Vinylogy in orthoester hydrolysis: Total syntheses of cyclophellitol, valienamine, gabosine K, valienone, gabosine G, 1-epi-streptol, streptol, and uvamalol A

Article abstract of DOI:10.1021/jo401272j

C7-cyclitols represent an important category of natural products possessing a broad spectrum of biological activities. As each member of these compounds is structurally unique, the usual practice is to synthesize them individually from appropriate polyhydroxylated chiral pools. We have observed an unusual vinylogy in acid mediated hydrolysis of enol ethers of myo-inositol 1,3,5-orthoesters giving a synthetically versatile polyhydroxylated cyclohexenal intermediate. We have exploited this unprecedented reaction for developing a general strategy for the rapid and efficient syntheses of several structurally diverse natural products of C7-cyclitol family. We have made an appropriately protected advanced intermediate 25 in five steps from the cheap and commercially available myo-inositol, and this common intermediate has been used to synthesize eight natural products in racemic form. We could synthesize (±)-cyclophellitol in seven steps, (±)-valienamine in five steps, (±)-gabosine I in five steps, (±)-gabosine G in six steps, (±)-gabosine K in three steps, (±)-streptol in six steps, (±)-1-epi-streptol in two steps, and (±)-uvamalol A in five steps from this intermediate.

Full text of DOI:10.1021/jo401272j

Article
pubs.acs.org/joc
Vinylogy in Orthoester Hydrolysis: Total Syntheses of Cyclophellitol,
Valienamine, Gabosine K, Valienone, Gabosine G, 1-epi-Streptol,
Streptol, and Uvamalol A
Soumik Mondal, Annamalai Prathap, and Kana M. Sureshan*
School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala 695016,
India
S
* Supporting Information
ABSTRACT: C7-cyclitols represent an important category of natural
products possessing a broad spectrum of biological activities. As each
member of these compounds is structurally unique, the usual practice is to
synthesize them individually from appropriate polyhydroxylated chiral
pools. We have observed an unusual vinylogy in acid mediated hydrolysis
of enol ethers of myo-inositol 1,3,5-orthoesters giving a synthetically
versatile polyhydroxylated cyclohexenal intermediate. We have exploited
this unprecedented reaction for developing a general strategy for the rapid
and efficient syntheses of several structurally diverse natural products of C7-cyclitol family. We have made an appropriately
protected advanced intermediate 25 in five steps from the cheap and commercially available myo-inositol, and this common
intermediate has been used to synthesize eight natural products in racemic form. We could synthesize ( )-cyclophellitol in seven
steps, ( )-valienamine in five steps, ( )-gabosine I in five steps, ( )-gabosine G in six steps, ( )-gabosine K in three steps,
( )-streptol in six steps, ( )-1-epi-streptol in two steps, and ( )-uvamalol A in five steps from this intermediate.
prominent members of gabosine family. They were isolated
from Streptomyces strain and shown to possess antibiotic,
anticancer and DNA binding properties.10 Streptol (valienol)
was also isolated from Streptomyces sp., and it has plant growth
inhibitory activity.11 1-epi-Streptol (1-epi-valienol) is an
intermediate involved in the biosynthesis of acarbose, an α-
glucosidase inhibitor, in Actinoplanes and Streptomyces.12 Many
of these natural cyclitols have been the targets of several total
syntheses due to their attractive biological properties.2,13
Because of their structural diversity, it has been a usual practice
to synthesize them individually from different polyhydroxylated
chiral pools such as D-glucose, D-xylose, quebrachitol, etc., and
these strategies often necessitate multiple protecting group
manipulations.14 We herein report an unusual conjugative ring-
opening of the orthoester cage in myo-inositol 1,3,5-orthoesters
giving a synthetically versatile polyhydroxylated cyclohexenal
intermediate and the exploitation of this unprecedented
reaction in developing a general strategy for the rapid and
efficient syntheses of eight structurally diverse natural products
of C7-cyclitol family, namely, ( )-cyclophellitol, ( )-valien-
amine, ( )-gabosine K, ( )-gabosine G, ( )-valienone, ( )-1-
epi-streptol, ( )-streptol and ( )-uvamalol A.
INTRODUCTION
■
C7-cyclitols, polyhydroxycyclohexane with an exocyclic methyl
or hydroxymethyl substituent, represent an important category
of natural products possessing a broad spectrum of biological
activities such as anticancer, antibacterial, antifungal, HIV
inhibitory, enzyme inhibitory activities, etc.1−5 Gabosines,2
pericosines,3 cyclophellitol,4 C7-aminocyclitols5 such as valien-
amine, valiolamine and validamine are some of the members of
this family of cyclitols (Figure 1). For instance, cyclophellitol,
isolated from the mushroom Phellinus sp.,6 is a potent β-
glucosidase inhibitor, and it also possesses HIV inhibitory
activity.7 Valienamine, a strong α-glucosidase inhibitor,8 is a
metabolite in the microbial9 degradation of validoxylamine A.
Gabosine I (valienone), gabosine G and gabosine K are the
RESULTS AND DISCUSSION
■
Because of the importance of carbohydrates in various
biological processes, sugar mimics received much attention as
Received: June 13, 2013
Figure 1. Representative C-7 cyclitol natural products.
© XXXX American Chemical Society
A
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a
Scheme 1. Unusual Vinylogy in the Hydrolysis of Differently Protected myo-Inositol Orthoesters
a
Reagents and conditions: (a) PPh3CH2OMeCl, tBuOK, THF, 0 °C to reflux, 2 h, (14; 92%, 20; 90%). (b) 0.1 M aq. HCl, THF, rt, 1 h. (c) NaBH4,
CeCl3, MeOH, 0 °C, 1 h (17 + 18; 90% 2 steps, 22; 91%, 2 steps).
potential inhibitors for the glycan processing enzymes.15
Inositols, cyclohexane hexols, are carbocyclic mimics of
hexopyranoses lacking the exocyclic hydroxymethyl group. As
part of our program to synthesize inhibitors of various
glycosidases, we planned to synthesize various carbasugars
from inositols by converting a hydroxyl group to an exocyclic
hydroxymethyl group via the one carbon homologation of the
corresponding protected inosose to the exocyclic aldehyde by
adopting the method of Barton et al. (Scheme 1A).16 In order
to test this hypothesis, readily available unsymmetrical inosose
1317 was converted to the Wittig product 14 as an inseparable
mixture of E/Z (1:1) isomers in 92% yield. Acidic hydrolysis of
14 surprisingly gave an inseparable mixture of α,β-unsaturated
aldehydes 15 and 16 (Scheme 1B) instead of the expected
aldehyde 10a. This mixture of aldehydes on reduction gave
alcohols 17 and 18, which could be separated by chromatog-
raphy. The stereochemistry of alcohols 17 and 18 were
assigned after acetylation. In order to check the generality of
this unusual reaction, the methoxy-Wittig product 20 obtained
from the known symmetrical inosose 1918 was treated with
dilute acid. Interestingly, in this case also, the corresponding
enal 21 (Scheme 1C) was formed along with its formate ester
as an inseparable mixture, which on reduction gave the triol 22
as the only product (91%) suggesting that the observed
vinylogous ring-opening reaction is general (see Supporting
Information for mechanistic details). This intriguing reaction is
very attractive as many natural C7-cyclitols and analogues can
be made from the α,β-unsaturated aldehydes produced in these
reactions (e.g., 15, 16, 21) by choosing appropriate protecting
groups. In order to illustrate the synthetic utility of this
interesting transformation, we have undertaken the syntheses of
cyclophellitol (1), valienamine (2), gabosine I (3), gabosine G
(4), streptol (5), 1-epi-streptol (6), gabosine K (7) and
uvamalol A (8). All these eight C7-cyclitols contain three
common contiguous stereogenic centers at C-2, C-3 and C-4
positions, which is present in the enal 21 too. Hence, minimal
synthetic manipulations of stereogenic centers are sufficient to
synthesize these target compounds from such α,β-unsaturated
aldehydes. The retrosynthetic analyses (see the Supporting
Information) reveal that all of these natural products can be
synthesized from the enal 25, which can be prepared from the
myo-inositol derived ketone 23.19
The ketone 23 was prepared, in 42% yield, from
commercially available myo-inositol as reported.19 The ketone
23 on Wittig reaction with methoxymethyltriphenylphospho-
nium chloride gave the enol ether 24 in 95% yield. The enol
ether 24 on acidic hydrolysis with a few drops of aqueous HCl
(0.1 M) in THF gave the advanced intermediate, enal 25, in
quantitative yield. The structure of the compound 25 was
established by both NMR experiments and X-ray crystallo-
graphic analysis (see the Supporting Information, Figure S1).
This advanced intermediate can be made in multigram
quantities from cheaply available myo-inositol in overall yields
up to 40%.
Luche reduction20 of the α,β-unsaturated aldehyde 25
resulted in the formation of the triol 26 in 92% yield (Scheme
2). Benzylation of triol 26 with excess of benzyl bromide gave
the tribenzyl ether 27 in 91% yield. Hydroboration21 of the
alkene 27 with BH3·Me2S followed by oxidation with H2O2/
NaOH gave the alcohol 28, as the exclusive diastereomer
(81%). While the anti-Markovnikov’s addition of the borane
dictated the regiochemistry, the steric hindrance by the bulky
PMB group dictated the stereochemistry. The relative stereo-
chemistry of 28 was assigned after acetylation using NMR
spectroscopy. As anticipated, the hydroboration of 28 has taken
place from the face opposite to the bulky PMB group at C-1.
The compound 28 was reacted with mesyl chloride to give the
mesylate 29 in quantitative yield. TFA mediated removal of
PMB ether protecting groups gave the diol 30 (88%), wherein
hydroxyl group at C-1 and mesyloxy group are disposed in anti
B
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a
Scheme 2. Total Syntheses of ( )-Cyclophellitol and ( )-Valienamine
a
Reagents and conditions: (a) PPh3CH2OMeCl, tBuOK, THF, 0 °C to reflux, 2 h, 95%. (b) 0.1 N aq. HCl, THF, rt, 8 h, quantitative. (c) NaBH4,
CeCl3·7H2O, MeOH, 0 °C, 1 h, 92%. (d) NaH, BnBr, DMF, 0 °C, 20 min, 91%. (e) BH3·SMe2, H2O2, NaOH, 10 h, (81%). (f) Pyridine, MsCl, 0
°C, 1 h, quantitative. (g) TFA, DCM, rt, 1 h, 88%. (h) NaH, DMF, 0 °C, 20 min, 91%. (i) Pd/C, H2 (1 atm), EtOAc, 0 °C, overnight, quantitative.
(j) TFA (10% in DCM), rt, 1 h, 91%. (k) DPPA, DBU, 0 °C, NaN3, Toluene, 83%. (l) BCl3 (1 M solution in toluene), −60 °C to rt, 4 h, 80%. (m)
Ac2O, Pyridine, DMAP, rt, overnight, 90%.
orientation. Diol 30 on treatment with NaH produced the
epoxide 31 in 91% yield. Finally, the global deprotection, by
hydrogenolysis, provided ( )-cyclophellitol (1) in quantitative
yield. Thus, we could synthesize cyclophellitol in an overall
yield of 54% in seven steps from the common intermediate 25.
Having successfully exploited the vinylogous opening of the
orthoester in synthesizing cyclophellitol, we set out to
generalize this methodology for the synthesis of other C-7
cyclitol natural products. Thus, we carried out the synthesis of
( )-valienamine as follows. Alkene 27, obtained from 25, on
acidic hydrolysis gave the diol 32 in 91% yield (Scheme 2). Diol
32 on Mitsunobu reaction using diphenylphosphorylazide
(DPPA) and 1,8-diaza-bicyclo-undec-7-ene (DBU) gave the
azide 33 regioselectively in 83% yield.22 The structural
assignment was done with the help of various 2D NMR
pentaacetyl derivative 34, whose 1H NMR spectrum was
identical to the reported13i spectrum. We, therefore, could
achieve the total synthesis of ( )-valienamine in an overall
yield of 50.6% in five steps from the enal 25.
Next, we turned our attention to the synthesis of
( )-gabosine G and ( )-gabosine I. Diol 32 on selective
oxidation of the allylic alcohol functionality using Dess−Martin
periodinane25 gave the enone 35 (Scheme 3). Absence of any
3JHH coupling for the olefinic proton indicates the chemo-
selective oxidation of allylic alcohol. The removal of benzyl
ether protecting groups using BCl3 gave ( )-gabosine I (3) in
75% yield. It is noteworthy that 3 could be synthesized in just
five steps from enal 25 in an overall yield of 53.7%, making it an
attractive synthesis over many previous syntheses. ( )-Gabo-
sine G (4) was obtained by selective acetylation of the primary
hydroxyl group in ( )-valienone 3 using acetyl chloride and
2,4,6-collidine26 in 70% yield (37.4% from the enal 25 in six
steps; Scheme 3). We have chosen ( )-streptol as our next
synthetic target because of its interesting biological property as
plant growth inhibitor. As streptol (5) and the diol 32 have a
single stereochemical difference (at C1), it is reasonable to
invert the stereochemistry at C1 by an oxidation reduction
sequence to streptol. Thus, the enone 35 obtained from 32 was
subjected to reduction. Surprisingly, reduction of enone 35
using NaBH4 gave back the diol 32 as the exclusive product.
3
techniques. The small value of JH1H2 coupling constant (4.15
Hz) is supportive of syn relationship of H1 (H on azide
connected carbon) and H2 in a cyclohexane skeleton. This high
selectivity in the nucleophilic substitution reaction arises from
the increased reactivity of allylic hydroxyl group and its less
steric hindrance compared to the other hydroxyl group. As BCl3
is known to deprotect the benzyl ether23 and reduce the azide
to amine,24 azide 33 was treated with BCl3, for one-pot benzyl
deprotection and azide reduction. This provided ( )-valien-
amine (2) in 80% yield, which was characterized as its
C
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Scheme 3. Total Syntheses of ( )-Gabosine I, ( )-Gabosine
G and ( )-Streptol
Scheme 4. Total Syntheses of ( )-1-epi-Streptol,
( )-Gabosine K, and ( )-Uvamalol A
a
a
a
Reagents and conditions: (a) DMP, CH2Cl2, rt, 1 h, 94%. (b) BCl3
(1.0 M in toluene), −40 °C, 2 h, 75%. (c) 2,4,6-collidine, AcCl, −60
°C to rt, 1 h, 70%. (d) K-Selectride, −78 °C, THF, 1 h, 90%. (e) BCl3
(1.0 M in toluene), DCM, −78 °C, 4 h, 70%.
However, to our satisfaction, reduction with K-selectride gave
the reqired diol 36 stereospecifically. The bulky reducing agent
ensured the hydride delivery from the side opposite to the
benzyloxy group at C2. Though the less bulky NaBH4 has the
opportunity to attack from either sides, the stability of the
product (product 32 with all equatorial substituents is more
stable than the product 36 with an axial subtituent) might be
controlling the stereochemistry. Finally, benzyl ether protecting
groups were removed using BCl3 (Scheme 3) to get
( )-streptol (5). Thus the synthesis of ( )-streptol could be
completed in six steps from the common intermediate 25 in an
overall 45% yield.
1-epi-Streptol and its monoacetate gabosine K are two other
C7-cyclitols of our choice for the illustration of the utility of our
methodology. The stereochemical similarity of these molecules
with the intermediate 25 allow their synthesis in very few steps.
The triol 26, which could be prepared from the enal 25 in 92%
yield, on treatment with 10% triflic acid in DCM gave ( )-1-
epi-streptol (6) in 89% yield (Scheme 4). The primary hydroxyl
group in pentol 6 was selectively acetylated using acetyl
chloride and 2,4,6-collidine to afford ( )-gabosine K (7) in
62% yield (Scheme 4). Thus 1-epi-streptol and gabosine K
could be synthesized from the common intermediate 25 in
overall yields of 82 and 50.8%, respectively, in two and three
steps.
We next turned our attention to the synthesis of uvamalol A,
which was isolated from the roots of Uvaria macrophylla27 and
for which no synthesis or biological activity has been reported
to date. Triol 26 on selective benzoylation of primary alcohol
with benzoyl chloride in presence of 2,4,6-collidine gave the
benzoate 37 (Scheme 4) in 95% yield. Reaction of the benzoate
37 with TESOTf in presence of imidazole gave an inseparable
mixture of regioisomers 38 and 39 in 1.2:1 ratio (by 1H NMR).
These isomers were purified by column chromatography after
bezoylation with benzoyl chloride in pyridine. The desired
compound 40 was obtained in 36% yield (two steps).
Deprotection of both PMB groups and TES group using 10%
TFA in DCM led to the formation of ( )-uvamalol A (8) in
86% yield. Thus we could achieve the synthesis of Uvamalol A
in five steps from the common intermediate 25 in 27% overall
a
Reagents and conditions: (a) TFA (10% in DCM), rt, 1 h, 89%. (b)
2,4,6-collidine, AcCl, −60 °C, 1 h, 62%. (c) 2,4,6-collidine, BzCl, −0
°C to rt, 1 h, 95%. (d) TESOTf, DCM, imidazole, 0 °C, 2 h, 38:39 =
1.2:1, 68% overall. (e) pyridine, DMAP, BzCl, rt, 1 h, 36% (two steps).
(f) TFA, DCM, rt, 1 h, 86%.
yield. To the best of our knowledge, this is the first synthesis of
uvamalol A. The agreement between H NMR and 13C NMR
1
spectra of 8 with the reported data substantiates the previously
assigned structure of uvamalol.
Because of the dense functionality, myo-inositol has been
exploited as the starting material for the syntheses of several
natural products such as polyoxin J,28 tetrodotoxin,29
nojirimycin,30 brahol, pinpollitol,31 etc. The novel vinylogous
orthoester hydrolysis reported here affords synthetically
versatile enal, which has tremendous potential to be exploited
for the synthesis of many complex natural products. The well-
known protection−deprotection strategy in the chemistry of
myo-inositol32 can be judiciously exploited further to make
orthogonally protected intermediates for complex natural
product synthesis. The eight natural products we have
synthesized are only a small sample of the variety of natural
products that can be made using our methodology.
CONCLUSION
■
We have encountered an interesting ring-opening of the
orthoester cage in myo-inositol orthoesters. The synthetic utility
of this transformation has been illustrated by the concise
syntheses of eight structurally diverse natural products. We
have prepared a common α,β-unsaturated aldehyde intermedi-
ate in multigram quantities in five steps from myo-inositol for
the synthesis of these compounds. This advanced intermediate
served as the synthon for the rapid and efficient syntheses of
( )-cyclophellitol in seven steps, ( )-valienamine in five steps,
( )-1-epi-streptol in two steps, ( )-gabosine K in three steps,
( )-gabosine I in five steps, ( )-gabosine G in six steps,
( )-streptol in six steps and ( )-uvamalol A in five steps in
very good yields in their racemic form. Many known elegant
methods for chiral desymmetrization of myo-inositol33 and its
D
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orthoesters32b,34 and enzymatic resolution35 might allow the
synthesis of these C7-cyclitols and analogues in enantiomeri-
cally pure form. We hope this report will attract chemists to
exploit this strategy in future synthetic design and this
methodology might take a prominent place in chemical lexicon.
grade CHCl3 as the mobile phase to get pure 17 (46 mg) and 18 (44
mg).
17: 1H NMR (500 MHz, CDCl3) δ 2.80 (br s, 1H, OH), 3.85 (dd, J
= 6.2 Hz, 4.3 Hz, 1H, H-6), 3.98 (dd, J = 10.4 Hz, 6.2 Hz, 1H, H-1),
4.05 (d, J = 3.9 Hz, 1H, H-5), 4.12−4.20 (m, J = 3.9 Hz, 3H, H-2, H-
7A and 7A′), 4.55−4.67 (m, 4H, -OCHAHBPh), 5.68 (s, 1H, H-3),
7.23−7.30 (m, 10H, Ar−H); 13C NMR (125 MHz, CDCl3) δ 64.7 (C-
7), 68.6 (C-1), 69.1 (C-5), 71.6 (-OCH2Ph), 73.3 (-OCH2Ph), 73.5
(C-2), 79.3 (C-6), 121.3 (C-3), 127.8, 127.9, 127.9, 128.0, 128.5,
128.6, 137.7, 138.1, 140.3. Elemental analysis calcd for C21H24O5: C,
70.77; H, 6.79. Found: C, 70.91; H, 6.64.
EXPERIMENTAL SECTION
■
General Methods. Chromatograms were visualized under UV
light and by dipping plates into ceric ammonium molybdate stain
followed by heating. The stain was prepared by slowly adding 10 mL
of con. H2SO4 into the solution of ceric sulfate (1 g) and ammonium
molybdate (5 g) in 90 mL of distilled water. The 1H NMR, 13C NMR,
COSY and HMQC spectra were recorded on a 500 MHz NMR
spectrometer. Proton chemical shifts are reported in ppm (δ) relative
to internal tetramethylsilane (TMS, δ 0.0 ppm) or with the solvent
reference relative to TMS employed as the internal standard (CDCl3, δ
7.26 ppm; D2O, δ 4.79 ppm). Data are reported as follows: chemical
shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), and
multiplet (m)], coupling constants [Hz], integration and peak
identification). All NMR signals were assigned on the basis of 1H
NMR, 13C NMR, DEPT, COSY and HMQC experiments. 13C spectra
were recorded with complete proton decoupling. Carbon chemical
shifts are reported in ppm (δ) relative to TMS with the respective
solvent resonance as the internal standard. All NMR data were
collected at 25 °C. Mass spectrometry were recorded by Q-TOF using
electrospray ionization (ESI) mode. Melting points were determined
using melting point apparatus and are uncorrected. Flash column
chromatography was performed using silica gel (200−400 mesh). All
reactions were carried out under argon or nitrogen atmosphere
employing oven-dried glassware.
18: 1H NMR (500 MHz, CDCl3) δ 2.12 (br s, 3H, OH), 3.88 (dd, J
= 4.0 Hz, 2.0 Hz, 1H, H-6), 3.97 (dd, J = 4.8 Hz, 1.6 Hz, 1H, H-1),
4.16−4.12 (m, 3H, H-2, H-7A and 7A′), 4.28 (d, J = 3.8 Hz, 1H, H-5),
4.52 (d, J = 11.6 Hz, 1H, -OCHAPh), 4.59 (d, J = 11.6 Hz, 1H,
-OCHBPh), 4.64 (d, J = 11.5 Hz, 1H, -OCHAPh), 4.78 (d, J = 11.5 Hz,
1H, -OCHBPh), 5.78 (d, J = 2.2 Hz, 1H, H-3), 7.23−7.25 (m, 10H,
Ar−H); 13C NMR (125 MHz, CDCl3) δ 64.6 (C-7), 67.3 (C-5), 71.6
(C-1), 71.7 (-OCH2Ph), 72.8 (-OCH2Ph), 76.2 (C-6), 76.9 (C-2),
122.5 (C-3), 127.8, 127.9, 128.0, 128.1, 128.5, 128.6, 137.8, 138.0,
140.1. Elemental analysis calcd for C21H24O5: C, 70.77; H, 6.79.
Found: C, 71.08; H, 6.88.
(
)-(1S,3R,4S,5S,6R,2E/Z)-2-Methoxymethyl-4,6-di-O-(ben-
zyl)-myo-inositol 1,3,5-orthoformate (20). To a suspension of
methoxymethyltriphenylphosphonium chloride (1.11 g, 3.2 mmol) in
dry THF (5 mL), a solution of potassium tert-butoxide (365 mg, 3.2
mmol) in dry THF (5 mL) was added slowly at 0 °C under N2
atmosphere. To this mixture, a solution of ketone 19 (240 mg, 0.65
mmol) in dry THF (10 mL) was added dropwise at 0 °C. The mixture
was warmed to room temperature and then refluxed for 2 h. THF was
evaporated off in vacuo. The orange residue thus obtained was
dissolved in ethyl acetate and washed with water and brine. The
organic layer was separated, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. Purification by flash column
chromatography (ethyl acetate/petroleum ether, 1:6; v/v) gave the
enol ether 20 (232 mg, 90%) as a gummy liquid: 1H NMR (500 MHz,
CDCl3) δ 3.58 (s, 3H, -OCH3), 4.13 (t, J = 2.7 Hz, 1H, H-6), 4.19−
4.20 (m, 2H, H-1, H-4), 4.34 (s, 1H, H-5), 4.49 (d, J = 3.3 Hz, 1H,
-OCHAPh), 4.52 (d, J = 3.1 Hz, 1H, -OCHBPh), 4.60 (d, J = 12.1 Hz,
1H, -OCHAPh), 4.64 (d, J = 11.9 Hz, 1H, -OCHBPh), 5.02 (d, J = 1.5
Hz, 1H, H-3), 5.52 (s, 1H, H-7), 6.17 (s, 1H, H-8), 7.21−7.19 (m,
10H, Ar−H); 13C NMR (125 MHz, CDCl3) δ 59.2, 65.6 (C-3), 68.6
(C-5), 70.1, 70.2, 70.7, 72.0 (C-1 and C-4), 72.3 (C-6), 76.2, 103.6,
105.3, 126.6, 126.7, 126.76, 126.8, 126.9, 127.0, 127.2, 127.3, 127.36,
127.4, 127.6, 136.9, 137.0, 144.7. Elemental analysis calcd for
C23H24O6: C, 69.68; H, 6.10. Found: C, 69.96; H, 6.38.
(
)-(1R,2S,5S,6S)-2,6-Bis(benzyloxy)-4-(hydroxymethyl)-
cyclohex-3-ene-1,5-diol (17) and ( )-(1S,2S,5R,6S)-2,6-Bis-
(benzyloxy)-4-(hydroxymethyl)cyclohex-3-ene-1,5-diol (18).
To a suspension of methoxymethyltriphenylphosphonium chloride
(6.3 g, 18.38 mmol) in dry THF (50 mL), a solution of potassium tert-
butoxide (2.07 g, 18.45 mmol) in dry THF (20 mL) was added slowly
at 0 °C under N2 atmosphere. To the resultant orange suspension, a
solution of ketone 13 (1.70 g, 4.6 mmol) in dry THF (15 mL) was
added dropwise at 0 °C. As the reaction was very sluggish at this
temperature, the mixture was allowed to warm to room temperature
and then refluxed for 2 h. THF was then evaporated off under reduced
pressure, and the orange residue thus obtained was dissolved in ethyl
acetate and washed successively with water and brine. The organic
layer was separated, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. Purification by flash column chromatography
(ethyl acetate/petroleum ether, 1:4; v/v) gave an inseparable E/Z
mixture of enol ether 14 (1.68 g, 92%) as a colorless gum. To the
solution of 14 (520 mg, 1.3 mmol) in THF (10 mL), 0.1 N aqueous
HCl (2 mL) was added, and the mixture was stirred for 3 h at room
temperature. THF was evaporated off under reduced pressure. The
residue was dissolved in ethyl acetate (EtOAc) and washed
successively with aqueous NaHCO3 solution, water and then with
brine. The organic layer was separated, dried over anhydrous Na2SO4
and concentrated under reduced pressure. The crude product was
purified by flash column chromatography (ethyl acetate/petroleum
ether, 1:2; v/v) to give an inseparable mixture of aldehydes 15 and 16
(440 mg) as a colorless gum. This gummy residue was dissolved in
methanol (20 mL), and CeCl3·7H2O (488 mg, 1.3 mmol) was added
slowly. Then NaBH4 (50 mg, 1.3 mmol) was added slowly to it at 0 °C
and stirred for 1 h at the same temperature. Excess NaBH4 was
quenched by the addition of acetone. Methanol was evaporated off in
vacuo, and the resultant residue was dissolved in ethyl acetate, washed
with water and brine. The organic layer was separated, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product thus obtained was purified by column chromatography
(ethyl acetate/petroleum ether, 3:2; v/v) to get a mixture of
diastereomers 17 and 18 (420 mg, 90%) in 1:1 ratio as a colorless
liquid. 100 mg of this diastereomeric mixture was further purified by
Recycling HPLC using chiral OA-JAIGEL-4100 column and HPLC
(
)-(3S,4R,5R,6S)-4,6-Bis(benzyloxy)-2-(hydroxymethyl)-
cyclohex-1-ene-3,5-diol (22). To a solution of 20 (155 mg, 0.39
mmol) in THF (10 mL), 0.1 N aqueous HCl (2 mL) was added, and
the mixture was stirred for 2 h at room temperature. THF was
evaporated off under reduced pressure. The residue was dissolved in
ethyl acetate and washed successively with saturated NaHCO3
solution, water and brine. The organic layer was separated, dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The crude mass was purified by flash column chromatography (ethyl
acetate/petroleum ether, 3:7; v/v) to give the aldehyde 21 (142 mg)
along with its formate ester as a colorless oil. This residue was
dissolved in methanol (10 mL), and to this solution, CeCl3·7H2O
(156 mg, 0.41 mmol) was slowly added. Then NaBH4 (19 mg, 0.50
mmol) was added slowly to it at 0 °C and stirred for 1 h at the same
temperature. Excess NaBH4 was quenched with acetone. Methanol
was evaporated off in vacuo, and the residue was dissolved in ethyl
acetate, washed with water and brine. The organic layer was separated,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column chromatography
(ethyl acetate/petroleum ether, 3:2; v/v) to give compound 22 (127
mg, 91%) as a white solid: mp 79−81 °C; 1H NMR (500 MHz,
CDCl3) δ 2.5 (br s, 3H, OH), 3.41 (dd, J = 10.1 Hz, 7.9 Hz, 1H, H-4),
3.73 (dd, J = 10.2 Hz, 7.9 Hz, 1H, H-5), 4.02 (d, J = 7.6 Hz, 1H, H-6),
4.06 (s, 2H, H-7A and 7A′), 4.32 (d, J = 7.6 Hz, 1H, H-3), 4.64 (d, J =
E
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11.6 Hz, 1H, -OCHAPh), 4.67 (d, J = 11.8 Hz, 1H, -OCHBPh), 4.78
(d, J = 11.6 Hz, 1H, -OCHAPh), 4.82 (d, J = 11.5 Hz, 1H, -OCHBPh),
5.56 (s, 1H, H-1), 7.3−7.22 (m, 10H, Ar−H); 13C NMR (125 MHz,
CDCl3) δ 64.1 (C-7), 72.3, 73.2 (C-3), 74.9 (C-5), 75.0, 76.7, 77.0,
77.2, 79.3 (C-6), 84.1 (C-4), 124.1 (C-1), 127.8, 127.9, 128.0, 128.1,
128.5, 128.7, 138.2, 138.4, 138.5. Elemental analysis calcd for
C21H24O5: C, 70.77; H, 6.79. Found: C, 70.90; H, 6.71.
OH-2), 2.70 (br s, 1H, OH-4), 3.39 (dd, J = 10 Hz, 8.2 Hz, 1H, H-3),
3.67−3.72 (m, 7H, H-2, -OCH3), 3.99 (d, J = 7.5 Hz, 1H, H-1), 4.08
(s, 2H, H-7A and 7A′), 4.29 (d, J = 6.9 Hz, 1H, H-4), 4.57 (s, 2H,
-OCHAHB-p-MeOPh), 4.68 (d, J = 11.5 Hz, 1H, -OCHA-p-MeOPh),
4.76 (d, J = 11 Hz, 1H, -OCHB-p-MeOPh), 5.55 (s, 1H, H-6), 6.80 (d,
J = 8.7 Hz, 2H, Ar−H), 6.82 (d, J = 8.25 Hz, 2H, Ar−H), 7.19 (d, J =
8.7 Hz, 2H, Ar−H), 7.23 (d, J = 8.9 Hz, 2H, Ar−H); 13C NMR (125
MHz, CDCl3) δ 55.3, 64.2 (C-7), 71.9, 73.3 (C-4), 74.7, 74.9 (C-2),
78.9 (C-1), 83.7 (C-3), 113.9, 114.1, 124.2 (C-6), 129.5, 129.7, 130.2,
130.5, 138.3 (C-5), 159.3, 159.5. Elemental analysis calcd for
C23H28O7: C, 66.33; H, 6.78. Found: C, 66.29; H, 6.80.
( )-(1R,3S,4R,5S,6S,2E/Z)-2-Methoxymethyl-4,6-di-O-(4-me-
thoxybenzyl)-myo-inositol 1,3,5-orthoformate (24). To a
suspension of methoxymethyltriphenylphosphonium chloride (14.86
g, 43.35 mmol) in dry THF (50 mL) was added a solution of
potassium tert-butoxide (4.86 g, 43.35 mmol) in dry THF (20 mL)
slowly at 0 °C under N2 atmosphere. To the resultant orange
suspension, a solution of ketone 23 (6.12 g, 14.2 mmol) in dry THF
(20 mL) was added slowly at 0 °C. The mixture was warmed to room
temperature and then refluxed for 2 h. The THF was evaporated in
vacuo. The orange residue was dissolved in ethyl acetate and washed
with water and brine. The organic layer was separated, dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
Purification by flash column chromatography (ethyl acetate/petroleum
ether, 1:4; v/v) gave the enol ether 24 (6.19 g, 95%) as a white
(
)-(1R,2S,3S,4R)-4-(Benzyloxymethyl)-2,4-bis(benzyloxy)-
1,3-bis((4-methoxybenzyl)oxy)cyclohex-5-ene (27). To a sol-
ution of 26 (500 mg, 1.2 mmol) in DMF (10 mL), NaH (60%
dispersion in mineral oil, 192 mg, 4.8 mmol) was added slowly at 0 °C
over a period of 5 min. To this solution, BnBr (0.58 mL, 4.8 mmol)
was added dropwise at 0 °C, and the reaction mixture was further
stirred for 20 min at the same temperature, by which time TLC
showed completion of the reaction. Excess NaH was quenched by
adding ice cold water, and the solvents were evaporated off in vacuo.
The residue was taken in dichloromethane (150 mL), washed with
water and brine. Organic layer was separated, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (ethyl acetate/
petroleum ether, 1:5; v/v) to get 27 (754 mg, 91%) as a white
1
crystalline solid: mp 80−82 °C; H NMR (500 MHz, DMSO-d6) δ
3.61 (s, 3H, -OCH3), 3.74 (s, 3H, -OCH3), 3.75 (s, 3H, -OCH3), 4.07
(d, J = 3.2 Hz, 1H, H-4), 4.14 (dd, J = 3.2 Hz, 2.3 Hz, 1H, H-6), 4.37
(dd, J = 3.2 Hz, 1.7 Hz, 1H, H-3), 4.48 (d, J = 12.5 Hz, 2H, OCHAHB-
p-MeOPh), 4.51 (d, J = 14.3 Hz, 2H, OCHAHB-p-MeOPh), 4.54 (dd, J
= 3.3 Hz, 1.7 Hz, 1H, H-5), 4.89 (dd, J = 3.1 Hz, 1.6 Hz, 1H, H-1),
5.66 (s, 1H, H-7), 6.38 (s, 1H, H-8), 6.82 (d, J = 8.7 Hz, 2H, Ar−H),
6.86 (d, J = 8.7 Hz, 2H, Ar−H), 7.19 (d, J = 8.7 Hz, 2H, Ar−H), 7.22
(d, J = 8.7 Hz, 2H, Ar−H); 13C NMR (125 MHz, DMSO-d6) δ 54.9,
54.9, 59.7, 66.0 (C-1), 68.5 (C-5), 69.4, 69.6, 70.5 (C-3), 72.8 (C-4
and C-6), 103.8 (C-2), 106.4, 113.4, 113.5, 129.2, 129.3, 130.1, 130.2,
145.4, 158.6, 158.6. Elemental analysis calcd for C25H28O8: C, 65.78;
H, 6.18. Found: C, 65.79; H, 6.12.
1
solid: mp 54−56 °C; H NMR (500 MHz, CDCl3) δ 3.66 (dd, J =
10.4 Hz, 7.7 Hz, 1H, H-3), 3.71−3.74 (m, 7H, H-2, -OCH3), 3.84 (d, J
= 12.1 Hz, 1H, H-7A), 4.11−4.13 (m, 2H, H-4, H-7A′), 4.20 (d, J =
7.5 Hz, 1H, H-1), 4.27 (d, J = 11.8 Hz, 1H, -OCHAPh), 4.44 (d, J =
11.8 Hz, 1H, -OCHBPh), 4.56 (s, 2H, -OCHAHBPh), 4.60−4.66 (m,
2H, -OCHAHBPh), 4.75 (d, J = 9.9 Hz, 1H, -OCHAPh), 4.81−4.83 (m,
3H, -OCHAHBPh), 5.68 (s, 1H, H-5), 6.74 (d, J = 8.6 Hz, 2H, Ar−H),
6.77 (d, J = 8.6 Hz, 2H, Ar−H), 7.13−7.29 (m, 19H, Ar−H); 13C
NMR (125 MHz, CDCl3) δ 55.5 (-OCH3), 69.9 (C-7), 72.1, 72.2,
74.8, 75.2, 75.4, 79.5 (C-4), 80.1 (C-1), 83.8 (C-2), 84.2 (C-3), 113.8,
113.8, 125.2 (C-5), 127.5, 127.6, 127.7, 127.8, 127.9, 128.3, 129.4,
129.5, 129.6, 130.4, 130.8, 136.3, 138.1, 138.5, 138.8, 159.2. Elemental
analysis calcd for C44H46O7: C, 76.94; H, 6.75. Found: C, 77.24; H,
7.02.
( )-(1R,2S,3S,4R)-2,4-Dihydroxy-1,3-bis((4-methoxybenzyl)-
oxy)cyclohex-5-ene-carb-5-aldehyde (25). To a solution of 24
(2.4 g, 5.26 mmol) in THF (20 mL) was added 0.1 N aqueous HCl (5
mL) at room temperature, and the mixture was stirred for 8 h at the
same temperature. THF was evaporated off in vacuo. The residue was
dissolved in ethyl acetate and washed with aqueous NaHCO3 solution,
water and then with brine. The organic layer was separated, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude material thus obtained was purified by flash column
chromatography (ethyl acetate/petroleum ether, 1:3; v/v) to give
the compound 25 (2.17 g, 100%) as a white solid: mp 126−128 °C;
1H NMR (500 MHz, CDCl3) δ 3.58 (dd, J = 10.3 Hz, 7.4 Hz, 1H, H-
3), 3.77 (dd, J = 10.3 Hz, 8.3 Hz, 1H, H-2), 3.84 (s, 6H, -OCH3), 4.30
(td, J = 8.2 Hz, 2.2 Hz, 1H, H-1), 4.72−4.88 (m, 3H, H-4, -OCHAHB-
p-MeOPh), 4.87 (d, J = 11.3 Hz, 1H, -OCHA-p-MeOPh), 5.04 (d, J =
11 Hz, 1H, -OCHB-p-MeOPh), 6.57 (s, 1H, H-6), 6.92 (d, J = 2.1 Hz,
2H, Ar−H), 6.93 (d, J = 2.1 Hz, 2H, Ar−H), 7.34 (d, J = 3.1 Hz, 2H,
Ar−H), 7.36 (d, J = 3.4 Hz, 2H, Ar−H), 9.47 (s, 1H, H-7); 13C NMR
(125 MHz, CDCl3) δ 55.3 (-OCH3), 71.2 (C-4), 73.1, 73.5 (C-2),
74.6, 77.5 (C-1), 81.9 (C-3), 113.9, 114.0, 129.7, 129.8, 129.9, 130.2,
139.5, 148.2 (C-6), 157.4, 159.5, 194.4 (C-7); IR (neat) 3404, 1743,
1685, 1612 cm−1. Elemental analysis calcd for C23H26O7: C, 66.65; H,
6.32. Found: C, 66.71; H, 6.52.
(
)-(1R,2S,3S,4R,5S,6S)-2,4-Bis(benzyloxy)-5-((benzyloxy)-
methyl)-1,3-bis((4-methoxybenzyl)oxy)cyclohexan-6-ol (28).
To a solution of BH3·SMe2 (1.0 M in THF, 1.23 mL, 1.23 mmol)
in anhydrous THF (5 mL) at 0 °C, a solution of 27 (850 mg, 1.23
mmol) in THF (10 mL) dropwise was added. The reaction mixture
was stirred for 8 h at room temperature and then cooled to 10 °C. To
this solution, 30% H2O2 (0.4 mL) and 3 M NaOH (1.2 mL) were
added slowly, and the mixture was further stirred for 8 h at ambient
temperature. THF was evaporated off under reduced pressure, and the
aqueous layer was extracted with ethyl acetate (200 mL). The organic
layer was separated, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue thus obtained on flash column
chromatography (ethyl acetate/petroleum ether, 1:3; v/v) yielded 28
1
(706.5 mg, 81%) as pure white solid: mp 82−84 °C; H NMR (500
MHz, DMSO-d6) δ 1.52 (dd, J = 9.4 Hz, 9.2 Hz, 1H, H-5), 3.31−3.34
(m, 2H, H-1, H-4), 3.50−3.52 (m, 3H, H-2, H-3, H-6), 3.67 (d, J = 7.6
Hz, 1H, H-7A), 3.72 (s, 3H, -OCH3), 3.73 (s, 3H, -OCH3), 3.78 (d, J
= 8.1 Hz, 1H, H-7A′), 4.42−4.54 (m, 3H, -OCHAHBPh), 4.63−4.83
(m, 7H, -OCHAHBPh), 5.17 (d, J = 6.3 Hz, 1H, OH-6), 6.82 (d, J =
4.7 Hz, 2H, Ar−H), 6.84 (d, J = 4.5 Hz, 2H, Ar−H), 7.17 (d, J = 8.4
Hz, 2H, Ar−H), 7.20 (d, J = 10 Hz, 2H, Ar−H), 7.26−7.38 (m, 15H,
Ar−H); 13C NMR (125 MHz, DMSO-d6) δ 51.3 (C-5), 60.2
(-OCH3), 69.7 (C-7), 73.6, 77.5, 79.2, 79.4, 79.8, 82.4, 87.5, 90.2, 90.6,
118.5, 118.7, 132.5, 132.8, 133.4, 134.2, 134.4, 136.0, 136.4, 143.9,
144.1, 163.7, 163.8. Elemental analysis calcd for C44H48O8: C, 74.98;
H, 6.86. Found: C, 74.93; H, 6.90.
(
)-(1R,2S,3S,4R)-4-(Hydroxymethyl)-1,3-bis((4-
methoxybenzyl)oxy)cyclohex-5-ene-2,4-diol (26). To a solution
of 25 (1 g, 2.41 mmol) in MeOH (15 mL) was slowly added
CeCl3·7H2O (1.7 g, 4.56 mmol) and then NaBH4 (132 mg, 3.48
mmol) at 0 °C, and the mixture was stirred for 1 h at the same
temperature. Excess NaBH4 was quenched by the addition of acetone.
Methanol was evaporated off in vacuo, and the residue was dissolved in
ethyl acetate, washed with water and brine. The organic layer was
separated, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product thus obtained was purified by
flash column chromatography (ethyl acetate/petroleum ether, 1:1; v/
v) to give compound 26 (0.92 g, 92%) as a white solid: mp 83−85 °C;
1H NMR (500 MHz, CDCl3) δ 2.32 (br s, 1H, OH-7), 2.65 (s, 1H,
(
)-(1S,2R,3S,4R,5R,6S)-2,4-Bis(benzyloxy)-5-((benzyloxy)-
methyl)-1,3-bis((4-methoxybenzyl)oxy)-cyclohex-6-yl metha-
nesulfonate (29). To a solution of 28 (620 mg, 0.88 mmol) in
pyridine (10 mL), MsCl (0.136 mL, 1.76 mmol) was added at 0 °C,
and the mixture was stirred for 1 h at the same temperature. Pyridine
F
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was evaporated off under reduced pressure, and the residue was
dissolved in ethyl acetate, washed with diluted HCl, water and brine.
The organic layer was separated, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. Crude product thus obtained
was purified by flash column chromatography (ethyl acetate/
petroleum ether, 1:3; v/v) to get 29 (688 mg, 100%) as a white
solid: mp 80−82 °C; 1H NMR (500 MHz, CDCl3) δ 1.84 (dd, J = 11
Hz, 10.9 Hz, 1H, H-5), 2.81 (s, 3H, -CH3), 3.55−3.61 (m, 3H, H-1, H-
2, H-3), 3.65 (d, J = 9.3 Hz, 1H, H-7A), 3.71 (dd, J = 11 Hz, 9.5 Hz,
1H, H-4), 3.77 (s, 3H, -OCH3), 3.78 (s, 3H, -OCH3), 3.85 (dd, J = 9.3
Hz, 2.0 Hz, 1H, H-7A′), 4.35 (d, J = 13.1 Hz, 1H, -OCHA-p-MeOPh),
4.53 (d, J = 10.6 Hz, 1H, CHPh), 4.58 (d, J = 11.3 Hz, 1H, -OCHB-p-
MeOPh), 4.65 (d, J = 10.7 Hz, 1H, CHPh), 4.79−4.87 (m, 5H, H-6,
CH2Ph), 4.92 (d, J = 10.7 Hz, 1H, CHPh), 4.97 (d, J = 10.7 Hz, 1H,
CHPh), 6.80 (d, J = 15.2 Hz, 2H, Ar−H), 6.83 (d, J = 8.6 Hz, 2H, Ar−
H), 7.16−7.35 (m, 19H, Ar−H); 13C NMR (125 MHz, CDCl3) δ
38.7, 45.3 (C-5), 55.2, 63.8, 73.0, 74.9, 75.4, 75.6, 75.8, 76.4, 76.7, 77.0,
77.2, 77.5, 79.5, 82.4, 82.6, 85.3, 113.8, 113.82, 127.6, 127.7, 127.8,
127.9, 128.1, 128.3, 128.4, 128.9, 129.3, 130.0, 130.5, 138.1, 138.2,
138.3, 159.1, 159.2. Elemental analysis calcd for C45H50O10S: C, 69.03;
H, 6.44; S, 4.10. Found: C, 69.32; H, 6.41; S, 3.84.
reported values:13c mp 150−151 °C; 1H NMR (500 MHz, D2O)
2.01−2.05 (m, 1H), 3.14−3.18 (m, 2H), 3.28 (dd, J = 10.5 Hz, 9 Hz,
1H), 3.47 (d, J = 2.0 Hz, 1H), 3.69−3.91 (m, 2H), 3.93 (dd, J = 11.5
Hz, 4 Hz, 1H).
( )-(1R,2S,3S,4R)-2,4-Bis(benzyloxy)-5-((benzyloxy)methyl)-
cyclohex-5-ene-1,3-diol (32). To a 10% solution of TFA in DCM
(10 mL), tribenzyl ether 27 (470 mg, 0.68 mmol) was added at room
temperature, and the reaction mixture was stirred for 1 h at the same
temperature. Excess TFA was quenched by adding aqueous NaHCO3,
and the solution was extracted with ethyl acetate (150 mL). The
organic layer was separated, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product thus
obtained was purified by flash column chromatography (ethyl
acetate/petroleum ether, 1:2; v/v) to get diol 32 (280 mg, 91%) as
1
a colorless oil: H NMR (500 MHz, DMSO-d6) δ 3.26 (dd, J = 10.5
Hz, 8 Hz, 1H, H-2), 3.66−3.72 (m, 1H, H-3), 3.88 (d, J = 12 Hz, 1H,
H-7A), 4.04−4.10 (m, 3H, H-1, H-4, H-7A′), 4.42 (d, J = 12 Hz, 1H,
-OCHAPh), 4.47 (d, J = 11.5 Hz, 1H, -OCHBPh), 4.60 (d, J = 11 Hz,
1H, -OCHAPh), 4.79−4.85 (m, 3H, -OCHAHBPh), 5.2 (d, J = 5.5 Hz,
1H, OH-1), 5.29 (d, J = 5.5 Hz, 1H, OH-3), 5.59 (s, 1H, H-6), 7.25−
7.47 (m, 15H, Ar−H); 13C NMR (500 MHz, DMSO-d6) δ 69.7 (C-7),
70.9 (C-1), 71.8, 73.5, 74.0, 75.6 (C-3), 80.9 (C-4), 84.9 (C-2), 127.5,
127.7, 127.9, 127.9, 128.0, 128.1, 128.3, 128.5, 128.7, 129.5, 134.6 (C-
6), 138.8, 139.5, 139.9. Elemental analysis calcd for C28H30O5: C,
75.31; H, 6.77. Found: C, 75.14; H, 6.80.
(
)-(1S,2R,3S,4R,5R,6S)-2,4-Bis(benzyloxy)-5-((benzyloxy)-
methyl)-1,3-dihydroxycyclohex-6-yl methanesulfonate (30).
To a solution of 29 (660 mg, 0.84 mmol) in dichloromethane (10
mL), TFA (1 mL) was added at room temperature, and then the
reaction mixture was stirred for 1 h at the same temperature.
Dichloromethane was evaporated off in vacuo, and the residue was
dissolved in ethyl acetate and washed successively with aqueous
sodium bicarbonate solution, water and brine. The organic layer was
separated, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product thus obtained was purified by
flash column chromatography (ethyl acetate/petroleum ether, 1:2; v/
v) to get 30 (400 mg, 88%) as a colorless liquid: 1H NMR (500 MHz,
CDCl3) δ 1.73 (dd, J = 10.7 Hz, 10.6 Hz, 1H, H-5), 2.37 (s, 1H, OH),
2.7 (s, 1H, OH), 3.01 (s, 3H, -CH3), 3.17 (dd, J = 9.2 Hz, 9.2 Hz, 1H,
H-2), 3.4−3.61 (m, 4H, H-1, H-3, H-4, H-7A), 3.75 (d, J = 9.4 Hz, 1H,
H-7A′), 4.33 (d, J = 11.3 Hz, 1H, -OCHAPh), 4.54 (d, J = 11.3 Hz, 2H,
-OCHBPh), 4.64−4.77 (m, 3H, -OCHAHBPh, H-6), 4.86 (d, J = 11.3
Hz, 1H, -OCHAPh), 7.16−7.32 (m, 15H, Ar−H); 13C NMR (125
MHz, CDCl3) δ 37.8, 43.7 (C-5), 62.7 (C-7), 72.4, 73.5, 74.2, 74.3,
75.7, 75.8, 79.0 (C-6), 80.4 (C-2), 126.7, 126.9, 127.0, 127.1, 127.3,
127.4, 127.6, 127.7, 136.9, 137.1. Elemental analysis calcd for
C29H34O8S: C, 64.19 H, 6.32 S, 5.91. Found: C, 64.50; H, 6.12; S,
5.67.
( )-(1S,2S,3S,4R)-1-Azido-2,4-bis(benzyloxy)-5-((benzyloxy)-
methyl)cyclohex-5-en-3-ol (33). To a solution of diol 32 (35 mg,
0.07 mmol) in toluene (3 mL), diphenylphosphorylazide (0.05 mL,
0.23 mmol) and 1,8-diazabicycloundec-7-ene (0.03 mL, 0.23 mmol)
were added at 0 °C.22 The reaction mixture was stirred for 4 h at the
same temperature. Then, NaN3 was added to the reaction mixture at 0
°C, and it was further stirred for 4 h at room temperature. The
reaction was quenched by adding 2 N HCl (1 mL) and diluted with
ethyl acetate (50 mL). The organic layer was washed with water and
brine, separated, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product thus obtained was purified
by flash column chromatography (ethyl acetate/petroleum ether, 1:4;
1
v/v) to get 33 (30.6 mg, 83%) as a colorless liquid: H NMR (500
MHz, CDCl3) δ 3.43 (dd, J = 10.3 Hz, 4.1 Hz, 1H, H-2), 3.93 (d, J =
12.9 Hz, 1H, H-7A), 3.99 (d, J = 7.8 Hz, 1H, H-4), 4.08 (d, J = 13 Hz,
1H, H-7A’), 4.10 (dd, J = 10.3 Hz, 7.8 Hz, 1H, H-3), 4.12 (dd, J = 4.7
Hz, 4.2 Hz, 1H, H-1), 4.38−4.44 (m, 2H, -OCHAHBPh), 4.54 (d, J =
11.5 Hz, 1H, -OCHAPh), 4.62 (d, J = 11.4 Hz, 1H, -OCHAPh), 4.7 (d,
J = 11.5 Hz, 1H, -OCHBPh), 4.83 (d, J = 11.3 Hz, 1H, -OCHBPh),
5.78 (dd, J = 4.7 Hz, 1.1 Hz, 1H, H-6), 7.18−7.31 (m, 15H, Ar−H);
13C NMR (125 MHz, CDCl3) δ 56.2 (C-1), 69.8 (C-7), 72.3 (C-3),
73.0, 73.6, 78.7 (C-2), 79.4 (C-4), 119.7 (C-6), 127.6, 127.7, 127.9,
128.1, 128.2, 128.3, 128.4, 128.45, 128.5, 128.6, 128.7, 137.2, 137.9,
138.5, 141.7; IR (neat) 3012, 2106, 1496, 1454 cm−1. Elemental
analysis calcd for C28H29N3O4: C, 71.32; H, 6.20 N, 8.91. Found: C,
71.07; H, 6.37; N, 8.79.
Valienamine (2). To a solution of azide 33 (20 mg, 0.05 mmol) in
DCM (5 mL), a 1 M solution of BCl3 in toluene (0.2 mL, 0.2 mmol)
was added at −60 °C, and the reaction mixture was allowed to warm
to room temperature slowly over a period of 4 h. Excess BCl3 was
quenched by adding aqueous NH3 solution. The reaction mixture was
evaporated to dryness completely under reduced pressure. The residue
thus obtained was chromatographed to get valienamine (2) as a syrupy
material (5.9 mg, 80%). Because of its hygroscopic nature and
broadened signals in 1H NMR, it was characterized as its pentaacetate
34. The above syrupy 2 was dissolved in pyridine (5 mL), and to this
solution acetic anhydride (1 mL) and DMAP (2 mg) were added, and
the reaction mixture was stirred for overnight at room temperature.
Pyridine was evaporated off under reduced pressure, and the residue
was dissolved in ethyl acetate and washed with water and brine. The
organic layer was separated, dried over anhydrous Na2SO4 and
concentrated. Flash column chromatography (acetone/petroleum
ether, 1:6; v/v) gave pentaacetate 34 (11.6 mg, 90%) as a white
solid, whose 1H NMR data was identical with the reported data:13i mp
92−94 °C; 1H NMR (500 MHz, CDCl3) δ 1.95−2.00 (m, 15H), 4.33
(
)-(1R,2R,3S,4R,5R,6R)-2,4-Bis(benzyloxy)-5-((benzyloxy)-
methyl)-7-oxabicyclo[4.1.0]heptan-3-ol (31). To a solution of 30
(360 mg, 0.66 mmol) in DMF (10 mL), NaH (60% dispersion in
mineral oil, 39.6 mg, 0.99 mmol) was added at 0 °C, and the mixture
was stirred for 20 min at the same temperature. Excess NaH was
quenched by adding ice cold water. Ethyl acetate (150 mL) was added
to it, and the mixture was washed with water and brine. The organic
layer was separated, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product thus obtained was purified
by flash column chromatography (ethyl acetate/petroleum ether, 1:5;
1
v/v) to get 31 (270 mg, 91%) as a white solid: mp 64−66 °C; H
NMR (500 MHz, CDCl3) δ 2.19−2.22 (m, 1H), 3.11−3.16 (m, 2H),
3.39 (d, J = 2.9 Hz, 1H), 3.55−3.64 (m, 3H), 3.70 (dd, J = 8.9 Hz, 3.6
Hz, 1H), 4.42 (d, J = 11.1 Hz, 1H), 4.48 (s, 2H), 4.70 (d, J = 11.6 Hz,
1H), 4.70 (d, J = 11.6 Hz, 1H), 4.75 (d, J = 11.6 Hz, 1H), 7.17−7.34
(m, 15H, Ar−H). NMR data are similar to the reported values.36
Elemental analysis calcd for C28H30O5: C, 75.31; H, 6.77. Found: C,
75.55; H, 6.78.
Cyclophellitol (1). To a solution of 31 (25 mg, 0.05 mmol) in
ethyl acetate (5 mL), 10% Pd/C (15 mg) was added, and the resulting
suspension was stirred under hydrogen atmosphere (1 atm, hydrogen
balloon) for overnight at 0 °C. The reaction mixture was then filtered
through a sterile syringe filter (0.20 μm), the residue was washed with
MeOH. The combined filtrate was concentrated in vacuo at low
temperature, and the product, 1 was isolated as a white solid (9.8 mg,
1
100%) without further purification. H NMR data are similar to the
G
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(d, J = 13.3 Hz, 1H), 4.57 (d, J = 13.3 Hz, 1H), 4.96−5.03 (m, 2H),
5.29 (d, J = 6.2 Hz, 1H), 5.39 (dd, J = 9.9 Hz, 6.4 Hz, 1H), 5.57 (d, J =
8.9 Hz, 1H), 5.82 (d, J = 4.9 Hz, 1H).
Streptol (5). To a solution of diol 36 (90 mg, 0.20 mmol) in DCM
(10 mL), a 1.0 M solution of BCl3 in toluene (1 mL, 1.0 mmol) was
added at −78 °C, and the reaction mixture was stirred for 4 h at the
same temperature. Excess BCl3 was quenched by adding aqueous NH3.
The solvents were evaporated under reduced pressure to get a white
solid. This residue was purified by flash column chromatography
(CHCl3/MeOH, 4:1; v/v) to obtain pure streptol 5 (25 mg, 70%) as a
colorless oil, whose 1H NMR data were similar to the reported data:13n
1H NMR (500 MHz, CD3OD) δ 3.22−3.24 (m, 1H), 3.65 (dd, J =
10.0 Hz, 7.3 Hz, 1H), 3.90 (d, J = 7.6 Hz, 1H), 4.09−4.13 (m, 3H),
5.73−5.74 (m, 1H).
(
)-(2R,3S,4R)-2,4-Bis(benzyloxy)-5-((benzyloxy)methyl)-3-
hydroxycyclohex-5-en-1-one (35). To a solution of diol 32 (165
mg, 0.37 mmol) in DCM (5 mL), Dess−Martin periodinane (227.8
mg, 0.55 mmol) was added at room temperature, and the reaction
mixture was stirred for 1 h at the same temperature. When the TLC
showed, completion of the reaction (1 h), the reaction mixture was
diluted by adding chloroform (50 mL), and then the mixture was
washed successively with aqueous Na2S2O3, water and brine. The
organic layer was separated, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product thus
obtained was purified by flash column chromatography (ethyl
acetate/petroleum ether, 1:4; v/v) to get ketone 35 (155 mg, 94%)
1-epi-Streptol (6). To a 10% solution of TFA in DCM (10 mL),
triol 26 (40 mg, 0.09 mmol) was added at room temperature, and the
reaction mixture was stirred for 1 h at the same temperature. DCM
was evaporated off to dryness to get a white residue. This residue was
further purified by washing with DCM (10 mL × 3) to get pure 1-epi-
1
as a light brown liquid: H NMR (500 MHz, CDCl3) δ 3.87 (d, J =
1
streptol 6 (15 mg, 89%) as a white solid: mp 134−136 °C; H NMR
10.7 Hz, 1H, H-2), 4.08−4.14 (m, 2H, H-3, H-7A), 4.28−4.32 (m, 2H,
H-4, H-7A′), 4.52 (d, J = 12.1 Hz, 1H, -OCHAPh), 4.54 (d, J = 13.7
Hz, 1H, -OCHBPh), 4.65 (d, J = 11.2 Hz, 1H, -OCHAPh), 4.74 (d, J =
11.3 Hz, 1H, -OCHAPh), 4.98 (d, J = 11.3 Hz, 1H, -OCHBPh), 5.15
(d, J = 11.2 Hz, 1H, -OCHBPh), 6.22 (d, J = 1.8 Hz, 1H, H-6), 7.25−
7.43 (m, 15H, Ar−H); 13C NMR (125 MHz, CDCl3) δ 68.9 (C-7),
73.2, 73.9, 75.0, 76.9 (C-3), 78.9 (C-4), 82.6 (C-2), 123.7 (C-6),
127.7, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 128.51, 128.6, 137.4,
137.5, 137.8, 158, 196 (C-1); IR (neat) 3587, 3010, 2866, 1718, 1496,
1454 cm−1. Elemental analysis calcd for C28H28O5: C, 75.65; H, 6.35.
Found: C, 75.58; H, 6.25.
(500 MHz, DMSO-d6) δ 3.10 (dd, J = 9.3 Hz, 8.3 Hz, 1H, H-2), 3.19
(dd, J = 9.6 Hz, 7.8 Hz, 1H, H-3), 3.86−3.97 (m, 4H, H-1, H-4, H-7A,
H-7A′), 4.57 (dd, J = 5.2 Hz, 4.8 Hz, 1H, OH), 4.58−4.83 (m, 4H,
OH), 5.39 (s, 1H, H-6); 13C NMR (125 MHz, DMSO-d6) δ 60.6 (C-
7), 71.2 (C-1), 72.2 (C-4), 75.9 (C-2), 76.1 (C-3), 123.7 (C-6), 139.2
(C-5). Elemental analysis calcd for C7H12O5: C, 47.72; H, 6.87.
Found: C, 47.82; H, 6.92.
Gabosine K (7). To a solution of 6 (65 mg, 0.36 mmol) in 2,4,6-
collidine (2 mL), AcCl (0.02 mL, 0.4 mmol) was added at −60 °C,
and the reaction mixture was stirred for 1 h at the same temperature.
When the reaction was complete (judged by TLC), collidine was
evaporated off under reduced pressure. The crude residue thus
obtained was purified by flash column chromatography (ethyl acetate/
MeOH, 10:1; v/v) to get gabosine K (7) (50 mg, 62%) as a colorless
oil: 1H NMR (500 MHz, CD3OD) δ 1.96 (s, 3H), 3.24−3.27 (m, 1H),
3.31−3.35 (m, 1H), 3.96−3.99 (m, 2H), 4.43 (d, J = 13 Hz, 1H), 4.63
Gabosine I (3). To a solution of ketone 35 (60 mg, 0.13 mmol) in
DCM (5 mL), a 1.0 M solution of BCl3 in toluene (0.67 mL, 0.67
mmol) was added at −40 °C and stirred for 2 h at the same
temperature. Excess BCl3 was quenched by adding aqueous NH3
solution. When the TLC showed completion of the reaction (2 h), the
solvents were evaporated, and the crude residue was purified by flash
column chromatography (CHCl3/MeOH, 8:1; v/v) to get valienone
1
(d, J = 13 Hz, 1H), 5.50 (s, 1H). H NMR data are identical to the
1
reported values.13n
(3) (17.6 mg, 75%) as a pale brown oil, whose H NMR data were
identical to the reported data:13o 1H NMR (500 MHz, CD3OD) δ
3.51 (dd, J = 10.8 Hz, 8.3 Hz, 1H), 3.94 (d, J = 10.8 Hz, 1H), 4.22−
4.43 (m, 2H), 4.41 (d, J = 18.3 Hz, 1H), 6.07 (d, J = 2 Hz, 1H).
Gabosine G (4). To a solution of 3 (65 mg, 0.37 mmol) in 2,4,6-
collidine (2 mL), AcCl (0.02 mL, 0.4 mmol) was added at −60 °C,
and the reaction mixture was stirred for 1 h at the same temperature.
When the reaction was complete (judged by TLC), collidine was
evaporated off under reduced pressure. The crude residue thus
obtained was purified by flash column chromatography (ethyl acetate)
to get gabosine G (4) (56.4 mg, 70%) as a colorless oil:13o 1H NMR
(500 MHz, CD3OD) δ 2.04 (s, 3H), 3.53 (dd, J = 10.7 Hz, 8.4 Hz,
1H), 3.95 (d, J = 10.9 Hz, 1H), 4.31−4.33 (m, 1H), 4.84−4.87 (m,
2H), 5.92 (d, J = 1.9 Hz, 1H).
( )-((1R,2S,3S,4R)-2,4-Dihydroxy-1,3-bis((4-methoxybenzyl)-
oxy)cyclohex-5-en-5-yl)methyl benzoate (37). To a solution of
26 (432 mg, 1.03 mmol) in DCM (10 mL), 2,4,6-collidine (1 mL) and
benzoyl chloride (0.18 mL, 1.54 mmol) were added at 0 °C, and the
reaction mixture was stirred for 1 h at the same temperature. When the
reaction was complete (by TLC), ethyl acetate (100 mL) was added to
the reaction mixture, and the organic layer was washed successively
with diluted HCl, water and brine. The organic layer was separated,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product thus obtained was purified by flash
column chromatography (ethyl acetate/petroleum ether, 1:1; v/v) to
get pure 37 (513 mg, 95%) as a white solid: mp 88−90 °C; 1H NMR
(500 MHz, CDCl3) δ 3.44 (dd, J = 10.3 Hz, 7.8 Hz, 1H, H-3), 3.72−
3.73 (m, 7H, H-2, -OCH3), 4.02 (d, J = 7.8 Hz, 1H, H-1), 4.26 (d, J =
7.6 Hz, 1H, H-4), 4.57−4.60 (m, 2H, -OCHA-p-MeOPh, H-7A), 4.64
(d, J = 11.3 Hz, 1H, -OCHB-p-MeOPh), 4.74 (d, J = 11.2 Hz,1H,
-OCHB-p-MeOPh), 4.80 (d, J = 11.2 Hz, 1H, -OCHA-p-MeOPh), 5.07
(d, J = 12.8 Hz, 1H, H-7A′), 5.72 (s, 1H, H-6), 6.80 (d, J = 8.6 Hz, 2H,
Ar−H), 6.82 (d, J = 8.6 Hz, 2H, Ar−H), 7.22 (d, J = 8.6 Hz, 2H, Ar−
H), 7.24 (d, J = 8.6 Hz, 2H, Ar−H), 7.37 (t, J = 7.8 Hz, 2H, Ar−H),
7.49−7.52 (m, 1H, Ar−H), 7.96 (dd, J = 7.3 Hz, 0.7 Hz, 2H, Ar−H);
13C NMR (125 MHz, CDCl3) δ 55.3 (-OCH3), 64.4 (C-7), 71.8 (C-
4), 72.1 (-OCH2-p-MeOPh), 74.6 (C-2), 74.8 (-OCH2-p-MeOPh),
78.6 (C-1), 83.4 (C-3), 113.9, 114.1, 127.1 (C-6), 128.4, 129.5, 129.6,
129.7, 129.8, 130.1, 130.2, 130.4, 133.3, 135.1, 159.3, 159.4, 166.9.
Elemental analysis calcd for C30H32O8: C, 69.22; H, 6.20. Found: C,
69.22; H, 6.21.
((1R,2S,3R,4R)-2-(Benzoyloxy)-1,3-bis((4-methoxybenzyl)-
oxy)-4-((triethylsilyl)oxy)cyclohex-5-en-5-yl)methyl benzoate
(40). To a solution of benzoate 37 (150 mg, 0.28 mmol) in DCM,
imidazole (114.4 mg, 1.68 mmol) and TESOTf (0.09 mL, 0.42 mmol)
were added at 0 °C, and the reaction mixture was stirred for 1 h at the
same temperature. When the TLC showed disappearance of the
starting material, ethyl acetate (50 mL) was added to the reaction
mixture, and the organic layer was washed successively with water and
( )-(1S,2S,3S,4R)-2,4-Bis(benzyloxy)-5-((benzyloxy)methyl)-
cyclohex-5-ene-1,3-diol (36). To a solution of 35 (100 mg, 0.22
mmol) in THF (5 mL), K-selectride (0.3 mL, 1.0 M in THF, 0.3
mmol) was added at −78 °C, and the reaction mixture was stirred for
1 h at the same temperature. THF was evaporated off under reduced
pressure, and the residue was dissolved in ethyl acetate (100 mL),
washed twice with brine solution. The organic layer was separated,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product thus obtained was purified by flash
column chromatography (EtOAc/petroleum ether, 1:4; v/v) to get
1
diol 36 (90 mg, 90%) as a colorless liquid: H NMR (500 MHz,
CDCl3) δ 3.32 (dd, J = 10.3 Hz, 3.9 Hz, 1H, H-2), 3.9 (d, J = 12.5 Hz,
1H, H-7A), 4.01 (d, J = 7.4 Hz, 1H, H-4), 4.09−4.15 (m, 2H, H-3, H-
7A′), 4.23 (dd, J = 5.0 Hz, 4.5 Hz, 1H, H-1), 4.39 (d, J = 11.8 Hz, 1H,
-OCHAPh), 4.43 (d, J = 11.8 Hz, 1H, -OCHBPh), 4.59−4.68 (m, 3H,
-OCHAHBPh), 4.81 (d, J = 11.4 Hz, 1H, -OCHAPh), 5.89 (dd, J = 4.5
Hz, 1.0 Hz, 1H, H-6), 7.18−7.3 (m, 15H, Ar−H); 13C NMR (125
MHz, CDCl3) δ 62.4 (C-1), 69.1, 70.6 (C-3), 71.2, 71.8, 72.6, 78.2 (C-
2), 78.6 (C-4), 122.7 (C-6), 126.5, 126.6, 126.7, 127.0, 127.2, 127.3,
127.4, 127.7, 136.5, 137, 137.6, 139.3. Elemental analysis calcd for
C28H30O5: C, 75.31; H, 6.77. Found: C, 75.09; H, 6.92.
H
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brine, separated, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product was purified by column
chromatography (ethyl acetate/petroleum ether, 1:5; v/v) to get an
inseparable mixture of regioisomers 38 and 39 (1.2:1, 124 mg, overall
yield = 68%) as a colorless liquid.
To a solution of the above mixture of 38 and 39 (85 mg, 0.13
mmol) in pyridine (5 mL), BzCl (0.02 mL, 0.22 mmol) and DMAP (5
mg) were added at room temperature. The reaction mixture was
stirred for 4 h at rt. When the reaction was complete (monitored by
TLC), pyridine was evaporated under reduced pressure. The residue
was dissolved in ethyl acetate (100 mL) and washed with water and
brine. The organic layer was separated, dried over anhydrous Na2SO4
and concentrated under reduced pressure. The crude product thus
obtained was purified by flash column chromatography (ethyl acetate/
petroleum ether, 1:9; v/v) to get the required isomer 40 (52.3 mg,
36% after two steps) as a colorless oil and also isomer 40A (43.6 mg,
30% after two steps).
Structural Assignment of 17 by Acetylation. To a solution of
17 (5 mg, 0.014 mmol) and triethylamine (1 mL) in DCM (5 mL),
acetic anhydride (0.01 mL) was added, and the reaction mixture was
stirred for overnight at room temperature. The solvent was evaporated
under reduced pressure, the residue was dissolved in ethyl acetate and
washed successively with water, aqueous NaHCO3 solution and brine.
The organic layer was separated, dried over anhydrous Na2SO4 and
concentrated. Flash column chromatography (ethyl acetate/petroleum
ether, 1:9, v/v) gave triacetate 46 (structure was confirmed by COSY
and comparing the coupling constants of various protons) as a
1
colorless gum (6 mg, 88%): H NMR (500 MHz, CDCl3) δ 1.91 (s,
3H, -OCOCH3), 1.97 (s, 3H, -OCOCH3), 1.98 (s, 3H, -OCOCH3),
4.00 (dd, J = 7.9 Hz, 5.1 Hz, 1H, H-6), 4.25 (t, J = 3.7 Hz, 1H, H-2),
4.32 (d, J = 13.2 Hz, 1H, H-7A), 4.50 (d, J = 11.9 Hz, 1H, -OCHAPh),
4.57−4.63 (m, 4H, H-7A′, -OCHAHBPh), 5.09 (dd, J = 7.9 Hz, 3.8 Hz,
1H, H-1), 5.45 (d, J = 4.8 Hz, 1H, H-5), 5.88 (d, J = 3.3 Hz, 1H, H-3),
7.27−7.20 (m, 10H, Ar−H).
Inseparable Mixture of 38 and 39. 1H NMR (500 MHz,
CDCl3) δ 0.55−0.60 (m, 12H), 0.85−0.89 (m, 18H), 3.42−3.48 (m,
2H), 3.71−3.73 (m, 12H), 3.78 (dd, J = 9.4 Hz, 7.1 Hz, 1H), 3.82−
3.88 (m, 2H), 4.00−4.01 (m, 1H), 4.11−4.13 (m, 1H), 4.37 (d, J = 6.4
Hz, 1H), 4.47−4.55 (m, 5H), 4.64−4.78 (m, 6H), 4.92 (d, J = 13.4
Hz, 1H), 5.70 (s, 1H), 5.75 (s, 1H), 6.77−6.82 (m, 8H), 7.18−7.24
(m, 10H), 7.37 (dd, J = 14.4 Hz, 7.65 Hz, 4H), 7.47−7.50 (m, 2H),
7.94−7.97 (m, 4H).
Stereochemical Assignment of 18 by Acetylation. To a
solution of 18 (5 mg, 0.014 mmol) and triethylamine (1 mL) in DCM
(5 mL), acetic anhydride (0.01 mL) was added, and the reaction
mixture was stirred at room temperature for 12 h. The solvent was
evaporated off under reduced pressure, the residue was dissolved in
ethyl acetate and washed successively with water, aqueous NaHCO3
solution and brine. The organic layer was separated, dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
Purification by flash column chromatography (ethyl acetate/petroleum
ether, 1:9; v/v) gave triacetate 47 (structure was confirmed by COSY
and comparing the coupling constants of various protons) as colorless
oil (5 mg, 75%): 1H NMR (500 MHz, CDCl3) δ 1.92 (s, 3H,
-OCOCH3), 1.97 (s, 3H, -OCOCH3), 1.98 (s, 3H, -OCOCH3), 4.11
(dd, J = 3.7 Hz, 2.0 Hz, 1H, H-6), 4.36−4.38 (m, 2H, H-2, H-7A),
4.51−4.63 (m, 5H, -OCHAHBPh, H-7A′), 5.08 (dd, J = 7.2 Hz, 2.0 Hz,
1H, H-1), 5.61 (s, 1H, H-5), 5.88 (s, 1H, H-3), 7.23−7.27 (m, 10H,
Ar−H).
40: 1H NMR (500 MHz, CDCl3) δ 0.63 (q, J = 8 Hz, 6H,
-CH2CH3), 0.92 (t, J = 8.0 Hz, 9H, -CH2CH3), 3.73−3.76 (m, 7H,
-OCH3, H-3), 4.35 (d, J = 8.5 Hz, 1H, H-1), 4.49 (d, J = 11.6 Hz, 1H,
-OCHA-p-MeOPh), 4.59−4.62 (m, 3H, -OCHAHB-p-MeOPh, H-4),
4.68 (d, J = 10.7 Hz, 1H, -OCHA-p-MeOPh), 4.88 (d, J = 13.4 Hz, 1H,
H-7A), 4.92 (d, J = 13.3 Hz, 1H, H-7A′), 5.64 (dd, J = 9.7 Hz, 7.7 Hz,
1H, H-2), 5.92 (s, 1H, H-6), 6.68 (d, J = 8.6 Hz, 2H, Ar−H), 6.72 (d, J
= 8.6 Hz, 2H, Ar−H), 7.04 (d, J = 8.6 Hz, 2H, Ar−H), 7.14 (d, J = 8.6
Hz, 2H, Ar−H), 7.44 (t, J = 7.8 Hz, 2H, Ar−H), 7.49 (t, J = 7.7 Hz,
2H, Ar−H), 7.56−7.61 (m, 2H, Ar−H), 8.0 (dd, J = 7.1 Hz, 1.25 Hz,
2H, Ar−H), 8.09 (dd, J = 7.1 Hz, 1.25 Hz, 2H, Ar−H); 13C NMR
(125 MHz, CDCl3) δ 5.0 (-CH2CH3), 6.9 (-CH2CH3), 55.1 (-OCH3),
55.2 (-OCH3), 64.4 (C-7), 70.6, 72.4 (C-4), 74.3, 74.5 (C-5), 77.2 (C-
2), 82.2 (C-4), 113.4, 113.7, 125.0 (C-6), 128.2, 128.4, 128.9, 129.5,
129.6, 129.7, 129.9, 129.9, 130.1, 130.14, 132.9, 133.1, 136.4, 158.8,
159.1, 165.6, 166.1. Elemental analysis calcd for C43H50O9Si: C, 69.89;
H, 6.82. Found: C, 69.62; H, 7.00.
Stereochemical Assignment of 28 by Acetylation. In order to
assign the stereochemistry of alcohol 28, we made its acetyl derivative
48. For this, a solution of 28 (10 mg, 0.01 mmol) and acetic anhydride
(0.05 mL) in pyridine (5 mL) was stirred at room temperature for 3 h.
The solvents were evaporated, the residue was dissolved in ethyl
acetate and washed successively with water and brine. The organic
layer was separated, dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The crude material thus obtained was purified
by flash column chromatography (ethyl acetate/petroleum ether, 1:3;
v/v) to obtain the pure acetate 48 (10 mg, 94%) as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 1.64−1.69 (m, 1H, H-5), 1.82 (s, 3H,
OCOCH3), 3.22 (d, J = 7.7 Hz, 1H, H-7A), 3.42−3.44 (m, 1H, H-1),
3.48−3.50 (m, 2H, H-2, H-3), 3.60−3.61 (m, 2H, H-4, H-7A′), 3.71
(s, 3H, -OCH3), 3.71 (s, 3H, -OCH3), 4.29−4.30 (m, 2H,
-OCHAHBPh), 4.49 (dd, J = 10.1 Hz, 9.6 Hz, 2H, -OCHAHBPh),
4.67−4.82 (m, 6H, -OCHAHBPh), 5.17 (dd, J = 10.9 Hz, 9.8 Hz, 1H,
H-6), 6.73 (d, J = 8.7 Hz, 2H, Ar−H), 6.76 (d, J = 8.7 Hz, 2H, Ar−H),
7.08−7.18 (m, 19H, Ar−H); 13C NMR (125 MHz, CDCl3) δ 20.9,
44.5 (C-5), 55.2, 64.4, 70.3 (C-6), 73.3, 75.0, 75.4, 75.5, 75.8, 77.0 (C-
4), 82.9, 83.2, 85.55, 113.7, 113.8, 127.5, 127.6, 127.6, 127.8, 127.9,
127.9, 128.2, 128.4, 128.4, 129.2, 129.3, 130.7, 130.8, 138.1, 138.5,
159.1, 169.7.
1
40A: H NMR (500 MHz, CDCl3) δ 0.69 (q, J = 8.0 Hz, 6H,
-CH2CH3), 0.98 (t, J = 8.0 Hz, 9H, -CH2CH3), 3.67 (s, 3H), 3.77 (dd,
J = 10.0 Hz, 8.0 Hz, 1H, H-3), 3.82 (s, 3H), 3.99 (dd, J = 9.5 Hz, 7.5
Hz, 1H, H-2), 4.09 (d, J = 8.0 Hz, 1H, H-1), 4.57−4.67 (m, 3H),
4.75−4.78 (m, 3H), 5.93 (s, 1H, H-6), 6.03 (d, J = 7.1 Hz, 1H, H-4),
6.59 (d, J = 8.6 Hz, 2H, Ar−H), 6.89 (d, J = 8.6 Hz, 2H, Ar−H), 7.09
(d, J = 8.6 Hz, 2H, Ar−H), 7.31 (d, J = 8.6 Hz, 1H, Ar−H), 7.38 (dd, J
= 16.9 Hz, 8.1 Hz, 4H, Ar−H), 7.49−7.56 (m, 3H, Ar−H), 7.86−7.88
(m, 2H, Ar−H), 7.93 (m, 2H, Ar−H).
Uvamalol A (8). To a solution of 40 (10 mg, 0.013 mmol) in
DCM (5 mL), TFA (0.25 mL) was added at rt, and the reaction was
stirred for 30 min at the same temperature. When the reaction was
complete (by TLC), TFA was quenched by adding aqueous NaHCO3
solution, and then ethyl acetate (20 mL) was added to the reaction
mixture. The organic layer was washed successively with water and
brine, and then separated, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product thus
obtained was purified by flash column chromatography (ethyl
acetate/petroleum ether, 1:1, v/v) to obtain uvamalol A (8) (4.5
mg, 86%) as a white solid. 1H NMR and 13C NMR spectrum of 8 was
In 1H NMR spectrum of the acetate 48, the most deshielded
methyne proton (because of acetylation of the OH connected to the
same carbon) at δ 5.17 (H-6; as per cyclophellitol numbering) showed
3
a dd signal with JHH coupling constants 10.9 and 9.8 Hz, typical of a
proton having two diaxially oriented protons on its either sides.
42. To a solution of 41 (500 mg, 2.0 mmol) in dry DMF, 60% NaH
(170 mg, 4.2 mmol) was added at 0 °C in small portions. To this
suspension, benzyl bromide (0.52 mL, 4.2 mmol) was added and
stirred for an hour at 0 °C. Excess NaH was quenched with ice cold
water. DMF was evaporated off in vacuo, and the residue was dissolved
in EtOAc, washed with water and brine. The organic layer was
separated, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography (EtOAc/petroleum ether, 2:3; v/v) to give
identical to the reported data:27 mp 146−148 °C; H NMR (500
1
MHz, CD3OD) δ 3.80 (dd, J = 10.8 Hz, 7.9 Hz, 1H), 4.38 (d, J = 7.8
Hz, 1H), 4.49 (d, J = 8.3 Hz, 1H), 4.88−4.92 (m, 1H), 5.06 (d, J =
13.4 Hz, 1H), 5.23 (dd, J = 10.8 Hz, 8.3 Hz, 1H), 5.83 (s, 1H), 7.49−
7.54 (m, 4H), 7.61−7.67 (m, 2H), 8.09−8.12 (m, 4H); 13C NMR
(125 MHz, CD3OD) δ 65.1, 71.0, 73.6, 75.8, 78.8, 78.84, 128.6, 129.4,
129.7, 130.6, 130.8, 131.4, 131.9, 134.1, 134.4, 136.8, 167.8, 168.0.
I
dx.doi.org/10.1021/jo401272j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
compound 42 (452 mg, 51%) as a white solid: mp 56−58 °C; H
NMR (500 MHz, DMSO-d6) δ 0.74 (t, J = 7 Hz, 3H,
-CH2CH2CH2CH3), 1.14−1.17 (m, 2H, -CH2CH2CH2CH3), 1.22−
1.25 (m, 2H, -CH2CH2CH2CH3), 1.45 (t, J = 7.4 Hz, 2H,
-CH2CH2CH2CH3), 3.87 (s, 1H, H-5), 4.03 (s, 2H, H-4, H-6), 4.09
(s, 2H, H-1, H-3), 4.46 (s, 1H, H-2), 4.49 (d, J = 11.7 Hz, 2H,
-OCHAHBPh), 4.56 (d, J = 11.7 Hz, 2H, -OCHAHBPh), 5.11 (s, 1H,
OH), 7.19 (s, 10H, Ar−H); 13C NMR (125 MHz, DMSO-d6) δ 14.3
(−CH3 CH2 CH2 CH2 ), 22.4 (-CH3 CH2 CH2 CH2 ), 25.0
(-CH3CH2CH2CH2), 37.1 (-CH3CH2CH2CH2), 59.0 (C-5), 67.4
(C-2), 71.0 (-OCH2Ph), 73.3 (C-4, C-6), 74.3 (C-1, C-3), 109.5,
127.9, 123.0, 128.6, 138.6 (C-7). Elemental analysis calcd for
C25H30O6: C, 70.40; H, 7.09. Found: C, 70.44; H, 7.01.
1H, OH-3), 6.81 (s, 1H, H-1), 7.18−7.26 (m, 10H, Ar−H), 9.48 (s,
1H, -CHO); 13C NMR (125 MHz, DMSO-d6) δ 14.0 (-CH2CH3),
22.0 (−CH2CH3), 26.9 (-COCH2CH2), 33.8 (-COCH2), 69.2 (C-3),
71.2 (−CH2Ph), 73.3 (C-5), 73.9 (−CH2Ph), 76.5 (C-6), 82.4 (C-4),
127.7, 127.8, 128.1, 128.5, 128.7, 138.4, 139.1, 141.0, 143.7 (C-1),
172.5, 193.2 (C-7). HRMS (ESI) calcd for C26H31O6 439.2121, found
439.2118 (MH+).
ASSOCIATED CONTENT
* Supporting Information
Retrosynthetic analysis, the mechanistic illustration, crystal data
(CIF) of 25 and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
(
)-(1R,3S,4R,5S,6S,2E/Z)-2-Methoxymethyl-4,6-di-O-(ben-
zyl)-myo-inositol 1,3,5-orthopentanoate (44). To a solution of
oxalyl chloride (0.07 mL, 0.84 mmol) in dichloromethane (5 mL), a
solution of DMSO (0.06 mL, 0.84 mmol) in dichloromethane (5 mL)
was added carefully at −78 °C, and the mixture was stirred for 5 min at
the same temperature. Solution of compound 42 (140 mg, 0.32 mmol)
in dichloromethane (5 mL) was added to the reaction mixture slowly
at the same temperature, and the reaction mixture was stirred for 10
min before adding triethyl amine (0.22 mL). When the TLC showed
completion of the reaction (10 min), the reaction mixture was diluted
by adding chloroform (20 mL), and then the mixture was washed
successively with aqueous NaHCO3, water and brine. The organic
layer was separated, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product thus obtained was purified
by flash column chromatography (ethyl acetate/petroleum ether, 1:4;
v/v) to get ketone 43 (139 mg, 100%) along with the inseparable gem-
diol as a white gummy material. This gummy material was dissolved in
dry THF (5 mL) and was added dropwise to the orange suspension
obtained by slowly adding a solution of potassium tert-butoxide (183
mg, 1.63 mmol) in dry THF (2 mL) to a solution of
methoxymethyltriphenylphosphonium chloride (561 mg, 1.63 mmol)
in dry THF (5 mL) at 0 °C under N2 atmosphere. The mixture was
allowed to warm to room temperature and then refluxed for 2 h. THF
was evaporated in vacuo. The orange residue was taken in ethyl acetate
and washed with water and brine. Organic layer was separated, dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
Purification by flash column chromatography (ethyl acetate/petroleum
ether, 1:4; v/v) gave enol ether 44 (140 mg, 94%) as a resin-like mass.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kms@iisertvm.ac.in
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
K.M.S. thanks the Department of Science and Technology,
India, for financial support and Ramanujan Fellowship and
CSIR for an EMR project grant.
REFERENCES
■
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