Total synthesis of (-)-cinatrin C1 based on an In(OTf) 3-catalyzed Conia-ene reaction

Article abstract of DOI:10.1021/jo400263w

The stereocontrolled total synthesis of (-)-cinatrin C₁, a phospholipase A₂ inhibitor, has been accomplished. The key feature includes the stereoselective construction of the highly substituted tetrahydrofuran core by In(OTf)₃-catalyzed Conia-ene reaction of the oxygen-tethered acetylenic malonic ester followed by dihydroxylation with concomitant lactonization.

Full text of DOI:10.1021/jo400263w

Article
pubs.acs.org/joc
Total Synthesis of (−)-Cinatrin C1 Based on an In(OTf)3‑Catalyzed
Conia-Ene Reaction
Fumiya Urabe, Shunsuke Nagashima, Keisuke Takahashi, Jun Ishihara, and Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
S
* Supporting Information
ABSTRACT: The stereocontrolled total synthesis of (−)-ci-
natrin C1, a phospholipase A2 inhibitor, has been accom-
plished. The key feature includes the stereoselective
construction of the highly substituted tetrahydrofuran core
by In(OTf)3-catalyzed Conia−ene reaction of the oxygen-
tethered acetylenic malonic ester followed by dihydroxylation
with concomitant lactonization.
INTRODUCTION
■
Recently, in connection with a project directed toward the
synthesis of biologically intriguing natural products having a
highly functionalized heterocyclic core such as lactacystin,
salinosporamide A, and oxazolomycin,1 we have developed a
new methodology for heterocycle synthesis that relies upon
In(OTf)3-catalyzed Conia−ene reaction2−5 of heteroatom-
tethered acetylenic malonic ester 1 giving 2 (Scheme 1). This
Scheme 1. In(OTf)3-Catalyzed Conia−Ene Reactions
Figure 1. Cinatrin family.
cinatrins good targets for synthesis. In 1997, Evans and co-
workers reported the first synthesis of (+)-cinatrin C1 and
(−)-cinatrin C3 using a tartrate aldol methodology,9 thus
establishing the absolute structures of natural cinatrins to be
enantiomeric to those originally reported.6 Then Rizzacasa and
method is applicable to chiral terminal and nonterminal alkynes
co-workers achieved the first enantiospecific synthesis of
giving various five- to seven-membered nitrogen- or oxygen-
containing heterocyclic compounds stereoselectively without
significant amounts of racemization. To further demonstrate
the synthetic utility of this methodology, we became interested
in the synthesis of the cinatrins6 possessing highly function-
alized γ-lactone cores, which structurally belong to the alkyl
citrate family of natural products. The reason we focused on the
cinatrins arose from our continuing study on the synthesis of
this family of natural products (Figure 1).7
In 1992, Itazaki and co-workers reported the isolation of
cinatrins A, B, C1, C2, and C3 from the fermentation broth of
Circinotrichum falcatisporum RF-641.6 The cinatrins were found
to be potent inhibitors of rat platelet phospholipase A2 (PLA2)
with maximal inhibition shown by cinatrin C3 (IC50 70 μM).
Since PLA2 plays a key role in biosynthesis of eicosanoids such
as the prostanoids,8 this class of natural products are expected
to be potential anti-inflammatory agents. The intriguing
biological activities and molecular architectures make the
10b
(−)-cinatrin B,10a (−)-cinatrin C1,10b and (+)-cinatrin C3
in naturally occurring forms from D-arabinose via Ireland−
Claisen rearrangement of the tetrahydrofuran-2-carboxylic acid
dodec-1-en-3-yl ester derivative.10 Recently, Yakura and co-
workers reported the synthesis of 2-epi-cinatrin C1 dimethyl
ester via [2,3]-sigmatropic rearrangement of the in situ
generated oxonium ylide from the 5-(allyloxy)-2-diazo-3-
oxopentanoic acid ester derivative.11 Herein we report a
novel total synthesis of (−)-cinatrin C1, which features the
stereoselective construction of the highly substituted tetrahy-
drofuran core by In(OTf)3-catalyzed Conia-ene cyclization of
the oxygen-tethered acetylenic malonic ester followed by
dihydroxylation with concomitant lactonization.
Received: February 6, 2013
Published: April 2, 2013
© 2013 American Chemical Society
3847
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
to furnish compound 5 required for the crucial In(OTf)3-
catalyzed Conia-ene reaction.
Upon treatment of 5 with a catalytic amount of In(OTf)3 in
the presence of DBU in boiling toluene, regio- and stereo-
selective cyclization took place cleanly to produce tetrahy-
drofuran 4 in excellent yield (Scheme 4). It is important to note
RESULTS AND DISCUSSION
■
From a retrosynthetic perspective, we envisioned lactone 3 as a
precursor of cinatrin C1 by the disconnection at the C4−C5
bond via Wittig olefination−hydrogenation and functional
group interconversions involving oxidation of the tetrahydro-
furan ring (Scheme 2). To stereoselectively access 3 we
Scheme 4. Preparation of Tetrahydrofuran Intermediate 16
Scheme 2. Retrosynthetic Analysis
envisioned an approach from alkyne 7 via Rh(II)-catalyzed O−
H insertion reaction of dimethyl diazomalonate (6), In(OTf)3-
catalyzed Conia−ene reaction of 5, and stereoselective
dihydroxylation of 4 accompanied by lactonization leading to
the discrimination of the geminal esters. This approach is
appealing since the two contiguous quaternary centers could be
created stereoselectively by one dihydroxylation process under
the influence of the C1 stereochemistry.
Following the above-mentioned retrosynthetic analysis, the
route toward cinatrin C1 began with the preparation of
enantiopure 5 (Scheme 3). Thus, racemic acetate 9, derived
Scheme 3. Preparation of O-Tetherd Acetylenic Malonic
Ester 5
that in this particular case the reaction again occurred without
racemization.16 The subsequent dihydroxylation of 4 turned
out to be very sluggish at room temperature, thus requiring the
reaction to be heated in order to proceed at a reasonable rate.
The diastereoselectivity therefore became moderate although
the lactonization of 11 took place simultaneously as expected to
produce a 70:30 mixture of the desired compound 3 and its
diastereomer 12. Since the selective reduction of the γ-lactone
in the presence of the methyl ester turned out to be difficult,
the latter functionality was converted to the primary alcohol by
alkaline hydrolysis followed by NaBH4 reduction of the
corresponding acid chloride to give alcohol 13. At this point,
13 became a crystalline solid, the X-ray analysis of which
allowed us to unambiguously determine its stereostructure.17
After protection of 13 as its acetonide, DIBALH reduction of
14 afforded the corresponding lactol which was then subjected
to Wittig reaction using the ylide, generated from phosphonium
bromide 1518 by the action of n-butyllithium, in DMSO at 120
°C,19 to afford 16 as an inseparable 1:1 E/Z-mixture in good
yield.
from known aldehyde 812 in three steps, was subjected to
lipase-mediated kinetic resolution under hydrolytic conditions
using Novozym13 to give (S)-9 and (R)-1014 both in almost
enantiopure forms. (S)-Acetate 9 was then converted to alcohol
7 via methanolysis, benzylation, and removal of the p-
methoxybenzyl protecting group. O−H insertion reaction15
between 7 and methyl diazomalonate (6) was conducted in the
presence of a catalytic amount of Rh2(OAc)4 in boiling benzene
With compound 16 possessing the carbon framework of
cinatrin C1 in hand, we then investigated the remaining
transformations including oxidation of the tetrahydrofuran ring
(Scheme 5). Thus, the primary alcohol of 16 was converted to
the methyl ester by a three-step sequence involving Dess−
Martin oxidation, Pinnick−Kraus oxidation,20 and esterification
to give 17 in good yield. Hydrogenation of 17 followed by
removal of the acetonide group afforded diol 18, the
3848
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
We also attempted to oxidize the tetrahydrofuran ring of 20
using the C−H amination methodology reported by Du Bois
and co-workers22,23 (Scheme 6). Thus, diol 20 was first
Scheme 5. Attempts toward the Synthesis of γ-Lactone
Intermediates via Oxidation of the Tetrahydrofuran Rings
Scheme 6. Alternative Approach via Du Bois’ C−H
Amination
converted to carbamate 27 by the reaction with trichloroacetyl
isocyanate followed by methanolysis. Upon treatment of 27
with a catalytic amount of Rh2(esp)2 in the presence of
iodosobenzene diacetate and MgO in benzene at 65 °C, the C−
H amination took place cleanly to afford cyclic carbamate 28 in
acceptable yield. However, the subsequent conversion of 28 to
hemiacetal 29 failed under various acidic and basic hydrolysis
conditions.
In order to overcome the encountered problem in the
oxidation of a tetrahydrofuran ring, we envisioned an alternative
approach centered around Baeyer−Villiger oxidation of
aldehyde 30 giving formate 31, from which cinatrin C1 would
be accessible (Scheme 7).
Scheme 7. Approach via a Baeyer−Villiger Oxidation
hydroxymethyl group of which was then transformed to the
methyl ester in the same manner as described for the
conversion of 16 to 17 giving rise to diester 19. After BCl3-
promoted debenzylation of 19, the resulting diol 20 was
acetylated to give diacetate 21 possessing all requisite
functionalities besides a γ-lactone carbonyl group. However,
oxidation of 21 to γ-lactone 23 turned out to be very difficult
To realize this approach, the investigation began with the
preparation of compound 41 from aldehyde 3324 available by D-
proline-catalyzed self-aldolization of 32, following the method-
ology developed for the synthesis of 16 (Scheme 8). Thus,
Ohira−Bestmann reaction25 of 33 gave alkyne 34 which was
then subjected to Rh2(OAc)4-catalyzed O−H insertion reaction
using 6 to provide 35. In(OTf)3-catalyzed Conia−ene reaction
of 35 again proceeded cleanly to afford tetrahydrofuran 36 in
excellent yield. Although dihydroxylation of 36 under the
conditions employed for 4 exhibited somewhat lower
diastereoselectivity (dr = 2:1), Narasaka’s modified procedure26
remarkably improved this dihydroxylation-lactonization step.
Thus, when 36 was treated with a catalytic amount of OsO4 in
the presence of NMO and phenylboronic acid in CH2Cl2 at
room temperature, lactone 37 and 38 were obtained in a ratio
of 5:1 in good yield.27 Following the procedure shown in
Scheme 4, compound 37 was then transformed to 41 via 39
and 40.
after we had examined various oxidation conditions.21 For
21a
example, RuO4
oxidation of 21 under conventional
conditions produced ketone 22 in which some position of
the alkyl chain was oxidized in low yield. It was assumed that
the unexpected difficulty in the oxidation of 21 would be
attributed to the highly electron deficient nature of the
tetrahydrofuran ring having four electron-withdrawing ester
substituents. In fact, RuO4 oxidation of 24 with two ester
groups was found to produce the desired γ-lacone 25 along
with ketone 26, although the yields of both compounds were
very low.
3849
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
Scheme 8. Synthesis of Tetrahydrofuran Intermediate 41
Scheme 9. Completion of the Total Synthesis of Cinatrin C1
reaction for heterocycle synthesis which we have previously
developed.1c
Because all attempts to simultaneously oxidize two C2- and
C3-hydroxymethyl groups were unsuccessful, we were obliged
to adopt a stepwise oxidation sequence. The primary alcohol of
41 was first converted to the tert-butyl ester by successive
Dess−Martin oxidation, Pinnick−Kraus oxidation, and ester-
ification using N,N′-diisopropyl-O-2-tert-butylisourea28
(Scheme 9) to afford 42 in good yield. Pd(OH)2-catalyzed
reaction of 42 under hydrogen atmosphere allowed hydro-
genation of the olefinic double bond and hydrogenolytic
removal of the primary benzyl group to give alcohol 43. After
Dess−Martin oxidation of 43, the resulting aldehyde was
subjected to Baeyer−Villiger oxidation using m-chloroperben-
zoic acid to afford formate 44. Methanolytic removal of the
formyl group of 44 followed by TPAP oxidation29 of the lactol
led to the formation of γ-lactone 44, which was converted to
diester 46 by removal of the acetonide followed by the above-
mentioned three-step conversion of the hydroxymethyl group
to the tert-butyl ester. Finally, removal of the benzyl group and
two tert-butyl groups, followed by HPLC purification
completed the total synthesis of (−)-cinartin C1. The
spectroscopic data and the specific rotation of the synthetic
substance were in accord with those reported6,9,10b for natural
cinartin C1. Since saponification of cinartin C1 are known to
produce cinartin C3,6,10b our present synthesis constitutes the
formal synthesis of (+)-cinartin C3.
EXPERIMENTAL SECTION
■
General Methods. Where appropriate, reactions were performed
in flame-dried glassware under argon atmosphere. All extracts were
dried over MgSO4 or Na2SO4 and concentrated by rotary evaporation
below 30 °C at 25 Torr unless otherwise noted. Commercial reagents
and solvents were used as supplied with the following exceptions. N,N-
Dimethylformamide (DMF), dichloromethane (CH2Cl2), acetonitrile
(MeCN), benzene, and triethylamine (Et3N) were distilled from
CaH2. Thin-layer chromatography (TLC) was performed using glass-
packed silica gel plates (0.25 or 0.5 mm thickness). Column
chromatography was performed using silica gel (particle size 100−
210 μm (regular), 40−50 μm (flush)). Optical rotations were recorded
on a digital polarimeter at ambient temperature. Infrared spectra were
measured on a Fourier transform infrared spectrometer. 1H NMR and
13C NMR spectra were measured using CDCl3 or CD3OD as solvent,
and chemical shifts are reported as δ values in ppm based on internal
1
(CH3)4Si (0.00 ppm, H) or solvent peak. HRMS spectra were taken
in EI (dual focusing sector field), ESI (TOF) or FAB (dual-focusing
sector field) mode.
1-(4-Methoxybenzyloxy)-4-(trimethylsilyl)but-3-yn-2-ol. To
a stirred solution of ethynyltrimethylsilane (0.60 mL, 4.34 mmol) in
THF (9.0 mL) at −10 °C was added n-BuLi (1.66 M in hexane; 2.20
mL, 3.65 mmol). After the solution was stirred at −10 °C for 30 min, a
solution of 812 (551 mg, 3.06 mmol) in THF (6.0 mL) was added, and
the mixture was stirred at −10 °C for 1.5 min. The reaction was
quenched with saturated NH4Cl, and the mixture was extracted with
AcOEt. The extract was washed with brine, dried, concentrated, and
chromatographed (SiO2 30 g, hexane/AcOEt = 6:1) to give the title
CONCLUSION
■
1
compound as a pale yellow oil (731 mg, 86%): H NMR (400 MHz,
We have accomplished the total synthesis of (−)-cinatrin C1 in
24 steps and 2% overall yield from benzyloxyacetaldehyde (32).
The present synthesis illustrates the synthetic utility of the
methodology based on an In(OTf)3-catalyzed Conia−ene
CDCl3) δ 7.27 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 4.54−4.53
(m, 3H), 3.81 (s, 3H), 3.62 (dd, J = 10.0, 3.4 Hz, 1H), 3.52 (dd, J =
10.0, 7.8 Hz, 1H), 2.49 (d, J = 3.4 Hz, 1H), 0.16 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 159.3, 129.7, 129.4, 113.8, 103.0, 90.4, 73.2,
3850
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
73.0, 62.0, 55.2, −0.2; FTIR (neat) 3427, 2958, 1611, 1513, 1460,
1249, 1175, 1099, 1033 cm−1; HRMS (EI) calcd for C15H21O3Si [(M
− H)+] 277.1260, found 277.1275.
(S)-2-(Benzyloxy)but-3-yn-1-ol (7). The benzyl ether (100 mg,
0.334 mmol) was dissolved in a mixture of CH2Cl2 (3.2 mL) and H2O
(0.2 mL). DDQ (309 mg, 1.36 mmol) was added at 0 °C, and the
mixture was stirred at 0 °C for 1.5 h. The mixture was filtered through
Celite, and the filter cake was washed thoroughly with CH2Cl2. The
combined filtrate and washings were washed with saturated NaHCO3
and brine, dried, concentrated, and chromatographed (SiO2 5 g,
hexane/AcOEt = 9:1) to give 7 (57.6 mg, 100%) as a colorless oil:
[α]D26 +145.9 (c 0.99, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37−
7.33 (m, 5H), 4.87 (d, J = 11.2 Hz, 1H), 4.54 (d, J = 11.2 Hz, 1H),
4.23 (brs, 1H), 3.77 (t, J = 5.4 Hz, 2H), 2.52 (s, 1H), 2.15 (t, J = 5.4
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 137.1, 128.5, 128.2, 128.0,
79.7, 75.6, 71.0, 69.4, 65.2; FTIR (neat) 3286, 2871, 1455, 1375, 1073
cm−1; HRMS (FAB) calcd for C11H13O2 [(M + H)+] 177.0916, found
177.0930.
1-(4-Methoxybenzyloxy)but-3-yn-2-yl Acetate (rac-9). To an
ice-cooled solution of 1-(4-methoxybenzyloxy)-4-(trimethylsilyl)but-3-
yn-2-ol (1.00 g, 3.59 mmol) in MeOH (36 mL) was added K2CO3
(500 mg, 3.62 mmol). After the mixture was stirred at room
temperature for 2 h, saturated NH4Cl was added and the mixture was
extracted with AcOEt. The extract was washed with brine, dried, and
concentrated to give the corresponding terminal alkyne (rac-10) (800
mg). This product was dissolved into CH2Cl2 (78 mL), and Et3N
(0.830 mL, 5.95 mmol), Ac2O (0.440 mL, 4.65 mmol), and DMAP
(24.4 mg, 0.20 mmol) were added at room temperature. After being
stirred at room temperature for 3 h, the mixture was diluted with
hexane, washed with 1 M HCl, H2O, saturated NaHCO3, and brine,
dried, and concentrated. Purification of the residue by column
chromatography (SiO2 30 g, hexane:AcOEt = 4:1) gave rac-9 (858 mg,
96%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J =
8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.55 (m, 1H), 4.55 (d, J = 11.7
Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H), 3.81 (s, 3H), 3.66 (m, 2H), 2.46
(d, J = 2.4 Hz, 1H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
169.7, 159.2, 129.4, 129.3, 113.7, 78.5, 74.4, 72.8, 70.3, 62.5, 55.1, 20.8;
FTIR (neat) 3277, 2938, 2866, 1738, 1516, 1233, 1027 cm−1; HRMS
(EI) calcd for C14H16O4 (M+) 248.1049, found 248.1049.
(S)-1-(4-Methoxybenzyloxy)but-3-yn-2-yl Acetate ((S)-9). To
a mixture of rac-9 (200 mg, 0.806 mmol) in phosphate buffer
(NaH2PO4/Na2HPO4, pH 7.7, 5.4 mL) was added Novozym (100
mg) at room temperature. After being stirred at 40 °C for 7 h, the
mixture was filtered through Celite, extracted with AcOEt, dried, and
concentrated. Purification of the residue by column chromatography
(SiO2 8 g, hexane/AcOEt = 8:1 to 3:1) gave (S)-9 (98.3 mg, 49%) and
(R)-10 (84 mg, 51%) each as a colorless oil. The enantiopurities of
(S)-9, [α]24D +53.9 (c 1.35, CHCl3), and (R)-10, [α]24D −4.8 (c 1.61,
CHCl3) (lit.14 [α]D −4.6 (c 2.22, CHCl3)), were determined to be
96% ee and 99% ee, respectively, by HPLC analysis: CHIRALCEL
OD-H, hexane/i-PrOH = 10:1 (0.5 mL/min), tR = 30.4 min ((R)-10)
and 34.8 min ((S)-10).
Dimethyl 2-((S)-2-(Benzyloxy)but-3-ynyloxy)malonate (5).
To a stirred solution of 7 (3.20 g, 18.3 mmol) and methyl
diazomalonate (6) (3.50 g, 22.0 mmol) in benzene (37 mL) was
added Rh2(OAc)4 (40 mg, 0.091 mmol). After the solution was heated
under reflux for 1 h, most of the solvent was evaporated, and the
residue was subjected to column chromatography (SiO2 200 g,
toluene/AcOEt = 6:1) to give 5 (3.58 g, 64%) as a colorless oil: [α]26
D
+54.2 (c 0.90, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35−7.26 (m,
5H), 4.83 (d, J = 11.7 Hz, 1H), 4.81 (s, 1H), 4.52 (d, J = 11.7 Hz, 1H),
4.42−4.40 (m, 1H), 3.95 (dd, J = 11.7, 3.4 Hz, 1H), 3.83 (dd, J = 7.8,
3.4 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 2.51 (d, J = 3.4 Hz, 1H);
13CNMR (100 MHz, CDCl3) δ 166.9, 166.7, 137.3, 128.4, 127.9,
127.8, 79.6, 79.2, 75.6, 73.3, 71.0, 68.8, 52.9, 52.8; FTIR (neat) 3272,
2953, 2114, 1738, 1435, 1088 cm−1; HRMS (EI) calcd for C16H18O6
(M+) 306.1103, found 306.1091.
(S)-Dimethyl 4-(Benzyloxy)-dihydro-3-methylenefuran-
2,2(3H)-dicarboxylate (4). To a solution of 5 (3.60 g, 11.7 mmol)
in toluene (129 mL) were added DBU (106 μL, 0.68 mmol) and
In(OTf)3 (361 mg, 0.64 mmol). After the solution was heated under
reflux for 3 h, most of the solvent was evaporated, and the residue was
subjected to column chromatography (SiO2 = 200 g, hexane/AcOEt =
4:1) to give 4 (3.50 g, 97%) as a colorless oil: [α]28 +11.1 (c 1.05,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36−7.31 (m, 5H), 5.78 (s,
1H), 5.65 (s, 1H), 4.63 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H),
4.40 (brs, 1H), 4.15−4.13 (m, 2H), 3.80 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 168.1, 167.4, 143.1, 137.4, 128.3, 127.8, 127.7, 116.9,
86.2, 78.5, 73.7, 70.0, 53.2; FTIR (neat) 2952, 1743, 1434, 1232, 1094,
1059 cm−1; HRMS (FAB) calcd for C16H19O6 [(M + H)+] 307.1181,
found 307.1203. The enantiomeric purity was determined to be 94%
ee by HPLC analysis: CHIRALCEL OD-H, hexane/i-PrOH = 9:1 (0.5
mL/min), tR = 33.1 min (enantiomer of 4) and 42.3 min (compound
4).
(S)-1-(4-Methoxybenzyloxy)but-3-yn-2-ol ((S)-10). To an ice-
cooled solution of (S)-9 (354 mg, 1.43 mmol) in MeOH (14 mL) was
added K2CO3 (193 mg, 1.40 mmol). After the mixture was stirred at
room temperature for 2 h, saturated NH4Cl was added, and the
mixture was extracted with AcOEt. The extract was washed with brine,
dried, concentrated, and chromatographed (SiO2 10 g, hexane/AcOEt
= 3:1) to give (S)-10 (248 mg, 84%) as a colorless oil: [α]24D +4.9 (c
1
1.05, CHCl3); H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.8 Hz,
2H), 6.89 (d, J = 8.8 Hz, 2H), 4.58−4.51 (m, 3H), 3.81 (s, 3H), 3.63
(dd, J = 9.8, 3.6 Hz, 1H), 3.55 (dd, J = 9.8, 6.8 Hz, 1H), 2.52 (brs,
1H), 2.45 (d, J = 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.4,
129.51, 129.48, 113.9, 81.6, 73.6, 73.1, 73.0, 61.3, 55.2; FTIR (neat)
3438, 3279, 2933, 2860, 1610, 1510, 1240, 1105, 1028 cm−1; HRMS
(EI) calcd for C12H14O3 (M+) 206.0943, found 206.0936.
Methyl (3R,3aS,6aR)-3-(Benzyloxy)hexahydro-3a-hydroxy-6-
oxofuro[3,4-b]-furan-6a-carboxylate (3). To a solution of 4 (3.50
g, 11.3 mmol) in THF (189 mL) and H2O (63 mL) at room
temperature were added NMO (3.98 g, 34.0 mmol) and OsO4 (0.15
M in H2O, 7.60 mL, 1.13 mmol), and the mixture was heated at 70 °C
for 7 h. The mixture was diluted with 20% Na2S2O3 and AcOEt. The
organic layer was washed with H2O and brine, dried, concentrated, and
chromatographed (SiO2 200 g, hexane/AcOEt = 2:1) to give 3 (1.87 g,
54%) and its diastereomer 12 (798 mg, 23%) each as a white solid.
Compound 3: [α]24D −14.2 (c 0.90, MeOH); mp 115−117 °C; 1H
NMR (400 MHz, CDCl3) δ 7.36−7.26 (m, 5H), 4.81 (d, J = 9.3 Hz,
1H), 4.66 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.29 (dd, J =
10.2, 4.4 Hz, 1H), 4.22 (d, J = 9.3 Hz, 1H), 4.14 (m, 1H), 4.01 (dd, J =
10.2, 4.4 Hz, 1H), 3.87 (s, 3H), 3.25 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 170.0, 166.3, 136.6, 128.7, 128.2, 127.6, 88.5, 87.5, 84.0,
72.5, 72.2, 70.6, 53.6; FTIR (neat) 3437, 2955, 1768, 1457, 1247,
1119, 1018 cm−1; HRMS (EI) calcd for C15H16O7 (M+) 308.0896,
found 308.0883.
1-(((S)-2-(Benzyloxy)but-3-ynyloxy)methyl)-4-methoxyben-
zene. To an ice-cooled solution of (S)-10 (2.00 g, 9.70 mmol) in
DMF (32 mL) was added NaH (60% in mineral oil, 480 mg, 12.0
mmol), and the mixture was stirred at the same temperature for 10
min. Benzyl bromide (14.0 mL, 11.8 mmol) and tetra-n-
butylammonium iodide (72.0 mg, 0.20 mol) were added at 0 °C,
and the mixture was stirred at room temperature for 5 h. The mixture
was diluted with AcOEt, washed with saturated NaHCO3 and brine,
dried, concentrated, and chromatographed (SiO2 10 g, hexane/AcOEt
= 3:1) to give the corresponding benzyl ether (2.66 g, 93%) as a
25
1
colorless oil: [α]D +69.1 (c 1.05, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.37−7.26 (m, 7H), 6.87, (d, J = 7.8 Hz, 2H), 4.83, (d, J =
11.7 Hz, 1H), 4.59−4.53 (m, 3H), 4.32 (brs, 1H), 3.80 (s, 3H), 3.69−
3.66 (m, 2H), 2.49 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 159.2,
137.5, 130.0, 129.4, 128.4, 128.0, 127.8, 113.7, 80.4, 74.8, 73.1, 71.9,
70.8, 68.2, 55.2; FTIR (neat) 3283, 2862, 1612, 1513, 1455, 1247,
1091, 1034 cm−1; HRMS (EI) calcd for C19H20O3 (M+) 296.1399,
found 296.1412.
Compound 12: [α]24 −76.6 (c 1.34, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 7.42−7.33 (m, 3H), 7.32−7.30 (m, 2H), 4.73 (d, J =
11.7 Hz, 1H), 4.63 (d, J = 11.7 Hz, 1H), 4.35 (d, J = 9.8 Hz, 1H), 4.20
(d, J = 9.8 Hz, 1H), 4.16 (dd, J = 9.8, 4.8 Hz, 1H), 4.09−4.02 (m, 1H),
3.86 (s, 3H), 3.77 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 170.0,
3851
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
165.0, 135.8, 128.88, 128.85, 128.2, 88.0, 84.3, 81.0, 73.4, 73.1, 72.2,
53.2; FTIR (neat) 3468, 2956, 1791, 1458, 1303, 1123, 1025 cm−1;
HRMS (EI) calcd for C15H16O7 (M+) 308.0896, found 308.0890.
(3R,3aS,6aS)-3-(Benzyloxy)tetrahydro-3a-hydroxy-6a-
(hydroxymethyl)furo[3,4-b]furan-6(6aH)-one (13). To an ice-
cooled solution of 3 (1.90 g, 6.10 mmol) in THF (97 mL) was added
1 M LiOH (24 mL). After being stirred at room temperature for 30
min, the mixture was diluted with Et2O, acidified (pH = 1) with 1 M
HCl, and extracted with AcOEt. The extract was dried and
concentrated to give the carboxylic acid as a white solid (1.92 g).
The product was dissolved in CH2Cl2 (10 mL) and THF (0.5 mL),
and oxalyl chloride (1.60 mL, 18.7 mmol) and DMF (47.0 μL, 0.61
mmol) were added at 0 °C. After the solution was stirred at room
temperature for 1 h, the most of the solvent was evaporated, and THF
(61 mL) and MeOH (6 mL) were added to the residue. The resulting
solution was cooled to −78 °C, and NaBH4 (688 mg, 18.2 mmol) was
added. After being stirred at −78 °C for 1 h, the mixture was acidified
by the addition of 0.5 M HCl (10 mL), extracted with AcOEt, washed
with saturated NaHCO3 and brine, dried, and concentrated.
Purification of the residue by column chromatography (SiO2 100 g,
CH2Cl2/AcOEt = 6:1) gave 13 as a white solid (1.04 g, 61%), which
was recrystallized from AcOEt for X-ray analysis: [α]24D +11.0 (c 1.02,
MeOH); mp 106−109 °C, 1H NMR (400 MHz, CDCl3) δ 7.39−7.30
(m, 5H), 4.85 (d, J = 9.8 Hz, 1H), 4.63 (d, J = 12.2 Hz, 1H), 4.61 (d, J
= 12.2 Hz, 1H), 4.19−4.11 (m, 3H), 4.12 (d, J = 11.7 Hz, 1H), 3.97
(d, J = 11.7 Hz, 1H), 3.70 (d, J = 6.8 Hz, 1H), 3.68 (d, J = 6.8 Hz,
1H), 2.61 (brs, 1H), 13C NMR (100 MHz, CDCl3) δ 174.8, 137.0,
128.6, 128.2, 127.7, 85.5, 85.0, 85.0, 72.5, 71.7, 70.3, 61.6; FTIR (neat)
3419, 2877, 1766, 1461, 1382, 1017 cm−1; HRMS (EI) calcd for
C14H16O6 (M+) 280.0947, found 280.0946.
concentrated, and chromatographed (SiO2 230 g, hexane/AcOEt =
20:1 to 0:1) to give 16 (1.3 g, 80%, 1:1 E/Z-mixture) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.35−7.26 (m, 5H), 5.81−5.73(m,
0.5H), 5.53−5.37 (m, 0.5H), 5.38 (d, J = 16.1 Hz, 0.5H), 5.09 (d, J =
12.2 Hz, 0.5H), 4.62 (d, J = 12.2 Hz, 1H), 4.58 (d, J = 12.2 Hz, 1H),
4.20−4.16 (m, 1H), 4.11−3.66 (m, 5H), 2.39−2.30 (m, 1H), 2.21−
2.12 (m, 1H), 2.05−1.98 (m, 1H), 1.54 (s, 3H), 1.44−1.39(m, 1H),
1.42 (s, 3H), 1.37−1.19 (m, 16H), 0.88 (t, J = 5.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 138.1, 138.1, 135.6, 132.3, 128.3, 128.3, 127.3,
127.5, 127.5, 127.3, 127.2, 126.8, 124.4, 98.4, 98.3, 98.3, 86.1, 85.9,
84.6, 84.2, 81.2, 79.4, 72.1, 72.0, 71.0, 70.6, 63.7, 63.7, 60.6, 60.5, 32.5,
31.9, 30.0, 29.6, 29.6, 29.6, 29.6, 29.4, 29.3, 29.2, 29.1, 29.0, 28.0, 24.6,
24.5, 22.7, 14.1; FTIR (neat) 3488, 2925, 2856, 1459, 1375, 1205,
1112, 1051 cm−1; HRMS (EI) calcd for C28H44O5 (M+) 460.3189,
found 460.3187.
Methyl (4aS,7R,7aS)-7-(Benzyloxy)-4a-(dodec-1-enyl)-tetra-
hydro-2,2-dimethyl-4H-furo[3,2-d][1,3]dioxine-7a-carboxylate
(17). To an ice-cooled solution of 16 (215 mg, 0.467 mmol) in
CH2Cl2 (9.3 mL) were added NaHCO3 (216 mg, 2.57 mmol) and
Dess−Martin periodinane (DMPI) (990 mg, 2.33 mmol). After being
stirred at room temperature for 5 h, the reaction was quenched with
saturated Na2S2O3, and the mixture was extracted with AcOEt. The
extract was washed with NaHCO3 and brine, dried, and concentrated
to give the corresponding aldehyde (243 mg). The crude aldehyde was
dissolved in t-BuOH (3.9 mL) and H2O (0.8 mL). 2-Methyl-2-butene
(1.5 mL, 14.3 mmol), NaH2PO4 (219 mg, 1.40 mmol), and NaClO2
(169 mg, 1.87 mmol) were added, and the mixture was stirred at room
temperature for 2 h. The reaction was quenched with saturated
NH4Cl, and the mixture was extracted with AcOEt. The extract was
washed with brine, dried, and concentrated to give the corresponding
carboxylic acid (239 mg), which was dissolved in THF (4 mL) and
MeOH (1 mL). To this solution was added trimethylsilyldiazo-
methane (2.0 M in Et2O, 0.40 mL, 0.80 mmol), and the mixture was
stirred at room temperature for 1 h, and then concentrated.
Purification of the residue by column chromatography (SiO2 230 g,
hexane/CH2Cl2 = 3:1 to 1:2) gave 17 (210 mg, 92%, 1:1 E/Z-mixture)
(4aS,7R,7aS)-7-(Benzyloxy)-2,2-dimethyldihydro-4H-4a,7a-
(methanooxymethano)furo[3,2-d][1,3]dioxin-10-one (14). To a
solution of 13 (1.10 g, 3.75 mmol) in acetone (37 mL) were added
2,2-dimethoxypropane (1.40 mL, 11.2 mmol) and p-TsOH·H2O (72.0
mg, 0.380 mmol). After the solution was stirred at room temperature
for 11 h, 2,2-dimethoxypropane (0.92 mL, 7.50 mmol) was added, and
the mixture was refluxed for 1.5 h. The reaction was quenched with
NaHCO3 (150 mg, 1.79 mmol), and the mixture was diluted with
saturated NaHCO3 and extracted with AcOEt. The extract was washed
with brine, dried, concentrated, and chromatographed (SiO2 63 g,
1
as a pale yellow oil: H NMR (400 MHz, CDCl3) δ 7.28−7.10 (m,
5H), 6.00−5.92 (m, 1H), 5.81−5.74 (m, 0.5H), 5.50−5.38 (m, 0.5H),
4.43 (t, J = 11.7 Hz, 1H), 4.43 (t, J = 11.7 Hz, 1H), 4.19−4.11 (m,
1H), 4.01−3.95 (m, 2H), 3.88 (d, J = 9.3 Hz, 0.5H), 3.80 (d, J = 7.8
Hz, 0.5H), 3.80 (d, J = 13.2 Hz, 0.5H), 3.68 (s, 1.5H), 3.66 (s, 1.5H),
3.55 (d, J = 12.7 Hz, 0.5H), 2.35−2.25 (m, 1H), 2.00−1.90 (m, 1H),
1.34 (s, 3H), 1.31 (s, 3H), 1.20−1.15 (m, 16H), 0.80 (t, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 170.3, 137.7, 137.6,
135.5, 132.3, 128.4, 128.3, 128.2, 127.7, 127.7, 127.5, 127.4, 127.1,
127.0, 125.3, 98.5, 98.4, 86.6, 85.9, 84.2, 83.8, 80.0, 79.1, 72.4, 72.3,
70.7, 70.6, 63.3, 62.2, 52.0, 52.0, 32.4, 31.9, 30.0, 29.9, 29.9, 29.6, 29.6,
29.5, 29.4, 29.3, 29.1, 28.2, 22.7, 20.6, 20.4, 14.1; FTIR (neat) 2926,
1744, 1457, 1374, 1254, 1070 cm−1; HRMS (EI) calcd for C29H44O6
(M+) 488.3138, found 488.3143.
CH2Cl2/AcOEt = 6:1) to give 14 as a colorless oil (1.10 g, 88%):
1
[α]24 −8.2 (c 1.12, CHCl3); H NMR (400 MHz, CDCl3) δ 7.36−
D
7.30 (m, 5H), 4.76 (d, J = 10.2 Hz, 1H), 4.61 (d, J = 12.2 Hz, 1H),
4.57 (d, J = 12.2 Hz, 1H), 4.32 (d, J = 10.2 Hz, 1H), 4.25 (t, J = 6.4
Hz, 1H), 4.14−4.09 (m, 2H), 3.92 (d, J = 12.7 Hz, 1H), 3.71 (dd, J =
9.3, 6.4 Hz, 1H), 1.47 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.2, 136.9, 128.6, 128.1, 127.7, 100.2, 84.6, 78.8, 72.4,
70.3, 70.1, 61.5, 27.3, 26.6; FTIR (neat) 2991, 1780, 1460, 1374, 1220,
1089, 1011 cm−1; HRMS (EI) calcd for C17H20O6 (M+) 320.1260,
found 320.1263.
((4aS,7R,7aS)-7-(Benzyloxy)-4a-(dodec-1-enyl)tetrahydro-
2,2-dimethyl-4H-furo[3,2-d][1,3]dioxin-7a-yl)methanol (16). To
a solution of 14 (1.10 g, 3.31 mmol) in toluene (33 mL) at −78 °C
was added dropwise DIBALH (1.02 M in hexane; 4.90 mL, 4.80
mmol) over 5 min, and the mixture was stirred at the same
temperature for 1 h. MeOH (5 mL) was added at −78 °C, and the
mixture was stirred at the same temperature for 10 min. Rochelle salt
(20%) was then added, and the mixture was stirred at room
temperature for 30 min and filtered through Celite. The filtrate was
extracted with AcOEt, washed with brine, dried, and concentrated to
give the corresponding lactol as a colorless oil (1.00 g).
n-BuLi (2.76 M in hexane; 8.00 mL, 22.1 mmol) was added to
DMSO (23 mL) at room temperature, and the mixture was stirred at
room temperature for 30 min. The resulting solution of dimsyllithium
was added to 1518 (11.7 g, 23.6 mmol, dried at 200 °C under reduced
pressure for 1.5 h), and the mixture was then stirred at room
temperature for 30 min to generate the ylide. To this solution was
added a solution of the lactol (1.00 g) in DMSO (9 mL) at room
temperature, and the mixture was stirred at 120 °C for 4 h. The
mixture was diluted with AcOEt, washed with H2O and brine, dried,
Dimethyl (2R,3S,4R)-4-(Benzyloxy)-2-dodecyltetrahydro-3-
hydroxyfuran-2,3-dicarboxylate (19). Under argon atmosphere,
20% Pd(OH)2/C (10.0 mg) was added to a solution of 17 (72.0 mg
0.15 mmol) in AcOEt (2.0 mL), and then a hydrogen gas balloon was
attached. The mixture was stirred for 30 h, filtered through Celite, and
concentrated to give the corresponding hydrogenated alkane (71 mg)
as a yellow oil, which was dissolved in MeOH (2.0 mL). To this
solution was added p-TsOH·H2O (3.0 mg, 0.016 mmol) at room
temperature, and the mixture was stirred for 3 h. The mixture was
diluted with AcOEt, washed with saturated NaHCO3 and brine, dried,
and concentrated to give 18 (65.0 mg) as a yellow oil which was used
for the next reaction without purification. Pure 18, a colorless oil,
obtained by column chromatography (SiO2, hexane/AcOEt = 3:1 to
0:1) exhibited the following spectral data: [α]26 −8.1 (c 1.05,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36−7.24 (m, 5H), 4.64 (d,
J = 12.0 Hz, 1H), 4.59 (t, J = 8.5 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H),
4.13 (t, J = 8.5 Hz, 1H), 3.98 (s, 1H), 3.93 (s, 3H), 3.85 (t, J = 8.5 Hz,
1H), 3.67 (d, J = 6.5 Hz, 2H), 2.37 (t, J = 6.6 Hz, 1H), 1.60−1.51 (m,
1H), 1.28−1.23 (m, 21H), 0.88 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 173.3, 137.6, 128.4, 127.9, 127.7, 87.7, 85.2, 73.1,
3852
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
68.8, 65.0, 53.2, 32.4, 31.9, 30.3, 29.6, 29.5, 29.4, 29.3, 23.2, 22.7, 14.1;
FTIR (neat) 3487, 2925, 2853, 1727, 1456, 1245, 1146, 1245, 1146,
1065 cm−1; HRMS (ESI) calcd for C26H42NaO6 [(M + Na)+]
473.2879, found 473.2889.
room temperature for 1 day, additional NaIO4 (27 mg, 0.13 mmol)
and RuCl3·nH2O (1 mg, 0.005 mmol) were added, and the mixture
was stirred for 3 days. The mixture was diluted with H2O (5 mL) and
extracted with CH2Cl2. The extract was washed with brine, dried,
concentrated, and chromatographed (SiO2 1.0 g, hexane/AcOEt = 6:1
to 5:1) to give the recovered 21 (17 mg, 56%) and 22 (7 mg, 22%) as
a colorless oil which was a mixture of several positional isomers of the
To an ice-cooled solution of 18 (65.0 mg) in CH2Cl2 (5 mL) was
added DMPI (188 mg, 0.444 mmol) at room temperature. After the
solution was stirred at room temperature for 4 h, the reaction was
quenched with saturated Na2S2O3, and the mixture was extracted with
AcOEt. The extract was washed with NaHCO3 and brine, dried, and
concentrated to give the corresponding aldehyde (78 mg). The
aldehyde was dissolved in t-BuOH (3.0 mL) and H2O (0.5 mL), and
2-methyl-2-butene (0.47 mL, 4.43 mmol), NaH2PO4 (69.0 mg, 0.42
mmol), and NaClO2 (53.0 mg, 0.59 mmol) were added at room
temperature. After being stirred at room temperature for 2 h, the
mixture was diluted with saturated NH4Cl and AcOEt, washed with
brine, dried, and concentrated to give the corresponding carboxylic
acid, which was dissolved in THF (1 mL) and MeOH (1 mL). To this
solution was added trimethylsilyldiazomethane (2.0 M in Et2O, 125
μL, 0.25 mmol) at room temperature. After being stirred a room
temperature for 1 h, the mixture was concentrated and chromato-
1
ketone carbonyl group: H NMR (400 MHz, CDCl3) δ 5.81 (dd, J =
4.0, 6.4 Hz, 1H), 4.56 (dd, J = 6.4, 9.2 Hz, 1H), 3.93 (ddd, J = 1.6, 3.4,
6.4 Hz, 1H), 3.803 (s, 3H), 3.797 (s, 3H), 2.42−2.35 (m, 4H), 2.12 (s,
3H), 2.07 (s, 3H), 1.95 (dt, J = 4.4, 12.4 Hz, 1H), 1.76 (dt, J = 4.4,
12.4 Hz, 1H), 1.62−1.43 (m, 4H), 1.31−1.20 (m, 9H), 1.18−1.03 (m,
1H), 0.93−0.86 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 211.6,
211.5, 211.0, 210.5, 182.2, 170.4, 169.7, 168.7, 165.21, 165.14, 90.39,
90.35, 90.31, 90.23, 90.16, 87.4, 77.2, 75.9, 71.3, 52.8, 52.80, 52.67,
52.52, 52.48, 52.47, 50.9, 44.7, 42.9, 42.82, 42.80, 42.77, 42.70, 42.55,
42.50, 42.48, 42.43, 37.3, 35.9, 33.7, 33.63, 33.60, 33.5, 33.4, 32.8, 31.8,
31.7, 31.6, 31.5, 29.74, 29.70, 29.57, 29.4, 29.36, 29.36, 29.30, 29.26,
29.23, 29.21, 29.14, 29.09, 29.08, 28.9, 26.0, 24.1, 24.0, 23.94, 23.91,
23.87, 23.85, 23.83, 23.78, 23.7, 23.6, 22.65, 22.62, 22.50, 22.47, 22.39,
20.92, 20.85, 20.80, 18.6, 17.3, 14.09, 14.07, 14.04, 13.93, 13.87, 13.79,
7.9; FTIR (neat) 2931, 2961, 1751, 1440, 1369, 1224, 1059 cm−1.
HRMS (FAB) calcd for C24H39O10 [(M + H)+] 487.2543, found
487.2581.
Methyl (4aS,7R,7aS)-7-Acetoxy-4a-dodecyl-tetrahydro-2,2-
dimethyl-4H-furo-[3,2-d][1,3]dioxine-7a-carboxylate (24).
Under argon atmosphere, 20% Pd(OH)2/C (12.0 mg) was added to
a solution of 17 (58 mg, 0.117 mmol) in MeOH (2.4 mL), and the
mixture was stirred for 15 h under 15 atm of hydrogen atmosphere.
The mixture was filtered through Celite, and the filtrate was
concentrated to give the corresponding alcohol (19 mg) as a colorless
oil, which was dissolved in CH2Cl2 (1.2 mL). This solution was cooled
to 0 °C and Et3N (15 μL, 0.11 mmol), DMAP (4 mg, 0.033 mmol),
and Ac2O (7 μL, 0.074 mmol) were added. After the solution was
stirred at room temperature for 4 h, additional Et3N (5 μL, 0.036
mmol) and Ac2O (3 μL, 0.032 mmol) were added, and the mixture
was stirred at room temperature for 1 h. The mixture was diluted
AcOEt, washed saturated NaHCO3 and brine, dried, concentrated, and
chromatographed (SiO2 6 g, hexane/AcOEt = 12:1) to give 24 (16
mg, 31%) as a colorless oil: [α]23D +4.0 (c 0.5, CHCl3); 1H NMR (400
MHz, CDCl3) δ 5.21 (dd, J = 5.6, 2.2 Hz, 1H), 4.43 (dd, J = 10.5, 5.6
Hz, 1H), 3.96 (d, J = 12.8 Hz, 1H), 3.94 (d, J = 12.8 Hz, 1H), 3.75 (s,
3H), 3.70 (dd, J = 10.5, 2.2 Hz, 1H), 2.03 (s, 3H), 1.97−1.88 (m, 1H),
1.59−1.40 (m, 1H), 1.42 (s, 3H), 1.36 (s, 3H), 1.35−1.20 (m, 20H),
0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.6, 169.1,
99.0, 83.3, 80.6, 79.5, 77.2, 70.7, 62.7, 52.1, 31.9, 31.4, 30.2, 29.68,
29.65, 29.63, 29.61, 29.44, 29.36, 22.7, 22.3, 20.8, 14.1; FTIR (neat)
2925, 2854, 1747, 1459, 1374, 1230, 1144, 1082, 1046 cm−1. HRMS
(FAB) calcd for C24H43O7 [(M + H)+] 443.3009, found 443.3026.
Methyl (4aS,7S,7aS)-7-Acetoxy-4a-dodecyltetrahydro-2,2-
dimethyl-6-oxo-4H-furo[3,2-d][1,3]dioxine-7a-carboxylate
(25). To a solution of 24 (12 mg, 0.028 mmol) in CCl4 (200 μL) were
added MeCN (200 μL), H2O (300 μL), and NaIO4 (24 mg, 0.11
mmol), NaHCO3 (15 mg, 0.18 mmol), and RuCl3·nH2O (3 mg, 0.014
mmol) at room temperature. After the solution was stirred at room
temperature for 22 h, additional NaIO4 (24 mg, 0.11 mmol) and
RuCl3·nH2O (3 mg, 0.014 mmol) were added, and the mixture was
stirred at room temperature for 27 h. The mixture was diluted with
H2O (5 mL) and extracted with CH2Cl2. The extract was washed with
brine, dried, concentrated, and chromatographed (SiO2 = 1.5 g,
hexane/AcOEt = 10:1 to 4:1) to give 25 (2 mg, 16%) and 26 (2 mg,
16%) each as a colorless oil.
graphed (SiO2 8 g, hexane/AcOEt = 10:1) to give 19 (49 mg, 69%
1
from 17) as a colorless solid: [α]26 −8.6 (c 1.05, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 7.36−7.23 (m, 5H), 4.64 (d, J = 11.7 Hz, 1H),
4.53−4.43 (m, 3H), 3.98 (d, J = 7.3 Hz, 1H) 3.95 (s, 3H), 3.84 (s,
1H), 3.77 (s, 3H), 1.91−1.88 (m, 1H), 1.51−1.42 (m, 2H), 1.33−1.11
(m, 20H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.1, 172.0, 137.6, 128.4, 127.9, 127.6, 89.3, 86.0, 84.4, 73.1, 70.3,
53.4, 52.3, 32.5, 31.9, 29.9, 29.6, 29.5, 29.3, 24.1, 22.7, 14.1; FTIR
(neat) 3488, 2925, 2856, 0738, 1453, 1370, 1243, 1145, 1072, cm−1;
HRMS (EI) calcd for C27H42O7 (M+) 478.2931, found 478.2923.
Dimethyl (2R,3S,4R)-3,4-Diacetoxy-2-dodecyl-tetrahydrofur-
an-2,3-dicarboxylate (21). To a solution of 19 (48 mg, 0.10 mmol)
in CH2Cl2 (2.0 mL) at −78 °C was added BCl3 (1.0 M in CH2Cl2;
0.30 mL, 0.30 mmol). After the solution was stirred at −78 °C for 8 h,
BCl3 (0.10 mL, 0.10 mmol) was again added, and additional BCl3
(0.30 mL, 0.30 mmol) was added 1 h later. The mixture was stirred at
−78 °C for 30 min, diluted with AcOEt, washed with saturated
NaHCO3 and brine, dried, and concentrated to give 20 (42 mg),
which was used for the next reaction without purification. Pure 20, a
colorless oil, obtained by silica gel column chromatography (hexane/
AcOEt = 2:1) exhibited the following spectral data: [α]24 −17.0 (c
D
0.84, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.45 (t, J = 4.8 Hz, 1H),
4.34 (dd, J = 4.8, 8.8 Hz, 1H), 4.01 (dd, J = 4.8, 8.8 Hz, 1H), 3.95 (s,
3H), 3.78 (s, 3H), 3.67 (s, 1H), 1.73 (m, 2H), 1.60−1.50 (m, 1H),
1.34−1.13 (m, 19H), 1.13−1.00 (m, 1H), 0.88 (t, J = 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 171.9, 171.5, 91.6, 84.6, 78.6, 73.1, 53.5,
52.4, 34.6, 31.9, 29.8, 29.63, 29.61, 29.57, 29.47, 29.40, 29.3, 24.4, 22.7,
14.1; FTIR (neat) 3476, 2925, 2856, 1733, 1445, 1243, 1149, 1056
cm−1; HRMS (EI) calcd for C20H36O7 (M+) 388.2461, found
388.2466.
Crude 20 (42 mg) was dissolved in CH2Cl2 (3.3 mL) and cooled to
0 °C, and Et3N (56 μL, 0.40 mmol), DMAP (4 mg, 0.033 mmol) and
AcCl (21 μL, 0.30 mmol) were added. After being heated under reflux
for 3 h, the mixture was diluted with AcOEt, washed with saturated
NaHCO3 and brine, dried, concentrated, and chromatographed (SiO2
5 g, hexane/AcOEt = 6:1) to give 21 (30 mg, 0.063 mmol, 63%) as a
1
pale yellow oil: [α]26 −11.5 (c 1.39, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 5.81 (dd, J = 5.8, 3.9 Hz, 1H), 4.45 (dd, J = 9.3, 5.8 Hz, 1H),
3.94 (dd, J = 9.3, 3.9 Hz, 1H), 3.803 (s, 3H), 3.799 (s, 3H), 2.12 (s,
3H), 2.07 (s, 3H), 1.95 (dt, J = 12.4, 4.2 Hz, 1H), 1.77 (dt, J = 12.4,
4.2 Hz, 1H), 1.56−1.45 (m, 1H), 1.33−1.20 (m, 18H), 1.15−1.03 (m,
1H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4,
169.6, 168.7, 165.2, 90.4, 87.3, 75.83, 75.79, 71.3, 52.6, 52.4, 33.6, 31.9,
29.7, 29.62, 29.60, 29.5, 29.4, 29.3, 24.0, 22.7, 20.93, 20.85, 14.1.; FTIR
(neat) 2926, 2856, 1757, 1442, 1371, 1237, 1065 cm−1; HRMS (EI)
calcd for C24H40O9 (M+) 472.2671, found 472.2643.
Compound 25: [α]24D +9.9 (c 0.22, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 6.40 (s, 1H), 4.08 (d, J = 13.4 Hz, 1H), 4.02 (d, J = 13.4 Hz,
1H), 3.82 (s, 3H), 2.15 (s, 3H), 1.90−1.83 (m, 1H), 1.76−1.68 (m,
1H), 1.55 (s, 3H), 1.48 (s, 3H), 1.38−1.20 (m, 20H), 0.88 (t, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.6, 168.4, 166.9, 101.9,
83.3, 82.4, 71.6, 65.1, 52.6, 34.0, 31.9, 30.0, 29.63, 29.59, 29.47, 29.3,
28.5, 23.8, 22.7, 22.3, 20.5, 14.1; FTIR (neat) 2925, 2855, 1799, 1762,
RuO4 Oxidation of 21. To an ice-cooled solution of 21 (30 mg,
0.064 mmol) in a mixture of CCl4 (0.4 mL), MeCN (0.4 mL), and
H2O (0.5 mL) were added NaIO4 (54 mg, 0.25 mmol) and
RuCl3·nH2O (1 mg, 0.005 mmol). After the solution was stirred at
3853
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
1457, 1376, 1205, 1065 cm−1; HRMS (EI) calcd for C24H40O8 (M+)
456.2723, found 456.2702.
diazomalonate (6) (2.70 g, 17.1 mmol) was added dropwise at 70 °C
over 10 min, and then additional 6 (448 mg, 2.83 mmol) was added 20
min later. After being heated under reflux for 30 min, the mixture was
concentrated and chromatographed (SiO2 250 g, toluene/AcOEt =
30:1) to give 35 (4.17 g, 69%) as a colorless oil: [α]27D +46.7 (c 0.96,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32−7.26 (m, 10H), 5.06 (s,
1H), 4.81 (d, J = 11.7 Hz, 1H), 4.54 (s, 2H), 4.53 (d, J = 11.7 Hz, 1H),
4.49−4.43 (m, 1H), 4.01−3.08 (m, 1H), 3.84−3.77 (m, 2H), 3.73 (s,
3H), 3.70 (s, 3H), 2.51 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 167.2, 166.8, 137.9, 137.2, 128.31, 128.30, 127.9, 127.8,
127.6, 81.2, 79.4, 79.0, 76.0, 73.4, 71.1, 69.82, 69.79, 52.6; FTIR (neat)
3652, 3277, 3031, 2923, 2861, 2115, 1741, 1446, 1021 cm−1; HRMS
(ESI) calcd for C24H26NaO7 [(M + Na)+] 449.1576, found 449.1589.
Dimethyl (4S,5R)-4-(Benzyloxy)-5-((benzyloxy)methyl)-
dihydro-3-methylene-furan-2,2-(3H)-dicarboxylate (36). To a
solution of 35 (139 mg, 0.326 mmol) in toluene (3.3 mL) were added
DBU (2.4 μL, 0.016 mmol) and In(OTf)3 (10 mg, 0.018 mmol) at
room temperature. The mixture was heated under reflux for 3 h,
concentrated, and chromatographed (SiO2 9 g, toluene/AcOEt =
20:1) to give 36 (134 mg, 96%) as a colorless oil: [α]27D +13.2 (c 1.00,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36−7.26 (m, 10H), 5.74 (s,
1H), 5.59 (s, 1H), 4.63 (d, J = 11.7 Hz, 1H), 4.53 (s, 2H), 4.48 (d, J =
11.7 Hz, 1H), 4.42−4.39 (m, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.63 (dd,
J = 10.6, 3.9 Hz, 1H), 3.54−3.50 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 168.0, 167.8, 143.1, 137.9, 137.6, 128.4, 128.3, 127.9, 127.8,
127.63, 127.57, 116.8, 83.4, 83.3, 80.33, 80.28, 73.4, 70.6, 69.1, 53.2;
FTIR (neat) 3643, 3030, 2866, 1743, 1444, 1270, 1036 cm−1; HRMS
(ESI) calcd for C24H26NaO7 [(M + Na)+] 449.1576, found 449.1579.
Methyl (2R,3R,3aS,6aR)-3-(Benzyloxy)-2-((benzyloxy)-
methyl)-3a-hydroxy-6-oxohexahydrofuro[3,4-b]furan-6a-car-
boxylate (37). To a stirred solution of 36 (3.5 g, 8.21 mmol) in
CH2Cl2 (80 mL) at room temperature were added NMO (1.92 g, 16.4
mmol), PhB(OH)2 (2.0 g, 16.4 mmol), and OsO4 (0.157 M in
CH2Cl2, 5.2 mL, 0.816 mmol). After the solution was stirred at room
temperature for 19 h, the reaction was quenched with saturated
Na2S2O3, and the mixture was extracted with CH2Cl2. The extract was
washed with brine, dried, and concentrated. The residue was dissolved
in acetone (41 mL) and AcOEt (41 mL), and 30% H2O2 (2.5 mL) was
added at room temperature. After 8 h, 30% H2O2 (3.2 mL) was again
added, and the mixture was stirred at room temperature for 4 h. The
reaction was quenched with 10% Na2S2O3 and the mixture was
extracted with AcOEt. The extract was washed with brine, dried,
concentrated, and chromatographed (SiO2 120 g, hexane/AcOEt =
4:1) to give an inseparable 5:1 mixture of 37 and 38 (2.80 g, 80%) as a
Compound 26. A mixture of several positional isomers of the
1
ketone carbonyl group: H NMR (400 MHz, CDCl3) δ 5.21 (dd, J =
2.2, 5.9 Hz, 1H), 4.46−4.41 (m, 1H), 3.97−3.92 (m, 2H), 3.75 (s,
1H), 3.70 (dd, J = 2.2, 10.2 Hz, 1H), 2.43−2.35 (m, 5H), 2.04 (s, 3H),
1.97−1.85 (m, 1H), 1.41 (s, 3H), 1.36 (s, 3H), 1.33−1.10 (m, 16H),
1.03 (t, J = 7.6 Hz, 0.4H), 0.93−0.85 (m, 2.6H); FTIR (neat) 2926,
2857 1745, 1457, 1375, 1240, 1088 cm−1; HRMS (FAB) calcd for
C24H41O8 [(M + H)+] 457.2802, found 457.2800.
Dimethyl (2R,3S,4R)-4-(Carbamoyloxy)-2-dodecyl-3-hydrox-
ytetrahydrofuran-2,3-dicarboxylate (27). To an ice-cooled
solution of 20 (36 mg, 0.093 mmol) in CH2Cl2 (2 mL) was added
trichloroacetyl isocyanate (11 μL, 0.093 mmol). After the solution was
stirred at room temperature for 2 h, additional trichloroacetyl
isocyanate (22 μL, 0.187 mmol) was added. After the solution was
stirred at room temperature for 11 h, most of the solvent was
evaporated. The residue was dissolved in MeOH (2 mL), and K2CO3
(4 mg, 0.029 mmol) was added. After being stirred at room
temperature for 3 h, saturated NH4Cl was added, and the mixture
was extracted with CH2Cl2. The extract was washed with brine, dried,
concentrated, and chromatographed (SiO2 5 g, hexane/AcOEt = 1:1)
to give 27 (36 mg, 90%) as a pale yellow oil: [α]25 −14.4 (c 0.84,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.23 (t, J = 4.4 Hz, 1H), 4.74
(brs, 2H), 4.58 (dd, J = 9.4, 6.4 Hz, 1H), 4.23 (s,1H), 4.02 (dd, J = 9.4,
4.4 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 1.91 (dt, J = 12.4, 4.4 Hz, 1H),
1.65 (dt, J = 12.4, 4.4 Hz, 1H), 1.60−1.48 (m, 1H), 1.32−1.20 (m,
18H), 1.18−1.04 (m, 1H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 171.3, 170.3, 155.9, 91.2, 83.9, 80.5, 70.7, 53.4, 52.3,
33.6, 31.9, 29.9, 29.65, 29.61, 29.60, 29.5, 29.4, 29.3, 24.3, 22.3, 14.1;
FTIR (neat) 3369, 2924, 2853, 1828, 1732, 1601, 1440, 1362, 1243,
1068 cm−1; HRMS (EI) calcd for C21H37NO8 (M+) 431.2519, found
431.2530.
Dimethyl (3aR,5R,6S,6aS)-5-Dodecyl-6-hydroxy-2-
oxohexahydrofuro[2,3-d]-oxazole-5,6-dicarboxylate (28). To a
solution of 27 (22 mg, 0.051 mmol) in benzene (2 mL) were added
PhI(OAc)2 (20 mg, 0.062 mmol), MgO (5.0 mg, 0.124 mmol), and
Rh2(esp)2 (2.0 mg, 0.003 mmol) at room temperature. After being
heated at 65 °C for 2 h, the mixture was concentrated and
chromatographed (SiO2 5 g, hexane/AcOEt = 2:1) to give 28 (16
mg, 74%) as a pale yellow oil: [α]23D −29.5 (c 0.80, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 6.08 (d, J = 6.1 Hz, 1H), 5.82 (brs, 1H), 4.97 (d,
J = 6.1 Hz, 1H), 4.17 (s, 1H), 4.00 (s, 3H), 3.77, (s, 3H), 2.00−1.93
(m, 1H), 1.68−1.62 (m, 1H), 1.35−1.20 (m, 20H), 0.88 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 170.4, 169.8, 156.2, 91.8, 86.0,
85.4, 83.9, 54.2, 52.6, 33.3, 31.9, 29.7, 29.65, 29.61, 29.58, 29.47, 29.3,
24.5, 22.7, 14.1; FTIR (neat) 3352, 2923, 2853, 1740, 1438, 1239,
1146, 1034; HRMS (EI) calcd for C21H35NO8 (M+) 429.2362, found
429.2351.
(2R,3S)-1,3-Bis(benzyloxy)pent-4-yn-2-ol (34). To a solution of
dimethyl (1-diazo-2-oxopropyl)phosphonate (516 mg, 2.69 mmol) in
MeOH (10 mL) was added K2CO3 (369 mg, 2.67 mmol) at room
temperature. After the solution was stirred at room temperature for 15
min, a solution of aldehyde 3324 (519 mg, 1.79 mmol) in MeOH (7
mL) was added. The mixture was stirred at room temperature for 9 h.
Saturated NH4Cl was added, and the mixture was extracted with
AcOEt. The extract was washed with brine, dried, concentrated, and
chromatographed (SiO2 18 g, hexane/AcOEt = 8:1) to give 34 (391
mg, 78%) as a pale yellow oil: [α]25D +70.2 (c 1.08, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.40−7.27 (m, 10H), 4.84 (d, J = 11.7 Hz, 1H),
4.54 (s, 2H), 4.52 (d, J = 11.7 Hz, 1H), 4.27 (dd, J = 5.0, 2.2 Hz, 1H),
4.01 (quint, J = 5.0 Hz, 1H), 3.68 (m, 2H), 2.53 (d, J = 2.2 Hz, 1H),
2.50 (d, J = 5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 137.8, 137.2,
128.4, 128.4, 128.1, 127.9, 127.7, 79.6, 75.9, 73.5, 72.0, 71.0, 70.2, 69.9;
FTIR (neat) 3450, 3288, 3030, 2867, 2111, 1603, 1454, 1210, 1093
cm−1; HRMS (ESI) calcd for C19H20NaO3 [(M + Na)+] 319.1310,
found 319.1280.
1
pale yellow oil: H NMR (400 MHz, CDCl3) δ 7.38−7.23 (m, 10H),
5.18 (s, 0.83H), 4.71−4.63 (m, 3H), 4.59 (d, J = 9.0 Hz, 0.17H),
4.54−4.45 (m, 2H), 4.40 (dt, J = 10.2, 2.9 Hz, 0.17H), 4.25 (d, J = 9.0
Hz, 0.83H), 4.18 (dd, J = 9.5, 13.2 Hz, 0.17H), 4.02 (d, J = 0.1 Hz,
0.83H), 3.92−3.82 (dd, J = 2.0, 11.0 Hz, 0.83H), 3.84 (s, 0.51H), 3.82
(s, 2.49H), 3.76 (dd, J = 3.2, 11.5 Hz, 0.17H), 3.64−3.57 (m, 1H) ;
13C NMR (100 MHz, CDCl3) δ 171.1, 165,6, 165.2, 137.6, 136.3,
136.2, 136.0, 128.9, 128.8, 128.6, 128.5, 128.40, 128.38, 128.27,
128.15, 127.9, 127.8, 127.6, 89.3, 87.4, 86.3, 85.5, 84.9, 83.9, 80.6, 74.4,
73.8, 73.7, 73.0, 72.4, 70.9, 69.0, 67.6, 53.1; FTIR (neat) 3338, 3032,
2872, 1790, 1452, 1293, 1124 cm−1; HRMS (EI) calcd for C23H24O8
(M+) 428.1471, found 428.1460.
(2R,3R,3aS,6aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-
tetrahydro-3a-hydroxy-6a-(hydroxymethyl)furo[3,4-b]furan-6-
(6aH)-one (39). To an ice-cooled solution of a 5:1 mixture of 37 and
38 (2.80 g, 6.54 mmol) in THF (52 mL) and H2O (23 mL) was added
LiOH (1.10 g, 26.22 mmol), and the mixture was stirred at 0 °C for 3
h. The mixture was diluted with Et2O (30 mL) and H2O (60 mL). The
aqueous layer was acidified with 1 M HCl (pH = 1) and then extracted
with AcOEt. The extract was dried and concentrated to give the
corresponding carboxylic acid as a colorless solid (2.76 g). The
carboxylic acid thus obtained was dissolved in CH2Cl2 (65 mL), and
oxalyl chloride (1.7 mL, 19.8 mmol) and DMF (50 μL, 0.646 mmol)
were added at room temperature. After being stirred at room
temperature for 4 h, the mixture was concentrated and the residue was
dissolved in THF (60 mL). To this solution was added NaBH4 (742
Dimethyl 2-((2R,3S)-1,3-Bis(benzyloxy)pent-4-yn-2-yloxy)-
malonate (35). To a solution of 34 (4.20 g, 14.2 mmol) in benzene
(29 mL) was added Rh2(OAc)4 (31 mg, 0.070 mmol). Dimethyl
3854
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
mg, 19.6 mmol) at −78 °C, and then MeOH (6 mL) was added
dropwise over 5 min. After being stirred at −78 °C for 1 h, the mixture
was diluted with 1 M HCl (5 mL) and H2O (50 mL) and extracted
with AcOEt. The extract was washed with saturated NaHCO3 and
brine, dried, concentrated, and chromatographed (SiO2 100 g, hexane/
AcOEt = 5:1) to give 39 (1.70 g, 65%) and its diastereomer derived
from 38 (421 mg, 16%) each as a colorless oil.
1455, 1376, 1234, 1086 cm−1; HRMS (ESI) calcd for C25H30NaO7
[(M + Na)+] 465.1889 found 465.1865.
n-BuLi (2.69 M in hexane, 1.1 mL, 2.96 mmol) was added to
DMSO (3 mL) at room temperature, and the mixture was stirred at
room temperature for 30 min. The resulting solution of dimsyl lithium
was added to 1518 (782 mg, 1.63 mmol, dried at 140 °C under
reduced pressure for 2 h), and the mixture was stirred at room
temperature for 30 min to generate the ylide. To this solution was
added a solution of the lactol (0.11 g) in DMSO (2 mL), and the
mixture was stirred for 4 h at 120 °C. The mixture was diluted with
AcOEt, washed with H2O and brine, dried, concentrated, and
chromatographed (SiO2 10 g, hexane/AcOEt = 15:1 to 3:1) to give
the unreacted lactol (25 mg, 34%) and 41 (63 mg, 66%; 1:1 E/Z
Compound 39: [α]27D +57.4 (c 1.16, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.38−7.23 (m, 10H), 4.77 (d, J = 11.5 Hz, 1H), 4.71 (d, J =
12.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.52 (d, J = 11.5 Hz, 1H),
4.42 (d, J = 11.5 Hz, 1H), 4.34 (d, J = 7.3 Hz, 1H), 4.27 (d, J = 10.8
Hz, 1H), 4.02 (dt, J = 7.3, 2.0 Hz, 1H), 3.96 (d, J = 11.5 Hz, 1H), 3.79
(dd, J = 10.8, 2.0 Hz, 1H), 3.75 (d, J = 10.8 Hz, 1H), 3.60 (d, J = 10.8
Hz, 1H), 3.55 (s, 1H), 3.47 (dd, J = 10.8, 2.0 Hz, 1H).; 13C NMR (100
MHz, CDCl3) δ 173.5, 137.0, 136.5, 128.7, 128.6, 128.4, 128.2, 128.0,
127.9, 86.1, 85.7, 84.3, 80.8, 73.6, 72.8, 71.5, 68.5, 62.0; FTIR (neat)
3427, 3032, 2872, 1777, 1457, 1371, 1081, 1021 cm−1; HRMS (ESI)
calcd for C22H24NaO7 [(M + Na)+] 423.1420, found 423.1425.
1
mixture) as a colorless oil: H NMR (400 MHz, CDCl3) δ 7.34−7.25
(m, 10H), 5.81 (dt, J = 15.6, 6.8 Hz, 0.5H), 5.53 (dt, J = 12.0, 7.3 Hz,
0.5H), 5.29 (d, J = 15.6 Hz, 0.5H), 5.08 (d, J = 12.0 Hz, 0.5H), 4.65−
4.52 (m, 4H), 4.29 (dt, J = 1.5, 6.8 Hz, 0.5H), 4.19−4.10 (m, 1H),
4.00 (dd, J = 8.6, 11.5 Hz, 0.5H), 3.86−3.79 (m, 2H) 3.75−3.64 (m,
3H), 3.58−3.52 (m, 1H), 2.42−2.32 (m, 1H), 2.21 (d, J = 6.4 Hz,
0.5H), 2.13 (d, J = 7.3 Hz, 0.5H), 2.03−1.99 (m, 1H), 1.52 (s, 3H),
1.37 (s, 1.5H), 1.36 (s, 1.5H), 1.37−1.20 (m, 16H), 0.88 (t, J = 6.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 138.2, 138.2, 138.1, 136.3,
128.3, 128.3, 128.2, 127.7, 127.7, 127.6, 127.5, 127.5, 127.5, 127.4,
125.6, 123.8, 98.1, 98.1, 86.7, 86.1, 85.7, 85.6, 82.2, 81.9, 81.6, 80.3,
73.3, 73.3, 72.0, 72.0, 71.4, 71.2, 63.3, 63.1, 60.6, 60.5, 32.5, 31.9, 30.0,
29.6, 29.6, 29.5, 29.4, 29.3, 29.3, 29.1, 29.0, 29.0, 28.7, 28.0, 24.4, 24.2,
22.7, 14.1; FTIR (neat) 3491, 2925, 2857, 1728, 1458, 1374, 1249,
1200, 1109 cm−1; HRMS (ESI) calcd for C36H52NaO6 [(M + Na)+]
603.3662 found 603.3632.
Diastereomer of 39 derived from 38: [α]24 −26.9 (c 0.71,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.37−7.25 (m, 10H), 4.68
(d, J = 11.6 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.57 (d, J = 12.0 Hz,
1H), 4.47 (d, J = 12.0 Hz, 1H), 4.27−4.24 (m, 1H), 4.12−4.04 (m,
3H), 3.99 (d, J = 11.6 Hz, 1H), 3.95 (d, J = 11.6 Hz, 1H), 3.78 (s, 1H),
3.58 (dd, J = 3.6, 11.6 Hz, 1H), 3.51 (dd, J = 3.6, 11.6 Hz, 1H), 2.38
(brs, 1H); 13C NMR (100 MHz, CDCl3) 174.0, 137.5, 136.3, 128.9,
128.8, 128.5, 128.3, 128.0, 127.9, 85.5, 84.0, 82.3, 82.1, 74.0, 73.8, 73.7,
68.7, 61.5; FTIR (neat) 3471, 3032, 2874, 1782, 1459, 1366, 1080
cm−1; HRMS (EI) calcd for C22H24O7 (M+) 400.1522, found
400.1537.
tert-Butyl (4aS,6R,7R,7aS)-7-(Benzyloxy)-6-((benzyloxy)-
methyl)-4a-(dodec-1-enyl)tetrahydro-2,2-dimethyl-4H-furo-
[3,2-d][1,3]dioxine-7a-carboxylate (42). To an ice-cooled solution
of 41 (402 mg, 0.692 mmol) in CH2Cl2 (7 mL) were added NaHCO3
(581 mg, 6.92 mmol) and DMPI (594 mg, 1.40 mmol). After the
solution was stirred at room temperature for 5 h, saturated Na2S2O3
was added, and the mixture was extracted with AcOEt. The extract was
washed with saturated NaHCO3 and brine, dried, and concentrated to
give the corresponding aldehyde (400 mg). The aldehyde was
dissolved in t-BuOH (5.5 mL) and H2O (1.1 mL), and 2-methyl-2-
butene (2.2 mL, 20.8 mmol), NaH2PO4 (324 mg, 2.08 mmol), and
NaClO2 (250 mg, 2.76 mmol) were added at room temperature. After
being stirred at room temperature for 2 h, saturated NH4Cl was added,
and the mixture was extracted with AcOEt. The extract was washed
with brine, dried, and concentrated to give the corresponding
carboxylic acid (474 mg), which was dissolved in CH2Cl2 (7 mL).
To this solution was added 2-tert-butyl-1,3-diisopropylisourea (1.55
mL, 6.92 mmol) at room temperature, and the mixture was stirred at
room temperature for 1 h. The mixture was filtered through Celite,
concentrated, and chromatographed (SiO2 15 g, hexane/AcOEt = 15:1
to 10:2) to give 42 (379 mg, 84%; 1:1 E/Z-mixture) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.34−7.20 (m, 10H), 6.03 (d, J = 14.4
Hz, 1H), 5.91−5.85 (m, 0.5H), 5.57−5.51 (m, 0.5H), 4.60−4.44 (m,
4H), 4.28−4.23 (m, 0.5H), 4.18−4.13 (m, 0.5H), 4.02 (t, J = 13.2 Hz,
1H), 3.87−3.84 (m, 1.5H), 3.72−3.67 (m, 1H), 3.62 (d, J = 12.7 Hz,
0.5H), 3.53 (t, J = 7.8 Hz, 1H), 2.40−2.35 (m, 1H), 2.08−2.03 (m,
1H), 1.44−1.24 (m, 31H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 169.0, 168.7, 138.3, 138.3, 138.0, 135.3, 132.1, 128.3,
128.3, 128.1, 127.7, 127.6, 127.5, 127.5, 127.4, 127.4, 127.2, 127.2,
98.6, 98.4, 88.6, 88.0, 85.0, 84.5, 82.0, 81.9, 80.9, 80.5, 79.9, 77.2, 73.4,
73.3, 71.9, 71.8, 71.3, 71.1, 63.2, 62.1, 32.5, 31.9, 30.1, 29.9, 29.8, 29.7,
29.6, 29.6, 29.5, 29.4, 29.3, 29.3, 29.2, 29.1, 28.3, 27.9, 22.7, 21.7, 21.6,
14.1; FTIR (neat) 2925, 2857, 1732, 1457, 1372, 1253, 1111 cm−1;
HRMS (ESI) calcd for C40H58NaO7 [(M + Na)+] 673.4080, found
673.4064.
(4aR,6R,7R,7aS)-7-(Benzyloxy)-6-((benzyloxy)methyl)-2,2-di-
methyldihydro-4H-4a,7a-(methanooxymethano)furo[3,2-d]-
[1,3]dioxin-10-one (40). To a solution of 39 (81 mg, 0.202 mmol)
in acetone (2 mL) were added 2,2-dimethoxypropane (125 μL, 1.02
mmol) and p-TsOH·H2O (8 mg, 0.03 mmol), and the mixture was
heated under reflux for 16 h. Saturated NaHCO3 was added and the
mixture was extracted with AcOEt. The extract was washed with brine,
dried, concentrated, and chromatographed (SiO2 5 g, hexane/AcOEt =
5:1) to give 40 (73 mg, 82%) as a colorless oil: [α]27 +41.2 (c 1.00,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.35−7.26 (m, 10H), 4.76
(d, J = 10.7 Hz, 1H), 4.62 (d, J = 11.7 Hz, 1H), 4.59 (d, J = 10.7 Hz,
1H), 4.56 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 7.3 Hz, 1H), 4.42 (d, J =
7.3 Hz, 1H), 4.29 (d, J = 10.8 Hz, 1H), 4.11 (d, J = 10.8 Hz, 1H), 3.90
(d, J = 12.0 Hz, 1H), 3.90−3.87 (m, 1H), 3.70 (dd, J = 12.0, 2.7 Hz,
1H), 3.55 (dd, J = 12.0, 2.7 Hz, 1H), 1.42 (s, 3H), 1.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 174.6, 137.8, 137.0, 128.5, 128.4, 128.1,
127.9, 127.7, 127.7, 100.3, 84.8, 84.0, 80.6, 77.7, 73.6, 72.8, 71.6, 68.3,
61.2, 27.8, 26.1; FTIR (neat) 2993, 2870, 1788, 1456, 1376, 1221,
1089 cm−1; HRMS (EI) calcd for C25H28O7 (M+) 440.1835, found
440.1828.
((4aS,6R,7R,7aS)-7-(Benzyloxy)-6-((benzyloxy)methyl)-4a-
(dodec-1-enyl)tetrahydro-2,2-dimethyl-4H-furo[3,2-d][1,3]-
dioxin-7a-yl)methanol (41). To a solution of 40 (72 mg, 0.163
mmol) in toluene (2 mL) at −78 °C was added dropwise DIBALH
(1.02 M in hexane; 0.25 mL, 0.255 mmol) over 5 min, and the mixture
was stirred at −78 °C for 1 h. Rochelle salt (20%) was added, and the
mixture was stirred at room temperature for 3 h and filtered through
Celite. The filtrate was extracted with AcOEt, washed with brine,
dried, and concentrated to give the corresponding lactol (0.11 g) as a
colorless oil, which was used for the next reaction without further
purification. Pure lactol (1:1 epimeric mixture) obtained by silica gel
1
column chromatography exhibited the following data: H NMR (400
MHz, CDCl3) δ 7.35−7.22 (m, 10H), 5.32−4.47 (m, 6H), 4.29−4.22
(m, 1.5H), 4.05 (d, J = 9.5 Hz, 0.5H), 4.00 (d, J = 8.0 Hz, 0.5 H),
3.97−3.90 (m, 0.5 Hz), 3.84 (d, J = 12.4, 0.5 Hz), 3.80 (s, 0.5 H),
3.72−3.65 (m, 1.5H), 3.57 (m, 1.5H), 1.45 (s, 3H), 1.43 (s, 1.5 H),
1.43 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ 138.1, 137.9, 137.6,
137.4, 128.4, 128.33, 128.29, 127.9, 127.81, 127.75, 127.71, 127.66,
127.64, 127.57, 104.2, 100.5, 99.6, 99.5, 87.9, 87.6, 84.5, 83.3, 83.0,
82.0, 80.6, 78.8, 77.2, 73.49, 73.46, 72.2, 72.1, 71.7, 69.6, 69.3, 69.2,
62.4, 62.2, 27.74, 27.71, 27.3, 27.1; FTIR (neat) 3422, 2992, 2892,
tert-Butyl (4aS,6R,7R,7aS)-7-(Benzyloxy)-4a-dodecyltetrahy-
dro-6-(hydroxymethyl)-2,2-dimethyl-4H-furo[3,2-d][1,3]-
dioxine-7a-carboxylate (43). Under argon atmosphere, 20%
Pd(OH)2/C (140 mg) was added to a solution of 42 (467 mg
0.717 mmol) in AcOEt (7.2 mL), and then a hydrogen gas balloon was
attached to the flask. The mixture was stirred at room temperature for
3855
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
2 h, filtered through Celite, concentrated, and chromatographed (SiO2
was then dissolved in CH2Cl2 (2 mL), and NaHCO3 (28 mg, 0.33
mmol) and DMPI (42 mg, 0.099 mmol) were added at 0 °C. After the
solution was stirred at room temperature for 1 h, 10% Na2S2O3 was
added, and the mixture was extracted with AcOEt. The extract was
washed with saturated NaHCO3 and brine, dried, and concentrated to
give the aldehyde (17 mg). The aldehyde was dissolved in t-BuOH (1
mL) and H2O (0.3 mL), 2-methyl-2-butene (75 μL, 1.65 mmol),
NaH2PO4 (20 mg, 0.128 mmol), and NaClO2 (15 mg, 0.166 mmol)
were added at room temperature. After stirring at room temperature
for 2 h, saturated NH4Cl was added, and the mixture was extracted
with AcOEt. The extract was washed with brine, dried, and
concentrated to give the corresponding carboxylic acid (17 mg),
which was dissolved in CH2Cl2 (2 mL). To this solution was added 2-
tert-butyl-1,3-diisopropylisourea (75 μL, 0.313 mmol) at room
temperarure, and the mixture was stirred at room temperature for 4
h. The mixture was filtered through Celite, concentrated, and
chromatographed (SiO2 3 g, hexane/AcOEt = 15:1) to give 46 (14
mg, 76% from 45) as a colorless oil: [α]25D −22.7 (c 1.07, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.37−7.26 (m, 5H), 4.97 (d, J = 11.6 Hz,
1H), 4.75 (d, J = 11.6 Hz, 1H), 4.68 (s, 1H), 3.87 (s, 1H), 2.05−1.98
(m, 1H), 1.63−1.50 (m, 1H), 1.46 (s, 9H), 1.42 (s, 9H), 1.38−1.20
(m, 20H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
171.4, 168.4, 166.9, 136.7, 128.3, 128.2, 128.0, 86.3, 86.1, 83.8, 83.4,
78.1, 73.4, 31.9, 30.8, 29.8, 29.6, 29.6, 29.4, 29.3, 29.1, 27.8 (6C), 23.5,
22.7, 14.1; FTIR (neat) 3477, 2927, 1809, 1739, 1461, 1373, 1254,
1152 cm−1; HRMS (ESI) calcd for C33H53O8 [(M + H)+] 577.3740,
found 577.3770.
15 g, hexane/AcOEt = 6:1) to give 43 (353 mg, 87%) as a yellow oil:
1
[α]22 +34.1 (c 1.16, CHCl3); H NMR (400 MHz, CDCl3) δ 7.36−
D
7.28 (m, 5H), 4.65 (d, J = 12.0 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H),
3.96 (q, J = 3.7 Hz, 1H), 3.93 (s, 2H), 3.88 (d, J = 3.7 Hz, 1H), 3.62
(dt, J = 11.7, 3.7 Hz, 1H), 3.35 (quint, J = 5.4 Hz, 1H), 2.32 (t, J = 5.4
Hz, 1H), 2.18−2.10 (m, 1H), 1.94−1.86 (m, 1H), 1.47 (s, 9H), 1.43
(s, 3H), 1.41 (s, 3H), 1.35−1.19 (m, 20H), 0.88 (t, J = 6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 168.7, 137.5, 128.4, 127.9, 127.8, 98.9,
88.1, 84.9, 82.6, 82.1, 79.8, 76.8, 76.7, 73.7, 62.9, 62.4, 31.9, 30.6, 30.2,
29.7, 29.6, 29.3, 27.95, 27.91, 27.8, 22.7, 22.2, 21.2, 14.1; FTIR (neat)
3482, 2924, 2856, 1732, 1460, 1373, 1252 cm−1; HRMS (ESI) calcd
for C33H54NaO7 [(M + Na)+] 585.3767, found 585.3744.
tert-Butyl (4aS,7S,7aS)-7-(Benzyloxy)-4a-dodecyltetrahydro-
2,2-dimethyl-6-oxo-4H-furo[3,2-d][1,3]dioxine-7a-carboxylate
(45). To an ice-cooled solution of 43 (352 mg, 0.625 mmol) in
CH2Cl2 (6.3 mL) were added NaHCO3 (525 mg, 6.25 mmol) and
DMPI (594 mg, 1.40 mmol). After the solution was stirred at room
temperature for 1 h, additional NaHCO3 (79 mg, 0.94 mmol) and
DMPI (881 mg, 2.08 mmol) were added at 0 °C, and the mixture was
stirred at room temperature for 1 h. Na2S2O3 (10%) was added, and
the mixture was extracted with AcOEt. The extract was washed with
saturated NaHCO3 and brine, dried, and concentrated to give the
aldehyde (361 mg). The aldehyde was dissolved in CH2Cl2 (6.3 mL),
and NaHCO3 (263 mg, 3.13 mmol) and m-chloroperbenzoic acid (m-
CPBA) (75%; 216 mg, 0.939 mmol) were added at −40 °C. After
being stirred at −40 °C for 1 h, additional m-CPBA (75%, 144 mg,
0.626 mmol) was added, and the mixture was stirred at 0 °C for 1 h.
Na2S2O3 (10%) was added, and the mixture was extracted with AcOEt.
The extract was washed with saturated NaHCO3, dried, and
concentrated to give formate 44 (353 mg), which was used for the
next reaction without purification. Pure 44, a colorless oil, obtained by
(−)-Cinatrin C1. Under argon atmosphere, 20% Pd(OH)2/C (5
mg) was added to a solution of 46 (14 mg 0.026 mmol) in MeOH (1
mL), and then a hydrogen gas balloon was attached to the flask. The
mixture was stirred at room temperature for 2 h, filtered through
Celite, and concentrated to give the corresponding diol (11 mg). The
diol was dissolved in HCO2H (1 mL) at 0 °C, and the mixture was
stirred at 40 °C for 7 h. After most of the HCO2H was azeotropically
removed using toluene, the residue was purified by HPLC
(COSMOSIL 5C18-MS-II 20 × 250 mm, MeCN−H2O−TFA
(80:20:0.1), 4 mL/min, UV 210 nm, tR = 22.5 min) and lyophilized
to give cinatrin C1 as a white powder (4.2 mg, 44%): [α]25 −5.9 (c
0.30, MeOH) [lit. [α]24 −11.2 (c 0.31, MeOH),6a [α]26 D −1.6 (c
silica gel column chromatography (hexane/AcOEt = 15:1) exhibited
1
the following spectral data: [α]21 +50.5 (c 0.23, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 8.06 (d, J = 0.5 Hz, 1H), 7.45−7.26 (m, 5H),
6.22 (s, 1H), 4.79 (d, J = 11.5 Hz, 1H), 4.65 (d, J = 11.5 Hz, 1H), 4.08
(s, 1H), 3.97 (s, 2H), 2.08−2.00 (m, 1H), 1.96−1.89 (m, 1H), 1.45 (s,
3H), 1.44 (s, 12H), 1.34−1.25 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.5, 160.1, 137.2, 128.4, 127.8, 127.3,
99.4, 98.9, 90.5, 83.0, 82.8, 82.3, 73.8, 62.7, 33.3, 31.9, 30.2, 29.67,
29.64, 29.52, 29.34, 27.9, 22.7, 22.5, 21.6, 14.1; FTIR (neat) 2926,
2856, 1732, 1460, 1374, 1254, 1119 cm−1; HRMS (EI) calcd for
C33H51O8 [(M − H)+] 575.3584, found. 575.3564.
Crude formate 44 (353 mg) was dissolved in MeOH (6.3 mL), and
K2CO3 (37 mg, 0.268 mmol) was added at 0 °C. After stirring at 0 °C
for 15 min, saturated NH4Cl was added, and the mixture was extracted
with AcOEt. The extract was washed with brine, dried, and
concentrated to give the lactol (363 mg), which was dissolved in
CH2Cl2 (6.3 mL). To this solution were added 4A molecular sieves,
NMO (146 mg, 1.25 mmol), and TPAP (22 mg, 0.063 mmol) at room
temperature. After being stirred at room temperature for 1 h, the
mixture was filtered through Celite, concentrated, and chromato-
D
D
0.11, MeOH),10b [α]23 +9.7 (c 0.319, MeOH)9 for (+)-cinartin C1];
D
mp 163−164 °C (lit.6a mp 162−164 °C); 1H NMR (400 MHz,
CD3OD) δ 4.67 (s, 1H), 2.08 (appt, J = 13.2 Hz, 1H), 1.67−1.58 (m,
1H), 1.48−1.37 (m, 1H), 1.36 (m, 1H), 1.27 (m, 22H), 0.80 (appt, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 175.3, 171.7, 88.5,
74.5, 33.1, 32.5, 30.81, 30.77, 30.75, 30.6, 30.5, 30.4, 25.0, 23.7, 14.4;
FTIR (KBr) 3416, 2924, 2856, 1781, 1722, 1389, 1268, 1131, 1034
cm−1; HRMS (ESI) calcd for C18H29O8 [(M − H)−] 373.1862, found
373.1853.
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray analysis of 13 and 1H and 13C NMR spectra of synthetic
intermediates and cinatrin C1. This material is available free of
charge via the Internet at http://pubs.acs.org.
graphed (SiO2 15 g, hexane/AcOEt = 20:1) to give lactone 45 (234
1
mg, 68% from 43) as a yellow oil: [α]22 −22.9 (c 0.97, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 7.34−7.26 (m, 5H), 4.97 (d, J = 11.5 Hz,
1H), 4.72 (d, J = 11.5 Hz, 1H), 4.33 (s, 1H), 4.03 (d, J = 13.2 Hz, 1H),
3.98 (d, J = 13.2 Hz, 1H), 2.06−2.01 (m, 2H), 1.45 (s, 3H), 1.43 (s,
9H), 1.36 (s, 3H), 1.36−1.20 (m, 20H), 0.88 (t, J = 6.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 171.5, 166.1, 136.5, 128.3, 128.1, 128.0,
100.1, 83.4, 82.6, 81.6, 80.3, 73.1, 63.2, 33.5, 31.9, 30.0, 29.61, 29.59,
29.5, 29.35, 29.32, 29.2, 27.8, 22.7, 22.5, 22.4, 14.1; FTIR (neat) 2926,
2856, 1785, 1735, 1461, 1376, 1253, 1146 cm−1; HRMS (ESI) calcd
for C32H51O7 [(M + H)+] 547.3635, found 547.3636.
AUTHOR INFORMATION
Corresponding Author
*E-mail: susumi@nagasaki-u.ac.jp.
■
Notes
The authors declare no competing financial interest.
Di-tert-butyl (2R,3S,4S)-2-Dodecyltetrahydro-3,4-dihydroxy-
5-oxofuran-2,3-dicarboxylate (46). To a solution of 45 (18 mg,
0.033 mmol) in THF (1 mL) was added 3 M HClO4 (0.11 mL, 0.33
mmol) at room temperature. After the solution was stirred at room
temperature for 24 h, saturated NaHCO3 was added, and the mixture
was extracted with AcOEt. The extract was washed with brine, dried,
and concentrated to give the corresponding diol (18 mg). This diol
ACKNOWLEDGMENTS
■
This work was supported by the Grant-in-Aid for Scientific
Research (A) (22249001) from JSPS and the Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysis” (No. 2304) (24105526)
and “Organic Synthesis based on Reaction Integration” (No.
3856
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857

The Journal of Organic Chemistry
Article
(b) Dennis, E. A.; Cao, J.; Hsu, Y.-H.; Magrioti, V.; Kokotos, G. Chem.
Rev. 2011, 111, 6130−6185.
2105) (24106736) from MEXT. K.T. acknowledges a Grant-in-
Aid for Young Scientists (B) (21790019) from JSPS and
financial support from the Research Foundation for Pharma-
ceutical Sciences.
(9) Evans, D. A.; Trotter, B. W.; Barrow, J. C. Tetrahedron 1997, 53,
8779−8794.
(10) (a) Cuzzupe, A. N.; Di Florio, R.; Rizzacasa, M. A. J. Org. Chem.
2002, 67, 4392−4398. (b) Cuzzupe, A. N.; Di Florio, R.; White, J. M.;
Rizzacasa, M. A. Org. Biomol. Chem. 2003, 1, 3572−3577.
(11) Yakura, T.; Ozono, A.; Matsui, K.; Yamashita, M.; Fujiwara, T.
Synlett 2013, 24, 65−68.
REFERENCES
■
(1) (a) Ooi, H.; Ishibashi, N.; Iwabuchi, Y.; Ishihara, J.; Hatakeyama,
S. J. Org. Chem. 2004, 69, 7765−7768. (b) Onyango, E. O.;
Tsurumoto, J.; Imai, N.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.
Angew. Chem., Int. Ed. 2007, 46, 6703−6705. (c) Takahashi, K.;
Midori, M.; Kawano, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem., Int.
Ed. 2008, 47, 6244−6246. (d) Hatakeyama, S. Pure Appl. Chem. 2009,
81, 217−226. (e) Takahashi, K.; Hatakeyama, S. J. Synth. Org. Chem.
Jpn. 2010, 68, 951−961. (f) Eto, K.; Yoshino, M.; Takahashi, K.;
Ishihara, J.; Hatakeyama, S. Org. Lett. 2011, 13, 5398−5401.
(12) Shibahara, S.; Fujino, M.; Tashiro, Y.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Org. Lett. 2008, 10, 2139−2142.
(13) Raminelli, C.; Comasseto, J. V.; Andrade, L. H.; Porto, A. L. M.
Tetrahedron: Asymmetry 2004, 15, 3117−3122.
(14) Barbazanges, M.; Meyer, C.; Cossy, J.; Turner, P. Chem.Eur. J.
2011, 17, 4480−4495.
(15) For a review, see: Miller, D. J.; Moody, C. J. Tetrahedron 1995,
51, 10811−10843.
(2) For a review on a thermal Conia−ene reaction, see: Conia, J. M.;
Le Perchec, P. Synthesis 1975, 1−19.
(16) The enantiomeric purity was determined to be 94% ee by
HPLC on a chiral stationary.
(3) For intramolecular Conia−ene reactions, see: (a) Kennedy-
Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
4526−4527. (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D.
Angew. Chem, Int. Ed. 2004, 43, 5350−5352. (c) Gao, Q.; Zheng, B.-F.;
Li, J.-H.; Yang, D. Org. Lett. 2005, 7, 2185−2188. (d) Corkey, B. K.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168−17169. (e) Ochida,
A.; Ito, H.; Sawamura, M. J. Am. Chem. Soc. 2006, 128, 16486−16487.
(f) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2764−
2765. (g) Tsuji, H.; Yamagata, K.; Itoh, Y.; Endo, K.; Nakamura, M.;
Nakamura, E. Angew. Chem., Int. Ed. 2007, 46, 8060−8062. (h) Deng,
C.-L.; Song, R.-J.; Guo, S.-M.; Wang, Z.-Q.; Li, J.-H. Org. Lett. 2007, 9,
5111−5114. (i) Itoh, Y.; Tsuji, H.; Yamagata, K.; Endo, K.; Tanaka, I.;
Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 17161−
17167. (j) Leduc, A. B.; Lebold, T. P.; Kerr, M. A. J. Org. Chem. 2009,
74, 8414−8416. (k) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.;
Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 9140−9141. (l) Deng, C.-L.;
Zou, T.; Wang, Z.-Q.; Song, R.-J.; Li, J.-H. J. Org. Chem. 2009, 74,
412−414. (m) Matsuzawa, A.; Mashiko, T.; Kumagai, N.; Shibasaki,
M. Angew. Chem., Int. Ed. 2011, 50, 7616−7619. (n) Hess, W.; Burton,
J. W. Adv. Synth. Cat 2011, 353, 2966−2970. (o) Chin, C.-L.; Liao, C.-
F.; Liu, H.-J.; Wong, Y.-C.; Hsieh, M.-T.; Amancha, P. K.; Chang, C.-
P.; Shia, K.-S. Org. Biomol. Chem. 2011, 9, 4778−4781. (p) Chan, L.
Y.; Kim, S.; Park, Y.; Lee, P. H. J. Org. Chem. 2012, 77, 5239−5244.
(4) For intermolecular Conia−ene reactions, see: (a) Endo, K.;
Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007,
129, 5264−5271. (b) Fujimoto, T.; Endo, K.; Tsuji, H.; Nakamura, M.;
Nakamura, E. J. Am. Chem. Soc. 2008, 130, 4492−4496. (c) Tsuji, H.;
Fujimoto, T.; Endo, K.; Nakamura, M.; Nakamura, E. Org. Lett. 2008,
10, 1219−1221. (d) Angell, P.; Blazecka, P. G.; Lovdahl, M.; Zhang, J.
J. Org. Chem. 2007, 72, 6606−6609.
(17) The crystallographic data (CCDC 918857) can be obtained free
of charge from the Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(18) Ahad, A. M.; Zuohe, S.; Du-Cuny, L.; Moses, S. A.; Zhou, L. L.;
Zhang, S.; Powis, G.; Meuillet, E. J.; Mash, E. A. Bioorg. Med. Chem.
2011, 19, 2046−2054.
(19) Ferraz, H. M. C.; Souza, A. J. C.; Tenius, B. S. M.; Bianco, G. G.
Tetrahedron 2006, 62, 9232−9236.
(20) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091−2096 and references therein.
(21) (a) Carlsen, P. H. J.; Katsuki, T.; Martín, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936−3938. (b) Jung, J. C.; Choi, H. C.; Kim, Y.
H. Tetrahedron Lett. 1993, 34, 3581−3584. (c) Bovicelli, P.; Lupattelli,
P.; Fracassi, D. Tetrahedron Lett. 1994, 35, 935−938. (d) Yoshimitsu,
T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2003, 68, 7548−7550.
(e) Ito, K.; Fukuda, T.; Katsuki, T. Synlett 1977, 387−389. (f) Tromel,
̈
M.; Russ, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 1007−1009.
(g) Salim, H.; Piva, O. J. Org. Chem. 2009, 74, 2257−2260.
(22) (a) Espino, C. G.; Du Bois. J. Angew. Chem., Int. Ed. 2001, 40,
598−600. (b) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am.
Chem. Soc. 2001, 123, 6935−6936. (c) Espino, C. G.; Fiori, K. W.;
Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378−15379.
(d) Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562−568.
(e) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 7558−
7559.
(23) For reviews, see: (a) Zalantan, D. N.; Du Bois, J. Top. Curr.
Chem. 2010, 292, 347−378. (b) Du Bois. Org. Process Res. Dev. 2011,
15, 758−762.
(24) (a) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D.
W. C. Angew. Chem., Int. Ed. 2004, 43, 2152−2154. (b) Mangion, I. K.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696−3697.
(5) For synthetic studies of natural products based on a Conia−ene
reaction, see: (a) Li, W.; Liu, X.; Zhou, X.; Lee, C.-S. Org. Lett. 2010,
12, 548−551. (b) Huang, S.; Du, G.; Lee, C.-S. J. Org. Chem. 2011, 76,
6534−6541. (c) Grover, H. K.; Lebold, T. P.; Kerr, M. A. Org. Lett.
2011, 13, 220−223. (d) Liu, X.; Lee, C.-S. Org. Lett. 2012, 14, 2886−
2889. (e) Huwyler, N.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51,
13066−13069.
(6) (a) Itazaki, H.; Nagashima, K.; Kawamura, Y.; Matsumoto, K.;
Nakai, H.; Terui, Y. J. Antibiot. 1992, 45, 38−49. (b) Tanaka, K.;
Itazaki, H.; Yoshida, T. J. Antibiot. 1992, 45, 50−55.
́ ́
(c) Cordova, A.; Ibrahem, I.; Casas, J.; Sunden, H.; Engqvist, M.;
Reyes, E. Chem.Eur. J. 2005, 11, 4772−4784. (d) Mainkar, P. S.;
Johny, K.; Rao, T. P.; Chandrasekhar, S. J. Org. Chem. 2012, 77, 2519−
2525.
(25) (a) Ohira, S. Synth. Commun. 1989, 19, 561−564. (b) Muller, S.;
̈
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521−522.
(26) Iwasawa, N.; Kato, T.; Narasaka, K. Chem. Lett. 1988, 1721−
1724.
(27) The observed better diastereoselectivity can be attributable to
the milder reaction conditions compared with those without using
PhB(OH)2. PhB(OH)2 is assumed to facilitate the dissociation of an
osmate ester,26 thus accelerating the catalytic cycle of dihydroxylation.
(28) Santini, C.; Ball, R. G.; Berger, G. D. J. Org. Chem. 1994, 59,
2261−2266.
(7) (a) Esumi, T.; Iwabuchi, Y.; Irie, H.; Hatakeyama, S. Tetrahedron
Lett. 1998, 39, 877−880. (b) Hirai, K.; Ooi, H.; Esumi, T.; Iwabuchi,
Y.; Hatakeyama, S. Org. Lett. 2003, 5, 857−859. (c) Morokuma, K.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Chem. Commun. 2005,
2265−2267. (d) Amer, M. F. A.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Heterocycles 2007, 72, 181−185. (e) Morokuma, K.;
Taira, Y.; Uehara, Y.; Shibahara, S.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Tetrahedron Lett. 2008, 49, 6043−6045.
(29) For a review, see: Ley, S. V.; Norman, J.; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639−666.
(8) For reviews, see: (a) Murakami, M.; Taketomi, Y.; Miki, Y.; Sato,
H.; Hirabayashi, T.; Yamamoto, K. Prog. Lipid Res. 2011, 50, 152−192.
3857
dx.doi.org/10.1021/jo400263w | J. Org. Chem. 2013, 78, 3847−3857