Stereoselective synthesis of (±)-urechitol A employing [4+3] cycloaddition

Article abstract of DOI:10.1016/j.tet.2016.09.026

Urechitol A was synthesized as a racemate employing a [4+3] cycloaddition reaction and a methanol assisted intramolecular epoxide opening as key steps for efficient construction of the core tricyclic framework. The overall yield was 2.4% over 12 steps.

Full text of DOI:10.1016/j.tet.2016.09.026

Tetrahedron 72 (2016) 6982e6987
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of (ꢀ)-urechitol A employing [4þ3]
cycloaddition
,
,
*
Tatsunobu Sumiya a b, Ken Ishigami b, Hidenori Watanabe b
a Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi, 329-0114, Japan
b Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo,
113-8657, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2016
Received in revised form 12 September 2016
Accepted 13 September 2016
Available online 14 September 2016
Urechitol A was synthesized as a racemate employing a [4þ3] cycloaddition reaction and a methanol
assisted intramolecular epoxide opening as key steps for efficient construction of the core tricyclic
framework. The overall yield was 2.4% over 12 steps.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Urechitol A
Cycloaddition
Epoxides
Natural products
Total synthesis
1. Introduction
cycloaddition reaction between a furan and a silyloxyallyl cation
substituted with a
p
-donating alkoxy group.2,4,5 Considering that
Urechitol A (1) was isolated from the root extract of Pentalinon
andrieuxii, which has been used commonly as a traditional medicine
there are two tetrahydrofuran rings in A, two types of [4þ3] cy-
cloaddition, CþD (route a) and FþG (route b), are possible. In both
cases, cycloadducts B and E would be expected to possess oxygen
functional groups and double bonds in the appropriate positions for
further transformations into 1. As described below, the route
a resulted in failure, and total synthesis of urechitol A was achieved
by employing route b.
~
for cutaneous leishmaniasis in the Yucatan Peninsula, by Pena-
Rodríguez’s group in 2009.1 This compound has a novel and unique
structure including a highly functionalized cycloheptane ring with
two oxygen bridges, and its relative configuration has been de-
termined by X-ray crystal structural analysis. Biological activity of 1
itself has not been reported, however, our attentionwas focused on its
unique 2,6-dioxatricyclo[3.3.1.03,7]nonane framework that is, dioxa-
analogue of noradamantane.2 We have already published a rapid
communication,3 in which we succeeded in the racemic synthesis of
urechitol A employing a [4þ3] cycloaddition reaction, and here, we
wish to report a full account of our synthesis of (ꢀ)-urechitol A.
2. Results and discussion
Our synthetic strategy of urechitol A (1) is illustrated in Scheme
1. We decided to form the six-membered hemiacetal from an in-
termediate A at the later stage of the synthesis. In order to construct
2,6-dioxatricyclo[3.3.1.03,7]nonane
A,
we
selected
[4þ3]
* Corresponding author. Fax: þ81 3 5841 8019; e-mail address: ashuten@mail.
Scheme 1. Structure of urechitol A (1) and synthetic strategies for 1.
ecc.u-tokyo.ac.jp (H. Watanabe).
http://dx.doi.org/10.1016/j.tet.2016.09.026
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

T. Sumiya et al. / Tetrahedron 72 (2016) 6982e6987
6983
At first, we examined [4þ3] cycloaddition based on route a, by
using acetylfuran 3. Albizati’s group reported [4þ3] cycloaddition
reaction between dimethyl acetal 2 and simple furans in the
presence of Lewis acid.4 We selected 2 as a model compound of
siloxyallyl cation precursor, and their reaction conditions were
applied to a cycloaddition to 3 (Scheme 2). The reaction ended up
recovery of the furan 3, the desired cycloadduct 4 was not obtained.
It was thought that Lewis acid reacted with 3 to form 30 before
generation of the silyloxyallyl cation. Next we designed alternative
cation precursor, mono-thioacetal 5,6,7 which was thought to
generate siloxyallyl cation in the presence of alkylating reagents or
metal triflates. The reaction between furan 3 and mono-thioacetal
5, however, resulted in undesired aldol reaction (MeOTf) or de-
composition of the enol ether (AgOTf).
Scheme 4. Intramolecular [4þ3] cycloaddition based on route a (failed).
Table 1
[4þ3] Cycloaddition between 11 and 12 based on route b
Entry
Lewis acid
Solvent
Conc.
Temp.
Yield
1
2
TMSOTf
BF3$OEt2
TiCl4
TiCl4
TiCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtNO2
EtNO2
0.1 M
0.1 M
0.1 M
1.0 M
0.1 M
0.1 M
ꢁ78 ꢂC
w10%
w20%
32%
w30%
40%
0
ꢂC
3
ꢁ78 ꢂC
ꢁ78 ꢂC
ꢁ78 ꢂC
ꢁ78 ꢂC
4a
5
6b
TiCl4
46%
a
As an inseparable mixture with unidentified by-products.
NaHCO3 (10 equiv) was used as an additive.
Scheme 2. [4þ3] Cycloaddition of acetylfuran 3 based on route a (failed).
b
As the results of these reactions, the acetyl group of 3 was found
to be problematic, and the furan unit was partially modified in
order to suppress enolization. Cycloaddition between the mono-
thioacetal 5 and the alternative furan unit, furoate 6, was shown
in Scheme 3. The [4þ3] cycloaddition of 5 and 6 did proceed in the
presence of Meerwein reagent, and oxabicyclo[3.2.1]octene skele-
ton 7 was obtained only in miserable yield, and unfortunately, the
product 7 was found to have both undesired regio- and stereo-
chemistry by NOESY experiment.
proceeded in the presence of TMSOTf to afford desired oxabicyclo
[3.2.1]octene 13 as a sole regio- and stereoisomer in a low yield. The
reaction yield was slightly improved by using BF3$OEt2 or TiCl4 as
a Lewis acid (entry 2 and 3), and the reaction in higher concen-
tration resulted in a decrease in yield and a generation of un-
identified by-products (entry 4). The use of nitroethane as a solvent
afforded 13 in a moderate yield (entry 5), and finally, addition of
sodium bicarbonate further improved the reaction yield to give 13
as a single isomer (entry 6).
Having succeeded in the key [4þ3] cycloaddition, we proceeded
to examine further transformation toward urechitol A. Synthetic
plan of 1 from 13 is illustrated in Scheme 5. Tricyclic ether I would
be obtained from 13 via epoxidation followed by acetal formation.
After introduction of allyl and methyl groups, lactol moiety of 1
would be constructed via H.
Scheme 5. Synthetic plan of urechitol A (1) from cycloadduct 13.
Scheme 3. [4þ3] Cycloaddition of furoate 6 based on route a.
In the intermolecular [4þ3] cycloaddition between 5 and 6
shown in Scheme 3, there were problems of miserable yield and
undesired selectivity. In order to solve these problems, we also tried
intramolecular [4þ3] cycloaddition employing tethered substrates
8 and 9 (Scheme 4). Dimethyl acetal 8 was treated with several
Lewis acids (TMSOTf, Sc(OTf)3, Yb(OTf)3 or TiCl4), and mono-
thioacetal 9 was treated with alkylating reagents (MeOTf or
Me3O$BF3) under various conditions. However, only decomposition
of 8 and 9 was observed in any case, and cycloadduct 10 was not
obtained. Therefore, route a was abandoned here, and route b was
adopted for the synthesis of urechitol A, as described below.
Our synthetic study of urechitol A based on route b was com-
menced also with the key [4þ3] cycloaddition as shown in Table 1.
The known compounds 118 and 124 were selected as the substrates
for cycloaddition, and they were treated with several Lewis acids.5
As shown in entry 1, [4þ3] cycloaddition between 11 and 12
According to this plan, the allylic alcohol 13 was then oxidized
into an unstable epoxy alcohol 14 under Sharpless conditions9 in
the presence of sodium bicarbonate, which prevented the de-
composition of the product during the reaction (Scheme 6). In
absence of sodium bicarbonate, the yield decreased to 30%. The use
of MCPBA resulted in exclusive BaeyereVilliger oxidation instead of
epoxidation.
Then we examined methanol assisted intramolecular epoxide
opening in the presence of acid (Scheme 6). Treatment of the ep-
oxide 14 with PPTS in methanol afforded trace amount of desired
tricyclic ether 15 and methoxy ketone 16 (entry 1). On the other
hand, treatment with TsOH$H2O afforded desired 15 together with
16 in good yield as an inseparable mixture (15: 16¼7: 3, entry 2).
Similar result was obtained by treatment of the epoxide 14 with
camphorsulfonic acid in dry methanol (entry 3). As the reaction
proceeded even under anhydrous conditions like entry 3, it was

6984
T. Sumiya et al. / Tetrahedron 72 (2016) 6982e6987
Scheme 6. Construction of the core tricyclic framework (*yield of an inseparable
mixture of 15 and 16; **ratio was calculated based on integration value of the 1H NMR
signals of the mixture). Reagents and conditions: a) VO(acac)2, TBHP, NaHCO3, CH2Cl2,
rt., 47%; b) TsOH$H2O, MeOH, 40 ꢂC; c) TBSCl, imidazole, DMF, rt., 49% in two steps.
thought to have taken place by equatorial attack of methanol,
mainly from the sterically less hindered exo face, and subsequent
epoxide opening by the hydroxy group of the resulting hemiacetal J
(Scheme 7). In contrast, epoxide opening with methanol to form 16
probably also occurred in an intramolecular manner via the di-
astereomeric hemiacetal intermediate K, which was generated by
the axial attack of methanol or by isomerization (dehy-
drationehydration) of J. The inseparable mixture 15/16 given as
above was subjected to the next reaction without separation. After
protection, a tricyclic ether 17 was isolated in moderate yield [49%
(in two steps) after separation of the TBS ether of 16].
Scheme 8. Total synthesis of (ꢀ)-urechitol A (1) from tricyclic ether 15. Reagents and
conditions: a) TPAP, NMO, MS4A, CH2Cl2, rt.; b) MS4A, toluene, 80 ꢂC, quant. in two
steps; c) allylmagnesium bromide, THF, 0 ꢂC, 73%; d) NaH, MeI, THF, 0 ꢂC to rt., 87%; e)
TBAF, THF, rt., 92%; f) TPAP, NMO, MS4A, CH2Cl2, rt., 92%; g) MeMgCl, THF, 0 ꢂC to rt.,
73%; h) OsO4, NaIO4, 2,6-luitidine, dioxane, H2O, rt., 65%; i) H2, Pd(OH)2, EtOH, rt., 87%.
intramolecular epoxide opening as key steps. We wish our study on
the construction of highly functionalized ring system would offer
any useful information for further investigation on the related
fields.
3. Experimental
3.1. General
Scheme 7. Plausible mechanism of the epoxide opening.
Dry THF was freshly prepared by distillation from benzophe-
none ketyl and dry CH2Cl2 was freshly prepared by distillation from
P2O5 before use. Melting points were measured with a Yanaco
micro-melting point apparatus and are uncorrected values. IR
spectra were measured with a JASCO FT/IR-230 spectrophotometer
or PerkineElmer spectrum 100 spectrometer. 1H and 13C NMR were
recorded on JEOL JNM AL300 or JEOL JNM GSX500. Chemical shifts
Having succeeded in the construction of the tricyclic ether, the
remaining task to accomplish the synthesis was construction of the
lactol moiety (Scheme 8). The tricyclic ether 17 was oxidized into
a ketone 18 with TPAP.10 This ketone readily absorbed water to form
a hydrate 180, and therefore, this compound had to be dehydrated
by heating with molecular sieves in toluene before use in the next
step. The ketone 18 was then treated with allylmagnesium bromide
to afford a tertiary alcohol 19 in 73% yield along with 7% of a sep-
arable diastereomer 20. It was thought that allylation occurred
preferentially from the less hindered face of the tricyclic ketone 18
(conformation like L). The alcohol 19 was converted to the corre-
sponding methyl ether 21, and removal of TBS group and sub-
sequent oxidation afforded aldehyde 23. This aldehyde was
subjected to Grignard reaction to afford a secondary alcohol 24 in
73% yield along with 24% of a separable diastereomer 25. A lower
temperature or use of methyllithium did not improve the stereo-
selectivity of the reaction.
Lemieux-Johnson oxidation of 24 afforded a lactol 26, and fi-
nally, debenzylation accomplished a total synthesis of (ꢀ)-urechitol
A (1). Spectroscopic data of synthetic 1 were identical to those of
the natural product.1
In summary, we have succeeded in a stereoselective synthesis of
(ꢀ)-urechitol A (1). The overall yield was 2.4% over 12 steps. The
efficient construction of the core tricyclic structure was constructed
(d) were referenced to the residual solvent peaks as the internal
standard (CDCl3: dH¼7.26, dC¼77.0). Mass spectra were recorded on
JEOL JMS SX102. Column chromatography was performed using
Kanto silica gel 60N (0.060e0.200 mm). TLC was carried out on
Merck glass plates precoated with silica gel 60 F254 (analytical:
0.25 mm, preparative: 0.5 mm).
3.2. Synthetic studies
3.2.1. (1S*,2R*,5S*,6Z)-2-Benzyloxy-7-hydroxymethyl-1-methyl-8-
oxabicyclo[3.2.1]oct-6-en-3-one (13). A solution of 1.00 M TiCl4 in
CH2Cl2 (17.5 mL, 17.5 mmol) was added dropwise to a solution of
furan 118 (1.56 g, 13.9 mmol), 124 (6.10 g, 15.9 mmol) and NaHCO3
(13.4 g, 160 mmol) in nitroethane (160 mL) at ꢁ78 ꢂC under Ar
atmosphere. After stirring for 30 min at ꢁ78 ꢂC, the reaction was
quenched with satd NaHCO3 aq and the resulting mixture was fil-
tered through Celite. The organic materials were extracted with
ethyl acetate, and the combined organic layer was washed with
H2O and brine, dried over MgSO4, and concentrated in vacuo.
by
a
[4þ3] cycloaddition reaction and
a methanol assisted

T. Sumiya et al. / Tetrahedron 72 (2016) 6982e6987
6985
Purification by silica gel column chromatography (ethyl
acetate:hexane¼1:1) gave compound 13 (1.75 g, 6.38 mmol, 46%) as
1253, 1090, 1004, 928, 834. HRCIMS: m/z calcd for C23H37O6Si
[MþH]þ 437.2354, found: 437.2376.
a pale-yellow oil. 1H NMR (CDCl3, 300 MHz):
d
(ppm)¼1.47 (3H, s),
2.43 (1H, d, J¼15.0 Hz), 2.65 (1H, br t, J¼5.5 Hz), 2.84 (1H, dd,
J¼15.0, 4.9 Hz), 3.88 (1H, s), 4.17 (2H, d, J¼5.5 Hz), 4.62 (1H, d,
J¼11.4 Hz), 4.90 (1H, br d, J¼4.9 Hz), 5.11 (1H, d, J¼11.4 Hz), 6.12 (1H,
3.2.4. (1S*,3S*,5S*,7R*,8R*)-8-Benzyloxy-3-(tert-butyldimethyl-sily-
loxymethyl)-1-methoxy-7-methyl-2,6-dioxatricyclo[3.3.1.03,7]-
nonan-4-one (18). To a mixture of 17 (653 mg, 1.50 mmol), NMO
(264 mg, 2.25 mmol) and MS 4A (7.50 g) in CH2Cl2 (15.0 mL) was
added TPAP (105 mg, 0.300 mmol) at room temperature under Ar
atmosphere. After stirring for 2 h at room temperature, the reaction
mixture was filtered through silica gel with Et2O and concentrated
in vacuo. The residue was dissolved in toluene (15.0 mL) and MS 4A
(7.50 g) was added to the solution at room temperature under Ar
atmosphere. After stirring for 2.5 h at 80 ꢂC, the mixture was fil-
tered and concentrated in vacuo to give pure compound 18
(652 mg, 1.50 mmol, quant.) as a colorless oil. 1H NMR (CDCl3,
m), 7.30e7.42 (5H, m). 13C NMR (CDCl3, 125 MHz):
d
(ppm)¼18.9,
46.0, 57.6, 74.6, 76.7, 86.6, 87.9,128.1,128.2,128.4,129.3,136.8,147.7,
205.3. IR (ATR): nmax (cmꢁ1)¼3450, 2933, 2869, 1721, 1453, 1376,
1197, 1098, 1027, 738, 698. HRCIMS: m/z calcd for C16H19O4 [MþH]þ
275.1278, found: 275.1280.
3.2.2. (1R*,2S*,4S*,5S*,8R*)-8-Benzyloxy-2-hydroxymethyl-1-methyl-
3,9-dioxatricyclo[3.3.1.02,4]nonan-7-one (14). A solution of TBHP in
decane (5.5 M, 20 mL, 0.11 mmol) was added to a solution of 13
(20 mg, 0.073 mmol), VO(acac)2 (1.9 mg, 0.0073 mmol) and
NaHCO3 (61 mg, 0.73 mmol) in CH2Cl2 (1.00 mL) at 0 ꢂC under Ar
atmosphere. After stirring for 1 h at room temperature, dimethyl
sulfide was added to the mixture at room temperature. After stir-
ring for 30 min at room temperature, satd NaHCO3 aq was added,
and the organic materials were extracted with ethyl acetate. The
combined organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. Purification by silica gel column
chromatography (ethyl acetate:hexane¼1:1) gave compound 14
(10 mg, 0.034 mmol, 47%) as a colorless oil. 1H NMR (CDCl3,
300 MHz):
d
(ppm)¼0.07 (3H, s), 0.08 (3H, s), 0.86 (9H, s), 1.57 (3H,
s), 2.14 (1H, dd, J¼13.2, 4.2 Hz), 2.67 (1H, dd, J¼13.2, 1.1 Hz), 3.45
(3H, s), 3.61 (1H, s), 3.83 (1H, d, J¼10.6 Hz), 4.00 (1H, d, J¼10.6 Hz),
4.12 (1H, dd, J¼4.2, 1.1 Hz), 4.67 (1H, d, J¼12.5 Hz), 4.94 (1H, d,
J¼12.5 Hz), 7.28e7.44 (5H, m). 13C NMR (CDCl3, 125 MHz):
d
(ppm)¼ꢁ5.7, 15.3, 18.2, 25.7, 41.1, 51.8, 58.2, 74.2, 74.2, 82.0, 85.2,
88.0, 106.8, 127.7, 128.0, 128.3, 138.2, 200.5. IR (film): nmax (cmꢁ1)¼
3537, 2929, 2856, 1784, 1496, 1464, 1256, 1115, 1003, 839. HRE-
SIIMS: m/z calcd for C23H34NaO6Si [MþNa]þ 457.2017, found:
457.2002.
300 MHz):
d
(ppm)¼1.43 (3H, s), 2.42 (1H, t, J¼7.0 Hz), 2.53 (1H, d,
J¼16.1 Hz), 2.87 (1H, dd, J¼16.1, 5.9 Hz), 3.61 (1H, s), 3.76e3.88 (2H,
m), 4.05 (1H, dd, J¼13.2, 7.0 Hz), 4.46 (1H, d, J¼5.9 Hz), 4.56 (1H, d,
J¼11.4 Hz), 5.07 (1H, d, J¼11.4 Hz), 7.32e7.41 (5H, m). 13C NMR
3.2.5. (1S*,3R*,4R*,5S*,7R*,8R*)-4-Allyl-8-benzyloxy-3-(tert-butyldi-
methylsilyloxymethyl)-1-methoxy-7-methyl-2,6-dioxatricyclo
[3.3.1.03,7]nonan-4-ol (19). A THF (2.50 mL) solution of compound
18 (200 mg, 0.460 mmol) was added to a THF (2.50 mL) solution of
allylmagnesium bromide in Et2O (1.0 M, 0.51 mL, 0.51 mmol) at 0 ꢂC
under Ar atmosphere. After stirring for 30 min at 0 ꢂC, the reaction
was quenched with satd NH4Cl aq and the organic materials were
extracted with ethyl acetate. The combined organic layer was
washed with H2O and brine, dried over MgSO4, and concentrated in
vacuo. Purification by silica gel column chromatography (ethyl
acetate:hexane¼1:10) gave compound 19 (160 mg, 0.336 mmol,
73%) and its diastereomer 20 (15 mg, 0.032 mmol, 7%) as colorless
(CDCl3, 125 MHz):
d
(ppm)¼16.5, 44.4, 58.2, 58.6, 65.1, 71.6, 74.7,
81.2, 85.3, 128.3, 128.3, 128.6, 136.6, 204.5. IR (ATR): nmax (cmꢁ1)¼
3464, 2935, 1787, 1724, 1454, 1377, 1256, 1203, 1106, 1027, 911, 731.
HRCIMS: m/z calcd for C16H19O5 [MþH]þ 291.1227, found: 291.1206.
3.2.3. (1S*,3R*,4S*,5S*,7R*,8R*)-8-Benzyloxy-3-(tert-butyldi-methyl-
silyloxymethyl)-1-methoxy-7-methyl-2,6-dioxatricyclo-[3.3.1.03,7
]
nonan-4-ol (17). To a solution of 14 (925 mg, 3.19 mmol) in MeOH
(60.0 mL) was added TsOHꢃH2O (607 mg, 3.19 mmol) at room
temperature. After stirring for 30 min at 40 ꢂC, the reaction mixture
was concentrated in vacuo and filtered through silica gel. The fil-
trate was concentrated in vacuo to give a crude mixture of 15 and 16
as a colorless oil. A small portion of this mixture was purified by
preparative TLC for analysis to give 15 and 16 as colorless oil. 15: 1H
oil.19: 1H NMR (CDCl3, 300 MHz):
d
(ppm)¼0.09 (3H, s), 0.10 (3H, s),
0.91 (9H, s), 1.26 (3H, s), 1.65 (1H, dd, J¼12.9, 4.2 Hz), 2.34 (1H, dd,
J¼13.5, 8.7 Hz), 2.44e2.57 (2H, m), 3.24 (1H, s), 3.42 (1H, s), 3.50
(3H, s), 3.79 (1H, d, J¼11.1 Hz), 3.82 (1H, d, J¼11.1 Hz), 4.04 (1H, d,
J¼4.2 Hz), 4.60 (1H, d, J¼12.9 Hz), 4.93 (1H, d, J¼12.9 Hz), 5.05e5.18
(2H, m), 5.97 (1H, m), 7.27e7.40 (5H, m). 13C NMR (CDCl3,
NMR (CDCl3, 300 MHz):
d
(ppm)¼1.44 (3H, s), 1.94 (1H, m), 2.24
(1H, m), 3.46 (3H, s), 3.52 (1H, s), 3.80e4.03 (3H, m), 4.22 (1H, m),
125 MHz):
d
(ppm)¼ꢁ5.7, e5.4, 15.5, 18.1, 25.8, 32.2, 37.5, 51.4, 62.6,
4.66 (1H, d, J¼12.3), 4.92 (1H, d, J¼12.3), 7.29e7.39 (5H, m). 16: 1H
73.8, 75.8, 78.6, 86.1, 86.8, 87.9, 105.6,118.1, 127.4, 127.7, 128.2,133.3,
138.7. IR (ATR): nmax (cmꢁ1)¼3561, 2931, 1463, 1343, 1252, 1071,
1004, 833, 777. HRCIMS: m/z calcd for C26H41O6Si [MþH]þ 477.2667,
NMR (CDCl3, 300 MHz):
d
(ppm)¼1.36 (3H, s), 2.55 (1H, m), 2.77
(1H, m), 3.38 (3H, s), 3.67 (1H, s), 3.95e4.05 (2H, m), 4.17 (1H, m),
4.30 (1H, m), 4.50 (1H, d, J¼11.4 Hz), 5.05 (1H, d, J¼11.4 Hz),
7.28e7.41 (5H, m).
found: 477.2668. 20: 1H NMR (CDCl3, 300 MHz):
d
(ppm)¼0.10 (3H,
s), 0.11 (3H, s), 0.91 (9H, s), 1.45 (3H, s), 1.75 (1H, dd, J¼13.2, 4.5 Hz),
2.32 (1H, dd, J¼13.2, 1.0 Hz), 2.73 (2H, d, J¼6.9 Hz), 3.469 (1H, s),
3.474 (3H, s), 3.84 (1H, s), 3.94e3.97 (2H, m), 3.98 (1H, br d,
J¼4.5 Hz), 4.62 (1H, d, J¼12.3 Hz), 4.90 (1H, d, J¼12.3 Hz), 5.12 (1H,
m), 5.16 (1H, m), 6.02 (1H, m), 7.31e7.36 (5H, m).
To a solution of the mixture 15 and 16 in DMF (1.50 mL) were
added TBSCl (481 mg, 3.19 mmol) and imidazole (434 mg,
6.38 mmol) at room temperature under Ar atmosphere. After stir-
ring for 1.5 h at room temperature, the reaction mixture was diluted
with H2O and the organic materials were extracted with ethyl ac-
etate. The combined organic layer was washed with H2O and brine,
dried over MgSO4, and concentrated in vacuo. Purification by silica
gel column chromatography (ethyl acetate:hexane¼1:2) gave
compound 17 (687 mg, 1.57 mmol, 49% in 2 steps) as a colorless oil.
3.2.6. (1S*,3S*,4R*,5S*,7R*,8R*)-4-Allyl-8-benzyloxy-3-(tert-butyldi-
methylsilanyloxymethyl)-1,4-dimethoxy-7-methyl-2,6-dioxatricyclo
[3.3.1.03,7]nonane (21). To a mixture of compound 19 (20 mg,
0.042 mmol) and NaH (55% in mineral oil, 2.8 mg, 0.063 mmol) in
1H NMR (CDCl3, 300 MHz):
d
(ppm)¼0.11 (3H, s), 0.13 (3H, s), 0.91
THF (2.5 mL) was added MeI (8 m
L, 0.13 mmol) at 0 ꢂC under Ar
(9H, s), 1.40 (3H, s), 1.87 (1H, dd, J¼12.8, 4.8 Hz), 2.18 (1H, d,
J¼12.8 Hz), 3.44 (3H, s), 3.50 (1H, s), 3.99 (2H, s), 4.16 (1H, s), 4.24
(1H, d, J¼4.8 Hz), 4.62 (1H, d, J¼12.5 Hz), 4.90 (1H, d, J¼12.5 Hz),
atmosphere. After stirring for 1 h at room temperature, the reaction
was quenched with satd NH4Cl aq and the organic materials were
extracted with ethyl acetate. The combined organic layer was
washed with H2O and brine, dried over MgSO4, and concentrated in
vacuo. Purification by silica gel column chromatography (ethyl
acetate:hexane¼1:10) gave compound 21 (18 mg, 0.037 mmol,
7.28e7.41 (5H, m). 13C NMR (CDCl3, 125 MHz):
d
(ppm)¼ꢁ5.6, 15.7,
18.1, 25.8, 35.4, 51.4, 63.4, 73.9, 78.1, 78.7, 86.2, 87.5, 88.0, 105.8,
127.5, 127.8, 128.2, 138.6. IR (ATR): nmax (cmꢁ1)¼3463, 2929, 1455,

6986
T. Sumiya et al. / Tetrahedron 72 (2016) 6982e6987
87%) as a colorless oil. 1H NMR (CDCl3, 300 MHz):
d
(ppm)¼0.07
0.097 mmol, 24%) as colorless oil. 24: 1H NMR (CDCl3, 300 MHz):
(3H, s), 0.08 (3H, s), 0.90 (9H, s), 1.40 (3H, s), 1.55 (1H, dd, J¼12.6,
3.9 Hz), 2.25 (1H, dd, J¼15.5, 8.1 Hz), 2.62 (1H, d, J¼12.6 Hz), 2.91
(1H, dd, J¼15.5, 5.7 Hz), 3.36 (1H, s), 3.49 (3H, s), 3.84 (1H, d,
J¼11.3 Hz), 3.94 (1H, d, J¼11.3 Hz), 4.02 (1H, d, J¼3.9 Hz), 4.61 (1H,
d, J¼12.5 Hz), 4.92 (1H, d, J¼12.5 Hz), 5.06e5.14 (2H, m), 5.80 (1H,
d
(ppm)¼1.32 (3H, d, J¼6.2 Hz), 1.37 (3H, s), 1.75 (1H, dd, J¼12.6,
4.4 Hz), 2.37 (1H, d, J¼12.6 Hz), 2.58 (1H, dd, J¼15.3, 7.5 Hz), 2.69
(1H, dd, J¼15.3, 7.5 Hz), 3.32 (1H, d, J¼3.3 Hz), 3.39e3.42 (4H, m),
3.57 (3H, s), 4.10 (1H, m), 4.25 (1H, d, J¼3.9 Hz), 4.60 (1H, d,
J¼12.1 Hz), 4.93 (1H, d, J¼12.1 Hz), 5.13e5.29 (2H, m), 6.03 (1H, m),
m), 7.28e7.40 (5H, m). 13C NMR (CDCl3, 125 MHz):
d
(ppm)¼ꢁ5.7,
7.27e7.41 (5H, m). 13C NMR (CDCl3, 125 MHz):
d
(ppm)¼16.4, 18.2,
16.1, 18.2, 25.8, 31.7, 32.3, 51.4, 51.4, 63.5, 73.8, 76.2, 82.5, 86.1, 86.3,
90.5, 105.9, 117.9, 127.3, 127.7, 128.1, 133.2, 138.8. IR (ATR): nmax
(cmꢁ1)¼2931, 2856, 1455, 1304, 1249, 1149, 1099, 1020, 832, 777.
HRCIMS: m/z calcd for C27H43O6Si [MþH]þ 491.2823, found:
491.2838.
33.3, 36.2, 51.8, 53.2, 67.3, 74.0, 74.9, 84.0, 86.5, 89.3, 89.6, 104.6,
118.9, 127.4, 127.4, 128.2, 132.9, 138.5. IR (ATR): nmax (cmꢁ1)¼3509,
2938,1454,1349,1303,1244,1124,1091,1005, 910, 735. HRCIMS: m/
z calcd for C22H31O6 [MþH]þ: 391.2115, found: 391.2153. 25: 1H
NMR (CDCl3, 300 MHz):
d
(ppm)¼1.29 (3H, d, J¼6.6 Hz), 1.57 (3H, s),
1.74 (1H, dd, J¼12.6, 4.2 Hz), 2.36e2.47 (2H, m), 2.53 (1H, ddt,
J¼15.6, 6.6, 1.5 Hz), 3.09 (1H, d, J¼8.7 Hz), 3.35 (3H, s), 3.43 (1H, s),
3.53 (3H, s), 3.89 (1H, dq, J¼8.7, 6.6 Hz), 4.25 (1H, br d, J¼4.2 Hz),
4.68 (1H, d, J¼11.7 Hz), 4.92 (1H, d, J¼11.7 Hz), 5.14 (1H, m), 5.18
(1H, m), 5.93 (1H, m), 7.30e7.35 (5H, m).
3.2.7. [(1S*,3S*,4R*,5S*,7R*,8R*)-4-Allyl-8-benzyloxy-1,4-dimethoxy-
7-methyl-2,6-dioxatricyclo[3.3.1.03,7]non-3-yl]methanol (22). A so-
lution of TBAF in THF (1.0 M, 2.86 mL, 2.86 mmol) was added
dropwise to a solution of 21 (280 mg, 0.571 mmol) in THF (6.00 mL)
at room temperature under Ar atmosphere. After stirring for 1 h at
room temperature, the reaction mixture was diluted with H2O and
the organic materials were extracted with ethyl acetate. The com-
bined organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. Purification by silica gel column
chromatography (ethyl acetate:hexane¼1:3) gave compound 22
(200 mg, 0.531 mmol, 92%) as a colorless oil. 1H NMR (CDCl3,
3.2.10. (ꢀ)-Urechitol A benzyl ether (26). To a solution of 24
(115 mg, 0.295 mmol), 2,6-lutidine (69 mL, 0.59 mmol) and OsO4 in
t-BuOH (10 g/L, 0.75 mL, 0.030 mmol) in dioxane/H2O¼3/1
(3.00 mL) was added NaIO4 (252 mg, 1.18 mmol) at room temper-
ature under Ar atmosphere. After stirring for 5.5 h at room tem-
perature, the reaction was quenched with H2O and the organic
materials were extracted with ethyl acetate. The combined organic
layer was washed with brine, dried over MgSO4, and concentrated
in vacuo. Purification by silica gel column chromatography (ethyl
acetate:hexane¼3:1) gave compound 26 (75.0 mg, 0.191 mmol,
300 MHz):
d
(ppm)¼1.51 (3H, s), 1.63 (1H, dd, J¼12.9, 4.2 Hz), 2.24
(1H, dd, J¼15.0, 7.5 Hz), 2.43 (1H, dd, J¼15.0, 6.0 Hz), 2.64 (1H, d,
J¼12.8 Hz), 2.75 (1H, dd, J¼8.1, 1.8 Hz), 3.40 (3H, s), 3.42 (1H, s), 3.51
(3H, s), 3.62 (1H, dd, J¼11.7, 8.1 Hz), 3.98 (1H, dd, J¼11.7,1.8 Hz), 4.07
(1H, d, J¼4.2 Hz), 4.67 (1H, d, J¼12.0 Hz), 4.96 (1H, d, J¼12.0 Hz),
5.09e5.20 (2H, m), 5.78 (1H, m), 7.27e7.39 (5H, m). 13C NMR (CDCl3,
65%) as a colorless oil. 1H NMR (CDCl3, 300 MHz):
d
(ppm)¼1.46
(3H, d, J¼7.0 Hz), 1.50 (3H, s), 1.63e1.77 (2H, m), 2.34 (1H, dd,
J¼14.3, 2.6 Hz), 2.39 (1H, d, J¼12.8 Hz), 3.32 (3H, s), 3.40 (1H, s),
3.53 (3H, s), 4.06 (1H, d, J¼3.7 Hz), 4.20 (1H, q, J¼7.0 Hz), 4.62 (1H,
d, J¼12.5 Hz), 4.89 (1H, d, J¼12.5 Hz), 5.28 (1H, dd, J¼10.3, 2.6 Hz),
125 MHz):
d
(ppm)¼16.4, 31.6, 31.9, 51.5, 51.5, 59.3, 73.9, 76.5, 81.5,
84.6, 88.7, 90.4,105.7, 118.7, 127.5, 127.5, 128.3, 131.8, 138.2. IR (ATR):
nmax (cmꢁ1)¼3506, 2937, 2839,1453,1350,1123,1023, 915, 887, 738.
HRCIMS: m/z calcd for
C
21H29O6 [MþH]þ: 377.1959, found:
7.27e7.41 (5H, m). 13C NMR (CDCl3, 125 MHz):
d
(ppm)¼14.2, 15.4,
377.1972.
31.5, 32.2, 51.5, 51.8, 70.0, 74.0, 74.4, 80.2, 82.5, 85.9, 87.5, 90.0,
105.0, 127.5, 127.8, 128.2, 138.4. IR (ATR): nmax (cmꢁ1)¼3414, 2938,
1454, 1314, 1237, 1126, 1050, 1021, 943, 836, 737. HRCIMS: m/z calcd
for C21H29O7 [MþH]þ: 393.1908, found: 393.1920.
3.2.8. (1S*,3S*,4R*,5S*,7R*,8R*)-4-Allyl-8-benzyloxy-1,4-dimethoxy-
7-methyl-2,6-dioxatricyclo[3.3.1.03,7]nonane-3-carbaldehyde
(23). To a mixture of 22 (60 mg, 0.16 mmol), NMO (28 mg,
0.24 mmol) and MS 4A (750 mg) in CH2Cl2 (1.50 mL) was added
TPAP (5.6 mg, 0.016 mmol) at room temperature under Ar atmo-
sphere. After stirring for 30 min at room temperature, the reaction
mixture was directly loaded on a silica gel column. Elution with
ethyl acetate/hexane (1:3) gave compound 23 (55.0 mg,
0.147 mmol, 92%) as a colorless oil. 1H NMR (CDCl3, 300 MHz):
3.2.11. (ꢀ)-Urechitol
A (1). To a solution of 26 (70.0 mg,
0.178 mmol) in EtOH (3.00 mL) was added 20wt % Pd(OH)2eC
(14.0 mg) at room temperature under H2 atmosphere. After stirring
for 30 min at room temperature, the mixture was filtered and
concentrated in vacuo. Purification by silica gel column chroma-
tography (ethyl acetate) gave (ꢀ)-urechitol
A (1) (46.8 mg,
0.155 mmol, 87%) as a colorless amorphous solid. Recrystallization
d
(ppm)¼1.28 (3H, s), 1.64 (1H, dd, J¼12.6, 3.9 Hz), 2.32 (1H, dd,
J¼15.4, 8.4 Hz), 2.62e2.82 (2H, m), 3.20 (3H, s), 3.46 (1H, s), 3.57
(3H, s), 4.14 (1H, d, J¼3.9 Hz), 4.65 (1H, d, J¼12.1 Hz), 4.94 (1H, d,
J¼12.1 Hz), 5.06e5.22 (2H, m), 5.72 (1H, m), 7.28e7.38 (5H, m), 9.67
from hexane/acetone gave colorless prisms, mp: 80e82 ꢂC. 1H NMR
(CDCl3, 500 MHz):
d
(ppm)¼1.41 (3H, d, J¼7.0 Hz), 1.57 (3H, s), 1.72
(1H, dd, J¼14.5, 9.8 Hz), 1.74 (1H, dd, 12.8, 4.0 Hz), 2.29 (1H, br s),
2.34 (1H, dd, J¼14.5, 2.8 Hz), 2.40 (1H, dd, J¼12.8, 0.75 Hz), 3.14 (1H,
br s), 3.32 (3H, s), 3.48 (3H, s), 3.58 (1H, s), 4.11 (1H, d, J¼4.0 Hz),
4.17 (1H, q, J¼7.0 Hz), 5.27 (1H, dd, J¼9.8, 2.8 Hz). 13C NMR (CDCl3,
(1H, s). 13C NMR (CDCl3, 125 MHz):
d
(ppm)¼16.4, 29.9, 31.1, 51.7,
53.2, 73.9, 76.8, 83.8, 86.7, 90.2, 92.4, 107.3, 118.7, 127.6, 127.8, 128.3,
131.9, 138.1, 200.0. IR (ATR): nmax (cmꢁ1)¼2937, 2839, 1719, 1456,
1350, 1235, 1121, 1099, 1020, 839, 736. HRCIMS: m/z calcd for
125 MHz):
d
(ppm)¼14.1, 14.7, 30.5, 31.4, 51.5, 51.8, 70.0, 74.5, 79.1,
C
21H27O6 [MþH]þ 375.1802, found: 375.1813.
80.3, 83.2, 87.5, 89.7, 104.4. IR (film): nmax (cmꢁ1)¼3457, 2942, 2837,
1463, 1164, 1051, 944. HREIMS: m/z calcd for C14H22O7 [M]þ:
302.1360, found: 302.1404.
3.2.9. (S*)-1-[(1S*,3S*,4R*,5S*,7R*,8R*)-4-Allyl-8-benzyloxy-1,4-
dimethoxy-7-methyl-2,6-dioxatricyclo[3.3.1.03,7]non-3-yl]ethanol
(24). A solution of MeMgCl in THF (3.0 M, 0.33 mL, 1.00 mmol) was
added dropwise to a solution of 23 (150 mg, 0.401 mmol) in THF
(4.00 mL) at 0 ꢂC under Ar atmosphere. After stirring for 30 min at
room temperature, the reaction was quenched with satd NH4Cl aq
and the organic materials were extracted with ethyl acetate. The
combined organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. Purification by silica gel column
chromatography (ethyl acetate:hexane¼1:3) gave compound 24
(115 mg, 0.295 mmol, 73%) and its diastereomer 25 (38 mg,
Acknowledgements
~
We are grateful to Dr. L. M. Pena-Rodríguez for providing NMR
spectra of natural urechitol A.
Supplementary data
Supplementary data (synthetic methods and 1H NMR data for
compounds 3, 5, 6, 7, 8 and 9 in unsuccessful routes.) associated

T. Sumiya et al. / Tetrahedron 72 (2016) 6982e6987
6987
4. Vidal-Pascual, M.; Martinez-Lamenca, C.; Hoffmann, H. M. R. Org. Synth. 2006,
83, 61e69.
5. Murray, D. H.; Albizati, K. F. Tetrahedron Lett. 1990, 31, 4109e4112.
6. Kimpe, N. D.; Georgieva, A.; Boeykens, M.; Kozekov, I.; Aelterman, W. Synthesis
1996, 9, 1131e1134.
with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2016.09.026.
References and notes
7. Tehrani, K. A.; Boeykens, M.; Tyvorskii, V. I.; Kulinkovichb, O.; De Kimpea, N.
Tetrahedron 2000, 56, 6541e6548.
8. Mann, J.; Holland (nee Overton), H. J.; Lewis, T. Tetrahedron 1987, 43,
2533e2542.
9. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136e6137.
10. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthsis 1994, 639e666.
ꢀ
1. Yam-Puc, J. A.; Escalante-Erosa, F.; Pech-Lopez, M.; Chan-Bacab, M. J.; Ar-
ꢀ
~
unachalampillai, A.; Wendt, O. F.; Sterner, O.; Pena-Rodríguez, L. M. J. Nat. Prod.
2009, 72, 745e748.
2. Pascual, M. V.; Proemmel, S.; Beil, W.; Wartchow, R.; Hoffmann, H. M. R. Org.
Lett. 2004, 6, 4155e4158.
3. Sumiya, T.; Ishigami, K.; Watanabe, H. Angew. Chem., Int. Ed. 2010, 49,
5527e5528.