A facile and practical synthesis of Nicolaou's key intermediates, 2-methyl- and 2,6-dimethyltetrahydropyrans, toward the total synthesis of ladder-shaped polyethers

Article abstract of DOI:10.1055/s-0033-1338503

A facile and robust method to prepare 2-methyl- and 2,6- dimethyltetrahydropyrans, most useful Nicolaou intermediates for the synthesis of ladder-shaped polyethers, is disclosed. The established highly practical recipe, adopting chemo- and stereoselective catalytic oxidations and one-pot reactions with few chromatographic purifications, would significantly facilitate the large-scale supply of pivotal monocyclic building blocks, which is a rate-determining process of gigantic tetrahydropyran-containing natural products synthesis.

Full text of DOI:10.1055/s-0033-1338503

PAPER
▌2417
paper
A Facile and Practical Synthesis of Nicolaou’s Key Intermediates, 2-Methyl-
and 2,6-Dimethyltetrahydropyrans, toward the Total Synthesis of Ladder-
Shaped Polyethers
Facile Synthesis of Tetrahydropyrans toward Ladder-Shaped Polyethers
Takeharu Nakashima,a,b Tomomi Baba,a Hisaaki Onoue,a Wataru Yamashita,a Kohei Torikai*a
a
Department of Chemistry, Graduate Faculty and School of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-Ku, Fukuoka 812-8581,
Japan
b
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
Fax +81(92)6422607; E-mail: torikai@chem.kyushu-univ.jp
Received: 04.06.2013; Accepted after revision: 13.06.2013
This paper is dedicated to the memory of Choji Ueno.
changed for two decades. The Nicolaou group first report-
Abstract: A facile and robust method to prepare 2-methyl- and 2,6-
ed the synthesis of THPs 1 and 28b from commercially
dimethyltetrahydropyrans, most useful Nicolaou intermediates for
available 2-deoxy-D-ribose (Scheme 1). Briefly, 2-deoxy-
D-ribose was converted into alcohol 5 via Wittig olefina-
the synthesis of ladder-shaped polyethers, is disclosed. The estab-
lished highly practical recipe, adopting chemo- and stereoselective
catalytic oxidations and one-pot reactions with few chromatograph- tion and protection of the 1,3-diol moiety. For the synthe-
ic purifications, would significantly facilitate the large-scale supply
of pivotal monocyclic building blocks, which is a rate-determining
process of gigantic tetrahydropyran-containing natural products
tion (7), Katsuki–Sharpless asymmetric epoxidation9 (8),
synthesis.
sis of compound 1, the key intermediate, vinyl epoxide 11,
was prepared from 5 through silyl protection (6), reduc-
Parikh–Doering oxidation (9), Wittig reaction (10), and
Key words: total
synthesis,
ladder-shaped
polyethers,
desilylation (11). Finally, the THP ring was regio- and ste-
reoselectively constructed via the acid-mediated 6-endo-
tet-mode cyclization of 11, furnishing 1. In order to syn-
thesize compound 2, Swern oxidation (alcohol 5 to ketone
12) and the stereoselective installation of a methyl group
(13) were additionally conducted before the sequential
transformation via 14, 15, 16, and 17, to give 2. Following
this pioneering work, other THPs possessing some varia-
tion of the methyl groups at the 2,6-positions, such as 3
and 4, were synthesized using the same strategy.10
trans/syn/trans-fused-ring system, one pot, selective oxidation
In recent decades, one of the hottest issues in the natural
products chemistry field has been ladder-shaped poly-
ethers (LSPs). LSPs, unique secondary metabolites of di-
noflagellates,1 are notorious marine toxins possessing
gigantic structures (Figure 1). Of these, brevetoxins are
known to cause red tide,2 while ciguatoxins3 and
maitotoxin4 exert extraordinarily potent neurotoxicity and
are thought to be the causative toxins of ‘ciguatera’ sea-
food poisoning. Recently, brevisulcenal-F, a new toxic
member with strong mouse lethality, was also isolated
from a red-tide dinoflagellate.5 Despite the potent toxicity
of LSPs and societal needs for the detection and develop-
ment of detoxification methods, there have been few
mode-of-action studies.6 The short supply of natural spec-
imens, as well as the gigantic and complex structures, has
hampered detailed investigations of biological function
but, at the same time, has made LSPs attractive targets of
total synthesis. Indeed, as a result of tight competition be-
tween rival groups, a considerable number of total synthe-
ses of LSPs have been achieved to date,6g,7 in which keen
attention has been paid to the development of convergent
strategies for the expeditious coupling of building blocks.
As an alternative method of THP construction, around a
decade later the Nakata group reported SmI2-mediated
radical cyclization of δ-acryloxy aldehyde 18 (Scheme
1).11 This method can even be applied to the large-scale
synthesis of 19,11,12 in only five steps from 2-deoxy-D-ri-
bose, in excellent yield (70%).13 Unfortunately, it was
found that this radical cyclization method could not access
THP rings equipped with an axial methyl group at the far-
side anomeric position from the benzylidene acetal, such
as compound 21.11c Other than these, although many
methodologies to construct 2,6-substituted THPs have
also been developed,14 few robust strategies have become
widespread in the synthetic community for LSPs, proba-
bly due to scalability problems.
Consequently, to the best of our knowledge, the pioneer-
ing method of Nicolaou’s group, adopting the 6-endo-tet
cyclization of vinyl epoxides,8 has been utilized in almost
all the syntheses of LSPs, including brevetoxins,15 cigua-
toxins,16 gambierol,17 gymnocin-A,18 brevenal,19 brevi-
sin,20 gambieric acid A,21 and probe molecules for
elucidating the mode of action,22 as well as in the world-
wide-progressing synthetic studies of yessotoxins23 and
maitotoxin.24
On the other hand, however, the basic methods for con-
structing tetrahydropyrans (THPs) with/without axial
methyl group(s) at the 2,6-positions, the most commonly
occurring structural units of LSPs, have remained un-
SYNTHESIS 2013, 45, 2417–2425
Advanced online publication: 19.07.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
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DOI: 10.1055/s-0033-1338503; Art ID: SS-2013-F0387-OP
© Georg Thieme Verlag Stuttgart · New York

2418
T. Nakashima et al.
PAPER
Me
CHO
HO
Me
Me
H
H
H
H
H
OH
O
K
I
HO
F
H
O
Me
G
O
H
O
L
J
O
H
K
J
O
O
M
H
H
H
O
H
H
Me
Me
H
H
I
H
O
O
H
Me
O
H
H
H
H
O
O
H
H
Me
H
H
H
H
O
OH
Me
H
H
H
H
H
H
O
B
E
F
G
O
H
H
Me
H
O
O
B
E
A
C
O
D
O
A
C
O
D
H
Me
O
H
O
O
H
O
Me
H
OH
brevetoxin-B
ciguatoxin (CTX)
HO
OH
OH
Me
H
H
O
OH
H
H
O
O
P
Q
O
N
O
H
O
H
H
M
H
OH
H
K
HO
H
O
OH
H
O
Me
Me
H
O
L
H
Me
H
H
H
Me
Me
H
H
OH
OH
O
O
O
O
O
H
A
H
H
R
H
B
C
I
G
O
E
J
O
O
Me
HO
H
D
H
Me
OH
Me
O
H
O
O
Me
H
H
H
H
Me
H
O
OH
H
OH
S
H
O
brevisulcenal-F
T
H
O H
U
H
H
O
H
V
H
HO
Me
O
X
O
W
H
H
Me
OH
OH
H
H
Me
O
O
W
H
X
V
Me
O
O
O
H
Me
Y
O
U
H
Me
H
H
H
O
Z
Me
T
H
Me
HO
H
H
O
H
O
Me
A'
H
H
H
H
H
H
O
S
H
O
O
Me
R
O
OH
Q
F'
E'
O
D'
C'
B'
P
H
O
H
Me
OH
H
Me
HO
O
O
H
Me
Me
Me
H
O
HO
NaO3S
OH
OH
OH
HO
H
O
Me
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
O
O
E
O
O
O
OH
H
OH
OH
OH
Me
Me
OH
H
O
N
B
C
D
O
F
G
O
H
I
K
H
H
J
Me
HO
O
L
OH
O
H
A
O
O
O
O
H
H
H
H
H
M
H
OH Me
OSO3Na
OH
OH
OH
OH
HO
HO
O
OH
H
H
OH
OH OH
maitotoxin
Figure 1 Structures of naturally occurring ladder-shaped polyethers
Although this clearly indicates that Nicolaou’s method To establish a facile and robust route for THP derivatives
was, and still is, amazingly useful and sophisticated, in the 1 and 2, we envisaged that the following points of the tra-
course of our synthetic studies of yessotoxin and mai- ditional method needed to be improved: i) the laborious,
totoxin, we encountered some difficulties managing the long sequence (9 and 11 steps), which requires huge-scale
large-scale preparation of THPs via this methodology.
chromatography in every step, ii) the air- and moisture-
sensitive reactions using freshly purified reagents, iii) the
offensive odor of dimethyl sulfide after DMSO-mediated
oxidations, iv) the instability of ketone 12 and TMS ethers
(e.g., 14), which decreases the reproducibility, v) the
emulsion formation after the Katsuki–Sharpless asym-
metric epoxidation, and vi) the usage of expensive re-
agents. Focusing upon these points, we developed an
improved recipe for THP 1 by making use of modern
chemistries, as outlined in Scheme 2.
To solve the problems in the large-scale supply of build-
ing blocks, which is one of the most critical rate-determin-
ing processes in LSP synthesis through hundreds of steps,
we believed reassessment of the conventional recipe tak-
ing into consideration the idea of blending modern syn-
thetic methods, such as catalytic and time-integrated25
process chemistries, was necessary. Herein, we report a
facile and large-scale-friendly improved recipe for the
most pivotal Nicolaou monocyclic intermediates to in-
form and aid synthetic chemists engaged in the prepara- Wittig reaction of 2-deoxy-D-ribose with ethyl 2-(triphe-
tion of LSPs and other THP-containing compounds.
nylphosphoranylidene)propionate gave crude triol, which
Synthesis 2013, 45, 2417–2425
© Georg Thieme Verlag Stuttgart · New York

PAPER
Facile Synthesis of Tetrahydropyrans toward Ladder-Shaped Polyethers
2419
O
OH
R
H
R
H
H
H
R
H
Me
H
SmI2-mediated
HO
O
O
SmI2 chemistry
O
O
CO2Et
reductive cyclization
O
CO2Et
OH
O
CO2Et
OH
OH
O
Ph
2-deoxy-D-ribose
O
O
Ph
O
Ph
21: R = H or Me
19: R = H
18: R = H or Me
20: R = Me
Wittig
protection of 1,3-diol
H
H
H
H
Katsuki–Sharpless
AE
O
OR
OTBS
OTBS
Swern oxidation
Ph
reduction
O
O
O
O
O
CO2Et
CO2Et
Ph
O
H
O
Ph
O
OH
Ph
O
H
OH
H
Me
Me
Me
Me
12
8
5: R = H
6: R = TBS
7
silyl protection
Me3Al
Parikh–Doering
oxidation
DIBAL-H reduction
Katsuki–Sharpless AE
Parikh–Doering oxidation
Me
OR
Me
OR
H
H
6-endo-tet cyclization
of vinyl epoxides
O
OR
O
O
O
O
CO2Et
Ph
O
H
R1
R2
Ph
O
X
O
Ph
O
X
H
Me
silyl protection
O
Me
Me
13: R = H
14: R = TMS
15 R = TMS, X = O
16: R = TMS, X = CH2
17: R = H, X = CH2
Wittig
9: R = TBS, X = O
10: R = TBS, X = CH2
11: R = H, X = CH2
OH
Ph
O
Wittig
H
H
deprotection
1: R1 = H, R2 = Me
2: R1 = R2 = Me
3: R1 = Me, R2 = H
4: R1 = R2 = H
deprotection
Scheme 1 Conventional synthesis of tetrahydropyran intermediates 1 and 2 with/without angular methyl group(s) at the 2,6-positions. For 1,
total 9 steps, 8 chromatographic purifications; total yield: 55%. For 2, total 11 steps, 8 chromatographic purifications; total yield: 43%.
H
H
H
H
H
O
OH
OH
e
d
OH
OH
a,b
c
O
O
O
O
CO2Et
HO
Ph
O
Ph
O
O
OH
Ph
O
OH
H
OH
Me
Me
Me
23
5
22
2-deoxy-D-ribose
Me
Me
O
O
H
OH
H
O
Me
H
O
g
O
O
O
O
Ph
O
X
OH
O
Ph
O
H
H
Me
Me
f
Me
Shi's ketone (24)
1
25: X = O
26: X = CH2
Scheme 2 Improved recipe for tetrahydropyran 1. Reagents and conditions: a) Ph3P=C(Me)CO2Et, THF, reflux; b) PhCHO, CH(OMe)3, CSA,
CH2Cl2, r.t., 86% (2 steps); c) DIBAL-H (3.3 equiv), CH2Cl2, –64 to –50 °C, 90%; d) Shi’s ketone 24 (25 mol%), Oxone®, DMM, MeCN, KOH,
K2CO3–AcOH buffer (pH 9.3), –10 °C; e) TEMPO (0.9 mol%), NaOCl, KBr (9 mol%), NaHCO3, CH2Cl2, H2O, 0 °C; f) Ph3PMeBr, t-BuOK,
THF, 0 °C; g) silica gel 60N (neutral, spherical, particle size 40–50 μm), 120 °C, 44% (4 steps); total 7 steps, 3 chromatographic purifications;
total yield: 34%.
was directly treated with benzaldehyde and trimethyl or- and ii) the highly chemoselective, inexpensive, and odor-
thoformate (instead of expensive benzaldehyde dimethyl less catalytic oxidation of primary alcohol into the corre-
acetal) in the presence of 10-camphorsulfonic acid (CSA) sponding aldehyde 25 using 0.9 mol% of 2,2,6,6-
to furnish alcohol 5 in 86% yield for the two steps. Al- tetramethylpiperidine 1-oxyl (TEMPO).23b,28 In this se-
though the traditional recipe prescribes the protection of 5 quential manipulation, both the stereoselectivity and the
as the TBS ether 6, we envisaged that the protection is not functional group compatibility of the Shi epoxidation
necessary if the asymmetric epoxidation of 22 and the se- were excellent (dr >12:1, even in the presence of the two
lective oxidation of primary alcohol 23 could proceed. hydroxy groups), and the key to success for the TEMPO
Thus, we first carried out DIBAL-H reduction of ester 5 oxidation was the precise restriction of the amount of re-
without protecting the secondary hydroxy group to give oxidant (NaOCl) to avoid overoxidation of the resultant
diol 22 (90% yield). As a result of considerable experi- aldehyde into carboxylic acid. The subsequent sequential
mentation, the desired conversion was achieved via the two steps were also able to be fulfilled without chroma-
combination of two modern reactions: i) Shi asymmetric tography, i.e. the Wittig reaction [using inexpensive t-
epoxidation (resulting in 23)26 catalyzed by ketone 24,27 BuOK instead of sodium hexamethyldisilazide (NaH-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2417–2425

2420
T. Nakashima et al.
PAPER
MDS) as a base], and solid-phase 6-endo-tet cyclization The next task was the axial selective installation of a
of vinyl epoxide 26 on silica gel 60N (instead of treatment methyl group to the ketone moiety of 12, and the subse-
with PPTS in the solution phase) at 120 °C for 4 hours, quent 1,2-reduction of the α,β-unsaturated ester. Despite
gave a crude material containing 1, which had already the conventional procedure, in which the hydroxy group
been absorbed by the silica gel. Therefore, after the final generated after methylation is protected as the TMS ether
step was finished, the solid reaction mixture was simply 14, we surmised that silylation had to be avoided, since
settled onto the top of a silica gel column and purified the installed TMS group was found to cleave too easily
chromatographically to afford pure compound 1 (44% during chromatographic purification. In addition, we no-
yield for 4 steps).
ticed that if a silylating step could be skipped, there would
be a second advantage. That is, ‘time-integrated’25 one-
pot conversion of ketone 12 into diol 27 seemed to emerge
since, in this methylation–reduction sequence, the same
solvent (CH2Cl2) and the same workup procedure (treat-
ment with MeOH followed by aqueous Rochelle salt)
were to be utilized. Hence, a solution of the crude ketone
12 was first treated with Me3Al at –20 °C; then, to the re-
sulting mixture, DIBAL-H was added at –65 °C. As ex-
pected, the reaction proceeded smoothly and cleanly to
give diol 27 in excellent yield (79% for 3 steps). More-
over, this ‘time-integrated chemistry’ resulted in a third
benefit, namely, ‘saving of the reagent.’ In other words,
this one-pot reaction required only 2.2 equivalents of
DIBAL-H, in contrast to the reduction of hydroxy ester 5
(3.3 equiv; Scheme 2, step c), probably because the gen-
erated tertiary alcoholic moiety was in situ protected, tem-
porarily but effectively, as the dimethylaluminum species
28.
The total yield for the above sequence from 2-deoxy-D-ri-
bose to THP 1 was 34%, and the average yield was 86%
for each step. The number of steps (seven) and chromato-
graphic purifications (three), as well as the cost (ca. >20%
less29), have all been reduced relative to the conventional
method with nine steps and eight chromatographic purifi-
cations. Finally, it should be emphasized that the devel-
oped recipe significantly facilitates the large-scale
preparation of THP, with considerable operational sim-
plicity and reproducibility.
After developing the effective and expeditious method to
prepare 1, we turned our attention to applying this meth-
odology to the synthesis of THP derivative 2, equipped
with two angular methyl groups (Scheme 3). Commenc-
ing from a common intermediate 5, the first task was the
oxidation of secondary alcohol 5 into the corresponding
ketone 12. In this step, the ideal conditions to be pursued
should result in the clean formation of ketone 12 without
chromatographic purification, since ketone 12 was re-
vealed to be labile under both mildly basic and acidic con-
ditions; that is, treatment of 12 under the basic conditions
resulted in the epimerization of 12 into 12′ and, further-
more, a critical loss of 12 was also observed upon sluggish
purification using neutral silica gel.30 As a result of exam-
ining various modern catalytic oxidations to overcome the
above problems,31 we finally found that only 0.05 mol%
of 2-azaadamantane N-oxyl (AZADO)32 in the presence
Finally, the end game of this synthesis was carried out via
the same manipulations as for THP 1: epoxidation and
TEMPO/NaOCl oxidation of allylic alcohol 27 followed
by Wittig olefination and silica-gel-assisted 6-endo-tet
cyclization of vinyl epoxide 30 furnished THP 2 in suc-
cessful yield (32% for 4 steps). Interestingly, in the case
of 2, the final 6-endo cyclization required treatment with
silica gel 60 (Kanto Chemical Co., Inc.) at 60 °C, instead
of silica gel 60N at 120 °C.34
of sodium hypochlorite as a reoxidant33 worked satisfac- Consequently, dozens of grams of THP 2 became accessi-
torily to convert alcohol 5 into the corresponding ketone ble via only eight steps and three chromatographic purifi-
12, which was pure enough to be utilized in the next reac- cations from the commercially available 2-deoxy-D-
tion without further purification.
ribose in 22% total yield (cf. the original work of
Nicolaou’s group: the total yield was 43%, but in 11 steps
H
Me
Me
O
OH
a
b
O
OH
O
O
O
AlMe2
Me
O
CO2Et
CO2Et
CO2Et
Ph
O
Ph
O
Ph
O
Ph
O
OH
R
H
H
H
Me
Me
Me
12: R = β-H
12': R = α-H
5
28
27
Me Me
O
Me
OH
c,d
f
O
O
O
OH
Ph
O
Ph
O
X
H
H
H
Me
2
29: X = O
30: X = CH2
e
Scheme 3 Improved recipe for tetrahydropyran 2. Reagents and conditions: a) AZADO (0.05 mol%), NaOCl, KBr (10 mol%), NaHCO3,
CH2Cl2, H2O, 0 °C; b) Me3Al, CH2Cl2, –20 °C; then DIBAL-H, –65 °C, 79% (3 steps); c) Shi’s ketone 24 (25 mol%), Oxone®, DMM, MeCN,
KOH, K2CO3–AcOH buffer (pH 9.3), –10 °C; d) TEMPO (1 mol%), NaOCl, KBr, NaHCO3, CH2Cl2, H2O, 0 °C; e) Ph3PMeBr, t-BuOK, THF,
0 °C; f) silica gel 60 (spherical, particle size 40–50 μm), 50 to 60 °C, 32% (4 steps); total 8 steps, 3 chromatographic purifications; total yield:
22%.
Synthesis 2013, 45, 2417–2425
© Georg Thieme Verlag Stuttgart · New York

PAPER
Facile Synthesis of Tetrahydropyrans toward Ladder-Shaped Polyethers
2421
for 2 steps)] as a colorless powder, whose spectroscopic data were
fully identical to those in the literature.8b
requiring 8 chromatographic purifications). Additionally,
the cost of the new recipe is comparable to the traditional
procedure.29
Diol 22
Alcohol 5 (47.45 g, 0.1549 mol) was dried by azeotropy with tolu-
ene. At –64 °C under an argon atmosphere, to a soln of alcohol 5 in
CH2Cl2 (150 mL) was added 1.0 M DIBAL-H in toluene (510 mL,
0.510 mol) over a period of 20 min. After being stirred at –64 to
–50 °C for 75 min, the reaction mixture was quenched with MeOH.
After vigorous gas evolution had ceased, sat. aq NH4Cl was added
and the mixture was then allowed to warm to 0 °C with care due to
further evolution of gas. At 0 °C, to the mixture were added EtOAc
and sat. aq sodium potassium tartrate (500 mL), and the reaction
mixture was allowed to warm to r.t. The mixture was vigorously
stirred at r.t. (overnight), until the layers became separable. The
mixture was extracted with EtOAc, and the extract was washed with
sat. aq NaCl, dried over Na2SO4, and filtered. The filtrate was con-
centrated and the residue was purified by silica gel (550 g) column
chromatography (hexane–EtOAc, 3:1 to 1:1) to give diol 22; yield:
36.86 g (0.139 mol, 90%); colorless, amorphous.
In conclusion, we have disclosed a facile, odorless, and
robust recipe to synthesize tetrahydropyran derivatives
with axial methyl group(s) at the 2,6-positions. The devel-
oped practical recipe, adopting the chemoselective cata-
lytic oxidations, the one-pot reaction, and only three
chromatographic purifications, realized rapid access to
THP 1 and 2 in only seven and eight steps, respectively.
This revamped route, highlighting promptness and repro-
ducibility, will accelerate the race for the total syntheses
not only of LSPs, but also of other natural products.35 At
the same time, it indicates that the synergistic power of
blending modern ideas, such as catalytic and time-inte-
grated chemistries, should be recognized and used by syn-
thetic chemists in the fight against structurally complex
natural products, in the next generation.
[α]D21 –30.6 (c 0.35, CHCl3); Rf = 0.20 (hexane–EtOAc, 1:1).
IR (film): 3333, 2937, 2921, 2858, 2831, 1455, 1398, 1366, 1314,
1294, 1217, 1182, 1129, 1074, 1022 cm–1.
Synthetic studies of ladder-shaped polyethers toward
mechanistic elucidation of their biological activities, us-
ing large amounts of tetrahydropyran derivatives supplied
by the improved recipe, are now in progress in our labora-
tory.
1H NMR (600 MHz, CDCl3): δ = 7.48–7.47 (m, 2 H), 7.40–7.38 (m,
3 H), 5.62 (dt, J = 6.9, 1.4 Hz, 1 H), 5.46 (s, 1 H), 4.21 (dd, J = 10.3,
4.1 Hz, 1 H), 3.98 (br s, 2 H), 3.64–3.59 (m, 2 H), 3.54 (dd, J = 10.3,
10.3 Hz, 1 H), 2.65 (br s, 1 H), 2.64–2.60 (m, 1 H), 2.48–2.43 (m, 1
H), 2.12 (br s, 1 H), 1.70 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 137.7, 137.1, 129.0, 128.9, 128.2,
126.1, 121.0, 100.9, 81.4, 71.1, 68.5, 65.4, 30.3, 14.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H20O4Na+:
287.1254; found: 287.1258.
For all the moisture-sensitive reactions, the substrates were dried by
azeotropic removal of water with toluene (ca. 100 mL, 2 ×). Anhyd
CH2Cl2 and THF were purchased from Kanto Chemical Co., Inc.
and used without further drying. All other chemicals were obtained
from local venders and used as supplied. Analytical thin-layer chro-
matography (TLC) was performed using E. Merck silica gel 60 F254
precoated plates (0.25-mm thickness). For column chromatogra-
phy, Kanto silica gel 60N (neutral, spherical, 100–210 μm) was uti-
lized. Optical rotations were recorded on a JASCO P-1010
polarimeter. IR spectra were recorded on a JASCO FT-IR-4100
Fourier transform infrared spectrometer. NMR spectra were record-
ed on a JEOL JNM-ECA600 spectrometer. Chemical shifts are re-
ported in ppm from TMS with reference to internal residual solvent
[1H NMR, CHCl3 (7.26); 13C NMR, CDCl3 (77.0)]. The following
abbreviations are used to designate the multiplicities: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet. High-resolution
mass spectra (HRMS) were recorded on a Bruker micrOTOF II in-
strument under ESI-TOF conditions.
Tetrahydropyran 1
Diol 22 (18.00 g, 68.10 mmol) and Shi’s ketone 24 (4.40 g, 17.3
mmol) were placed in a 2-L, three-necked, round-bottomed flask
equipped with two dropping funnels. DMM (330 mL), MeCN (165
mL), and pH 9.3 aq K2CO3–AcOH buffer [330 mL, prepared by
mixing 0.1 M aq K2CO3 (500 mL) with AcOH (2.4 mL)] were add-
ed, and the reaction mixture was cooled to –10 °C. To the stirred so-
lution were slowly added Oxone® soln [50.6 g, 0.0823 mol, in 0.4
M aq EDTA·2Na (187 mL)] and 1.47 M aq KOH (187 mL, 0.275
mol) from separate dropping funnels over a period of 3 h. After the
reaction was quenched with sat. aq Na2S2O3, the mixture was ex-
tracted with EtOAc, and the extract was washed with sat. aq NaCl,
dried over Na2SO4, and filtered. The filtrate was concentrated to
give crude epoxide 23, which was used in the next reaction without
further purification. Two times operation of the above process fur-
nished 39.95 g of crude epoxide 23.
α,β-Unsaturated Ester 5
Under an argon atmosphere, to a soln of 2-deoxy-D-ribose (25.00 g,
0.1863 mol) in THF (150 mL) was added ethyl 2-(triphe-
nylphosphoranylidene)propionate (81.71 g, 0.2255 mol). After be-
ing stirred under reflux for 2 h, the reaction mixture was cooled to
r.t., the solvent was removed in vacuo, and the residue was dried by
azeotropy with toluene.
To a mixture of crude alcohol 23 (39.95 g) and TEMPO (192 mg,
1.23 mmol) were added CH2Cl2 (450 mL) and 0.5 M aq KBr (24.5
mL, 12.3 mmol). At 0 °C, to this mixture was added a mixture of
1.96 M aq NaOCl (74.0 mL, 0.145 mol) and sat. aq NaHCO3 (74.0
mL). After being stirred at 0 °C for 30 min, the reaction mixture was
quenched with sat. aq Na2S2O3 and extracted with EtOAc, and the
extract was washed with sat. aq NaCl, dried over Na2SO4, and fil-
tered. The filtrate was concentrated to give crude aldehyde 25
(34.94 g), which was used in the next reaction without further puri-
fication.
Under an argon atmosphere at 0 °C, to a soln of the above crude ma-
terial in CH2Cl2 (167 mL) were added benzaldehyde (23.0 mL,
0.225 mol), trimethyl orthoformate (24.7 mL, 0.225 mol), and (±)-
10-camphorsulfonic acid (15.0 g, 0.0646 mol). After being stirred
at r.t. for 22 h, the reaction mixture was quenched with Et3N (13.5
mL, 0.0974 mol) at 0 °C and concentrated in vacuo. A mixed sol-
vent (hexane–EtOAc–CHCl3, 8:1:0.1, 50 mL) was added to the re-
sultant oil to give a less viscous syrup, which was then absorbed
onto dry silica gel (150 g). This silica gel, possessing crude materi-
al, was settled onto the top of a silica gel (750 g) column; the sub-
sequent chromatographic purification (hexane–EtOAc, 8:1 to 5:1 to
3:1) gave α,β-unsaturated ester 5 [yield: 49.05 g (0.1601 mol, 86%
At 0 °C under an argon atmosphere, to a soln of methyltriphe-
nylphosphonium bromide (110.0 g, 0.3079 mol, dried by warming
in vacuo using a hair dryer) in THF (525 mL) was added t-BuOK
(32.00 g, 0.2851 mol). After being stirred at 0 °C for 50 min, to the
yellow suspension was added a soln of crude aldehyde 25 (34.94 g,
dried by azeotropy with toluene) in THF (200 mL) over a period of
10 min, and the resulting reaction solution was stirred at 0 °C for 1
h. The reaction mixture was quenched with sat. aq NH4Cl and dilut-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2417–2425

2422
T. Nakashima et al.
PAPER
ed with EtOAc. The resulting mixture was extracted with EtOAc,
and the extract was washed with sat. aq NaCl, dried over Na2SO4,
and filtered. The filtrate was concentrated to give crude vinyl epox-
ide 26, which was used in the next reaction without further purifica-
tion.
the reaction mixture was cooled to –10 °C. To the stirred solution
were slowly added Oxone® soln [46.00 g, 74.82 mmol, in 0.4 M aq
EDTA·2Na (170 mL)] and 1.47 M aq KOH (170 mL, 0.250 mol)
from separate dropping funnels over a period of 3 h. After the reac-
tion was quenched with sat. aq Na2S2O3, the mixture was extracted
with EtOAc, and the extract was washed with sat. aq NaCl, dried
over Na2SO4, and filtered. The filtrate was concentrated to furnish
crude epoxide, which was used in the next reaction without further
purification. Two times operation of the above process furnished
46.80 g of crude epoxide.
To a soln of the crude vinyl epoxide 26 (all of previous) in EtOAc
was added silica gel 60N (150 g, neutral, spherical, particle size 40–
50 μm, Kanto Chemical Co., Inc.). The volatiles were removed in
vacuo, and the residue was heated at 120 °C for 4 h. The residue was
settled onto the top of a silica gel (650 g) column, and purified by
chromatography (hexane–EtOAc, 7:1 to 5:1 to 4:1) to afford tetra-
hydropyran 1 (16.72 g, 60.5 mmol, 44% for 4 steps) as a colorless
powder, whose spectroscopic data were fully identical to those in
the literature.8b
To a mixture of the crude epoxide (46.80 g) and TEMPO (200 mg,
1.28 mmol) were added CH2Cl2 (450 mL) and 0.5 M aq KBr (26.0
mL, 13.0 mmol). At 0 °C, to this mixture was added a mixture of
1.86 M aq NaOCl (74.0 mL, 0.138 mol) and sat. aq NaHCO3 (74.0
mL). After being stirred at 0 °C for 17 min, the reaction mixture was
quenched with sat. aq Na2S2O3 and extracted with EtOAc, and the
extract was washed with sat. aq NaCl, dried over Na2SO4, and fil-
tered. The filtrate was concentrated to give crude aldehyde 29,
which was used in the next reaction without further purification.
Diol 27
To a soln of alcohol 5 (50.10 g, 0.1635 mol) in CH2Cl2 (370 mL)
were added AZADO (13.7 mg, 90.0 μmol) and 0.50 M aq KBr (33.0
mL, 16.5 mmol). At 0 °C, to this mixture was added a mixture of
1.96 M aq NaOCl (115 mL, 0.225 mol) and sat. aq NaHCO3 (420
mL). After being stirred at 0 °C for 2 h, the reaction mixture was
quenched with sat. aq Na2S2O3 and extracted with EtOAc, and the
extract was washed with sat. aq NaCl, dried over Na2SO4, and fil-
tered. The filtrate was concentrated to give crude ketone 12 (50.86
g), which was used in the next reaction without further purification.
At 0 °C under an argon atmosphere, to a soln of methyltriphe-
nylphosphonium bromide (100.0 g, 0.2799 mol, dried by warming
in vacuo using a hair dryer) in THF (525 mL) was added t-BuOK
(30.00 g, 0.267 mol). After being stirred at 0 °C for 40 min, to the
yellow suspension was added a soln of crude aldehyde 29 (all of
previous; dried by azeotropy with toluene) in THF (200 mL) over a
period of 12 min, and the resulting reaction solution was stirred at
0 °C for 30 min. The reaction mixture was quenched with sat. aq
NH4Cl, and diluted with EtOAc. The resulting mixture was extract-
ed with EtOAc and the extract was washed with sat. aq NaCl, dried
over Na2SO4, and filtered. The filtrate was concentrated to give
crude vinyl epoxide 30 (105.25 g), which was used in the next reac-
tion without further purification.
Under an argon atmosphere at –20 °C, to a soln of the crude ketone
12 (50.86 g, dried by azeotropy with toluene) in CH2Cl2 (300 mL)
was added 1.05 M Me3Al in hexane (240 mL, 0.252 mol) over a pe-
riod of 12 min. After being stirred at –20 °C for 1 h, the reaction
mixture was cooled to –65 °C and 1.0 M DIBAL-H in toluene (370
mL, 0.370 mol) was added over a period of 16 min. After being
stirred at –65 °C for 40 min, the reaction mixture was quenched
with MeOH. After vigorous gas evolution had ceased, sat. aq NH4Cl
was added and the mixture was then allowed to warm to 0 °C with
care due to further evolution of gas. At 0 °C, to the mixture were
added EtOAc and sat. aq sodium potassium tartrate (500 mL), and
the reaction mixture was allowed to warm to r.t. The mixture was
divided into two flasks, and to both flasks was added additional sat.
aq sodium potassium tartrate (500 mL each). Both reaction mixtures
were vigorously stirred at r.t. (overnight), until the layers became
separable. The mixture was extracted with EtOAc, and the extract
was washed with sat. aq NaCl, dried over Na2SO4, and filtered. The
filtrate was concentrated and the residue was purified by silica gel
(400 g) column chromatography (hexane–EtOAc, 2:1 to 1:1) to give
diol 27; yield: 36.10 g (0.130 mol, 79% for 3 steps); colorless, amor-
phous.
To a soln of the crude vinyl epoxide 30 (all of previous) in EtOAc
was added silica gel 60 (150 g, spherical, particle size 40–50 μm,
Kanto Chemical Co., Inc.). The volatiles were removed from the
smooth slurry in vacuo, and the residue was heated at 50 °C for 25
h, then at 60 °C for 18 h. The residue was settled onto the top of a
silica gel (700 g) column, and purified by chromatography (hexane–
EtOAc, 7:1 to 5:1 to 4:1) to afford tetrahydropyran 2 (12.00 g, 41.3
mmol, 32% for 4 steps) as a colorless powder, whose spectroscopic
data were fully identical to those in the literature.8b
Acknowledgment
We are grateful to Prof. Dr. Yoshiharu Iwabuchi of Tohoku Univer-
sity for kindly providing us with AZADO and 1-Me-AZADO. We
are grateful to Prof. Dr. Tohru Oishi in our laboratory for invaluable
discussion and support. We thank Mr. Nicholas Shillingford in the
Office for Program Promotion of the Graduate School of Sciences,
Kyushu University, for his support during the manuscript prepara-
tion. This work was financially supported by the Grant-in-Aid for
Young Scientists (B) (No. 23710274) from JSPS, MEXT project of
Integrated Research on Chemical Synthesis, SUNBOR GRANT
from the Suntory Institute for Bioorganic Research, Grant-in-Aid
from the Tokyo Biochemical Research Foundation, and Kyushu
University Interdisciplinary Programs in Education and Projects in
Research Development. A fellowship to T.N. from the GCOE pro-
gram at Osaka University, ‘Global Education and Research Center
for Bio-Environmental Chemistry’, is acknowledged.
[α]D20 –68.4 (c 0.13, CHCl3); Rf = 0.27 (hexane–EtOAc, 1:2).
IR (neat): 3373, 2975, 2925, 2858, 1454, 1396, 1310, 1213, 1095,
1074, 1025, 989, 960, 916, 888, 797, 748, 697, 666 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.49–7.47 (m, 2 H), 7.38–7.33 (m,
3 H), 5.57 (ddd, J = 6.8, 6.2, 1.4 Hz, 1 H), 5.47 (s, 1 H), 3.97 (s, 2
H), 3.86 (d, J = 10.3 Hz, 1 H), 3.63 (dd, J = 8.9, 4.1 Hz, 1 H), 3.61
(d, J = 10.3 Hz, 1 H), 2.51 (ddd, J = 15.1, 8.3, 4.1 Hz, 1 H), 2.25
(ddd, J = 15.1, 8.9, 7.6 Hz, 1 H), 1.69 (s, 3 H), 1.41 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 137.8, 136.4, 128.9, 128.2, 126.1,
121.9, 101.7, 84.0, 77.3, 68.4, 66.7, 27.5, 19.6, 13.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H22O4Na+:
301.1410; found: 301.1403.
Tetrahydropyran 2
Diol 27 (18.0 g, 64.7 mmol) and Shi’s ketone 24 (4.00 g, 15.5
mmol) were placed in a 2-L, three-necked, round-bottomed flask
equipped with two dropping funnels. DMM (330 mL), MeCN (165
mL), and pH 9.3 aq K2CO3–AcOH buffer (330 mL) were added, and
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
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Synthesis 2013, 45, 2417–2425
© Georg Thieme Verlag Stuttgart · New York

PAPER
Facile Synthesis of Tetrahydropyrans toward Ladder-Shaped Polyethers
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(b) Kadota, I.; Ueno, H.; Sato, Y.; Yamamoto, Y.
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(m) Nicolaou, K. C.; Gelin, C. F.; Seo, J. H.; Huang, Z.;
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(28) (a) de Nooy, A. E.; Besemer, A. C.; van Bekkum, H.
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(29) Total costs, including those of reagents, reaction solvents,
salts for workup, silica gel, and eluents for chromatography,
were calculated on the basis of the Sigma-Aldrich Japan
catalog prices, under the following assumption: that as much
salts, eluents, and silica gel as we consumed were used
during workup and chromatography in Nicolaou’s work; we
used much less expensive EtOAc as an eluent in
chromatography, instead of the Et2O used in Nicolaou’s
original work. The actual costs of 1 and 2 (10 g) were
256000 and 343000 yen, respectively, in our new recipe,
while they are ca. 357000 and 346000 yen, respectively, in
Nicolaou’s original procedure, although a precise
calculation is difficult.
(30) The yield of 12 in the traditional recipe (68–97%) highly
depends on personal technique. For good yield, speed in
carrying out the large-scale column chromatography (using
more than 500 g of silica gel, within approximately 10 min)
is required. Ketone 12 was found to epimerize slowly to 12′
even under the basic conditions (e.g., CH2Cl2, sat. aq
NaHCO3, 0 °C, 40 h; 12/12′ = 4:1).
(31) For instance, catalytic IBX or 2-iodoxybenzenesulfonic acid
in the presence of Oxone® as a co-oxidant failed to transform
alcohol 5 to ketone 12, resulting in the decomposition of the
substrate. For details of the catalytic use of IBX-type
oxidants with Oxone®, see: (a) Thottumkara, A. P.;
Bowsher, M. S.; Vinod, T. K. Org. Lett. 2005, 7, 2933.
(b) Uyanik, M.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc.
2009, 131, 251.
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its physical properties as a stable radical, see: (a) Dupeyre,
R. M.; Rassat, A. Tetrahedron 1978, 34, 1901. (b) Stetter,
H.; Tacke, P.; Gärtner, J. Chem. Ber. 1964, 97, 3480.
(c) Henkel, J. G.; Faith, W. C. J. Org. Chem. 1981, 46, 4953.
Synthesis 2013, 45, 2417–2425
© Georg Thieme Verlag Stuttgart · New York

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Facile Synthesis of Tetrahydropyrans toward Ladder-Shaped Polyethers
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(33) Although 0.1 mol% of 1-Me-AZADO was also found to
work effectively to oxidize alcohol 5 into ketone 12,
AZADO was selected due to its higher reactivity and
inexpensiveness when it was used as supplied from Wako
Pure Chemical Industries, Ltd. For the practical synthesis of
AZADO and 1-Me-AZADO, and their application in the
oxidation of alcohols, see: Shibuya, M.; Tomizawa, M.;
Iwao, S.; Iwabuchi, Y. J. Am. Chem. Soc. 2006, 128, 8412.
(34) Attempted cyclization of 30 to 2 with silica gel 60N at
120 °C was sluggish, and resulted in an unclean reaction
with many unidentifiable byproducts.
(35) For instance, see: (a) Gilley, C. B.; Buller, M. J.; Kobayashi,
Y. J. Synth. Org. Chem., Jpn. 2009, 67, 1183. (b) Sheddan,
N. A.; Czybowski, M.; Mulzer, J. Chem. Commun. 2007,
2107. (c) Fürstner, A.; Schlede, M. Adv. Synth. Catal. 2002,
344, 657. (d) Mulzer, J.; Czybowski, M.; Bats, J.-W.
Tetrahedron Lett. 2001, 42, 2961.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2417–2425