (m, 1H), 6.01 (q, J = 1.0 Hz, 1H),
7.40−7.50 (m, 3H), 7.65−7.75 (m, 2H); 13C NMR (100 MHz,
CDCl3) (major) δ 24.2, 36.4, 36.7, 44.5, 76.9, 78.7, 126.5, 129.3, 129.5
(2C), 135.9 (2C), 142.3, 175.2; (minor) δ 24.5, 35.2, 36.9, 44.8, 76.9,
78.8, 126.8, 129.1, 129.4 (2C), 135.9 (2C), 142.3, 175.2; CI-HRMS
m/z calcd for C14H16O2SeI [M + H]+ 422.9361, found 422.9350.
(S)-5-((2E,4E)-4-((2R,3R,4R)-3-(3-((tert-Butyldimethylsilyloxy)-
methyl)furan-2-yl)-2-(2-hydroxyethyl)-4-(triisopropylsilyloxy)-
cyclobutylidene)-2-methylbut-2-enyl)-3-(phenylselanyl)-
dihydrofuran-2(3H)-one (38). To a mixture of vinyl iodide 35 (6.14
mg, 0.014 mmol) and furan 28 (6.0 mg, 0.012 mmol) in 0.2 mL of
DMF were added KOAc (2.35 mg, 0.024 mmol) and Pd(OAc)2 (0.26
mg, 0.00012 mmol). The reaction mixture was heated in a sealed
vessel at 100 °C for 6 h, cooled, and diluted with water (10 mL). The
mixture was extracted with Et2O (2 × 10 mL), and the combined
organic extract was dried (Na2SO4), filtered, and concentrated.
Purification of the residue by silica gel chromatography (3:7 ethyl
acetate/hexanes) afforded 38 (2.0 mg, 34%) as a colorless oil. Rf 0.16
1
cm−1; H NMR (400 MHz, CDCl3) δ 1.86 (d, J = 0.8 Hz, 3H), 2.38
(d, J = 6.1 Hz, 2H), 2.48 (s, 3H), 3.92 (dd, J = 5.6, 9.4 Hz, 1H), 4.03
(m, 2H), 6.00 (s, 1H), 7.39 (d, J = 8.06 Hz, 2H), 7.82 (d, J = 7.9 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 21.7, 24.0, 42,7, 67.1, 72.7, 78.4,
128.0 (2C), 130.0 (2C), 132.4, 143.1, 145.2; CI-HRMS m/z calcd for
C13H18O4SI [M + H]+ 396.9971, found 396.9956.
(R,E)-5-(3-Iodo-2-methylallyl)dihydrofuran-2(3H)-one (34).
To a stirred solution of ethoxyacetylene (40% w/w solution in
hexanes, 78.9 μL, 0.33 mmol) in THF (2.0 mL) at −78 °C was added
a solution of n-BuLi (2.5 M) in hexanes (0.13 mL, 0.32 mmol). The
mixture was stirred at −78 °C for 1 h, and a solution of 33 (22.0 mg,
0.05 mmol) in THF (1.0 mL) was added dropwise. The reaction
mixture was stirred at −78 °C for 2 h and then warmed to 0 °C, and
BF3·OEt2 (27.9 μL, 0.22 mmol) was added. The mixture was stirred at
0 °C for 1 h, after which the reaction was quenched by addition of a
satd aqueous solution of NaHCO3. The resulting mixture was diluted
with Et2O (10 mL) and water (10 mL), and the separated aqueous
phase was extracted with Et2O (2 × 20 mL). The combined organic
extract was dried (Na2SO4), filtered, and concentrated to leave a crude
oil.
To an EtOH (1.00 mL) solution of the oil obtained above was
added p-toluenesulfonic acid (10.0 mg), and the mixture was stirred at
room temperature for 18 h. The reaction was quenched with satd
aqueous NaHCO3, and the mixture was diluted with EtOAc (5 mL).
The separated aqueous phase was extracted with EtOAc (2 × 10 mL),
and the combined organic extract was dried (Na2SO4), filtered, and
1
(3:7 hexanes/ethyl acetate); IR (neat) 2925, 2855, 1769 cm−1; H
NMR (700 MHz, CDCl3) δ 0.09−0.10 (m, 14H), 0.93−0.94 (m,
20H), 0.96−0.97 (m, 37H), 1.75 (s, 3H), 1.76 (s, 3H), 1.92−1.96 (m,
4H), 1.9−2.03 (m, 1H), 2.15−2.17 (m, 1H), 2.26−2.29 (m, 1H), 2.38
(dd, J = 5.5, 7.5 Hz, 4H), 2.47−2.50 (m, 1H), 2.76−2.81 (m, 1H),
3.34−3.37 (m, 1H), 3.57−3.60 (m, 1H), 3.66−3.70 (m, 2H), 3.73−
3.77 (m, 1H), 3.98 (t, J = 5.9 Hz, 1H), 4.04 (t, J = 8.9 Hz, 1H), 4.42−
4.46 (m, 1H), 4.48−4.51 (m, 1H), 4.53 (dd, J = 2.2, 4.0 Hz, 2H), 5.21
(d, J = 7.2 Hz, 1H), 5.88 (d, J = 11.3 Hz, 1H), 5.96 (d, J = 11.5 Hz,
1H), 6.33 (d, J = 1.8 Hz, 1H), 6.34 (d, J = 1.8 Hz, 1H), 6.36 (t, J = 1.6
Hz, 1H), 6.38 (t, J = 2.2 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.32 (d, J =
1.8 Hz, 1H), 7.34−7.42 (m, 8H), 7.68−7.71 (m, 5H); 13C NMR (176
MHz, CDCl3) δ −5.1, 11.9, 12.0, 14.1, 16.8, 17.5, 17.7, 17.8, 18.4, 25.9,
I
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Article
29.7, 30.3, 31.9, 35.5, 36.4, 36.9, 37.2, 37.5, 40.3, 43.6, 45.6, 45.9, 57.3,
61.1, 71.9, 77.3, 110.8, 117.8, 121.3, 124.4, 126.7, 129.2, 129.4, 131.2,
135.8, 135.9, 140.9, 149.3, 149.5, 176.0, 176.1; EI-HRMS m/z calcd for
C41H64O6SeSi2Na [M + Na]+ 811.3407, found 811.3398.
1.8 Hz, 1H), 7.09 (t, J = 1.5 Hz, 1H), 7.32 (d, J = 1.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ −5.1, 12.0, 17.7, 18.5, 24.6, 25.9, 29.7,
30.3, 39.8, 42.6, 42.7, 43.0, 57.2, 65.6, 73.3, 79.3, 79.4, 107.5, 111.5,
121.1, 125.5, 135.7, 136.8, 140.8, 141.8, 147.9, 149.6, 154.2, 171.6.
(S)-5-((E)-3-(4-((tert-Butyldimethylsilyloxy)methyl)-5-
( ( 1 R , 2 R , 4 R ) - 2 - ( 2 - h y d r o x y e t h y l ) - 3 - m e t h y l e n e - 4 -
(triisopropylsilyloxy)cyclobutyl)furan-2-yl)-2-methylallyl)-3-
(phenylselanyl)dihydrofuran-2(3H)-one (42). To a solution of 28
(9.0 mg, 0.018 mmol) in dry THF (0.2 mL) at −78 °C were added
dropwise freshly distilled TMEDA (16.0 μL, 0.108 mmol) and sec-
BuLi (50.0 μL, 0.054 mmol, 1.08 M solution in cyclohexane). The
mixture was stirred at −78 °C for 15 min and then at 0 °C for 30 min.
The solution was cooled to −78 °C, and Me3SnCl (90.0 μL, 0.09
mmol, 1.0 M solution in hexane) was added. The reaction mixture was
stirred at −78 °C for 1 h and then warmed to room temperature. After
the mixture was stirred at room temperature for 1 h, the reaction was
quenched with water (10 mL), and the layers were separated. The
aqueous layer was extracted with Et2O (3 × 10 mL), and the
combined organic extract was dried over Na2SO4, filtered, and
concentrated to leave a crude oil that was immediately used for the
next reaction.
2-((1R,2R,3R)-2-(3-((tert-Butyldimethylsilyloxy)methyl)furan-
2-yl)-4-methylene-3-(triisopropylsilyloxy)cyclobutyl)-
acetaldehyde (39). To a CH2Cl2 solution (0.5 mL) of 28 (15.0 mg,
0.03 mmol) were added 4 Å molecular sieves, TPAP (1.06 mg, 0.003
mmol), and NMO (10.54 mg, 0.09 mmol). The reaction mixture was
stirred at room temperature for 1 h, after which the suspension was
loaded on a silica gel column and eluted (95:5 hexanes/ethyl acetate)
to give aldehyde 39 (9.0 mg, 60%) as a colorless oil. Rf 0.66 (15:85
hexanes/ethyl acetate); [α]D20 −10.2 (c 0.4, CHCl3); IR (neat) 2947,
2866, 1721, 1462 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 3H),
0.09 (s, 3H), 0.92 (s, 9H), 0.95 (s, 21H), 2.72 (dd, J = 1.8, 7.3 Hz,
2H), 3.50 (t, J = 7.0 Hz, 1H), 3.78−3.85 (m, 1H), 4.53 (d, J = 8.2 Hz,
2H), 5.06 (t, J = 2.0 Hz, 1H), 5.09 (dd, J = 2.4, 7.5 Hz, 1H), 5.23 (t, J
= 2.0 Hz, 1H), 6.33 (d, J = 1.7 Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 9.75
(t, J = 1.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ −5.2, −5.1, 11.9
(3C), 17.7 (6C), 18.3, 25.9 (3C), 39.1, 42.7, 48.1, 57.2, 72.9, 108.3,
110.9, 121.7, 141.1, 148.0, 153.9, 200.7; CI-HRMS m/z calcd for
C27H49O4Si2 [M + H]+ 493.3169, found 493.3172.
To a solution of the oil obtained above (13.0 mg, 0.019 mmol) and
35 (9.0 mg, 0.021 mmol) in degassed DMF (0.3 mL) under an argon
atmosphere were added Pd(PPh3)4 (1.09 mg, 0.00095 mmol) and CuI
(0.36 mg, 0.0019 mg). After 4 h of stirring at room temperature, the
mixture was diluted with water (10 mL) and Et2O (10 mL). The
separated aqueous layer was extracted with Et2O (3 × 10 mL), and the
combined organic extract was dried over Na2SO4, filtered, and
concentrated. The residue was purified by silica gel chromatography
(3:22:75 NEt3/ethyl acetate/hexanes) under argon to afford 42 (8.0
mg, 54% based on 28) as a colorless oil. Rf 0.28 (7:3 hexanes/ethyl
acetate); [α]2D2 −10.2 (c 0.46, CHCl3); IR (neat) 3478, 2929, 2855,
1769, 1462, 1170 cm−1; 1H NMR (700 MHz, CDCl3) δ 0.10−0.12 (m,
19H), 0.92−0.95 (m, 76H), 1.80−1.85 (m, 3H), 1.92−1.94 (m, 2H),
1.96 (s, 6H), 2.00−2.04 (m, 2H), 2.14−2.18 (dd, J = 7.1, 13.6 Hz,
1H), 2.31−2.35 (m, 2H), 2.38−2.42 (m, 1H), 2.54 (dd, J = 5.9, 13.9
Hz, 1H), 2.60 (dd, J = 6.4, 14.4 Hz, 1H), 2.72 (ddd, J = 6.6, 9.3, 13.5
Hz, 1H), 3.37−3.41 (m, 2H), 3.45 (dd, J = 5.9, 7.1 Hz, 2H), 3.66−
3.72 (m, 4H), 3.96 (dd, J = 2.5, 8.3 Hz, 1H), 4.04 (t, J = 9.5 Hz, 1H),
4.42−4.46 (m, 1H), 4.49 (d, J = 12.0 Hz, 2H), 4.59 (d, J = 12.0 Hz,
2H), 4.60 (dd, J = 6.5, 7.3 Hz, 1H), 5.00 (s, 2H), 5.08 (d, J = 7.4 Hz,
2H), 5.17 (s, 2H), 5.92 (s, 1H), 5.98 (s, 1H), 6.13−6.15 (m, 2H),
7.34−7.37 (m, 4H), 7.38−7.42 (m, 2H), 7.62−7.64 (m, 2H), 7.68−
7.71 (m, 4H); 13C NMR (176 MHz, CDCl3) δ −5.1, 11.9, 17.7, 18.4,
26.0, 26.4, 29.7, 30.3, 35.2, 36.2, 36.9, 37.3, 42.5, 43.2, 45.9, 46.4, 57.2,
61.1, 73.1, 77.6, 77.9, 106.6, 110.4, 117.4, 117.5, 122.6, 126.7, 127.0,
127.7, 128.9, 129.2, 129.4, 130.1, 131.4, 135.7, 135.9, 148.5, 151.0,
155.2, 175.7, 175.8; EI-HRMS m/z calcd for C41H64O6SeSi2 [M]+
788.3407, found 788.3388.
(S)-3-(2-((1R,2R,3R)-2-(3-((tert-Butyldimethylsilyloxy)-
methyl)furan-2-yl)-4-methylene-3-(triisopropylsilyloxy)-
cyclobutyl)-1-hydroxyethyl)-5-((E)-3-iodo-2-methylallyl)furan-
2(5H)-one (40). To a solution of 35 (13.0 mg, 0.03 mmol) in dry
THF (0.2 mL) at −78 °C was added dropwise LiHMDS (46.1 μL,
0.046 mmol, 1.0 M solution in THF). The mixture was stirred at −78
°C for 40 min, and a solution of 39 (9.0 mg, 0.018 mmol) in dry THF
(0.2 mL) was added dropwise over 10 min. The mixture was stirred at
−78 °C for 1.5 h and then at 0 °C for 15 min. The reaction was
quenched with satd aqueous NH4Cl solution (10 mL), and the layers
were separated. The aqueous layer was extracted with Et2O (3 × 10
mL), and the combined organic extract was dried over Na2SO4,
filtered, and concentrated to leave a crude oil (20.0 mg) that was
immediately used for the next reaction.
To a solution of the crude residue obtained above (20.0 mg) in
THF (0.3 mL) at 0 °C was added dropwise H2O2 (0.10 mL, 30% w/w
in water), and the mixture was warmed to room temperature. After the
mixture was stirred at room temperature for 20 min, the reaction was
quenched with satd aqueous NaHCO3 solution (5.0 mL). The
separated aqueous layer was extracted with Et2O (2 × 5 mL), and the
combined organic extract was dried (Na2SO4), filtered, and
concentrated. The crude mixture was purified by silica gel
chromatography (14−16% ethyl acetate in hexanes) to afford
separable diastereomers of 40 (less polar 4.0 mg, more polar 3.0
mg, total 51% based on 39) as colorless oils.
Less Polar Isomer. Rf 0.46 (75:25 hexanes/ethyl acetate); [α]D23
+6.9 (c 0.26, CHCl3); IR (neat) 3464, 2922, 2855, 1752, 1468, 1258
1
cm−1; H NMR (700 MHz, CDCl3) δ 0.13 (s, 3H), 0.14 (s, 3H),
2-((1R,2R,3R)-2-(3-((tert-Butyldimethylsilyloxy)methyl)-5-
((E)-2-methyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)prop-1-enyl)-
furan-2-yl)-4-methylene-3-(triisopropylsilyloxy)cyclobutyl)-
acetaldehyde (43). To a solution of 42 (6.0 mg, 0.0076 mmol) in
0.15 mL of CH2Cl2 at 0 °C was added NaHCO3 (2.0 mg, 0.0152
mmol) followed by Dess−Martin periodinane (4.6 mg, 0.01 mmol).
The slurry was stirred at 0 °C for 1.5 h and then diluted with CH2Cl2
(5.0 mL). The reaction was quenched with satd Na2S2O3 solution (5.0
mL) by stirring the biphasic mixture vigorously for 20 min, and the
layers were separated. The aqueous phase was extracted with CH2Cl2
(2 × 5.0 mL), and the combined organic extract was washed with satd
NaHCO3 solution, water, and brine and dried over Na2SO4. The
drying agent was removed by filtration, and the filtrate was
concentrated in vacuo. Purification of the residue by silica gel
chromatography (72:25:3 hexanes/ethyl acetate/NEt3) provided 43
(2.0 mg, 43%) as a colorless oil. Rf 0.27 (7:3 hexanes/ethyl acetate);
[α]2D5 −4.6 (c 0.35, CHCl3); IR (neat) 3478, 2929, 2855, 1746, 1721,
1271 cm−1; 1H NMR (700 MHz, CDCl3) δ 0.90 (s, 3H), 0.10 (s, 3H),
0.93−0.95 (m, 30H), 2.09 (d, J = 0.7 Hz, 3H), 2.45 (dd, J = 7.3, 13.7
Hz, 1H), 2.70 (dd, J = 6.6, 13.8 Hz, 1H), 2.75 (dd, J = 1.5, 7.0 Hz,
2H), 3.49 (dd, J = 3.4, 7.6 Hz, 1H), 3.78−3.82 (m, 1H), 4.51 (d, J =
0.93−0.94 (m, 30H), 1.92 (d, J = 1.0 Hz, 3H), 1.94 (ddd, J = 7.5, 10.1,
14.0 Hz, 1H), 2.27 (td, J = 5.0, 14.0 Hz, 1H), 2.50 (dd, J = 7.4, 14.9
Hz, 2H), 3.07 (d, J = 5.8 Hz, OH), 3.46−3.50 (m, 1H), 3.53 (dd, J =
7.1, 7.5 Hz, 1H), 4.50 (d, J = 12.2 Hz, 1H), 4.52 (dd, J = 4.8, 11.9 Hz,
1H), 4.60 (d, J = 11.9 Hz, 1H), 4.94 (ddd, J = 1.3, 6.1, 7.6 Hz, 1H),
5.06 (dd, J = 2.0, 4.0 Hz, 1H), 5.08 (t, J = 1.9 Hz, 1H), 5.22 (t, J = 1.9
Hz, 1H), 6.11 (q, J = 1.0 Hz, 1H), 6.33 (d, J = 1.8 Hz, 1H), 6.95 (t, J =
1.4 Hz, 1H), 7.32 (d, J = 1.8 Hz, 1H); 13C NMR (176 MHz, CDCl3) δ
−5.1, 11.9, 17.7, 18.5, 24.5, 26.0, 29.7, 30.3, 39.4, 42.7, 42.8, 43.1, 57.1,
66.4, 73.2, 79.3, 79.4, 107.8, 111.4, 121.1, 125.5, 131.7, 136.4, 140.8,
141.8, 149.9, 154.3, 171.7; EI-HRMS m/z calcd for C35H57IO6Si2 [M]+
756.2738, found 756.2759.
More Polar Isomer. Rf 0.42 (75:25 hexanes/ethyl acetate); [α]D23
−2.0 (c 0.3, CHCl3); IR (neat) 3457, 2930, 2862, 1752, 1456 cm−1;
1H NMR (700 MHz, CDCl3) δ 0.12 (s, 3H), 0.14 (s, 3H), 0.94−0.93
(m, 30H), 1.93 (d, J = 1.0 Hz, 3H), 1.99−2.03 (m, 1H), 2.10 (ddd, J =
3.8, 10.4, 14.0 Hz, 1H), 2.54 (dd, J = 5.9, 10.4 Hz, 2H), 3.52 (dd, J =
7.0, 7.4 Hz, 1H), 3.59−3.63 (m, 1H), 4.47−4.48 (m, 1H), 4.50 (d, J =
12.1 Hz, 1H), 4.67 (d, J = 12.1 Hz, 1H), 4.99 (tt, J = 1.8, 5.7 Hz, 1H),
5.04−5.05 (m, 2H), 5.20 (s, 1H), 6.12 (q, J = 1.0 Hz, 1H), 6.33 (d, J =
J
dx.doi.org/10.1021/jo402485h | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
9.6 Hz, 2H), 5.04 (t, J = 2.0 Hz, 1H), 5.10 (qd, J = 2.0, 7.6 Hz, 1H),
5.19−5.22 (m, 2H), 6.07 (q, J = 0.7 Hz, 1H), 6.16 (dd, J = 1.9, 5.7 Hz,
1H), 6.18 (s, 1H), 7.18 (s, 1H), 7.50 (dd, J = 1.4, 5.7 Hz, 1H), 9.77 (t,
J = 1.8 Hz, 1H); 13C NMR (176 MHz, CDCl3) δ −5.1, 11.9, 14.1,
17.7, 18.4, 19.1, 22.7, 25.9, 29.4, 39.0, 42.6, 44.5, 48.1, 57.2, 73.1, 82.2,
108.1, 110.5, 117.9, 121.7, 123.2, 129.5, 147.3, 151.1, 156.1, 172.9,
200.8; CI-HRMS m/z calcd for C35H56O6Si2Na [M + Na]+ 651.3513,
found 651.3529.
Q.-N.; Lazareva, A. Synlett 2006, 3382. (c) Ferreira, E. M.; Zhang, H.;
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1994, 639.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: james.white@oregonstate.edu.
■
(22) Electron-withdrawing substituents on the furan of 12 provide
alternative sites to the cyclobutanone for attack by the nucleophilic
phosphorane.
Notes
The authors declare no competing financial interest.
(23) (a) Cases, M.; Turiso, G.; Pattenden, G. Synlett 2001, 1869.
(b) Cases, M.; Turiso, G.; Hadjisoteriou, M. S.; Pattenden, G. Org.
Biomol. Chem. 2005, 3, 2786. (c) Astley, M.; Pattenden, G. Synthesis
1992, 101.
(24) Heathcock, C. H.; Mclaughlin, M.; Medina, J.; Hubbs, J. L.;
Wallace, G. A.; Scott, R.; Claffey, M. M.; Hayes, C. J.; Ott, G. R. J. Am.
Chem. Soc. 2003, 125, 12844.
(25) Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc.
1985, 107, 6638.
(26) Schweizer, E.; Gaich, T.; Brecker, L.; Mulzer, J. Synthesis 2007,
3087.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation for
financial support of this work (0413994-CHE). Support for the
Oregon State University NMR Facility from the Murdock
Charitable Trust (Grant 2005265) and from the National
Science Foundation (CHE-0722319) is gratefully acknowl-
edged.
(27) (a) Lieg
J. Org. Chem. 2009, 74, 1826. (b) Rene,
12, 2116.
́
ault, B.; Laponte, D.; Caron, L.; Vlassova, A.; Fagnou, K.
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