Total synthesis of the putative structure of xylarinol B

Article abstract of DOI:10.1002/asia.201301647

The total synthesis of the putative structure of xylarinol B is described and the need to revise its structure is demonstrated. The central benzoxepine skeleton was constructed by employing a cobalt-mediated bimolecular [2+2+2] Reppe-Vollhardt alkyne cycloaddition reaction. Mismatch! A chiral pool approach starting from D-glucose has been executed to synthesize the proposed structure of xylarinol B. A cobalt-mediated intermolecular [2+2+2]-alkyne cyclotrimerization reaction is a key step to construct the central seven-membered benz-2-oxepine core (see picture; TBS=tert-butyldimethylsilyl ether, PMB=p-methoxylbenzyl ether). The spectral data of synthetic xylarinol B and its C5-epimer revealed that the structure of the natural product has been wrongly proposed.

Full text of DOI:10.1002/asia.201301647

FULL PAPER
DOI: 10.1002/asia.201301647
Total Synthesis of the Putative Structure of Xylarinol B
Atul A. More and Chepuri V. Ramana*[a]
Abstract: The total synthesis of the putative structure of xylarinol B is described
Keywords: chiral pool · cobalt ·
natural products · structure elucida-
tion · total synthesis
and the need to revise its structure is demonstrated. The central benzoxepine skel-
eton was constructed by employing a cobalt-mediated bimolecular [2+2+2]
Reppe–Vollhardt alkyne cycloaddition reaction.
Introduction
in one step with complete atom economy.[5–7] More impor-
tantly, when the cyclotrimerization is intermolecular in
nature, it provides an easy access to the structural variants
of the targeted molecules without any deviation from the
original route. The synthesis of the benzoxepine unit em-
ploying the intramolecular [2+2+2] cyclotrimerization has
been well documented.[7] Nonetheless, the intermolecular
version has not yet been documented. This prompted us to
explore the possibility of constructing the complete 2-ben-
zoxepine skeleton by employing the [2+2+2] cyclotrimeriza-
tion reaction of a linear diyne.
In 2009, the group of Yun isolated two 2-benzoxepine deriv-
atives from the fruiting bodies of the Xylaria polymorpha
species and named them xylarinols A (1) and
B (2)
(Figure 1).[1] The 2-benzoxepine unit of xylarinols is a rare
structural moiety present in natural products.[2] There are
Results and Discussion
The salient features of our retrosynthetic disconnections for
2 are depicted in Scheme 1. The installation of the phenolic
hydroxy group has been identified as the final step in the
total synthesis. This has been planned through the oxidation
Figure 1. Some natural products with the 2-benzoxepin core.
several methods for the synthesis of the 2-benzoxepine
unit.[3] However, reports on the total synthesis of related
natural products are limited. Recently, Hsu and Lin report-
ed the synthesis of cladoacetals A and B, which are closely
related to 2.[4] Starting with a suitably functionalized ben-
zene derivative, a Suzuki coupling followed by an acid-cata-
lyzed intramolecular acetalization have been employed as
the key steps for the oxepine ring annulation. The synthesis
of benzo-fused compounds through metal-catalyzed
[2+2+2] cyclotrimerization of triynes is an important
method that addresses the construction of polycyclic systems
Scheme 1. Retrosynthetic strategy for the xylarinol B (2). TBS=tert-bu-
tyldimethylsilyl ether, PMB=p-methoxylbenzyl ether.
of benzyl alcohol 3 and the Dakin oxidation of the resulting
benzaldehyde derivative. Keeping the [2+2+2] cyclotrimeri-
zation reaction as a key step, the penultimate intermediate 3
could be assembled from diyne 4 and acetylene. One of the
alkyne components in diyne 4 was planned through O-alky-
lation of 5 with propargyl iodide derivative 6, while the
other alkyne could be accessed from the Ohira–Bestmann
[a] A. A. More, Dr. C. V. Ramana
Division of Organic Chemistry
CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune - 411 008 (India)
Fax : (+91)20-25902629
E-mail: vr.chepuri@ncl.res.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201301647.
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Chepuri V. Ramana et al.
Table 1. Optimization of the [2+2+2] cyclotrimerization of the diyne 4
with acetylene.[a]
Catalyst
Equiv
Solvent
T[b]
[8C]
t
Yield[c]
[%]
[h]
1
2
3
4
5
6
7
8
9
N
G
0.05
0.05
0.05
0.05
0.10
0.10
0.10
0.50
1
PhCH3
PhCH3
DCE
CH2Cl2
DCE
PhCH3
PhCH3
PhCH3
PhCH3
80
mw
80
25
80
80
mw
hv
hv
6
6
15
15
6
8
8
15
15
ꢁ10
–
–
–
ꢁ10
ꢁ10
ꢁ10
32
74
[a] Cp=cyclopentadienyl, Cp*=pentamethylcyclopentadienyl, COD=
cyclooctadienyl, DCE=1,2-dichloroethane. [b] hv=200 W, the bulb was
kept 2 cm away from the sealed tube (approx. 1158C); mw=microwave
irradiation (1508C). [c] Yields of product isolated. [d] 10 mol% PPh3 was
added.
sluggish, with less than 10% conversion (Table 1, entry 1) of
the diyne 4. Changing from conventional heating to micro-
wave heating (Table 1, entry 2) did not lead to any improve-
Scheme 2. Synthesis of key intermediate 4. p-TSA=para-toluenesulfonic
acid, Piv-Cl=pivaloyl chloride, DMAP=4-dimethylaminopyridine,
THF=tetrahydrofuran, DIAD=diisopropyl azodicarboxylate, PNBA=
para-nitrobenzoic acid, DMF=N,N-dimethylformamide, NNDMBA=
1,3-dimethylbarbituric acid, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone.
ment. Similarly, [RuClACTHNUGRTENUNG(cod)Cp*] was found to be ineffective
in either of the solvents employed, DCE or CH2Cl2 (Table 1,
entries 3 and 4, respectively). If [Co(CO)2Cp] was employed
as the catalyst[12] (10 mol%), the formation of the desired
product was observed. However, the yield was poor
(Table 1, entry 5). Neither the addition of PPh3 (10 mol%),
(Table 1, entry 6)[12] nor microwave irradiation (Table 1,
entry 7) improved the product yields.[7p] However, enhanced
conversion (32%) along with unreacted starting material
and undesired dimerized products were observed under irra-
diation if 50 mol% [Co(CO)2Cp] in toluene was employed
(Table 1, entry 8).[12f] Eventually, the use of [Co(CO)2Cp]
(1 equiv) in a sealed tube under conventional irradiation
gave the required product 15 in 74% yield (Table 1,
entry 9).[12b,13]
Next, the cyclotrimerization product 15 was subjected to
acetylation followed by deprotection of the TBS group from
the resulting diacetate 16 to prepare the penultimate benzyl
alcohol 3 (Scheme 3). Finally, the sequential one-pot step-
wise oxidation of benzyl alcohol 3, first with Dess–Martin
periodinane (DMP), followed by addition of meta-chloro-
peroxybenzoic acid (mCPBA), and then saponification of
the crude Dakin oxidation[14] product by using 10% KOH in
ethanol provided the targeted 2. In the report on the isola-
tion of 2, the 1H/13C NMR spectra of the natural product
were recorded in CD3OD only.[2] However, synthetic 2 was
neither completely soluble in CD3OD nor in CDCl3 alone
except at very high dilution. Hence, the NMR spectrum was
recorded in a mixture of CD3OD and CDCl3. The NMR
spectroscopy data obtained for synthetic 2 deviated substan-
tially from the data reported for the natural product. For ex-
alkynylation of a suitably protected lactal derived from 7,
which was identified as the key starting precursor.
The synthetic procedure began with 7 (Scheme 2), which
was prepared from d-glucose diacetonide in five steps.[8] The
ꢀ
protection of the free OH group as its pivaloate ester fol-
lowed by acetonide hydrolysis of resulting compound 8 in
the presence of allylic alcohol and catalytic p-TSA led to
the formation of an anomeric mixture of allylribofurano-
sides 9 (a/b, 4:1). The major 9a anomer was subjected to
ꢀ
the Mitsunobu reaction to invert the configuration of C(2)
OH. Subsequently, saponification of the resulting benzoate
derivative 10 gave diol 11. The two free hydroxyl groups in
compound 11 were protected as their p-anisyl ethers. Palla-
dium-catalyzed one-pot olefin isomerization and allyl trans-
fer to a nucleophilic allyl scavenger[9] of the resulting diani-
syl ether derivative 12 followed by Ohira–Bestmann alkyny-
lation[10] of the intermediate lactal gave the corresponding
key alkynol 5 in good yields. With alkynol 5 in hand, our
next concern was the synthesis of diyne 4 and its cyclotrime-
rization with acetylene. To this end, treatment of alkynol 5
with propargyl iodide (6)[11] provided diyne 14 in 84% yield.
Key cyclotrimerization substrate 4 was prepared by selective
removal of the p-anisyl ether group by using DDQ in a sus-
pension of pH 7 buffer/dichloromethane.
The cyclotrimerization of diyne 4 with acetylene needed
substantial optimization (Table 1). The reaction with the
[RhClACHTUNGTRENNUNG(PPh3)3] catalyst (5 mol%) in toluene at 808C was
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All anhydrous solvents were distilled prior to use: CH2Cl2 and DMF
from CaH2; MeOH on Mg cake; THF on Na/benzophenone, and (Et)3N
over KOH. Petroleum ether refers to distilled light petroleum of fraction
30–408C. Bulk solutions were evaporated under reduced pressure by
using a rotary evaporator. Brine refers to a saturated aqueous solution of
NaCl. Na2SO4 was used for drying. Column chromatography was per-
formed on 60–120, 100–200, 230–400 mesh size silica gel. Reactions were
monitored by TLC, visualized under dual short/long wavelength UV light
1
(lmax =254 and 365 nm.) and stained with p-anisaldehyde stains. H NMR
spectroscopy measurements were carried out on 200, 400, and 500 MHz
NMR spectrometers, and CDCl3 (d 7.26) was used as an internal stan-
dard. 13C NMR spectra were recorded on 200 (50 MHz), 400 (100 MHz),
and 500 (125 MHz) NMR spectrometers. Chemical shifts (d) are given in
ppm downfield from tetramethylsilane (TMS), and coupling constants (J)
are given in Hz. Multiplicity is abbreviated as follows: s=singlet, brs=
broad singlet, d=doublet, dd=doublet of doublets, ddd=doublet of
a doublet of doublets, t=triplet, dt=doublet of triplet, ddt=doublet of
a doublet of triplets, q=quartet, dq=doublet of quartet, quin=quintet,
qd=quartet of doublets, m=multiplet. The multiplicity of the 13C NMR
signals was assigned with the help of DEPT spectra and the abbreviations
used were as follows: s=singlet, d=doublet, t=triplet, q=quartet, for C
(quaternary), CH, CH2, and CH3 respectively. Specific optical rotations
(½aꢂ2D5) were measured by using sodium light (D line l=589 nm) in CHCl3
or CH3OH. Mass spectra were recorded on a Hybrid Quadrupole-TOF
LC/MS/MS spectrometer. HRMS was recorded on ESI-TOF mass spec-
trometers.
Scheme 3. Completion of total synthesis of xylarinol B (2). TBAF=tetra-
n-butylammonium fluoride.
ample, in the 13C NMR spectrum, the triplet corresponding
to C(1) of the oxepine unit was found to resonate at d=
64.6 ppm, whereas the same carbon in the natural product
resonated at d=71.6 ppm. Additionally, the C(5) hydrogen
in synthetic 2 was seen to resonate at d=3.5 ppm downfield
to that reported for the natural product. Additionally,
a large difference in the specific rotation value between the
natural and synthetic compound, with no reported melting
point for the natural compounds, clearly indicates that the
structure of 2 was wrongly assigned.
Next, the C(5)-diastereomer of 2 was synthesized starting
with compound 9b to evaluate the probable structure of
2.[15] The spectral data obtained for C(5) epimer was differ-
ent from synthetic 2 and also deviated substantially from
naturally occurring 2. At this stage, Professor B.-S Yun was
contacted and he informed us that the structure of 2 was
wrongly assigned and that its spectral data matched with
previously isolated sordariol, with a dihydroisobenzofuran
structure.[16] Interestingly, there are several reports on the
isolation of sordariols from different sources; however, the
relative structure of these compounds has been not pro-
posed.
3,6-Dideoxy-1,2-O-isopropylidene-5-O-pivaloyl-a-d-ribo-hexofuranose (8)
At 08C,
a solution of alcohol 7 (18 g, 95.6 mmol), Et3N (26.7 mL,
191.3 mmol), and DMAP (0.23 g, 1.9 mmol) in anhydrous CH2Cl2
(100 mL) was treated with Piv-Cl (14.1 mL, 114.8 mmol) and stirred at
the same temperature for 1 h and at RT for an additional 4 h. The reac-
tion mixture was quenched at 08C with a saturated solution of NaHCO3
(50 mL) and filtered through Celite. The organic layer was separated and
the aqueous layer was extracted with EtOAc (4ꢁ75 mL). The combined
organic layer was washed with brine (2ꢁ100 mL), dried over Na2SO4,
and concentrated in vacuo. Purification of the residue by column chroma-
tography on silica gel (5!15% EtOAc in petroleum ether) gave ester 8
(23.6 g, 91%) as a yellow syrup. Rf =0.7 (EtOAc/petroleum ether, 1:4);
½aꢂ2D5 = +1.15 (c=0.6, CHCl3); FTIR (KBr, CHCl3): n˜max =2980, 2932,
1731, 1480, 1373, 1282, 1216, 1161, 1060, 1025 cmꢀ1 1H NMR (200 MHz,
;
CDCl3): d=1.16 (s, 9H), 1.21 (d, J=6.4 Hz, 3H), 1.3 (s, 3H), 1.50 (s,
3H), 1.72 (ddd, J=15.0, 8.7, 4.7 Hz, 1H), 2.09 (dd, J=13.4, 4.5 Hz, 1H),
4.15 (quin, J=5.2 Hz, 1H), 4.71 (t, J=4.1 Hz, 1H), 4.97 (t, J=6.3 Hz,
1H), 5.77 ppm (d, J=3.4 Hz, 1H); 13C NMR (50 MHz, CDCl3): d=16.8
(q), 26.1 (q), 26.7 (q), 27.0 (q, 3C), 34.5 (t), 38.7 (s), 70.2 (d), 79.9 (d),
80.2 (d), 105.5 (d), 111.2 (s), 171.5 ppm (s); ESI-MS: m/z (%): 295.14
(100) [M+Na]+; HRMS: m/z calcd for C14H24NaO5: 295.152; found:
295.1519.
Allyl 3,6-Dideoxy-5-O-pivaloyl-a/b-d-ribohexofuranose (9)
Conclusion
p-TSA (1.9 g, 11.0 mmol) and allyl alcohol (7.5 mL, 110 mmol) were
added to a solution of 8 (15.0 g, 55.1 mmol) in anhydrous THF (100 mL).
The reaction mixture was heated at reflux for 4 h. After completion of
the reaction, as indicated by TLC, the reaction mixture was neutralized
with an aqueous solution of NaHCO3 (20 mL). The solvent was removed
under reduced pressure, diluted with EtOAc (200 mL), and washed with
water (2ꢁ50 mL). The organic layer was dried over Na2SO4 and evapo-
rated under reduced pressure. The crude product was purified by chro-
matography on silica gel. First eluting with 10!20% EtOAc in petrole-
um ether gave minor hexofuranoside 9b (2.46 g, 17%) as a thick yellow
oil. Rf =0.3 (EtOAc/petroleum ether, 1:4); ½aꢂ2D5 =ꢀ75.0 (c=0.77, CHCl3);
FTIR (KBr, CHCl3): n˜max =3524, 2977, 2935, 2873, 1730, 1646, 1480, 1457,
A cobalt-mediated bimolecular [2+2+2]-alkyne cyclotrime-
rization reaction has been successfully employed for the
construction of the central benz-2-oxepine core of the pro-
posed structure of 2. This is the first example for construct-
ing a seven-membered ring by employing intermolecular
alkyne cyclotrimerization.
Experimental Section
1397, 1282, 1237, 1160, 1080, 1035, 927, 869, 770 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d=1.16 (s, 9H), 1.25 (d, J=6.3 Hz, 3H), 1.97 (m,
2H), 2.12 (brs, 1H), 3.92 (ddt, J=18.9, 12.9, 6.2 Hz, 1H), 4.16 (ddt, J=
17.9, 12.9, 5.1 Hz, 1H), 4.26 (m, 2H), 4.80 (quin, J=6.3 Hz, 1H), 4.93 (s,
1H), 5.20 (dt, J=10.5, 1.5 Hz, 1H), 5.28 (dt, J=17.1, 1.3 Hz, 1H),
5.84 ppm (ddt, J=17.1, 10.6, 5.4 Hz, 1H); 13C NMR (50 MHz, CDCl3):
General Methods
Reactions were carried out under a nitrogen/argon atmosphere in oven-
dried glassware at RT unless otherwise stated. Standard inert atmosphere
techniques were used in handling all air- and moisture-sensitive reagents.
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Chepuri V. Ramana et al.
d=16.8 (q), 27.0 (q, 3C), 34.8 (t), 38.7 (s), 67.9 (t), 72.5 (d), 75.8 (d), 81.4
(d), 107.4 (d), 117.3 (t), 133.9 (s), 177.8 ppm (s); ESI-MS: m/z (%):
295.12 (30) [M+Na]+; HRMS: m/z calcd for C14H24NaO5: 295.1521;
found: 295.1516.
Allyl 3,6-Dideoxy-2,5-di-O-(p-methoxybenzyl)-a-d-arabinohexofuranoside
(12)
NaH (1.44 g, 60.1 mmol, 60% dispersion in mineral oil) was added por-
tionwise to a solution of 11 (2.83 g, 15.0 mmol) in anhydrous DMF/THF
(1:1, 30 mL) cooled on an ice bath and stirred for 5 min. Then p-anisyl
chloride (1.2 mL, 60.1 mmol) was added dropwise and stirring was con-
tinued at RT for 3 h. After completion of the reaction, the reaction mix-
ture was cooled and quenched with an aqueous solution of NH4Cl. The
solvent was removed under reduced pressure, the crude product was di-
luted with EtOAc, and washed with water (3ꢁ50 mL). The aqueous layer
was extracted with EtOAc (2ꢁ100 mL) and the combined organic layer
was washed with brine (2ꢁ50 mL) and concentrated in vacuo. Purifica-
tion of the residue by column chromatography on silica gel (5!10%
EtOAc in pet. ether) gave 12 (6.1 g, 95%) as a yellow oil. Rf =0.3
(EtOAc/petroleum ether, 1:9); ½aꢂ2D5 = +18.4 (c=0.23, CHCl3); FTIR
(KBr, CHCl3): n˜max =2912, 1611, 1513, 1464, 1369, 1297, 1247, 1174, 1096,
Further eluting with 20!30% EtOAc in petroleum ether gave the major
hexofuranoside 9a (12.1 g, 80%) as
a yellow viscous oil. Rf =0.2
(EtOAc/petroleum ether, 1:4); ½aꢂ2D5 = +61.1 (c=0.66, CHCl3); FTIR
(KBr, CHCl3): n˜max =3460, 2979, 2935, 2875, 1730, 1481, 1457, 1397, 1283,
1162, 1086, 1034, 936, 865, 803, 770 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d=1.15 (d, J=6.7 Hz, 3H), 1.17 (s, 9H), 1.87 (ddd, J=15.7, 7.2, 5.4 Hz,
1H), 1.14 (ddd, J=12.9, 5.2, 4.9 Hz, 1H), 2.47 (d, J=9 Hz, 1H), 4.06
(ddt, J=12.9, 6.1, 1.3 Hz, 1H), 4.17 (dd, J=4.5 Hz, 1H), 4.3 (m, 2H),
4.92 (ddd, J=12.9, 6.5, 4.2 Hz, 1H), 4.97 (d, J=4.3 Hz, 1H), 5.18 (dq, J=
10.4, 1.5 Hz, 1H), 5.27 (dq, J=17.2, 1.5 Hz, 1H), 5.92 ppm (ddt, J=17.1,
10.6, 5.4 Hz, 1H); 13C NMR (50 MHz, CDCl3): d=16.2 (q), 27.1 (q, 3C),
32.9 (t), 38.7 (s), 68.6 (t), 70.9 (d), 71.8 (d), 78.8 (d), 100.8 (d), 117.3 (t),
134.0 (s), 177.7 ppm (s); ESI-MS: m/z (%): 295.14 (100) [M+Na]+;
HRMS: m/z calcd for C14H24NaO5: 295.1521; found: 295.1520. The diaste-
reomeric ratio was evaluated by the yields of the pure diastereomers (a/
b, 4:1).
1034, 821, 792 cmꢀ1 1H NMR (200 MHz, CDCl3): d=1.21 (d, J=6.2 Hz,
;
3H), 1.92 (ddd, J=9.7, 6.6, 3.2 Hz, 1H), 2.28 (quin, J=7.5 Hz, 1H), 3.59
(quin, J=6.2 Hz, 1H), 3.77 (s, 3H), 3.79 (s, 3H), 3.92 (ddt, J=17.4, 12.9,
5.9 Hz, 1H), 3.98–4.06 (m, 2H), 4.16 (ddt, J=18.1, 12.9, 5.2 Hz, 1H), 4.40
(s, 2H), 4.52 (dd, J=15.8, 11.4 Hz, 2H), 5.09 (s, 1H), 5.15 (dq, J=10.2,
1.6 Hz, 1H), 5.26 (dq, J=11.3, 1.8 Hz, 1H), 5.9 (ddt, J=17.1, 10.6,
5.4 Hz, 1H), 6.81 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 7.20 (d, J=
8.7 Hz, 2H), 7.24 ppm (d, J=8.8 Hz 2H); 13C NMR (50 MHz, CDCl3):
d=16.7 (q), 32.4 (t), 55.2 (q, 2C), 67.8 (t), 70.8 (t), 70.9 (t), 76.2 (d), 81.5
(d), 82.9 (d), 105.9 (d), 113.7 (d, 2C), 113.7 (t, 2C), 117.0 (t), 129.2 (d,
2C), 129.3 (d, 2C), 130.1 (d), 130.9 (s), 134.4 (s), 159.0 (s), 159.1 ppm (s);
ESI-MS: m/z (%): 451.19 (100) [M+Na]+; HRMS: m/z calcd for
C25H32NaO6: 451.2096; found: 451.2092.
Allyl 3,6-Dideoxy-2-O-(p-nitrobenzoyl)-5-O-pivaloyl-a-d-
arabinohexofuranoside (10)
A solution of alcohol 9a (2.5 g, 9.2 mmol), p-nitrobenzoic acid (8.41 g,
45.9 mmol), and PPh3 (8.43 g, 32.1 mmol) in THF (50 mL) was treated
with diisopropylazodicarboxylate (6.33 mL, 32.1 mmol) and the contents
were stirred at 08C for 1 h and then at RT for 5 h. After completion, the
reaction mixture was concentrated and the resulting crude product was
dissolved in EtOAc (200 mL), washed with an aqueous solution of
NaHCO3 (30 mL) and water (50 mL), dried (Na2SO4), and concentrated
in vacuo. Purification of the residue by column chromatography on silica
gel (8!10% EtOAc in petroleum ether) gave ester 10 (2.78 g, 72%) as
a yellow oil. Rf =0.6 (EtOAc/petroleum ether, 1:2); ½aꢂ2D5 = +21.7 (c=
0.16, CHCl3); FTIR (KBr, CHCl3): n˜max =2972, 2318, 1728, 1607, 1530,
(2R,3S,5S)-2,5-Bis(4-methoxybenzyl)hept-6-yn-2,3,5-triol (5)
A solution of 12 (0.2 g, 0.47 mmol) in EtOH was added to a suspension
of NNDMBA (90 mg, 0.56 mmol), [PdACTHUNTRGNEUNG(PPh3)4] (6 mg, 5 mol%), and PPh3
(25 mg, 0.93 mmol) in absolute EtOH (15 mL) and stirred for 6 h at RT.
After completion of the reaction, as indicated by TLC, the content was
filtered through Celite and the filtrate was concentrated. The residue was
passed through a short column of silica gel (10!30% EtOAc in pet.
ether) to give the crude lactal (180 mg) as a yellow liquid, which was
used in the next reaction without further purification.
1271, 1104, 1042, 869, 770 cmꢀ1 1H NMR (200 MHz, CDCl3): d=1.16 (s,
;
9H), 1.27 (d, J=6.3 Hz, 3H), 1.88 (ddd, J=7.8, 5.8, 2.0 Hz, 1H), 2.57
(ddd, J=14.6, 7.9, 6.9 Hz, 1H), 4.02 (ddt, J=18.9, 12.9, 5.9 Hz, 1H), 4.18
(m, 2H), 5.02 (quin, J=6.3 Hz, 1H), 5.2 (dq, J=2.8, 1.5, 1.2 Hz, 1H),
5.22 (s, 1H), 5.3 (dq, J=3.2, 1.6 Hz, 1H), 5.35 (m, 1H), 5.89 (ddt, J=
17.1, 10.6, 5.4 Hz, 1H), 8.2 (dt, J=9.1, 3.9 Hz, 2H), 8.30 ppm (dt, J=9.1,
3.9 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=16.7 (q), 27.0 (q, 3C), 32.2
(t), 38.7 (s), 67.9 (q), 70.8 (d), 79.1 (d) 79.9 (d), 105.1 (d), 117.5 (d), 123.6
(d, 2C), 130.8 (d, 2C), 133.8 (s), 134.9 (s), 150.7 (s), 164.0 (s), 177.6 ppm
(s); ESI-MS: m/z (%): 444.16 (50) [M+Na]+; HRMS: m/z calcd for
C21H27NNaO8: 444.1634; found: 444.1632.
A solution of 13 (180 mg, 0.93 mmol) in THF (1 mL) was added in three
portions to a suspension of the above crude lactal (180 mg) and oven-
dried K2CO3 (0.32 g, 2.3 mmol) in THF and MeOH (1:1, 10 mL) over
45 min at RT. After 15 h, the solvent was removed under reduced pres-
sure, diluted with CH2Cl2 (25 mL), and filtered through Celite. The or-
ganic layer was washed with water (3ꢁ5 mL), dried over Na2SO4, and
concentrated in vacuo. Purification of the residue by column chromatog-
raphy on silica gel (20!30% EtOAc in petroleum ether) gave alkynol 5
(145 mg, 81%, over 2 steps) as a yellow oil. Rf =0.7 (EtOAc/petroleum
Allyl 3,6-Dideoxy-a-d-arabinohexofuranoside (11)
At 08C, a solution of 10 (2.0 g, 4.7 mmol) in dry THF (10 mL) was treat-
ed with LiAlH4 (0.45 g, 11.9 mmol) and the contents were stirred for 4 h
at RT. The reaction mixture was quenched with a saturated solution of
Na2SO4 and concentrated under reduced pressure. The crude product
was dissolved in EtOAc (100 mL) and filtered through Celite. The organ-
ic layer was washed with water (30 mL), dried over Na2SO4, and concen-
trated in vacuo. Purification of the residue by column chromatography
on silica gel (40!50% EtOAc in petroleum ether) afforded diol 11
(0.86 g, 96%) as a yellow syrup. Rf =0.2 (EtOAc/petroleum ether, 1:1);
½aꢂ2D5 = +91.7 (c=0.38, CHCl3); FTIR (KBr, CHCl3): n˜max =3369, 2972,
ether, 3:7); ½aꢂ2D5 =ꢀ75.7 (c=0.82, CHCl3); FTIR (KBr, CHCl3): n˜max
=
3280, 2923, 2840, 1611, 1513, 1456, 1382, 1294, 1247, 1173, 1073, 1033,
820, 773 cmꢀ1 1H NMR (200 MHz, CDCl3): d=1.15 (d, J=6.3 Hz, 3H),
;
1.89 (m, 2H), 2.48 (d, J=2.0 Hz, 1H), 2.52 (d, J=4.0 Hz, 1H), 3.45 (qd,
J=5.9, 1.8 Hz, 1H), 3.79 (s, 6H), 3.98 (td, J=7.6, 3.7 Hz, 1H), 4.33 (m,
1H), 4.37 (d, J=11.5 Hz, 1H), 4.42 (d, J=11.4 Hz, 1H), 4.63 (d, J=
11.4 Hz, 1H), 4.74 (d, J=11.1 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H), 6.85 (d,
J=8.7 Hz, 2H), 7.22 (d, J=7.4 Hz, 2H), 7.24 ppm (d, J=8.5 Hz, 2H);
13C NMR (50 MHz, CDCl3): d=14.4 (q), 37.9 (t), 55.2 (q, 2C), 65.7 (d),
70.2 (d), 70.4 (t), 70.5 (t), 74.1 (d), 77.0 (d), 82.6 (s), 113.8 (d, 4C), 129.2
(d, 2C), 129.5 (s), 129.7 (d, 2C), 130.6 (s), 159.1 (s), 159.3 ppm (s); ESI-
MS: m/z (%): 407.11 (100) [M+Na]+; HRMS: m/z calcd for C23H28NaO5:
407.1834; found: 407.1834.
2925, 1599, 1457, 1096, 1044, 1018, 933 cmꢀ1
;
1H NMR (200 MHz,
CDCl3): d=1.14 (d, J=6.7 Hz, 3H), 1.8 (dd, J=13.9, 2.9 Hz, 1H), 2.29
(dq, J=14.0, 5.6 Hz, 1H), 2.57 (brs, 1H), 3.69 (brs, 1H), 3.96 (ddt, J=
18.9, 13.0, 6.1 Hz, 1H), 4.0–4.2 (m, 4H), 4.97 (s, 1H), 5.17 (dq, J=10.2,
1.8 Hz, 1H), 5.26 (dq, J=17.2, 1.6 Hz, 1H), 5.86 ppm (ddt, J=16.2, 11.2,
5.0 Hz, 1H); 13C NMR (50 MHz, CDCl3): d=19.3 (q), 30.6 (t), 67.4 (d),
67.8 (t), 73.8 (d), 81.8 (d), 107.4 (d), 117.1 (t), 134.3 ppm (d); ESI-MS: m/
AHCTUNGERTG(NNUN 3S,5S)-3-Ethynyl-5-{(R)-1-[(4-methoxybenzyl)oxy]ethyl}-1-(4-
methoxyphenyl)-12,12,13,13-tetramethyl-2,6,11-trioxa-12-silatetradec-8-yne
(14)
z
(%): 211.08 (10) [M+Na]+; HRMS: m/z calcd for C9H16NaO4:
211.0946; found: 211.0943.
NaH (60% dispersion in mineral oil, 63 mg, 1.6 mmol) was added por-
tionwise to a solution of alkynol 5 (0.3 g, 0.78 mmol) in anhydrous THF/
DMF (1:1, 6 mL) cooled on an ice bath. After 15 min, compound 6
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Chepuri V. Ramana et al.
(364 mg, 1.2 mmol) was introduced and the contents were stirred for 6 h
at RT. After completion of the reaction, the reaction mixture was
quenched with an aqueous solution of NH4Cl, concentrated under re-
duced pressure, and diluted with EtOAc (50 mL). The organic layer was
washed with water (2ꢁ30 mL) and brine (25 mL), dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column chromatogra-
phy on silica gel (10!20% EtOAc in petroleum ether) to give diyne 14
(370 mg, 84%) as a yellow oil. Rf =0.5 (EtOAc/petroleum ether, 1:6);
½aꢂ2D5 =ꢀ54.9 (c=0.32, CHCl3); FTIR (KBr, CHCl3): n˜max =2929, 2851,
143.5 ppm (s); ESI-MS: m/z (%): 375.10 (100) [M+Na]+; HRMS: m/z
calcd for C19H32NaO4Si: 375.1967; found: 379.1965.
(R)-1-(3S,5S)-5-Acetoxy-9-{[(tert-butyldimethylsilyl)oxy]methyl)-1,3,4,5-
tetrahydrobenzo[c]oxepin-3-yl}ethyl acetate (16)
Ac2O (0.1 mL) was added to a solution of diol 15 (45 mg, 0.13 mmol),
Et3N (0.2 mL, 1.3 mmol), and DMAP (2 mg) in CH2Cl2 (5 mL) at RT.
After 2 h, water was added to the reaction mixture, which was extracted
with CH2Cl2 (2ꢁ10 mL). The combined organic layer was washed with
brine (3ꢁ10 mL), dried (Na2SO4), and concentrated in vacuo. Purifica-
tion of the residue by column chromatography on silica gel (10!30%
EtOAc in petroleum ether) gave 16 (54 mg, 97%) as a colorless thick oil.
Rf =0.5 (EtOAc/petroleum ether, 1:4); ½aꢂ2D5 =ꢀ24.9 (c=0.52, CHCl3);
FTIR (KBr, CHCl3): n˜max =3439, 2923, 2840, 1739, 1613, 1492, 1456, 1360,
2648, 2049, 1611, 1513, 1457, 1363, 1248, 1176, 1077, 1034, 836, 775 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d=0.08 (s, 6H), 0.88 (s, 9H), 1.12 (d, J=
6.4 Hz, 3H), 1.9 (m, 2H), 2.43 (d, J=1.9 Hz, 1H), 3.60 (qd, J=3.7,
2.8 Hz, 1H), 3.71 (m, 1H), 3.79 (s, 6H), 4.09 (dt, J=15.7, 3.8 Hz, 1H),
4.23–4.35 (m, 4H), 4.43 (d, J=11.1 Hz, 1H), 4.48 (s, 2H), 4.73 (d, J=
11.0 Hz, 1H), 6.83 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 7.23 (d,
J=7.4 Hz, 2H), 7.26 ppm (d, J=8.6 Hz, 2H); 13C NMR (50 MHz,
CDCl3): d=ꢀ5.2 (q, 2C), 15.1 (q), 18.3 (s), 25.8 (q, 3C), 37.7 (t), 51.7 (t),
55.3 (d, 2C), 58.3 (t), 64.9 (d), 70.4 (t), 70.7 (t), 73.5 (d), 76.2 (d), 77.4
(d), 81.4 (s), 83.2 (s, 2C), 113.7 (d, 2C), 113.8 (d, 2C), 129.1 (d, 2C),
129.7 (s), 129.9 (d, 2C), 130.5 (s), 159.3 ppm (s, 2C); ESI-MS: m/z (%):
589.28 (100) [M+Na]+; HRMS: m/z calcd for C33H46NaO6Si: 589.2961;
found: 589.2960.
1237, 1116, 1031, 861, 757, 724, 691, 661 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=0.02 (s, 3H), 0.07 (s, 3H), 0.89 (s, 9H), 1.20 (d, J=6.4 Hz,
3H), 1.85 (dt, J=13.1, 11 Hz, 1H), 2.01–2.08 (m, 1H), 2.05 (s, 3H), 2.22
(s, 3H), 3.95 (ddd, J=6.4, 4.6, 1.8 Hz, 1H), 4.41 (d, J=14.4 Hz, 1H), 4.71
(d, J=12.8 Hz, 1H), 4.84 (d, J=12.2 Hz, 1H), 4.85 (ddd, J=12.9, 6.5,
4.5 Hz, 1H), 5.20 (d, J=14.4 Hz, 1H), 6.21 (dd, J=10.4, 1.5 Hz, 1H),
7.24–7.30 ppm (m, 3H); 13C NMR (125 MHz, CDCl3): d=ꢀ5.3 (q), ꢀ5.2
(q), 15.6 (q), 18.2 (s), 21.2 (q), 21.3 (q), 25.9 (q, 3C), 37.2 (t), 63.4 (t),
66.4 (t), 72.4 (d), 72.5 (d), 82.5 (d), 123.0 (d), 127.0 (d), 127.8 (d), 134.1
(s), 138.9 (s) 141(s), 169.8 (s), 170.4 ppm (s); HRMS: m/z calcd for
C23H36NaO6Si: 459.2178; found: 459.2181.
(2R,3S,5S)-3-({4-[(tert-Butyldimethylsilyl)oxy]but-2-yn-1-yl}oxy)hept-6-
yne-2,5-diol (4)
At 08C, DDQ (0.7 g, 3.1 mmol) was added to a vigorously stirred solu-
tion of diyne 14 (0.35 g, 0.62 mmol) in CH2Cl2/phosphate buffer solution
(20:1, 5 mL, pH 7.2) and the contents were allowed to come to RT and
stirred for 12 h. The reaction mixture was quenched with a saturated
aqueous solution of NaHCO3 (10 mL), diluted with CH2Cl2, and filtered
through Celite. The organic layer was washed with water (60 mL) and
the aqueous layer was extracted with CH2Cl2 (3ꢁ30 mL). The combined
organic layer was washed with brine (50 mL), dried (Na2SO4), and con-
centrated in vacuo. Purification of the resulting crude by column chroma-
tography (30!60% EtOAc in petroleum ether) gave diol 4 (185 mg,
92%) as a thick colorless oil. Rf =0.3 (EtOAc/petroleum ether, 3:2);
½aꢂ2D5 =ꢀ27.4 (c=0.24, CHCl3); FTIR (KBr, CHCl3): n˜max =3296, 2926,
(R)-1-((3S,5S)-5-Acetoxy-9-(hydroxymethyl)-1,3,4,5-
tetrahydrobenzo[c]oxepin-3-yl)ethyl acetate (3)
TBAF (44 mg, 0.17 mmol, 1m in THF) was added to a solution of 16
(48 mg, 0.11 mmol) in anhydrous THF (3 mL) cooled on an ice bath. The
reaction mixture was then stirred at RT for 30 min and concentrated. The
crude product was dissolved in EtOAc (30 mL), washed with water (2ꢁ
10 mL), dried over Na2SO4, and concentrated in vacuo. Purification of
the residue by column chromatography on silica gel (50!70% EtOAc in
petroleum ether) gave 3 (32 mg, 90%) as a yellow oil. Rf =0.3 (EtOAc/
petroleum ether, 1:1); ½aꢂD25 =ꢀ29.5 (c=0.36, CHCl3); FTIR (KBr,
CHCl3): n˜max =3434, 2917, 2846, 1739, 1607, 1454, 1374, 1240, 1116, 1039,
2855, 1717, 1603, 1457, 1257, 1127, 1084, 1023, 837, 776 cmꢀ1 1H NMR
;
751, 655 cmꢀ1 1H NMR (500 MHz, CDCl3): d=1.22 (d, J=6.4 Hz, 3H),
;
(400 MHz, CDCl3): d=0.12 (s, 6H), 0.91 (s, 9H), 1.15 (d, J=6.4 Hz, 3H),
1.81 (ddd, J=11.3, 8.8, 2.5 Hz, 1H), 1.93 (ddd, J=13.2, 10.2, 2.8 Hz, 1H),
2.03 (brs, 1H), 2.43 (d, J=2.0 Hz, 1H), 3.28 (brs, 1H), 3.81 (dt, J=10.3,
5.3 Hz, 1H), 4.06 (qd, J=3.5, 3.0 Hz, 1H), 4.30 (d, J=1.1 Hz, 2H), 4.33
(s, 2H), 4.65 ppm (d, J=8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
ꢀ5.3 (q, 2C), 17.6 (q), 18.4 (s), 25.8 (q, 3C), 35.9 (t), 51.8 (t), 57.7 (t),
58.8 (d), 67.5 (d), 72.4 (d), 79.3 (d), 81.2 (s), 84.8 (s), 85.1 ppm (s); ESI-
MS: m/z (%): 349.15 (100) [M+Na]+; HRMS: m/z calcd for
C17H30NaO4Si: 349.181; found: 349.1809.
1.85 (dt, J=13.4, 10.7 Hz, 1H), 2.03 (s, 1H), 2.05 (s, 3H), 2.23 (s, 3H),
3.98 (ddd, J=6.9, 2.3 Hz, 1H), 4.47 (d, J=14.4 Hz, 1H), 4.76 (d, J=
6.9 Hz, 2H), 4.83 (qd, J=6.6, 4.7 Hz, 1H), 5.28 (d, J=14.6 Hz, 1H), 6.22
(dd, J=10.6, 2.1 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.5 Hz,
1H), 7.32 ppm (t, J=7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=15.6
(q), 21.2 (q), 21.3 (q), 37.2 (t), 63.5 (t), 66.6 (t), 72.3 (d), 72.4 (d), 82.8
(d), 123.8 (d), 128.1 (d, 2C), 134.8 (s), 138.4 (s), 141.5 (s), 169.7 (s),
170.4 ppm (s); ESI-MS: m/z (%): 345.09 (30) [M+Na]+; HRMS: m/z
calcd for C17H22NaO6: 345.1313; found: 345.1312.
ACHTUNGTRENNUNG(3S,5S)-9-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-[(R)-1-hydroxyethyl]-
1,3,4,5-tetrahydrobenzo[c]oxepin-5-ol (15)
Synthetic Xylarinol B (2)
A sealed tube containing a solution of diol 4 (78 mg, 0.24 mmol) in tolu-
ene (2 mL) and [Cp(CO)2Co] (0.7 mL, 0.35m in toluene, 0.24 mmol) was
fitted with a septum and cooled to ꢀ788C. Acetylene gas was bubbled
through the reaction mixture for 20 min. The tube was then sealed with
a screw cap and stirred while irradiated with a 200 W bulb kept 2 cm
away from the tube. After 15 h, the reaction mixture was cooled and con-
centrated in vacuo. The crude product was purified by column chroma-
tography on silica gel (40!50% EtOAc in petroleum ether) to afford 15
(62 mg, 74%) as a thick colorless oil. Rf =0.3 (EtOAc/petroleum ether,
1:1); ½aꢂ2D5 =ꢀ29.8 (c=0.26, CHCl3); FTIR (KBr, CHCl3): n˜max =3406,
3016, 2912, 2846, 1602, 1489, 1456, 1218, 1113, 1031, 757, 724, 694,
DMP (52 mg, 0.12 mmol) was added to a solution of alcohol 3 (26 mg,
0.08 mmol) in dry CH2Cl2 (5 mL) cooled on an ice bath. After complete
consumption of 3, as indicated by TLC, mCPBA (40 mg, 70%,
0.16 mmol) was added and the solution was stirred at RT for another 6 h.
The reaction mixture was diluted with CH2Cl2 and filtered through
Celite. The resulting crude product, after evaporation of CH2Cl2, was
taken up in ethanol (5 mL), cooled to 08C, and treated with 10% KOH
in water (5 mL). After 10 h, the reaction was neutralized with 10% HCl
(36%, 5 mL) and the solvent was removed under reduced pressure. The
crude product was dissolved in EtOAc (50 mL), filtered through Celite,
dried over Na2SO4, and concentrated in vacuo. Purification of the residue
by column chromatography on silica gel (60!80% EtOAc in petroleum
ether) afforded 2 (12 mg, 67% over 3 steps) as a yellow solid. Rf =0.3
(EtOAc/petroleum ether, 4:1); m.p. 62–638C; ½aꢂ2D5 =ꢀ47.8 (c=0.43,
MeOH); FTIR (KBr, CHCl3): n˜max =3401, 2912, 1640, 1492, 1465, 1273,
663 cmꢀ1 1H NMR (500 MHz, CDCl3): d=0.04 (s, 3H), 0.07 (s, 3H), 0.9
;
(s, 9H), 1.15 (d, J=6.4 Hz, 3H), 2.08 (m, 3H), 3.81 (dt, J=9.8, 4.1 Hz,
1H), 3.87 (qd, J=3.0, 2.9 Hz, 1H), 4.56 (d, J=15 Hz, 1H), 4.66 (d, J=
12.8 Hz, 1H), 4.77 (d, J=12.8 Hz, 1H), 5.03 (dd, J=6.7, 2.7 Hz, 1H),
5.23 (d, J=14.9 Hz, 1H), 7.27 (d, J=5.8 Hz, 1H), 7.28 (t, J=5.5 Hz, 1H),
7.42 ppm (dd, J=5.5 Hz, 1H);13C NMR (125 MHz, CDCl3): d=ꢀ5.3 (q),
ꢀ5.2 (q), 17.9 (q), 18.3 (s), 25.9 (q, 3C), 37.9 (t), 63.5 (t), 68.3 (t), 69.9
(d), 72.4 (d), 83.8 (d), 125.2 (d), 127.0 (d), 127.6 (d), 134.3 (s), 138.3 (s),
1215, 1124, 1034, 856, 762, 727, 663 cmꢀ1 1H NMR (500 MHz, CDCl3 +
;
CD3OD): d=1.16 (d, J=6.4 Hz, 3H), 1.71 (dt, J=13.5, 10.4 Hz, 1H),
2.16 (dt, J=13.4, 2.2 Hz, 1H), 3.68 (m, 2H), 4.26 (d, J=13.7 Hz, 1H),
5.00 (d, J=9.5 Hz, 1H), 5.41 (d, J=14.0 Hz, 1H), 6.69 (d, J=7.9 Hz,
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Chepuri V. Ramana et al.
1H), 7.05 (d, J=7.3 Hz, 1H), 7.08 ppm (t, J=7.9 Hz, 1H); 13C NMR
(125 MHz, CDCl3/CD3OD): d=18.6 (q), 40.3 (t), 64.6 (t), 70.4 (d), 71.3
(d), 86.1 (d), 114.4 (d), 115.7 (d), 122.8 (s), 128.8 (d), 147.2 (s), 154.6 ppm
(s); ESI-MS: m/z (%): 247.01 (25) [M+Na]+; HRMS: m/z calcd for
C12H16NaO4: 247.0946; found: 247.0944.
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Acknowledgements
We would like to acknowledge the CSIR (India) for providing the finan-
cial support for this project under the 12FYP ORIGIN program. A.A.M.
thanks UGC (New Delhi) for financial assistance in the form of a Re-
search Fellowship.
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Received: December 11, 2013
Revised: January 31, 2014
Published online: March 27, 2014
Chem. Asian J. 2014, 9, 1557 – 1562
1562
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