Asymmetric Synthesis of Nabscessin A from Inositol and d -Camphor

Article abstract of DOI:10.1021/acs.joc.0c01839

An enantiomer of nabscessin A (1), an aminocyclitol amide with antimicrobial activity, was synthesized from myo-inositol and dimethyl d-camphor acetal in 14 steps. Formal synthesis of natural nabscessin A was also achieved through the new approach to access both enantiomers of 4,5-di-O-benzyl-myo-inositol, derived from the same set of starting materials. This synthesis features utilizations of the existing framework of myo-inositol and a regioselective esterification.

Full text of DOI:10.1021/acs.joc.0c01839

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Article
Asymmetric Synthesis of Nabscessin A from Inositol and D-Camphor.
Hsin-Ying Wu, Wei-Yi Wang, Chia-Chi Feng, and Duen-Ren Hou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01839 • Publication Date (Web): 16 Sep 2020
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Asymmetric Synthesis of Nabscessin A from Inositol and
D-Camphor
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Hsin-Ying Wu, Wei-Yi Wang, Chia-Chi Feng and Duen-Ren Hou*
Department of Chemistry, National Central University, No. 300 Jhong-Da Road, Jhong-li,
Taoyuan, Taiwan 32001.
Table of contents (TOC)
OH
HO
OH
HO
BnO
O
O
NH2
O
HO
OH
HO
HO
OH
OH
BnO
HN
HO
O
O
OMe
10 steps
4 steps
+
or
OH
HO
OMe
dimethyl
D-camphor acetal
BnO
BnO
OH
myo-inositol
OH
OH
HO
HO
ent-Nabscessin A
ABSTRACT. Enantiomer of nabscessin A (1), an aminocyclitol amide with antimicrobial
activity, was synthesized from myo-inositol and dimethyl D-camphor acetal in 14 steps.
Formal synthesis of natural nabscessin A was also achieved through the new approach to
access both enantiomers of 4,5-di-O-benzyl-myo-inositol, derived from the same set of
starting materials. This synthesis features utilizations of the existing framework of myo-
inositol and a regioselective esterification.
Introduction
Nabscessins A-C are a family of aminocyclitol amides recently isolated from metabolites of a
pathogenic actinomycete, Nocardia abscessus IFM 10029T (Figure 1).1-2 Preliminary study on
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nabscessins A and B showed that they possess antimicrobial activity against Cryptococcus
neoformans.1 These compounds are structural isomers and only differ in the linkage of the 2-
hydroxy-6-methylbenzoyl group to the aminocyclitol, 2-deoxy-scyllo-inosamine (DOIA), which
is also present in a group of aminoglycoside antibiotics, inosamycins.3-4 DOIA is also the
biosynthetic precursor to 2-deoxystreptamine (DOS),5-6 the aglycon of related and clinically
important antibiotics, including gentamicin, kanamycin and neomycin, etc.7-13
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H2N
O
O
OH
O
NH
R1O
OR2
OR3
2
3
1
O
OH
1
, R = R = H
, R1 = R3 = H
, R1 = R2 = H
Nabscessin A ( ), R =
Nabscessin B,
Nabscessin C,
R2 =
R3 =
H3C
R
NH2
OH
HO
OH
2-deoxy-scyllo-inosamine (DOIA), R = OH
2-deoxystreptamine (DOS), R = NH2
Figure 1. Structures of nabscessins A-C and aminocyclitols.
Thus, synthesis and functional group transformations of 2-deoxy-scyllo-inosamine are essential
to prepare nabscessins. In this regard, the six-membered carbocycle of DOIA and its derivatives
were either adopted from natural materials14-19 or constructed by chemical methods,20-21 such as
ring-closing metathesis (RCM).22-23 For example, Banwell’s group reported synthesis of
nabscessin B, in which the key carbocycle, 1,2-diacetal--hydroxy-cyclohexenone, was derived
from L-tartaric acid in six steps and 14 more steps were required to achieve nabscessin B.23
Here, we report our approach to access nabscessin A via inexpensive, natural D-camphor and
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myo-inositol (2), the most abundant cyclitol occurring in nature.24-26 In addition to saving effort
to form the carbocycle by using 2, this pair of starting materials also makes it possible to prepare
both enantiomers of nabscessin A.
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Results and discussion
Desymmetrization of meso myo-inositol was achieved with dimethyl D-camphor acetal (3) to
give 1,2-camphor acetal 4 according to the procedures reported by Bruzik’s and Konradsson’s
groups (Scheme 1).27-28 The obtained compound 4, collected from recrystallization, was
diastereomerically pure (see H and 13C NMR in Supporting Information) and applied in the
1
following synthesis. We were glad to find that the reaction of compound 4, dibutyltin oxide and
benzyl/4-methoxybenzyl bromides provided di-benzylated compounds 5a/5b. The
regiochemistry of the dibenzylation reactions was established by hydrolyzing the 1,2-camphor
acetal of 5a to yield the known L-3,6-Di-O-benzyl-myo-inositol (6).29 The regioselectivity
observed here is the same as that noticed in the corresponding reaction of 1,2-acetonide protected
myo-inositol.30 Further benzylations of 5b and acid hydrolysis to remove the camphor acetal and
PMB groups afforded (+)-4,5-di-O-benzyl-myo-inositol 8, which was prepared asymmetrically
for the first time.31 On the other hand, the enantiomer (-)-8 was also synthesized from 4 through
the following sequence: protection of the two hydroxyl groups at C-3 and C-4 to form the known
silyl ether 9,28 dibenzylations under a phase-transfer condition32 and following hydrolysis
(Scheme 2). The phase-transfer condition and low temperature (-10 °C) were required to keep
the silyl-protecting group intact during the dibenzylations.
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OH
HO
HO
OH
OH
2
3
ref 27
1
6
RBr, Bu2SnO
TBAI, toluene
+
4
5
OMe
O
2
O
O
O
7
37%
1
HO
HO
RO
HO
OMe
8
9
OH
OH
OR
HO
HO
3
2
myo-inositol ( )
4
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5a
5b
(R = Bn, 96%)
(R = PMB, 69%)
OH
AcOH, H2O
HO
BnO
HO
5a
OBn
100 °C, 2 h
HO
6
(83%)
OH
HO
AcOH, H2O
100 °C, 2 h
BnBr, NaH
TBAI, DMF
HO
5b
BnO
O
O
OH
BnO
PMBO
BnO
OPMB
8
(+)- (72%)
BnO
7
(96%)
Scheme 1. Synthesis of (+)-4,5-di-O-benzyl-myo-inositol (8).
1. BnBr, TBAI
i-Pr i-Pr
toluene, NaOH(aq)
Cl
Si O Si Cl
OH
HO
-10 °C, 16 h
i-Pr i-Pr
BnO
O
O
2
BnO
O
O
2. HF, MeOH, rt
OH
py
1
HO
HO
HO
HO
HO
O
OH
8
(-)- (64%)
O
HO
4
Si(i-Pr)2
(i-Pr)2Si
O
9
(92%)
Scheme 2. Synthesis of (-)-4,5-di-O-benzyl-myo-inositol (8).
Compound (+)-8 was chosen to continue the synthesis because its preparation is more efficient
and convenient than that of (-)-8. The vicinal, trans-diol of (+)-8 was protected by butanedione
to yield diacetal 10.33 The stereoselective deoxygenation of myo-inositol monotosylates,
developed by Yu and Spencer,34 was applied to convert 10 to tosylate 11 and the following
reduction with lithium triethylborohydride to yield deoxy-inositol 12. The axial hydroxyl group
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was transformed to a triflate and replaced with an azido group to form 13 in 70% yield over the
two steps. Palladium catalyzed hydrogenation and hydrogenolysis of azide 13 generated amino-
diol 14, which was coupled with 3-(methoxymethoxy)benzoic acid to form amide 15, assisted by
N,N,N’,N’-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and N,N-
diisopropylethylamine (DIPEA). The selective esterification between 15 and 6-methylsalicyclic
acid by various carbodiimides was critical (Table 1).35-37 Mixtures of monoesters 16a, 16b and
diester 17 were produced by DCC and DIC (entries 1 and 2, Table 1). To identify regioisomers
16a and 16b, the two compounds were separated by column chromatography and analyzed by
NMR. The proton of the O-methine (CH-OR2) was resolved according to its adjacent couplings
to the methylene group, but no coupling with the amide proton, in their respective 1H-1H COSY
spectrum (Supporting Information). The compound with a more downfielded CH-OR2 ( 5.23
versus 3.63) was assigned as 16b for its attachment to the acyl group. We found that the N-(3-
(dimethylamino)propyl)-N’-ethylcarbodiimide (EDC) or its hydrochloride salt provided the
product free of 16b, and 68% yield of 16a was harvested when the reaction was conducted at 10
°C for 48 h (entry 3–5, Table 1). All the screened carbodiimides providing 16a as the major
product indicated that the hydroxyl group neighboring to the diacetals of 15 is more reactive in
the esterification. This may be attributed to the hydrogen-bonding interaction between diacetals
and carbodiimide-activated 6-methylsalicylic acid. The dimethylamino group of EDC, which
should be protonated during the reaction, increased the interaction to give a better selectivity.
This conjecture is supported by the result that the regioselectivity imposed by EDC diminished
when a base, DBU, was added to trap protons (entry 6). A carbamate group was then installed by
the addition of 2,2,2-trichloroacetyl isocyanate to 16a and treatment of potassium carbonate in
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methanol to yield 18.38 Removal of the diacetals and methoxymethyl group with aqueous
trifluoroacetic acid (TFA) gave ent-nabscessin A (ent-1) in 61% yield.
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The NMR and mass spectroscopic data of ent-1 were consistent with the reported natural
nabscessin A, and the specific rotation of synthetic ent-1 was opposite to that of reported, natural
nabscessin A, [α]D +10.7 (c 0.13, MeOH) and −10.8 (c 1.0, MeOH), respectively.1 With our
access to both enantiomerically pure building blocks (+)-8 and (-)-8 (Scheme 1 and 2), the
procedure shown in Scheme 3 is also applicable to prepare natural nabscessin A. Therefore,
nabscessin A was synthesized for the first time in 14 steps.
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R
R
OH
butanedione, MeOH
CH(OMe)3, CSA
TsCl, Bu2SnO
OH
O
LiEt3BH
THF
O
8
O
(+)-
O
R
BnO
OTs
R
BnEt3NCl, MeCN
OH
BnO
BnO
BnO
11
(R=OMe, 93%)
10
(R = OMe, 52%)
R
R
R
OH
O
H2, Pd(OH)2
O
O
O
1. Tf2O, py, DCM
2. NaN3, DMF
O
O
NH3 Cl
N3
R
R
R
BnO
HO
BnO
HCl(aq), MeOH
BnO
HO
BnO
12
(R=OMe, 77%)
14
13
(R=OMe, 84%)
(R=OMe, 70%)
R
R
OMOM
O
O
6-methyl-
salicylic acid
O
O
HO2C
O
O
N
N
R1O
R
R
HO
H
H
HBTU, DIPEA
EDC, DMAP
R2O
R=OMe
(R = 2-hydroxy-6-methylbenzoyl, R = H, 68%)
HO
OMOM
OMOM
15
(R=OMe, 77%)
1
2
16a
16b
1
2
(R = H, R = 2-hydroxy-6-methylbenzoyl)
1
2
17
(R = R = 2-hydroxy-6-methylbenzoyl)
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O
R
O
OH
O
HO
O
N
(1) Cl3CCONCO
(2) H2O, K2CO3
TFA
H2O
O
O
N
H
R
16a
O
O
H
OC(O)NH2
HO
OC(O)NH2
OH
HO
MeOH
OMOM
1
ent- (61%)
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(R=OMe, 66%)
NH2
O
O
HO
HN
HO
O
O
O
OH
HO
Scheme 3. Synthesis of ent-nabscessin A.
Table 1. Regioselective esterification of 15.a
yield of esters (%)b
entry
coupling reagent
16a
16b
33
30
-
17
DCC
DIC
1
2
50
49
51
58
68
33
6
8
EDC
3
12
12
9
EDC · HCl
EDC
4
-
5c
6d
-
EDC
16
31
aReaction condition: 15 (1.0 equiv), 6-methylsalicyclic acid (1.2 equiv)
and coupling reagent (1.5 equiv) in CH2Cl2, rt, 16 h. bIsolated yields. c10
°C, 48 h. dAdding DBU (3.0 equiv).
DCC = N,N’-dicyclohexyl-carbodiimide, DIC = N,N’-diisopropyl-
carbodiimide, EDC = N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide,
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
In summary, we report an asymmetric synthesis of nabscessin A, where we utilized the
carbocycle of myo-inositol, natural camphor to achieve desymmetrization and prepare both
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enantiomers of key intermediate 8, and a regioselective esterification. The chemistry of inositol
accumulated by previous researchers was also essential in utilizing the oxygenated carbocycle.
This approach should be applicable to prepare other aminocyclitol-related natural products.
Experimental Section
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General information: Dichloromethane and toluene were dried over calcium hydride and
distilled prior to use. Tetrahydrofuran and diethyl ether were dried over sodium, monitored with
benzophenone ketyl radicals and distilled prior to use. DMF was dried over molecular sieves (3
Å). TLC was conducted using pre-coated silica gel 60 F254 plates containing a fluorescent
indicator; purification by chromatography was conducted using silica gel (230–400 mesh).
1
Chemical shifts for H-NMR and 13C{1H} NMR spectra are reported in δ units (parts per
million) with reference to residual solvent peaks. All spectra were obtained at 25 °C. The
multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, dd = doublet of doublets, td = triplet of doublets. High-resolution mass spectrometry
(HRMS) data were recorded on a JMS-700 quadrupole mass spectrometer. D-camphor myo-
inositol acetal (4) was prepared according to the literature procedure.27
(1'R,2R,3aR,4S,4'R,5R,6R,7S,7aS)-4,7-Bis(benzyloxy)-1',7',7'-
trimethylhexahydrospiro[benzo[d][1,3]dioxole-2,2'-bicyclo[2.2.1]heptane]-5,6-diol (5a). A
reaction flask containing compound 4 (408.2 mg, 1.30 mmol), dibutyltin oxide (808.1 mg, 3.25
mmol), methanol (2.5 mL) and toluene (2.6 mL) was heated to reflux for 3 h in an oil bath (130
°C). The reaction mixture was concentrated, added with toluene (10 mL) and concentrated under
a vacuum for 1 h to remove the solvents. The residue was diluted with toluene (5.1 mL), added
with benzyl bromide (340 μL, 488.6 mg, 2.86 mmol) and tetrabutylammonium iodide (527.6 mg,
1.43 mmol), and heated to reflux for another 16 h in an oil bath (130 °C). The solvent was
removed under a vacuum, and the crude product was purified with column chromatography
(SiO2, EtOAc/hexanes, 1:1, Rf 0.38) to give 5a as a light-yellow liquid (618.3 mg, 1.25 mmol,
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96%). H NMR (500 MHz, CDCl3) δ 7.38‒7.25 (m, 10H), 4.95 (d, J = 11.5 Hz, 1H), 4.73‒4.64
(m, 3H), 4.31 (t, J = 5.0 Hz, 1H ), 3.96 (t, J = 6.0 Hz, 1H ), 3.85 (t, J = 9.5 Hz, 1H ), 3.56 (dd, J
= 9.5 Hz, J = 4.5 Hz, 1H ), 3.47‒3.37 (m, 2H), 2.81 (br, 1H), 2.76 (br, 1H), 1.96‒1.91 (m, 1H),
1.89‒1.85 (m, 1H), 1.74‒1.69 (m, 2H), 1.46 (d, J = 13.0 Hz, 1H), 1.41‒1.35 (m, 1H), 1.25‒1.20
13
(m, 1H), 1.04 (s, 3H), 0.86 (s, 3H), 0.79 (s, 3H); C{1H} NMR (CDCl3, 126 MHz) δ 138.3,
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137.9, 128.53, 128.46, 128.1, 128.0, 127.9, 127.8, 118.1, 83.1, 77.5, 73.4, 73.2, 72.8, 71.7, 71.2,
20
51.6, 48.1, 45.3, 45.2, 29.7, 27.1, 20.5, 10.0; [α]D -18.3 (c 1.1, CHCl3); HRMS-ESI m/z calcd
for [M+H]+ (C30H39O6) 495.2741, found 495.2722.
(1'R,2R,3aR,4S,4'R,5R,6R,7S,7aS)-4,7-Bis((4-methoxybenzyl)oxy)-1',7',7'-
trimethylhexahydrospiro[benzo[d][1,3]dioxole-2,2'-bicyclo[2.2.1]heptane]-5,6-diol (5b). A
reaction flask containing compound 4 (1.20 g, 3.82 mmol), dibutyltin oxide (2.38 g, 9.54 mmol),
methanol (7.5 mL) and toluene (7.5 mL) was heated to reflux for 3 h in an oil bath (130 °C). The
reaction mixture was concentrated, diluted with toluene (15 mL) and concentrated under a
vacuum for 1 h to remove the solvents. The residue was diluted with toluene (15 mL), added
with 4-methoxybenzyl bromide (1.69 g, 8.40 mmol) and tetrabutylammonium iodide (1.55 g,
4.21 mmol), and heated to reflux for another 16 h in an oil bath (130 °C). The solvent was
removed under a vacuum, and the crude product was purified with column chromatography
(SiO2, EtOAc/hexanes, 1:1, Rf 0.33) to give 5b as a light-yellow liquid (1.46 g, 2.64 mmol,
1
69%). H NMR (500 MHz, CDCl3) δ 7.28‒7.26 (m, 4H); 6.86 (d, J = 8.5 Hz, 4H), 4.87 (d, J =
11.5 Hz, 1H), 4.65 (d, J = 11.5 Hz, 1H), 4.55 (d, J = 11.0 Hz, 1H), 4.57 (d, J = 11.0 Hz, 1H),
4.30 (t, J = 5.0 Hz, 1H), 3.93 (t, J = 6.5 Hz, 1H), 3.81 (t, J = 9.5 Hz, 1H), 3.78 (s, 3H), 3.77 (s,
3H), 3.53 (dd, J = 9.5 Hz, J = 5.0 Hz, 1H), 3.42 (dd, J = 9.5 Hz, J = 6.5 Hz, 1H), 3.36 (t, J = 10.0
Hz, 1H), 2.74 (br, 1H), 2.68 (br, 1H), 1.96‒1.92 (m, 1H), 1.89‒1.85 (m, 1H), 1.74‒1.72 (m, 2H),
1.47 (d, J = 13.0 Hz, 1H), 1.41‒1.36 (m, 1H), 1.25‒1.20 (m, 1H), 1.04 (s, 3H), 0.85 (s, 3H), 0.80
(s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 159.5, 159.3, 130.5, 129.9, 129.7, 129.5, 118.0,
114.0, 113.9, 82.9, 77.1, 76.4, 73.3, 72.9, 72.8, 71.22, 71.18, 55.3, 51.6, 48.1, 45.3, 45.2, 29.7,
27.1, 20.5, 20.4, 10.1; [α]D20 -9.1 (c 1.79, CHCl3); HRMS-ESI m/z calcd for [M+H]+ (C32H43O8)
555.2952, found 555.2928.
L-3,6-Di-O-benzyl-myo-inositol (6). A reaction mixture of compound 5a (500.0 mg, 1.0
mmol), acetic acid (28 mL) and water (7 mL) was heated in an oil bath (100 °C) for 2 h and
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concentrated. The crude product was recrystallized in ethyl acetate to give 6 as a colorless solid
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(300.1 mg, 0.83 mmol, 83%). Mp 172.0‒174.5 °C; [α]D -5.5 (c 0.45, DMSO); H NMR (500
MHz , (CD3)2SO) δ 7.46‒7.10 (m, 10H), 4.84 (d, J = 4.9 Hz, 1H), 4.81‒4.73 (m, 5H), 4.66‒4.63
(m, 2H), 4.56 (d, J = 12.0 Hz, 1H), 3.97 (br, 1H), 3.63‒3.58 (m, 1H), 3.44 (t, J = 9.0 Hz, 1H),
3.31‒3.28 (m, 1H), 3.16‒3.10 (m, 2H); 13C{1H} NMR (126 MHz, (CD3)2SO) δ 139.9, 139.3,
127.9, 127.8, 127.6, 127.5, 127.4, 127.0, 126.9, 81.8, 79.7, 75.0, 73.5, 72.2, 71.4, 70.7, 69.7. The
spectroscopic data were consistent with the reported values.29
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(1'R,2R,3aR,4S,4'R,5R,6R,7S,7aS)-5,6-Bis(benzyloxy)-4,7-bis((4-methoxybenzyl)oxy)-
1',7',7'-trimethylhexahydrospiro[benzo[d][1,3]dioxole-2,2'-bicyclo[2.2.1]heptane]
(7).
Sodium hydride (60 % dispersion in mineral oil, 807.7 mg, 20.2 mmol) was added to a solution
of 5b (1.40 g, 2.52 mmol), tetrabutylammonium iodide (93.2 mg, 0.25 mmol) and N,N-
dimethylformamide (DMF, 25.2 mL) at 0 °C. The reaction mixture was stirred for 15 min, added
with benzyl bromide (901 μL, 1.30 g, 7.57 mmol) at 0 °C, stirred for another 16 h at rt, quenched
with water (20 mL) at 0 °C and extracted with ethyl acetate (40 mL, 20 mL × 2). The combined
organic layers were washed with saturated NaCl(aq) (20 mL × 3), dried over sodium sulfate,
filtered and concentrated. The crude product was purified with column chromatography (SiO2,
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EtOAc/hexanes, 1:5, Rf 0.39) to give 6 as a light-yellow liquid (1.80 g, 2.45 mmol, 96%). H
NMR (500 MHz , CDCl3) δ 7.30‒7.27 (m, 14H), 6.85 (ddd, J = 6.5 Hz, J = 6.5 Hz, J = 2.5 Hz,
4H), 4.84‒4.61 (m, 8H), 4.28 (dd, J = 6.5 Hz, J = 4.5 Hz, 1H), 3.94 (t, J = 6.5 Hz, 1H), 3.80 (s,
3H), 3.79 (s, 3H), 3.74 (dd, J = 9.5 Hz, J = 4.5 Hz, 1H), 3.70 (dd, 9.5 Hz, J = 6.5 Hz, 1H), 1.49
(d, J = 15.0 Hz, 1H), 1.42‒1.36 (m, 1H), 1.25 (m, 1H), 1.09 (s, 3H), 0.88 (s, 3H), 0.86 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 159.2, 138.8, 131.0, 130.6, 129.6, 129.4, 128.0, 127.5,
117.6, 113.8, 113.8, 83.0, 82.1, 80.8, 76.3, 75.2, 75.0, 73.7, 72.0, 55.3, 51.6, 48.0, 45.2, 45.0,
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29.8, 27.1, 20.7, 20.4, 10.2; [α]D +2.7 (c 0.87, CHCl3); HRMS-ESI m/z calcd for [M+H]+
(C46H55O8) 735.3891, found 735.3868.
(1R,2R,3S,4R,5S,6S)-5,6-Bis(benzyloxy)cyclohexane-1,2,3,4-tetraol (+)-8. A reaction
mixture of compound 7 (862.0 mg, 1.17 mmol), acetic acid (36 mL) and water (4 mL) was
heated in an oil bath (100 °C) for 2 h and concentrated. The residue was added with methanol (2
mL), stirred and concentrated to remove the solvents. The light yellow, viscous liquid was
further washed with diethyl ether (15 mL × 3), and the residue was concentrated to dryness to
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give (+)-8 as a colorless solid (305.5 mg, 0.85 mmol, 72%). Mp 154.5‒156.0 °C; 1H NMR (500
MHz, (CD3)2SO) δ 7.33‒7.21 (m, 10H), 4.85‒4.79 (m, 2H), 4.72‒4.66 (m, 2H), 4.54 (d, J = 5.5
Hz, 1H), 3.72 (d, J = 2.5 Hz, 1H), 3.61 (ddd, J = 9.5 Hz, J = 9.5 Hz, J = 5.5 Hz, 1H), 3.56 (t, J =
9.5 Hz, 1H), 3.23‒3.21 (m, 1H), 3.18 (t, J = 9.5 Hz, 1H); 13C{1H} NMR (126 MHz, (CD3)2SO) δ
140.0, 140.0, 128.4, 128.4, 127.9, 127.9, 127.8, 127.8, 127.5, 127.5, 84.1, 82.2, 74.5, 73.5, 73.4,
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72.3, 72.2; [α]D +34.3 (c 0.25, DMSO); HRMS-ESI m/z calcd for [M+H]+ (C20H25O6)
361.1646, found 361.1649.
(1R,2R,4R,6'S,7'S,7a'R,10a'R,10b'R)-2',2',4',4'-Tetraisopropyl-1,7,7-
trimethylhexahydrospiro[bicyclo[2.2.1]heptane-2,9'-[1,3]dioxolo[4',5':3,4]benzo[1,2-
f][1,3,5,2,4]trioxadisilepine]-6',7'-diol (9). 1,3-Dichloro-1,1,3,3-tetraisopropyldisoxane (296.5
μL, 292.2 mg, 0.99 mmol) was added to a solution of 4 (242.7 mg, 0.77 mmol) and pyridine (4.9
mL) at ‒30 ℃. The reaction mixture was slowly warmed up to rt, stirred for another 16 h at rt,
diluted with ethyl acetate (15 mL) and washed with water (15 mL × 3). The organic layer was
washed with saturated NaCl(aq) (15 mL), dried over sodium sulfate, filtered and concentrated.
The crude product was purified with column chromatography (SiO2, EtOAc/hexanes, 1:3, Rf
0.36) to give 9 as a colorless liquid (394.1 mg, 0.71 mmol, 92%). 1H NMR (500 MHz, CDCl3) δ
4.20 (t, J = 5.0 Hz, 1H), 3.91 (dd, J = 9.0 Hz, J = 4.5 Hz, 1H), 3.82 (t, J = 7.0 Hz, 1H), 3.78 (t, J
= 9.5 Hz, 1H), 3.57 (dd, J = 10.5 Hz, J = 7.0 Hz, 1H), 3.25 (t, J = 9.5 Hz, 1H), 2.64 (br, 2H),
1.93‒2.01 (m, 2H), 1.66‒1.69 (m, 2H), 1.47 (d, J = 12.5 Hz, 1H), 1.34‒1.39 (m, 1H), 1.18‒1.23
(m, 1H), 0.96‒1.08 (m, 31H), 0.83 (s, 3H), 0.80 (s, 3H); C{1H} NMR (126 MHz, CDCl3) δ
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117.6, 76.6, 75.8, 75.7, 75.5, 73.6, 73.4, 51.4, 48.0, 45.4, 45.2, 29.4, 27.1, 20.5, 20.2, 17.6,
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17.37, 17.31, 17.3, 17.2, 17.1, 17.0, 13.0, 12.7, 12.2; [α]D +9.0 (c 1.05, CHCl3); HRMS-ESI
m/z calcd for [M+H]+ (C28H53O7Si2) 557.3324, found 557.3309.
(1S,2R,3S,4S,5R,6R)-5,6-Bis(benzyloxy)cyclohexane-1,2,3,4-tetraol (-)-8. A mixture of
tetrabutylammonium iodide (37.9 mg, 0.103 mmol), benzyl bromide (352 μL, 506.8 mg, 2.96
mmol) and sodium hydroxide (0.55 mL, w/w 50% in water) was cooled to -10 ℃ and added with
a solution of 9 (44.0 mg, 0.079 mmol) in toluene (0.55 mL). The reaction mixture was stirred at -
10 ℃ for 16 h, diluted with diethyl ether (5 mL) and washed with water (1 mL × 4). The organic
layer was washed with saturated NaCl(aq) (2 mL), dried over sodium sulfate, filtered and
concentrated to give the benzylated intermediate (123.4 mg). The intermediate was redissolved
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in methanol (0.5 mL) and added with hydrofluoric acid (40% wt in H2O, 73 μL, 33.5 mg, 1.67
mmol). The reaction mixture was stirred at rt for 3 h and concentrated. The crude product was
purified with column chromatography (SiO2, EtOAc, Rf 0.31) to give (-)-8 as a colorless solid
(18.2 mg, 0.051 mmol, 64%).1H NMR (500 MHz, (CD3)2SO) δ 7.33‒7.22 (m, 10H), 4.86‒4.77
(m, 2H), 4.70‒4.65 (m, 2H), 4.51 (d, J = 9.5 Hz, 1H), 3.73‒3.72 (m, 1H), 3.65‒3.59 (m, 1H),
3.52‒3.51 (m, 1H), 3.42 (br, 4H), 3.23-3.13 (m, 2H); [α]D20 -34.6 (c 0.23, DMSO); HRMS-ESI
m/z calcd for [M+H]+ (C20H25O6) 361.1646, found 361.1639.
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(2R,3R,4aS,5S,6R,7S,8R,8aS)-7,8-Bis(benzyloxy)-2,3-dimethoxy-2,3-
dimethyloctahydrobenzo[b][1,4]dioxine-5,6-diol (10). A reaction mixture of (+)-8 (582.0 mg,
1.61 mmol), 2,3-butanedione (157 μL, 154.4 mg, 1.78 mmol), trimethyl orthoformate (751 μL,
728.3 mg, 1.58 mol), camphorsulfonic acid (18.7 mg, 0.08 mmol) and methanol (7.5 mL) was
heated in an oil bath (90 ℃) for 16 h, quenched with triethylamine (43 μL) and concentrated. The
crude product was purified with column chromatography (SiO2, EtOAc/hexanes, 1:1, Rf 0.50) to
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give 10 as a light-yellow liquid (397.3 mg, 0.84 mmol, 52%). H NMR (500 MHz , CDCl3) δ
7.36‒7.26 (m, 10H), 4.99 (d, J = 11.0 Hz, 1H), 4.94 (d, J = 11.0 Hz, 1H), 4.76 (d, J = 11.0 Hz,
1H), 4.69 (d, J = 11.0 Hz, 1H), 4.15 (t, J = 11.0 Hz, 1H), 4.09 (s, 1H), 3.76 (t, J = 9.3 Hz, 1H),
3.59‒3.52 (m, 3H), 3.28 (s, 3H), 3.25 (s, 3H), 2.59 (br, 1H), 2.51 (br, 1H), 1.33 (s, 3H), 1.32 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 138.8, 138.6, 128.6, 128.3, 128.0, 127.9, 127.8, 127.6,
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100.0, 99.2, 81.9, 81.0, 75.8, 75.5, 72.1, 69.9, 69.7, 68.3, 48.1, 47.9, 17.9, 17.6; [α]D -17.5 (c
0.36, CHCl3); HRMS-ESI m/z calcd for [M+H]+ (C26H35O8) 475.2326, found 475.2373.
(2R,3R,4aS,5R,6R,7R,8R,8aS)-7,8-Bis(benzyloxy)-5-hydroxy-2,3-dimethoxy-2,3-
dimethyloctahydrobenzo[b][1,4]dioxin-6-yl 4-methylbenzenesulfonate (11). A reaction
mixture of 10 (338.5 mg, 0.71 mmol), dibutyltin oxide (353.5 mg, 1.42 mmol),
benzyltriethylammonium chloride (193.6 mg, 0.85 mmol), 4-toluenesulfonyl chloride (162.1 mg,
0.85 mmol) and acetonitrile (21.6 mL) was heated to reflux for 16 h in an oil bath (90 °C) and
concentrated. The crude product was purified with column chromatography (SiO2,
EtOAc/hexanes, 1:3, Rf 0.48) to give 11 as a white solid (415.1 mg, 0.66 mmol, 93%). Mp
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189.5‒193.0 ℃; H NMR (500 MHz , CDCl3) δ 7.74 (d, J = 8.0 Hz, 2H), 7.25‒7.23 (m, 8H),
7.11 (d, J = 8.0 Hz, 2H), 7.07‒7.05 (m, 2H), 4.89 (d, J = 11.0 Hz, 1H), 4.67 (d, J = 11.0 Hz, 2H),
4.51‒4.47 (m, 2H), 4.35 (d, J = 2.5 Hz, 1H), 4.13 (t, J = 9.5 Hz, 1H), 3.92 (t, J = 9.5 Hz, 1H),
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3.56 (dd, J = 11.0 Hz, J = 2.5 Hz, 1H), 3.52 (t, J = 9.5 Hz, 1H), 3.26 (s, 6H), 2.53 (br, 1H), 2.33
(s, 3H), 1.32 (s, 3H), 1.32 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 144.8, 138.5, 138.2,
133.7, 129.7, 129.7, 128.3, 128.2, 128.1, 127.8, 127.6, 127.5, 127.4, 100.0, 99.2, 81.5, 80.7, 80.0,
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75.7, 69.6, 68.7, 67.5, 48.3, 47.9, 21.6, 17.8, 17.6; [α]D -3.9 (c 0.34, CHCl3); HRMS-ESI m/z
calcd for [M+H]+ (C33H41O10S) 629.2415, found 629.2359.
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(2R,3R,4aS,5S,7S,8R,8aS)-7,8-Bis(benzyloxy)-2,3-dimethoxy-2,3-
dimethyloctahydrobenzo[b][1,4]dioxin-5-ol (12). Lithium triethylborohydride (1 M in THF,
3.1 mL, 3.1 mmol) was added to a solution of 11 (195.4 mg, 0.31 mmol) and THF (1.2 mL) at 0
°C. The reaction mixture was heated to reflux for 24 h in an oil bath (85 °C), quenched with
water (2 mL) at 0 °C, concentrated to remove THF and extracted with ethyl acetate (5 mL × 3).
The combined organic layers were washed with saturated NaCl(aq) (5 mL), dried with sodium
sulfate, filtered and concentrated. The crude product was purified with column chromatography
(SiO2, EtOAc/hexanes, 1:1, Rf 0.32) to give 12 as a colorless liquid (109.5 mg, 0.24 mmol, 77%).
1H NMR (500 MHz, CDCl3) δ 7.39‒7.24 (m, 10H), 4.95 (d, J = 11.0 Hz, 1H), 4.81 (d, J = 11.0
Hz, 1H), 4.72 (d, J = 11.5 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H), 4.06 (t, J = 10.0 Hz, 1H), 4.00 (dd,
J = 5.0 Hz, J = 3.0 Hz, 1H), 3.88 (ddd, J = 11.5 Hz, J = 9.5 Hz, J = 5.0 Hz, 1H), 3.59 (dd, J =
10.0 Hz, J = 2.5 Hz, 1H), 3.55 (t, J = 9.5 Hz, 1H), 3.27 (s, 3H), 3.25 (s, 3H), 2.32 (ddd, J = 14.0
Hz, J = 5.0 Hz, J = 2.5 Hz, 1H), 1.47 (ddd, J = 15.0 Hz, J = 11.5 Hz, J = 2.5 Hz, 1H), 1.34 (s,
3H), 1.31 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 139.3, 138.9, 128.3, 128.2, 127.9, 127.8,
127.5, 127.4, 99.9, 99.9, 99.2, 83.1, 75.4, 73.4, 71.1, 69.5, 66.9, 48.0, 47.8, 33.6, 17.9, 17.6;
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[α]D -5.6 (c 0.69, CHCl3); HRMS-ESI m/z calcd for [M+H]+ (C26H35O7) 459.2377, found
459.2340.
(2R,3R,4aR,5R,6S,8R,8aS)-8-Azido-5,6-bis(benzyloxy)-2,3-dimethoxy-2,3-
dimethyloctahydrobenzo[b][1,4]dioxine (13). Trifluoromethanesulfonic anhydride (41 μL, 69.0
mg, 0.25 mmol) was added to a solution of 12 (74.8 mg, 0.16 mmol), pyridine (105 μL, 103.2
mg, 1.31 mmol) and dichloromethane (4.9 mL) at 0 °C. The reaction mixture was stirred at 0 ℃
for 3 h, concentrated, added with anhydrous DMF (6.2 mL) and sodium azide (160.0 mg, 1.63
mmol), stirred at rt for another 2 h, quenched with water (10 mL) and extracted with ethyl
acetate (20 mL, 10 mL × 2). The combined organic layers were washed with saturated NaCl(aq)
(10 mL), dried with sodium sulfate, filtered and concentrated. The crude product was purified
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with column chromatography (SiO2, EtOAc/hexanes, 1:5, Rf 0.66) to give 13 as a colorless liquid
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(54.2 mg, 0.11 mmol, 70%). H NMR (500 MHz , CDCl3) δ 7.36‒7.25 (m, 10H), 4.91 (d, J =
11.0 Hz, 1H), 4.78 (d, J = 11.0 Hz, 1H), 4.67 (d, J = 11.0 Hz, 1H), 4.61 (d, J = 11.0 Hz, 1H),
3.64‒3.59 (m, 2H), 3.53 (t, J = 9.1 Hz, 1H), 3.46‒3.42 (m, 2H), 3.34 (s, 3H), 3.28 (s, 3H), 2.21
(ddd, J = 9.0 Hz, J = 9.0 Hz, J = 4.5 Hz, 1H), 1.39 (t, J = 11.5 Hz, 1H), 1.35 (s, 3H), 1.33 (s,
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3H); C{1H} NMR (126 MHz, CDCl3) δ 138.9, 138.3, 128.4, 128.3, 128.0, 127.7, 127.6, 99.7,
99.4, 82.1, 77.5, 75.6, 73.2, 72.8, 71.7, 56.7, 48.1, 48.0, 33.3, 33.3, 17.7, 17.6; [α]D20 -1.3 (c 0.55,
CHCl3); HRMS-ESI m/z calcd for [M+Na]+ (C26H33N3O6Na) 506.2262, found 506.2230.
(2R,3R,4aS,5R,7S,8R,8aS)-7,8-Dihydroxy-2,3-dimethoxy-2,3-
dimethyloctahydrobenzo[b][1,4]dioxin-5-aminium (14). A reaction suspension of 13 (40.1
mg, 0.083 mmol), palladium on carbon (10% wt, 26.5 mg, 0.025 mmol), methanol (5.5 mL) and
HCl(aq) (1N, 170 μL, 0.166 mmol) was stirred at rt for 8 h under an atmosphere of hydrogen (1
atm) and filtered through a pad of celite. The filtrate was concentrated to give compound 14
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(21.9 mg, 0.070 mmol, 84%) as a colorless of solid. Mp >220 ℃ (decomposed); H NMR (500
MHz , CD3OD) δ 3.81 (dd, J = 10.5 Hz, J = 6.0 Hz, 1H), 3.52‒3.50 (m, 1H), 3.45 (d, J = 5.5 Hz,
2H), 3.36 (s, 3H), 3.31 (s, 3H), 3.28 (br, 1H), 2.81‒2.76 (m, 1H), 2.12 (ddd, J = 8.5 Hz, J = 8.5
Hz, J = 4.0 Hz, 1H), 1.34 (s, 3H), 1.33 (s, 3H); 13C{1H} NMR (126 MHz, CD3OD) δ 99.2, 99.1,
98.2, 74.7, 73.6, 72.4, 71.3, 70.3, 65.5, 37.4, 16.6, 16.6; HRMS-ESI m/z calcd for [M]+
(C12H24NO6) 278.1598, found 278.1592.
N-((2R,3R,4aS,5R,7S,8R,8aS)-7,8-Dihydroxy-2,3-dimethoxy-2,3-
dimethyloctahydrobenzo[b][1, 4]dioxin-5-yl)-3-(methoxymethoxy)benzamide (15).
A
solution of 14 (40.1 mg, 0.081 mmol), N,N-diisopropylethylamine (DIPEA, 18.4 μL, 13.6 mg,
0.106 mmol) in THF (2.2 mL) was added to the mixture of 3-(methoxymethoxy)benzoic acid
(19.2 mg, 0.106 mmol), DIPEA (18.4 μL, 13.6 mg, 0.106 mmol), HBTU (43.1 mg, 0.114 mmol)
and THF (2.2 mL) at rt. The reaction mixture was stirred at rt for 16 h, concentrated, added with
water (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were
washed with saturated NaCl(aq) (10 mL), dried over sodium sulfate, filtered and concentrated. The
crude product was purified with column chromatography (SiO2, EtOAc, Rf 0.35) to give 15 as a
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colorless liquid (27.6 mg, 0.063 mmol, 77%). H NMR (500 MHz, CDCl3) δ 7.39 (s, 1H), 7.31
(t, J = 6.5 Hz, 1H), 7.25‒7.20 (m, 1H), 7.09 (t, J = 6.5 Hz, 1H), 6.65 (br, 1H), 5.09 (dd, J = 10.5
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Hz, J = 7.5 Hz, 2H), 4.06‒4.05 (m, 1H), 3.71‒3.70 (m, 2H), 3.54‒3.52 (m, 2H), 3.39 (s, 3H),
3.24 (s, 6H), 2.42‒2.41 (m, 1H), 1.54 (dd, J = 24.0 Hz, J = 12.0 Hz, 1H), 1.29 (s, 3H), 1.24 (s,
13
3H); C{1H} NMR (126 MHz, CDCl3) δ 167.5, 157.4, 136.0, 129.7, 120.3, 119.6, 114.8, 99.6,
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99.4, 94.4, 74.7, 71.2, 70.4, 70.1, 56.1, 48.0, 47.9, 47.6, 35.5, 17.7, 17.6; [α]D -21.1 (c 0.58,
CHCl3); HRMS-ESI m/z calcd for [M+H]+ (C12H24NO6) 278.1598, found 278.1593.
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(2R,3R,4aR,5R,6S,8R,8aS)-6-Hydroxy-2,3-dimethoxy-8-(3-
(methoxymethoxy)benzamido)-2,3-dimethyloctahydrobenzo[b][1,4]dioxin-5-yl 2-hydroxy-
6-methylbenzoate (16a). N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide (12.0 μL, 10.6 mg,
0.068 mmol) was added to a solution of 2-hydroxy-6-methylbenzoic acid (7.6 mg, 0.050 mmol),
4-(dimethylamino)pyridine (DMAP, 0.60 mg, 0.0046 mmol) and dichloromethane (2.2 mL) at 0
°C. The reaction mixture was stirred at 0 °C for 15 min, added with a solution of 15 (20.1 mg,
0.046 mmol) in dichloromethane (2.2 mL) dropwise at 0 °C, stirred at 10 °C for 48 h and
concentrated.
The crude product was purified with column chromatography (SiO2,
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EtOAc/hexanes, 3:2, Rf 0.55) to give 16a as a colorless liquid (17.8 mg, 0.031 mmol, 68%). H
NMR (500 MHz , CDCl3) δ 10.75 (br, 1H), 7.40 (s, 1H), 7.32‒7.26 (m, 3H), 7.14 (d, J = 7.0 Hz,
1H), 6.81 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 7.0 Hz, 1H), 6.27 (br, 1H), 5.31 (t, J = 9.5 Hz, 1H),
5.16 (s, 2H), 4.05‒4.03 (m, 1H), 4.08‒4.07 (m, 1H), 3.94‒3.93 (m, 1H), 3.87‒3.80 (m, 1H), 3.44
(s, 3H), 3.27 (s, 3H), 3.17 (s, 3H), 2.65‒2.64 (m, 1H), 2.55 (s, 3H), 1.39‒1.37 (m, 1H), 1.26 (s,
3H), 1.25 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 171.1, 167.5, 162.0, 157.5, 140.9, 136.0,
134.1, 129.8, 122.9, 120.1, 119.7, 115.7, 114.8, 113.1, 99.7, 99.6, 94.5, 70.5, 69.4, 69.2, 56.1,
49.3, 48.1, 48.0, 47.6, 36.4, 23.7, 17.6, 17.5; [α]D20 -13.4 (c 1.08, CHCl3); HRMS-ESI m/z calcd
for [M+H]+ (C29H38NO11) 576.2439, found 576.2434. Compound 17 (2.8 mg, 0.0039 mmol, 9%)
1
was also isolated after column chromatography (SiO2, EtOAc/hexanes, 3:2, Rf 0.68) H NMR
(500 MHz , CDCl3) δ 10.95 (br, 1H), 10.92 (br, 1H), 7.40 (br, 2H), 7.35‒7.31 (m, 2H), 7.23 (dd,
16.5 Hz, J = 7.5 Hz, 2H), 7.16 (dt, J = 7.0 Hz, J = 2.5 Hz, 1H), 6.77 (dd, J = 12.5 Hz, J = 8.5 Hz,
1H), 6.65 (dd, J = 12.5 Hz, J = 7.5 Hz, 1H), 6.09 (br, 1H), 5.77 (t, J = 10.0 Hz, 1H), 5.55‒5.49
(m, 1H), 5.18 (s, 2H), 4.07‒4.04 (m, 1H), 4.01 (t, J = 9.5 Hz, 1H), 3.94 (t, J = 9.5 Hz, 1H), 3.45
(s, 3H), 3.27 (s, 3H), 3.14 (s, 3H), 2.91 (dt, J = 12.5 Hz, J = 4.5 Hz, 1H), 2.48 (s, 3H), 2.44 (s,
13
3H), 1.95 (dd, J = 24.5 Hz, J = 12.5 Hz, 1H), 1.28 (s, 3H), 1.25 (s, 3H); C{1H} NMR (126
MHz, CDCl3) δ 170.6, 170.5, 167.5, 163.1, 162.8, 157.6, 141.5, 141.0, 135.9, 134.7, 134.5,
129.9, 123.1, 120.1, 119.8, 115.7, 115.7, 114.6, 111.9, 111.5, 99.8, 99.7, 94.5, 73.1, 70.7, 69.7,
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56.1, 48.1, 47.9, 36.6, 29.7, 24.7, 24.2, 24.0, 23.3, 17.6, 17.5; HRMS-ESI m/z calcd for [M+H]+
(C38H47NO13) 725.3042, found 725.2910.
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Compound 16b (6.9 mg, 0.012 mmol, 33%) was also isolated as a colorless liquid from the
corresponding reaction of 15 (16.3 mg, 0.037 mmol), 2-hydroxy-6-methylbenzoic acid (6.7 mg,
0.044 mmol), DCC (11.4 mg, 0.055 mmol) and DMAP (0.4 mg, 0.0012 mmol) after column
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chromatography (SiO2, EtOAc/hexanes, 3:2, Rf 0.46). H NMR (500 MHz, CDCl3) δ 10.95 (br,
1H), 7.38 (s, 1H), 7.34‒7.27 (m, 3H), 7.15 (d, J = 6.5 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.69 (d,
J = 7.5 Hz, 1H), 6.06 (br, 1H), 5.21‒5.26 (m, 1H), 5.17 (s, 2H), 3.98‒3.89 (m, 3H), 3.62 (t, J =
9.5 Hz, 1H), 3.45 (s, 3H), 3.28 (s, 3H), 3.26 (s, 3H), 2.77 (m, 1H), 2.52 (s, 3H), 1.93 (dd, J =
24.5 Hz, J = 12.0 Hz, 1H), 1.33 (s, 3H), 1.30 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 17.6,
23.9, 29.7, 31.2, 38.2, 48.1, 48.4, 56.1, 59.6, 69.2, 71.4, 72.6, 72.8, 94.5, 99.5, 112.4, 114.7,
115.7, 119.7, 120.0, 123.0, 129.8, 134.3, 136.1, 141.3, 157.5, 162.7, 167.5, 170.7; HRMS-ESI
m/z calcd for [M+H]+ (C29H38NO11) 576.2439, found 576.2413.
(2R,3R,4aR,5R,6S,8R,8aS)-6-(Carbamoyloxy)-2,3-dimethoxy-8-(3-
(methoxymethoxy)benzamido)-2,3-dimethyloctahydrobenzo[b][1,4]dioxin-5-yl 2-hydroxy-
6-methylbenzoate (18). Trichloroacetyl isocyanate (2.62 μL, 4.14 mg, 0.022 mmol) was added
to a solution of 17 (11.5 mg, 0.019 mmol) and dichloromethane (0.5 mL) at 0 °C. The reaction
mixture was warmed up to rt, stirred for 3 h, added with methanol (0.5 mL) and K2CO3(aq) (0.1
M, 0.5 mL), stirred for another 2 h at rt, concentrated to remove methanol and extracted with
dichloromethane (10 mL x 3). The combined organic layers were washed with saturated NaCl(aq)
(10 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified
with column chromatography (SiO2, EtOAc/hexanes, 3:2, Rf 0.48) to give 18 as a colorless liquid
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(7.8 mg, 0.012 mmol, 66%). H NMR (500 MHz , CDCl3) δ 11.04 (br, 1H), 7.39 (s, 1H),
7.34‒7.21 (m, 2H), 7.24‒7.22 (m, 2H), 7.15‒7.14 (m, 1H), 6.79 (d, J = 7.5 Hz, 1H), 6.66 (d, J =
7.5 Hz, 1H), 6.12 (br, 1H), 5.34‒5.29 (m, 1H), 5.21 (t, J = 10.0 Hz, 1H), 5.17 (s, 2H), 4.66 (br,
2H), 4.03‒4.02 (m, 1H), 3.89 (t, J = 10.0 Hz, 1H), 3.75 (t, J = 10.0 Hz, 1H), 3.44 (s, 3H), 3.24 (s,
3H), 3.23 (s, 3H), 2.83‒2.80 (m, 1H), 2.49 (s, 3H), 1.81 (dd, J = 24.5 Hz, J = 12.0 Hz, 1H), 1.27
(s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 170.7, 167.4, 163.0, 157.5, 155.5, 141.8, 136.0,
134.5, 129.8, 123.2, 119.7, 115.6, 114.7, 111.9, 99.5, 94.5, 73.3, 70.8, 69.8, 69.5, 59.5, 56.1,
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47.9, 47.8, 38.2, 32.9, 31.2, 29.7, 24.1, 17.5; [α]D20 -10.9 (c 0.37, CHCl3); HRMS-ESI m/z calcd
for [M+H]+ (C30H39N2O12) 619.2498, found 619.2472.
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(1S,2R,3S,4R,6S)-6-(Carbamoyloxy)-2,3-dihydroxy-4-(3-hydroxybenzamido)cyclohexyl 2-
hydroxy-6-methylbenzoate (ent-1). A reaction mixture of 18 (6.3 mg, 0.0102 mmol),
trifluoroacetic acid, (0.9 mL) and water (0.1 mL) was stirred at rt for 19 h and concentrated. The
crude product was purified with column chromatography (SiO2, CHCl3/methanol, 4:1, Rf 0.53) to
give ent-1 as a colorless solid (2.9 mg, 0.0062 mmol, 61%). Mp 205.5‒208.0 ℃; IR (neat) 3340,
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1722, 1591, 1062 cm-1; H NMR (500 MHz , (CD3)2CO) δ 10.72 (br, 1H), 8.64 (br, 1H), 7.67
(br, 1H), 7.40 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H),
7.00 (d, J = 8.0 Hz, 1H), 6.82‒6.78 (m, 2H), 6.03 (br, 1H), 5.34 (t, J = 9.5 Hz, 1H), 5.10‒5.05
(m, 1H), 4.77 (br, 1H), 4.60 (br, 1H), 4.20‒4.15 (m, 1H), 3.84 (t, J = 9.5 Hz, 1H), 3.76 (t, J = 9.5
Hz, 1H), 2.58 (s, 3H), 2.49‒2.45 (m, 1H), 1.79 (dd, J = 24.5 Hz, J = 12.0 Hz, 1H); 13C{1H} NMR
(126 MHz, (CD3)2CO) δ 170.7, 168.2, 161.2, 158.4, 157.0, 141.4, 137.0, 134.1, 130.1, 123.4,
119.1, 118.9, 115.8, 115.2, 77.4, 75.5, 74.7, 70.5, 50.1, 34.0, 22.9; [α]D20 +10.7 (c 0.13, MeOH);
HRMS-ESI m/z calcd for [M+H]+ (C22H25N2O9) 461.1555, found 461.1555.
Supporting Information. 1H and 13C{1H} NMR spectra for compounds 4, 6, 8, ent-1 and all
the new compounds.
Acknowledgements. Financial support from the Ministry of Science and Technology (MOST
108-2113-M-008-003 and MOST 107-2113-M-008-014), Taiwan, is gratefully acknowledged.
We thank the Institute of Chemistry, Academia Sinica and the Valuable Instrument Center at
National Central University, for mass analysis.
AUTHOR INFORMATION
Corresponding Author
Duen-Ren Hou ‒ Department of Chemistry, College of Natural Science, National Central
University, Jhong-li, Taoyuan, 32001, Taiwan; orcid.org/0000-0003-1072-2915; Email:
drhou@ncu.edu.tw
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Hsin-Ying Wu ‒ Department of Chemistry, College of Natural Science, National Central
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University, Jhong-li, Taoyuan, 32001, Taiwan
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Wei-Yi Wang ‒ Department of Chemistry, College of Natural Science, National Central
University, Jhong-li, Taoyuan, 32001, Taiwan
Chia-Chi Feng ‒ Department of Chemistry, College of Natural Science, National Central
University, Jhong-li, Taoyuan, 32001, Taiwan
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