Enantioselective total synthesis of macrolide (+)-neopeltolide

Article abstract of DOI:10.1039/c3ob41541d

The asymmetric total synthesis of the anti-proliferative macrolide (+)-neopeltolide has been completed. The stereochemically defined trisubstituted tetrahydropyran ring was constructed via a catalytic hetero-Diels-Alder reaction creating two new chiral ce

Full text of DOI:10.1039/c3ob41541d

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Enantioselective total synthesis of macrolide
(+)-neopeltolide†
Cite this: Org. Biomol. Chem., 2013, 11,
7768
Arun K. Ghosh,* Khriesto A. Shurrush and Zachary L. Dawson
The asymmetric total synthesis of the anti-proliferative macrolide (+)-neopeltolide has been completed.
The stereochemically defined trisubstituted tetrahydropyran ring was constructed via a catalytic hetero-
Diels–Alder reaction creating two new chiral centers in a highly diastereoselective manner. The other key
features of this synthesis included Brown’s asymmetric allylation to install the requisite C-11 and C-13
stereocenters. The synthesis of the oxazole side chain consisted of a hydrozirconation of an alkynyl stan-
nane to establish the Z stereochemistry, followed by a palladium catalyzed cross coupling to introduce
the desired Z olefin in the oxazole side chain.
Received 26th July 2013,
Accepted 19th September 2013
DOI: 10.1039/c3ob41541d
www.rsc.org/obc
production of ATP in the cell.4 Preliminary SAR and structural
studies of (+)-neopeltolide established that the oxazole side
Introduction
The five oceans and seven seas that surround the earth encom- chain along with the macrolactone are essential for its biologi-
pass about 90% of all living organisms.1 These organisms cal activity.4 Of note, leucascandrolide A, which was isolated in
produce various primary and secondary metabolites that have 1996, off the east coast of New Caledonia in the Coral Sea from
been found to have complex structural features and biological the calcareous sponge Leucascandra caveolata by Pietra and co-
importance. One of these metabolites, (+)-neopeltolide was iso- workers,5 shares structural similarities with (+)-neopeltolide
lated in 2007 off the north coast of Jamaica by Wright and co- (Fig. 1). Both neopeltolide and leucascandrolide A contain the
workers, from a deep water sponge that was approximately half same unsaturated oxazole side chain attached to a tetrahydro-
a kilometer below the ocean surface.2 Subsequently, it was pyran ring and, interestingly, both molecules target mitochon-
shown that (+)-neopeltolide is a potent in vitro anti-prolifera- drial cytochrome bc1. Although these molecules were isolated
tive agent against the growth of several cancer cell lines includ- from opposite sides of the world, Kozmin and co-workers
ing A549 human lung adenocarcinoma (IC50 = 1.2 nM), NCI/ hypothesized that (+)-neopeltolide was a simplified analog of
ADR-RES ovarian sarcoma (IC50 = 5.1 nM) and P388 murine
leukemia (IC50 = 0.56 nM). In the PANC-1 pancreatic cancer
cell line and the DLD-1 colorectal adenocarcinoma cell line,
both of which have p53 mutations,2 (+)-neopeltolide exhibited
nanomolar inhibition of cell proliferation that was indepen-
dent of dose concentration, suggesting that it may act as a
cytostatic inhibitor of these cell lines. In addition to anti-
proliferatory activity, neopeltolide has also shown anti-fungal
activity against Candida albicans.2,3
Neopeltolide’s outstanding biological activity has led to
structure–activity relationship (SAR) studies and the identifi-
cation of its molecular target. In a study led by Kozmin and co-
workers it was shown that mitochondrial cytochrome bc1 is the
principal target of (+)-neopeltolide, ultimately inhibiting the
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette,
Indiana, USA. E-mail: akghosh@purdue.edu; Fax: +1 765-496-1612;
Tel: +1 765-494-5323
†Electronic supplementary information (ESI) available: Characterization of
selected compounds; copies of 1H and 13C NMR spectra of selected compounds.
See DOI: 10.1039/c3ob41541d
Fig. 1 Structures of (+)-neopeltolide and leucascandrolide A.
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leucascandrolide A. The complex structural features of
(+)-neopeltolide, its interesting biological activity, and limited
material available from the natural source have led to several
total syntheses,6 and formal syntheses.7 Herein, we report the
enantioselective total synthesis of (+)-neopeltolide.
Results and discussion
Retrosynthetic analysis of neopeltolide revealed some key dis-
connections, shown in Fig. 2. Disconnection of the alkyl ester
oxygen bond of the oxazole side chain would give acid 3,
which can undergo Mitsunobu esterification with the corres-
ponding macrolactone. Yamaguchi macrolactonization of acid
4 would in turn give the desired macrolactone. The tetrahydro-
pyran ring present in acid 4 could be constructed via a hetero-
Diels–Alder reaction between aldehyde 7 and silyloxy diene
ether 8 using Jacobsen’s chromium catalyst.8 Silyloxy diene 8
could be derived from the desymmetrization of glutaric
anhydride, followed by a series of Brown’s asymmetric allyla-
tions to afford the desired stereochemistry at C-11 and C-13.
The oxazole side chain 3 would come from a palladium cata-
lyzed cross coupling between oxazole 6 and stannane 5; fol-
lowed by a two carbon homologation and Still–Gennari
olefination to give the corresponding Z olefin. The Z geometry
in stannane 5 could be established via a hydrozirconation
reduction of the corresponding alkyne.
Scheme 1 Diastereoselective synthesis of silyloxy diene 8.
enantioselectivity (85% ee). Treatment of the corresponding
acid with borane–dimethylsulfide complex at 0 °C in tetra-
hydrofuran selectively reduced the acid in the presence of the
propyl ester to furnish alcohol 10 in 98% yield in two steps.
Swern oxidation of the alcohol at −78 °C followed by protec-
tion of the aldehyde gave acetal 11 in 89% yield in two steps.10
During our initial efforts, reduction of ester 11 on a large scale
(∼6 g) with DIBALH (1 M in toluene or dichloromethane) to its
aldehyde gave low yields (<20%).
The synthesis of the macrolactone ring of (+)-neopeltolide
(1) commenced with commercially available 3-methylglutaric
anhydride 9, as shown in Scheme 1. This achiral starting
material was desymmetrized using PS-30 “Amano” lipase.9 The
resulting acid was obtained in excellent yield and
To circumvent this problem we employed a two-step pro-
cedure; first, LAH reduction of ester 11 at 0 °C to the corres-
ponding alcohol in 88% yield followed by Swern oxidation
gave the desired aldehyde in 76% yield. Treatment of the
resulting aldehyde with (+)-Ipc2BOMe and allyl magnesium
bromide at −78 °C gave alcohol 12 in 87% yield which was
purified by flash chromatography (99 : 1 dr by 1H NMR).11
Methylation of alcohol 12 with MeI, followed by Lemieux–
Johnson oxidation, afforded the aldehyde in 70% yield in two
steps,12 which was subjected to Brown’s allylation protocol to
afford alcohol 13 in 91% yield which was purified by flash
chromatography (99 : 1 dr by 1H NMR) (Scheme 1). Deprotec-
tion of 13 under acidic conditions revealed the aldehyde which
was subjected to Horner–Wadsworth–Emmons olefination
giving the α,β-unsaturated ketone 15 in 83% yield in two
steps.13 Treatment of ketone 15 with TESOTf and triethylamine
furnished the desired silyloxy diene 8 in 98% yield.
After the synthesis of silyloxy diene 8 was complete, several
aldehydes were screened for the hetero-Diels–Alder reaction
(Scheme 2). Unfortunately after stirring for seven days alde-
hydes 7a–7c gave poor yields (entries 1–3, Table 1). Therefore,
Fig. 2 Retrosynthetic analysis of (+)-neopeltolide.
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Scheme 2 Hetero-Diels–Alder reaction and synthesis of tetrahydropyranone
17a–e.
Scheme 3 Synthesis of macrolactone 19.
Table 1 Hetero-Diels–Alder reactions with various aldehydesa
Treatment of 18 with 10% NaOH gave the desired acid, which
was subsequently deprotected under acidic conditions to
reveal ketone 4 in 74% yield in two steps. Yamaguchi macro-
lactonization afforded the desired macrolactone 19 in 40%
yield.15
Entry
1
Aldehyde
Solvent
Time
Yieldc,d
Trace
MTBEb or acetone
7 days
2
3
4
5
MTBE
7 days
7 days
40 h
31%
35%
82%
83%
With macrolactone 19 in hand, we turned our attention to
the synthesis of the unsaturated oxazole side chain. Treatment
of known alkyne 20 with LDA at −78 °C followed by the
addition of Bu3SnCl afforded the desired alkynyl stannane in
48% yield (Scheme 4).16 Hydrozirconation of the corres-
ponding alkynyl stannane gave a mixture of carbamates 5 and
21 in 38% and 18% yield, respectively.17 To our delight, treat-
ment of isobutyl carbamate 21 with KOH in methanol followed
by methylchloroformate returned the desired methyl carba-
mate 5 in 69% yield in two steps.
MTBE
MTBE
Ethyl acetate
36 h
a All reactions were carried out at 2.5 M concentration. b Methyl tert-
butyl ether. c Isolated yields reported. d A mixture of diastereomeric
diene 8 was employed for entries 1–4.
we decided to try an aldehyde with a shorter alkyl chain in an
effort to increase the reactivity of the carbonyl by placing the
oxygen closer, which will create a slight electron withdrawing
effect, making the aldehyde more reactive. To our delight,
aldehydes 7d and 7e gave satisfactory results with 82% and
83% yields, respectively. Hetero-Diels–Alder product 17e
showed excellent diastereoselectivity after purification by flash
1
chromatography (97 : 3 dr by H NMR). Although the reaction
proceeded well with the TBS protected alcohol, we chose to
proceed with the tosyloxyacetaldehyde 7e because subsequent
reactions with the tosyl group were more efficient.14
At this point, we tried to displace the tosylate 17e with
NaCN without protecting the ketone, which proved to be
unsuccessful due to the acidic nature of the associated ketone
α-protons that resulted in decomposition of the starting
material. To avoid this problem, ketone 17e was protected as
the corresponding ketal and then treated with NaCN in DMF
at 75 °C to give nitrile 18 in 48% yield in two steps (Scheme 3).
Scheme 4 Stille cross coupling of oxazole 6 and vinyl stannane 5.
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centers, and an asymmetric hetero-Diels–Alder reaction using
Jacobsen’s catalyst to form the core tetrahydropyran ring. The
synthesis of the oxazole side chain consisted of a hydrozirco-
nation of an alkynyl stannane followed by Stille coupling to
install the Z olefin at the C-26 position. The synthesis of the
side chain involved a Stille coupling as the key step. The syn-
thesis will provide convenient access to a variety of derivatives.
Experimental section
General experimental methods
All moisture sensitive reactions were carried out in a flame
dried flask under a nitrogen or argon atmosphere. Anhydrous
solvents were obtained as follows: THF and diethyl ether by
distillation from sodium and benzophenone; dichloromethane
and toluene from CaH2. All other solvents were of HPLC grade.
Column chromatography was performed with 240–400 mesh
silica gel under a low pressure of 5–10 psi. TLC was carried out
with silica gel 60-F-254 plates visualized under UV light and
stained with either phosphomolybdic acid or acidic p-anisalde-
Scheme 5 Synthesis of (+)-neopeltolide.
Iodo oxazole 6 was synthesized according to a literature pro-
cedure in 25% yield from ethyl 2-aminooxazole-4-carboxylate
using Sandmeyer’s modified reaction conditions.18 With the
desired coupling partners in hand, we attempted several Pd
coupling conditions, shown in Scheme 4. When Pd(PPh3)2Cl2
in dioxane at 90 °C was used, this resulted in decomposition
of the vinyl stannane 5. We turned our attention to other Pd
sources that had been previously used in similar coupling
strategies.19 Pd(MeCN)2Cl2 formed 22 in 51% yield, while
Pd(PhCN)2Cl2 gave the same product in 35% yield. Compara-
tively, we believe that the decreased yield can be attributed to
the steric bulk of phenyl versus methyl substituents on the
cyano ligands. Oxazole 22 was converted to side chain 3 fol-
lowing a previously reported procedure.4b
1
hyde. H NMR spectra were recorded at 300, 400 or 500 MHz
with chemical shifts reported in ppm (δ). 13C NMR spectra
were recorded at 75, 100 or 125 MHz with chemical shifts
reported in ppm (δ). Infrared spectra were recorded as thin
films on NaCl plates using a Fourier transform spectrometer.
Optical rotations were measured using a sodium (589, D line)
lamp polarimeter. Mass spectra were recorded at the Mass
Spectrometry Center facility. HPLC data were collected using a
system composed of a degasser, a quaternary pump, a thermo-
stable column compartment, and
detector.
a variable wavelength
(R)-Propyl 5-hydroxy-3-methylpentanoate (10).9 To a solu-
tion of 3-methylglutaric anhydride (23 g, 180 mmol) in diiso-
propyl ether (1.8 L) was added immobilized PS-30 “Amano”
Lipase (50 g) and n-PrOH (29.2 mL, 361 mmol) at 23 °C. The
solution was continued to stir at 23 °C for 30 h and then fil-
tered on celite and concentrated. The residue was taken up in
saturated NaHCO3 and washed with Et2O. The water layer was
made acidic with 6 M HCl and extracted with Et2O. The
organic extracts were dried with Na2SO4 and concentrated
in vacuo to yield a colorless oil (85% ee, reported lit. 92% ee),9
which was used directly for the next step. Benzyl ester of the
corresponding acid was measured by a chiral column AY-3
250 mmL × 4.6 mm, 3 microns; 1 mL min−1; isocratic 9 : 1,
hexanes–iPrOH; UV 256 nm; retention time, 3.37 min (minor);
retention time, 6.74 min (major).
The synthesis of (+)-neopeltolide is shown in Scheme 5. The
terminal olefin of macrolactone 19 was hydrogenated in the
presence of 10% Pd/C in ethyl acetate to provide the corres-
ponding saturated side chain in 95% yield. Reduction of the
resulting ketone with NaBH4 in ethanol at −10 °C afforded
1
alcohol 23 as a mixture of diastereomers (9 : 1 dr by H NMR)
in 75% yield. Mitsunobu esterification of 23 with acid 3 furn-
ished (+)-neopeltolide {1, [α]2D3 +22.7 (c 0.41, MeOH); lit.2
([α]2D0 +24.0 (c 0.24, MeOH)} in 78% yield. The 1H and 13C NMR
spectra of our synthetic (+)-neopeltolide are identical to the
reported spectra for natural (+)-neopeltolide, thus confirming
the absolute configuration of our synthetic material.2
To a solution of the corresponding acid in dry THF
(450 mL) under an argon atmosphere was added BH3–Me2S
Conclusions
In summary, we have accomplished an enantioselective syn- (19.5 mL, 206 mmol) dropwise at 0 °C. The solution was
thesis of the anti-proliferatory agent (+)-neopeltolide (2.1% stirred at 0 °C for 1.5 h and then warmed to 23 °C and stirred
overall yield in 21 steps by the longest linear sequence). The for a further 5 h until TLC indicated that the reaction was com-
synthetic route was convergent and scalable, and utilized com- plete. After cooling the reaction mixture to 0 °C, water was
mercially available starting materials. The key features of this carefully added and the solution was warmed to 23 °C. The
synthesis were desymmetrization of methylglutaric anhydride, resulting alcohol was extracted from the water layer with ethyl
Brown’s asymmetric allylation to form the C-13 and C-11 chiral acetate (×4). The organic extracts were washed with brine,
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dried with Na2SO4 and concentrated. The resulting thick oil the organic and aqueous phases separated. The aqueous layer
was passed through a short column of silica, eluting with 1 : 1 was extracted with 3× EtOAc, the organic layer was then
ethyl acetate–hexanes to give alcohol 10 as a clear thick oil washed with 1× H2O and 1× brine, dried over Na2SO4 and con-
(30.7 g) in 98% yield in two steps. [α]2D0 +7.71 (c 3, CHCl3); centrated. Silica gel column chromatography (4 : 6, ethyl
1H NMR (400 MHz, CDCl3) δ 3.87 (t, J = 6.7 Hz, 2H), 3.54–3.42 acetate–hexanes) gave the corresponding alcohol as a clear oil
(m, 2H), 3.28 (s, 1H), 2.24–2.13 (m, 1H), 2.06–1.90 (m, 2H), (4.69 g) in 88% yield which was directly used in the next step.
1.56–1.44 (m, 2H), 1.44–1.36 (m, 1H), 1.32 (dt, J = 13.6, 6.8 Hz,
To a stirred solution of oxalyl chloride (6.5 mL, 58 mmol)
1H), 0.86–0.74 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 173.1, in dichloromethane (280 mL) at −78 °C was added DMSO
65.6, 59.8, 41.3, 39.0, 26.8, 21.61, 19.5, 10.0; IR (NaCl) 3225, (8.3 mL, 120 mmol) dropwise. After stirring at −78 °C for
2962, 1737, 1235, 1175, 1055 cm−1; ESI-HRMS (m/z): calcd for 45 min, the above alcohol (4.69 g, 29 mmol) in 20 mL of
C9H18O3: ([M + H − CH3CH2CH2OH]+), 115.0754; Found, dichloromethane was added via cannula over 5 min. The reac-
115.0753.
tion was stirred at −78 °C for 1 h and then Et3N (24.0 mL,
(R)-Propyl 4-(1,3-dioxolan-2-yl)-3-methylbutanoate (11). To a 174 mmol) was added, and the solution was warmed to 23 °C
stirred solution of oxalyl chloride (19 mL, 172 mmol) in overnight. Water was added and the mixture was stirred for
CH2Cl2 (280 mL) at −78 °C was added DMSO (27 mL, 30 min at 23 °C, after which the organic layer was separated
344 mmol) dropwise. After stirring at −78 °C for 45 min, the and the aqueous layer was extracted with 3× dichloromethane.
above alcohol 10 (15 g, 86 mmol) in 80 mL of dichloromethane The combined organic layers were washed with brine and
was added via cannula over 15 min. The reaction was stirred at dried over Na2SO4 and concentrated. The concentrate was fil-
−78 °C for 5 h and then Et3N (72 mL, 516 mmol) was added, tered through a thin pad of silica eluting with 1 : 4 ethyl
and the solution was warmed to 23 °C overnight. Water was acetate–hexanes to give the corresponding aldehyde (3.50 g) as
added and the mixture was stirred for 30 min at 23 °C, after a thick clear oil in 76% yield.
which the organic layer was separated and the aqueous layer
(+)-Ipc2BOMe (2.05 g, 6.5 mmol) was carefully weighed out
was extracted with CH2Cl2. The combined organic layers were in a glove bag and placed in a 50 mL round-bottomed flask
dried with Na2SO4 and concentrated. The concentrate was fil- under an argon atmosphere. Dry Et2O (15 mL) was added and
tered through a thin pad of silica, eluting with 1 : 2 ethyl the solution was cooled to 0 °C, followed by dropwise addition
acetate–hexanes to remove salts, and concentrated to give the of allylmagnesium bromide (6 mL, 6.0 mmol, 1 M in Et2O).
corresponding aldehyde (13.90 g) as a thick clear oil in 94% After addition, the grey heterogeneous solution was warmed to
yield which was used without further purification.
23 °C and stirred for 2 h. The mixture was then cooled to
The above aldehyde (6.5 g, 38 mmol) was taken up in −78 °C and the above aldehyde (788 mg, 5.0 mmol) in Et2O
benzene (280 mL), and then ethylene glycol (10.5 mL, (10 mL) was added via cannula, and the resulting solution was
190 mmol) and PPTS (2.8 g, 11 mmol) were added. The solu- stirred for 8 h at −78 °C. Ethanol (1.5 mL) was added, followed
tion was heated to reflux for 6 h during which water was by a 3 M NaOH solution (4 mL) and H2O2 (8 mL, 30% in H2O).
removed using a Dean–Stark trap. Crude NMR analysis showed The solution was warmed to 23 °C and stirred for 12 h and
that no aldehyde remained. The solution was cooled to 23 °C then extracted with Et2O. The combined organic extracts were
and concentrated. Cold saturated NaHCO3 was added and the dried with Na2SO4 and concentrated. Flash chromatography
aqueous solution was extracted with Et2O (3 × 150 mL). The (1 : 5, ethyl acetate–hexanes) gave alcohol 12 as a clear oil
1
organic layers were washed with a saturated CuSO4 solution (1.1 g) in 87% yield and 99 : 1 dr. [α]2D0 +0.7 (c 1.7, CHCl3); H
and brine, dried with Na2SO4 and concentrated. Silica gel NMR (400 MHz, CDCl3) δ 5.85–5.68 (m, 1H), 5.12–4.97 (m, 2H),
column chromatography (1 : 5, ethyl acetate–hexanes) gave 11 4.85 (t, J = 5.1 Hz, 1H), 3.94–3.86 (m, 2H), 3.79–3.73 (m, 2H),
as a clear oil (8.14 g) in 95% yield. [α]2D0 −1.4 (c 1.6, CHCl3); 3.72–3.63 (m, 1H), 2.14 (ddq, J = 21.1, 13.9, 7.1 Hz, 2H),
1H NMR (400 MHz, CDCl3) δ 4.89 (t, J = 5.0 Hz, 1H), 4.01 (t, J = 1.92–1.79 (m, 1H), 1.64–1.40 (m, 3H), 1.19 (ddd, J = 14.1, 9.4,
6.7 Hz, 2H), 3.96 (t, J = 8.0 Hz, 2H), 3.81 (t, J = 8.0 Hz, 2H), 3.3 Hz, 1H), 0.91 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz,
2.48–2.29 (m, 1H), 2.26–2.08 (m, 2H), 1.73–1.50 (m, 4H), 1.00 CDCl3) δ 134.7, 117.6, 103.4, 68.4, 64.5, 64.4, 44.0, 42.5, 41.2,
(d, J = 6.3 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, 25.8, 19.7; IR (NaCl) 3362, 2972, 2929, 2862, 1378, 1149,
CDCl3) δ 172.6, 103.2, 65.6, 64.5, 41.6, 40.2, 26.6, 21.8, 20.0, 1053 cm−1; CI-HRMS (m/z): calcd for C11H20O3: ([M + H]+),
10.3. IR (NaCl) 2966, 2945, 1731, 1171, 1138, 1036 cm−1
;
201.1490; Found, 201.1480.
(4S,6S,8S)-9-(1,3-Dioxolan-2-yl)-6-methoxy-8-methylnon-1-en-
4-ol (13). To a solution of alcohol 12 (5.76 g, 29 mmol) in THF
CI-HRMS (m/z): calcd for C11H20O4: ([M + H]+), 217.1440;
Found, 217.1429.
(4R,6S)-7-(1,3-Dioxolan-2-yl)-6-methylhept-1-en-4-ol (12). To and DMF (100 mL, 5 : 1) at 0 °C was added NaH (2.3 g,
a 250 mL round bottom flask was added 11 (7.30 g, 33 mmol) 58 mmol, 60% in mineral oil) portion-wise. The solution was
and 100 mL ether, which was cooled to 0 °C. Then lithium stirred at 0 °C for 15 min and then warmed to 23 °C and
aluminum hydride (1.54 g, 41 mmol) was added in five stirred for 2 h. The solution was then cooled back to 0 °C and
(300 mg) portions. The reaction mixture was stirred for 1 h at MeI (5.4 mL, 86 mmol) was added dropwise. The solution was
0 °C and then the reaction was quenched at 0 °C with 10 mL warmed to 23 °C and stirred for 18 h and then cooled to 0 °C.
MeOH and 100 mL sodium potassium tartrate. The reaction Saturated NH4Cl solution was added followed by ethyl acetate.
mixture was allowed to warm to 23 °C and stirred for 1 h until After separation, the aqueous layer was extracted with ethyl
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acetate (3×) and the combined organic layers were washed with
To LiCl (636 mg, 15 mmol) in MeCN (85 mL) at 23 °C was
water and brine and then dried with Na2SO4 and concentrated. added
dimethyl(2-oxopropyl)phosphonate
(2.07
mL,
Column chromatography (1 : 10, ethyl acetate–hexanes) gave 15 mmol). The resulting solution was stirred for 10 min and
the corresponding methyl ether (6.09 g) as a clear oil in DIPEA (2.35 mL, 13.5 mmol) was added. After stirring for an
99% yield, which was directly used in the next step.
additional 15 min at 23 °C, the above aldehyde (∼12.5 mmol)
To the above acetal (3.60 g) in dioxane and water (100 mL, in 20 mL of MeCN was added by a syringe over 5 min. The
3 : 1) was added 2,6-lutidine (3.8 mL, 33 mmol), OsO4 (2.1 mL, solution was stirred at 23 °C for 18 h and then diluted with
0.17 mmol, 2.5% solution in t-BuOH), and NaIO4 (14.3 g, water and extracted with 3× Et2O. The organic layers were
67 mmol) at 0 °C. The mixture was warmed to 23 °C and dried with Na2SO4, filtered, and concentrated. Column chrom-
stirred for 3 h, at which time water was added and the alde- atography (1 : 3, ethyl acetate–hexanes) gave 2.65 g (83% yield,
hyde was extracted with 3× dichloromethane. The combined in two steps) of the unsaturated ketone 15 as a colorless oil.
organic extracts were concentrated and taken up in dichloro- [α]2D0 +10.3 (c 2.43, CHCl3); 1H NMR (400 MHz, CDCl3) δ
methane, washed with CuSO4 saturated solution and brine, 6.81–6.66 (m, 1H), 6.07–5.99 (m, 1H), 5.87–5.70 (m, 1H),
dried with Na2SO4, and concentrated. Column chromato- 5.12–5.01 (m, 2H), 3.96–3.82 (m, 1H), 3.60–3.49 (m, 1H), 3.33
graphy (1 : 4 to 1 : 2, ethyl acetate–hexanes) gave the corres- (s, 3H), 2.91 (br.s, 1H), 2.29–2.12 (m, 6H), 2.12–1.99 (m, 1H),
ponding aldehyde as a colorless oil (2.57 g) in 71% yield, 1.87–1.72 (m, 1H), 1.71–1.57 (m, 2H), 1.55–1.44 (m, 1H), 1.18
which was directly used in the next step.
250 mL round-bottomed flask was charged with NMR (100 MHz, CDCl3) δ 198.5, 146.6, 134.7, 132.6, 117.6,
(ddd, J = 13.7, 8.5, 4.6 Hz, 1H), 0.91 (d, J = 6.7 Hz, 3H). 13C
A
(−)-Ipc2BOMe (6.04 g, 19 mmol) and Et2O (53 mL), and cooled 67.6, 56.9, 42.3, 42.2, 40.9, 40.1, 39.4, 29.2, 26.8, 19.7; IR
to 0 °C. Next, allylmagnesium bromide (17.5 mL, 17.5 mmol, (NaCl) 3437, 2930, 1672, 1365, 1245, 1088 cm−1; ESI-HRMS
1 M in Et2O) was added dropwise and the solution was (m/z): calcd for C15H26O3: ([M + Na]+), 277.1780; Found,
warmed to 23 °C and stirred for 2 h. The mixture was then 277.1768.
cooled to −78 °C and then the above aldehyde (3.44 g,
(9R,11S,13S,E)-13-Allyl-3,3,15,15-tetraethyl-11-methoxy-
16 mmol) in Et2O (40 mL) was added via cannula. The result- 9-methyl-5-methylene-4,14-dioxa-3,15-disilaheptadec-6-ene (8).
ing solution was stirred for 7.5 h at −78 °C. Ethanol (3 mL) Unsaturated ketone 15 (1.85 g, 7.3 mmol) in 35 mL of dichloro-
was added followed by 3 M NaOH solution (8 mL) and H2O2 methane was cooled to −78 °C. To this solution was added tri-
(16 mL, 30% in H2O). The solution was warmed to 23 °C and ethylamine (5.06 mL, 36 mmol) and dropwise triethylsilyl
stirred for 12 h and extracted with Et2O. The combined trifluoromethane sulfonate (4.11 mL, 18 mmol) at −78 °C. The
organic extracts were dried with Na2SO4 and concentrated. solution was warmed to 0 °C and stirred for 1.5 h before an
Flash chromatography (1 : 4, ethyl acetate–hexanes) gave ice-cold saturated NaHCO3 solution was added. The layers
alcohol 13 as colorless oil (3.74 g) in 91% yield and 99 : 1 dr. were separated and the aqueous layer was extracted with 3×
[α]2D0 +1.1 (c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.87–5.72 dichloromethane. The combined organic layers were washed
(m, 1H), 5.13–5.01 (m, 2H), 4.86 (t, J = 5.0 Hz, 1H), 3.99–3.84 with 1× brine, dried with Na2SO4 and concentrated. The result-
(m, 3H), 3.83–3.73 (m, 2H), 3.59–3.48 (m, 1H), 3.33 (s, 3H), ing yellow oil was passed through a short silica column
2.96 (br.s, 1H), 2.27–2.10 (m, 2H), 1.85–1.56 (m, 4H), 1.55–1.42 (1 : 20 : 0.2, ethyl acetate–hexanes–Et3N) and concentrated to
(m, 2H), 1.24–1.13 (m, 1H), 0.96 (d, J = 6.5 Hz, 3H). 13C NMR give 8 as a yellowish oil (3.51 g) in 98% yield, which was
(100 MHz, CDCl3) δ 134.8, 117.4, 103.4, 77.1, 67.9, 64.6, 64.5, directly used in the next step.
56.7, 42.2, 41.2, 41.0, 39.1, 26.1, 20.3. IR (NaCl) 3340, 2915,
2823, 1442, 1163, 1086 cm−1; ESI-HRMS (m/z): calcd for solution of (DL)-1,2-isopropylideneglycerol (10 g, 76 mmol) in
C14H26O4: ([M + Na]+), 281.1729; Found, 281.1719.
pyridine (60 mL) at 0 °C was added tosyl chloride (22 g,
(6R,8S,10S,E)-10-Hydroxy-8-methoxy-6-methyltrideca-3,12- 113 mmol) followed by DMAP (500 mg, 4.1 mmol). The solu-
dien-2-one (15). To solution of alcohol 13 (3.23 g, tion was stirred at 23 °C for 24 h before ice cold H2O was
2-Oxoethyl 4-methylbenzenesulfonate (7e).14b To a stirring
a
12.5 mmol) in acetone (125 mL) was added 5 mL of water, added followed by extraction with 3× EtOAc. The organic
1 mL of AcOH, and PPTS (2.5 g, 10 mmol). The solution extracts were washed with a saturated CuSO4 solution and
was warmed to 70 °C and stirred for 4 h. Crude NMR showed brine and then dried with Na2SO4 and concentrated. The thick
that the starting material had been partially converted to oil was used in the next step without further purification.
the desired aldehyde (∼50% conversion). Another gram of
The tosyl compound from the above was dissolved in THF
PPTS and 1 mL of AcOH were added and the solution was (60 mL) and then 2 M HCl (20 mL) was added. The solution
heated to reflux for another 12 h. The acetone was removed was stirred overnight at 23 °C and then cooled to 0 °C and
under vacuum and the resulting residue was quenched with quenched slowly with saturated NaHCO3. Ethyl acetate was
saturated NaHCO3 solution, and extracted with 3× dichloro- added and the layers were separated. The aqueous layer was
methane. The combined organic layers were washed with further extracted with 3× EtOAc and the combined organic layers
CuSO4 saturated solution and brine, and then dried with were dried with Na2SO4 and concentrated to yield a clear thick
Na2SO4 and concentrated to give the corresponding aldehyde oil, which was used in the next step without further purification.
as a yellowish oil that was used without further purification in
the next step.
To the above diol was added a mixture of H2O–dichloro-
methane (2 : 1, 210 mL/105 mL) followed by NaIO4. The
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solution was stirred at 23 °C for 24 h and then separated, and then NaCN (195 mg, 4.0 mmol) was added. The solution was
the water layer was extracted with dichloromethane. The heated to 75 °C for 36 h and then cooled to 23 °C. After satu-
organic layers were dried and concentrated. The resulting oil rated aqueous NaHCO3 was added the mixture was extracted
was taken up in dichloromethane (150 mL), and 4 Å MS (25 g) with 3× EtOAc. The combined extracts were washed with 1×
was added. The mixture was heated to reflux for 3 h and fil- water and 1× brine, dried with Na2SO4, and concentrated. The
tered. The filtrate was concentrated to give aldehyde 7e resulting residue was purified by flash chromatography (1 : 2,
(10.24 g), in 63% yield, in 3 steps which was stored at −20 °C ethyl acetate–hexanes) to give 18 as a colorless oil (195.5 mg)
1
until used. H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 7.81 (d, in 80% yield. [α]2D0 +12.1 (c 0.84, CHCl3); 1H NMR (400 MHz,
J = 8.2 Hz, 2H), 7.37 (d, J = 8.2, 2H), 4.50 (s, 2H), 2.45 (s, 3H); CDCl3) δ 5.90–5.80 (m, 1H), 5.16–5.05 (m, 2H), 3.98–3.91 (m,
13C NMR (100 MHz, CDCl3) δ 195.0, 145.7, 131.9, 130.1, 128.1, 5H), 3.87–3.74 (m, 1H), 3.72–3.61 (m, 1H), 3.61–3.50 (m, 1H),
71.9, 21.6.
((2R,6R)-6-((2S,4S,6S)-6-Hydroxy-4-methoxy-2-methylnon-8-en- (dddd, J = 8.5, 5.9, 2.9, 1.4 Hz, 2H), 1.91–1.81 (m, 1H),
1-yl)-4-oxotetrahydro-2H-pyran-2-yl)methyl 4-methylbenzene- 1.81–1.74 (m, 2H), 1.75–1.38 (m, 6H), 1.23–1.09 (m, 2H), 0.93
3.36 (s, 3H), 2.99 (br.s, 1H) 2.53 (dd, J = 8.0, 4.0 Hz, 2H), 2.23
sulfonate (17e). To a flame dried 25 mL round-bottomed flask (d, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 134.8, 117.3,
charged with activated 4 Å MS (1.5 g), diene 8 (2.39 g, 116.9, 106.6, 77.4, 73.2, 70.3, 67.9, 64.4, 64.2, 56.7, 43.1, 42.2,
4.9 mmol), and tosyl aldehyde 7e (1.59 g, 7.4 mmol) in ethyl 41.2, 41.2, 40.2, 38.9, 25.9, 24.4, 19.9; IR (NaCl) 3467, 3071,
acetate (2 mL) were added. The solution was cooled to 0 °C 2924, 2247, 1377, 1147, 1068 cm−1; ESI-HRMS (m/z): calcd for
and Diels–Alder catalyst (16, 241 mg, 0.5 mmol) was added in C20H33NO5: ([M + Na]+), 390.2256; Found, 390.2245.
one portion. The brown mixture was capped and sealed with
parafilm and stirred at 23 °C for 36 h. The mixture was filtered en-1-yl)-4-oxotetrahydro-2H-pyran-2-yl)acetic
2-((2R,6R)-6-((2S,4S,6S)-6-Hydroxy-4-methoxy-2-methylnon-8-
acid (4). 18
through a 1-inch pad of celite (eluting with dichloromethane) (185 mg, 0.50 mmol) was taken up in EtOH (2.0 mL) and
and concentrated. The crude mixture was taken up in dichloro- 640 µL of a 10% NaOH solution was added. The mixture was
methane (15 mL) and TFA (2.0 mL) was added. The mixture stirred at 75 °C for 24 h, and then cooled to 0 °C. The solution
was stirred at 23 °C for 1 h, cooled to 0 °C and quenched with was then acidified to pH = 3 with 1 M HCl. The mixture was
a saturated NaHCO3 solution. After separation of the organic extracted with 4× ethyl acetate. The organic layers were washed
layer, the aqueous layer was extracted with 3× dichloro- with 1× brine, dried with Na2SO4 and then concentrated give
methane, and the organic layer was washed with 1× brine and the acid as a clear oil, which was used in the next step without
dried over Na2SO4 and concentrated. Column chromatography further purification.
(6 : 4, 1 : 1, 4 : 6; hexanes–ethyl acetate) gave 17e as a yellow
The above acid was dissolved in 3 mL of acetone and
colored oil (2.0 g) in 83% yield and 97 : 3 dr. [α]2D0+5.2 (c 7.5, 0.5 mL of H2O. PTSA (150 mg, 0.79 mmol) was added and the
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.9 Hz, 2H), solution was heated to 65 °C for 12 h. The solution was con-
7.35 (d, J = 7.9 Hz, 2H), 5.90–5.56 (m, 1H), 5.20–5.05 (m, 2H), centrated and H2O was added along with EtOAc. The layers
4.10–4.02 (m, 2H), 3.97–3.91 (m, 1H), 3.85–3.82 (m, 1H), were separated and the aqueous layer was further extracted
3.72–3.59 (m, 1H), 3.59–3.50 (m, 1H), 3.36 (s, 3H), 2.44 (s, 3H), with 3× EtOAc. The organic layers were combined, and washed
2.38–2.26 (m, 2H), 2.26–2.15 (m, 2H), 1.82–1.89 (m, 1H), with 1× brine, dried with Na2SO4, and concentrated. Column
1.77–1.43 (m, 4H), 1.34–1.14 (m, 4H), 0.90 (d, J = 4.0 Hz, 3H); chromatography (2 : 1, ethyl acetate–hexanes) gave acid 4 as a
13C NMR (100 MHz, CDCl3) δ 205.2, 144.98, 134.8, 132.5 129.8, colorless oil (127 mg) in 74% yield in 2 steps. [α]D20 +23.1 (c 2.1,
127.8, 117.4, 77.2, 74.9, 73.8, 70.9, 67.8, 56.8, 47.9, 43.5, 43.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.89–5.74 (m, 1H),
42.2, 41.2, 39.1, 25.8, 21.5, 19.7; IR (NaCl) 3352, 2978, 2927, 5.17–5.03 (m, 2H), 4.07–3.95 (m, 2H), 3.77–3.63 (m, 1H),
1722, 1360, 1177, 1096 cm−1; ESI-HRMS (m/z): calcd for 3.60–3.46 (m, 1H), 3.35 (s, 3H), 2.66–2.48 (m, 2H), 2.44 (dt, J =
C24H36O7S: ([M + Na]+), 491.2079; Found, 491.2056.
2-((7S,9R)-9-((2S,4S,6S)-6-Hydroxy-4-methoxy-2-methylnon-8-
14.4, 2.3 Hz, 1H), 2.38–2.27 (m, 2H), 2.26–2.19 (m, 2H),
1.89–1.72 (m, 2H), 1.70–1.55 (m, 3H), 1.56–1.46 (m, 2H), 0.93
en-1-yl)-1,4,8-trioxaspiro[4.5]decan-7-yl)acetonitrile (18). To a (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 206.2, 170.1,
solution of 17e (520 mg, 1.1 mmol) in benzene (20 mL) was 134.8, 117.4, 77.1, 74.5, 73.2, 67.9, 60.6, 56.7, 48.0, 46.9, 43.5,
added ethylene glycol (0.65 mL, 11.1 mmol) and PTSA (84 mg, 42.2, 41.3, 39.2, 25.8, 19.5; IR (NaCl) 3415, 3071, 2928, 1720,
0.33 mmol). The solution was heated to reflux for 10 h with a 1369, 1255, 1074 cm−1; ESI-HRMS (m/z): calcd for C18H30O6:
Dean–Stark trap attached. After 10 h the solution was cooled ([M + Na]+), 365.1940; Found, 365.1954.
to 23 °C, filtered through celite, and then concentrated. The
(1R,5S,7S,9S,11R)-5-Allyl-7-methoxy-9-methyl-4,15-dioxabicyclo-
residue was treated with a NaHCO3 solution and extracted with [9.3.1]pentadecane-3,13-dione (19). Acid 4 (44 mg, 0.13 mmol)
3× EtOAc. The extracts were dried with Na2SO4 and concen- and Et3N (53 µL, 0.38 mmol) were dissolved in THF (5 mL)
trated. The residue was purified by column chromatography and cooled to 0 °C and then 2,4,6-trichlorobenzoyl chloride
(1 : 2, ethyl acetate–hexanes) to give the desired acetal as a (30 µL, 0.19 mmol) was added dropwise. The reaction mixture
thick clear oil (342 mg) in 60% yield, which was directly used was allowed to warm to 23 °C and stirred for 1.5 h. Then
in the next step.
15 mL of toluene was added and the reaction mixture, which
To a 25 mL round bottom flask was added the above acetal was taken up in a 50 mL syringe, was added dropwise over an
(340 mg, 0.66 mmol) which was dissolved in DMF (5 mL) and 8 h period to a solution of toluene (200 mL) and DMAP
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(305 mg, 2.50 mmol) at 80 °C. After the addition was complete 23 °C, the aqueous layer was extracted with 3× EtOAc and the
the reaction mixture was stirred for an additional 2 h at 80 °C combined organic layers were washed with 1× water and 1×
and then cooled to 23 °C. Then the reaction mixture was fil- brine and dried over anhydrous Na2SO4. The residue was chro-
tered through a short pad of silica with hexanes–ethyl acetate matographed on silica gel (98 : 2 to 9 : 1; hexanes–EtOAc; note
(1 : 1) and concentrated. The residue was chromatographed on all solutions contained 1% Et3N) to give the corresponding
silica gel (85 : 15, 8 : 2, 75 : 25, 7 : 3; hexanes–ethyl acetate) to alkyne as a pale yellow oil (5.60 g) in 48% yield.
give lactone 19 in 40% yield. [α]2D0 +38.2 (c 0.1, CHCl3); 1H
To a 250 mL round bottom flask under argon was added
NMR (500 MHz, CDCl3) δ 5.80–5.72 (m, 1H), 5.33–5.16 (m, 1H), ZrCp2Cl2 (freshly recrystallized from toluene, 2.60 g,
5.17–4.99 (m, 2H), 4.04 (dddd, J = 11.4, 10.5, 4.2, 2.8 Hz, 1H), 8.86 mmol) and dissolved in 30 mL THF and cooled to 0 °C.
3.60–3.55 (m, 1H), 3.52–3.48 (m, 1H), 3.33 (s, 3H), 2.70 (dd, J = Then DIBALH (8.90 mL, 1 M in dichloromethane, 8.86 mmol)
14.7, 4.1 Hz, 1H), 2.58–2.49 (m, 1H), 2.50–2.40 (m, 2H), was added dropwise, the resulting solution was stirred for
2.40–2.21 (m, 4H), 1.88 (ddd, J = 14.9, 10.9, 1.8 Hz, 1H), 30 min and a white suspension was formed. Then in a separate
1.75–1.53 (m, 3H), 1.54–1.39 (m, 1H), 1.37–1.28 (m, 1H), round bottom flask the above alkyne (1.98 g, 4.92 mmol) was
1.23–1.18 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, dissolved in THF (15 mL) and then DIBALH (4.92 mL, 1 M in
CDCl3) δ 205.8, 169.7, 133.7, 117.6, 79.5, 75.6, 73.2, 72.6, 56.2, dichloromethane, 4.92 mmol) was added dropwise at 0 °C and
48.6, 46.9, 44.1, 42.4, 41.6, 39.1, 39.09, 29.6, 30.0, 25.2; stirred for 20 min. Then via cannula the solution of DIBALH
IR (NaCl) 2950, 2923, 2846, 1727, 1462, 1366, 1248, 1089 cm−1
ESI-HRMS (m/z): calcd for C18H28O5: ([M + Na]+), 347.1834; DIBALH and ZrCp2Cl2 at 0 °C. After the addition was complete
Found, 347.1818. the reaction mixture was stirred at 0 °C for 1 h and then
;
and alkynyl stannane at 0 °C was added to the suspension of
(1R,5S,7S,9S,11R,13S)-13-Hydroxy-7-methoxy-9-methyl-5-propyl- allowed to warm to 23 °C and stirred for an additional 7 h. The
4,15-dioxabicyclo[9.3.1]pentadecan-3-one (23). Lactone 19 reaction was quenched with MeOH (10 mL) and sodium pot-
(16 mg, 0.05 mmol) was dissolved in EtOAc (3 mL) and then assium tartrate (∼50 mL) and stirred for 1 h. Once the organic
10% Pd/C (5 mg) was added. The reaction was flushed with and aqueous phases were separated the aqueous phase was
argon followed by H2 and then placed under 1 atm. of H2 for extracted with 3× EtOAc. The combined organic layers were
1 h at 23 °C. Then the reaction mixture was filtered through a washed with 1× H2O and 1× brine, dried over Na2SO4, and con-
short pad of celite with EtOAc and concentrated to give centrated under vacuum. The residue was chromatographed
15.5 mg of the corresponding lactone in 95% yield which was on silica gel (98 : 2, 95 : 5, 94 : 6, 92 : 8, 9 : 1; hexanes–EtOAc;
used in the next step without further purification.
note all solutions contained 1% Et3N) to give alkene 5
1
To a solution of the above lactone (15.5 mg, 0.05 mmol) in (755 mg) in 38% yield. H NMR (400 MHz, CDCl3) δ 6.48 (dt,
EtOH (0.6 mL) at −10 °C was added NaBH4 (4 mg, 0.10 mmol). J = 12.5, 6.5 Hz, 1H), 6.02 (d, J = 12.5 Hz, 1H), 4.63 (br.s, 1H),
The resulting solution was stirred at −10 °C for 30 min before 3.73 (d, J = 5.5 Hz, 2H), 3.67 (s, 3H), 1.44–1.49 (m, 9H),
the solution was treated with 2–3 drops of AcOH. The mixture 1.27–1.32 (m, 9H), 0.87 (t, J = 7.3 Hz, 9H); 13C NMR (100 MHz,
was concentrated and purified by column chromatography CDCl3) δ 156.6, 143.7, 132.7, 52.0, 46.2, 29.0, 27.1, 13.6, 10.2;
(7 : 3, 6 : 4, 55 : 45, 1 : 1, 4 : 6; hexanes–ethyl acetate) to give IR (NaCl) 3336, 2956, 2925, 2853, 1711, 1600, 1530, 1463, 1251,
lactone 23 as a clear oil (12.8 mg) in 75% yield and 9 : 1 dr. 1044 cm−1; CI-HRMS (m/z): calcd for C17H35NO2Sn: ([M + H −
1
[α]2D0 +21.5 (c 0.41, CHCl3); H NMR (400 MHz, CDCl3) δ 5.15 C4H10]+), 348.0985; Found, 348.0994.
(td, J = 9.9, 4.8 Hz, 1H), 3.91–3.75 (m, 1H), 3.72 (m, 1H),
Isobutyl (Z)-(3-(tributylstannyl)allyl)carbamate (21). 18%
1
3.62–3.51 (m, 1H), 3.31 (s, 3H), 3.17 (t, J = 10.4 Hz, 1H), 2.62 yield, 397 mg, H NMR (400 MHz, CDCl3) δ 6.52–6.45 (m, 1H),
(dd, J = 14.5, 4.3 Hz, 1H), 2.43 (dd, J = 14.5, 10.7 Hz, 1H), 6.02 (d, J = 12.5 Hz, 1H), 4.64 (br.s, 1H) 3.83 (d, J = 6.7 Hz, 2H),
2.06–1.90 (m, 1H), 1.92–1.76 (m, 2H), 1.77–1.63 (m, 1H), 3.75–3.72 (m, 2H), 2.02–1.73 (m, 1H), 1.65–1.34 (m, 6H),
1.57–1.39 (m, 3H), 1.40–1.28 (m, 3H), 1.24–1.05 (m, 4H), 1.34–1.24 (m, 6H), 1.12–0.68 (m, 21H); 13C NMR (100 MHz,
1.06–0.93 (m, 3H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 156.3, 143.8, 132.5, 70.9, 46.1, 29.0, 27.9, 27.1, 18.9,
CDCl3) δ 170.7, 78.5, 75.4, 73.1, 72.2, 67.9, 56.1, 43.9, 42.1, 13.5, 10.2; IR (NaCl) 3332, 2953, 2919, 2830, 1718, 1596, 1528,
41.8, 40.6, 39.9, 36.8, 31.1, 25.4, 18.8, 13.8; IR (NaCl) 3429, 1467, 1245, 1044 cm−1. ESI-HRMS (m/z): calcd for C20H41
2961, 2920, 2871, 1731, 1457, 1372, 1272, 1090 cm−1
Methyl (Z)-(3-(tributylstannyl)allyl)carbamate (5). To
.
NO2Sn: ([M + Na]+), 470.2061; Found, 470.2063.
Conversion of isobutyl (Z)-(3-(tributylstannyl)allyl)carbamate
a
stirred solution of THF (50 mL) and diisopropylamine (21) to methyl (Z)-(3-(tributylstannyl)allyl)carbamate (5). To a
(8.90 mL, 61 mmol) at 0 °C under argon was added n-BuLi stirred solution of 21 (406 mg, 0.9 mmol) in methanol (20 mL)
(24.3 mL, 2.5 M solution in hexanes, 63 mmol) dropwise, and and water (1 mL) was added KOH (510 mg, 9.1 mmol). The
the mixture was stirred for 15 min and then cooled to −78 °C. resulting mixture was stirred at 80 °C for 24 h. The mixture
Then alkyne 20 (3.27 g, 29 mmol) was dissolved in 20 mL THF was evaporated and the aqueous layer was extracted with 3×
added dropwise over a 10 min period. The reaction mixture EtOAc, and the organic solvent was evaporated to give the
was stirred for an additional 0.5 h at −78 °C. Tributyltin chlo- crude amine. To this crude amine, dioxane and saturated
ride (8.70 mL, 32 mmol) was added dropwise and the reaction aqueous NaHCO3 (1 : 1 mixture) were added followed by
mixture was stirred for 3 h at −78 °C. The reaction was methylchloroformate (100 mL). The reaction was stirred at
quenched with saturated aqueous NaHCO3 and warmed to 23 °C for 12 h. After this period, the reaction mixture was
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concentrated and the residue was extracted with 3× EtOAc.
Evaporation of the solvent gave an oil which was purified by
column chromatography (98 : 2, 95 : 5, 94 : 6, 92 : 8, 9 : 1;
hexanes–EtOAc; note that all solutions contained 1% Et3N) to
give methyl carbamate 5 in two steps (255 mg, 69% yield).
Notes and references
1 Y. Qi and S. Ma, ChemMedChem, 2011, 6, 399.
2 A. E. Wright, J. C. Botelho, E. Guzman, D. Harmody,
P. Linley, P. J. McCarthy, T. P. Pitts, S. A. Pomponi and
J. K. Reed, J. Nat. Prod., 2007, 70, 412.
Ethyl
(Z)-2-(3-((methoxycarbonyl)amino)prop-1-en-1-yl)-
oxazole-4-carboxylate (22). Oxazole 6 (445 mg, 1.67 mmol) and
stannane 5 (741 mg, 1.83 mmol) under argon were dissolved
in 10 mL DMF and then in one portion Pd(MeCN)2Cl2 (87 mg,
0.33 mmol) was added. The reaction mixture was then stirred
for 12 h at 23 °C and then diluted with H2O (15 mL) and
extracted with 4× EtOAc; the combined organic layers were
washed with 1× H2O and 1× brine, dried over Na2SO4 and con-
centrated under vacuum. The residue was chromatographed
on silica gel (65 : 35, 60 : 40, 55 : 45, 1 : 1, 4 : 6; hexanes–EtOAc)
3 K. H. Altmann and E. M. Carreira, Nat. Chem. Biol., 2008, 4,
388.
4 (a) O. A. Ulanovskaya, J. Janjic, M. Suzuki, S. S. Sabharwal,
P. T. Schumacker, S. J. Kron and S. A. Kozmin, Nat. Chem.
Biol., 2008, 4, 418; (b) V. V. Vintonyak, B. Kunze, F. Sasse
and M. E. Maier, Chem.–Eur. J., 2008, 14, 11132;
(c) D. W. Custar, T. P. Zabawa, J. Hines, C. M. Crews and
K. A. Scheidt, J. Am. Chem. Soc., 2009, 131, 12406;
(d) H. Fuwa, A. Saito, S. Naito, K. Konoki, M. Yotsu-Yama-
shita and M. Sasaki, Chem.–Eur. J., 2009, 15, 12807;
(e) Y. Cui, W. Tu and P. E. Floreancig, Tetrahedron, 2010, 66,
4867; (f) Y. Cui, R. Balachandran, B. W. Day and
P. E. Floreancig, J. Org. Chem., 2012, 77, 2225.
1
to give oxazole 22 as a white solid (239 mg) in 51% yield. H
NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 6.36 (dt, J = 12.1, 1.8 Hz,
1H), 6.21 (dt, J = 12.2, 6.4 Hz, 1H), 5.33 (s, 1H), 4.46–4.31 (m,
4H), 3.68 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.0, 160.6, 157.0, 143.1, 139.1, 134.3, 115.3, 61.2,
52.1, 39.5, 14.1; IR (NaCl) 3348, 3155, 2983, 2945, 1721, 1526,
5 M. D’Ambrosio, A. Guerriero, C. Debitus and F. Pietra,
Helv. Chim. Acta, 1996, 79, 51.
1465, 1371, 1273, 1191, 1021 cm−1
Neopeltolide (1). To solution of acid
.
6 (a) W. Youngsaye, J. T. Lowe, F. Pohlki, P. Ralifo and
J. S. Panek, Angew. Chem., Int. Ed., 2007, 46, 9211;
(b) D. W. Custar, T. P. Zabawa and K. A. Scheidt, J. Am.
Chem. Soc., 2008, 130, 804; (c) S. K. Woo, M. S. Kwon and
E. Lee, Angew. Chem., Int. Ed., 2008, 47, 3242; (d) I. Paterson
and N. A. Miller, Chem. Commun., 2008, 4708; (e) H. Fuwa,
S. Naito, T. Goto and M. Sasaki, Angew. Chem., Int. Ed.,
2008, 47, 4737; (f) X. Guinchard and E. Roulland, Org. Lett.,
2009, 11, 4700.
7 (a) V. V. Vintonyak and M. E. Maier, Org. Lett., 2008, 10,
1239; (b) R. Kartika, T. R. Gruffi and R. E. Taylor, Org. Lett.,
2008, 10, 5047; (c) W. Tu and P. E. Floreancig, Angew.
Chem., Int. Ed., 2009, 48, 4567; (d) H. Kim, Y. Park and
J. Hong, Angew. Chem., Int. Ed., 2009, 48, 7577;
(e) J. S. Yadav, G. G. Krishana and S. N. Kumar, Tetrahedron,
2010, 66, 480; (f) H. Fuwa, A. Saito and M. Sasaki, Angew.
Chem., Int. Ed., 2010, 49, 3041; (g) D. Martinez-Solorio and
M. P. Jennings, J. Org. Chem., 2010, 75, 4095; (h) Z. Yang,
B. Zhang, G. Zhao, J. Yang, X. Xie and X. She, Org. Lett.,
2011, 13, 5916; (i) S. Raghavan and P. K. Samanta, Org.
Lett., 2012, 14, 2346; ( j) G. V. M. Sharma, S. V. Reddy and
K. V. S. Ramakrishna, Org. Biomol. Chem., 2012, 10, 3689.
8 A. G. Dossetter, T. F. Jamison and E. N. Jacobsen, Angew.
Chem., Int. Ed., 1999, 38, 2398.
a
3
(4 mg,
0.014 mmol), alcohol 23 (3 mg, 0.01 mmol) and PPh3 (4 mg,
0.016 mmol) in 0.5 mL benzene was added diisopropyl azodi-
carboxylate (31 µL, 0.5 M solution in benzene, 0.016 mmol) at
23 °C. After stirring for 1 h at 23 °C an additional amount of
PPh3 (4 mg, 0.016) and diisopropyl azodicarboxylate (31 µL,
0.5 M solution in benzene, 0.016 mmol) was added at 23 °C.
The reaction was stirred for an additional 1 h at 23 °C, and
then concentrated under vacuum. The residue was chromato-
graphed on silica gel (8 : 2, 7 : 3, 6 : 4, 1 : 1, 4 : 6; pet ether (b.p.
fraction 30 °C–60 °C)–ethyl acetate) to afford neopeltolide 1
(4.1 mg) as a clear oil in 78% yield. [α]2D3 +22.7 (c 0.41, MeOH);
1H NMR (500 MHz, CD3OD) δ 7.67 (s, 1H), 6.37 (dt, J = 11.5,
7.4 Hz, 1H), 6.28 (dt, J = 11.9, 2.5 Hz, 1H), 6.06–6.01 (m, 1H),
5.89 (dt, J = 11.6, 1.6 Hz, 1H), 5.22–5.15 (m, 2H), 4.31–4.30 (m,
2H), 4.10–4.04 (m, 1H), 3.69–3.63 (m, 4H), 3.61–3.54 (m, 1H),
3.28 (s, 3H), 3.04–2.97 (m, 2H), 2.76–2.68 (m, 3H), 2.31 (dd, J =
14.8, 10.4 Hz, 1H), 1.90–1.76 (m, 2H), 1.77–1.62 (m, 2H),
1.62–1.43 (m, 4H), 1.43–1.18 (m, 6H), 1.17–1.08 (m, 1H), 0.97
(d, J = 6.7 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz,
CD3OD) δ 173.0, 166.8, 161.9, 159.6, 150.0, 142.3, 139.2, 135.9,
121.7, 115.9, 77.1, 77.0, 73.9, 71.3, 69.2, 56.4, 52.6, 45.2, 43.5,
43.2, 41.0, 37.9, 37.4, 36.2, 32.6, 29.0, 26.4, 26.0, 20.0, 14.2; IR
(NaCl) 3336, 2925, 2854, 1725, 1513, 1461, 1250, 1183,
9 H. Ito, T. Inoue and K. Iguchi, Org. Lett., 2008, 10, 3873.
10 K. Omura and D. Swern, Tetrahedron, 1978, 34, 1651.
11 P. K. Jadhav, K. S. Bhat, P. T. Perumal and H. C. Brown,
J. Org. Chem., 1986, 51, 432.
1082 cm−1
.
12 W. Yu, Y. Mei, Y. Kang, Z. Hua and Z. Jin, Org. Lett., 2004,
6, 3217.
13 S. Masamune, W. R. Roush, M. A. Blanchette, W. Choy,
J. T. Davis, A. P. Essenfeld and T. Sakai, Tetrahedron Lett.,
1984, 25, 2183.
Acknowledgements
Financial support of this work was provided in part by the
National Institutes of Health and Purdue University. We would
like to thank Dr Kalapala Venkateswara Rao (Purdue Univer- 14 (a) R. J. Maguire and E. J. Thomas, J. Chem. Soc., Perkin
sity) for experimental help and discussions.
Trans. 1, 1995, 2487; (b) R. J. Maguire and E. J. Thomas,
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Paper
J. Chem. Soc., Perkin Trans. 1, 1995, 2477; (c) S. K. Woo and 17 Z. Huang and E. Negishi, Org. Lett., 2006, 8,
E. Lee, J. Am. Chem. Soc., 2010, 132, 4564. 3675.
15 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and 18 C. K. Skepper, T. Quach and T. F. Molinski, J. Am. Chem.
M. Yamaguchi, Bull. Chem. Soc. Jpn., 1990, 55, 7. Soc., 2010, 132, 10286.
16 K. R. Hornberger, C. L. Hamblett and J. L. Leighton, J. Am. 19 S. Jeong, C. Xin and P. G. Harran, J. Org. Chem., 1998, 63,
Chem. Soc., 2000, 122, 12894.
8640.
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