Synthetic studies towards radicicol through biomimetic macrolactonization and transannular aromatization reactions

Article abstract of DOI:10.1002/ejoc.201402205

Studies towards the total synthesis of the natural product radicicol are described that employ a late-stage esterification and aromatization by trapping a ketene intermediate. The subsequent biomimetic aromatization of the resultant triketo ester gave hig

Full text of DOI:10.1002/ejoc.201402205

FULL PAPER
DOI: 10.1002/ejoc.201402205
Synthetic Studies towards Radicicol through Biomimetic Macrolactonization
and Transannular Aromatization Reactions
Rosa Cookson,[a] Christoph Pöverlein,[a][‡] Jennifer Lachs,[a] and Anthony G. M. Barrett*[a]
Keywords: Natural products / Biomimetic synthesis / Macrocycles / Lactones / Cyclization / Ketenes
Studies towards the total synthesis of the natural product rad-
icicol are described that employ a late-stage esterification
and aromatization by trapping a ketene intermediate. The
subsequent biomimetic aromatization of the resultant triketo
ester gave highly functionalized resorcylates. Two distinct
methods were examined that trap the ketene intermediate
through either an intermolecular or intramolecular process.
In the first approach, the synthesis of the resorcylate was fol-
lowed by a ring-closing metathesis, which gave the macro-
lactone and protected precursors to monocillin I. In the sec-
ond approach, an intramolecular ketene trapping was exam-
ined as an alternative to close the macrocycle and form the
resorcylate macrolactone. These studies showcased a wide
range of sensitive functional groups that tolerated the aroma-
tization reaction conditions, which started from the corre-
sponding dioxinone precursors.
Danishefsky,[6] and Winssinger[7] have previously reported
syntheses of radicicol, each of which functionalized a pre-
formed resorcylate core followed by a macrocyclization
step. Lett utilized a Mitsunobu reaction, whereas both
Danishefsky and Wissinger utilized a ring-closing alkene
metathesis reaction. These routes towards radicicol have in-
herent problems, such as difficulty preventing the formation
of isocoumarin side products. More importantly, the pre-
vious syntheses of radicicol are not readily adaptable to the
syntheses of its analogues. Although radicicol (2) shows ac-
tivity in vitro, it does not show activity in vivo, which makes
its analogues attractive targets, with their potential to retain
the anticancer activity and improve upon the pharmacoki-
netic properties.[8] Herein, we describe two routes towards
the total synthesis of radicicol (2) from diketo-dioxinone
precursors that proceed through either the intermolecular
or intramolecular trapping of a ketene intermediate fol-
lowed by biomimetic aromatization reactions (see
Scheme 1). This approach was inspired by the earlier work
of Harris and Harris on the biomimetic syntheses of resor-
cylates and of Hyatt on dioxinone thermolysis reactions as
Introduction
Radicicol (2), first isolated in 1953 from Monicillium nor-
dinii,[1] is a member of the large family of natural products
named resorcylic acid lactones, each of which contains a 6-
alkyl-2,4-dihydroxybenzoic acid or β-resorcylate unit that is
fused to a macrocyclic lactone ring (see Figure 1). Many
such resorcylates exhibit a wide array of biological activi-
ties.[2] For this reason, along with their interesting and often
complex structures, this class of compounds has inspired
many research groups to undertake their total syntheses.[2a]
Figure 1. Radicicol (2) with β-resorcylate unit shown in red.
Radicicol was initially shown to have mildly sedative and
antibiotic activities.[1,3] In the 1990s, it selectively inhibited
Hsp90 (IC50 of 20 nM), a molecular chaperone, thereby pre-
venting the proliferation of cancer cells to become a promis-
ing anticancer hit structure.[4] The three groups of Lett,[5]
[a] Department of Chemistry, Imperial College London,
South Kensington, London SW7 2AZ, England
E-mail: agm.barrett@imperial.ac.uk
www3.imperial.ac.uk/people/agm.barrett
[‡] Current address: Sanofi-Aventis Deutschland GmbH,
Industriepark Hoechst, 65926 Frankfurt am Main, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402205.
Scheme 1. General synthesis of resorcylates from dioxinone precur-
sors.
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well as the pioneering studies by Boeckman on using the of the resultant diketo-dioxinone with cesium acetate fol-
Hyatt approach to macrocyclization reactions.[9]
lowed by treatment with acetic acid and subsequent acetyl-
Our group has extended these studies to the biomimetic ation of the phenol unit gave the protected resorcylate 13
syntheses of several complex resorcylate natural products, in a one-pot procedure (68% yield). The subsequent macro-
which also have a diverse range of biological activities.[10] cyclization was carried out by using Grubbs–Hoveyda II
Triketo-ketene 4 was produced from the retro-Diels–Alder catalyst (16) to provide lactone 14 in a 27% unoptimized
fragmentation of diketo-dioxinone 3 and then trapped by yield. Unfortunately, problems arose with the attempted de-
the addition of an alcohol to form triketo ester 5. A subse- protection of ketal 14 under acidic conditions, which re-
quent base-catalyzed aldol cyclization and acid-promoted sulted in the preferential cleavage of the reactive epoxide
dehydration of the triketo ester gave resorcylate 6. This ver- ring. However, in spite of this problem, the methods in
satile method tolerated diverse and sensitive functional Scheme 3 represent a concise approach to resorcylate lact-
groups. Herein, we report that the preparation of resorcyl- ones related to radicicol (2).
ates from dioxinone precursors may be applied to the total
synthesis of radicicol (2), which contains sensitive function-
ality, as well as to the syntheses of a number of related
resorcylates.
As a consequence of the problems with the attempted
deprotection of ketal 14, we examined the aromatization
and macrocyclization steps by using the corresponding silyl-
protected alcohol. In this venture, we first focused our at-
tention on the generation of Weinreb amide 18a. Hydroxy-
alkylation of the enolate derived from N-methoxy-N-meth-
ylacetamide[12] (17) with sorbic aldehyde followed by pro-
tection of the alcohol as triisopropylsilyl ether 18a (see
Scheme 4) proceeded in 75% yield. Subsequent C-acylation
of the dianion derived from keto-dioxinone 10 with amide
18a gave the required adduct 19a in 66% yield.
The coheating of diketo-dioxinone 19a with alcohol 8
and the subsequent aromatization proceeded without diffi-
culty to give the desired resorcylate 20a in 74% yield by
following the same procedure as before. In this instance, it
was not possible to protect the phenol groups in the same
flask. Nevertheless, acetyl protection was carried out in
98% yield, and the ring-closing metathesis by using the
Grubbs–Hoveyda II catalyst (16) gave macrocyclic lactone
21a in 57% yield as a mixture of the two diastereomers (see
Scheme 5).
Results and Discussion
In the first approach, we considered that the resorcylate
unit could be constructed by trapping the ketene intermedi-
ate from diketo-dioxinone 9 with known alcohol 8.[6] This
highly convergent route would combine the three key frag-
ments, keto-dioxinone 10,[10d] Weinreb amide 11, and
alcohol 8. Upon its generation, diketo-dioxinone 9 could be
submitted to the retro-Diels–Alder and aromatization reac-
tion to give resorcylate 7. Macrolactonization could be ac-
complished through a ring-closing alkene metathesis, which
is closely modelled on the Danishefsky synthesis, to yield
the (E,Z) double-bond geometry, as illustrated in the retro-
synthetic analysis (see Scheme 2).
Weinreb amide 11 was synthesized in three steps from
sorbic acid (12, see Scheme 3). The Claisen condensation of
the dianion derived from keto-dioxinone 10 with Weinreb
The attempted desilylation of 21a by using tetrabutylam-
amide 11 proceeded in superior yield in the presence of di- monium fluoride was unsuccessful, and the starting mate-
ethylzinc, as previously reported by our group.[11] This reac- rial was recovered. In contrast, the use of alternative
tion gave diketo-dioxinone 9, which was used immediately sources of fluoride such as tetrabutylammonium difluoro-
in subsequent reactions without characterization because of triphenylsilicate, hexafluorosilicic acid, and pyridinium
its high reactivity. The reaction of diketo-dioxinone 9 and hydrogen fluoride resulted in the opening of the reactive
alcohol 8[6] in toluene at reflux proceeded through a retro- epoxide ring. We were unable to use basic conditions for
Diels–Alder reaction and alcohol trapping. Aromatization the desilylation to avoid the well-known isocoumarin for-
Scheme 2. An intermolecular ketene trapping approach to radicicol (2).
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Synthetic Studies towards Radicicol
Scheme 3. Synthesis of resorcylate 14 (THF = tetrahydrofuran, pTSA = p-toluenesulfonic acid, DMAP = 4-(dimethylamino)pyridine,
DMSO = dimethyl sulfoxide).
Scheme 4. Synthesis of diketo-dioxinones 19a and 19b.
mation.[6] As a consequence of these difficulties, we next
investigated tert-butyldimethylsilyl-protected analogue 19b,
which was readily synthesized by an equivalent pathway
(see Scheme 4).
The ketene trapping and aromatization sequence of diox-
inone 19b and alcohol 8 proceeded smoothly, and subse-
quent protection of the phenol groups gave resorcylate 22b.
Interestingly, the attempted macrocyclization of triene 22b
through the ring-closing metathesis proceeded in very poor
yield (Ͻ5% yield), despite varying the catalyst loading, di-
lution, reaction time, and solvent for this process (see
Scheme 5).
Scheme 5. Synthesis of macrocycle 21a and attempted synthesis of
21b (TIPS = triisopropylsilyl, TBS = tert-butyldimethylsilyl).
Porco reported similar problems with regard to the at-
tempted ring-closing metatheses and proposed that this was hyde 26[6] and the ylide derived from phosphonium salt
possibly the result of the formation of a low reactivity ruth- 25[14] along with the subsequent desilylation gave alcohol
enium complex such as 24b.[13] To bypass this problem, the 27 in 67% yield for the two steps (see Scheme 6). Alcohol
use of a tether and metathesis relay strategy was employed 27 and diketo-dioxinone 19b were converted into the corre-
to favor the formation of the initial ruthenium complex at sponding resorcylate (64% yield) by using the standard pro-
the desired terminus. This would be driven by the elimi- cedure. The subsequent acetylation gave resorcylate
nation of cyclopentene before the actual ring-closing could tetraene 28 in 97% yield. Much to our delight, the alkene
occur. Thus, the Wittig reaction between the known alde- relay and ring-closing metathesis by using the Hoveyda–
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Grubbs II catalyst (16) proceeded smoothly at 60 °C to give incorporated into the generation of resorcylate lactones by
the resorcylate lactone 21b (75% yield).
the Barrett group.[16]
The Wittig reaction of aldehyde 26 with the ylide derived
from phosphonium salt 34 under Stork conditions[17] gave
the desired cis-alkene 32 as an inseparable mixture with
trans-alkene 35, an unidentifiable impurity, and diiodo-sub-
stituted alkene 36, a side product which has previously been
reported (see Scheme 8).[18] The assignments of these struc-
tures were tentatively determined by 1H NMR spectro-
scopic analysis of the crude mixture.
Scheme 6. Synthesis of tethered alcohol 27 and macrocycle 21b.
Lactone 21b also could not be converted into monocil-
lin I (1), as the desilylation of ether 21b proved again to
be insurmountably difficult because of the reactivity of the
epoxide ring. Against expectations, the tert-butyldimethyl-
silyl protecting group was not sufficiently labile, and its re-
moval was not possible. These results highlight the particu-
larly unstable nature of the conjugated diene-epoxide moi-
ety under multiple deprotection conditions. In contrast, our
aromatization reaction proceeded under sufficiently mild
conditions, and the epoxide survived intact.
Following these studies, we examined the intramolecular
trapping of a triketo-ketene intermediate with an alcohol to
form the radicicol (2) core. This is illustrated in the retro-
Scheme 8. Synthesis of iodo-substituted alkene 32.
Since we were unable to produce pure cis-alkene 32 by
synthetic analysis shown in Scheme 7. We considered that this method, an alternative route was used. Aldehyde 26
fragments 32 and 33 could be linked through a Suzuki cou- was converted into alkyne 38 in 66% yield by using the
pling reaction followed by an aldol reaction of keto-diox- Ohira–Bestmann reagent 37. The alkyne was readily iodin-
inone 30[15] with aldehyde 31. The early incorporation of ated to give iodoalkyne 39 in excellent yields with N-iodo-
chlorine would serve to bypass the known, moderate yield succinimide and silver nitrate. This was subsequently re-
for the chlorination reaction of monocillin I (1) to produce duced to give the desired cis-alkene 32 in 78% over the two
radicicol (2). The intramolecular trapping of a ketene was steps by employing the diimide that was derived from sulf-
first reported by Paquette and has since been successfully onamide 40 (see Scheme 8).
Scheme 7. Intramolecular approach to radicicol (2) (TBDPS = tert-butyldiphenylsilyl, TES = triethylsilyl).
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Synthetic Studies towards Radicicol
With the iodide component for the Suzuki coupling in ation at this stage. Fortunately, hydroxyalkylation of the di-
hand, our attention turned to synthesis of boronate ester anion derived from keto-dioxinone 10 with aldehyde 31 was
33 (see Scheme 9). β-Propiolactone (41) was treated with successful and gave the required adduct 49 in 73% yield.
N,O-dimethylhydroxylamine hydrochloride, and the result-
ant amide was protected by treatment with triethylsilyl
chloride to give Weinreb amide 42 in 72% yield over the
two steps. This was converted into alkyne 43 by the reaction
with ethynyltrimethylsilane and nBuLi (94% yield). The un-
stable alkynone was protected through the reaction with
ethylene glycol, trimethyl orthoformate, and a catalytic
quantity of 4-toluenesulfonic acid to give its ketal derivative
in 68% yield. This reaction also resulted in loss of the tri-
ethylsilyl protecting group. The removal of the trimethylsilyl
group gave the free alkyne in 83% yield, whereupon the
alcohol was reprotected by triethylsilylation in quantitative
yield to give ketal-alkyne 44. Alkyne 44 was converted into
boronic ester 33 in 76% yield by treatment with neat pin-
acol borane at 70 °C for 6 d.
Scheme 11. Formation of β-hydroxy keto-dioxinone 49.
The oxidation of alcohol 49 with Dess–Martin
periodinane (DMP) gave unstable diketo-dioxinone 50,
which decomposed upon an attempted desilylation. In con-
trast, the desilylation of keto-dioxinone 49 with tetrabut-
ylammonium fluoride gave the corresponding alcohol 51 in
79% yield (see Scheme 12). We briefly examined the ther-
molysis of diol-dioxinone 51, as we expected that ketene
trapping to form the macrocyclic lactone would be favored
Scheme 9. Generation of pinacol boronic ester 33 (TMS = trimeth-
over the eight-membered ring lactone. However, when diol
51 was heated in toluene, only an intractable mixture of
products was obtained.
ylsilyl, pin = pinacol).
Boronic ester 33 and iodo-substituted alkene 32 success-
fully underwent a Suzuki coupling by using Pd(PPh3)4 and
aqueous cesium carbonate in THF at 55 °C to furnish
(E,Z)-diene 45 in 71% yield (see Scheme 10). The removal
of the triethylsilyl group at 0 °C by treatment with tetra-
butylammonium fluoride gave the primary alcohol, which
was readily oxidized to give aldehyde 31 in 76% yield for
the two steps.
Scheme 10. Coupling of fragments 32 and 33.
Scheme 12. Generation of diketo-dioxinone 50 and diol 51.
The attempted addition of the dianion that was derived
from chloro-substituted keto-dioxinone 30 with aldehyde 31
was not successful (see Scheme 11). The attempted aldol re-
action of the dianion derived from 30 with butyraldehyde
(47) was very slow and ultimately gave epoxide 48, but in
Conclusions
Two concise strategies towards the synthesis of radicicol
only 19% yield, which showed the impracticality of chlorin- (2) and related macrolactones have been investigated. The
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R. Cookson, C. Pöverlein, J. Lachs, A. G. M. Barrett
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4.14 (q, J = 7.1 Hz, 2 H), 4.02–3.87 (m, 4 H), 2.77 (s, 2 H), 1.75
(d, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(100.7 MHz, CDCl3): δ = 168.9, 131.7, 131.2, 130.1, 128.5, 106.5,
64.7 (2 C), 60.5, 44.3, 18.1, 14.2 ppm. HRMS [CI+ (chemical ion-
ization)]: calcd. for C12H19O4 [M + H]+ 227.1278; found 227.1285.
biomimetic intermolecular route provides a simple and
functional group tolerant pathway towards the resorcylates
and incorporates both the esterification and aromatization
steps through a reliable one-pot procedure. It is particularly
noteworthy that the protected precursor (i.e., ketal 14) to
monocillin I (1) was obtained in 10 steps as its longest lin-
ear sequence. Further studies of resorcylate chemistry for
use with both total synthesis and medicinal chemistry will
be reported in due course.
N-Methoxy-N-methyl-2-(2-penta-1,3-dienyl-1,3-dioxolan-2-yl)acet-
amide (11): nBuLi (1.6 m in hexane, 2.4 mL, 3.80 mmol, 3.0 equiv.)
was added to Me(MeO)NH·HCl (180 mg, 1.89 mmol, 1.5 equiv.) in
dry THF (25 mL) at –78 °C. The reaction mixture was warmed to
room temperature, and ethyl (2-penta-1,3-dienyl-[1,3]dioxolan-2-yl)
acetate (290 mg, 1.26 mmol, 1.0 equiv.) was added. The mixture
was then stirred for 16 h. Saturated aqueous NH4Cl (10 mL), brine
(10 mL), and EtOAc (75 mL) were added, and the pH of the aque-
ous layer was adjusted to Ͻ3 by the addition of aqueous HCl (2 m).
The layers were separated, and the organic layer was washed with
brine (10 mL), dried with MgSO4, and filtered. All volatiles were
removed in vacuo, and the residue was purified by chromatography
(hexanes/EtOAc, 2:1) to provide 11 (61 mg, 0.25 mmol, 20% yield)
as a colorless oil that consisted of the (Z) and (E) geometric iso-
mers in a ratio of 1:3.7. The NMR spectroscopic data are given for
Experimental Section
General Methods: All reactions were carried out at room tempera-
ture in oven-dried glassware under dry N2 or Ar, unless otherwise
stated. The reaction solvents THF and PhMe were distilled over
Na/Ph2CO under N2, and MeOH, CH2Cl2, and Et3N were distilled
over CaH2 under N2. H2O refers to redistilled H2O. Other solvents
and all reagents were obtained from commercial suppliers, and they
were used as obtained if the purity was Ͼ98%. Flash chromatog-
raphy was performed with Merck silica gel 60 particle size 40–
63 mm (eluents are given in parentheses). Hexanes refer to petro-
the major (E) geometric isomer. IR (neat): ν = 1664, 1438, 1383,
˜
1181, 1117, 1033, 995, 950 cm–1. 1H NMR (400 MHz, CDCl3): δ =
6.34 (dd, J = 10.6, 15.3 Hz, 1 H), 6.05 (m, 1 H), 5.75 (m, 1 H),
5.66 (d, J = 15.3 Hz, 1 H), 4.02–3.85 (m, 4 H), 3.68 (s, 3 H), 3.17
(s, 3 H), 2.95 (s, 2 H), 1.74 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100.7 MHz, CDCl3): δ = 169.7, 131.4, 130.7, 130.3, 129.3, 107.1,
64.6 (2 C), 61.2, 40.9, 32.0, 18.2 ppm. HRMS (ESI+): calcd. for
C12H19NNaO4 [M + Na]+ 264.1206; found 264.1220.
leum spirits with
a boiling range of 40–60 °C. Thin layer
chromatography was performed on precoated aluminum-backed
plates (Merck Kieselgel 60 F254), and the visualization was ac-
complished under UV light (254 nm) and by staining with aqueous
potassium permanganate or vanillin followed by gentle heating
with a heat gun. IR spectra were recorded neat. The 1H and 13C
NMR spectroscopic data were recorded at 400 or 500 MHz and at
100 or 125 MHz, respectively. The chemical shifts (δ) are reported
in parts per million (ppm) and referenced to the solvent peak (re-
(2R,4R,5R)-1-Methyl-2-(3-ethenyloxiranyl)ethyl 2,4-Diacetoxy-6-
(2-penta-1,3-dienyl-1,3-dioxolan-2-ylmethyl)benzoate (13): Keto-di-
oxinone 10 (260 mg, 1.40 mmol, 1.0 equiv.) was added to freshly
prepared LiN(iPr)2 (3.10 mmol, 2.2 equiv.) in dry THF (30 mL) at
–78 °C, and the temperature was increased to –60 °C over 1 h.
Et2Zn (1 m in THF, 2.8 mL, 2.80 mmol, 2.0 equiv.) was added drop-
wise. After 30 min at –40 °C, N-methoxy-N-methyl-2-(2-penta-1,3-
dienyl-1,3-dioxolan-2-yl)acetamide (11, 350 mg, 1.45 mmol,
1.1 equiv.) was added with stirring, and the temperature was kept
below –10 °C for 2.5 h. Aqueous citric acid (10% solution, 20 mL)
and EtOAc (100 mL) were added, and the layers were separated.
The organic layer was washed with brine (10 mL), dried with
MgSO4, and filtered. All volatiles were removed in vacuo, and the
residue was purified by chromatography (CH2Cl2/EtOAc, 5:1) to
obtain dioxinone 9 (320 mg, 0.88 mmol, 63% yield) as a pale yellow
oil. This compound was too unstable for full characterization and
was used in the subsequent reaction immediately upon isolation.
Dioxinone 9 (198 mg, 0.54 mmol, 1.0 equiv.) and alcohol 8 (77 mg,
0.600 mmol, 1.1 equiv.) were heated in PhMe (5 mL) at 110 °C for
2 h. After complete consumption of dioxinone 9, as determined by
TLC analysis, CH2Cl2 (5 mL), iPrOH (5 mL), and CsOAc (500 mg,
2.50 mmol, 5.0 equiv.) were added. The resulting mixture was
stirred for 2 h, and then AcOH (3.0 mL, approximately 100 equiv.)
1
sidual CHCl3 for H NMR, δ = 7.26 ppm; CDCl3 for 13C NMR,
δ = 77.00 ppm). Coupling constants (J) are reported in Hertz (Hz)
to the nearest 0.1 Hz.
Ethyl 2-[(1E,3E)-Penta-1,3-dienyl]-1,3-dioxolan-2-yl)acetate: Oxalyl
chloride (10.3 mL, 120 mmol, 1.2 equiv.) was added dropwise with
stirring to a suspension of sorbic acid 12 (11 g, 100 mmol) in
CH2Cl2 (50 mL). After 16 h, all volatiles were removed in vacuo,
and the crude acid chloride was used directly in the following reac-
tion. EtOAc (12 mL, 120 mmol, 1.2 equiv.) was added with stirring
to freshly prepared LiN(SiMe3)2 (220 mmol, 2.2 equiv.) in dry THF
(200 mL) at –78 °C. After 30 min, the crude sorbyl chloride
(100 mmol, 1.0 equiv.) in THF (20 mL) was added dropwise, and
the reaction mixture was stirred at –78 °C for 1 h. Saturated aque-
ous NH4Cl (50 mL), brine (50 mL), and Et2O (500 mL) were
added, and the pH of the aqueous layer was adjusted to Ͻ3 by the
addition of aqueous HCl (2 m). The layers were separated, and the
organic layer was washed with brine (100 mL), dried with MgSO4,
and filtered. All volatiles were removed in vacuo, and the residue
was dissolved in dry PhMe (100 mL). A mixture of (EtO)3CH
(33 mL, 200 mmol, 2.0 equiv.), ethylene glycol (34 mL, 600 mmol), was added. After 1 h, the reaction mixture was concentrated in
and pTSA·H2O (1.0 g, 5.30 mmol, 0.05 equiv.), which was kept at
20 mbar and at 40 °C for 1 h, was added with stirring to the PhMe
solution of the crude β-keto ester. After 16 h, the reaction mixture
was concentrated in vacuo, and the residue was purified by
chromatography (hexanes/EtOAc, 20:1 to 5:1) to obtain the title
compound (17 g, 74.0 mmol, 74% yield) as a colorless oil that con-
sisted of both the (Z) and (E) geometric isomers in a ratio of 1:4.0.
The NMR spectroscopic data are given for the major (E) geometric
vacuo, and the residue was dissolved in THF (20 mL). Ac2O
(4.0 mL) and DMAP (61 mg) were added. After 30 min, the reac-
tion mixture was concentrated in vacuo, and the residue was puri-
fied by chromatography (hexanes/EtOAc, 5:1) to give ester 13
(190 mg, 0.370 mmol, 68% yield) as a colorless oil that consisted
of a mixture of (Z) and (E) geometric isomers in a 1:3.9 ratio. The
NMR spectroscopic data are given for the major (E) geometric
isomer. [α]2D5 = –1.4 (c = 0.95, CH Cl ). IR (neat): ν = 1771, 1722,
˜
2
2
1
isomer. IR (neat): ν = 1734, 1370, 1174, 1097, 1035, 991, 948 cm–1. 1612, 1369, 1281, 1187, 1135, 1035, 990, 907, 753 cm–1. H NMR
˜
1H NMR (400 MHz, CDCl3): δ = 6.34 (dd, J = 10.4, 15.3 Hz, 1 (400 MHz, CDCl3): δ = 6.98 (d, J = 2.1 Hz, 1 H), 6.86 (d, J =
H), 6.02 (m, 1 H), 5.80–5.72 (m, 1 H), 5.57 (d, J = 15.3 Hz, 1 H),
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2.1 Hz, 1 H), 6.28 (dd, J = 10.6, 15.2 Hz, 1 H), 6.01 (m, 1 H), 5.57
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Synthetic Studies towards Radicicol
(qd, J = 6.7, 13.4 Hz, 1 H), 5.61–5.43 (m, 3 H), 5.34–5.25 (m, 2
–78 °C, and the temperature was increased to –60 °C over 1 h.
H), 3.73–3.66 (m, 2 H), 3.50–3.45 (m, 2 H), 3.36 (d, J = 14.0 Hz, Et2Zn (1 m in THF, 4.0 mL, 4.02 mmol, 2.0 equiv.) was added drop-
1 H), 3.20 (d, J = 14.0 Hz, 1 H), 3.12 (dd, J = 2.0, 7.3 Hz, 1 H), wise. After 30 min at –40 °C, Weinreb amide 18a (710 mg,
2.95 (td, J = 2.0, 5.9 Hz, 1 H), 2.27 (s, 3 H), 2.25 (s, 3 H), 2.00– 2.01 mmol, 1.0 equiv.) was added, and the mixture was stirred for
1.87 (m, 2 H), 1.76 (d, J = 6.9 Hz, 3 H), 1.43 (d, J = 6.4 Hz, 3 2.5 h, as the temperature was kept below –10 °C. Saturated aqueous
H) ppm. 13C NMR (100.7 MHz, CDCl3): δ = 168.8, 168.6, 165.1, NH4Cl (10 mL), brine (10 mL), and Et2O (200 mL) were added,
151.0, 149.0, 137.3, 135.3, 132.3, 131.4, 130.5, 130.3, 130.1, 123.6,
119.5, 115.0, 108.0, 69.6, 64.9, 64.9, 58.3, 56.7, 41.8, 38.0, 21.1,
21.0, 19.6, 18.2 ppm. HRMS (ESI+): calcd. for C27H32NaO9 [M +
Na]+ 523.1939; found 523.1936.
and the pH of the aqueous layer was adjusted to Ͻ3 by the addition
of aqueous HCl (2 m). The layers were separated, and the organic
layer was washed with brine (10 mL), dried with MgSO4, and fil-
tered. All volatiles were removed in vacuo, and the residue was
purified by chromatography (hexanes/EtOAc, 15:1) to obtain dioxi-
none 19a (650 mg, 1.36 mmol, 66% yield) as a colorless oil that
consisted of both the (Z) and (E) geometric isomers in a 1:5.8 ratio.
The NMR spectroscopic data are given for the major (E) geometric
(1aR,2Z,4E,14R,15aR)-14-Methyl-12-oxo-1a,7,12,14,15,15a-hexa-
hydrospiro{benzo[c]oxireno[2,3-k][1]oxacyclotetradecine-6,2Ј-1,3-
dioxolane}-9,11-diyl Diacetate (14): Triene 13 (150 mg, 0.300 mmol)
was dissolved in CH2Cl2 (250 mL), and the solution was heated at
reflux for 20 min under N2. Grubbs–Hoveyda II catalyst (16,
56 mg, 0.0900 mmol, 30 mol-%) was added in one portion, and the
reaction mixture was kept at 40 to 45 °C for 4 h. DMSO (0.1 mL)
was added, and the mixture was stirred overnight. All volatiles were
removed in vacuo, and the residue was purified by chromatography
(hexanes/EtOAc, 5:1 to 5:2) to obtain macrocycle 14 (37 mg,
80.7 μmol, 27 % yield) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 7.48 (d, J = 2.2 Hz, 1 H), 6.87 (d, J = 2.2 Hz, 1 H),
6.61 (dd, J = 9.5, 15.9 Hz, 1 H), 6.00 (t, J = 10.2 Hz, 1 H), 5.61
(d, J = 15.9 Hz, 1 H), 5.39 (dd, J = 4.8, 10.9 Hz, 1 H), 5.23 (m, 1
H), 4.10–3.96 (m, 4 H), 3.43 (m, 1 H), 3.42 (d, J = 15.0 Hz, 1 H),
3.16 (d, J = 15.3 Hz, 1 H), 2.99 (m, 1 H), 2.31 (ddd, J = 3.6, 5.6,
15.0 Hz, 1 H), 2.27 (s, 3 H), 2.23 (s, 3 H), 1.68 (ddd, J = 3.5, 7.1,
15.0 Hz, 1 H), 1.51 (d, J = 6.4 Hz, 3 H) ppm. 13 C NMR
(100.7 MHz, CDCl3): δ = 168.5, 168.3, 165.2, 151.5, 148.4, 137.3,
132.8 130.9, 129.5, 128.2, 125.0, 121.1, 114.9, 108.7, 69.8, 65.1,
64.6, 55.7, 54.8, 38.2, 36.9, 21.1, 20.9, 19.1 ppm. HRMS (ESI+):
calcd. for C24H26NaO9 [M + Na]+ 481.1469; found 481.1475.
isomer: IR (thin film): ν = 2943, 2866, 1735, 1615, 1389, 1376,
˜
1272, 1204, 1015, 985, 883, 680 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 15.01 (br. s, 1 H), 6.11 (dd, J = 10.4, 15.1 Hz, 1 H), 6.03–5.95
(m, 1 H), 5.72–5.63 (m, 1 H), 5.56–5.47 (m, 1 H), 5.55 (s, 1 H),
5.36 (s, 1 H), 4.66 (q, J = 6.7 Hz, 1 H), 3.19 (s, 2 H), 2.56 (dd, J =
7.0, 13.7 Hz, 1 H), 2.42 (dd, J = 5.9, 13.7 Hz, 1 H), 1.74 (d, J =
6.4 Hz, 3 H), 1.68 (s, 6 H), 1.04–1.02 (m, 21 H) ppm. 13C NMR
(100.7 MHz, CDCl3): δ = 189.0, 188.7, 164.9, 160.7, 132.3, 130.6,
130.5, 130.2, 107.1, 101.5, 96.3, 70.9, 47.2, 43.6, 24.92, 24.85, 18.1,
18.0, 12.3 ppm. HRMS (ESI+): calcd. for C26H42NaO6Si+ [M +
Na]+ 501.2643; found 501.2637.
(2R,4R,5R)-1-Methyl-2-(3-ethenyloxiranyl)ethyl 2,4-Dihydroxy-6-
(2-triisopropylsilyloxy-hepta-3,5-dienyl)benzoate (20a): Dioxinone
19a (500 mg, 1.02 mmol, 1.0 equiv.) and alcohol 8 (150 mg,
1.20 mmol, 1.2 equiv.) were heated in PhMe (2.0 mL) at 110 °C for
2 h. The reaction mixture was concentrated in vacuo, and the resi-
due was dissolved in CH2Cl2 (5 mL) and iPrOH (5 mL). CsOAc
(960 mg, 5.00 mmol, 5.0 equiv.) was added. The mixture was stirred
for 2 h, whereupon AcOH (3.0 mL, approximately 50 equiv.) was
added. After 12 h, EtOAc (80 mL), water (5 mL), and brine (5 mL)
were added, and the layers were separated. The organic layer was
washed with brine (4 mL) and dried with MgSO4, and all volatiles
were removed in vacuo. The residue was dissolved in PhMe (2 mL),
and purification by chromatography (hexanes/Et2O, 7:1) produced
resorcylate 20a (400 mg, 0.750 mmol, 74% yield) as a colorless oil
that consisted of an inseparable mixture of diastereomers [CH-OSi-
(4E,6E)-N-Methoxy-N-methyl-3-[(triisopropylsilyl)oxy]octa-4,6-
dienamide (18a): Amide 17 (1.0 g, 10.0 mmol, 1.0 equiv.) was added
with stirring to freshly prepared LiN(iPr)2 (11.0 mmol, 1.1 equiv.)
in dry THF (25 mL) at –78 °C. After 30 min, sorbic aldehyde
(0.96 g, 10.0 mmol, 1.0 equiv.) was added in one portion, and after
10 min, the solution was warmed to 0 °C. iPr3SiCl (2.3 mL,
11.0 mmol, 1.1 equiv.) was added at 0 °C, and the mixture was
warmed to room temperature overnight. Saturated aqueous NH4Cl
(10 mL), brine (10 mL), and Et2O (150 mL) were added, and the
pH of the aqueous layer was adjusted to Ͻ3 by the addition of
aqueous HCl (2 m). The layers were separated, and the organic
layer was washed with brine (10 mL), dried with MgSO4, and fil-
tered. All volatiles were removed in vacuo, and the residue was
purified by chromatography (hexanes/EtOAc, 30:1 to 15:1) to ob-
tain amide 18a (2.7 g, 7.51 mmol, 75% yield) as a colorless oil that
consisted of both the (Z) and (E) geometric isomers in a 1:8.8 ratio.
The NMR spectroscopic data are given for the major (E) geometric
(iPr) ]. IR (thin film): ν = 3383, 1646, 1619, 1449, 1310, 1257, 1104,
˜
3
988, 882, 679 cm–1. 1H NMR (400 MHz, CDCl3): δ = [11.66, 11.53]
(s, 1 H), 6.30 (br. s, 2 H), 6.14–5.94 (m, 2 H), 5.70–5.61 (m, 1 H),
5.60–5.37 (m, 5 H), 5.30–5.24 (m, 1 H), 4.50–4.42 (m, 1 H), 3.53–
3.32 (m, 1 H), 3.16–3.08 (m, 1 H), 2.96–2.86 (m, 1 H), 2.75–2.67
(m, 1 H), 2.02–1.94 (m, 2 H), 1.78–1.72 (m, 3 H), 1.47–1.42 (m, 3
H), 0.93 (s, 21 H) ppm. 13C NMR (100.7 MHz, CDCl3): δ = [170.7,
170.6], [165.3, 164.9], [159.9, 159.8], [144.0, 143.9], [135.0, 134.8],
[133.9, 133.7], 130.8, [130.1, 129.9], [129.5, 129.4], [119.8, 119.7],
[113.7, 113.4], [106.0, 105.6], 101.9, [74.2, 74.0], [70.2, 70.1], [58.4,
58.2], [57.0, 56.9], [45.1, 44.7], [38.2, 38.2], [20.1, 20.1], 18.1, [18.0,
18.0] (6 C), 12.50 (3 C) ppm. N.B.: The data in square brackets
correspond to the signals for the diastereomers. HRMS (ESI+):
calcd. for C30H46NaO6Si [M + Na]+ 553.2956; found 553.2962.
isomer. IR (neat): ν = 1665, 1463, 1384, 1085, 1067, 990, 884, 746,
˜
680 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.16 (dd, J = 10.4,
15.2 Hz, 1 H), 6.03–5.95 (m, 1 H), 5.70–5.55 (m, 2 H), 4.80 (q, J
= 6.8 Hz, 1 H), 3.67 (s, 3 H), 3.15 (s, 3 H), 2.81 (dd, J = 6.3,
14.5 Hz, 1 H), 2.52 (dd, J = 6.6, 14.5 Hz, 1 H), 1.73 (d, J = 6.9 Hz,
3 H), 1.04 (s, 21 H) ppm. 13C NMR (100.7 MHz, CDCl3): δ =
171.6, 133.3, 130.8, 130.0, 129.5, 70.4, 61.3, 41.3, 31.9, 18.1, 18.0
(6 C), 12.3 (3 C) ppm. HRMS (ESI+): calcd. for C19H37NNaO3Si
[M + Na]+ 378.2435; found 378.2455.
(2R,4R,5R)-1-Methyl-2-(3-ethenyloxiranyl)ethyl 2,4-Diacetoxy-6-
(2-triisopropylsilyloxy-hepta-3,5-dienyl)benzoate: Resorcylate 20a
(290 mg, 0.506 mmol, 1.0 equiv.) was dissolved in THF (15 mL),
and Ac2O (3.0 mL, excess) and DMAP (13 mg, 0.101 mmol,
0.20 equiv.) were added. After 1 h, EtOAc (200 mL), H2O (20 mL),
saturated aqueous NaHCO3 (4 mL), and brine (20 mL) were
added, and the layers were separated. The organic layer was washed
with brine (2ϫ 20 mL), dried with MgSO4, and concentrated in
vacuo to give (2R,4R,5R)-1-methyl-2-(3-ethenyloxiranyl)ethyl 2,4-
6-{(2Z,7E,9E)-2-Hydroxy-4-oxo-6-[(triisopropylsilyl)oxy]undeca-
2,7,9-trien-1-yl}-2,2-dimethyl-4H-1,3-dioxin-4-one (19a): Keto-diox-
inone 10 (370 mg, 2.01 mmol, 1.0 equiv.) was added to freshly pre-
pared LiN(iPr)2 (4.22 mmol, 2.1 equiv.) in dry THF (40 mL) at
Eur. J. Org. Chem. 2014, 4523–4535
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4529

R. Cookson, C. Pöverlein, J. Lachs, A. G. M. Barrett
FULL PAPER
diacetoxy-6-(2-triisopropylsilyloxy-hepta-3,5-dienyl)benzoate
(330 mg, 0.537 mmol, 98% yield) as a colorless oil that consisted
of an inseparable mixture of diastereomers [CH-OSi(iPr)3]. The
product was used in the ring-closing metathesis step without fur-
THF (60 mL) at –78 °C. After 1 h, sorbic aldehyde (5.2 mL,
47.5 mmol, 1.0 equiv.) in THF (20 mL) was added dropwise, and
the reaction mixture was stirred at –78 °C for 30 min. The reaction
was quenched by the addition of saturated aqueous NH4Cl
(50 mL), and the mixture was warmed to room temperature. The
ther purification. IR (thin film): ν = 1778, 1725, 1613, 1464, 1429,
˜
1369, 1274, 1192, 1137, 1090, 989, 884, 681 cm–1
.
1H NMR layers were separated, and the aqueous layer was extracted with
(400 MHz, CDCl3): δ = 6.99–6.96 (m, 1 H), 6.87–6.86 (m, 1 H), Et2O (3ϫ 30 mL). The combined organic layers were washed with
6.08–5.93 (m, 2 H), 5.68–5.43 (m, 4 H), 5.33–5.24 (m, 2 H), 4.55–
4.44 (m, 1 H), 3.13–3.08 (m, 1 H), 2.96–2.82 (m, 3 H), 2.26 (s, 3
H), 2.24 (s, 3 H), 1.93–1.88 (m, 2 H), 1.76–1.72 (m, 3 H), 1.44–1.39
saturated aqueous NH4Cl (50 mL) and brine (50 mL), dried with
Na2SO4, and concentrated in vacuo. The residue was purified by
chromatography (EtOAc/hexanes, 1:3) to give the title amide (6.4 g,
(m, 3 H), 0.96–0.94 (m, 21 H) ppm. 13C NMR (100.7 MHz, 32.1 mmol, 68% yield) as a light brown oil that consisted of both
CDCl3): δ = [168.4, 168.4], 165.4, 151.0, 148.5, [139.4, 139.4], 135.2, the (Z) and (E) geometric isomers in a ratio of 1:7.5. The NMR
133.3, 133.1, 130.8, [130.4, 130.3], 129.6, [124.6, 124.6], [122.5,
122.4], [119.6, 119.5], 114.6, 73.9, 69.9, [58.1, 58.1], 56.6, [43.0,
42.9], [38.0, 38.0], 21.0, 20.9, [19.8, 19.7], 18.1, [18.0, 17.9] (6 C),
12.4 (3 C). N.B.: The data in square brackets correspond to
the signals for the diastereomers. HRMS (ESI+): calcd. for
C34H50NaO8Si [M + Na]+ 637.3167; found 637.3164.
spectroscopic data are given for the major (E) geometric isomer. IR
1
(thin film): ν = 3438, 1651, 1387, 1179, 1108, 987 cm–1. H NMR
˜
(400 MHz, CDCl3): δ = 6.27 (dd, J = 15.3, 10.4 Hz, 1 H), 6.05
(ddd, J = 14.9, 10.5, 1.4 Hz, 1 H), 5.73 (dq, J = 13.4, 6.6 Hz, 1 H),
5.61 (dd, J = 15.3, 6.2 Hz, 1 H), 4.67–4.51 (m, 1 H), 3.67 (s, 3 H),
3.18 (s, 3 H), 2.64 (dt, J = 16.7, 12.6 Hz, 2 H), 1.80–1.70 (m, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 173.2, 131.2, 130.8,
130.7, 130.1, 68.5, 61.3, 38.4, 31.8, 18.1 ppm. HRMS (ESI+): calcd.
for C10H17NO3 [M + Na]+ 222.1106; found 222.1105.
(1aR,2Z,4E,14R,15aR)-14-Methyl-12-oxo-6-[(triisopropylsilyl)oxy]-
6,7,12,14,15,15a-hexahydro-1aH-benzo[c]oxireno[2,3-k][1]oxa-
cyclotetradecine-9,11-diyl Diacetate (21a): (2R,4R,5R)-1-Methyl-2-
(3-ethenyloxiranyl)ethyl 2,4-diacetoxy-6-(2-triisopropylsilyloxy-
(4E,6E)-3-(tert-Butyldimethylsilyloxy)-N-methoxy-N-methylocta-
hepta-3,5-dienyl)benzoate (120 mg, 0.195 mmol, 1.0 equiv.) was 4,6-dienamide (18b): tBuMe2SiCl (1.1 g, 7.33 mmol, 1.1 equiv.) and
dissolved in CH2Cl2 (250 mL), and the solution was heated at re-
flux for 20 min under N2. Grubbs–Hoveyda II catalyst (16, 13 mg,
20.7 μmol, 10 mol-%) was added in one portion, and the reaction
mixture was kept at 40 to 45 °C for 7 h. DMSO (1 mL) was added,
and the mixture was stirred overnight. The solution was washed
with H2O (30 mL) and H2O/brine (1:1, 30 mL) and then dried with
MgSO4. All volatiles were removed in vacuo. The resultant dia-
stereomers 21aI and 21aII (65 mg, 0.113 mg, 57% yield) were sepa-
rated by chromatography (hexanes/EtOAc, 10:1) to obtain 21aI
imidazole (0.5 g, 7.33 mmol, 1.1 equiv.) were added with stirring to
(4E,6E)-3-hydroxy-N-methoxy-N-methylocta-4,6-dienamide (1.3 g,
6.66 mmol, 1.0 equiv.) in CH2Cl2 (20 mL). After 16 h, the reaction
was quenched by the addition of saturated aqueous NH4Cl
(20 mL), and the layers were separated. The aqueous layer was ex-
tracted with Et2O (3ϫ 20 mL), and the combined organic layers
were washed with saturated aqueous NH4Cl (40 mL) and brine
(50 mL), dried with Na2SO4, and concentrated in vacuo. The resi-
due was purified by chromatography (Et2O/hexanes, 1:10 to 1:5)
(30 mg) and 21aII (35 mg), which were both colorless oils. Data for give amide 18b (1.7 g, 5.53 mmol, 83% yield) as a pale yellow oil
21aI: IR (thin film): ν = 1777, 1721, 1611, 1464, 1428, 1369, 1282,
that consisted of both the (Z) and (E) geometric isomers in a ratio
of 1:6.8. The NMR spectroscopic data are given for the major (E)
˜
1194, 1137, 1084, 915, 884, 681 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.12 (d, J = 2.2 Hz, 1 H), 6.87 (d, J = 2.2 Hz, 1 H), 6.28 (dd,
geometric isomer. IR (thin film): ν = 1662, 1077, 987, 829,
˜
J = 9.3, 15.8 Hz, 1 H), 6.02 (m, 1 H), 5.71 (dd, J = 5.6, 15.8 Hz, 1 776 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.17 (dd, J = 15.2,
H), 5.34 (dd, J = 4.7, 10.8 Hz, 1 H), 5.19 (m, 1 H), 4.81 (q, J = 10.4 Hz, 1 H), 6.05–5.98 (m, 1 H), 5.71–5.63 (m, 1 H), 5.57 (dd, J
5.7 Hz, 1 H), 3.42 (m, 1 H), 3.33 (dd, J = 5.0, 14.8 Hz, 1 H), 3.06 = 14.8, 6.4 Hz, 1 H), 4.70 (dd, J = 12.8, 6.0 Hz, 1 H), 3.68 (s, 3
(dd, J = 6.9, 14.8 Hz, 1 H), 2.99 (ddd, J = 2.5, 3.5, 6.9 Hz, 1 H),
2.37 (ddd, J = 3.7, 7.5, 14.9 Hz, 1 H), 2.27 (s, 3 H), 2.25 (s, 3 H),
1.64 (ddd, J = 2.9, 7.2, 14.9 Hz, 1 H), 1.50 (d, J = 6.3 Hz, 3 H),
H), 3.17 (s, 3 H), 2.84 (dd, J = 14.4, 8.0 Hz, 1 H), 2.40 (dd, J =
14.4, 5.2 Hz, 1 H), 1.74 (d, J = 5.2 Hz, 3 H), 0.86 (s, 9 H), 0.04 (s,
3 H), 0.03 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 189.7,
1.06 (m, 21 H) ppm. 13C NMR (100.7 MHz, CDCl3): δ = 168.4, 133.1, 130.8, 129.5, 129.5, 70.3, 61.4, 40.7, 31.9, 25.8 (3 C), 25.6,
168.4, 165.6, 151.4, 148.8, 139.2, 137.2, 131.4, 127.7, 126.0, 124.5,
120.9, 114.7, 71.9, 70.1, 56.2, 54.5, 40.1, 37.2, 21.1, 20.9, 19.6, 18.0
(6 C), 12.3 (3 C) ppm. HRMS (ESI+): calcd. for C31H45O8Si [M +
18.1, –4.5, –5.0 ppm. HRMS (ESI+): calcd. for C16H31NO3Si [M
+ Na]+ 336.1971; found 336.1978.
6-[(2Z,7E,9E)-6-(tert-Butyldimethylsilyloxy)-2-hydroxy-4-oxo-
undeca-2,7,9-trienyl]-2,2-dimethyl-4H-1,3-dioxin-4-one (19b): Keto-
dioxinone 10 (2.1 g, 11.5 mmol, 2.0 equiv.) in dry THF (20 mL)
was added with stirring to freshly prepared LiN(iPr)2 (23.0 mmol,
4.0 equiv.) in dry THF (100 mL) at –78 °C, and the mixture was
warmed to –40 °C. After 1 h, amide 18b (1.8 g, 5.74 mmol,
1.0 equiv.) in dry THF (10 mL) was added with stirring at –40 °C.
After 2 h, the mixture was acidified to pH = 4 by the addition of
10% aqueous citric acid (approximately 100 mL), and the resulting
mixture was warmed to room temperature. The layers were sepa-
rated, and the aqueous layer was extracted with EtOAc (3 ϫ
50 mL). The combined organic layers were washed with brine
(100 mL), dried with Na2SO4, and concentrated in vacuo. The resi-
due was purified by chromatography (EtOAc/hexanes, 1:5) to give
dioxinone 19b (1.9 g, 4.31, 75% yield) as a pale yellow oil. IR (thin
H]+ 573.2878; found 573.2873. Data for 21aII: IR (thin film): ν =
˜
1775, 1723, 1611, 1464, 1426, 1369, 1277, 1193, 1138, 1087, 910,
883, 683 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.17 (d, J =
.
1.8 Hz, 1 H), 6.86 (d, J = 2.3 Hz, 1 H), 6.18 (dd, J = 7.5, 16.2 Hz,
1 H), 6.04 (m, 1 H), 5.67 (dd, J = 3.9, 15.7 Hz, 1 H), 5.17 (dd, J =
7.2, 11.1 Hz, 1 H), 5.04 (m, 1 H), 4.63 (m, 1 H), 3.55 (dd, J = 1.4,
7.1 Hz, 1 H), 3.41 (dd, J = 9.5, 14.5 Hz, 1 H), 3.07 (dd, J = 3.6,
14.5 Hz, 1 H), 2.98 (m, 1 H), 2.28 (s, 3 H), 2.26 (s, 3 H), 2.23 (m,
1 H), 1.92 (ddd, J = 2.1, 4.3, 15.6 Hz, 1 H), 1.44 (d, J = 6.3 Hz, 3
H), 1.11 (m, 21 H) ppm. 13C NMR (100.7 MHz, CDCl3): δ = 168.4,
168.3, 165.1, 151.6, 148.9, 139.9, 135.8, 132.4, 128.3, 124.9, 124.6,
120.6, 114.7, 73.5, 68.2, 56.1, 54.0, 39.0, 35.9, 21.2, 21.0, 19.9, 18.1
(6 C), 12.4 (3 C) ppm. HRMS (ESI+): calcd. for C31H45O8Si [M +
H]+ 573.2878; found 573.2868.
(4E,6E)-3-Hydroxy-N-methoxy-N-methylocta-4,6-dienamide:
Amide 17 (6.0 g, 50.0 mmol, 1.1 equiv.) in THF (20 mL) was added
dropwise with stirring to freshly prepared LiN(iPr)2 (65.0 mmol) in
film): ν = 1733, 1609, 1376, 1272, 1016, 837 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 6.12 (dd, J = 14.8, 10.4 Hz, 1 H), 5.99
(ddd, J = 14.8, 10.4, 1.2 Hz, 1 H), 5.72–5.64 (m, 1 H), 5.55 (s, 1
4530
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4523–4535

Synthetic Studies towards Radicicol
H), 5.47 (dd, J = 14.8, 6.8 Hz, 1 H), 5.36 (s, 1 H), 4.53 (dd, J = in THF, 3.0 mL, 3.01 mmol, 1.1 equiv.) were added sequentially
13.2, 6.8 Hz, 1 H), 3.19 (s, 2 H), 2.44–2.39 (m, 2 H), 1.76 (d, J =
6.8 Hz, 3 H), 1.68 (s, 6 H), 0.83 (s, 9 H), –0.01 (s, 3 H), –0.02 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 189.0, 189.0, 165.0,
with stirring to the crude tert-butyl[(R)-1-{(2R,3R)-3-[(Z)-hepta-
1,6-dienyl]oxiran-2-yl}propan-2-yloxy]diphenylsilane in THF
(20 mL). After 2 h, silica gel (400 mg) was added, and the solvent
160.6, 132.2, 130.5 (2 C), 130.2, 107.1, 101.6, 96.3, 70.6, 46.8, 43.6, was removed in vacuo. The residue was purified by chromatography
25.7 (3 C), 25.0, 24.8, 18.1 (2 C), –4.4, –5.2 ppm. HRMS (ESI+): to give diene 27 (360 mg, 1.84 mmol, 67% yield) as a colorless oil.
calcd. for C23H36O6Si [M + Na]+ 459.2179; found 459.2193.
[α]2D5 = +20.2 (c = 1.0, CHCl ). IR (thin film): ν = 3410, 1457, 1110,
˜
3
992, 908 cm–1. H NMR (400 MHz, CDCl3): δ = 5.85–5.86 (m, 2
1
5-{(3E,5E)-2-[(tert-Butyldimethylsilyl)oxy]hepta-3,5-dien-1-yl}-4-
[({(R)-1-[(2R,3R)-3-ethenyloxiran-2-yl]propan-2-yl}oxy)carbonyl]-
1,3-phenylene Diacetate (22b): Dioxinone 19b (221 mg, 0.504 mmol,
1.3 equiv.) and alcohol 8 (50 mg, 0.390 mmol, 1.0 equiv.) in dry
PhMe (5 mL) were heated to reflux for 3 h, and then the reaction
mixture was cooled to room temperature and concentrated in
vacuo. The residue was dissolved in MeOH (10 mL), and Cs2CO3
(640 mg, 1.95 mmol, 5.0 equiv.) was added. After 3 h, glacial AcOH
(2.5 mL) was added, and the mixture was stirred for 2 h. The reac-
tion was quenched by the addition of brine (5 mL), and the layers
were separated. The aqueous layer was extracted with EtOAc (2ϫ
10 mL). The combined organic layers were washed with saturated
aqueous NaHCO3 (10 mL) and brine (10 mL), dried with Na2SO4,
and concentrated in vacuo. The crude material was filtered through
a plug of silica and then used directly in the next step. The crude
(R)-1-[(2R,3R)-3-ethenyloxiran-2-yl]propan-2-yl-2-{(3E,5E)-2-
[(tert-butyldimethylsilyl)oxy]hepta-3,5-dien-1-yl}-4,6-dihydroxy
benzoate in dry THF (15 mL) was added with stirring to DMAP
(4.8 mg, 39.0 μmol, 10 mol-%) and Ac2O (0.11 mL, 1.17 mmol,
3.0 equiv.) at room temperature, and the mixture was stirred for
2 h. The reaction was quenched by the addition of water (15 mL),
and the layers were separated. The aqueous layer was extracted
with EtOAc (3 ϫ 15 mL). The combined organic layers were
washed with water (30 mL), saturated aqueous NaHCO3 solution
(30 mL), and brine (30 mL) and then dried with MgSO4. The or-
ganic phase was concentrated in vacuo, and the residue was puri-
fied by chromatography (EtOAc/hexanes, 1:6) to give resorcylate
H), 5.06–4.93 (m, 3 H), 4.12–4.04 (m, 1 H), 3.38 (dd, J = 1.6,
8.8 Hz, 1 H), 3.00–2.96 (m, 1 H), 2.30–2.06 (m, 4 H), 1.89–1.83 (m,
1 H), 1.63–1.47 (m, 3 H), 1.24 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 138.3, 136.7, 126.8, 114.9, 66.5, 58.2, 5.9,
40.8, 33.1, 28.6, 27.0, 23.4 ppm. HRMS (ESI+): calcd. for
C12H20O2 [M + H]+ 197.1542; found 197.1542.
(R)-1-{(2R,3R)-3-[(Z)-Hepta-1,6-dien-1-yl]oxiran-2-yl}propan-2-yl
4-Acetoxy-2-{(3E,5E)-2-[(tert-butyldimethylsilyl)oxy]hepta-3,5-dien-
1-yl}-6-hydroxybenzoate: Diketo-dioxinone 19b (140 mg,
0.330 mmol, 1.3 equiv.) and alcohol 27 (50 mg, 0.255 mmol,
1.0 equiv.) in PhMe (12 mL) were heated at reflux for 3 h, and the
reaction mixture was then cooled to room temperature and concen-
trated in vacuo. The residue was dissolved in dry CH2Cl2 (8 mL)
and iPrOH (4 mL), and the resulting mixture was heated over mo-
lecular sieves (4 Å, 200 mg) in a sealed tube to 100 °C for 16 h.
The reaction mixture was cooled to room temperature and filtered
through a plug of Celite® (CH2Cl2), and the filtrate was concen-
trated in vacuo. The residue was purified by chromatography
(Et2O/hexanes, 1:9) to give the title resorcylate (89 mg, 0.163 mmol,
64% yield) as a colorless oil. [α]2D5 = –26.4 (c = 1.0, CHCl3). IR
(thin film): ν = 3327, 1644, 1310, 1254, 1103, 833, 774 cm–1. 1H
˜
NMR (400 MHz, CDCl3): δ = [11.70 and 11.63] (2 s, 1 H), 6.31–
6.30 (m, 1 H), 6.26–6.24 (m, 1 H), 6.21–6.14 (m, 1 H), 6.09–6.02
(m, 1 H), 5.83–5.75 (m, 1 H), 5.72–5.66 (m, 2 H), 5.61–5.56 (m, 1
H), 5.49–5.41 (m, 1 H), 5.26–5.21 (m, 1 H), 5.04–4.96 (m, 3 H),
4.32–4.30 (m, 1 H), 3.51–3.46 (m, 1 H), 3.37–3.34 (m, 1 H), 2.95–
triene 22b (94 mg, 0.164 mmol 42% yield) as a colorless oil. IR 2.91 (m, 1 H), [2.82–2.76 and 2.65–2.59] (2 m, 1 H), 2.25–2.07 (m,
(thin film): ν = 1774, 1723, 1188, 1136, 837, 778 cm–1. 1H NMR
4 H), 2.03–1.92 (m, 2 H), 1.76 (d, J = 6.8 Hz, 3 H), 1.52–1.49 (m,
˜
(400 MHz, CDCl3): δ = 6.95–6.93 (m, 1 H), 6.88–6.87 (m, 1 H), 2 H), 1.46 (d, J = 6.4 Hz, 3 H), [0.78 and 0.77] (2 s, 9 H), [–0.19
6.16–6.07 (m, 1 H), 6.04–5.98 (m, 1 H), 5.69–5.63 (m, 1 H), 5.58–
5.43 (m, 3 H), 5.34–5.25 (m, 2 H), 4.38–4.28 (m, 1 H), 3.13–3.10
and –0.20] (2 s, 3 H), [–0.36 and –0.37] (2 s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = [170.7, 170.7], [165.4, 165.2], [159.8, 159.7],
(m, 1 H), 2.96–2.85 (m, 2 H), 2.74–2.68 (m, 1 H), 2.26 (s, 3 H), [144.3, 144.3], 138.3, 136.8, 133.6, 130.9, [139.8, 129.7], 129.4,
[2.25, 2.24] (m, 3 H), 1.94–1.89 (m, 2 H), 1.74 (d, J = 6.8 Hz, 3 H), 126.6, 114.9, [113.8, 113.5], [105.9, 105.5], 101.9, [73.6, 73.4], [70.1,
1.45–1.39 (m, 3 H), 0.79 (s, 9 H), [–0.15, –0.16] (2 s, 3 H), [–0.29, 70.1], 56.7, [53.8, 53.8], [44.9, 44.6], [38.4, 38.2], 33.1, 28.6, 27.0,
–0.30] (2 s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = [168.5, [25.8 (3 C), 25.8 (3 C)], [20.2, 20.2], [18.1, 18.1], [–4.8, –4.8], [–5.4
168.4], 165.4, 151.0, 148.6, [139.8, 139.7], 135.1, [133.2, 133.1],
–5.4] ppm. N.B.: The data in the square brackets correspond to
130.8, [130.0, 130.0], 129.5, 124.4, [122.7, 122.6], [119.6, 119.6], the signals for the diastereomers (CH-OSitBuMe2), one carbon is
114.7, 73.3, 70.0, [58.2, 58.1], 56.6, [42.7, 42.7], [38.0, 38.0], 25.8 (6
C), [21.0, 21.0], 19.8, 19.7, [18.1, 18.0], –4.8, –5.4 ppm; N.B.: The
data in square brackets correspond to the signals for the dia-
stereomers (CH-OSitBuMe2). HRMS (ESI+): calcd. for C31H44O8-
SiNa [M + Na]+ 595.2703; found 595.2693.
missing as a result of overlapping signals. HRMS (ESI+): calcd.
for C32H48O6SiNa [M + Na]+ 579.3118; found 579.3126.
5-{(3E,5E)-2-[(tert-Butyldimethylsilyl)oxy]hepta-3,5-dien-1-yl}-4-
{[(R)-1-{(2R,3R)-3-[(Z)-hepta-1,6-dien-1-yl]oxiran-2-yl}propan-2-
yloxy]carbonyl}-1,3-phenylene Diacetate (28): DMAP (5 mg,
10 mol-%) was added dropwise to (R)-1-{(2R,3R)-3-[(Z)-hepta-1,6-
(R)-1-{(2R,3R)-3-[(Z)-Hepta-1,6-dienyl]oxiran-2-yl}propan-2-ol
(27): NaN(SiMe3)2 (1.0 m in THF, 4.9 mL, 4.90 mmol, 1.8 equiv.) dien-1-yl]oxiran-2-yl}propan-2-yl 4-acetoxy-2-{(3E,5E)-2-[(tert-
was added dropwise with stirring to phosphonium salt 25 (2.5 g, butyldimethylsilyl)oxy]hepta-3,5-dien-1-yl}-6-hydroxybenzoate
5.21 mmol, 1.9 equiv.) in THF (20 mL) at 0 °C. After 30 min, the (210 mg, 0.357 mmol, 1.0 equiv.) in dry THF (40 mL) at 0 °C. Ac2O
solution was cooled to –10 °C, and aldehyde 26 (1.0 g, 2.74 mmol,
1.0 equiv.) in THF (10 mL) was added dropwise. The mixture was
stirred at –10 °C for 2 h, and the reaction was quenched by the
addition of saturated aqueous NH4Cl (10 mL). The layers were sep-
arated, and the aqueous layer was extracted with EtOAc (3 ϫ
10 mL). The combined organic layers were washed with brine
(20 mL), dried with Na2SO4, and concentrated in vacuo. The crude
material was filtered through a plug of silica and then used directly
in the next step. Molecular sieves (4 Å, 900 mg) and Bu4NF (1.0 m
(0.18 mL, 1.85 mmol, 5.0 equiv.) was added, and the mixture was
stirred for 1 h. The solvent was removed in vacuo, and the residue
was immediately purified by chromatography (EtOAc/hexanes, 1:9)
to furnish tetraene 28 (230 mg, 0.346 mmol, 97% yield) as a color-
less oil. [α]2D5 = –22.4 (c = 0.8, CHCl ). IR (thin film): ν = 2929,
˜
3
2856, 1774, 1724, 1187, 1133, 835, 776 cm–1. H NMR (400 MHz,
1
CDCl3): δ = 6.95–6.93 (m, 1 H), 6.88–6.87 (m, 1 H), 6.16–6.07 (m,
1 H), 6.04–5.98 (m, 1 H), 5.85–5.62 (m, 3 H), 5.56–5.49 (m, 1 H),
5.35–5.29 (m, 1 H), 5.05–4.96 (m, 3 H), 4.38–4.29 (m, 1 H), 3.38–
Eur. J. Org. Chem. 2014, 4523–4535
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4531

R. Cookson, C. Pöverlein, J. Lachs, A. G. M. Barrett
FULL PAPER
3.34 (m, 1 H), 2.96–2.94 (m, 1 H), 2.90–2.86 (m, 1 H), 2.74–2.68
(d, J = 6.2 Hz, 3 H), 1.06 (s, 9 H) ppm. 13C NMR (101 MHz,
(m, 1 H), 2.27 (s, 3 H), 2.25 (s, 3 H), 2.22–2.16 (m, 2 H), 2.10–2.03 CDCl3): δ = 135.8 (2 C), 135.8 (2 C), 134.3, 133.9, 129.7, 129.6,
(m, 2 H), 1.94–1.89 (m, 2 H), 1.74 (d, J = 6.4 Hz, 3 H), 1.54–1.47 127.7 (2 C), 127.5 (2 C), 80.4, 71.8, 67.2, 57.4, 44.7, 41.1, 27.0 (3
(m, 2 H), 1.45–1.41 (m, 3 H), 0.80 (s, 9 H), –0.13 to –0.16 (m, 3
H), –0.29 to –0.30 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 168.4, 165.4, 151.0, 148.6, 138.3, [136.8, 136.8], [133.2, 133.1],
130.8, [130.0, 130.0], [129.6, 129.8], 128.6, 126.7, 125.3, 124.4,
122.7, 114.9, 114.7, 73.3, 70.0, 56.3, 53.9, 42.7, [38.2, 38.1], 33.1,
28.6, 27.1, 25.7 (5 C), [21.0, 21.0], [19.8, 19.7], [18.1, 18.0], –4.8,
–5.4 ppm; N.B.: The data in square brackets correspond to the sig-
nals for the diastereomers (CH-OSitBuMe2). HRMS (ESI+): calcd.
for C36H52O8Si [M + Na]+ 663.3329; found 663.3337.
C), 23.2, 19.2 ppm. HRMS (CI+): calcd. for C23H32NO2Si [M +
NH4]+ 382.2202; found 382.2189.
tert-Butyl({(R)-1-[(2R,3R)-3-(iodoethynyl)oxiran-2-yl]propan-2-
yl}oxy)diphenylsilane (39): AgNO3 (160 mg, 0.914 mmol, 0.2 equiv.)
was added with stirring to acetylene 38 (1.7 g, 4.57 mmol,
1.0 equiv.) and N-iodosuccinimide (1.2 g, 5.48 mmol, 1.2 equiv.) in
Me2CO (40 mL) in the dark. After 1 h, the reaction mixture was
quenched by the addition of ice-cold water (40 mL). The aqueous
layer was extracted with EtOAc (3ϫ 50 mL), and the combined
organic layers were washed with brine (50 mL), dried with MgSO4,
and concentrated in vacuo. The residue was purified by chromatog-
raphy (hexanes/EtOAc, 50:1) to give alkynyl iodide 39 (2.2 g,
4.53 mmol, 98% yield) as a yellow oil. [α]2D5 = +48.3 (c = 0.77,
(1aR,2Z,4E,14R,15aR)-6-[(tert-Butyldimethylsilyl)oxy]-14-methyl-
12-oxo-6,7,12,14,15,15a-hexahydro-1aH-benzo[c]oxireno[2,3-k][1]-
oxacyclotetradecine-9,11-diyl Diacetate (21b): Tetraene 28 (12 mg,
20.0 μmol, 1.0 equiv.) in dry ClCH2CH2Cl (10 mL) was heated to
60 °C in a sealed tube. Hoveyda–Grubbs II catalyst (16, 2.3 mg,
0.2 mol-%) was added in one portion, and the mixture was heated
at 60 °C for 3 h. The solvent was removed in vacuo, and the residue
was purified by chromatography (EtOAc/hexanes, 1:9) to give
macrocycle 21b (8 mg, 0.0150 mmol, 75% yield) as a colorless oil
CH Cl ). IR (thin film): ν = 1428, 1112, 1025, 822, 740, 702 cm–1.
˜
2
2
1H NMR (500 MHz, CDCl3): δ = 7.69–7.66 (m, 4 H), 7.45–7.42
(m, 2 H), 7.40–7.36 (m, 4 H), 4.05 (app. sextet, J = 6.0 Hz, 1 H),
3.25 (td, J = 5.8, 2.1 Hz, 1 H), 3.11 (d, J = 2.1 Hz, 1 H), 1.73–1.68
(m, 1 H), 1.61–1.56 (m, 1 H), 1.14 (d, J = 6.2 Hz, 3 H), 1.06 (s, 9
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 135.8 (2 C), 135.8 (2
C), 134.2, 133.8, 129.7, 129.6, 127.7 (2 C), 127.5 (2 C), 90.9, 67.2,
57.7, 46.1, 41.1, 27.0 (3 C), 23.2, 19.2, 1.5 ppm. HRMS (ESI+):
calcd. for C23H28IO2Si [M + H]+ 491.0903; found 491.0901.
that consisted of an inseparable mixture of diastereomers. IR (thin
1
film): ν = 1776, 1724, 1367, 1258, 1191, 1137, 837 cm–1. H NMR
˜
(500 MHz, CDCl3): δ = [7.13 (d, J = 2.0 Hz, 1 H), 7.07 (d, J =
2.0 Hz, 1 H)], [6.88 (d, J = 2.1 Hz, 1 H), 6.87 (d, J = 2.1 Hz, 1 H)],
[6.30–6.25 (m, 1 H), 6.19–6.14 (m, 1 H)], 6.08–6.02 (m, 2 H), [5.68
(dd, J = 12.8, 4.4 Hz, 1 H), 5.61 (ddd, J = 12.4, 2.8, 1.0 Hz, 1 H)],
[5.37 (dd, J = 10.8, 4.4 Hz, 1 H)], [5.23–5.19 (m, 1 H)], [5.14 (dd,
J = 11.2, 7.6 Hz, 1 H)], [5.02–4.99 (m, 1 H)], [4.68–4.64 (m, 1 H),
4.52–4.48 (m, 1 H)], [3.59–3.57 (m, 1 H), 3.43–3.41 (m, 1 H)], [3.36
(dd, J = 11.2, 7.6 Hz, 1 H), 3.22 (dd, J = 11.6, 4.0 Hz, 1 H)], 3.03–
2.98 (m, 4 H), [2.40 (ddd, J = 8.8, 6.0, 2.8 Hz, 1 H), 2.27 (m, 1 H)],
2.29–2.25 (m, 12 H), [1.98–1.94 (m, 1 H), 1.63 (ddd, J = 12.0, 5.6,
2.0 Hz, 1 H)], [1.49 (d, J = 6.4 Hz, 3 H), 1.43 (d, J = 5.2 Hz, 3 H)],
[0.96 (s, 9 H), 0.88 (s, 9 H)], [0.17 (s, 3 H), 0.14 (s, 3 H)], [0.04 (s,
3 H), 0.02 (s, 3 H)] ppm. 13C NMR (126 MHz, CDCl3): δ = [168.4,
168.4], [168.3, 168.2], [165.7, 165.1], [151.7, 151.3], [149.0, 148.8],
[139.8, 138.8], [137.1, 135.4], [132.4, 131.3], [128.4, 127.6], [126.2,
125.5], [124.6, 124.6], [121.1, 120.7], [114.8, 114.8], [73.5, 72.3],
[70.3, 68.1], [56.3, 56.1], [54.4, 53.6], [40.5, 39.3], [37.4, 35.8], [25.8
(3 C), 25.8 (3 C)], [21.1, 21.1], [21.0, 20.9], [20.0, 19.7], [18.2, 18.1],
[–4.6, –4.6], [–4.6, –4.7] ppm. N.B.: The data in square brackets
correspond to the signals for the diastereomers (CH-OSitBuMe2).
HRMS (ESI+): calcd. for C28H38O8SiNa [M + Na]+ 553.2234;
found 553.2236.
tert-Butyl{[(R)-1-{(2R,3R)-3-[(Z)-2-iodoethenyl]oxiran-2-yl}-
propan-2-yl]oxy}diphenylsilane (32): In the dark, sulfonamide 40
(790 g, 3.66 mmol, 1.1 equiv.) was added with stirring to iodoal-
kyne 39 (1.6 g, 3.32 mmol, 1.0 equiv.) in iPrOH/THF (1:1, 40 mL).
Subsequently, Et3N (0.69 mL, 4.98 mmol, 1.5 equiv.) was added
with stirring. After 24 h, TLC analysis showed that the reaction
had not reached completion, and additional sulfonamide 40
(290 mg, 1.33 mmol, 0.4 equiv.) and Et3N (0.25 mL, 1.65 mmol,
0.5 equiv.) were added with stirring. After 16 h, the mixture was
diluted with Et2O (50 mL), and the solution was washed with 10%
aqueous NaCl (5 ϫ 50 mL). The organic phase was dried with
MgSO4 and concentrated in vacuo. The residue was purified by
chromatography (hexanes/EtOAc, 100:1) to give alkenyl iodide 32
(1.3 g, 2.66 mmol, 80 % yield) as a yellow solid; m.p. 50–52 °C
(CH2Cl2). [α]2D5 = –27.4 (c = 2.19, CH Cl ). IR (thin film): ν = 1428,
˜
2
2
1380, 1272, 1111, 1074, 1040, 1025 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 7.69–7.66 (m, 4 H), 7.45–7.36 (m, 6 H), 6.49 (dd, J =
7.9, 1.0 Hz, 1 H), 5.94 (t, J = 7.8 Hz, 1 H), 4.09 (app. sextet, J =
5.5 Hz, 1 H), 3.32 (ddd, J = 7.7, 2.1, 1.1 Hz, 1 H), 3.08 (dt, J =
5.9, 2.2 Hz, 1 H), 1.83–1.78 (m, 1 H), 1.75–1.69 (m, 1 H), 1.16 (d,
J = 6.2 Hz, 3 H), 1.06 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 138.3, 135.8 (2 C), 135.8 (2 C), 134.4, 134.0 129.7, 129.6, 127.7
(2 C), 127.5 (2 C), 84.8, 67.5, 60.1, 56.7, 41.4, 27.0 (3 C), 23.4,
19.2 ppm. HRMS (CI+): calcd. for C23H30IO2Si [M + H]+
493.1060; found 493.1048.
tert-Butyl({(R)-1-[(2R,3R)-3-ethynyloxiran-2-yl]propan-2-yl}oxy)-
diphenylsilane (38): K2CO3 (2.3 g, 16.6 mmol, 2.3 equiv.) was added
to aldehyde 26 (2.7 g, 7.21 mmol, 1.0 equiv.) in MeOH (90 mL) at
0 °C. Dimethyl (1-diazo-2-oxopropyl)phosphonate (37, 1.9 mg,
10.1 mmol, 1.4 equiv.) in MeOH (25 mL) was then added slowly,
and the reaction mixture was stirred at 0 °C for an additional 3 h.
The mixture was diluted with Et2O (100 mL), and the mixture was
washed with saturated aqueous NaHCO3 (150 mL). The phases
were separated, and the aqueous phase was extracted with Et2O
(3ϫ 150 mL). The combined organic layers were washed with brine
(150 mL), dried with MgSO4, and concentrated in vacuo. The resi-
due was purified by chromatography (hexanes/EtOAc, 50:1) to give
acetylene 38 (1.7 g, 4.75 mmol, 66% yield) as a colorless oil. [α]2D5
3-Hydroxy-N-methoxy-N-methylpropanamide: The reaction was
carried out in triplicate in parallel. Me2AlCl (1.0 m in hexanes,
200 mL, 200 mmol, 4.0 equiv.) was added with stirring to N,O-Me-
O(Me)NH·HCl (9.8 g, 100 mmol, 2.0 equiv.) in CH3CN (160 mL)
at 0 °C. The reaction mixture was then warmed to room tempera-
ture and stirred for 1 h. After cooling the mixture to 0 °C, β-pro-
piolactone 41 (3.6 g, 50.0 mmol, 1.0 equiv.) was added, and the
solution was warmed to room temperature over 16 h. The reaction
= +30.5 (c = 0.97, CH Cl ). IR (thin film): ν = 1427, 1380, 1110,
˜
2
2
1074, 997, 878, 821, 700 cm–1. 1H NMR (400 MHz, CDCl3): δ = was quenched by the addition of aqueous HCl (0.5 m, 400 mL) at
7.69–7.66 (m, 4 H), 7.45–7.36 (m, 6 H), 4.06 (app. sextet, J = 0 °C, and the phases were separated. The aqueous phase was ex-
6.0 Hz, 1 H), 3.27 (td, J = 5.6, 2.2 Hz, 1 H), 3.03 (dd, J = 2.3, tracted with CH2Cl2 (8ϫ 150 mL). The organic layers were com-
1.6 Hz, 1 H), 2.32 (d, J = 1.6 Hz, 1 H), 1.74–1.59 (m, 2 H), 1.14 bined, dried with MgSO4, and concentrated in vacuo. The residue
4532
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4523–4535

Synthetic Studies towards Radicicol
was purified by chromatography (EtOAc/MeOH, 99:1) to give the
title amide (14 g, 109 mmol, 73% yield) as a colorless oil. IR (thin
2-(2-Ethynyl-1,3-dioxolan-2-yl)ethanol: K2CO3 (1.6 g, 11.3 mmol,
1.2 equiv.) was added with stirring to 2-{2-[(trimethylsilyl)ethynyl]-
1,3-dioxolan-2-yl}ethanol (2.0 g, 9.38 mmol, 1.0 equiv.) in MeOH
(40 mL). After 2 h, water (100 mL) was added, and the aqueous
film): ν = 3421 (br.), 1638, 1463, 1387, 1179, 1055, 1036, 992 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 3.86 (app. q, J = 5.0 Hz, 2 H),
3.68 (s, 3 H), 3.18 (s, 3 H), 3.07 (t, J = 6.5 Hz, 1 H), 2.66 (t, J = phase was extracted with CH2Cl2 (3ϫ 100 mL). The combined or-
4.9 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 173.8, 61.2,
58.2, 33.8, 31.9 ppm. HRMS (ESI+): calcd. for C5H12NO3 [M +
H]+ 134.0817; found 134.0814.
ganic phases were washed with brine (100 mL), dried with MgSO4,
and concentrated in vacuo. The residue was purified by chromatog-
raphy (hexanes/Et2O, 1:1) to give the title acetylene (1.1 g,
7.78 mmol, 83% yield) as a pale yellow oil. IR (thin film): ν = 3403
˜
N-Methoxy-N-methyl-3-[(triethylsilyl)oxy]propanamide (42):
Et3SiCl (13 mL, 78.2 mmol, 1.1 equiv.) was added with stirring to
3-hydroxy-N-methoxy-N-methylpropanamide (9.5 g, 71.1 mmol,
1.0 equiv.) and Et3N (12 mL, 85.3 mmol, 1.2 equiv.) in CH2Cl2
(60 mL) at 0 °C. After 15 min, the ice bath was removed, and the
mixture was stirred for 16 h. The mixture was filtered, and the fil-
trate was washed with saturated aqueous NaHCO3 (300 mL), water
(br.), 3278, 1196, 1108, 1066, 1028, 946 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 4.18–4.12 (m, 2 H), 4.09–4.06 (m, 2 H), 3.91 (td, J =
5.8, 5.3 Hz, 2 H), 2.59 (s, 1 H), 2.45 (t, J = 5.6 Hz, 1 H), 2.24 (t, J
= 5.5 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 102.6, 80.8,
72.6, 64.6 (2 C), 58.3, 40.9 ppm. HRMS (EI+): calcd. for C7H10O3
[M]+ 142.0630; found 142.0642.
(300 mL), and brine (300 mL), dried with MgSO4, and concen- Triethyl[2-(2-ethynyl-1,3-dioxolan-2-yl)ethoxy]silane (44): Et3SiCl
trated in vacuo. The residue was purified by chromatography (hex-
anes/EtOAc, 8:1) to give amide 42 (18 g, 70.5 mmol, 99% yield) as
(1.7 mL, 10.0 mmol, 1.2 equiv.) was added with stirring to 2-(2-
ethynyl-1,3-dioxolan-2-yl)ethanol (1.2 g, 8.36 mmol, 1.0 equiv.) and
Et3N (1.5 mL, 10.9 mmol, 1.3 equiv.) in CH2Cl2 (12 mL) at 0 °C.
After 15 min, the ice bath was removed, and the mixture was stirred
for 16 h and then filtered through Celite®. The filtrate was washed
with saturated aqueous NaHCO3 (100 mL), water (100 mL), and
brine (100 mL), dried with MgSO4, and concentrated in vacuo. The
a colorless oil. IR (thin film): ν = 1665, 1461, 1416, 1383, 1093,
˜
1
1005 cm–1. H NMR (400 MHz, CDCl3): δ = 3.94 (t, J = 6.6 Hz,
2 H), 3.70 (s, 3 H), 3.18 (s, 3 H), 2.69 (t, J = 6.6 Hz, 2 H), 0.95 (t,
J = 7.9 Hz, 9 H), 0.61 (q, J = 7.9 Hz, 6 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 172.4, 61.3, 58.9, 35.2, 31.9, 6.6 (3 C),
4.3 (3 C) ppm. HRMS (ESI+): calcd. for C11H26NO3Si [M + H]+ residue was purified by chromatography (hexanes/EtOAc, 99:1) to
248.1682; found 248.1691.
give acetylene 44 (2.1 g, 8.36, mmol, 100% yield) as a colorless oil.
IR (thin film): ν = 3308, 1238, 1199, 1144, 1088, 1038, 1004, 976,
˜
5-[(Triethylsilyl)oxy]-1-(trimethylsilyl)pent-1-yn-3-one (43): nBuLi
(2.5 m in hexanes, 34 mL, 84.9 mmol, 3.0 equiv.) was added drop-
wise to ethynyltrimethylsilane (12 mL, 84.9 mmol, 3.0 equiv.) in
Et2O (120 mL) at –78 °C. The mixture was stirred at this tempera-
ture for 30 min, and then Weinreb amide 42 (7.0 g, 28.3 mmol,
1.0 equiv.) in Et2O (70 mL) was added dropwise with stirring. The
reaction mixture was warmed to –20 °C and stirred at this tempera-
ture for 30 min. It was then quenched by the addition of saturated
aqueous NH4Cl (250 mL). The two phases were separated, and the
aqueous phase was extracted with Et2O (2ϫ 300 mL). The com-
bined organic phases were washed with brine (250 mL), dried with
MgSO4, and concentrated in vacuo to give ynone 43 (7.5 g,
26.5 mmol, 94% yield) as an orange oil, which was used immedi-
944 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.09–4.03 (m, 2 H),
4.02–3.96 (m, 2 H), 3.86 (t, J = 7.9 Hz, 2 H), 2.50 (s, 1 H), 2.21 (t,
J = 7.9 Hz, 2 H), 0.96 (t, J = 7.8 Hz, 9 H), 0.61 (q, J = 7.8 Hz, 6
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 101.1, 81.1, 72.1, 64.5
(2 C), 58.4, 41.9, 6.7 (3 C), 4.3 (3 C) ppm. HRMS (ESI+): calcd.
for C13H25O3Si [M + H]+ 257.1573; found 257.1582.
(E)-Triethyl(2-{2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
ethenyl]-1,3-dioxolan-2-yl}ethoxy)silane (33): Acetylene 44 (1.2 g,
4.76 mmol, 1.0 equiv.) and pinacol borane (6.9 mL, 47.6 mmol,
10 equiv.) were stirred neat at 70 °C for 3 d. After this time, ad-
ditional pinacol borane (2.3 mL, 15.9 mmol, 3.3 equiv.) was added,
and the mixture was stirred for an additional 3 d. The reaction
mixture was cooled to room temperature and was then purified by
chromatography (hexanes/EtOAc, 10:1 then 5:1) to furnish borane
derivative 33 (1.4 g, 3.61 mmol, 76% yield) as a colorless oil. IR
ately upon isolation in the subsequent reaction without further pu-
1
rification. IR (thin film): ν = 1681, 1252, 1092, 1007, 844 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 3.98 (t, J = 6.3 Hz, 2 H), 2.78 (t, J
= 6.3 Hz, 2 H), 0.95 (t, J = 8.0 Hz, 9 H), 0.60 (q, J = 8.0 Hz, 6 H),
(thin film): ν = 1643, 1459, 1352, 1326, 1207, 1144, 1088, 1045,
˜
0.24 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 186.0, 101.9, 1003, 971 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.41 (d, J =
98.1, 58.0, 48.3, 6.7 (3 C), 4.3 (3 C), –0.8 (3 C) ppm. HRMS
18.1 Hz, 1 H), 5.72 (d, J = 18.1 Hz, 1 H), 3.92–3.87 (m, 2 H), 3.86–
3.81 (m, 2 H), 3.72 (t, J = 7.6 Hz, 2 H), 2.02 (t, J = 7.7 Hz, 2 H),
1.26 (s, 12 H), 0.94 (t, J = 8.0 Hz, 9 H), 0.58 (q, J = 8.0 Hz, 6
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 150.8, 118.4, 107.9,
83.4 (2 C), 64.5 (2 C), 58.2, 40.7, 24.8 (4 C), 6.8 (3 C), 4.4 (3
C) ppm. HRMS (ESI+): calcd. for C19H38BO5Si [M + H]+
385.2582; found 385.2588.
(ESI+): calcd. for C14H29O2Si2 [M + H]+ 285.1706; found 285.1714.
2-{2-[(Trimethylsilyl)ethynyl]-1,3-dioxolan-2-yl}ethanol:
pTsOH·H2O (61 mg, 0.356 mmol, 0.1 equiv.) was added with stir-
ring to ynone 43 (1.0 g, 3.56 mmol, 1.0 equiv.), CH(OMe)3 (3.9 mL,
35.6 mmol, 10 equiv.), and HOCH2CH2OH (3.0 mL, 53.4 mmol,
15 equiv.) in PhMe (10 mL). After 16 h, the mixture was washed
with saturated aqueous NaHCO3 (100 mL), and the aqueous phase
was extracted with Et2O (3ϫ 100 mL). The combined organic lay-
ers were washed with brine (100 mL), dried with MgSO4, and con-
centrated in vacuo. The residue was purified by chromatography
(hexanes/Et2O, 2:1) to give the title acetylene (520 mg, 2.42 mmol,
tert-Butyldiphenyl{[(R)-1-{(2R,3R)-3-[(1Z,3E)-4-(2-{2-[(triethyl-
silyl)oxy]ethyl}-1,3-dioxolan-2-yl)buta-1,3-dien-1-yl]oxiran-2-
yl}propan-2-yl]oxy}silane (45): A degassed solution of pinacol bor-
ane 33 (420 mg, 1.09 mmol, 1.4 equiv.) and aqueous Cs2CO3 (3.0 m,
6.1 mL, 18.2 mmol, 20 equiv.) in THF (4.1 mL) was added to de-
gassed iodide 32 (390 mg, 0.792 mmol, 1.0 equiv.) and Pd(PPh3)4
68% yield) as a colorless oil. IR (thin film): ν = 3425 (br.), 1251,
˜
1194, 1107, 1031, 863, 843 cm–1. 1H NMR (400 MHz, CDCl3): δ = (53 mg, 45.5 μmol, 5 mol-%) in THF (6.5 mL). The resulting mix-
4.13–4.07 (m, 2 H), 4.06–4.00 (m, 2 H), 3.86 (dt, J = 6.1, 5.4 Hz,
2 H), 2.46 (t, J = 6.1 Hz, 1 H), 2.19 (t, J = 5.5 Hz, 2 H), 0.18 (s, 9
ture was heated to 55 °C for 7 h and then cooled to room tempera-
ture, and the aqueous layer was extracted with EtOAc (3ϫ 25 mL).
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 102.7, 101.7, 89.6, 64.5 The combined organic layers were washed with brine (25 mL),
(2 C), 58.6, 41.0, –0.3 (3 C) ppm. HRMS (CI+): calcd. for dried with MgSO4, and concentrated in vacuo. The residue was
C10H22NO3Si [M + NH4]+ 232.1369; found 232.1367.
purified by chromatography (hexanes/EtOAc, 20:1) to give diene 45
Eur. J. Org. Chem. 2014, 4523–4535
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4533

R. Cookson, C. Pöverlein, J. Lachs, A. G. M. Barrett
FULL PAPER
(350 mg, 0.558 mmol, 71% yield) as an orange oil. [α]2D5 = +4.2 (c
134.0, 133.9, 132.2, 130.6, 129.6, 129.6, 127.6 (2 C), 127.5 (2 C),
= 1.40, CH Cl ). IR (film): ν = 1428, 1105, 1085, 1044, 1006, 950, 125.8, 106.5, 67.5, 65.0, 64.7, 57.6, 53.8, 51.0, 41.5, 27.0 (3 C), 23.3,
˜
2
2
822 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.69–7.66 (m, 4 H), 19.2 ppm. HRMS (ESI+): calcd. for C30H38NaO5Si [M + Na]+
7.45–7.35 (m, 6 H), 6.71 (dd, J = 15.1, 11.4 Hz, 1 H), 6.24 (t, J =
11.3 Hz, 1 H), 5.69 (d, J = 15.1 Hz, 1 H), 5.06 (dd, J = 10.0,
10.2 Hz, 1 H), 4.08 (app. sextet, J = 6.0 Hz, 1 H), 3.96–3.81 (m, 4
H), 3.76–3.72 (m, 2 H), 3.44 (dd, J = 9.2, 1.8 Hz, 1 H), 3.02 (dt, J
= 5.9, 2.0 Hz, 1 H), 2.07–2.03 (m, 2 H), 1.82–1.68 (m, 2 H), 1.16
(d, J = 6.2 Hz, 3 H), 1.06 (s, 9 H), 0.96 (t, J = 7.8 Hz, 9 H), 0.60
(q, J = 7.8 Hz, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 135.8
(2 C), 135.8 (2 C), 135.6, 134.4, 134.0, 132.9, 129.6, 129.5, 129.3,
127.6 (2 C), 127.5 (2 C), 124.5, 107.8, 67.5, 64.7, 64.4, 58.3, 57.6,
54.0, 41.6, 41.5, 27.0 (3 C), 23.3, 19.2, 6.7 (3 C), 4.4 (3 C) ppm.
HRMS (ESI+): calcd. for C36H55O5Si2 [M + H]+ 623.3588; found
623.3573.
529.2386; found 529.2389.
2,2-Dimethyl-6-[2-oxo-2-(3-propyloxiran-2-yl)ethyl]-4H-1,3-di-
oxin-4-one (48): Keto-dioxinone 30 (250 mg, 1.16 mmol, 2.1 equiv.)
in THF (1.8 mL) was added to freshly prepared LiN(iPr)2
(2.31 mmol, 4.2 equiv.) in THF (10 mL) at –78 °C, and the solution
was warmed to –40 °C over 1 h. The solution was cooled to –78 °C,
and nPrCHO (47, 50 μL, 0.550 mmol, 1.0 equiv.) in THF (1 mL)
was added with stirring. The mixture was warmed incrementally to
room temperature over 3 h. The reaction was quenched by the ad-
dition of saturated aqueous NH4Cl (15 mL), and the pH was ad-
justed to 3–4 with 10% aqueous AcOH. The mixture was diluted
with Et2O (10 mL), and the phases were separated. The aqueous
layer was extracted with Et2O (3ϫ 15 mL). The combined organic
layers were washed with brine (15 mL), dried with MgSO4, and
concentrated in vacuo. The residue was purified by chromatog-
raphy (hexanes/EtOAc, 5:1 to 2:1) to give epoxide 48 (30 mg,
0.107 mmol, 19% yield, pure trans isomer) as a yellow oil. IR (thin
2-{2-[(1E,3Z)-4-{(2R,3R)-3-[(R)-2-(tert-Butyldiphenylsilyloxy)-
propyl]oxiran-2-yl}buta-1,3-dien-1-yl]-1,3-dioxolan-2-yl}ethanol:
Bu4NF (1.0 m in THF, 0.92 mL, 0.918 mmol, 1.1 equiv.) was added
with stirring to diene 45 (520 mg, 0.835 mmol, 1.0 equiv.) in THF
(20 mL) at 0 °C. After 30 min, the reaction was quenched by the
addition of saturated aqueous NaHCO3 (25 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc (3ϫ
25 mL). The combined organic layers were washed with water
(25 mL) and brine (25 mL), dried with MgSO4, and concentrated
in vacuo. The residue was purified by chromatography (hexanes/
EtOAc, 1:1) to give the title alcohol (390 mg, 0.757 mmol, 91%
yield) as a colorless, viscous syrup. [α]2D5 = –2.0 (c = 1.3, CH2Cl2).
film): ν = 1719, 1638, 1390, 1374, 1272, 1253, 1201, 1014, 902 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 5.33 (s, 1 H), 3.32 (d, J =
17.0 Hz, 1 H), 3.25 (d, J = 1.9 Hz, 1 H), 3.21 (d, J = 17.0 Hz, 1
H), 3.12 (ddd, J = 6.3, 4.9, 1.9 Hz, 1 H), 1.69 (s, 6 H), 1.69–1.45
(m, 4 H), 0.97 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 200.8, 163.8, 1605, 107.3, 97.1, 59.5, 58.0, 41.1, 33.5,
25.1, 24.8, 19.0, 13.7 ppm. HRMS (CI+): calcd. for C13H22NO5 [M
+ NH4]+ 272.1498; found 272.1476.
IR (thin film): ν = 3473 (br.), 1738, 1428, 1111, 1037 cm–1. 1H
˜
NMR (400 MHz, CDCl3): δ = 7.69–7.65 (m, 4 H), 7.44–7.35 (m, 6
H), 6.74 (dd, J = 15.1, 12.1 Hz, 1 H), 6.24 (t, J = 11.2 Hz, 1 H),
5.67 (d, J = 15.1 Hz, 1 H), 5.10 (t, J = 10.1 Hz, 1 H), 4.08 (app.
sextet, J = 6.0 Hz, 1 H), 4.04–3.85 (m, 4 H), 3.77 (td, J = 10.9,
5.6 Hz, 2 H), 3.43 (dd, J = 9.2, 1.9 Hz, 1 H), 3.03 (td, J = 5.9,
2.1 Hz, 1 H), 2.67 (t, J = 5.8 Hz, 1 H), 2.04–2.01 (m, 2 H), 1.82–
1.68 (m, 2 H), 1.15 (d, J = 6.2 Hz, 3 H), 1.05 (s, 9 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 135.8 (2 C), 135.8 (2 C), 134.8,
134.3, 134.0, 132.6, 129.9, 129.6, 129.6, 127.6 (2 C), 127.5 (2 C),
125.4, 109.3, 67.5, 64.7, 64.4, 58.4, 57.6, 53.9, 41.5, 39.7, 27.0 (3
C), 23.3, 19.2 ppm. HRMS (ESI+): calcd. for C30H40NaO5Si [M +
Na]+ 531.2543; found 531.2531.
6-(5-{2-[(1E,3Z)-4-{(2R,3R)-3-[(R)-2-(tert-Butyldiphenylsilyloxy)-
propyl]oxiran-2-yl}buta-1,3-dien-1-yl]-1,3-dioxolan-2-yl}-4-
hydroxy-2-oxopentyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (49): Keto-
dioxinone 10 (160 mg, 0.860 mmol, 2.1 equiv.) in THF (1.5 mL)
was added to freshly prepared LiN(iPr)2 (1.81 mmol, 4.2 equiv.) in
THF (7.4 mL) at –78 °C. The solution was warmed to –40 °C over
1 h, and then aldehyde 31 (220 mg, 0.430 mmol, 0.1 equiv.) in THF
(0.7 mL) was added with stirring. After an additional 3 h at –40 °C,
HCO2H (0.072 mL, 1.94 mmol) in THF (0.7 mL) was added, and
the solution was warmed to room temperature. The organic phase
was washed with saturated aqueous NH4Cl (15 mL), and the aque-
ous phase was acidified to pH = 3–4 by using 10% aqueous AcOH.
The aqueous phase was then extracted EtOAc (2ϫ 15 mL). The
combined organic phases were washed with brine (15 mL), dried
with MgSO4, and concentrated in vacuo. The residue was purified
by chromatography (hexanes/EtOAc, 2:1 and subsequently 1:1) to
yield keto-dioxinone 49 (220 mg, 0.318 mmol, 73 % yield) as an
orange gum that consisted of an inseparable mixture of dia-
2-{2-[(1E,3Z)-4-{(2R,3R)-3-[(R)-2-(tert-Butyldiphenylsilyloxy)-
propyl]oxiran-2-yl}buta-1,3-dien-1-yl]-1,3-dioxolan-2-
yl}acetaldehyde (31): Dess–Martin periodinane (230 mg,
0.538 mmol, 1.2 equiv.) was added with stirring to 2-{2-[(1E,3Z)-4-
{(2R,3R)-3-[(R)-2-(tert-butyldiphenylsilyloxy)propyl]oxiran-2-
yl}buta-1,3-dien-1-yl]-1,3-dioxolan-2-yl}ethanol (230 mg,
0.448 mmol, 1.0 equiv.) in CH2Cl2 (3.0 mL). After 2 h, the mixture
was washed with saturated aqueous NaHCO3 (10 mL), and the two
phases were separated. The aqueous layer was extracted with Et2O
(3ϫ 10 mL), and the combined organic phases were washed with
water (10 mL) and brine (10 mL), dried with MgSO4, and concen-
trated in vacuo. The residue was purified by chromatography (hex-
anes/EtOAc, 3:1) to give aldehyde 31 (190 mg, 0.371 mmol, 83%
yield) as a colorless, viscous syrup. [α]2D5 = +1.6 (c = 1.25, CH2Cl2).
stereomers. IR (thin film): ν = 3490 (br.), 1727, 1638, 1428, 1376,
˜
1273, 1203, 1111, 1016 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.68–7.65 (m, 4 H), 7.44–7.34 (m, 6 H), 6.77–6.71 (m, 1 H), 6.23
(t, J = 11.3 Hz, 1 H), 5.63 (d, J = 15.2 Hz, 1 H), 5.34 (s, 1 H), 5.11
(t, J = 10.0 Hz, 1 H), 4.42–4.35 (m, 1 H), 4.08 (app. sextet, J =
5.8 Hz, 1 H), 4.03–3.83 (m, 4 H), 3.54 (d, J = 5.9 Hz, 1 H), 3.43–
3.41 (m, 1 H), 3.41 (s, 2 H), 3.05–3.01 (m, 1 H), 2.69 (ddd, J =
15.8, 8.2, 2.5 Hz, 1 H), 2.35 (dd, J = 15.8, 4.2 Hz, 1 H), 1.93–1.91
IR (thin film): ν = 1725, 1473, 1428, 1379, 1199, 1110, 1069, 1038
˜
997, 950 cm–1 1H NMR (400 MHz, CDCl3): δ = 9.73 (t, J = (m, 2 H), 1.81–1.68 (m, 2 H), 1.71 (s, 6 H), 1.15 (d, J = 6.2 Hz, 3
.
2.7 Hz, 1 H), 7.68–7.66 (m, 4 H), 7.44–7.35 (m, 6 H), 6.79 (dd, J
= 15.1, 11.8 Hz, 1 H), 6.24 (t, J = 11.2 Hz, 1 H), 5.71 (d, J =
H), 1.05 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 202.4,
164.4, 160.7, 135.8 (2 C), 135.7 (2 C), [134.3, 134.3], 134.0, [132.4,
15.1 Hz, 1 H), 5.13 (t, J = 10.0 Hz, 1 H), 4.08 (app. sextet, J = 132.3], 130.1, 129.6, 129.5, 127.6 (2 C), 127.5 (2 C), [125.7, 125.6],
5.7 Hz, 1 H), 4.04–3.90 (m, 4 H), 3.43 (dd, J = 9.1, 1.7 Hz, 1 H), 108.6, 107.1, 96.7, 67.4, [64.8, 64.6], [64.3, 64.2], [64.1, 64.1], [57.6,
3.03 (dt, J = 5.8, 2.0 Hz, 1 H), 2.78 (d, J = 2.8 Hz, 2 H), 1.83–1.69 57.6], [53.8, 53.8], [49.8, 49.7], 48.0, 43.7, 41.5, 26.9 (3 C), 25.0,
(m, 2 H), 1.16 (d, J = 6.2 Hz, 3 H), 1.06 (s, 9 H) ppm. 13C NMR 24.9, 23.2, 19.1 ppm. N.B.: There is a carbon assignment missing
(101 MHz, CDCl3): δ = 199.6, 135.8 (2 C), 135.7 (2 C), 134.3, because of overlapping signals, and the 13C NMR data in square
4534
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4523–4535

Synthetic Studies towards Radicicol
[3] F. McCapra, A. I. Scott, P. Delmotte, J. Delmotte-Plaquee,
brackets correspond to signals from epimers. HRMS (ESI+): calcd.
for C39H50O9NaSi [M + Na]+ 713.3122; found 713.3122.
N. S. Bhacca, Tetrahedron Lett. 1964, 15, 869–875.
[4]
a) T. Schulte, S. Akinaga, S. Soga, W. Sullivan, B. Stensgard,
D. Toft, L. Neckers, Cell Stress Chaperones 1998, 3, 100–108;
b) S. Sharma, T. Agatsuma, H. Nakano, Oncogene 1998, 16,
2639–2645; c) H. J. Kwon, M. Yoshida, Y. Fukui, S. Horinou-
chi, T. Beppu, Cancer Res. 1992, 52, 6926–6930.
6-(4-Hydroxy-5-{2-[(1E,3Z)-4-{(2R,3R)-3-[(R)-2-hydroxypropyl]-
oxiran-2-yl}buta-1,3-dien-1-yl]-1,3-dioxolan-2-yl}-2-oxopentyl)-
2,2-dimethyl-4H-1,3-dioxin-4-one (51): Bu4NF (1.0 m in THF,
0.28 mL, 0.280 mmol, 2.0 equiv.) was added with stirring to keto-
dioxinone 49 (97 mg, 0.140 mmol, 1.0 equiv.) and molecular sieves
(4 Å, 100 mg) in THF (3.0 mL). After 40 h, the reaction mixture
was filtered, and the filtrate was concentrated in vacuo without
heating to leave the crude material. The crude product was dis-
solved in THF (0.5 mL) and then purified by chromatography
(100% EtOAc) to afford keto-dioxinone 51 (50 mg, 0.111 mmol,
79% yield) as a colorless gum that consisted of an inseparable mix-
[5]
[6]
[7]
[8]
a) M. Lampilas, R. Lett, Tetrahedron Lett. 1992, 33, 773–776;
b) M. Lampilas, R. Lett, Tetrahedron Lett. 1992, 33, 777–780.
R. Garbaccio, S. Stachel, D. Baeschlin, S. Danishefsky, J. Am.
Chem. Soc. 2001, 123, 10903–10908.
S. Barluenga, E. Moulin, P. Lopez, N. Winssinger, Chem. Eur.
J. 2005, 11, 4935–4952.
a) K. Yamamoto, R. M. Garbaccio, S. J. Stachel, D. B. Solit,
G. Chiosis, N. Rosen, S. J. Danishefsky, Angew. Chem. Int. Ed.
2003, 42, 1280–1284; Angew. Chem. 2003, 115, 1318; b) S. Soga,
L. Neckers, T. W. Schulte, Y. Shiotsu, K. Akasaka, H. Narumi,
T. Agatsuma, Y. Ikuina, C. Murakata, T. Tamaoki, S. Akinaga,
Cancer Res. 1999, 59, 2931–2938; c) S. Barluenga, C. Wang, J.-
G. Fontaine, K. Aouadi, K. Beebe, S. Tsutsumi, L. Neckers, N.
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ture of diastereomers. IR (thin film): ν = 3475 (br.), 1718, 1634,
˜
1392, 1376, 1274, 1203, 1016 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 6.78–6.71 (m, 1 H), 6.22 (t, J = 11.3 Hz, 1 H), 5.63 (dd, J =
15.2, 4.8 Hz, 1 H), 5.32 (s, 1 H), 5.14 (dd, J = 10.0, 9.6 Hz, 1 H),
4.39–4.31 (m, 1 H), 4.10–4.05 (m, 1 H), 4.05–3.85 (m, 4 H), 3.59–
3.51 (m, 2 H), 3.39 (s, 2 H), 3.04–3.00 (m, 1 H), 2.72–2.65 (m, 1
H), 2.37–2.50 (m, 1 H), 1.92–1.90 (m, 2 H), 1.85 (dt, J = 14.2,
4.4 Hz, 1 H), 1.69 (s, 6 H), 1.69–1.60 (m, 1 H), 1.24 (d, J = 6.3 Hz,
3 H) ppm. N.B.: One OH signal is missing because of overlap. 13C
NMR (101 MHz, CDCl3): δ = 202.3, [164.4, 164.4], 160.7, [134.5,
134.3], 132.5, [129.8, 129.7], [125.7, 125.6], [108.6, 108.5], 107.2,
96.7, 66.2, [64.8, 64.6], 64.3, [64.1, 64.1], 58.3, 53.8, 49.7, 48.0, [43.7,
43.6], 40.7, 25.0, 24.9, 23.4 ppm. N.B.: The 13C NMR data in
square brackets correspond to signals from the diastereomers.
HRMS (ESI+): calcd. for C23H33O9 [M + H]+ 453.2125; found
413.2146.
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Supporting Information (see footnote on the first page of this arti-
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Received: March 5, 2014
Published Online: June 3, 2014
Eur. J. Org. Chem. 2014, 4523–4535
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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