Carbohydrate-Based Studies Toward the Synthesis of Hamigeromycin E: A Stereoselective Total Synthesis of an Isomer of Zeaenol

Article abstract of DOI:10.1002/hlca.201500267

A stereoselective synthesis of 14-membered macrolide hamigeromycin E (6) has been studied by employing ortho-lithiated formylation, Barbier allylation, Julia–Kocienski olefination, Mitsunobu esterification, and ring-closing metathesis (RCM) reactions. The

Full text of DOI:10.1002/hlca.201500267

Helv. Chim. Acta 2016, 99, 425 – 435
425
FULL PAPER
Carbohydrate-Based Studies Toward the Synthesis of Hamigeromycin E:
A Stereoselective Total Synthesis of an Isomer of Zeaenol
by Gannerla Saidachary, and Bhimapaka China Raju*
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
(phone: +91-40-27191725; fax: +91-40-27160512; e-mail: chinaraju@iict.res.in)
A stereoselective synthesis of 14-membered macrolide hamigeromycin E (6) has been studied by employing ortho-lithiated
formylation, Barbier allylation, Julia–Kocienski olefination, Mitsunobu esterification, and ring-closing metathesis (RCM)
reactions. The final RCM reaction did not provide the target molecule. This study has prompted us to synthesize a
stereoisomer of zeaenol and accomplish the total synthesis with the above protocols.
Keywords: Macrolides, Mitsunobu reaction, Wittig homologation, Julia–Kocienski olefination, Metathesis.
Results and Discussion
Introduction
Our retrosynthetic strategy of hamigeromycin E (6) was
depicted in Scheme 1. The conjugate enone 7 can be syn-
thesized from substituted aromatic acid 8 and alcohol 10
by employing Mitsunobu esterification, ring-closing
metathesis, and allylic oxidation. Further, the aromatic
acid 8 can be accomplished from commercially available
b-Resorcylic acid lactones (RALs) are fungal polyketide
metabolites possessing a C10 side chain to form 14-mem-
bered benzannulated macrolides (Fig. 1) [1]. RALs have
been known for decades, with the first isolation of radici-
col in 1953 [2]. Sugawara et al. [3] isolated the zear-
alenone derivatives, such as zeaenol, LL-Z1640-1, and
LL-Z1640-2, from the extract of Drechslera portulacae
and these macrolides have shown potent kinase inhibi-
tory properties. Caryospomycins were isolated from the
fungus of Caryospora callicarpa YMF1.01026 [4]. Fur-
ther, Isaka et al. isolated a series of new 14-membered
lactones (nonaketide macrolides) from the soil fungus
Hamigera avellanea BCC 17816. Scale-up fermentation
and chemical studies led to the isolation of macrolides,
such as hamigeromycin A – F. Hamigeromycins A, C, D,
and E are stereoisomers that differ in the absolute con-
figurations of the 4,5-diol moiety [5]. These macrolides
have received considerable attention due to their poten-
tial biological properties [6 – 10]. Hamigeromycins are
interesting molecules; however, there is no report avail-
able on their total synthesis. The synthesis of zeaenol
and cochliomycin A were reported by Jana and Nanda
[11a], however, the synthesis of zeaenol and cochliomy-
cin B were reported by Du et al. [11b]. Mohapatra et al.
[11c] reported the synthesis of zeaenol, 7-epi-zeaenol,
and its analogs by diastereoselctive Nozaki–Hiyama–
Kishi (NHK) reaction. Our long-term interest on total
synthesis of natural products [12] and biologically active
heterocyclic compounds [13] prompted us to study the
synthesis of hamigeromycin E and zeaenol starting from
readily available chemicals.
2,4,5-trimethoxybenzoic acid
9
using ortho-lithiated
formylation and one-carbon Wittig homologation proto-
cols. The secondary alcohol 10 could be obtained from
aldehyde 11 and sulfone 12 using Julia–Kocienski olefina-
tion. The aldehyde 11 can be prepared from commercially
available D-mannitol 13 using Barbier allylation and the
sulfone 12 from commercially available ethyl (–)-(R)-3-
hydroxybutyrate (14).
Synthesis of Aromatic Acid 8
The aromatic acid 8 was synthesized starting from 2,4,5-tri-
methoxybenzoic acid (9) (Scheme 2) as per the literature
reported methods described below. 2,4,5-Trimethoxyben-
zoic acid (9) in the presence of oxalyl chloride with
diethylamine provided amide 15 [14a]. Regioselective
ortho-lithiated formylation of amide 15 with DMF in the
presence of sec-BuLi and TMEDA at ꢀ78 °C afforded N,
N-diethyl-2-formyl-3,4,6-trimethoxybenzamide (16) [14b].
The obtained benzamide 16 upon hydrolysis with 10% HCl
under reflux conditions furnished 3-hydroxy-4,5,7-tri-
methoxyisobenzofuran-1(3H)-one (17) [14b]. Next, the
one-carbon Wittig homologation of lactol 17 with methyl-
triphenylphosphonium bromide afforded 3,4,6-trimethoxy-
2-vinylbenzoic acid (8) [14c].
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Helv. Chim. Acta 2016, 99, 425 – 435
Fig. 1. Structures of 14-membered macrolides.
Scheme 1. Retrosynthetic analysis of hamigeromycin E.
mercapto-1H-tetrazole under Mitsunobu conditions
Synthesis of Sulfone 12
(DIAD/TPP) at ꢀ20 °C to give sulfide 20 [11a]. The oxi-
dation of sulfide 20 with (NH4)6Mo7O24 ꢁ 4 H2O in the
presence of H2O2 afforded the sulfone 12 [11a].
The sulfone 12 was prepared starting from ethyl (–)-(R)-
3-hydroxybutyrate (14) as depicted in Scheme 3. The OH
group 14 was protected as TBDPS ether 18 using
TBDPSCl in the presence of imidazole [15]. The ester 18
upon reduction with DIBAL-H in dry CH2Cl2 at ꢀ78 °C
afforded the corresponding alcohol 19 [15]. The OH
group 19 was converted to its corresponding 1-phenyl-5-
Synthesis of Aldehyde 11
Synthesis of aldehyde 11 was accomplished from D-manni-
tol as depicted in Scheme 4. Acetonide protection of
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Helv. Chim. Acta 2016, 99, 425 – 435
Scheme 2. Synthesis of compound 8.
427
a) (COCl)2, Et2NH, dry DCM, 12 h; 80%. b) sec-BuLi, TMEDA, dry DMF, ꢀ78 °C, 2 h; 68%. c) 10% HCl, reflux, 24 h; 54%. d) CH3PPh3Br,
KOtBu, dry THF, 0 °C, 5 h; 60%.
Scheme 3. Synthesis of compound 12.
a) Imidazole, TBDPSCl, DCM, 0 °C to r.t., 6 h; 80%. b) DIBAL-H, dry DCM, ꢀ78 °C, 2 h; 90%. c) PTSH, PPh3, DIAD, dry THF, ꢀ20 °C to
r.t.; 85%. d) (NH4)6Mo7O24 ꢁ 4 H2O, H2O2, C2H5OH, 0 °C to r.t. 6 h; 88%.
Scheme 4. Synthesis of compound 11.
a) 2,2-Dimethoxypropane, p-TsOH, dry DMSO, 0 °C to r.t., 24 h; 80%. b) H5IO6, AcOEt, 3 h. c) Allyl bromide, Zn, NH4Cl, THF, 2 h; 76%.
d) DIPEA, MOMCl, dry CH2Cl2, 0 °C to r.t., 12 h; 80%. e) H5IO6, AcOEt, 0 °C to r.t., 6 h; 56%.
Scheme 5. Synthesis of compound 10.
D-mannitol 13 with 2,2-dimethoxypropane in the presence
of p-TsOH afforded 21 [16]. Oxidative cleavage [17] and
Barbier allylation [18] of compound 21 provided the sec-
ondary alcohol 22 (1H-NMR, anti/syn 95:5) [19]. The OH
group of 22 was protected as MOM ether 23 using
MOMCl in the presence of DIPEA [20]. The oxidative
cleavage of 23 with H5IO6 afforded the corresponding
aldehyde 11.
Synthesis of Alcohol 10
a) KHMDS, 18-Crown-6, dry THF, ꢀ78 °C to r.t., 2 h; 75%. b) TBAF,
dry THF, 24 h; 85%.
After the successful synthesis of aldehyde 11 and sulfone
12, the Julia–Kocienski olefination reaction of 11 with 12
has been carried out with KHMDS in the presence of 18-
spectrum showed a doublet–doublet at d(H) 5.40 (J = 7.8,
crown-6 at ꢀ78 °C. This provided olefin derivative 24 15.4) and a multiplet at d(H) 5.78 – 5.86 indicating the
(1H-NMR, E/Z = 94:6, Scheme 5) [21]. The 1H-NMR
formation of (E)-configured olefin C=C bond. The
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Helv. Chim. Acta 2016, 99, 425 – 435
TBDPS ether 24 was freed using TBAF in dry THF at
0 °C to give the corresponding alcohol 10 [22].
appeared as multiplet at d(H) 5.77 – 5.88. The ESI-MS
spectrum showed the molecular ion peak at m/z 329
[M + Na]+ and further the compound confirmed by HR-
MS.
RCM Reaction of Aromatic Acid 8 and Alcohol 10
Next, we have carried out the RCM reaction of 25
with Hoveyda–Grubbs catalyst (5 mol-%). This also fur-
nished 27 instead of 26. The reason could be that the
Mitsunobu esterification [23] of 3,4,6-trimethoxy-2-vinyl-
benzoic acid (8) and alcohol 10 in dry toluene provided
ester 25 in 88% yield (Scheme 6). Next, we proceeded the ruthenium regioselectively complexing with C=C bond
RCM reaction to achieve macrocyclization to complete instead terminal C=C bonds due to the steric effect of
the target molecule hamigeromycin E. Accordingly, the
RCM reaction of 25 has been carried out with Grubbs’ I
catalyst (10 mol-%) in dry CH2Cl2 at room temperature
[24] as well as in toluene under reflux conditions. How-
MeO group present on aromatic ring at ortho-position to
vinylic carbon.
The synthetic studies on hamigeromycin E prompted
us to synthesize the isomer of zeaenol, a 14-membered
ever, these reactions did not give the cyclized product 26. resorcylic acid lactone without MeO group on aromatic
Next, the RCM reaction was carried out with Grubbs’ II
catalyst (5 mol-%) in CH2Cl2 at room temperature [25].
The progress of the reaction was monitored by TLC, and
after completion of the reaction (6 h), the solvent was
removed under reduced pressure and the obtained residue
was purified by column chromatography. This provided
compound 27 as colorless liquid in 62% yield instead of
ring at ortho-position to vinylic carbon depicted below.
Stereoselective Total Synthesis of a Stereoisomer of
Zeaenol 28
The retrosynthetic approach for the synthesis of stereoiso-
mer of zeaenol [26] can be accomplished from aromatic
the cyclized compound 26. Compound 27 was well charac- acid 29 and alcohol 10a (Scheme 7). 2-Hydroxy-4-meth-
terized by spectroscopic data. The IR spectrum showed oxy-6-vinylbenzoic acid (29) could be accomplished from
the stretching frequency at 1723 cmꢀ1 correspond to the commercially available 2,4,6-trihydroxybenzoic acid (30).
ester C=O and 1588, 1264, and 1204 cmꢀ1 for C=C, C–C, The secondary alcohol 10a with PMB ether was prepared
and C–O stretching frequencies. The 1H-NMR spectrum
of compound 27 showed a doublet at d(H) 1.30 (J = 15.7)
corresponds to Me H-atoms and a multiplet at d(H)
2.28 – 2.54 corresponds to allylic CH2 H-atoms. The three
as per the Schemes 3 – 5.
Synthesis of Styrene Acid 29
aromatic MeO groups appeared as three singlets at d(9) The synthesis of styrene acid 29 (Scheme 8) has been car-
3.71, 3.81 and 3.88. The two olefin H-atoms appeared as ried out as per the reported method [27]. Acetonide pro-
multiplet at d(2) 5.07 – 5.15. The quartet appeared at d(H) tection of 2,4,6-trihydroxybenzoic acid (30) with acetone
5.18 corresponds to olefin H-atom. The CH H-atom in the presence of TFA and TFAA provided 31.
Scheme 6. RCM reaction of compound 25.
a) DIAD, TPP, dry toluene, 0 °C to r.t., 88%. b) Second-generation Grubbs’ catalyst (5 mol-%), dry CH2Cl2, 6 h; 62%.
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Helv. Chim. Acta 2016, 99, 425 – 435
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Scheme 7. Retrosynthetic analysis of compound 28.
Scheme 8. Synthesis of compound 29.
a) TFA, TFAA, Acetone, r.t., 48 h; 52%. b) i) PPh3, DIAD, dry MeOH, dry THF, 0 °C to r.t., 80%. ii) Tf2O, Pyridine, 0 °C, 3 h; 78%. c) Vinyl
tributylstannane, LiCl, PPh3, dry DMF, r.t., 4 h; 80%. d) LiOH.H2O, THF:H2O (2:1), r.t., 20 h; 75%.
Regioselective methylation under Mitsunobu conditions CH2Cl2/H2O (9:1) medium furnished alcohol 35 [28]. The
furnished the MeO derivative and protection of OH phenolic OH group 35 was protected as MOM ether with
group with trifluoromethanesulfonic anhydride in the MOMCl in the presence of DIPEA at 0 °C in dry CH2Cl2
presence of catalytic amount of pyridine provided 32. provided 36. The RCM reaction of 36 has been carried
Stille coupling of triflate 32 with vinyl tributylstannane in out with Grubbs’ II catalyst (5 mol-%) in dry CH2Cl2
the presence of Pd(PPh3)4, LiCl, and PPh3 at room tem-
under reflux conditions. The reaction was monitored by
perature afforded styrene 33. Deprotection of acetonide TLC (8 h), and after column chromatography purification,
33 with LiOH ꢁ H2O in the presence of THF/H2O (2:1) lactone 37 was furnished as yellow liquid in 66% yield.
provided 29.
The MOM ether and the acetonide group of 37 was
removed using 2N HCl at room temperature (20 h) to
afford the corresponding stereoisomer of zeaenol
(3S,5E,7R,8R,9R,11E)-7,8,9,16-tetrahydroxy-14-methoxy-
Synthesis of Compound 10a
The secondary alcohol 10a (Scheme 9) was prepared 3-methyl-3,4,7,8,9,10-hexahydro-1H-benzo[c][1]oxacyclote-
according to the synthetic path utilized for the synthesis
of alcohol 10 as depicted in Schemes 3 – 5.
tradecin-1-one (28) as colorless solid in 52% yield. The
IR spectrum of 28 showed absorption bands at 3432 cmꢀ1
corresponds to 4-OH groups, and 1253 and 1160 cmꢀ1
correspond to C–C and C–O stretching frequencies. The
1H-NMR spectrum of 28 showed four olefin H-atoms
RCM Reaction of Acid 29 and Alcohol 10a
Mitsunobu esterification of vinylbenzoic acid 29 and alco- appeared as doublet at d(H) 6.89 (J = 15.7), multiplet at d
hol 10a in dry toluene afforded the ester 34 (Scheme 10) (H) 5.89 – 6.03, and doublet–doublet at d(H) 5.76, 5.79
[23]. Deprotection of PMB ether 34 with DDQ in (J = 7.2, 15.7). The two aromatic H-atoms showed doublet
Scheme 9. Synthesis of compound 10a.
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Helv. Chim. Acta 2016, 99, 425 – 435
Scheme 10. Synthesis of stereoisomer of zeaenol 28.
a) DIAD, TPP, dry toluene, 2 h; 80%. b) DDQ, CH2Cl2:H2O (9:1) 2 h; 80%. c) DIPEA, MOMCl, dry CH2Cl2, 0 °C to r.t. 80%. d) Grubbs’ II cat-
alyst, dry CH2Cl2, reflux, 8 h; 66%. e) 2N HCl, THF, 20 h; 52%.
at d(H) 6.45 (J = 2.1) and doublet at d(H) 6.39 (J = 2.4). C. R. acknowledges ORIGIN (CSC-0108) of XII five-year
The C(7), C(8) CH H-atoms showed triplet at d(H) 4.23 plan and SERB-DST (SB/EMEQ-301/2013) New Delhi
(J = 7.8) and triplet at d(H) 4.04 (J = 5.8), and C(9) CH for financial support.
H-atom showed a multiplet at d(H) 3.64. The C(3) CH H-
atom showed multiplet at d(H) 5.39 – 5.46. The four CH2
H-atoms appeared as multiplet at d(H) 2.39 – 2.54,
Supporting Information
Additional Supporting Information (compound spectra)
may be found in the online version of this article.
2.28 – 2.37, and 2.66 – 2.74. The Me resonated as doublet
at d(H) 1.39 (J = 6.4) and OCH3 H-atoms resonated as
singlet at d(H) 3.82. The 13C-NMR spectrum showed a
signal at d(C) 170.8 corresponds to the C=O. The signals
at d(C) 35.7 and 36.6 correspond to C(4) and C(10). The
signals at d(C) 55.4 and 18.7 ppm correspond to OCH3
and CH3. The signals at d(C) 72.8, 77.2, and 72.5 are cor-
respond to C(7), C(8), and C(9). The C(5), C(6), C(11),
and C(12) olefin carbons resonated at d(C) 127.5, 128.3,
132.6, and 133.4. Finally, the compound was confirmed by
HR-ESI-MS spectrum (calcd. for C19H24O7Na [M + Na]
387.1414; found 387.1423).
Experimental Part
General
The chemicals were purchased from Sigma–Aldrich (St.
Louis, MO, USA). The solvents and reagents were puri-
fied by standard techniques. Anal. TLC: precoated SiO2
60F254 (0.5 mm) glass plates; visualization of the spots on
TLC plates was achieved by exposure to UV light. Col-
umn chromatography (CC): silica gel (SiO2; 60 – 120
mesh, Acme Synthetic Chemicals, Mumbai, India). Optical
rotations: HORIBA SEPA-300 digital polarimeter
(Horiba, Kyoto, Japan). M.p.: Mettler-Temp apparatus
(Mettler–Toledo, Mumbai, India); uncorrected. IR Spec-
tra: PerkinElmer-1600 FT-IR spectrometer (PerkinElmer,
Conclusions
In conclusion, a stereoselective synthesis of hamigeromy-
cin E has been studied by employing ortho-lithiated
formylation, Barbier allylation, Julia–Kocienski olefina-
tion, Mitsunobu esterification, and RCM reactions. The
final RCM reaction did not provide the target molecule.
This study has prompted us to synthesize a stereoisomer
of zeaenol and accomplish the total synthesis with the
above protocols.
ꢀ1
.
1H- and 13C-
NMR spectra: Bruker-300 and Avance-500 spectrometer
~
Waltham, MS, USA); in KBr; v in cm
€
(Bruker Corp. Fallanden, Switzerland); in CDCl3; chemi-
cal shifts, d, in ppm rel. to Me4Si as internal standard; J
in Hz. ESI-MS: 7070H spectrometer (Micromass UK Ltd.,
Manchester, UK) with a direct inlet system; in m/z (rel.
%). HR-ESI-MS: Agilent 6510 Q-TOF LC/MS instrument
(Agilent Technologies, Waldbronn, Germany).
The authors thank Dr. S. Chandrasekhar, Director, CSIR-
IICT for his constant encouragement. G. S. thanks CSIR,
New Delhi for financial support. The authors thank Mr.
K. V. Prasad, SRF, CSIR-IICT for useful discussions. B.
N,N-Diethyl-2-formyl-3,4,6-trimethoxybenzamide (16) [14b]. Sec-
BuLi (1.3M, 33 ml, 39 mmol) was added dropwise to the
€
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Helv. Chim. Acta 2016, 99, 425 – 435
431
soln. of TMEDA (5.9 ml, 39 mmol) in anh. THF at
ꢀ78 °C under N2 atmosphere. The mixture was continued
A soln. of aldehyde 21a (3.6 g, 15.5 mmol) in dry
THF (12 ml) was added to a stirred suspension of Zn
at the same temp. for 30 min. Amide 15 (7.0 g, (3.0 g, 46.5 mmol) in dry THF (30 ml) at 0 °C under N2
26.2 mmol) in dry THF was added dropwise to the reac-
tion mixture (20 min) and stirring was continued for
another 2 h. After completion of the reaction, the DMF
(8.0 ml, 104 mmol) was added to the reaction mixture at
atmosphere. Allyl bromide (4 ml, 46.5 mmol) was added
dropwise to the mixture. After stirring at 0 °C for 15 min,
sat. NH4Cl was added slowly to the mixture at 0 °C and
the resulting mixture was further stirred for another 2 h.
ꢀ78 °C and then allowed to r.t. After completion of the After completion of the reaction, the mixture was filtered
reaction, sat. NH4Cl (15 ml) was added to the reaction
mixture at 0 °C and diluted with AcOEt (80 ml). The org.
layer was separated, and dried (Na2SO4) and concentrated
through Celite, the filtrate was diluted with CHCl3,
washed with brine, and the org. layer was dried (Na2SO4)
and concentrated in vacuo. The residue was purified by
in vacuo. The residue was purified by CC affording 16 CC (hexane/AcOEt, 9:1) affording 22 (3.2 g, 76%) as col-
25
(5.25 g, 68%) as colorless solid. IR (KBr): 2967, 2930,
2860, 1688, 1629, 1594, 1328, 1276, 1218, 944. 1H-NMR
(300 MHz, CDCl3): 1.00 (t, 3 H, J = 7.2, CH3); 1.30 (t, 3
orless liquid. ½aꢂD = +12.67 (c = 1.1, CHCl3). IR (KBr):
2924, 2851, 1495, 1452, 1266, 1177, 1125, 776. 1H-NMR
(300 MHz, CDCl3): 1.38 (s, 6 H, CH3); 1.40 (s, 3 H,
H, J = 7.2, CH3); 3.08 (q, 2 H, J = 7.2, NCH2); 3.42 – 3.50 CH3); 1.44 (s, 3 H, CH3); 2.20 – 2.42 (m, 4 H, allylic);
(m, 1 H, NCH2); 3.68 – 3.76 (m, 1 H, NCH2); 3.82 (s, 3 H, 2.50 – 2.52 (m, 1 H, OH); 3.68 – 3.80 (m, 3 H, CH);
OCH3); 3.91 (s, 3 H, OCH3); 3.94 (s, 3 H, OCH3); 6.75 (s, 3.92 – 4.22 (m, 2 H, CH); 4.26 – 4.32 (dd, 1 H, J = 3.8,
1 H, aromatic); 10.40 (s, 1 H, CHO). 13C-NMR (75 MHz,
6.9, CH); 5.10 – 5.24 (m, 2 H, olefin); 5.88 – 6.08 (m, 1 H,
CDCl3): 12.1; 13.3; 38.6; 42.5; 56.2; 56.4; 62.5; 102.6;117.8; olefin). 13C-NMR (75 MHz, CDCl3): 25.1; 26.3; 26.7; 26.8;
126.8; 146.4; 151.9; 153.6; 166.5; 190.0. ESI-MS: 296 37.9; 67.8; 71.6; 76.3; 80.9; 82.7; 109.1; 110.1; 117.4; 134.6.
[M + H]+. HR-ESI-MS: calcd. for C15H22NO5 [M + H] ESI-MS: 295 [M + Na]+.
296.1492; found 296.1486.
(4S,40R,5S)-5-[(1R)-1-(Methoxymethoxy)but-3-en-1-yl]-2,2,
2-Ethenyl-3,4,6-trimethoxybenzoic Acid (8) [14c]. To the 20,20-tetramethyl-4,40-bi-1,3-dioxolane (23). Diisopropyl
mixture of methyltriphenylphosphonium iodide (16.9 g, ethylamine (1.5 ml, 8.82 mmol) was added to a stirred
41.6 mmol) and potassium tert-butoxide (3.36 g, soln. of alcohol 22 (2.0 g, 7.3 mmol) in dry CH2Cl2
30 mmol) was added dry THF (60 ml) at 0 °C under N2 (20 ml) at 0 °C under N2 atmosphere. MOMCl (0.66 ml,
atmosphere. The mixture was allowed to r.t. and stirring
was continued for 1 h. The mixture was again cooled to
0 °C, the lactol 17 (1.5 g, 6.25 mmol) in dry THF
(15 ml) was added dropwise to the mixture over 15 min.
The mixture was allowed to warm to r.t. and stirring was
continued for another 5 h. After completion of the reac-
tion, H2O (20 ml) was added and the mixture extracted
with AcOEt (3 9 50 ml). The org. layer was dried
(Na2SO4) and concentrated in vacuo. The residue was
purified by CC affording 8 (0.89 g, 60%) as colorless
8.82 mmol) was added slowly to the mixture at the same
temp. The reaction was stirred at r.t. for 12 h. After com-
pletion of the reaction (TLC), the mixture was diluted
with H2O and extracted with CH2Cl2 (3 9 40 ml). The
combined org. layers were dried (Na2SO4) and concen-
trated in vacuo. The residue was purified by CC (hexane/
AcOEt, 96:4) affording 23 in 80% yield as yellow color
20
liquid. ½aꢂD = +7.5 (c = 2.0, CHCl3). IR (KBr): 2987, 2935,
1641, 1380, 1371, 1247, 1214, 1155, 1067, 1041, 848. 1H-
NMR (300 MHz, CDCl3): 1.35 (s, 3 H, CH3); 1.38 (s, 3 H,
solid. M.p. 106 – 108 °C. IR (KBr): 2940, 2847, 1694, CH3); 1.40 (s, 3 H, CH3); 1.42 (s, 3 H, CH3); 2.41 – 2.45
1584, 1464, 1332, 1299, 1205, 1047, 1024, 742. 1H-NMR
(m, 2 H, allylic); 3.40 (s, 3 H, OCH3); 3.81 – 3.85 (m, 1 H,
(300 MHz, CDCl3): 3.71 (s, 3 H, OCH3); 3.89 (s, 3 H, CH); 3.92 – 3.99 (m, 2 H, OCH2); 4.06 (dd, 1 H, J = 3.9,
OCH3); 3.92 (s, 3 H, OCH3); 5.50 (d, 1 H, J = 11.3, ole- 6.7, CH); 4.12 (dd, 2 H, J = 2.1, 6.7, CH); 4.72 (dd, 2 H,
fin); 5.75 (d, 1 H, J = 18.9, olefin); 6.48 (s, 1 H, aro-
matic); 6.86 (dd, 1 H, J = 11.3, 18.9, aromatic). 13C-NMR
J = 7.0, 12.8, CH); 5.06 – 5.17 (m, 2 H, olefin); 5.89 – 5.93
(m, 1 H, olefin). 13C-NMR (75 MHz, CDCl3): 25.3; 26.5;
(75 MHz, CDCl3): 55.9; 56.7; 60.4; 96.4; 113.9; 120.4; 27.2; 34.8; 55.8; 67.1; 77.0; 77.2; 78.3; 81.3; 96.4; 109.6;
130.4; 131.7; 140.9; 153.5; 154.7; 171.5. ESI-MS: 239 117.3; 134.8. ESI-MS: 317 [M + H]+. HR-ESI-MS: calcd.
[M + H]+. HR-ESI-MS: calcd. for C12H14NaO5 [M + Na] for C16H29O6 [M + H] 317.1959; found 317.1956.
261.0739; found 261.0736.
(1R)-1-[(4S,40R,5S)-2,2,20,20-Tetramethyl-4,40-bi-1,3-dioxol-
5-yl]but-3-en-1-ol (22) [17,18]. To a stirred soln. of
5-[1-(Methoxymethoxy)but-3-en-1-yl]-2,2-dimethyl-1,3-dioxo-
lane-4-carbaldehyde (11). Periodic acid (1.6 g, 7.1 mmol)
was added portion wise to a stirred soln. of 23 (1.5 g,
1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol
20.7 mmol) in AcOEt (90 ml) was added periodic acid
(6.1 g, 27 mmol) portion wise at 0 °C under N2 atmo- completion of the reaction, the mixture was filtered
sphere. After stirring for 3 h at r.t., the mixture was fil- through Celite, and the filtrate was washed with water and
21
(6.2 g, 4.75 mmol) in AcOEt (20 ml) at 0 °C under N2 atmo-
sphere. The stirring was continued for 6 h at r.t. After
tered through Celite, and the filtrate was concentrated in brine. The org. layer was dried (Na2SO4) and concen-
vacuo to give crude aldehyde 21a, which was used in the trated in vacuo. The residue was purified by CC affording
20
next step without further purification.
11 (648 mg, 56%) as yellow syrup. ½aꢂD = +5.5 (c = 1.2,
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432
Helv. Chim. Acta 2016, 99, 425 – 435
CHCl3). IR (KBr): 2924, 2851, 1690, 1456, 1267, 1189,
1129, 776. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 3 H, yl]-2,2-dimethyl-1,3-dioxolan-4-yl}pent-4-en-2-ol (10). TBAF
CH3); 1.49 (s, 3 H, CH3); 1.09 (d, 3 H, J = 6.0, CH3); (1M, 0.6 ml, 0.6 mmol) was added to stirred soln. of 24
(2R,4E)-5-{(4R,5R)-5-[(1R)-1-(Methoxymethoxy)but-3-en-1-
2.34 – 2.40 (m, 2 H, allylic); 3.36 – 3.42 (m, 1 H, CH); (150 mg, 0.3 mmol) in dry THF (5 ml) at 0 °C under N2
3.40 (s, 3 H, OCH3); 3.86 (q, 1 H, J = 5.8, CH); 4.17 (dd, atmosphere. The mixture was stirred for 24 h at r.t. After
1 H, J = 4.7, 6.5, CH); 4.41 (dd, 1 H, J = 1.6, 6.5, OCH2); completion of the reaction (TLC), solvent was removed
4.73 (q, 2 H, J = 6.8, OCH2); 5.10 – 5.18 (m, 2 H, olefin); under in vacuo, H2O (5 ml) was added and the mixture
5.80 – 5.88 (m, 1 H, olefin); 9.77 (d, 1 H, J = 1.8, CHO). was extracted with AcOEt (50 ml). The org. layer was
ESI-MS: 245 [M + H]+.
5-{[(3R)-3-{[tert-Butyl(diphenyl)silyl]oxy}butyl]sulfonyl}-
washed with brine, and dried (Na2SO4) and concentrated
in vacuo. The residue was purified by CC affording 10
20
1-phenyl-1H-tetrazole (12) [11a]. (NH4)6Mo7O24 ꢁ 4 H2O (62 mg, 85% yield) as yellow color liquid. ½aꢂD = +8.4
(0.430 g, 0.348 mmol) and H2O2 soln. (30%, 3.0 ml) were (c = 1.2, CHCl3). IR (KBr): 3444, 2926, 2851, 1639, 1371,
sequentially added to the stirred soln. of sulfide 20 (1.7 g, 1241, 1217, 1057, 1034, 771. H-NMR (300 MHz, CDCl3):
1
3.48 mmol) in dry EtOH (20 ml) at 0 °C under N2 atmo- 1.20 (d, 3 H, J = 7.8 Hz, CH3); 1.41 (s, 6 H, CH3);
sphere. The mixture was slowly allowed to r.t. and stirred
for 6 h. After completion of the reaction, the reaction
was diluted with Na2S2O3 soln. (10%) and extracted with
2.21 – 2.38 (m, 4 H, allylic); 3.38 (s, 3 H, OCH3);
3.80 – 3.90 (m, 3 H, CH); 4.42 (t, 1 H, J = 7.8, CH); 4.68
(d, 1 H, J = 6.7, OCH2); 4.75 (d, 1 H, J = 6.7, OCH2);
AcOEt. The org. layer was washed with sat. NaHCO3 5.07 – 5.13 (m, 3 H, CH); 5.60 (ddd, 1 H, J = 0.9, 7.8,
soln. and brine. The org. layer was dried (Na2SO4) and 15.4, olefin); 5.78 – 5.90 (m, 2 H, olefin). 13C-NMR
concentrated in vacuo. The residue was purified by CC
affording 12 in 88% yield as colorless liquid.
½aꢂD = +15.5 (c = 2.2, CHCl3). IR (KBr): 2931, 2857, 1497,
(75 MHz, CDCl3): 22.86; 26.88; 27.01; 35.86; 42.12; 55.78;
67.09; 76.12; 78.31; 81.79; 96.52; 108.72; 117.53; 131.47;
131.53; 134.35. ESI-MS: 323 [M + Na]+. HR-ESI-MS:
a
20
1
1342, 1151, 1108, 762, 704. H-NMR (300 MHz, CDCl3): calcd. for C16H28NaO5 [M + Na] 323.1834; found
1.08 (s, H, CH3); 1.14 (d, H, J = 6.4, CH3); 323.1846.
9
3
1.98 – 2.16, (m, 2 H, CH2); 3.68 – 3.72 (m, 1 H, CH2); (2S,4E)-5-{(4R,5R)-5-[(1R)-1-(Methoxymethoxy)but-3-en-
3.82 – 3.92 (m, 1 H, CH2); 4.02 – 4.18 (m, 1 H, CH); 1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}pent-4-en-2-yl 2-Ethe-
7.34 – 7.48 (m, 6 H, aromatic); 7.58 – 7.70 (m, 9 H, aro-
matic). 13C-NMR (75 MHz, CDCl3): 19.2; 22.9; 26.9; 30.9; (88 mg, 0.336 mmol) and DIAD (0.06 ml, 0.336 mmol)
52.6; 67.2; 125.0; 127.6; 127.8; 129.6; 129.7; 129.9; 131.4; were sequentially added to a stirred soln. of acid 8
nyl-3,4,6-trimethoxybenzoate (25). Triphenylphosphine
132.9; 133.3; 133.8; 135.7; 135.8; 153.3. ESI-MS: 543 (40 mg, 0.168 mmol) and alcohol 10 (50 mg, 0.168 mmol)
[M + Na]+.
in dry toluene (6 ml) at 0 °C under N2 atmosphere. After
completion of the reaction (TLC, 2 h) the solvent was
removed in vacuo. The residue was purified by CC
tert-Butyl{[(2R,4E)-5-{(4R,5R)-5-[(1R)-1-(methoxymethoxy)
but-3-en-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}pent-4-en-2-yl]
oxy}diphenylsilane (24). KHMDS (0.5M, 1.6 ml, 0.8 mmol)
(AcOEt/petroleum ether 20:80) affording 25 as yellow
20
was added to a stirred soln. of sulfone 12 (419 mg, color liquid (76 mg, 88%). ½aꢂD = +8.7 (c = 1.4, CHCl3).
0.8 mmol) and 18-crown-6 (319 mg, 1.20 mmol) in dry
THF (40 ml) at ꢀ78 °C under N2 atmosphere. A soln. of
aldehyde 11 (195 mg, 0.8 mmol) in THF (10 ml) was
added. The mixture was allowed to warm to r.t. and stirred
for 2 h. After completion of the reaction (TLC), sat.
NH4Cl soln. was added and the mixture was extracted with
IR (KBr): 2982, 2933, 1724, 1231, 1109, 1042, 770. 1H-
NMR (300 MHz, CDCl3): 1.30 (d, 3 H, J = 6.4, CH3);
1.40 (s, 3 H, CH3); 1.42 (s, 3 H, CH3); 2.26 – 2.50 (m, 4
H, allylic); 3.37 (s, 3 H, OCH3); 3.71 (s, 3 H, OCH3); 3.80
(m, 1 H, CH); 3.82 (s, 3 H, OCH3); 3.89 (s, 3 H, OCH3);
4.42 (t, 1 H, J = 7.6, CH); 4.68 (d, 3 H, J = 6.7, OCH2);
AcOEt. The org. layer was washed with sat. NaHCO3 soln., 4.74 (d, 1 H, J = 6.7, OCH2); 4.94 – 5.00 (m, 1 H, CH);
and dried (Na2SO4) and concentrated in vacuo. The resi- 5.04 – 5.12 (m, 1 H, olefin); 5.16 (dd, 1 H, J = 6.4, 12.5,
due was purified by CC affording 24 (324 mg, 75%) as col- olefin); 5.44 (dd, 1 H, J = 1.3, 11.5, olefin); 5.56 – 5.62 (m,
20
orless oil. ½aꢂD = +8.6 (c = 2.2, CHCl3). IR (KBr): 2983,
1
H, olefin); 5.70 (dd,
1 H, J = 1.5, 17.8, olefin);
2929, 1642, 1374, 1244, 1160, 1033, 918. 1H-NMR
5.78 – 5.90 (m, 2 H, olefin); 6.44 (s, 1 H, aromatic); 6.76
(300 MHz, CDCl3): 1.05 (s, 9 H, CH3); 1.06 (d, 3 H, (dd, 1 H, J = 11.6, 17.8, olefin). 13C-NMR (75 MHz,
J = 6.7, CH3); 1.38 (s, 3 H, CH3); 1.40 (s, 3 H, CH3); CDCl3): 19.14; 26.79; 26.94; 35.78; 38.39; 55.68; 55.97;
2.18 – 2.38 (m, 4 H, allylic); 3.38 (s, 3 H, OCH3); 56.38; 60.36; 71.03; 75.93; 77.99; 81.69; 96.45; 108.60;
3.78 – 3.92 (m, 3 H, CH); 4.38 (t, 1 H, J = 7.8, CH); 4.66 (d, 113.69; 115.67; 117.47; 120.38; 130.18; 130.46; 130.92;
1 H, J = 6.8, OCH2); 4.74 (d, 1 H, J = 6.8, CH3); 131.17; 134.28; 140.60; 153.02; 153.89; 167.13. ESI-MS: 521
5.04 – 5.10 (m, 2 H, olefin); 5.40 (dd, 1 H, J = 7.8, 15.4, ole- [M + H]+. HR-ESI-MS: calcd. for C28H41O9 [M + H]
fin); 5.78 – 5.86 (m, 2 H, olefin); 7.34 – 7.44 (m, 6 H, aro-
matic); 7.65 – 7.70 (m, 4 H, aromatic). 13C-NMR (75 MHz,
CDCl3): 19.1; 22.9; 26.9; 27.0; 27.1; 35.9; 42.4; 55.8; 69.0;
521.2745; found 521.2725.
(2S)-Pent-4-en-2-yl 2-Ethenyl-3,4,6-trimethoxybenzoate (27).
The aromatic ester 25 (30 mg, 0.058 mmol) was dissolved
76.0; 78.2; 81.9; 96.6; 108.6; 117.5; 127.5; 127.6; 129.5; 129.6; in dry CH2Cl2 (300 ml), and degasified under Ar atmo-
130.4; 132.1; 134.5; 135.8. ESI-MS: 561 [M + Na]+.
sphere. The second-generation Grubbs’ catalyst (2.4 mg,
€
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Helv. Chim. Acta 2016, 99, 425 – 435
433
5 mol-%) in dry CH2Cl2 was added to the mixture and
stirred at r.t. for 6 h. After completion of the reaction,
the mixture was filtered through Celite and the solvent 399.2145.
J = 7.5, aromatic). ESI-MS: 399 [M + Na]+. HR-ESI-MS:
calcd. for C22H32NaO5 [M + Na] 399.2147; found
was removed under in vacuo to give crude residue. The
residue was purified by CC affording 27 (10 mg, 62%) as
(2S,4E)-5-[(4R,5R)-5-{(1R)-1-[(4-Methoxybenzyl)oxy]but-
3-en-1-yl}-2,2-dimethyl-1,3-dioxolan-4-yl]pent-4-en-2-yl 2-
20
colorless liquid. ½aꢂD = +2.1 (c = 0.6, CHCl3). IR (KBr): Ethenyl-6-hydroxy-4-methoxybenzoate (34). Triphenylphos-
2925, 2853, 1723, 1588, 1463, 1333, 1264, 1204, 1025, 770.
1H-NMR (300 MHz, CDCl3): 1.30 (d, 1 H, J = 6.0, aro-
phine (266 mg, 1.2 mmol) and DIAD (0.2 ml, 1.2 mmol)
were added sequentially to a stirred soln. of acid 29
matic); 2.28 – 2.54 (m, 2 H, allylic); 3.72 (s, 3 H, OCH3); (100 mg, 0.510 mmol) and alcohol 10a (96 mg,
3.80 (s, 3 H, OCH3); 3.89 (s, 3 H, OCH3); 3.90 – 4.00 (m, 0.510 mmol) in dry toluene (14 ml) at 0 °C under N2 atmo-
1 H, CH); 5.06 – 5.22 (m, 2 H, olefin); 5.44 (dd, 1 H, sphere. After completion of the reaction (TLC, 2 h), the
J = 1.5, 11.3, olefin); 5.72 (dd, 1 H, J = 1.5, 17.3, olefin);
solvent was removed under in vacuo. The residue was puri-
5.78 – 5.90 (m, 1 H, olefin); 6.46 (s, 1 H, aromatic); 6.76 fied by CC affording 34 as colorless syrup (228 mg, 80%).
20
(dd, 1 H, J = 11.3, 17.3, aromatic). 13C-NMR (75 MHz,
CDCl3): 19.26; 40.07; 56.08; 56.44; 60.42; 71.21; 96.65;
116.00; 117.59; 120.44; 130.24; 130.52; 133.80; 140.75;
½aꢂD = +8.9 (c = 1.2, CHCl3). IR (KBr): 3420, 2982, 2933,
1
1716, 1651, 1342, 1212, 786. H-NMR (300 MHz, CDCl3):
1.24 (d, 3 H, J = 6.6, CH3); 1.38 (s, 3 H, CH3); 1.40 (s, 3 H,
153.07; 153.93; 167.28. ESI-MS: 329 [M + Na]+. HR-ESI- CH3); 2.22 – 2.34 (m, 4 H, allylic); 3.46 – 3.62 (m, 1 H,
MS: calcd. for C17H22O5Na [M + Na] 329.1365; found CH); 3.79 (s, 3 H, OCH3); 3.81 (s, 3 H, OCH3); 4.40 (t, 1
329.1351.
2-Ethenyl-6-hydroxy-4-methoxybenzoic Acid (29) [27]. olefin); 5.40 (d, 1 H, J = 15.4, olefin); 5.58 – 5.64 (dd, 1 H,
LiOH ꢁ H2O (126 mg, 3 mmol) was added to the stirred J = 7.6, 15.4, olefin); 5.70 – 5.82 (m, 2 H, olefin); 6.40 (d, 1
soln. of 33 (300 mg, 1.28 mmol) in THF: H2O (2:1) at r.t. H, J = 2.6, aromatic); 6.42 (d, 2 H, J = 2.6, aromatic); 6.82
H, J = 7.5, CH); 4.48 (m, 2 H, OCH2); 5.00 – 5.22 (m, 3 H,
The mixture was heated to 60 °C and stirred for 20 h.
After completion of the reaction, dil. HCl was added and
the mixture extracted with AcOEt. The org. layer was
dried (Na2SO4) and concentrated in vacuo. The residue
was purified by CC affording 29 as colorless solid
(d, 2 H, J = 7.8, aromatic); 7.16 – 7.24 (m, 3 H, aromatic);
11.74 (s, 1 H, OH). 13C-NMR (75 MHz, CDCl3): 19.7; 26.9;
29.7; 35.6; 38.7; 55.2; 55.4; 71.9; 72.4; 78.1; 78.5; 81.9; 100.2;
103.9; 108.3; 108.7; 113.6; 115.4; 117.3; 129.4; 130.4; 132.1;
134.4; 138.6; 143.7; 159.1; 164.0; 165.0; 170.6. ESI-MS: 575
(186 mg, 75%). M.p. 130 – 132 °C. IR (KBr): 2924, 1639, [M + Na]+.
1
1462, 1259, 1161, 844. H-NMR (300 MHz, CDCl3 + (D4) (2S,4E)-5-{(4R,5R)-5-[(1R)-1-Hydroxybut-3-en-1-yl]-2,
MeOH): 3.84 (s, 3 H, OCH3); 5.7 (d, 1 H, J = 11.0, ole- 2-dimethyl-1,3-dioxolan-4-yl}pent-4-en-2-yl 2-Ethenyl-
fin); 5.48 (d, 1 H, J = 1.5, 18.0, olefin); 6.41 (d, 1 H, 6-hydroxy-4-methoxybenzoate (35). DDQ (122 mg,
J = 3.0, aromatic); 6.52 (d, 1 H, J = 3.0, aromatic); 7.35 0.554 mmol) was added to a stirred soln. of 34 (150 mg,
(dd, 1 H, J = 11.0, 18.0, olefin); 11.40 (s, 1 H, OH). 13C-
0.272 mmol) in CH2Cl2/H2O (10 ml, 9:1) at 0 °C. The mix-
NMR (75 MHz, CDCl3 + (D4)MeOH): 54.30; 99.32; ture was allowed to r.t. and stirred for 2 h. After comple-
105.52; 113.97; 137.66; 142.64; 162.31; 164.29. ESI-MS: 195 tion of the reaction (TLC), the mixture was filtered
[M + H]+.
(2R,4E)-5-[(4R,5R)-5-{(1R)-1-[(4-Methoxybenzyl)oxy]but-
through Celite, and the filtrate was washed with 5%
NaHCO3 soln., water, and brine. The org. layer was sepa-
3-en-1-yl}-2,2-dimethyl-1,3-dioxolan-4-yl]pent-4-en-2-ol (10a). rated, and dried (Na2SO4), and concentrated in vacuo. The
TBAF (1M, 0.6 ml, 0.6 mmol) was added to the stirred residue was purified by CC affording 35 (93 mg, 80%) as
20
soln. of (4S,5R)-5-((R)-1-((4-methoxybenzyl)oxy)but-3-en- colorless liquid. ½aꢂD = +21.43 (c = 0.8, CHCl3). IR (KBr):
1-yl)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (200 mg, 3482, 2927, 1648, 1609, 1257, 1213, 1161, 1055, 767. 1H-
0.3 mmol) in dry THF (5 ml) at 0 °C under N2 atmo- NMR (300 MHz, CDCl3): 1.38 (d, 3 H, J = 6.2, CH3); 1.40
sphere. The mixture was stirred for 24 h at r.t. After com-
(s, 3 H, CH3); 1.41 (s, 3 H, CH3); 2.10 – 2.16 (m, 1 H,
pletion of the reaction (TLC), solvent was removed under allylic); 2.18 (br. s, 1 H, OH); 2.42 – 2.52 (m, 2 H, allylic);
in vacuo. The residue was purified by CC affording 10a 3.64 – 3.68 (m, 1 H, CH); 3.76 – 3.82 (m, 1 H, CH); 3.82 (s,
20
(101 mg, 82% yield) as colorless liquid. ½aꢂD = +7.82 3 H, OCH3); 4.44 (t, 1 H, J = 7.8, CH); 5.06 – 5.10 (m, 2 H,
(c = 1.1, CHCl3). IR (KBr): 2982, 2933, 1718, 1432, 1345,
1232, 1042, 778. 1H-NMR (300 MHz, CDCl3): 1.16 (d, 3
olefin); 5.20 – 5.28 (m, 2 H, olefin); 5.44 (dd, 1 H, J = 1.5,
17.0, olefin); 5.58 – 5.66 (m, 1 H, olefin); 5.74 – 5.84 (m, 2
H, J = 6.0, CH3); 1.40 (s, 3 H, CH3); 1.42 (s, 3 H, CH3); H, olefin); 6.40 (d, 1 H, J = 2.6, aromatic); 6.44 (d, 1 H,
1.69 (br. s, 1 H, OH); 2.19 (t, 2 H, J = 6.8, allylic); 2.34 (t, J = 2.6 Hz, aromatic); 7.24 – 7.28 (m, 2 H, olefin). 13C-
2
H, J = 6.8, allylic); 3.65 (q,
1
H, J = 5.2, CH); NMR (75 MHz, CDCl3): 19.8; 26.8; 26.9; 37.2; 38.8; 55.4;
70.3; 71.8; 77.8; 82.5; 100.2; 103.9; 108.4; 108.8; 115.5; 118.2;
3.76 – 3.84 (m, 2 H, CH); 3.80 (s, 3 H, OCH3); 4.42 (t, 1
H, J = 7.5, CH); 4.57 (s, 2 H, OCH2); 5.04 – 5.16 (m, 2 H, 130.2; 131.3; 132.0; 134.0; 138.7; 143.7; 164.1; 165.0; 170.6.
olefin); 5.58 (dd, 1 H, J = 7.5, 15.1, olefin); 5.74 – 5.90 (m, ESI-MS: 455 [M + Na]+. HR-ESI-MS: calcd. for
2 H, olefin); 6.87 (d, 2 H, J = 9.0, aromatic); 7.25 (d, 2 H, C24H32NaO7 [M + Na] 455.2046; found 455.2036.
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Helv. Chim. Acta 2016, 99, 425 – 435
(2S,4E)-5-{(4R,5R)-5-[(1R)-1-Hydroxybut-3-en-1-yl]-2,2-dim-
ethyl-1,3-dioxolan-4-yl}pent-4-en-2-yl 2-Ethenyl-4-methoxy-6-
(methoxymethoxy)benzoate (36). Diisopropylethylamine
(3S,5E,7R,8R,9R,11E)-7,8,9,16-tetrahydroxy-14-methoxy-
3-methyl-3,4,7,8,9,10-hexahydro-1H-2-benzoxacyclotetra-
decin-1-one (28). 2N HCl (2 ml) was added dropwise to a
(0.03 ml, 0.178mmol) was added to the stirred soln. of 35 soln. of 37 (20 mg, 0.198 mmol) in THF (2 ml) at 0 °C,
(70 mg, 0.162 mmol) in dry CH2Cl2 (4 ml) at 0 °C under and the mixture was stirred for 20 h at r.t. After comple-
N2 atmosphere. After 10 min, MOMCl (14 mg in CH2Cl2, tion of the reaction, aq. NaHCO3 soln. was added and the
0.178 mmol) was added slowly to the mixture and allowed mixture extracted with AcOEt. The org. layer was sepa-
to r.t. and stirred for 24 h. After completion of the reaction rated and dried (Na2SO4). The solvent was removed
(TLC), diluted with H2O and extracted with CHCl3. The under reduced pressure, and the crude product was puri-
org. layer was separated, and dried (Na2SO4) and concen- fied by CC affording 28 (8.4 mg, 52% yield) as a colorless
20
trated in vacuo. The residue was purified by CC affording
20
solid. M.p. 82 – 84 °C. ½aꢂD = ꢀ10.67 (c = 0.6, CHCl3). IR
1
(KBr): 3432, 2926, 1610, 1253, 1202, 1160, 1053, 959. H-
36 (61 mg, 80% yield) as colorless liquid. ½aꢂD = +11.43
(c = 0.7, CHCl3). IR (KBr): 3430, 2922, 2852, 2364, 1702,
NMR (300 MHz, CDCl3): 1.39 (d, 3 H, J = 6.4 Hz, CH3);
1562, 1358, 1218, 788. 1H-NMR (300 MHz, CDCl3): 1.34 2.28 – 2.54 (m, 3 H, allylic); 2.66 – 2.74 (m, 1 H, allylic);
(d, 3 H, J = 6.4, CH3); 1.42 (s, 3 H, CH3); 1.43 (s, 3 H, 3.60 (m, 1 H, CH); 3.82 (s, 3 H, OCH3); 4.00 – 4.06 (m, 1
CH3); 2.16 – 2.30 (m, 2 H, allylic); 2.36 – 2.52 (m, 2 H, H, CH); 4.18 – 4.26 (m, 1 H, CH); 5.38 – 5.46 (m, 1 H,
allylic); 3.48 (s, 3 H, OCH3); 3.68 – 3.74 (m, 1 H, CH); CH); 5.77 (dd, 1 H, J = 7.2, 15.7, olefin); 5.88 – 6.02 (m, 2
3.82 (s, 3 H, OCH3); 3.83 – 3.88 (m, 1 H, CH); 4.44 (t, 1
H, olefin); 6.39 (d, 1 H, J = 2.4, aromatic); 6.44 (d, 1 H,
H, J = 7.7, CH); 5.06 – 5.16 (m, 1 H, olefin); 5.16 (s, 2 H, J = 2.4, aromatic); 6.88 (d, 1 H, J = 15.7, olefin). 13C-
OCH2); 5.22 (t, 1 H, J = 6.2, olefin); 5.34 (d, 1 H, J = 11.5, NMR (75 MHz, CDCl3): 18.7; 35.7; 36.6; 55.4; 71.3; 72.5;
olefin); 5.56 – 5.66 (m, 1 H, olefin); 5.70 (d, 1 H, J = 15.4, 72.8; 77.2; 99.9; 104.4; 107.6; 127.5; 128.3; 132.6; 133.4;
olefin); 5.76 – 5.96 (m, 2 H, olefin); 6.64 (d, 1 H, J = 2.0, 142.3; 163.9; 164.6; 170.8. ESI-MS: 363 [M ꢀ H]+. HR-
aromatic); 6.70 – 6.78 (d,
1
H, J = 2.4, aromatic); ESI-MS: calcd. for C19H24NaO7 [M + Na] 387.1422; found
6.70 – 6.78 (m, 1 H, olefin). 13C-NMR (75 MHz, CDCl3): 387.1423.
19.5; 26.9; 26.9; 37.2; 38.6; 55.4; 56.1; 70.3; 71.1; 77.7; 82.4;
94.6; 101.1; 103.4; 108.7; 117.0; 118.1; 130.4; 131.3; 133.6;
134.1; 137.5; 155.4; 161.1; 167.1. ESI-MS: 499 [M + Na]+.
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Received October 17, 2015
Accepted April 1, 2016
€
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